cord-000799-s70onyix	2012	title: Particulate matter air pollution disrupts endothelial cell barrier via calpain-mediated tight junction protein degradation OBJECTIVES: We explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction. We investigated the role of ROS and calpain in PM-induced pulmonary inflammation by examining protein leakage, white blood cell infiltration (inflammatory leukocytes), and the release of proinflammatory cytokines into BAL fluids ( Figure 5 ). These data represent the first evidence that calpain signaling, via calcium leakage from activated TRPM2 by ROS, plays a critical role in modulating endothelial cell barrier function, resulting in tight junction protein ZO-1 degradation (Additional file 1 Figure S7 ). Particulate matter induces endothelial cell intracellular oxidative stress, which leads to the activation of calpain, one of the major cytoskeletal regulators.
cord-001347-ssrs0cwf	2014	title: Effects of flavonoid-induced oxidative stress on anti-H5N1 influenza a virus activity exerted by baicalein and biochanin A Recently, we showed that the structurally similar flavonoids baicalein and biochanin A inhibit highly pathogenic avian H5N1 influenza A virus replication by different mechanisms in A549 lung cells. Next, we investigated whether the reduction of baicalein-or biochanin A-induced enhanced ROS levels in H5N1-infected A549 cells by NAC influences the antiviral effects of these flavonoids. Notably, NAC also inhibited baicalein-and biochanin A-induced oxidative stress in H5N1-infected primary human monocytederived macrophages but did not affect H5N1 replication in this cell type (Figure 3 ). These findings emphasise that flavonoids, a class of natural compounds known to exert anti-influenza effects [16] [17] [18] [19] 28] , induce a complex range of pharmacological actions by which they modify influenza A virus replication including highly pathogenic avian H5N1 strains. Differential antiviral and anti-inflammatory mechanisms of the flavonoids biochanin A and baicalein in H5N1 influenza A virus-infected cells
cord-001769-2sdg5ll7	2015	We show that wild-type mice infected with murine hepatitis virus strain-3 (MHV-3), a model for viral FH, manifest with severe disease and high mortality in association with a significant elevation in IL-1β expression in the serum and liver. Further experiments show that mice deficient of p47 (phox), a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit that controls acute ROS production, present with reductions in NLRP3 inflammasome activation and subsequent IL-1β secretion during viral infection, which appears to be responsible for acquiring resilience to viral FH. The hallmarks of MHV-3-induced FH in susceptible BALB/cJ and C57BL/6 mice include the appearance of liver sinusoidal thrombosis and hepatocellular necrosis, resulting from over expression of a virus-induced, monocyte/macrophage-specific procoagulant, fibrinogen-like protein-2 (FGL2).
cord-003841-7uaj9hmx	2019	The findings indicate that tulathromycin, in the absence of a direct anti-viral effect, is able to restore the phagocytic function and to attenuate the pro-inflammatory phenotype of PRRSV-infected monocyte-derived porcine macrophages. However, Immuno-modulating properties of Tulathromycin in PRRSV-infected porcine monocyte-derived macrophages PRRSV-induced IL-10 inhibition was abolished when the cells were pre-treated with tulathromycin at 2 and 12 hours post infection (Fig 6) . Another set of experiments assessed the effects of PRRSV, and of tulathromycin, on the nonopsonized and opsonized phagocytic functions of MDMs. PRRSV infection significantly Immuno-modulating properties of Tulathromycin in PRRSV-infected porcine monocyte-derived macrophages inhibited both phagocytic functions of the cells (Figs 10 and 11 ). The findings indicate that TUL inhibits PRRSV-induced inflammatory responses in porcine monocyte-derived macrophages and protects against the phagocytic impairment caused by the virus, in the absence of any direct anti-viral effects.
