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Vitamin E and Influenza Virus Infection Vitamin E and Influenza Virus Infection

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Abstract

Influenza is an infectious disease causing huge medical and economic losses. Influenza pathogenesis is associated with two processes in the human body: (i) lung damage due to viral replication in the columnar ciliary epithelium of bronchi and bronchioles and (ii) inflammatory burst inducing an increase in reactive oxygen species generation that causes extensive damage in cellular membranes of the small vessels. The oxidative stress in influenza virus-infected organism provokes free-radical oxidation of unsaturated lipid chains in the cell membranes. As vitamin E is a lipid-soluble substance and possesses a hydrophobic tail, it tends to accumulate within lipid membranes. There, it acts as the most important chain breaker, reacting with lipid peroxyl radicals much faster than they can react with adjacent fatty acid side chains. Among the antioxidants tested in influenza virus infections in mice, vitamin E occupies the leading position because of its efficacy in preventing oxidative damage through its free-radical scavenging activity. Although vitamin E is not possessing specific antiviral action, its antioxidant effect probably plays important role in lung and liver protection. Attention should be paid to the synergistic character of antiviral effect of the combination vitamin E and oseltamivir. Vitamin E could be recommended as a component in multitarget influenza therapy.

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... Moreover,cytochromes modifications were noticed alonga reduction in activities of hepaticcytochrome P-450dependent mono-oxygenases. Along with the abovementioned, in the disease course, the organism's antioxidant protection buffering capacity is diminished [67]. The aboveinformationshows that, during influenza infection virus, a reduction in antioxidant of natural vit. ...
... NRF2 can control the induced and basal response of antioxidant element-dependent expression of genes for regulatingpatho-physiological and physiological outcomes of exposure to oxidant. NRF2 is ofa significant impact on toxicity and oxidative stress, organizingthe defense byantioxidant [67]. ...
... The antioxidant system of NRF2-mediated is necessary to save the lungs from oxidative storm and injury induced viaviralinfluenza. [67]. ...
... Although most clinical research on vitamin E shows an effective reduction in risk of viral infections of the upper respiratory tract (mostly the common cold), it may hold promise for a protective role against influenza viruses. Influenza viruses induce significant oxidative burst in the lungs, which can rapidly result in organ damage and impaired function [79]. Vitamin E is the most prevalent scavenger of lipid peroxyl radicals in the lipid membrane and quickly breaks peroxyl chain propagation reactions in vivo [79]. ...
... Influenza viruses induce significant oxidative burst in the lungs, which can rapidly result in organ damage and impaired function [79]. Vitamin E is the most prevalent scavenger of lipid peroxyl radicals in the lipid membrane and quickly breaks peroxyl chain propagation reactions in vivo [79]. In animal studies, vitamin E was the most efficient antioxidant at reducing lipid peroxidation levels induced by influenza virus A infection [79]. ...
... Vitamin E is the most prevalent scavenger of lipid peroxyl radicals in the lipid membrane and quickly breaks peroxyl chain propagation reactions in vivo [79]. In animal studies, vitamin E was the most efficient antioxidant at reducing lipid peroxidation levels induced by influenza virus A infection [79]. More research is needed to understand the role of vitamin E in influenza virus infections. ...
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A well-functioning immune system is essential for human health and well-being. Micronutrients such as vitamins A, C, D, E, and zinc have several functions throughout the immune system, yet inadequate nutrient intakes are pervasive in the US population. A large body of research shows that nutrient inadequacies can impair immune function and weaken the immune response. Here, we present a new analysis of micronutrient usual intake estimates based on nationally representative data in 26,282 adults (>19 years) from the 2005–2016 National Health and Nutrition Examination Surveys (NHANES). Overall, the prevalence of inadequacy (% of population below estimated average requirement [EAR]) in four out of five key immune nutrients is substantial. Specifically, 45% of the U.S. population had a prevalence of inadequacy for vitamin A, 46% for vitamin C, 95% for vitamin D, 84% for vitamin E, and 15% for zinc. Dietary supplements can help address nutrient inadequacy for these immune-support nutrients, demonstrated by a lower prevalence of individuals below the EAR. Given the long-term presence and widening of nutrient gaps in the U.S.—specifically in critical nutrients that support immune health—public health measures should adopt guidelines to ensure an adequate intake of these micronutrients. Future research is needed to better understand the interactions and complexities of multiple nutrient shortfalls on immune health and assess and identify optimal levels of intake in at-risk populations.
... Studies on animal and human nutrition models have shown that vitamin E deficiency damages humoral and cell immune functions, especially in T cells (46). Vitamin E supplementation may include simultaneous effects on increasing immunity and decreasing inflammation caused by viral diseases, which can include beneficial effects on strengthening the immune system and preventing diseases, especially Covid-19 (47). ...
