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• W2132518830 abstract "Japanese encephalitis (JE) is prevalent throughout eastern and southern Asia and the Pacific Rim. It is caused by the JE virus (JEV), which belongs to the family Flaviviridae. Despite the importance of JE, little is known about its pathogenesis. The role of oxidative stress in the pathogenesis of viral infections has led to increased interest in its role in JEV infections. This review focuses mainly on the role of oxidative stress in the pathogenesis of JEV infection and the antiviral effect of antioxidant agents in inhibiting JEV production. First, this review summarizes the pathogenesis of JE. The pathological changes include neuronal death, astrocyte activation, and microglial proliferation. Second, the relationship between oxidative stress and JEV infection is explored. JEV infection induces the generation of oxidants and exhausts the supply of antioxidants, which activates specific signaling pathways. Finally, the therapeutic efficacy of a variety of antioxidants as antiviral agents, including minocycline, arctigenin, fenofibrate, and curcumin, was studied. In conclusion, antioxidants are likely to be developed into antiviral agents for the treatment of JE. Japanese encephalitis (JE) is prevalent throughout eastern and southern Asia and the Pacific Rim. It is caused by the JE virus (JEV), which belongs to the family Flaviviridae. Despite the importance of JE, little is known about its pathogenesis. The role of oxidative stress in the pathogenesis of viral infections has led to increased interest in its role in JEV infections. This review focuses mainly on the role of oxidative stress in the pathogenesis of JEV infection and the antiviral effect of antioxidant agents in inhibiting JEV production. First, this review summarizes the pathogenesis of JE. The pathological changes include neuronal death, astrocyte activation, and microglial proliferation. Second, the relationship between oxidative stress and JEV infection is explored. JEV infection induces the generation of oxidants and exhausts the supply of antioxidants, which activates specific signaling pathways. Finally, the therapeutic efficacy of a variety of antioxidants as antiviral agents, including minocycline, arctigenin, fenofibrate, and curcumin, was studied. In conclusion, antioxidants are likely to be developed into antiviral agents for the treatment of JE. Japanese encephalitis (JE) is prevalent throughout eastern and southern Asia and the Pacific Rim, with an estimated 50 000 cases and 15 000 deaths annually.1Misra U.K. Kalita J. Overview: Japanese encephalitis.Prog Neurobiol. 2010; 91: 108-120Crossref PubMed Scopus (265) Google Scholar In humans, JE can range from a mild febrile illness to severe encephalitis, including seizures, a polio-like illness, and a variety of movement disorders.2Misra U.K. Kalita J. Movement disorders in Japanese encephalitis.J Neurol. 1997; 244: 299-303Crossref PubMed Scopus (86) Google Scholar In fatal cases of JE, pathological changes are seen in various parts of the nervous system, including a severe degree of vascular congestion, cerebral edema, neuron death, astrocyte activation, and microglial proliferation.1Misra U.K. Kalita J. Overview: Japanese encephalitis.Prog Neurobiol. 