cord-004508-ok3px98z	2020	Based on these findings, the aim of the present study was to investigate the impact of a persistent CDV-infection on oxidative stress mediated changes in the expression of hypoxia-inducible factor (HIF)-1α and its angiogenic downstream pathway in DH82 cells in vitro. In summary, these results suggest a reduced activation of the HIF-1α angiogenic downstream pathway in DH82Ond pi cells in vitro, most likely due to an excessive, unusually localized, and non-functional expression of HIF-1α triggered by a CDV-induced increased oxidative stress. In a hypothesis-driven approach, an online available microarray data set of quadruplicates of non-infected DH82 and DH82Ond pi cells (ArrayExpress; http://www.ebi.ac.uk/arrayexpress; accession number E-MTAB-3942 [11, 44] ) was investigated for differentially expressed genes related to ROS production and scavenging, ER-stress and HIF-1α pathway, with a special focus on the angiogenic downstream targets of the latter.
cord-005280-a23oy0sz	2019	Although ROS play an important role in pathogen resistance and cellular signalling, they are also broadly recognized as harmful reactive particles to cell as they damage intracellular proteins, lipids and nucleic acids. The homeostasis of ROS plays an important role in reducing oxidative damage and fulfil energy demand. Relatively high levels of ROS may cause oxidative damage or induce apoptosis during immunological defences or pathological conditions. However, ROS themselves could activate extracellular signal-regulated kinase (ERK) by targeting proteins Gαi and Gα0 and protect cardiac cell from oxidative damage [18] . Apart from oxidative damage, ROS also serve as signalling molecules and play an important role in homeostasis, metabolism, growth and differentiation [3] . PGC-1α could protect neural cells from oxidative damage by reducing ROS level via antioxidative enzymes GPx1 and SOD2 [15] . ROS regulate vascular cell proliferation and apoptosis with their fundamental role in metabolism.
cord-006230-xta38e7j	2012	Here, we will present our analysis of Ca 2+ signaling following stimulation of the FcεRI receptor and application of secretagogues that are supposed to affect Ca 2+ -dependent mast cell activation such as adenosine, endothelin-1, substance P and compound 48/80 in BMMCs and PMCs derived from mouse lines with inactivation of TRPC1, TRPC3, TRPC4, TRPC5 or TRPC6 since specific antagonists are still lacking for these TRP channels. These data indicate that increased PP2A activity is associated with modified gene expression in TG hearts possibly affecting stress response and regulation of cell signalling. As demonstrated by qPCR and Western blot experiments, mesangial cells showed a marked time-and dose-dependent upregulation of CSE mRNA and protein levels after treatment with platelet-derived growth factor (PDGF-BB). The transcription factor cAMP response element (CRE)-binding protein (CREB) plays a critical role in regulating gene expression in response to activation of the cAMPdependent signaling pathway, which is implicated in the pathophysiology of heart failure.
cord-012495-r6nkdeaw	2020	Mitochondrial calcium overload and ROS levels can trigger either the activation of intrinsic apoptotic pathway (left side) through the recruitment of Bcl-2 family proteins at the mitochondria, or permeability transition pore complex (PTPC) formation which could lead to mitochondrial outer membrane permeabilization (MOMP), energetic imbalance, and subsequent release of proapoptotic cofactors from the inter membrane space, such as SMAC/DIABLO, CytC, and ENDOG (right side). MPT is associated with the opening of the mitochondrial permeability transition pore complex (PTPC), a voltage-dependent, high-conductance Mitochondrial calcium overload and ROS levels can trigger either the activation of intrinsic apoptotic pathway (left side) through the recruitment of Bcl-2 family proteins at the mitochondria, or permeability transition pore complex (PTPC) formation which could lead to mitochondrial outer membrane permeabilization (MOMP), energetic imbalance, and subsequent release of proapoptotic cofactors from the inter membrane space, such as SMAC/DIABLO, CytC, and ENDOG (right side).