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Due to the lack of definite therapy and prevention protocols for Covid-19, nutrition and exercise are considered preventative measures in dealing with the epidemic. Healthy diets, dietary supplements and exercises boost the immune system. These factors can be effective in improving functions of the immune system. The current study investigated immune-enhancing characteristics of exercises, dietary supplements (proteins, vitamins, minerals, oils, coenzyme Q10 (CoQ10), probiotics, ginseng, antioxidants and Chlorella vulgaris) and food additives (titanium dioxide, sodium nitrite, monosodium glutamate, tartrazine, sweeteners and emulsifiers). The current study investigated functions of dietary supplements and exercises in strengthening the immune system, as well as assessing roles of food additives in illness prevention, particularly Covid-19, when combined with a balanced nutrition strategy. Light exercises, healthy lifestyles and nutritional supplements have been shown to boost the immune system.
... The vitamin E acts as an effective antioxidant therapy in influenza diseases. Thus, vitamin E supplementation protects the respiratory system and prevents the occurrence of oxidative damage due to influenza [60]. ...
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The vitamin E is a fat-soluble vitamin which occurs as a tocopherol component abundant in humans. The vitamin E supplements in humans and animals have provided numerous health benefits. The vitamin E is rich in antioxidants which slow the aging process and reduce the free radical damage. Vitamin E isoforms play an important role in respiratory health. It is also important in health and well-being of preterm neonates. Vitamin E deficiency in new born includes hemolytic anemia, disease of retina, bronchopulmonary dysplasia. Further, in vitro studies, vitamin E has increased the oxidative resistance and prevents the atherosclerotic plaque. The consumption of vitamin E rich foods reduces coronary heart diseases. This chapter focuses on the treatment of vitamin E deficiency in preterm babies and the role of vitamin E in preventing coronary heart diseases.
... Vitamin E is a lipid-soluble vitamin and carries an important role in reducing oxidative stress through quenching free radicals as an antioxidant (Galmes et al., 2018), it tends to accumulate within lipid membranes and reacts with lipid peroxyl radicals much faster than they can react with adjacent fatty acid side chains. Thus, among the antioxidants tested in influenza virus infections in mice, vitamin E occupies the leading position because of its efficacy and can be recommended as a component in multitarget influenza therapy (Mileva and Galabov, 2018). Another study suggested that inadequate amount of Vitamin E promotes the infection caused by coxsackievirus B3, a kind of RNA viruses in mice (Beck et al., 1994). ...
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... Vitamin E is a lipid-soluble vitamin and carries an important role in reducing oxidative stress through quenching free radicals as an antioxidant (Galmes et al., 2018), it tends to accumulate within lipid membranes and reacts with lipid peroxyl radicals much faster than they can react with adjacent fatty acid side chains. Thus, among the antioxidants tested in influenza virus infections in mice, vitamin E occupies the leading position because of its efficacy and can be recommended as a component in multitarget influenza therapy (Mileva and Galabov, 2018). Another study suggested that inadequate amount of Vitamin E promotes the infection caused by coxsackievirus B3, a kind of RNA viruses in mice (Beck et al., 1994). ...
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... Vitamin E is a lipid-soluble vitamin and carries an important role in reducing oxidative stress through quenching free radicals as an antioxidant (Galmes et al., 2018), it tends to accumulate within lipid membranes and reacts with lipid peroxyl radicals much faster than they can react with adjacent fatty acid side chains. Thus, among the antioxidants tested in influenza virus infections in mice, vitamin E occupies the leading position because of its efficacy and can be recommended as a component in multitarget influenza therapy (Mileva and Galabov, 2018). Another study suggested that inadequate amount of Vitamin E promotes the infection caused by coxsackievirus B3, a kind of RNA viruses in mice (Beck et al., 1994). ...
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Rice and its by products and its utilization
... Attention should be paid to the synergistic character of antiviral effect of the combination vitamin E and oseltamivir. Vitamin E could be recommended as a component in multitarget influenza therapy (Mileva and Galabov, 2018). 8-Venous thromboembolism: Vitamin E high doses may interfere with vitamin K and affect the coagulation. ...
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... Vitamin E is a potent lipid-soluble antioxidant that protects cell membranes against oxidative damage and supports the integrity of respiratory epithelial barriers [37,133,134]. It enhances the natural killer cell cytotoxic activity and decreases prostaglandin E2 production by macrophages [36,37,54,61,66,78]. ...
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... However, antiviral effects of zerumbone have not been reported yet. Although escin, pinitol, and tocotrienols exhibit anti-inflammatory and antiviral activities, the beneficial biological effects of naringenin on human health appear to be more extensive (Michelini, Alche, & Bueno, 2018;Mileva & Galabov, 2018;Sethi et al., 2008). In fact, flavonoid compounds have received much attention due to having many types of pharmacological activities including antioxidative, anti-inflammatory, anti-mutagenic, antimicrobial, hepatoprotective, and anti-carcinogenic effects (Panche et al., 2016). ...
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... Attention should be paid to the synergistic character of antiviral effect of the combination vitamin E and oseltamivir. Vitamin E could be recommended as a component in multitarget influenza therapy (Mileva and Galabov, 2018). 8-Venous thromboembolism: Vitamin E high doses may interfere with vitamin K and affect the coagulation. ...
