Molnupiravir,favipiravir and other antiviral drugs with proposed potentials for management of COVID-19: a concern on antioxidant aspect

COVID-19 is an important global public health problem that causes millions of infections worldwide. The specific antiviral drug for this new infection is still under research. Some new antiviral drugs, including molnupiravir and favipiravir, are proposed for usefulness in management of COVID-19. Additionally, some classic antiviral drugs used for other viral infections are also reproposed for the potentials for management of COVID-19. In the management of COVID-19, there are several pharmacological actions. An important consideration in antiviral therapy is the management of oxidative stress, which plays important roles in viral infections including to COVID-19. The analysis of antioxidative properties of alternative drugs for management of COVID-19 is interesting and can give basic data for further new antiviral drug researching. Here, the authors perform a molecular analysis on molnupiravir, favipiravir and other antiviral drugs with proposed potentials for management of COVID-19 to determine their antioxidative properties. Data from electron acceptor and donor calculation for each drug is used for further estimating overall antioxidative characteristic. Based on the present study, all studied drugs have overall antioxidative properties. Hence, the advantage of molnupiravir, favipiravir and other antiviral drugs with proposed potentials for the management of COVID-19 is their direct action on viral molecule via binding-blocking process as well as antixodiative process. For management of COVID-19 antioxidative stress, other non-antiviral drugs that are proposed for clinical advantage might also be useful.     

Effects of a novel gaseous antioxidative system containing a rosemary extract on the oxidation induced by nitrogen dioxide and ultraviolet radiation

Rosemary is commonly used as a spice and a flavoring agent in food processing. Although the antioxidative properties of its extracts have been investigated, there have been few reports on the volatile components of rosemary. We designed a novel antioxidative system which can generate the volatile constituents in the gaseous phase from a rosemary extract and evaluated the gaseous antioxidative activities against both lipid peroxidation and cell death induced by nitrogen dioxide and ultraviolet radiation. The antioxidative effects of the major volatile components on the oxidation of linoleic acid induced by azo compounds were also investigated in a solution. The volatile components in the novel antioxidative system suppressed the Jurkat cell death induced by nitrogen dioxide and the intracellular formation of reactive oxygen species in fibroblast cells induced by ultraviolet radiation. 1,8-Cineole among the volatile components exerted an antioxidative effect against the oxidation of linoleic acid in a solution induced by azo compounds and ultraviolet radiation. These data suggest that the volatile constituents of a rosemary extract had antioxidative properties and that gaseous exposure antioxidant is a promising method for promoting health.     

Evaluating antioxidative activities of amino acid substitutions on mastoparan-B

Mastoparan-B is a peptide toxin isolated from the venom of Vespa basalis, the most dangerous hornet found in Taiwan. This study is aimed to evaluate the antioxidative activities of several amino acid substitutions on MP-B, and examined the influences of mast cell degranulation and hemolytic activities in parallel with antioxidative activities. The correlations between the biological function and amino acid sequence were assessed. Our study shows original MP-B is a valuable antioxidant at low concentration in competing with nitric-oxide for oxygen molecules and possesses good antioxidative enzyme activities resembled to superoxidase dismutase and glutathione peroxidase. And there are no predominant rates of mast cell degranulation and hemolytic effects in such condition. With proper substitutions, the reducing power, DPPH scavenging activity and glutathione reductase-like enzyme activity of MP-B can increase clearly. The results demonstrate that MP-B analogs are very potential to be applicable antioxidants for other antioxidative usages.     

Down's syndrome: a pathology involving the lack of balance of reactive oxygen species

Mongolism, or Down's syndrome (DS) is an inborn pathology due to trisomy 21. Apart from mental deficiency and anatomical abnormalities, premature aging is characteristic for this disease. This paper mainly reviews data on the generation of reactive oxygen species (ROS) and antioxidative defense mechanisms in DS, and on the sensitivity of DS cells to model sources of ROS. Changes in the antioxidative defense of DS cells are due mainly to the location of the gene for (Cu,Zn)-superoxide dismutase on chromosome 21. It is suggested that a disturbance of balance of ROS may be a key point in the pathogenesis of DS.     