cord-013415-110b95cg	2020	Although the host immune response rapidly protects against bacterial invasion, oxidative stress generated during inflammation can indirectly deteriorate periodontal tissues through the damage to vital cell macromolecules, including DNA. In contrast to transient DNA damage, persistent genomic lesions promote constitutive DNA damage signaling and cellular senescence, which is correlated with increased secretion of inflammatory signals [26, 30] In agreement with this observation, several studies have reported that premature senescence can also be induced by exposing human cells to subtoxic H 2 O 2 concentrations [31, 32] . As a consequence of chronological aging, the burden of senescent cells increases in different tissues in humans, mice, and other species, where they contribute to the development of chronic pathologies including arthritis, osteoporosis, Alzheimer''s disease, atherosclerosis, cancer, and diabetes [58, 59] Similar to other agerelated pathologies, the etiology of diabetes may be the result of the impact of different aging mechanism, including stem cell exhaustion, chronic low-grade inflammation, macromolecular damage, and cellular senescence.
cord-014661-mrh2pbi6	2013	FOXO proteins are considered unique cellular targets, regulating a wide variety of critical cellular processes, such as: apoptosis, oxidative stress, DNA damage repair, cell cycle, stem cell proliferation and maintenance, metabolism, angiogenesis, vascular tone, cardiovascular development, fertility, immune response and neuronal survival 4, 20 . Hence, the FOXO transcription factors control the expression of a wide spectrum of genes that regulate essential physiological cellular processes, such as cell death/cell survival, cell cycle, cell proliferation, cell differentiation/development, angiogenesis, cell metabolism, stress response and stem cell maintenance 33,34,35,36,37,38 (Figure 2) . Moreover, the consensus FOXO recognition element (FRE) -(G/C)(T/A)AA(C/T)AA -which differs from that of other forkhead proteins, seems to have a very important role in both apoptotic pathways, since matching functional FRE sites have been identified in the promoters of FOXO target genes encoding Fas ligand (FasL), insulin like growth factorbinding protein 1 (IGFBP1), the apoptotic regulator Bcl-2 interacting mediator of cell death (Bim) and others 30 .
cord-017817-ztp7w9yh	2018	Autophagy is an evolutionarily highly conserved self-digestive process in response to environmental stress to eukaryotic cells, by which cytoplasmic components such as defective/damaged or redundant organelles or protein aggregates are delivered to the lysosome for recycling and degradation. More recent studies then revealed that these transcription factors, notably Nrf2, are activated by Keap1 as the primary negative regulator of Nrf2, that is, a molecule that simultaneously operates as a sensor protein able to perceive dyshomeostatic Subclass IIC-4 DAMPs, for example, in terms of redox changes reflecting electrophilic stress. Strikingly, a complex relationship reportedly exists between autophagy and DAMPs in cellular adaption to stress and injury and cell death characterized by a crosstalk between autophagy induction and secretion or release of DAMPs. In fact, growing evidence indicates that autophagic mechanisms are involved in regulating release and degradation of DAMPs including CALR, HMGB1, ATP, and DNA in several cell types [37, 148, 175] .
cord-020646-s7eopu9y	2005	Die Wirkung des Histamins auf Zielzellen erfolgt über spezifi sche Rezeptoren, von denen zwei Arten bekannt und gut studiert sind. Bei plötzlicher Aufhebung der Rezeptorblockade nach Ende einer Therapie sind die betroffenen Zellen mit einer hohen Rezeptorzahl bestückt und reagieren folglich auf Histamin verstärkt, was zum massiven Wiederauftreten der Krankheitssymptomatik führen kann (sog. Disponierte Personen, die als "Atopiker" bezeichnet werden, reagieren auf gewisse Antigene (AG) mit der Bildung spezifi scher Antikörper (AK) vom IgE-Typ. Die atopische Veranlagung ist angeboren, tritt oft familiär auf und zeigt eine Konvergenz mit gewissen MHC I Typen. Dem PAF wird heute eine wesentliche Rolle beim Pathomechanismus des Asthma bronchiale und der COPD zugeschrieben, wobei die Wirkung auch indirekt, nämlich über eine Potenzierung anderer Mediatoren wie LT, PG, Histamin zu laufen scheint. Diese Bindung ist der Mechanismus, über den die Zelle ein Partikel erkennt und von Material unterscheidet, das nicht phagozytiert werden soll, und der den Phagozytosereiz auslöst.