Article
Vitamin E (tocopherol) is a fat-soluble vitamin with antioxidant properties; it protects cell membranes from oxidation and destruction, found in a variety of foods including oils, meat, eggs, and leafy vegetables. Their serums levels are strongly influenced by concentration of serum lipids, and do not accurately reflect tissue vitamin levels. Effective vitamin E levels are calculated as the ratio of serum alpha-tocopherol per gram total lipids. Absorption of dietary vitamin E requires effective pancreatic exocrine function and fat absorption , unless provided in a synthetic water-soluble form. Also, a specific protein (alpha-tocopherol transfer protein) is required for effective transport and use. Signs and symptoms of vitamin E deficiency include hemolysis, neuromuscular disorders, ataxia, and peripheral neu-ropathy. Because of an abundance of tocopherols in the human diet, its deficiency is rare except in individuals with pancreatic insufficiency or other conditions causing substantial fat malab-sorption, or protein-energy malnutrition and may be caused by rare genetic defects affecting vitamin E metabolism or transport. No syndrome of acute vitamin E toxicity has been described. In premature infants, high-dose vitamin E treatment was associated with increased risk for sepsis. Chronic intake of supplements in excess of 400 IU daily has been associated with increased risk of hemorrhage and all-cause mortality.
... Rehman et al. (2018) suggested that supplementation with vitamin E can ameliorate Newcastle disease virus (NDV) infection by improving oxidative stress and histopathological changes in the duodenum and jejunum of infected chickens. In addition, the effect of vitamin E on influenza virus infection was reviewed by Mileva and Galabov (2018). ...
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Influenza A virus pandemics and emerging anti-viral resistance highlight the urgent need for novel generic pharmacological strategies that reduce both viral replication and lung inflammation. We investigated whether the primary enzymatic source of inflammatory cell ROS (reactive oxygen species), Nox2-containing NADPH oxidase, is a novel pharmacological target against the lung inflammation caused by influenza A viruses. Male WT (C57BL/6) and Nox2(-/y) mice were infected intranasally with low pathogenicity (X-31, H3N2) or higher pathogenicity (PR8, H1N1) influenza A virus. Viral titer, airways inflammation, superoxide and peroxynitrite production, lung histopathology, pro-inflammatory (MCP-1) and antiviral (IL-1β) cytokines/chemokines, CD8(+) T cell effector function and alveolar epithelial cell apoptosis were assessed. Infection of Nox2(-/y) mice with X-31 virus resulted in a significant reduction in viral titers, BALF macrophages, peri-bronchial inflammation, BALF inflammatory cell superoxide and lung tissue peroxynitrite production, MCP-1 levels and alveolar epithelial cell apoptosis when compared to WT control mice. Lung levels of IL-1β were ∼3-fold higher in Nox2(-/y) mice. The numbers of influenza-specific CD8+D(b)NP(366)+ and D(b)PA(224)+ T cells in the BALF and spleen were comparable in WT and Nox2(-/y) mice. In vivo administration of the Nox2 inhibitor apocynin significantly suppressed viral titer, airways inflammation and inflammatory cell superoxide production following infection with X-31 or PR8. In conclusion, these findings indicate that Nox2 inhibitors have therapeutic potential for control of lung inflammation and damage in an influenza strain-independent manner.
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2009 pandemic influenza A(H1N1) has led to a global increase in severe respiratory illness. Little is known about kidney outcomes and dialytic requirements in critically ill patients infected with pandemic H1N1. Prospective observational study. 50 patients with pandemic H1N1 admitted to any of 7 intensive care units in Manitoba, Canada, were prospectively followed. Outcomes were kidney injury and kidney failure defined using RIFLE (risk, injury, failure, loss, end-stage disease) criteria or need for dialysis therapy. The pandemic H1N1 group was composed of 50 critically ill patients with pandemic H1N1 with severe respiratory syndrome (47 confirmed cases, 3 probable). Kidney injury, kidney failure, and need for dialysis occurred in 66.7%, 66%, and 11% of patients, respectively. Mortality was 16%. Kidney failure was associated with increased death (OR, 11.29; 95% CI, 1.29-98.9), whereas the need for dialysis was associated with an increase in length of stay (RR, 2.38; 95% CI, 2.13-25.75). Small population studied from single Canadian province; thus, limited generalizability. In critically ill patients with pandemic H1N1, kidney injury, kidney failure, and the need for dialysis are common and associated with an increase in mortality and length of intensive care unit stay.
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The effect of vitamin E supplementation on the immune response of healthy older adults was studied in a double-blind, placebo-controlled trial. Subjects (n = 32) resided in a metabolic research unit and received placebo or vitamin E (800 mg dl-alpha-tocopheryl acetate) for 30 d. Alpha-tocopherol content of plasma and peripheral blood mononuclear cells (PBMCs), delayed-type hypersensitivity skin test (DTH), mitogen-stimulated lymphocyte proliferation, as well as interleukin (IL)-1, IL-2, prostaglandin (PG) E2, and serum lipid peroxides were evaluated before and after treatment. In the vitamin E-supplemented group 1) alpha-tocopherol content was significantly higher (p less than 0.0001) in plasma and PBMCs, 2) cumulative diameter and number of positive antigen responses in DTH response were elevated (p less than 0.05), 3) IL-2 production and mitogenic response to optimal doses of concanavalin A were increased (p less than 0.05), and 4) PGE2 synthesis by PBMCs (p less than 0.005) and plasma lipid peroxides (p less than 0.001) were reduced. Short-term vitamin E supplementation improves immune responsiveness in healthy elderly individuals; this effect appears to be mediated by a decrease in PGE2 and/or other lipid-peroxidation products.
