ascorbic-acid and Orthomyxoviridae-Infections

COVID-19 is a severe pandemic which has caused a devastating amount of loss in lives around the world, and yet we still don't know how to appropriately treat this disease. We know very little about the pathogenesis of SARS-CoV-2, the virus which induces the COVID-19. However, COVID-19 does share many similar symptoms with SARS and influenza. Previous scientific discoveries learned from lab animal models and clinical practices shed light on possible pathogenic mechanisms in COVID-19. In the past decades, accumulated scientific findings confirmed the pathogenic role of free radicals damage in respiratory virus infection. Astonishingly very few medical professionals mention the crucial role of free radical damage in COVID-19. This hypothesis aims to summarize the crucial pathogenic role of free radical damage in respiratory virus induced pneumonia and suggest an antioxidative therapeutic strategy for COVID-19.

Topics: Acetylcysteine; Animals; Antioxidants; Ascorbic Acid; Azithromycin; Betacoronavirus; Clinical Trials as Topic; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cytokine Release Syndrome; Drug Therapy, Combination; Free Radicals; Glutathione; Humans; Hydroxychloroquine; Mice; Multiple Organ Failure; NF-E2-Related Factor 2; Nitric Oxide; Orthomyxoviridae Infections; Oxidative Stress; Pandemics; Pneumonia, Viral; Reactive Oxygen Species; SARS-CoV-2; Severe Acute Respiratory Syndrome

Topics: Adenoviridae; Adult; Amantadine; Animals; Ascorbic Acid; Cephalosporins; Common Cold; Cricetinae; Enterovirus; Fusidic Acid; Humans; Influenza Vaccines; Interferons; Isoquinolines; Orthomyxoviridae; Orthomyxoviridae Infections; Respirovirus; Rhinovirus; Thiosemicarbazones

Since the influenza viruses can rapidly evolve, it is urgently required to develop novel anti-influenza agents possessing a novel mechanism of action. In our previous study, two pentacyclic triterpene derivatives (Q8 and Y3) have been found to have anti-influenza virus entry activities. Keeping the potential synergy of biological activity of pentacyclic triterpenes and l-ascorbic acid in mind, we synthesized a series of novel l-ascorbic acid-conjugated pentacyclic triterpene derivatives (18-26, 29-31, 35-40 and 42-43). Moreover, we evaluated these novel compounds for their anti-influenza activities against A/WSN/33 virus in MDCK cells. Among all evaluated compounds, the 2,3-O,O-dibenzyl-6-deoxy-l-ascorbic acid-betulinic acid conjugate (30) showed the most significant anti-influenza activity with an EC50 of 8.7 μM, and no cytotoxic effects on MDCK cells were observed. Time-of-addition assay indicated that compound 30 acted at an early stage of the influenza life cycle. Further analyses revealed that influenza virus-induced hemagglutination of chicken red blood cells was inhibited by treatment of compound 30, and the interaction between the influenza hemagglutinin (HA) and compound 30 was determined by surface plasmon resonance (SPR) with a dissociation constant of KD = 3.76 μM. Finally, silico docking studies indicated that compound 30 and its derivative 31 were able to occupy the binding pocket of HA for sialic acid receptor. Collectively, these results suggested that l-ascorbic acid-conjugated pentacyclic triterpenes were promising anti-influenza entry inhibitors, and HA protein associated with viral entry was a promising drug target.

Topics: Animals; Antiviral Agents; Ascorbic Acid; Dogs; Drug Design; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Madin Darby Canine Kidney Cells; Molecular Docking Simulation; Orthomyxoviridae Infections; Pentacyclic Triterpenes; Virus Internalization

Because red ginseng and vitamin C have immunomodulatory function and anti-viral effect, we investigated whether red ginseng and vitamin C synergistically regulate immune cell function and suppress viral infection.. Red ginseng and vitamin C were treated to human peripheral blood mononuclear cells (PBMCs) or sarcoma-associated herpesvirus (KSHV)-infected BCBL-1, and administrated to Gulo(-/-) mice, which are incapable of synthesizing vitamin C, with or without influenza A virus/H1N1 infection.. Red ginseng and vitamin C increased the expression of CD25 and CD69 of PBMCs and natural killer (NK) cells. Co-treatment of them decreased cell viability and lytic gene expression in BCBL-1. In Gulo(-/-) mice, red ginseng and vitamin C increased the expression of NKp46, a natural cytotoxic receptor of NK cells and interferon (IFN)-γ production. Influenza infection decreased the survival rate, and increased inflammation and viral plaque accumulation in the lungs of vitamin C-depleted Gulo(-/-) mice, which were remarkably reduced by red ginseng and vitamin C supplementation.. Administration of red ginseng and vitamin C enhanced the activation of immune cells like T and NK cells, and repressed the progress of viral lytic cycle. It also reduced lung inflammation caused by viral infection, which consequently increased the survival rate.