cord-022940-atbjwpo5	2016	We have studied the effect of inhibition of IRE1 (inositol requiring enzyme 1), which is a central mediator of endoplasmic reticulum stress and controls cell proliferation and tumor growth, on hypoxic regulation of the expression of different proliferation related genes in U87 glioma cells. Transient inhibition of Akt and mTOR protein kinase activation in tumor cells followed by reactivation of signaling pathway did not result in a time-dependent difference on EGFR, HER2 and HER3 expression levels. In our study we aimed to determine cytotoxic effect of RES in K562 human CML cell line and to evaluate the expressions of miRNAs that are associated with genetics of leukemia after treatment with RES; to investigate target genes of miRNAs which show significant expression alterations and molecular mechanisms of RES treatment.
cord-032561-x3qbqy69	2020	demonstrated that nanodrug carriers with diselenides could release more drugs using poly (ester carbamate) triblock copolymers (PAUR-Se-Se) with Se-Se bonds compared with poly (ester carbamate) triblock copolymers (PAUR-S-S) [54, 55] Thioether Selenium Tellurium Besides the development of drug delivery systems, pH-responsive systems can also be used for tumor detection and image-guided surgery [46] . demonstrated that nanodrug carriers with diselenides could release more drugs using poly (ester carbamate) triblock copolymers (PAUR-Se-Se) with Se-Se bonds compared with poly (ester carbamate) triblock copolymers (PAUR-S-S) [65] PBA/PBE Besides the development of drug delivery systems, pH-responsive systems can also be used for tumor detection and image-guided surgery [46] . Therefore, pH responsive system can be combined with other stimulus conditions such as light, redox, enzymes and others with the aim of improved selectivity for drug release in diseased tissues [47, 48] . In addition to photothermal therapy and PDT, light-responsive strategies have also been applied in the design of prodrug systems and drug delivery carriers.
cord-034294-ti1cc24m	2020	Trx effectively prevents the progression of COPD by regulating redox status and protease/anti-protease balance, blocking the NF-κB and MAPK signalling pathways, suppressing the activation and migration of inflammatory cells and the production of cytokines, inhibiting the synthesis and the activation of adhesion factors and growth factors, and controlling the cAMP-PKA and PI3K/Akt signalling pathways. EPAC and PKA inhibit the human airway smooth muscle induced by a cigarette smoke extract (CSE) by blocking the activation of the NF-κB and ERK, respectively, and by releasing neutrophil chemokine IL-8, which together exert anti-inflammatory effects. 101 In COPD, increases in cAMP levels, activation of PKA and enhanced protein phosphorylation have the potential to reduce inflammation and immunomodulation, relax airway smooth muscle, inhibit chemotaxis and abnormal release of inflammatory and cytotoxic mediators, and reduce proliferation and migration of inflammatory cells. 135 The PI3K/Akt signalling pathway plays an important role in COPD by regulating inflammatory cell activation, inflammatory mediator release and airway remodelling.