Influence of Methionine upon the Activity of Antioxidative Enzymes in The Kidney of Rats Exposed to Sodium Fluoride

The intensified or uncontrolled formation of reactive oxygen species leads to disturbances of numerous biochemical processes. Among the factors inducing intensified free radical processes, fluoride ions are listed, among others. One of the organs most exposed to the toxic activity of fluorides is the kidney. In the study presented here, the influence of fluorine upon the activity of selected antioxidant enzymes in rat kidney has been examined, as well as antioxidant properties of methionine during intoxication with sodium fluoride. The experiment was carried out on Wistar FL rats (adult females) that for 35 days were administered water, NaF, NaF with methionine (doses: 10 mg NaF/kg bw/day, 10 mg Met/kg bw/day) . The influence of administered NaF and Met upon the antioxidative system in kidney was examined by analyzing the activity of the most important antioxidative enzymes (SOD, CAT, GPX, GR, GST). The studies carried out confirmed the disadvantageous effect of NaF upon the antioxidative system in rats (decrease in activity of antioxidative enzymes). Methionine increased the activity of antioxidative enzymes, most efficiently that of GPX, GR, and GST.     

Effects of pH and metal ions on antioxidative activities of catechins

The Effects of pH on antioxidative activities of catechol, pyrogallol, and four catechins, and effects of metal ions (Al3+, Ca2+, Cd2+, Co2+, Cr3+, Cu2+, Fe2+, Fe3+, K+, Mg2+, Mn2+, Na+, and Zn2+) on antioxidative activities of (-)-epigallocatechin gallate (EGCG) were studied by an oxygen electrode method. The antioxidative activities of catechins were high and constant at pH 6-12, but decreased in acidic and strong alkaline solutions. Copper(II) ion the most strongly increased the antioxidative activity of EGCG among these metal ions examined, but iron(II) ion largely inhibited the antioxidative activity of EGCG. These effects are discussed considering the formation of metal complexes with catechins and the change in oxidation potentials.     

Anti- and pro-oxidative effects of flavonoids on metal-induced lipid hydroperoxide-dependent lipid peroxidation in cultured hepatocytes loaded with alpha-linolenic acid

Lipid hydroperoxide (LOOH)-dependent lipid peroxidation was induced in alpha-linolenic acid (LNA)-loaded hepatocytes by adding Fe, Cu, V, or Cd ions at concentrations from 20 to 500 microM. The effects of structurally related flavonoids at concentrations from 10 to 500 microM on the lipid peroxidation were examined. The results with regard to each flavonoid subclass are as follows: (i) Flavonols such as myricetin, quercetin, fisetin, and kaempferol, but not morin, showed dose-dependent antioxidative activity against metal-induced lipid peroxidation at all metal concentrations. Myricetin, quercetin, and fisetin were the most effective antioxidants, although their efficacies depended on the metal ion. Kaempferol and morin had antioxidative activity equal to the other flavonols in the presence of Cu ions, but were much less effective for the other three metal ions. (ii) Flavones, luteolin, apigenin, and chrysin were antioxidative at low Fe concentrations, but were pro-oxidative at high Fe concentrations. Luteolin exhibited antioxidative activity similar to that of catechol-containing flavonols in the presence of the other three metal ions. Apigenin and chrysin also acted as pro-oxidants with V or with all metal ions, respectively. (iii) Taxifolin, a flavanone, also showed both anti- and prooxidative activity, depending on Fe concentrations, but with other metal showed only antioxidative activity ions. (iv) Epigallocatechin, a flavanol, was antioxidative with all metal ions, and its activity was similar to that of catechol-containing flavonols. The various effects of flavonoids on metal-induced lipid peroxidation in LNA-loaded hepatocytes is discussed with regard to the change in redox potential of flavonoid-metal complexes.     

Antioxidative activity of hydroxylamines. ESR spectra of radicals derived from hydroxylamines.

The antioxidative activity of hydroxylamines was evaluated for the oxidation of tetralin at 61 degrees C and linoleic acid micelles in an aqueous dispersion at 37 degrees C, induced by an azo initiator. The antioxidative efficacy of the hydroxylamines for the oxidation of tetralin was smaller than that of alpha-tocopherol. However, the hydroxylamines showed more potent antioxidative activity than that of the alpha-tocopherol against the oxidation of linoleic acid micelles. On the basis of the results of an ESR study and the oxidation product obtained, it is suggested that active position in hydroxylamines depend not only on hydroxyl hydrogen-atom, but also on the allylic hydrogen atom.     