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Randomised controlled trials (RCT) testing the effects of antioxidant supplements on endothelial function (EF) have reported conflicting results. We aimed to investigate the effects of supplementation with antioxidant vitamins C and E on EF and to explore factors that may provide explanations for the inconsistent results. We searched four databases (MEDLINE, Embase, Cochrane Library and Scopus) from inception until May 2014 for RCT involving adult participants aged ≥ 18 years who were supplemented with vitamins C and E alone or in combination for more than 2 weeks and reporting changes in EF measured using flow mediated dilation or forearm blood flow. Data were pooled as standardised mean difference (SMD) and analysed using a random-effects model. Significant improvements in EF were observed in trials supplementing with vitamin C alone (500–2000 mg/d) (SMD: 0·25, 95 % CI 0·02, 0·49, P = 0·043) and vitamin E alone (300–1800 IU/d; 1 IU vitamin E = 0·67 mg natural vitamin E) (SMD: 0·48, 95 % CI 0·23, 0·72, P = 0·0001), whereas co-administration of both vitamins was ineffective (vitamin C: 500–2000 mg/d; vitamin E: 400–1200 IU/d) (SMD: 0·12, 95 % CI − 0·18, 0·42, P = 0·428). The effect of vitamin C supplementation on EF increased significantly with age (β 0·023, 95 % CI 0·001, 0·05, P = 0·042). There was a significant negative correlation between baseline plasma vitamin E concentration and the effect of vitamin E supplementation on EF (β − 0·03, 95 % CI − 0·06, − 0·001, P = 0·029). Supplementation with either vitamin C or vitamin E alone improves EF. However, subgroup analysis emphasises the importance of careful characterisation and selection of a population group which may benefit from such supplementation.
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The influenza viruses are some of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. In humans, infection of the lower respiratory tract of can result in flooding of the alveolar compartment, development of acute respiratory distress syndrome and death from respiratory failure. Influenza-mediated damage of the airway, alveolar epithelium and alveolar endothelium results from a combination of: 1) intrinsic viral pathogenicity, attributable to its tropism for host airway and alveolar epithelial cells; and 2) a robust host innate immune response, which, while contributing to viral clearance, can worsen the severity of lung injury. In this review, we summarise the molecular events at the virus-host interface during influenza virus infection, highlighting some of the important cellular responses. We discuss immune-mediated viral clearance, the mechanisms promoting or perpetuating lung injury, lung regeneration after influenza-induced injury, and recent advances in influenza prevention and therapy. Copyright ©ERS 2015.
Conference Paper
Hypercholesterolemia is the major risk factor for the development of atherosclerosis and vitamin E is suggested to have a preventive role in this process (1), although the mechanism of action still remains unclear. The ubiquitin-proteasome system (UPS) may influence atherosclerosis by affecting disease-relevant cellular processes such as apoptosis, proliferation, and differentiation, or by affecting cellular stress responses and/or adaptive phenomena, such as ER stress, inflammation, and redox homeostasis (2). NF-E2‐related factor 2 (Nrf2) is a transcription factor that controls the expression of phase II detoxification and antioxidant genes. Nrf2 signaling has additionally been shown to upregulate the expression of the proteasome catalytic subunits (3). In the present study, we investigated the role of Nrf2 pathway on oxidative and ER stress conditions induced by cholesterol diet and the effects of vitamin E on related signaling pathways in in vivo model of atherosclerosis. All experimental procedures were approved by the Marmara University Ethics Committee. Twenty-one male albino rabbits (2–3 months old) were assigned randomly to four groups fed for 8 weeks: (i) vitamin E deficient diet, (ii) vitamin E deficient diet containing 2% cholesterol, and (iii) vitamin E deficient diet containing 2% cholesterol with daily intramuscular injections of vitamin E (50 mg/kg), (iv) vitamin E deficient diet with daily intramuscular injections of vitamin E (50 mg/kg). In order to elucidate in vivo role of oxidative stress and ER stress in cardiovascular system of hypercholesterolemic rabbits, we investigated serum levels of cholesterol, MDA and vitamin E and Nrf2, GST-1, GRP78, GRP94, PERK, IRE1 protein levels and the proteasomal activity in aortic tissues will be discussed. (1)Ozer, N.K. et al. (2006). Atherosclerosis 184, 15–20. (2) Lee, S. et al. (2012). Toxicology and Applied Pharmacology 264, 431–438. (3) Demasi, D. et al. (2012). Cardiovascular Research 95, 183–193.