2010; 91: 108-120Crossref PubMed Scopus (265) Google Scholar The etiologic agent, Japanese encephalitis virus (JEV), belongs to the family Flaviviridae and can be transmitted between animal and human hosts by Culex species of mosquitoes. Although vaccination is the most viable option to control JE, affordable vaccines are still not widely available.3Gao N. Chen W. Zheng Q. Fan D.Y. Zhang J.L. Chen H. et al.Co-expression of Japanese encephalitis virus prM-E-NS1 antigen with granulocyte-macrophage colony-stimulating factor enhances humoral and anti-virus immunity after DNA vaccination.Immunol Lett. 2010; 129: 23-31Crossref PubMed Scopus (21) Google Scholar Little is known about the pathogenesis of human JEV infection, including the mechanism of its spread to the central nervous system (CNS) and viral tropism within the brain.4Myint K.S. Gibbons R.V. Perng G.C. Solomon T. Unravelling the neuropathogenesis of Japanese encephalitis.Trans R Soc Trop Med Hyg. 2007; 101: 955-956Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar JEV is a single-stranded, positive-sense RNA virus that encodes three structural proteins (capsid protein (C), precursor to the membrane protein (PrM), and envelope protein (E)) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). JEV might have a peripheral replication cycle, since in vitro studies have revealed that peripheral blood mononuclear cells (PBMCs), including monocytes and macrophages, can be infected and invade the CNS via the antipodal transport of virions or through vascular endothelial cells. Neuronal apoptosis is one of the hallmarks of neurodegenerative infections and many flaviviruses have been shown to induce neuronal apoptosis in neurons in vitro and in rodent models in vivo.5Uttara B. Singh A.V. Zamboni P. Mahajan R.T. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options.Curr Neuropharmacol. 2009; 7: 65-74Crossref PubMed Scopus (2447) Google Scholar, 6Shrestha B. Gottlieb D. Diamond M.S. Infection and injury of neurons by West Nile encephalitis virus.J Virol. 2003; 77: 13203-13213Crossref PubMed Scopus (192) Google Scholar JEV NS2B–NS3 protease was found to reduce the reduction of mitochondrial membrane potential and stimulate the release of mitochondrial cytochrome C, which induces mitochondria-mediated apoptosis by activating the ASK1-p38 mitogen-activated protein kinase (MAPK) signaling pathway-mediated apoptosis.7Yang T.C. Shiu S.L. Chuang P.H. Lin Y.J. Wan L. Lan Y.C. et al.Japanese encephalitis virus NS2B-NS3 protease induces caspase 3 activation and mitochondria-mediated apoptosis in human medulloblastoma cells.Virus Res. 2009; 143: 77-85Crossref PubMed Scopus (44) Google Scholar JEV has also been shown to cause neuronal loss due to the rough endoplasmic reticulum stress pathway.8Su H.L. Liao C.L. Lin Y.L. Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response.J Virol. 2002; 76: 4162-4171Crossref PubMed Scopus (268) Google Scholar, 9Yasui K. Neuropathogenesis of Japanese encephalitis virus.J Neurovirol. 2002; 8: 112-114Crossref PubMed Scopus (22) Google Scholar Viral tropism in neural progenitor stem cells (NPSCs) and immature neurons has also been reported in experimental models of JEV infection.10Ogata A. Nagashima K. Hall W.W. Ichikawa M. Kimura-Kuroda J. Yasui K. Japanese encephalitis virus neurotropism is dependent on the degree of neuronal maturity.J Virol. 1991; 65: 880-886PubMed Google Scholar, 11Kimura-Kuroda J. Ichikawa M. Ogata A. Nagashima K. Yasui K. Specific tropism of Japanese encephalitis virus for developing neurons in primary rat brain culture.Arch Virol. 1993; 130: 477-484Crossref PubMed Scopus (42) Google Scholar, 12Das S. Basu A. Japanese encephalitis virus infects neural progenitor cells and decreases their proliferation.J Neurochem. 2008; 106: 1624-1636PubMed Google Scholar However, mature neurons become resistant to JEV-induced apoptosis due to the increased neuronal expression of cellular inhibitors of apoptosis, such as Bcl-2 and Bcl-x.13Levine B. Huang Q. Isaacs J.T. Reed J.C. Griffin D.E. Hardwick J.M. Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene.Nature. 