cord-034321-ohjik0pf	2020	NETosis is a program for formation of neutrophil extracellular traps (NETs), which consist of modified chromatin decorated with bactericidal proteins from granules and cytoplasm. NETosis includes release of the granule components into the cytosol, modification of histones leading to chromatin decondensation, destruction of the nuclear envelope, as well as formation of pores in the plasma membrane. 1178 Abbreviations: ARDS, acute respiratory distress syndrome; CGD, chronic granulomatous disease; COPD, chronic obstructive pulmonary disease; GSDMD, gasdermin D; LPS, lipopolysaccharide of the bacterial wall; MPO, myeloper oxidase; mPTP, nonselective mitochondrial permeability tran sition pore; NE, neutrophil elastase; NETs, Neutrophil Extra cellular Traps; PCD, programmed cell death; PKC, protein kinase C; PMA, phorbol 12 myristate 13 acetate; ROS, reac tive oxygen species. At the same time, we also showed that in neutrophils isolated from the blood of patients with X linked CGD formation of NETs in response to A23187 depended on the enhanced gener ation of mtROS without participation of NADPH oxi dase [16] .
cord-035015-slgywe0c	2020	Data is now showing that COVID-19 patients do have populations of T-cells displaying mitochondrial dysfunction, as well as altered mitochondrial markers in monocyteshinting that immune-metabolic phenotyping could be used to understand disease pathogenesis and possible treatments; this could include targeting mitochondria [32] . The underlying aetiology for "inflammaging" has long thought to be associated with mitochondrial dysfunction as suggested by Nick Lane in 2003 in his "double agent" theory [5] , and is now receiving renewed interest, for instance, in how decreasing mitochondrial function can reduce T-cell function and enhance immune senescence, as mitochondria are pivotal in metabolic reprogramming towards the Warburg effect [40] . Furthermore, as evidence indicates that many viruses, which most likely include SARs-CoV-2, modulate bioenergetics and redox in both the immune system and other cells they infect to enhance their own replication, they could potentially induce excessive stress in these systems if their mitochondria are already sub-optimally functional.
cord-048478-ftlb5b95	2008	One striking characteristic, which accompanies apoptosis in both vertebrates and yeast, is a fragmentation of cellular DNA and mammalian apoptosis is often associated with degradation of different RNAs. We show that in yeast exposed to stimuli known to induce apoptosis, such as hydrogen peroxide, acetic acid, hyperosmotic stress and ageing, two large subunit ribosomal RNAs, 25S and 5.8S, became extensively degraded with accumulation of specific intermediates that differ slightly depending on cell death conditions. For example, in metazoans the programmed cell death (PCD) called apoptosis, in addition to irreversible DNA damage, which is considered an apoptotic hallmark (3) , also involves specific cleavage of several RNA species, including 28S rRNA, U1 snRNA or Ro RNP-associated Y RNAs (4) . Together, this strongly suggests that rRNA degradation observed in apoptotic and oxidative stress conditions is not simply a result of cell death but is produced in the process that requires enzymatic activity and functional cellular machinery.
cord-102808-c7ajfvt5	2020	The formyl peptide receptor 2 (FPR2), belonging to the family of G protein-coupled receptors (GPCRs), regulates directional neutrophil migration (chemotaxis), granule secretion (degranulation), formation of F-actin filaments (through polymerization of G-actin), and activation of the reactive oxygen species (ROS) producing NADPH-oxidase [3, 5, 6] . The fact that F2Pal10 and Cmp 14 cannot induce -arrestin recruitment at these concentrations ([9-11], Fig 2A) , strongly suggests that the priming effect of Barbadin on FPR2-mediated ROS production is independent of the ability of the activating agonist to recruit -arrestin. Collectively, these results suggest that Barbadin primes neutrophils in their response to FPR2 agonists, and the increased NADPH-oxidase activation is regulated independently of FPR2 internalization and FPR2-induced -arrestin recruitment. Barbadin was added to WKYMVM-activated neutrophils at a time point when ROS production had returned to a background level; interestingly, these FPR2-desensitized cells could be resensitized to produce ROS also by Barbadin, similar to the effect of latrunculin A ( Fig 5A) .