Biological role of histidine-containing dipeptides

The biological role of histidine-containing dipeptides is reviewed. The role of carnosine and anserine in muscle function is discussed from the evolutionary viewpoint. Evidence on the antioxidative effect of carnosine and its protection of biological membranes against lipid peroxidation-induced damages is presented. The effects of presently known natural antioxidative agents and carnosine on lipid peroxidation are compared. Carnosine has been shown to be a more universal protector of membranes as compared to free radical scavengers.     

Phytotoxicity of pesticides mancozeb and chlorpyrifos: correlation with the antioxidative defence system in <Emphasis Type="Italic">Allium cepa</Emphasis>

Pesticides are a group of chemical substances which are widely used to improve agricultural production. However, these substances could be persistent in soil and water, accumulative in sediment or bio-accumulative in biota depending on their solubility, leading to different types of environmental pollution. The present study was done to assess the impact of pesticides-mancozeb and chlorpyrifos, via morphological and physiological parameters using Allium cepa test system. Phytotoxic effects of pesticides were examined via germination percentage, survival percentage, root and shoot length, root shoot length ratio, seedling vigor index, percentage of phytotoxicity and tolerance index. Oxidative stress on Allium seedlings caused by pesticides was also assessed by investigating the activity of antioxidative enzymes viz. catalase, peroxidase and superoxide dismutase. Correlation was worked out between morphological parameters and antioxidative enzymes to bring out the alliance between them. Mancozeb and chlorpyrifos concentrations were significantly and positively correlated with the activity of antioxidative enzymes and negatively correlated with morphological parameters. Significant positive correlation between various morphological parameters showed their interdependency. However, negative correlation was obtained between activity of antioxidative enzymes and morphological parameters. The enzymes however, showed positive correlation with each other. Based on our result we can conclude that all morphological parameters were adversely affected by the two pesticides as reflected by phytotoxicity in Allium. Their negative correlation with activity of antioxidative enzymes indicates that upregulation of antioxidative enzymes is not sufficient to overcome the toxic effect, thereby signifying the threat being caused by the regular use of these pesticides.     

Antioxidative activity of hydroxylamines. ESR spectra of radicals derived from hydroxylamines

The antioxidative activity of hydroxylamines was evaluated for the oxidation of tetralin at 61°C and linoleic acid micelles in an aqueous dispersion at 37°C, induced by an azo initiator. The antioxidative efficacy of the hydroxylamines for the oxidation of tetralin was smaller than that of α-tocopherol. However, the hydroxylamines showed more potent antioxidative activity than that of the α-tocopherol against the oxidation of linoleic acid micelles. On the basis of the results of an ESR study and the oxidation product obtained, it is suggested that active position in hydroxylamines depend not only on hydroxyl hydrogen-atom, but also on the allylic hydrogen atom.     

Total low-molecular-weight antioxidants as a summary parameter, quantified in biological samples by a chemiluminescence inhibition assay

Aerobic metabolism requires a complex antioxidative system to balance reactive oxygen species (ROS). When in excess, ROS disrupt cellular activities and molecular structures. Owing to the variety of ROS, there are different antioxidative activities that require various tests for their detection. The so-called 'total antioxidative capacity' inhibition assay presented in this paper can be used to quantify the overall activity of low-molecular-weight antioxidants (AOs) in biological samples. The assay is based on enhanced horseradish peroxidase-catalyzed luminol chemiluminescence. It can be fine-tuned so that the biological samples meet the requirements of the light detector. A detailed protocol describing all relevant parameters is provided. The procedure is quick, inexpensive and reproducible. The assay can be used with diverse biological materials such as plant extracts and blood plasma. Hence, it is applicable to fields as diverse as crop breeding, medical diagnostics or food sciences. The time needed for the assay depends on the number of samples and their AO content. The protocol takes one working day to complete when five samples with five replicates are measured sequentially.     