1993; 361: 739-742Crossref PubMed Scopus (424) Google Scholar In addition to neurons, astrocytes and microglial cells can also be infected by JEV.14Thongtan T. Cheepsunthorn P. Chaiworakul V. Rattanarungsan C. Wikan N. Smith D.R. Highly permissive infection of microglial cells by Japanese encephalitis virus: a possible role as a viral reservoir.Microbes Infect. 2010; 12: 37-45Crossref PubMed Scopus (46) Google Scholar, 74Mishra M.K. Kumawat K.L. Basu A. Japanese encephalitis virus differentially modulates the induction of multiple pro-inflammatory mediators in human astrocytoma and astroglioma cell-lines.Cell Biol Int. 2008; 32: 1506-1513Crossref PubMed Scopus (27) Google Scholar Astrocytes form part of the blood–brain barrier (BBB) and play multiple roles in the CNS, including maintaining homeostasis by storing energy in the form of glycogen and producing enzymes that exert detoxification effects. In a recent comparative study of human and mouse models, prominent astrocyte activation, particularly in areas of neuronal damage, was seen with JEV infection.15German A.C. Myint K.S. Mai N.T. Pomeroy I. Phu N.H. Tzartos J. et al.A preliminary neuropathological study of Japanese encephalitis in humans and a mouse model.Trans R Soc Trop Med Hyg. 2006; 100: 1135-1145Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Microglial cells are the resident macrophages of the CNS and as such might serve as a reservoir for the virus.16Thongtan T. Thepparit C. Smith D.R. The involvement of microglial cells in Japanese encephalitis infections.Clin Dev Immunol. 2012; 2012: 890586Crossref PubMed Scopus (27) Google Scholar Ghoshal et al. reported that the levels of various proinflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (Cox-2), interleukin 6 (IL-6), IL-1b, tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein 1 (MCP-1), were significantly elevated in microglial cells following JEV infection.17Ghoshal A. Das S. Ghosh S. Mishra M.K. Sharma V. Koli P. et al.Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis.Glia. 2007; 55: 483-496Crossref PubMed Scopus (299) Google Scholar Activation of microglial cells might play a significant role in inducing neuronal cell death by stimulating the production of proinflammatory mediators. The growing number of reviews describing a role for oxidative stress in the pathogenesis of viral infections has led to increased interest in the role of oxidative stress in JEV infections.18Srivastava R. Kalita J. Khan M.Y. Misra U.K. Free radical generation by neurons in rat model of Japanese encephalitis.Neurochem Res. 2009; 34: 2141-2146Crossref PubMed Scopus (18) Google Scholar Reactive oxygen species (ROS)-mediated neuronal cell death, including neurons and glial cells, has been observed in vitro after JEV infection.19Lin R.J. Liao C.L. Lin Y.L. Replication-incompetent virions of Japanese encephalitis virus trigger neuronal cell death by oxidative stress in a culture system.J Gen Virol. 2004; 85: 521-533Crossref PubMed Scopus (47) Google Scholar This is highly specific to neuronal cells and involves an unidentified receptor-mediated death-signaling pathway. In order to avoid ROS-mediated damage caused by virus infection, antioxidants in the host cell react with elevated oxidants and superoxides and inhibit virus production. Such agents could not only alleviate disease symptoms but also decrease the long-term effects of chronic oxidative stress.20Peterhans E. Oxidants and antioxidants in viral diseases: disease mechanisms and metabolic regulation.J Nutr. 1997; 127: 962S-965SPubMed Google Scholar, 21Beck M.A. Antioxidants and viral infections: host immune response and viral pathogenicity.J Am Coll Nutr. 2001; 20 (discussion 396S–397S): 