cord-257514-gw9xnb4x	2020	H(2) gas may regulate the anti-inflammatory and antioxidant activity, mitochondrial energy metabolism, endoplasmic reticulum stress, the immune system, and cell death (apoptosis, autophagy, pyroptosis, ferroptosis, and circadian clock, among others) and has therapeutic potential for many systemic diseases. found that HW inhibited cardiomyocyte apoptosis by activating the PI3K/AKT and JAK2-STAT3 signaling pathways and can also reduce the level of oxidative stress in myocardial tissue by upregulating the expression of the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway, which alleviated I/R injury in isolated rat hearts [39, 40, 91] . Effects of hydrogen-rich water on the PI3K/AKT signaling pathway in rats with myocardial 12 Oxidative Medicine and Cellular Longevity ischemia-reperfusion injury Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation
cord-260348-83ftjqev	2020	The results of qPCR and Western blot showed that, compared with the PCV2 infected group, the expression of Cap in Paeonol (0.4 mg/mL and 0.2 mg/mL), Cepharanthine (0.003 mg/mL, 0.0015 mg/mL and 0.00075 mg/mL) and Curcumin (0.02 mg/mL, 0.001 mg/mL and 0.005 mg/mL) treated groups were significantly lowered in a dose-dependent manner. The results of Annexin V-FITC/PI, JC-1, Western blot and ROS analysis showed that the expression of cleaved caspase-3 and Bax were up-regulated Bcl-2 was down-regulated in Cepharanthine or Curcumin treated groups, while ROS and MMP value were decreased at different degrees and the apoptosis rate was reduced. The results showed that Compared to the PCV2-infected group, the cell apoptosis rates were significantly decreased in the group treated with Cepharanthine, Curcumin or Ribavirin, demonstrating a dose-dependent response except the group of 0.005 mg/mL Paeonol (P < 0.05) ( Fig. 3a and b).
cord-262759-ec2c25q3	2013	The impairment of ROS removal is predicted to enhance apoptotic activity in G6PD-deficient cells, and this enhanced apoptosis was observed by annexin V/PI staining under a confocal fluorescence microscope and quantified by flow cytometry. We hypothesized that G6PD-deficient cells are less tolerant to oxidative stress upon bacterial infection, leading to the accumulation of more intracellular ROS when compared to the control scramble cells. To determine whether the reduced ROS accumulation and apoptotic activity, particularly in G6PD-deficient cells, was due to deceased αhemolysin expression upon VRSA infection in the presence of vancomycin, the production of intracellular ROS and cell apoptosis when the α-hemolysin inhibitor Oroxylin A was added to the media was quantified by flow cytometry. Our results presented here indicate that expression of active caspase-9, as well as the downstream caspase-3, was much higher in G6PD-deficient cells than in control scramble cells upon VRSA infection, suggesting that mitochondrial dysfunction may be the major cause of the increase in cell apoptosis (Figure 4) .
cord-268122-74nj66vb	2020	The NAD + decline during normal aging results in oxidative damage, metabolic disorder, circadian rhythm abnormalities, and mitochondrial dysfunction through regulating signaling pathways, such as p53, NF-κB, PGC-1α and HIF-1α, by sirtuins and PARPs. NAD + and its metabolites function as crucial regulators to maintain cellular redox homeostasis through replenishing the reducing power or modulating the activity of NAD + -consuming enzymes including sirtuins and PARPs. However, disequilibrium of NAD + metabolism could disturb physiological processes, including mitochondria function, circadian rhythm, inflammation, DNA repair and metabolism, leading to aging-associated dysfunction and cancer. c The deduced NAD + levels in kidney are attributed to the decreased expression of enzymes in NAD + de novo synthesis and increased consumption by DNA damage activated PARPs. NAD + depletion inhibits the SIRT1/PGC1α mediated mitochondrial quality control, ATP production and NAD + de novo biosynthesis.