Production of reactive oxygen species and development of antioxidative systems during <Emphasis Type="Italic">in vitro</Emphasis> growth and <Emphasis Type="Italic">ex vitro</Emphasis> transfer

Ex vitro transfer is often stressful for in vitro grown plantlets. Water stress and photoinhibition, often accompanying the acclimatization of in vitro grown plantlets to ex vitro conditions, are probably the main factors promoting production of reactive oxygen species (ROS) and in consequence oxidative stress. The extent of the damaging effects of ROS depends on the effectiveness of the antioxidative systems which include low molecular mass antioxidants (ascorbate, glutathione, tocopherols, carotenoids, phenols) and antioxidative enzymes (superoxide dismutase, ascorbate peroxidase, catalase, glutathione reductase, monodehydroascorbate reductase, dehydroascorbate reductase). This review is focused on ROS production and development of antioxidative system during in vitro growth and their further changes during ex vitro transfer.     

Anti- and pro-oxidative effects of flavonoids on metal-induced lipid hydroperoxide-dependent lipid peroxidation in cultured hepatocytes loaded with α-linolenic acid

Lipid hydroperoxide (LOOH)–dependent lipid peroxidation was induced in α-linolenic acid (LNA)-loaded hepatocytes by adding Fe, Cu, V, or Cd ions at concentrations from 20 to 500 μM. The effects of structurally related flavonoids at concentrations from 10 to 500 μM on the lipid peroxidation were examined. The results with regard to each flavonoid subclass are as follows: (i) Flavonols such as myricetin, quercetin, fisetin, and kaempferol, but not morin, showed dose-dependent antioxidative activity against metal-induced lipid peroxidation at all metal concentrations. Myricetin, quercetin, and fisetin were the most effective antioxidants, although their efficacies depended on the metal ion. Kaempferol and morin had antioxidative activity equal to the other flavonols in the presence of Cu ions, but were much less effective for the other three metal ions. (ii) Flavones, luteolin, apigenin, and chrysin were antioxidative at low Fe concentrations, but were pro-oxidative at high Fe concentrations. Luteolin exhibited antioxidative activity similar to that of catechol-containing flavonols in the presence of the other three metal ions. Apigenin and chrysin also acted as pro-oxidants with V or with all metal ions, respectively. (iii) Taxifolin, a flavanone, also showed both anti- and prooxidative activity, depending on Fe concentrations, but with other metal showed only antioxidative activity ions. (iv) Epigallocatechin, a flavanol, was antioxidative with all metal ions, and its activity was similar to that of catechol-containing flavonols. The various effects of flavonoids on metal-induced lipid peroxidation in LNA-loaded hepatocytes is discussed with regard to the change in redox potential of flavonoid–metal complexes.     

Antioxidative properties of Jaffa sweeties and grapefruit and their influence on lipid metabolism and plasma antioxidative potential in rats

The effective substances (polyphenols, phenolic and ascorbic acids, flavonoids and dietary fibers) and antioxidative activities, using different radical-scavenging tests, were determined for Jaffa sweeties and grapefruit. The antioxidative activities comprised the contributions from polyphenols, phenolic acids, flavonoids and ascorbate components, and were well-correlated with polyphenols and flavonoids. The correlation coefficient between the polyphenols and antioxidative activity varied from 0.73 to 0.99. All applied methods showed that sweeties had higher antioxidative activity than grapefruit. Experiments on laboratory animals show that diets supplemented with sweeties, and to a lesser extent with grapefruit, increased the plasma antioxidative potential and improved the lipid metabolism, especially in the rats fed with added cholesterol. These findings provide additional characterization of the nutritional value of citrus fruits and their influence on the lipid metabolism in rats.     

Ontogenic characteristics of lipid peroxidation and antioxidant system enzymes in the brain of geese

Peculiarities of antioxidant homeostasis of geese brain tissue during embryogenesis and early postnatal period have been studied. It has been shown that the cerebrum and hindbrain tissues are characterized by a higher level of lipid peroxidation compared to liver. Main antioxidative enzymes' activity (superoxide dismutase, catalase, glutathione peroxidase) in the brain already reaches its maximum in the middle period of embryogenesis. We have found that brain tissues are characterized by a lower activity of intracellular enzymes (superoxide dismutase, catalase) but increased glutathione peroxidase activity as compared to liver. The rate of Fe2+ initialized lipid peroxidation and coefficient of antioxidative activity were used as a criterion for evaluation of antioxidative system's status. According to the dynamics of these factors the highest tension of antioxidative system in the brain appears in the period of the contour (28 days) and juvenile (49 days) feather formation.     