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Influenza A viruses (IAV) cause respiratory tract infections annually associated with excess mortality and morbidity. Nonspecific, innate immune mechanisms play a key role in protection against viral invasion at early stages of infection. A soluble protein present in mucosal secretions of the lung, surfactant protein D (SP-D), is an important component of this initial barrier that helps to prevent and limit IAV infections of the respiratory epithelium. This collagenous C-type lectin binds IAVs and thereby inhibits attachment and entry of the virus but also contributes to enhanced clearance of SP-D-opsonized virus via interactions with phagocytic cells. In addition, SP-D modulates the inflammatory response and helps to maintain a balance between effective neutralization/killing of IAV, and protection against alveolar damage resulting from IAV-induced excessive inflammatory responses. The mechanisms of interaction between SP-D and IAV not only depend on the structure and binding properties of SP-D but also on strain-specific features of IAV, and both issues will be discussed. SP-D from pigs exhibits distinct anti-IAV properties and is discussed in more detail. Finally, the potential of SP-D as a prophylactic and/or therapeutic antiviral agent to protect humans against infections by IAV is discussed.
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Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body's needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol-based redox signaling. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element-dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how Nrf2 senses oxidants and regulates antioxidant defense.
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Vitamin E (α-tocopherol) was discovered nearly 100 years ago because it was required to prevent fetal resorption in pregnant, vitamin E-deficient rats fed lard-containing diets that were easily oxidizable. The human diet contains eight different vitamin E-related molecules synthesized by plants; despite the fact that all of these molecules are peroxyl radical scavengers, the human body prefers α-tocopherol. The biological activity of vitamin E is highly dependent upon regulatory mechanisms that serve to retain α-tocopherol and excrete the non-α-tocopherol forms. This preference is dependent upon the combination of the function of α-tocopherol transfer protein (α-TTP) to enrich the plasma with α-tocopherol and the metabolism of non-α-tocopherols. α-TTP is critical for human health because mutations in this protein lead to severe vitamin E deficiency characterized by neurologic abnormalities, especially ataxia and eventually death if vitamin E is not provided in large quantities to overcome the lack of α-TTP. α-Tocopherol serves as a peroxyl radical scavenger that protects polyunsaturated fatty acids in membranes and lipoproteins. Although specific pathways and specific molecular targets have been sought in a variety of studies, the most likely explanation as to why humans require vitamin E is that it is a fat-soluble antioxidant.
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Influenza virus is a major human pathogen that causes epidemics and pandemics with increased morbidity and, especially in the elderly and those with pre-existing medical conditions, increased mortality. Influenza is characterised by respiratory symptoms and constitutional symptoms. Whilst knowledge of the mechanisms underlying host and tissue specificity has advanced considerably of late we still know relatively little about other aspects of influenza virus virulence. In this review, we will explore what is known about the role of apoptosis in respiratory epithelial cell damage and the role of cytokines in inflammation and constitutional symptoms with particular emphasis on the link between apoptosis, inflammation, fever and cytokine production.
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The clinical outcome of different influenza virus infections ranges from subclinical upper respiratory tract disease to fatal lower respiratory tract disease. An important determinant in the pathogenesis of these diseases is the tissue tropism of the influenza virus. Furthermore, virulence is often correlated with virus replication and is regulated by multiple virus genes. Host defense against virus infection consists of both innate and adaptive immune responses. However, excessive or dysbalanced immune response may result in lung tissue damage, reduced respiratory capacity, and severe disease or even death. By interdisciplinary efforts to better understand the intricate interaction between virus, tissue, and immune response, we may be able to find new ways to improve the outcome of influenza virus infections.
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The potential for vitamin E to modulate prostaglandin metabolism and alter immune response in aged mice was studied. Semi-purified diets containing 30 ppm or 500 ppm dl-α-tocopheryl acetate (VitE) were fed for 6 weeks to young (3 months) and old (24 months) C57BL/6J mice. Delayed hypersensitivity skin test to DNFB and the proliferative response of splenocytes to T- and B-cell mitogens were assessed. Ex-vivo synthesis of Prostaglandin E2 (PGE2) was measured in spleen homogenates and serum vitamin E was measured by HPLC. Vitamin E supplementation of aged mice enhanced percent ear swelling to DNFB as well as the mitogenic response of splenocytes to Con A and LPS (P < 0.05). Furthermore, spleen homogenates from old mice fed 30 ppm VitE had a significantly higher PGE2 level than young mice fed 30 ppm VitE and old mice fed 500 ppm VitE (3.20 ± 0.07 μg/g vs. 2.60 ± 0.08 and 2.3 ± 0.10, respectively). Thus, the vitamin E enhanced immune response of aged mice appears to be mediated by decreased prostaglandin synthesis.