Topics: Animals; Antiviral Agents; Ascorbic Acid; Female; Humans; Influenza A Virus, H1N1 Subtype; Interferon-gamma; Killer Cells, Natural; Leukocytes, Mononuclear; Lung; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections; Panax; Pneumonia

To investigate the effects of pharmacologic ascorbate (vitamin C) against Influenza A/CA/7/09 (H1N12009).. BALB/c mice inoculated intranasally with influenza virus were treated with ascorbate (3 mg/g) twice daily by intraperitoneal (i.p.) injection for up to 14 d. Control groups received an equivalent volume of normal saline. Body weights were measured daily. To quantify the level of viral replication in the respiratory tract, the mice were euthanized and lungs removed and prepared as whole lung homogenates.Viral titers were determined by TCID50 assay in MDCK cells. Cytokine titers were determined by ELISA following the manufacturer's protocol (IL-1β, IL-6, TNF-α, IFN-α). For lung histopathologic evaluation, lungs were fixed with 10% neutral-buffered formalin at time of isolation, and then coded, processed into paraffin blocks, sectioned onto glass slides and stained (hematoxylin and eosin).Slides were examined and scored by a pathologist.. Mice infected with influenza virus and treated with pharmacologic ascorbate had higher survival and less weight loss, and had lung viral titers reduced by as much as 10 to 100-fold compared to the controls. Pathologic study of the lungs showed that the treated animals had little inflammation (bronchiolitis, perivasculitis, alveolitis, and vasculitis) compared to the controls.IL-1, IL-6, and IFN-alpha lung levels were lower in the treated animals compared to the controls.. Pharmacologic ascorbate is a pro-oxidant that eliminates influenza virus in the lung, and therefore reduces lung inflammation and lowers death rate in this mouse model.

Topics: Animals; Ascorbic Acid; Dose-Response Relationship, Drug; Inflammation; Influenza A virus; Interleukin-6; Lung; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Tumor Necrosis Factor-alpha; Viral Load

To study the oxidative stress level of the influenza virus A FM1 subset-infected mouse in intranasal inhalation as a model, we employ an ascorbyl radical's ESR (electron spin resonance) spectrum as an oxidative stress biomarker. These infected mice were pretreated with Ribavirin, ascorbic acid, superoxide dismutase (SOD) or Kegan Liyan oral prescription (KGLY, proprietary Chinese medicine for influenza and common cold) in the stomach tube for 3 days, and then followed by the virus-infecting for 4 days. On the 4th day, samples were collected. It is recognized the strength of ascorbyl radical's ESR signal (A(-.)) (a(H4 = 0.177) Gauss, g = 2.00517) denotes oxidative stress level in vivo and in vitro. The magnitude of ESR spectrum (28.65 +/- 10.71 AU) in mice infected with influenza virus was significantly higher than those of healthy control mice (19.10 +/- 3.61 AU). Serum A(-.) in mice treated with Ribavirin, ascorbic acid, SOD and KGLY declined to 19.70 +/- 6.05, 18.50 +/- 2.93 and 16.25 +/- 3.59, 18.40 +/- 2.14 AU respectively. It is close to A(-.) signal height in healthy controls via down-regulation of the influenza virus-caused oxidative stress level getting decline in the lung index of pneumonia as compare to those of untreated healthy and the influenza virus infected mice pneumonia. It is well known that SOD can prevent the influenza virus pneumonia enhancing mouse survival rate; Ribavirin can treat viral diseases. Data from this study suggested that KGLY may indirectly relieve influenza virus-infected pneumonia via down- regulation of virus caused oxidative stress coupled with a redox reaction cascade as ribavirin, ascorbic acid and SOD.