84S-388SGoogle Scholar This review focuses mainly on the role of oxidative stress in the pathogenesis of JEV infection and the potential of antioxidants for the treatment of JEV infection. Intracellular redox balance is the result of a dynamic equilibrium between oxidant and antioxidant molecules. Oxidative stress occurs when the production of ROS exceeds the capacity of cellular antioxidant defenses to remove these toxic species. Superfluous ROS are capable of causing oxidative damage to macromolecules, leading to lipid peroxidation and the oxidation of amino acid side chains and polypeptide backbones, resulting in protein fragmentation and DNA damage.22Vuillaume M. Reduced oxygen species, mutation, induction and cancer initiation.Mutat Res. 1987; 186: 43-72Crossref PubMed Scopus (260) Google Scholar, 23Temneanu O.R. Zamfir C. Eloaie Zugun F. Cojocaru E. Tocan L. Oxidants and antioxidants relevance in rats’ pulmonary induced oxidative stress.J Med Life. 2011; 4: 244-249PubMed Google Scholar, 24Berlett B.S. Stadtman E.R. Protein oxidation in aging, disease, and oxidative stress.J Biol Chem. 1997; 272: 20313-20316Crossref PubMed Scopus (2784) Google Scholar Growing evidence has suggested a close correlation between oxidative stress and viral infectious disease.25Finkel T. Holbrook N.J. Oxidants, oxidative stress and the biology of ageing.Nature. 2000; 408: 239-247Crossref PubMed Scopus (7323) Google Scholar The elevated oxidants induced by viral infection include nitric oxide radicals (NO), superoxide anions (O2·−), hydroxy radicals (OH·−) and their by-products (such as hydrogen peroxide, H2O2), which may all contribute to viral pathogenesis, the modulation of cellular responses, and the regulation of viral replication and the host defense.26Randow F. MacMicking J.D. James L.C. Cellular self-defense: how cell-autonomous immunity protects against pathogens.Science. 2013; 340: 701-706Crossref PubMed Scopus (182) Google Scholar, 27Akaike T. Role of free radicals in viral pathogenesis and mutation.Rev Med Virol. 2001; 11: 87-101Crossref PubMed Scopus (157) Google Scholar JEV infection can lead to death in approximately 20−30% of infected patients.28Chambers T.J. Hahn C.S. Galler R. Rice C.M. Flavivirus genome organization, expression, and replication.Annu Rev Microbiol. 1990; 44: 649-688Crossref PubMed Scopus (1590) Google Scholar, 29Burke D.S. Lorsomrudee W. Leake C.J. Hoke C.H. Nisalak A. Chongswasdi V. et al.Fatal outcome in Japanese encephalitis.Am J Trop Med Hyg. 1985; 34: 1203-1210Crossref PubMed Scopus (107) Google Scholar After a mosquito bite, the virus crosses the BBB to the CNS; the resulting neuronal apoptosis and inflammation are generally attributed to JEV-induced cytopathology.30Mathur A. Kulshreshtha R. Chaturvedi U.C. Evidence for latency of Japanese encephalitis virus in T lymphocytes.J Gen Virol. 1989; 70: 461-465Crossref PubMed Scopus (24) Google Scholar However, the extent of cell injury that can be accredited to viral cytopathology remains unclear.17Ghoshal A. Das S. Ghosh S. Mishra M.K. Sharma V. Koli P. et al.Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis.Glia. 2007; 55: 483-496Crossref PubMed Scopus (299) Google Scholar, 31Raung S.L. Kuo M.D. Wang Y.M. Chen C.J. Role of reactive oxygen intermediates in Japanese encephalitis virus infection in murine neuroblastoma cells.Neurosci Lett. 2001; 315: 9-12Crossref PubMed Scopus (42) Google Scholar Early in 2002, Liao et al. found that JEV infection induced the generation of superoxide anions (O2·−) in rat cortical glial cells.32Liao S.L. Raung S.L. Chen C.J. Japanese encephalitis virus stimulates superoxide dismutase activity in rat glial cultures.Neurosci Lett. 2002; 324: 133-136Crossref