Article
A major component of a US Army Medical Research and Development Command-supported program to discover and develop new drugs for the treatment of Rift Valley fever, sandfly fever, and Crimean-Congo hemorrhagic fever has been to study candidate test materials against hepatotropic infections of C57BL/6 mice induced by the related but less biohazardous Punta Toro virus (PTV). The effects of 75 compounds, some of which were considered immunomodulators in their primary mechanism of activity, were studied in the PTV infection model. Of these, ribavirin, ribamidine, ribavirin 2′,3′,5′-triacetate, tiazofurin, tiazofurin-5′-monophosphate, tiazofurin-2′,3′,5′-triacetate, selenazofurin, pyrazofurin, 3-deazaguanine, and 3-deazaguanosine were considered significantly inhibitory, acting against the infection by a direct antiviral (non-immunomodulatory) fashion. These compounds had therapeutic indices (TI) ranging from ≥ 5 to 65, using increased survivors as the evaluation parameter. Immunomodulators considered significantly inhibitory to this infection were poly (ICLC), ampligen, human recombinant interferon-α-A/D, MVE-1, MVE-2, AM-3, AM-5, mannozym, bropirimine, CL246,738, phenyleneamine, and 7-thia-8-oxoguanosine. Utilizing increased survivor numbers as measure of activity, these inhibitors had TI ranging from ≥ 16 to 1000. Other antiviral effects exerted by the active compounds included reduction of hepatic icterus, lowered serum glutamic oxaloacetic and pyruvic acid transaminases, and inhibition of recoverable serum and liver virus titers. The active immunomodulators were significantly effective when therapy was initiated as late as 48 h after virus inoculation, at a time when clinical signs of the PTV disease were being manifested in the animal.
Article
Vitamin E supplementation exhibits anti-inflammatory properties. In the lung, the beneficial effects of vitamin E supplementation on inflammation and infections are well documented, but potential consequences of alimentary vitamin E deficiency to the immunological status of lung cells are not known. It is unclear if temporary vitamin E deficiency exhibits deleterious consequences or can be compensated for by other cellular antioxidants. To address this question, the alimentary vitamin E supply to rats was modified. We then investigated the effects on major histocompatibility molecule (MHC) class II, cell adhesion molecules, interleukin (IL)10, tumor necrosis factor (TNF)α in various lung cells. The constitutive expression of MHC class II, intercellular adhesion molecule (ICAM)-1, L-selectin, α5-integrin, and CD 166, was demonstrated by flow cytometry on type II pneumocytes, alveolar macrophages, and on co-isolated lymphocytes. Vitamin E depletion increased ICAM-1 and CD166 on type II cells and macrophages, whereas the expression of L-selectin increased only on macrophages. Furthermore, the vitamin E depletion increased the cellular content and secretion of IL10 in type II cells, but decreased the content and secretion of TNFα. Vitamin E depletion decreased the cellular vitamin E content, but did not change the activity of antioxidant enzymes (catalase, superoxide dismutase) and the glutathion (GSH)/oxidized glutathion (GSSG) ratio in alveolar type II cells. The shift of protein kinase C (PKC) from the cytosol to membranes indicates that a PKC-dependent signaling pathway may be involved in the change of the immunological status of type II cells. All these effects were reversed by vitamin E repletion. In summary, these results are clearly compatible with the view that a temporary vitamin E deficiency induces a reversible immunological dysregulation in alveolar type II cells and lung macrophages. This deficiency might predispose the lung to develop acute or chronic inflammation.
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Please cite this paper as: Papic et al. (2011) Liver involvement during influenza infection: perspective on the 2009 influenza pandemic. Influenza and Other Respiratory Viruses 6(3), e2–e5. Elevation of liver transaminase levels is a frequent observation during systemic infections. The aim of our study was to investigate liver damage during pandemic 2009 influenza A/H1N1 infection in comparison with seasonal influenza. Serum levels of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase (GGT) were significantly higher in patients with pandemic influenza compared to seasonal influenza, which was strongly correlated with hypoxia. Moreover, a positive correlation between C-reactive protein and serum GGT, alkaline phosphatase, and lactate dehydrogenase was noticed. Our findings support the hypothesis that the pandemic 2009 influenza A/H1N1 is an illness with a significant immune response to infection leading to hepatocellular injury.
Article
Natural antioxidants like vitamin C, vitamin E, carotenoids, and polyphenols like flavonoids, are at present generally considered to be beneficial components from fruit and vegetables. The anti-oxidative properties of these compounds are often claimed to be responsible for various beneficial health effects of these food ingredients. Together these studies provide the basis for the present rapidly increasing interest for the use of natural antioxidants as functional food ingredients and/or as food supplements. However, at higher doses or under certain conditions antioxidant-type functional food ingredients may exert toxic pro-oxidant activities. The present manuscript gives an overview of especially this pro-oxidative chemistry and toxicity of well-known natural antioxidants including vitamin C, vitamin E, carotenoids and flavonoids.
Article
Asthma is a chronic inflammatory airway disease associated with increased generation of reactive oxidant species and disturbed antioxidant defenses. NRF2 is the master transcription factor that regulates the expression of Phase II antioxidant and detoxifying enzymes. Disruption of NRF2 augments oxidative stress and inflammation in a mouse model of asthma, suggesting a protective role for NRF2 in the lungs in vivo. Yet, little is known about the regulation and function of NRF2 in human asthmatics. Using segmental allergen challenge, a well-established experimental model of IgE-mediated asthma exacerbation in human atopic asthmatics, we investigated the effects of a specific allergen and the modulatory role of vitamin E on NRF2 and a NRF2-target gene, superoxide dismutase, in alveolar macrophages recovered from the airways at 24h after allergen instillation in vivo. Allergen-provoked airway inflammation in sensitive asthmatics caused a profound inhibition of macrophage NRF2 activity and superoxide dismutase, rendering them incapable of responding to the NRF2 inducers. Prolonged treatment with high doses of the antioxidant vitamin E lessened this allergen-induced drop in alveolar macrophage NRF2. These results are the first to demonstrate that NRF2 expression in human asthmatics is compromised upon allergen challenge but can be rescued by vitamin E in vivo.