Topics: Animals; Antioxidants; Antiviral Agents; Ascorbic Acid; Biomarkers; Down-Regulation; Drugs, Chinese Herbal; Electron Spin Resonance Spectroscopy; Female; Free Radicals; Influenza A virus; Lung; Magnoliopsida; Male; Mice; Mice, Inbred Strains; Orthomyxoviridae Infections; Oxidation-Reduction; Oxidative Stress; Phytotherapy; Pneumonia, Viral; Ribavirin; Superoxide Dismutase

Influenza, a long-standing common infection, poses a serious health problem causing significant morbidity and mortality, and imposing substantial economic costs. To date there are no effective antiviral therapies. A unique nutrient mixture (NM), containing lysine, proline, ascorbic acid, green tea extract, N-acetyl cysteine and selenium among other micro nutrients, has been shown to exert a wide range of biochemical and pharmacological effects, among them anti-carcinogenic and anti-atherogenic activity both in vitro and in vivo. In a previous study, NM was found to significantly inhibit influenza virus A associated neuraminidase enzyme as well as production of NP antigen in a dose-dependent manner. Influenza virus A not only infects pulmonary areas, but also manifests in extrapulmonary areas, which require basement membrane disruption by matrix metalloproteinases capable of degrading collagen type IV. This prompted us to study the effect of NM on cellular invasive parameters of virus-infected and non-infected MDCK and Vero cells. NM inhibited extracellular invasive parameters such as MMP-2 and MMP-9 secretion and Matrigel invasion. Results indicated that the relatively non-toxic nutrient mixture tested in this investigation has potential in influenza treatment by not only decreasing viral multiplication in infected cells but also by blocking the enzymatic degradation of the extracellular matrix.

Topics: Acetylcysteine; Animals; Apoptosis; Arginine; Ascorbic Acid; Cell Line; Cell Movement; Cell Survival; Chlorocebus aethiops; Dogs; Influenza A virus; Lysine; Matrix Metalloproteinase 9; Orthomyxoviridae Infections; Plant Extracts; Tea; Vero Cells

Twenty-month-old Swiss mice were allocated into three groups: (A) control; (B) infected group; and (C) infected but treated with 5 mg of the phytocompound MMT. Mice were infected intranasally with 30 microL of 75 HA viral units. MMT markedly blunted the nasal signs of virus infection and the febrile response. Formazan-positive cells, lung and plasma lipoperoxides, and TNF-alpha in lung tissue increased during viral infection, but improvement was seen in the MMT-treated group (P < 0.05). MMT also normalized SOD, catalase activities, and ascorbic acid and determined a significant decrease of lung but not nasal viral titer, although nasal inflammatory infiltrate dropped significantly. MMT has potential clinical applications with and has an excellent safety profile even in old animals.

Topics: Administration, Oral; Aging; Animals; Antioxidants; Ascorbic Acid; Bronchoalveolar Lavage Fluid; Catalase; Chemokine CCL5; Dietary Supplements; Disease Models, Animal; Drug Administration Schedule; Lung; Mice; Orthomyxoviridae Infections; Random Allocation; Superoxide Dismutase; Treatment Outcome; Tumor Necrosis Factor-alpha; Viral Load

This study was designed to determine the effects of vitamin C deficiency on the immune response to infection with influenza virus. l-Gulono-gamma-lactone oxidase gene-inactivated mice (gulo-/- mice) require vitamin C supplementation for survival. Five-wk-old male and female gulo-/- mice were provided water or water containing 1.67 mmol/L vitamin C for 3 wk before inoculation with influenza A/Bangkok/1/79. There were no differences in lung influenza virus titers between vitamin C-adequate and -deficient mice; however, lung pathology in the vitamin C-deficient mice was greater at 1 and 3 d after infection but less at d 7 compared with vitamin C-adequate mice. Male vitamin C-deficient mice had higher expression of mRNA for regulated upon activation normal T expressed and secreted (RANTES), IL-1beta, and TNF-alpha in the lungs at d 1 after infection compared with male controls. However, at d 3 after infection, male vitamin C-deficient mice had less expression of mRNA for RANTES, monocyte chemotactic protein-1 (MCP-1), and IL-12 compared with male controls. None of these differences were observed in female mice. Vitamin C-deficient male mice also had greater nuclear factor-kappaB activation as early as 1 d after infection compared with male controls. These data suggest that vitamin C is required for an adequate immune response in limiting lung pathology after influenza virus infection.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Chemokine CCL2; Chemokine CCL5; Gene Expression; Glutathione; Influenza A virus; Interleukin-1; L-Gulonolactone Oxidase; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Orthomyxoviridae Infections; Oxidation-Reduction; RNA, Messenger; Tumor Necrosis Factor-alpha