PubMed Scopus (41) Google Scholar Consistent with this, a subsequent study by Srivastava et al. revealed that free radicals, such as ROS and peroxynitrite (OONO−), were increased in acute JE rat models.18Srivastava R. Kalita J. Khan M.Y. Misra U.K. Free radical generation by neurons in rat model of Japanese encephalitis.Neurochem Res. 2009; 34: 2141-2146Crossref PubMed Scopus (18) Google Scholar After JEV infection, the elevation of O2·− in the host cell leads to the activation of host superoxide dismutase (SOD) in an attempt to suppress the elevated levels of superoxide.33Kumar S. Misra U.K. Kalita J. Khanna V.K. Khan M.Y. Imbalance in oxidant/antioxidant system in different brain regions of rat after the infection of Japanese encephalitis virus.Neurochem Int. 2009; 55: 648-654Crossref PubMed Scopus (30) Google Scholar H2O2, the product of the reaction between O2·− and SOD, can react with O2·− again if it is not rapidly cleared. The OH− produced by the reaction between O2·− and H2O2 then leads to host cell apoptosis. Table 1 summarizes some of the key characteristics of oxidative stress in JEV-infected cells and tissues, compiled from different studies.Table 1Characteristics of oxidative stress in JEV-infected cells and tissuesCell/tissueStimulus/conditionPhenotypea↓=downregulated, ↑=upregulated, with respect to normal controls.Ref.Human pro-monocyte cellsInfected with JEV at MOIs of 0.1 and 1 after 24, 48, and 72 h incubation↓ TRX35Corpus striatum, frontal cortex, thalamus, and midbrain of ratsInoculated intracerebrally with 3 × 106 PFU JEV↑ MDA, Mn-SOD; ↓ CAT, GPx, and GSH33Neuro2a (N2a) cellsInfected with JEV at MOI of 5 for 24 h↑ ROS56Forebrain neurons of ratsInoculated intracerebrally with 3 × 106 PFU JEV on days 3, 6, 10, and 20↑ ROS and OONO− on 6 DPI; NO on 10 DPI; ↓ ROS on 20 DPI18Rat glial cultures (85% astrocytes, 7% microglia and others)Infected with JEV at MOI of 10↑ Superoxide anion; NO; Mn-SOD32Mouse neuroblastoma N18 cellsInfected with JEV at MOI of 5↑ROS; LDH31Human astroglial cell lines (U87 and SVG cell lines)Incubated with JEV at MOI of 5 for 72h↑ROS, IL-6, IL-1b, IL-8; TRX, ceruloplasmin; EAAT-1 and EAAT-2b(A) ROS, IP-10, MCP-1, MIG, RANTES, EAAT-1 and EAAT-2 levels higher in U87 than in SVG cells. (B) Levels of TRX were less in U87 than in SVG cells.74N18 and human neuronal NT-2 cellsIncubated with UV-inactivated JEV↑ROS19JEV, Japanese encephalitis virus; MOI, multiplicity of infection; TRX, thioredoxin; PFU, plaque-forming unit; MDA, malondialdehyde; Mn-SOD, manganese superoxide dismutase; CAT, catalase; GPx, glutathione peroxidase; GSH, glutathione; ROS, reactive oxygen species; OONO−, peroxynitrite; DPI, days post inoculation; NO, nitric oxide; LDH, lactate dehydrogenase; IL, interleukin; EAAT-1, astrocytic transporters GLT-1; EAAT-2, astrocytic transporters GLAST; IP-10, interferon inducible protein 10; MCP-1, monocyte chemoattractant protein-1; MIG, membrane immunoglobulin; RANTES, regulated on activation, normal T cell expressed and secreted; UV, ultraviolet.a ↓ = downregulated, ↑ = upregulated, with respect to normal controls.b (A) ROS, IP-10, MCP-1, MIG, RANTES, EAAT-1 and EAAT-2 levels higher in U87 than in SVG cells. (B) Levels of TRX were less in U87 than in SVG cells. Open table in a new tab JEV, Japanese encephalitis virus; MOI, multiplicity of infection; TRX, thioredoxin; PFU, plaque-forming unit; MDA, malondialdehyde; Mn-SOD, manganese superoxide dismutase; CAT, catalase; GPx, glutathione peroxidase; GSH, glutathione; ROS, reactive oxygen species; OONO−, peroxynitrite; DPI, days post inoculation; NO, nitric oxide; LDH, lactate dehydrogenase; IL, interleukin; EAAT-1, astrocytic transporters GLT-1; EAAT-2, astrocytic