Article
Influenza infection is a major cause of morbidity and mortality worldwide, especially during pandemics outbreaks. Emerging data indicate that phase II antioxidant enzyme pathways could play a role in virus-associated inflammation and immune clearance. While Nrf2-dependent gene expression is known to modify inflammation, a mechanistic role in viral susceptibility and clearance has yet to be elucidated. Therefore, we utilized differentiated human nasal epithelial cells (NEC) and an enzymatic virus-like particle entry assay, to examine the role Nrf2-dependent gene expression has on viral entry and replication. Herein, lentiviral vectors that express Nrf2-specific short hairpin (sh)-RNA effectively decreased both Nrf2 mRNA and Nrf2 protein expression in transduced human NEC from healthy volunteers. Nrf2 knockdown correlated with a significant increase in influenza virus entry and replication. Conversely, supplementation with the potent Nrf2 activators sulforaphane (SFN) and epigallocatechin gallate (EGCG) significantly decreased viral entry and replication. The suppressive effects of EGCG on viral replication were abolished in cells with knocked-down Nrf2 expression, suggesting a causal relationship between the EGCG-induced activation of Nrf2 and the ability to protect against viral infection. Interestingly, the induction of Nrf2 via nutritional supplements SFN and EGCG increased antiviral mediators/responses: RIG-I, IFN-β, and MxA at baseline in the absence of infection. Our data indicate that there is an inverse relationship between the levels of Nrf2 expression and the viral entry/replication. We also demonstrate that supplementation with Nrf2-activating antioxidants inhibits viral replication in human NEC, which may prove to be an attractive therapeutic intervention. Taken together, these data indicate potential mechanisms by which Nrf2-dependent gene expression regulates susceptibility to influenza in human epithelial cells.
Article
Reactive oxygen species (ROS) are products of normal metabolism and xenobiotic exposure, and depending on their concentration, ROS can be beneficial or harmful to cells and tissues. At physiological low levels, ROS function as "redox messengers" in intracellular signaling and regulation, whereas excess ROS induce oxidative modification of cellular macromolecules, inhibit protein function, and promote cell death. Additionally, various redox systems, such as the glutathione, thioredoxin, and pyridine nucleotide redox couples, participate in cell signaling and modulation of cell function, including apoptotic cell death. Cell apoptosis is initiated by extracellular and intracellular signals via two main pathways, the death receptor- and the mitochondria-mediated pathways. Various pathologies can result from oxidative stress-induced apoptotic signaling that is consequent to ROS increases and/or antioxidant decreases, disruption of intracellular redox homeostasis, and irreversible oxidative modifications of lipid, protein, or DNA. In this review, we focus on several key aspects of ROS and redox mechanisms in apoptotic signaling and highlight the gaps in knowledge and potential avenues for further investigation. A full understanding of the redox control of apoptotic initiation and execution could underpin the development of therapeutic interventions targeted at oxidative stress-associated disorders.
Article
This review focuses on the medicinal plants growing and having history of folk medicine in Iran and found effective as anti free radical damage in animal or human. Embase, Scopus, Pubmed, Web of Science, Google Scholar, IranMedex, and SID databases were searched up to 2 February 2008. The search terms were antioxidant or "lipid peroxidation" and "plant, medicinal plant, herb, traditional, natural or herbal medicine" limited to Iran. Studies that assessed effects on cell lines or isolated organs, fetal toxicity, and reviews or letters were excluded. Antioxidative effect and lipid peroxidation inhibition were the key outcomes. Forty-six animal studies on the efficacy of medicinal plants were reviewed. Lipid peroxidation was reduced in different clinical circumstances by Ferula szovitsiana, Nigella sativa, Rosa damascene petal, Phlomis anisodonta, Rosemary, Zataria multiflora Boiss, Saffron, Amirkabiria odorastissima mozaffarian, Ficus carica Linn., Ziziphora clinopoides, Carica papaya, Chichorium intybus, Turmer, Eugenol, Curcumin, and Pistacia vera L. Human studies showed that Cinnamomum zeylanicum and Echium amoenum Fisch & C.A. Mey reduce lipid peroxidation and improve total antioxidant power in healthy subjects. Improvement of blood lipid profile was shown by Silybum marianum, garlic, and wheat germ. Amongst these useful herbs, some like Cinnamon, Silybum marianum, Garlic, Nigella, and Echium seem potential targets of future effective drugs for diseases in which free radical damage play a pathogenical role.
Article
The paper presents the experimental model of toxic influenza infection induced by A/Victory/35/72 (H3N2) strain adapted to CBA mice. The virus toxicosis was shown by means of ESR technique to be accompanied by a decrease of both the content of the active form of cytochrome P-450 and the activity of p-nitroanisole o-demethylase. In microsomes there was activation of lipid peroxidation (LP) and an increase of microviscosity of lipid matrix. LP activation in microsomes was not accompanied by the change of alpha-tocopherol content.