Successful antioxidant treatment of the so-called "free radical diseases" has been reported in the literature. In this study we examined the preventive effect of vitamin E and vitamin C, alone and in combination, on the damage caused by influenza virus infection (IVI). Male mice (ICR), infected with influenza virus A/2/68/(H3N2) (1.5 of LD(50)), were administered single once-daily doses of vitamin E (60 mg/kg b.w.) and vitamin C (80 mg/kg b.w.) intraperitoneally (3 days before virus inoculation). On the 5th and 7th day, respectively, after virus inoculation, animals were decapitated. Monooxygenase enzyme activity (ethylmorphine N-demethylase, amidopyrin N-demethylase, analgin N-demethylase, aniline hydroxylase, cytochrome P-450 content and NADPH-cytochrome C reductase [CCR]) was determined in liver 9000 x g supernatant. Primary and secondary products of lipid peroxidation (LPO; conjugated dienes [CD] and TBA-reactive substances) were measured in blood plasma, lung and liver 9000 x g supernatant. Vitamin E effectively restored LPO-levels increased by IVI. The effect of vitamin C was similar, but slighter. The combination (vitamin E + C) had greater effect on LPO levels than their separate administration. P-450-dependent monooxygenase activity was significantly restored and more pronounced cytochrome P-450 content and NADPH-CCR activity was noted. The preventive effect of vitamin E was stronger than the effect of vitamin C, but the combination (vitamin E + C) had the strongest effect. The superior protective effect of the combination is probably due to vitamin C's repairing effect on vitamin E's tocopheroxyl radical.

Topics: Animals; Antioxidants; Ascorbic Acid; Cytochrome P-450 Enzyme System; Drug Therapy, Combination; Influenza A virus; Injections, Intraperitoneal; Lipid Peroxidation; Liver; Lung; Male; Mice; Mice, Inbred ICR; Mixed Function Oxygenases; Orthomyxoviridae Infections; Thiobarbituric Acid Reactive Substances; Vitamin E

As oxidative stress has been implicated in the pathogenesis of certain viral diseases we determined antioxidant and prooxidant parameters in lungs and bronchoalveolar lavage fluid (BALF) of mice infected with a lethal dose of influenza A/PR8/34 virus. Viral infection was characterized by massive infiltration of leukocytes, mainly polymorphonuclear leukocytes, into the alveolar space. The total number of BALF cells increased up to 8-fold (day 3 post-infection) and these cells appeared activated as judged by their increased rates of superoxide anion radical (O2-.) generation upon stimulation. Maximal rates of radical generation by BALF cells during the early stages of infection were 15- or 70-fold higher than those of cells from control animals when expressed per cell or total BALF cells, respectively. At the terminal stages of infection the total capacity of BALF cells to release O2-. declined to approximately 35-fold the control values. Infection also resulted in increased in vivo formation of hydrogen peroxide (H2O2) within the lungs at a time that coincided with the maximal capacity of BALF cells to release O2-.. Whereas pulmonary activities of glutathione peroxidase and reductase remained unaltered, levels of ascorbate in the cell-free BALF decreased significantly during the early stages of the infection and then returned to normal levels and above, late in infection. The oxidation state of the dehydroascorbic acid/ascorbate couple increased concomitantly with the decrease in ascorbate concentrations early in infection and remained elevated throughout the infection. As assessed by the prevention of peroxyl radical-induced loss of phycoerythrin fluorescence, the total antioxidant capacity present in lung tissue homogenate from terminally ill animals was not diminished when compared to that prepared from lungs of control mice. We conclude that although early stages of influenza infection are associated with the presence of oxidative stress in the lung tissue and alveolar fluid lining the epithelial cells, this stress does not appear to overwhelm local antioxidant defenses. The results therefore do not support a direct causative role of oxidative tissue damage in the pathogenesis of influenza virus infection.

Topics: Animals; Ascorbic Acid; Bronchoalveolar Lavage Fluid; Female; Free Radicals; Hydrogen Peroxide; Influenza A virus; Lung; Mice; Mice, Inbred ICR; Orthomyxoviridae Infections; Oxidation-Reduction; Superoxides