Role of endogenous and exogenous antioxidants in the defence against functional damage and lipid peroxidation in rat liver mitochondria

Mitochondria are cellular organelles where the generation of reactive oxygen species may be high. They are, however, effectively protected by their high capacities of antioxidative systems, as enzymes and either water or lipid soluble low molecular weight antioxidants.These antioxidative defence systems can be effectively regenerated after or during an oxidative stress as long as the mitochondria are in an energized state. Energization of mitochondria mainly depends on the availability of suitable respiratory substrates which can provide hydrogen for the reduction of either the glutathione- or -tocopherol-system, since GSH is regenerated by glutathione reductase with the substrate NADPH and the -tocopheroxyl-radical likely by reduced coenzyme Q. It was shown that mitochondria do not undergo damages as long as they can keep a high energy state. The delicate balance between prooxidative/antioxidative activities can be shifted towards oxidation, if experimentally prooxidants were added. After exhaustion of the antioxidative defence systems damages of rnitochondrial functions become expressed followed by membrane injuries along with the oxidation and degradation of mitochondrial lipids and proteins leading finally to the total degradation of the mitoc hondria.Extramitochondrial antioxidants may assist the mitochondrial antioxidative defence systems in a complex way, whereby particularly ascorbic acid can act both as prooxidant and as antioxidant. (Mol Cell Biochem 174: 199–205, 1997)     

Comparative study of oxidative stress and antioxidative markers in patients infected with Toxoplasma gondii

Recently, oxidative stress and antioxidative compounds have been described as potential biomarkers. However, there is no consensus on the most appropriate oxidative and antioxidative biomarkers for patients with Toxoplasma gondii. In the present study, we evaluated the levels of lipid, protein, DNA oxidative damage and antioxidants in samples from patients infected with T. gondii with and without ocular toxoplasmosis. The levels of MDA, TBARS, micronuclei, carbonyl, GSH, vitamin C and vitamin E were measured on samples from 8 patients positive for T. gondii antibodies with ocular toxoplasmosis (OT), 20 patients positive for T. gondii antibodies without ocular toxoplasmosis (non OT), and 12 healthy individuals negative for T. gondii antibodies. The levels of MDA, TBARS, carbonyl and micronuclei were significantly higher in non OT patients, while MDA and TBARS levels were lower in OT patients. In contrast, the antioxidative factors, GSH and vitamin E levels were significantly lower in non OT patients, while vitamin C was lower in non OT and OT patients. Additionally, non OT patients were indicated to be high producers of oxidative markers (TBARS, MDA, micronuclei and carbonyl), while control group was indicated to be high producer of antioxidative markers (GSH, vitamins C and E). However, OT patients were not found as high producers of oxidative nor antioxidative markers. Our results provide a starting point of possible markers to better understand the disease pathogenesis in patients infected with T. gondii. Additional studies are needed to clarify the potential contribution of oxidative and antioxidative markers in these patients population.     

Antioxidant properties of a new antioxidative peptide from algae protein waste hydrolysate in different oxidation systems

Microalgae have been a popular edible food, but there are no known reports on the antioxidative peptides derived from microalgae. The algae protein waste, which is normally discarded as animal feed, is a by-product during production of algae essence from microalgae, Chlorella vulgaris. Algae protein waste was hydrolyzed using pepsin, and a potent antioxidative peptide of VECYGPNRPQF was separated and isolated. The peptide could efficiently quench a variety of free radicals, including hydroxyl radical, superoxide radical, peroxyl radical, DPPH radical and ABTS radicals, and performed more efficiently than that observed for BHT, Trolox and peptides from marine protein sources in most cases. The purified peptide also has significant protective effects on DNA and prevents cellular damage caused by hydroxyl radicals. In addition, the peptide has gastrointestinal enzyme-resistance and no cytotoxicity observed in human lung fibroblasts cell lines (WI-38) in vitro. These results demonstrate that inexpensive algae protein waste could be a new alternative to produce antioxidative peptides.