Article
Cold-restraint stress was found to produce a depression in hepatic glutathione content and to elevate circulating catecholamine levels in four mouse strains--ICR, NIH, B6C3F1, and ND/4. Serum norepinephrine concentrations were significantly elevated after cold-restraint (2--3 h) in all strains, and serum epinephrine levels were increased in the B6C3F1 and ND/4 strains. In time-course studies conducted using ND/4 mice, the decline in hepatic glutathione concentrations was found to slightly precede increases in serum epinephrine and norepinephrine concentrations. Also, pretreatment with phentolamine, an alpha-adrenoreceptor antagonist compound shown in previous studies to block epinephrine-induced hepatic glutathione suppression, had no effect on glutathione losses from cold-restraint. These observations are inconsistent with catecholamines as sole mediators of cold-restraint induced hepatic glutathione depression. Two other endogenous substances elevated during stress, corticosteroids and glucagon, were found to diminish glutathione concentrations in the liver in ND/4 mice when administered exogenously. The effects of catecholamines (epinephrine), corticosteroids (hydrocortisone) and glucagon were not additive, i.e. the depression in glutathione when these agents were administered in combination was generally no greater than that induced when the most effective agent was administered alone. It is postulated that during cold-restraint stress multiple endogenous agents are released which are independently capable of causing a depression in hepatic glutathione content.
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Most cytokines involved in the regulation of the immune responses and hematopoiesis have been molecularly cloned. The studies with recombinant molecules clearly demonstrate that the function of these cytokines is not specific to a certain lineage of cells as originally expected but they show a wide variety of biological functions on various tissues and cells. One of the most typical examples of these multifunctional cytokines is IL-6. As described, it regulates immune responses, hematopoiesis, and acute phase reactions, indicating that it plays a central role in host defense mechanism. Among many cytokines, IL-6 is the first one, the abnormal expression of which is directly related to the pathogenesis of several diseases, such as myeloma/plasmacytoma, Castleman's disease, and mesangium proliferative glomerulonephritis, in which IL-6 functions as an autocrine growth factor for kidney mesangium cells. Therefore, the study on the regulatory mechanism of the IL-6 gene expression is indispensable for unraveling the molecular pathogenesis of those diseases. Neutralization of IL-6 with specific inhibitors may be applied for the treatment of such diseases. Soluble receptors are possible candidates as the specific inhibitor. The signal transduction through cytokine receptors may be unique: (a) the number of receptors is approximately 100-fold less than that of hormone or growth factor receptors and (b) any known biochemical reactions, such as phosphatidyl inositol turnover, tyrosine phosphorylation, and Ca++-ion influx, are not invoked following stimulation with cytokines. Recently, cDNAs for cytokine receptors, such as IL-6, IL-1 and γ-IFN have been cloned. The receptor molecules do not have any unique structure for the signal transduction, such as tyrosine kinase domain. Therefore, the presence of associated molecules for the signal transduction is assumed. In fact, IL-6 stimulation triggers the association of the IL-6 receptor with a nonligand binding signal transducer. The unique mechanism of signal transduction through cytokine receptors will hopefully be elucidated in the near future.
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The pathogenicity of influenza virus infection in the mice involves, at least in part, overreaction of the immune responses of the host rather than a direct effect of virus multiplication. Xanthine oxidase, which is responsible for the generation of oxygen free radicals, was elevated in serum and lung tissue of mice infected with influenza virus. To test the theory that oxygen-free radicals are involved in pathogenesis, free radicals were removed by injecting superoxide dismutase (SOD), a specific superoxide radical scavenger, which was conjugated with a pyran copolymer. The conjugate protected mice against a potentially lethal influenza virus infection if administered 5 to 8 days after infection. These findings indicate that oxygen radicals are important in the pathogenesis of influenza virus infection, and that a polymer-conjugated SOD has therapeutic potential for this virus infection and other diseases associated with free radicals.
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Highly reactive molecules called free radicals can cause tissue damage by reacting with polyunsaturated fatty acids in cellular membranes, nucleotides in DNA, and critical sulfhydryl bonds in proteins. Free radicals can originate endogenously from normal metabolic reactions or exogenously as components of tobacco smoke and air pollutants and indirectly through the metabolism of certain solvents, drugs, and pesticides as well as through exposure to radiation. There is some evidence that free radical damage contributes to the etiology of many chronic health problems such as emphysema, cardiovascular and inflammatory diseases, cataracts, and cancer. Defenses against free radical damage include tocopherol (vitamin E), ascorbic acid (vitamin C), beta-carotene, glutathione, uric acid, bilirubin, and several metalloenzymes including glutathione peroxidase (selenium), catalase (iron), and superoxide dismutase (copper, zinc, manganese) and proteins such as ceruloplasmin (copper). The extent of tissue damage is the result of the balance between the free radicals generated and the antioxidant protective defense system. Several dietary micronutrients contribute greatly to the protective system. Based on the growing interest in free radical biology and the lack of effective therapies for many of the chronic diseases, the usefulness of essential, safe nutrients in protecting against the adverse effects of oxidative injury warrants further study.