Implications of oxidative stress on viral pathogenesis Camini, Fernanda Caetano; da Silva Caetano, Camila Carla; Almeida, Letícia Trindade ...
Archives of Virology,
04/2017, Letnik:
162, Številka:
4
Journal Article, Book Review
Recenzirano
Reactive species are frequently formed after viral infections. Antioxidant defences, including enzymatic and non-enzymatic components, protect against reactive species, but sometimes these defences ...are not completely adequate. An imbalance in the production of reactive species and the body’s inability to detoxify these reactive species is referred to as oxidative stress. The aim of this review is to analyse the role of oxidative stress in the pathogenesis of viral infections and highlight some major therapeutic approaches that have gained importance, with regards to controlling virus-induced oxidative injury. Attention will be focused on DNA viruses (papillomaviruses, hepadnaviruses), RNA viruses (flaviviruses, orthomyxoviruses, paramyxoviruses, togaviruses) and retroviruses (human immunodeficiency virus). In general, viruses cause an imbalance in the cellular redox environment, which depending on the virus and the cell can result in different responses, e.g. cell signaling, antioxidant defences, reactive species, and other processes. Therefore, the modulation of reactive species production and oxidative stress potentially represents a novel pharmacological approach for reducing the consequences of viral pathogenesis.
•Zika virus induces increase in ROS and biomarkers of oxidative stress, and decrease in antioxidant enzymes.•Zika virus infection triggers oxidative stress cellular response.•Oxidative stress may be ...an important factor in the Zika virus pathogenesis.
The first outbreak of Zika virus (ZIKV) infection in the Americas, especially in Brazil, was reported in 2015. Fever, headache, rash, and conjunctivitis are the common symptoms of ZIKV infection. Unexpected clinical outcomes, such as microcephaly and Guillain-Barré syndrome, have also been reported. The recent spread of ZIKV and its association with severe illness has created an urgent need to understand its pathogenesis and find potential therapeutic targets. Studies show that some viruses, including Flavivirus, trigger oxidative stress, which affects cellular metabolism, viral cycle, and pathogenesis. However, the role of oxidative stress in ZIKV infection needs to be investigated. Here, we analyzed ZIKV infection-triggered oxidative stress and modified antioxidant enzyme activities. U87-MG and HepG2 cells were infected to measure reactive oxygen species (ROS), malondialdehyde (MDA), and carbonyl protein levels, the activities of superoxide dismutase (SOD) and catalase (CAT), and the activation of nuclear factor erythroid 2p45-related factor 2 (Nrf2). ZIKV infection induced a significant increase in ROS, lipid peroxidation, and protein carbonylation products and a significant decrease in SOD and CAT activities accompanied by inhibition of Nrf2 activation in both cell lines. Further, MDA and carbonyl protein levels and SOD and CAT activities were evaluated in the brain and liver of ZIKV-infected C57BL/6 mice, and oxidative stress associated with antioxidant depletion was also found to occur in vivo. Together, our findings indicate the potential use of antioxidants as a novel therapeutic approach to Zika disease, and future studies in this direction are warranted.
Mayaro virus (MAYV) causes Mayaro fever in humans, a self-limiting acute disease, with persistent arthralgia and arthritis. Although MAYV has a remerging potential, its pathogenic mechanisms remain ...unclear. Here, we characterized a model of MAYV infection in 3-4-week BALB/c mice. We investigated whether the liver acts as a site of viral replication and if the infection could cause histopathological alterations and an imbalance in redox homeostasis, culminating with oxidative stress. MAYV-infected mice revealed lower weight gain; however, the disease was self-resolving. High virus titre, neutralizing antibodies, and increased levels of aspartate and alanine aminotransferases were detected in the serum. Infectious viral particles were recovered in the liver of infected animals and the histological examination of liver tissues revealed significant increase in the inflammatory infiltrate. MAYV induced significant oxidative stress in the liver of infected animals, as well as a deregulation of enzymatic antioxidant components. Collectively, this is the first study to report that oxidative stress occurs in MAYV infection in vivo, and that it may be crucial in virus pathogenesis. Future studies are warranted to address the alternative therapeutic strategies for Mayaro fever, such as those based on antioxidant compounds.
•Silymarin presents activity against ZIKV infection, reducing virus titre, viral RNA and plaque forming units.•Silymarin has virucidal effect and inhibits adsorption and penetration of ZIKV ...particles.•Silymarin has potential for use in therapy against ZIKV infections.
Zika virus (ZIKV) epidemic and its association with severe neurological syndromes have raised worldwide concern. Despite the great clinical relevance of this infection, no vaccine or specific treatment is available and the search for antiviral compounds against ZIKV is extremely necessary. Several natural compounds, such as silymarin, exhibit antioxidant, hepatoprotective, and antiviral properties; however, the antiviral potential of this compound remains partially investigated. Therefore, the objective of this study was to evaluate in vitro the antiviral activity of silymarin against ZIKV infection. Global antiviral activity, dose-dependent, plaque reduction, and time-of-drug-addition assays were used to determine the anti-ZIKV activity of silymarin. Additionally, to start characterizing the mechanisms of action we determined whether silymarin could have a virucidal effect and inhibit viral adsorption and penetration stages. Regarding its global antiviral activity, silymarin showed significant inhibition of ZIKV infection, protecting cells infected with EC50 equal to 34.17μg/mL, with a selectivity index greater than 17 and 4x greater than that of the positive control (ribavirin). Its greatest efficiency was achieved at 125μg/mL, whose cell viability did not differ from the control without infection and treatment. Furthermore, treatment with silymarin reduced viral load by up to two logs (> 90%) concerning viral control, when evaluating virucidal activity and the precocious times of infection. Thus, our results set to show the promising anti-ZIKV activity of silymarin, which does not seem to have a single inhibition mechanism, acting at different times of infection, and still has the advantage of silymarin be a phytotherapy already available on the market.