cord-268527-wbfnhedy	1991	Following subcellular fractionation of retinas, ConA purified rhodopsin from ROS was applied to one of two additional lectin columns: Ricinus communis agglutinin (RCA) or Griffonia simplicifolia I (GSA). To radiolabel existing galactose moieties on rhodopsin, bovine ROS purified by a discontinuous sucrose density gradient procedure, were subjected to enzymatic treatment with galactose oxidase followed by a reduction with tritium labeled sodium borohydride. In this method, ConA purified rhodopsin or in some cases the clarified extract of ROS from six rat retinas labeled with [35S]methionine was applied to columns of either Ricinus communis agglutinin I (RCA) or GrifSonia simplicijolia I (GSA), specific for P-linked or a-linked galactose residues, respectively. Rats injected intravitreally with [35S]methionine were maintained in darkness for 2 hr at which time 12 retinas were collected for subcellular fractionation and rhodopsin purification by ConA sepharose chromatography.
cord-271939-m1ko4yal	2020	Thus, manganosalen complexes have been shown to exhibit superoxide dismutase, catalase, and glutathione peroxidase activities, and they could potentially facilitate the scavenging of excess reactive oxygen species (ROS), thereby restoring the redox balance in damaged cells and organs. Manganosalen complexes exhibit high SOD, catalase, and peroxidase activities, which has led to their development as catalytic antioxidants [6] [7] [8] [9] [10] 13, [18] [19] [20] [21] 23] , a term used for all cases in which one single molecule of catalyst induces the detoxification of numerous ROS molecules. This manganese complex and the cyclic analogue EUK-207 were used in a study with C57BL/6N Sim middle-age mice [105] , which usually exhibit a dramatic decrease in learning and memory function between 8 and 11 months of age, associated with oxidative protein damage in the brain [106] . Salen-manganese complexes for controlling ROS damage: Neuroprotective effects, antioxidant activity and kinetic studies
cord-273093-u79r80ip	2020	The high neutrophil to lymphocyte ratio observed in critically ill patients with COVID-19 is associated with excessive levels of reactive oxygen species (ROS), which promote a cascade of biological events that drive pathological host responses. By producing excessive ROS, deregulated neutrophils can spread a local inflammatory response so that it becomes systemic, which explains why they have been involved The high neutrophil to lymphocyte ratio observed in critically ill patients with COVID-19 is associated with excessive levels of reactive oxygen species (ROS), which promote a cascade of biological events that drive pathological host responses. ROS induce tissue damage, thrombosis and red blood cell dysfunction, which contribute to COVID-19 disease severity. ROS induce tissue damage, thrombosis and red blood cell dysfunction, which contribute to COVID-19 disease severity. In conclusion, the presence of oxidative stress markers (for example, lipid peroxidation, rTEM and a high neutrophil to lymphocyte ratio) in patients with COVID-19 may help to identify high-risk individuals early in the course of the disease and prevent their sudden deterioration.
cord-273992-xddikzxs	2004	The main impact of the study is that the utilization of genetically modified (GM) yeast produced by recombinant DNA technology genomic strategies could circumvent the bioprocessing problems that otherwise result from the bioprocess perturbations: this is as a result of oxidative stress caused by ROS, which is avoidable by deployment of appropriate antioxidants such as vitamins E, C and D (and antioxidant proteins and enzymes often of microbial origin via recombinant DNA technology). Catalases ( Table 3 ) in yeasts and other micro-organisms (Antioxidants such as vitamins E and C chain terminate the formation of membrane-degrading ROS) relates to more than just structural damage that is sometimes obvious and predictable: functional damage may also follow. Avoidance biostrategies against ROS and RSS in many oxidatively stressed bioprocesses that utilise yeasts (and other micro-organisms) are essential where human therapeutic proteins are expected to be produced in high yield.