transporters GLAST; IP-10, interferon inducible protein 10; MCP-1, monocyte chemoattractant protein-1; MIG, membrane immunoglobulin; RANTES, regulated on activation, normal T cell expressed and secreted; UV, ultraviolet. Additional important mechanisms regarding JEV-induced apoptosis have been reported, including the initiation of endoplasmic reticulum stress, generation of ROS, and activation of nuclear factor kappa B (NF-κB).19Lin R.J. Liao C.L. Lin Y.L. Replication-incompetent virions of Japanese encephalitis virus trigger neuronal cell death by oxidative stress in a culture system.J Gen Virol. 2004; 85: 521-533Crossref PubMed Scopus (47) Google Scholar Furthermore, elevated ROS can react to form peroxynitrite, which triggers the loss of adenosine triphosphate (ATP) and mitochondrial membrane potential, leading to the release of cytochrome c from the mitochondria and activation of caspase 3, causing neuronal apoptosis.34Palomba L. Amadori A. Cantoni O. Early release of arachidonic acid prevents an otherwise immediate formation of toxic levels of peroxynitrite in astrocytes stimulated with lipopolysaccharide/interferon-gamma.J Neurochem. 2007; 103: 904-913Crossref PubMed Scopus (13) Google Scholar Yang et al. reported the activation of caspases 3, 8, and 9 in JEV-infected human pro-monocyte HL-CZ cells, which led to caspase-dependent apoptosis.35Yang T.C. Lai C.C. Shiu S.L. Chuang P.H. Tzou B.C. Lin Y.Y. et al.Japanese encephalitis virus down-regulates thioredoxin and induces ROS-mediated ASK1-ERK/p38 MAPK activation in human promonocyte cells.Microbes Infect. 2010; 12: 643-651Crossref PubMed Scopus (63) Google Scholar However, the overproduction of O2·− appears to non-selectively impair the physiological functions of host cells, regardless of infection, even though it suppresses viral replication in situ. NO and its toxic metabolite peroxynitrite are recognized as important mediators of neuronal injury. NO levels are elevated in the cerebrospinal fluid of human JE patients.36Saxena S.K. Mathur A. Srivastava R.C. Induction of nitric oxide synthase during Japanese encephalitis virus infection: evidence of protective role.Arch Biochem Biophys. 2001; 391: 1-7Crossref PubMed Scopus (38) Google Scholar Consistent with this, Liao et al. found that JEV infection induced the generation of NO in rat cortical glial cells.32Liao S.L. Raung S.L. Chen C.J. Japanese encephalitis virus stimulates superoxide dismutase activity in rat glial cultures.Neurosci Lett. 2002; 324: 133-136Crossref PubMed Scopus (41) Google Scholar A subsequent study then revealed that NO levels were increased in acute JE rat models.18Srivastava R. Kalita J. Khan M.Y. Misra U.K. Free radical generation by neurons in rat model of Japanese encephalitis.Neurochem Res. 2009; 34: 2141-2146Crossref PubMed Scopus (18) Google Scholar JEV induces the expression of iNOS, which is thought to be a key mediator in the host innate immune response. The molecular pathogenesis of JE remains unclear, although several potential mechanisms have been reported. JEV replication in human pro-monocyte cells has been shown to induce time-dependent apoptosis. In addition, it has been shown that the downregulation of thioredoxin and the upregulation of ROS is involved in the apoptosis induced by the oxidative stress response pathway.37Ghosh D. Basu A. Japanese encephalitis—a pathological and clinical perspective.PLoS Negl Trop Dis. 2009; 3: e437Crossref PubMed Scopus (212) Google Scholar JEV infection causes increased intracellular ROS production and activation of ASK1-ERK/p38 MAPK signaling, both of which are associated with JEV-induced apoptosis.35Yang T.C. Lai C.C. Shiu S.L. Chuang P.H. Tzou B.C. Lin Y.Y. et al.Japanese encephalitis virus down-regulates thioredoxin and induces ROS-mediated ASK1-ERK/p38 MAPK activation in human promonocyte cells.Microbes Infect. 