Mayaro virus (MAYV) is a neglected arbovirus belonging to the family Togaviridae. Its infection leads to Mayaro fever, with clinical manifestations such as fever, myalgia, headache, rash, arthralgia, ...vomiting, and diarrhea. The most prominent complaint from infected person is the long-lasting arthritis/arthralgia. The treatment for Mayaro fever is mainly symptom-based and there are no vaccines or antiviral drugs currently available, thus, natural products with anti-MAYV activity may provide a potential alternative. Recent evidences suggest that oxidative stress plays an important role in MAYV infection and compounds capable of modulating oxidative stress could represent a novel therapeutic approach in modulating MAYV-associated oxidative cellular damage. Silymarin is a complex extracted of Silybum marianum, or milk thistle, and its major active compound is silybin, which has a remarkable biological effect. Its antioxidant and antiviral effects, including its antiviral activity against the Chikungunya virus (CHIKV), prompted us to think whether silymarin could also reduce the replication of the MAYV and restore the pro-oxidant/antioxidant balance in the context of MAYV infection, leading to reduced cellular oxidative stress. We assessed the antiviral activity and protective effect of silymarin against oxidative stress in MAYV-infected HepG2 cells. Cytopathic effect inhibition, viral replication, and plaque reduction assays were used to determine the anti-MAYV activity of silymarin. Additionally, we determined whether silymarin could reduce MAYV-induced oxidative cell damage. Briefly, silymarin exhibited potent antiviral activity against MAYV and reduced MAYV-induced ROS formation and levels of malondialdehyde (MDA) and carbonyl protein, which are biomarkers of oxidative stress. In conclusion, the ability of silymarin to inhibit MAYV replication and attenuate MAYV-induce oxidative stress warrants further investigation of this compound as a novel therapeutic approach to Mayaro fever disease.
•Antiviral activity of sylimarin against Mayaro virus.•Silymarin protects cells from MAYV-induced oxidative stress.•Promising potential of silymarin in the therapeutic of Mayaro fever.
Infection caused by Mayaro virus (MAYV) is responsible for causing acute nonspecific fever, in which the majority of patients develop incapacitating and persistent arthritis/arthralgia. Mayaro fever ...is a neglected and underreported disease without treatment or vaccine, which has gained attention in recent years after the competence of Aedes aegypti to transmit MAYV was observed in the laboratory, coupled with the fact that cases are being increasingly reported outside of endemic forest areas, calling attention to the potential of an urban cycle arising in the near future. Thus, to mitigate the lack of information about the pathological aspects of MAYV, we previously described the involvement of oxidative stress in MAYV infection in cultured cells and in a non-lethal mouse model. Additionally, we showed that silymarin, a natural compound, attenuated MAYV-induced oxidative stress and inhibited MAYV replication in cells. The antioxidant and anti-MAYV effects prompted us to determine whether silymarin could also reduce oxidative stress and MAYV replication after infection in an immunocompetent animal model. We show that infected mice exhibited reduced weight gain, hepatomegaly, splenomegaly, anaemia, thrombocytopenia, leukopenia, increased liver transaminases, increased pro-inflammatory cytokines and liver inflammation, increased oxidative damage biomarkers, and reduced antioxidant enzyme activity. However, in animals infected and treated with silymarin, all these parameters were reversed or significantly improved, and the detection of viral load in the liver, spleen, brain, thigh muscle, and footpad was significantly reduced. This work reinforces the potent hepatoprotective, antioxidant, anti-inflammatory, and antiviral effects of silymarin against MAYV infection, demonstrating its potential against Mayaro fever disease.
•Silymarin improves MAYV infection in BALB/c mice.•Silymarin protects mice from liver damage, oxidative stress, inflammation, and virus replication after MAYV infection.•Promising potential of silymarin in the therapeutic treatment of Mayaro fever.
•Mayaro virus induces increase in reactive oxygen species and in antioxidant defences.•Mayaro virus infection triggers oxidative stress cellular response.•Oxidative stress may be an important factor ...in the Mayaro virus pathogenesis.
Mayaro virus (MAYV) is a neglected tropical arbovirus that causes a febrile syndrome that is sometimes accompanied by incapacitating arthritis/arthralgia. The pathogenesis of MAYV has not been completely defined and oxidative stress mediated by an increase in reactive oxygen species (ROS) and/or depletion of antioxidant defences has been found to contribute to several aspects of viral disease. To investigate whether MAYV induced oxidative stress in host cells, we monitored ROS production, oxidative stress markers and antioxidant defences at different time points after infection. Our results show that MAYV induced significant oxidative stress in infected HepG2 cells, as indicated by the increase of malondialdehyde (MDA) and protein carbonyl levels, and by a significant decrease of the reduced versus oxidized glutathione (GSH/GSSG) ratio. Generally, MAYV-infected HepG2 cells also showed an increase in antioxidant defences. We observed an increase in the superoxide dismutase (SOD) and catalase (CAT) activities and the total glutathione content. To determine whether similar effects occurred in other cell types, we evaluated the ROS, MDA and SOD activity levels in J774 cells after MAYV infection. Similar to our observations in HepG2 cells, the J774 cells showed an increase in ROS, MDA and total SOD activity following MAYV infection. Thus, since the cellular redox environment is influenced by the production and removal of ROS, we hypothesize that the overproduction of ROS was responsible for the oxidative stress in response to the MAYV infection despite the increase in the antioxidant status. This study is the first report on the involvement of oxidative stress during MAYV infection. Collectively, our data shed light on some mechanisms that are operational in host cells following exposure to MAYV.
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