We investigated the possible involvement of oxidative mechanisms in the pathogenesis of influenza A/PR8/34 virus infection in mice. As a biochemical marker of oxidative stress, we determined the endogenous concentrations of the antioxidants glutathione and vitamins C and E in their reduced and oxidized forms in the lungs, liver and blood plasma of control and infected animals. Following intranasal infection with 8 to 10 LD50, influenza virus was detected in the lungs, but not in the plasma, liver or other organs. Infection resulted in a decrease in the total concentration of glutathione and vitamins C and E, whereas no relevant change in the ratio of oxidized to total concentration of antioxidants was observed. Changes in the concentration of hepatic antioxidants were significant in the early stages of the infection. The results suggest that hepatic alterations may be caused indirectly by mechanisms related to the host response to virus infection. The observed general decrease in the antioxidant buffering capacity may reduce the ability of tissues to protect against potential oxidative stress. Such stress can occur during bacterial superinfections, which are common in influenza, thereby rendering the host more susceptible to the pathogenic effects of such agents. In addition, reactive oxygen species produced in the lung may inactivate protease inhibitors, resulting in increased protease activity. Using an in vitro system consisting of alpha 1-antiprotease, trypsin and HOCl as the oxidant, we have shown that the infectivity of influenza viruses can be increased up to 10,000-fold by proteolytic cleavage of haemagglutinin, leading to activation of the fusogenic properties of this protein.

Topics: Animals; Antioxidants; Ascorbic Acid; Chromatography, High Pressure Liquid; Female; Glutathione; Immunohistochemistry; Influenza A virus; Kinetics; Liver; Lung; Mice; Orthomyxoviridae Infections; Oxidation-Reduction; Respiratory Burst; Specific Pathogen-Free Organisms; Vitamin E

This study investigated the nonspecific immunomodulatory effects of Bacillus Calmette-Guerin (BCG), muramyl dipeptide (MDP) and ascorbic acid (vitamin C) on virus infection of the respiratory tract in Fischer-344 rats. Groups of young adult (12-16 months old) and aged (24-30 months old) rats were given BCG or MDP intranasally or vitamin C orally 6 weeks and again 3 days before an intranasal challenge with influenza virus A/Bangkok/H3N2 (10(6) 50% EID). Titers of hemagglutinin in lung homogenates and the presence of leukocytes in the respiratory tracts served as indices of infection. Lung macrophage functions of animals were determined by measuring random migration and phagocytic yeast cell killing in vitro. Clearance of Staphylococcus aureus from the respiratory tracts of the animals was also measured 4 hours after challenge. - Following BCG treatment, significantly fewer animals developed virus infection. MDP and vitamin C treatments also reduced the numbers of infected rats but did not differ significantly from the untreated control groups. BCG and MDP treatments significantly reduced the numbers of lung leukocytes in virus infected animals. Mean virus titers in the lung homogenates were significantly lower in all treatment groups by the third day of infection. Following all treatments, duration of virus infection was significantly shorter in the aged compared to the young adult groups. Lung macrophage functions increased in all treatment groups. The improvement of aged groups over their controls was greater than that of the young adults compared to their controls. BCG had the greatest protective effects in both the young adult and aged animals; MDP and vitamin C, in that order, were less effective.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Aging; Animals; Ascorbic Acid; BCG Vaccine; Influenza A virus; Lung; Macrophages; Orthomyxoviridae Infections; Rats; Rats, Inbred F344; Time Factors

Topics: Animals; Ascorbic Acid; Female; Mice; Mice, Inbred Strains; Mutation; Orthomyxoviridae Infections; Pregnancy

Topics: Animals; Ascorbic Acid; Chromosome Aberrations; Influenza A virus; Male; Mice; Orthomyxoviridae Infections; Spermatocytes

Topics: Adenoviridae; Adenoviridae Infections; Antiviral Agents; Ascorbic Acid; Common Cold; Cough; Culture Techniques; Humans; Infections; Orthomyxoviridae; Orthomyxoviridae Infections; Picornaviridae; Respiratory Tract Infections; Virus Diseases

Topics: Adenoviridae Infections; Aminophylline; Ascorbic Acid; Chlamydophila psittaci; Chloramphenicol; Drug Therapy; Epidemiologic Studies; Epidemiology; France; Humans; Influenza, Human; Military Medicine; Orthomyxoviridae; Orthomyxoviridae Infections; Pneumonia; Pneumonia, Viral; Psittacosis; Radiography, Thoracic; Respiratory Tract Diseases; Sendai virus; Serologic Tests; Vaccination; Virus Diseases

Topics: Animals; Antibodies; Antiviral Agents; Ascorbic Acid; Complement System Proteins; Folic Acid; Guinea Pigs; Mice; Orthomyxoviridae; Orthomyxoviridae Infections; Pantothenic Acid; Research; Vitamin A; Vitamin B 12; Vitamin B Complex; Vitamin K; Vitamins