2010; 12: 643-651Crossref PubMed Scopus (63) Google Scholar Matrix metalloproteinase 9 (MMP-9) leads to disruption of the BBB and also contributes to the neuroinflammatory responses in many neurological diseases. Tung et al. reported MMP-9 to be overexpressed in the brains of rats with neurodegenerative diseases, which was associated with a chronic inflammatory process and the above signaling pathways. In addition, they observed the activation of the p42/p44 MAPK and the c-Jun NH(2)-terminal kinases 1/2 (JNK1/2) pathways in response to MMP-9 expression.38Mandal M. Mandal A. Das S. Chakraborti T. Sajal C. Clinical implications of matrix metalloproteinases.Mol Cell Biochem. 2003; 252: 305-329Crossref PubMed Scopus (138) Google Scholar, 39Tung W.H. Tsai H.W. Lee I.T. Hsieh H.L. Chen W.J. Chen Y.L. et al.Japanese encephalitis virus induces matrix metalloproteinase-9 in rat brain astrocytes via NF-kappaB signalling dependent on MAPKs and reactive oxygen species.Br J Pharmacol. 2010; 161: 1566-1583Crossref PubMed Scopus (44) Google Scholar Finally, treating cells with H2O2 elicited an inflammatory response involving the NF-κB signaling pathway.40Enesa K. Zakkar M. Chaudhury H. Luong le A. Rawlinson L. Mason J.C. et al.NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling.J Biol Chem. 2008; 283: 7036-7045Crossref PubMed Scopus (169) Google Scholar, 41Clague M.J. Biochemistry: Oxidation controls the DUB step.Nature. 2013; 497: 49-50Crossref PubMed Scopus (13) Google Scholar Therefore, there are many different potential sources of ROS in JEV-infected host cells, many of which are capable of influencing, or being influenced by, NF-κB activity. JEV infection is also associated with microglial activation, resulting in the production of proinflammatory cytokines including IL-1b and IL-18, which is mediated by ROS production.42Kaushik D.K. Gupta M. Kumawat K.L. Basu A. NLRP3 inflammasome: key mediator of neuroinflammation in murine Japanese encephalitis.PLoS One. 2012; 7: e32270Crossref PubMed Scopus (106) Google Scholar The oxidation of proteins is widely viewed as a signature of irreversible damage, and cellular-degradation pathways operate to remove such proteins. Ubiquitination is generally involved in protein degradation pathways. Ubiquitin is a small polypeptide that covalently attaches to proteins, either singly or in the form of polymeric chains. In the reverse process, deubiquitinase enzymes (DUBs) disassemble ubiquitin chains and strip them from their substrate proteins, thus rescuing proteins from ubiquitin-dependent degradation pathways.43Lecker S.H. Goldberg A.L. Mitch W.E. Protein degradation by the ubiquitin–proteasome pathway in normal and disease states.J Am Soc Nephrol. 2006; 17: 1807-1819Crossref PubMed Scopus (890) Google Scholar Widespread inhibition of DUBs can be caused by excess ROS generation, but this can be readily reversed by an excess of a reducing agent such as dithiothreitol.41Clague M.J. Biochemistry: Oxidation controls the DUB step.Nature. 2013; 497: 49-50Crossref PubMed Scopus (13) Google Scholar Zhang et al. performed a SILAC-based quantitative proteomic study of JEV-infected HeLa cells and found that the JEV infection-induced host response was coordinated primarily by the immune response, the ubiquitin–proteasome system, the intracellular membrane system, and lipid metabolism-related proteins.44Zhang L.K. Chai F. Li H.Y. Xiao G. Guo L. Identification of host proteins involved in Japanese encephalitis virus infection by quantitative proteomics analysis.J Proteome Res. 2013; 12: 2666-2678Crossref PubMed Scopus (67) Google Scholar Expression of interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein, was found to be rapidly induced by interferon-α/β (IFN-α/β), and ISG15 conjugation to target proteins was associated with the antiviral immune response.45Lenschow D.J. Giannakopoulos N.V. Gunn L.J. Johnston C. O’Guin A.K. Schmidt R.E. et al.Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo.J Virol. 2005; 79: 13974-13983Crossref PubMed Scopus (224) Google Scholar Hsiao et al. reported that ISG15 overexpression significantly reduced the JEV-induced cytopathic effect and inhibited JEV replication. Furthermore, ISG15 overexpression increased the phosphorylation of interferon regulatory factor-3 (IRF-3, Ser396), the Janus/just another kinase-2 (JAK2, Tyr1007/1008), and signal transducers and activators of the transcription 1 (STAT1, Tyr701 and Ser727) in JEV-infected cells. ISG15 overexpression also induced the translocation of the transcription factor STAT1 to the nucleus and activated the expression of STAT1-dependent genes including IRF-3, IFN-β, IL-8, protein kinase R (PKR), and 2′,5′-oligoadenylate synthetase (OAS), both before and after JEV infection.46Hsiao N.W. Chen J.W. Yang T.C. Orloff G.M. Wu Y.Y. Lai C.H. et al.ISG15 over-expression inhibits replication of the Japanese encephalitis virus in human medulloblastoma cells.Antiviral Res. 2010; 85: 504-511Crossref PubMed Scopus (45) Google Scholar These data reveal that ubiquitination is involved in JEV infection, but the specific mechanism is unclear. Reducing conditions are normally maintained within the cell by antioxidant molecules. The antioxidant system is classified into two types: an enzyme system including SOD, catalase (CAT), and glutathione peroxidase (GPx), and other molecules including glutathione (GSH), N-acetylcysteine (NAC), and selenium.47Irshad M. Chaudhuri P.S. Oxidant–antioxidant system: role and significance in human body.Indian J Exp Biol. 2002; 40: 1233-1239PubMed Google Scholar In addition, dietary micronutrients also contribute to the antioxidant defense system including β-carotene, vitamin C, and vitamin E. Water-soluble molecules, such as vitamin C, are potent radical scavenging agents in the aqueous phase of the cytoplasm, whereas lipid soluble antioxidants, such as vitamin E and β-carotene, act as antioxidants within lipid environments.48Bouayed J. Bohn T. Exogenous antioxidants—double-edged swords in cellular redox state: health beneficial effects at physiologic doses versus deleterious effects at high doses.Oxid Med Cell Longev. 2010; 3: 228-237Crossref PubMed Scopus (712) Google Scholar Selenium, copper, zinc, and manganese are also important elements, since they act as cofactors for antioxidant enzymes.49Rahman K. Studies on free radicals, antioxidants, and co-factors.Clin Interv Aging. 2007; 2: 219-236PubMed Google Scholar In order to avoid harmful effects caused by oxidants, antioxidants in the host cell react with elevated oxidants and superoxides in several ways under normal conditions (Table 2).Table 2Antioxidants in the host cell react with the elevated oxidants2O2− + 2H+ ⟶SOD H2O2 + O22H2O2 ⟶CAT 2H2O + O2H2O2 + 2GSH ⟶GPx 2H2O + GS-SGaGS-SG, the product of these reactions, is converted to GSH (which does no damage to the host cell) under the effect of glutathione reductase.2GSH + R-O-OH ⟶GPx GS-SG + H2O + R-OHaGS-SG, the product of these reactions, is converted to GSH (which does no damage to the host cell) under" @default.
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• W2132518830 title "Antioxidants: potential antiviral agents for Japanese encephalitis virus infection" @default.
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