cord-278846-nqj7ctk3	2020	While these initial observations were made during steady state or using in vitro polarised macrophages, recent studies have indicated that during many chronic lung diseases (CLDs), AMs adapt their metabolic profile to fit their local niche. By generating reactive oxygen species (ROS) for pathogen defence, utilising aerobic glycolysis to rapidly generate cytokines, and employing mitochondrial respiration to fuel inflammatory responses, AMs utilise metabolic reprogramming for host defence, although these changes may also support chronic pathology. Indeed, many recent studies have indicated that in chronic lung diseases (CLDs), such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), and during infection such as with Mycobacterium Tuberculosis (Mtb), there are significant alterations in AM metabolic processes and that targeting these pathways could represent an exciting therapeutic approach 6, 7 . Iron metabolism is therefore likely a key pathway in IPF-AMs and targeting it would be a viable option to decrease ROS, oxidative stress and macrophage activation.
cord-288238-36hiiw91	2020	It is also reported that influenza infection significantly increases ROS production by inducing Nox4, and the proliferation of this virus in lung epithelial cells is dependent on redox-sensitive pathways activated by Nox4-derived ROS [16] . IFN can also exert its function on metabolic changes by producing several mediators including indoleamine-2,3-dioxygenase (IDO) and nitric oxide (NO), both of which appear to have either an inducible or an inhibitory role in viral replication [33] . In addition, increased temperature of cells during infection (which could be the result of virus replication and fever) causes heat stress which in turn can considerably downregulate carnitine palmitoyltransferase II (CPT II) activity and reduce the β-oxidation and ATP levels in fibroblasts of influenza-associated encephalopathy patients and healthy volunteers [110] . Through enhancing the activity of the mTORC1 complex, the influenza virus strengthens several metabolic pathways, including glycolysis, glutaminolysis, pentose phosphate, and fatty acid synthesis, to provide more ATP and structural materials for viral replication.
cord-289034-yl3emjef	2020	Two mitochondria quality control mechanisms are in place to meet the functional needs of any given cell under different physiological and pathological conditions: (a) mitochondrial biogenesis, fusion and fission [4] [5] [6] ; (b) mitophagy [7, 8] . The second mechanism, mitophagy, is a specific form of autophagy that removes damaged mitochondria and reduces the mitochondrial mass upon microenvironmental stresses, such as hypoxia and nutrient starvation, promoting cell survival [11] . In this context, mutations in three TCA cycle enzymes, namely succinate dehydrogenase, fumarate hydratase and isocitrate dehydrogenase, have been shown to play a causal role in carcinogenesis [54, 55] , thus providing compelling evidence for the involvement of mitochondrial metabolic alterations as cancer drivers. Mitochondrial dysfunction is implicated in several pathological conditions, ranging from neurodegenerative and cardiovascular diseases, to aging, cancer and inflammation.
cord-291190-f6km3c7z	2020	 SARS-CoV has been reported to modulate PARP function and thereby NAD+ biosynthesis  Cellular homeostasis and redox imbalances by SARS-CoV2 can cause stress responses  Antioxidants such as NAC could limit ROS mediated tissue damage during COVID-19 Hereby, based on literature review from the current pandemic and previous outbreaks with corona viruses we analyze the impact of the virus infection on cell stress responses and redox balance. PLA2G2D expression was shown to be increased in the lungs of middle aged mice, resulting in decreased survival and impaired T cell responses upon infection with SARS-CoV1 [20] . Interestingly, NAC administration to aged mice, diminished PLAG2D expression in both lung cells and CD11c+ DCs. In addition, increased levels of oxidized phospholipidsare a common feature associated with acute respiratory distress syndrome (ARDS) caused by viruses including SARS and H5N1.
cord-291559-h6czy5bh	2017	A study investigated the protective effect of ES in alcoholic fatty liver and found that ES treatment suppressed adipogenesis and increased the expression of fatty acid oxidation-related genes, e.g., peroxisome proliferator-activated receptor (PPAR)-a and CPT-1, but decreased the expression of sterol regulatory element-binding protein (SREBP)-1, a triglyceride (TG) synthesis-related gene, suggesting that ES extract could be useful in preventing fatty acid oxidation and reducing lipogenesis in ethanol-induced fatty liver (Bang et al. Fucoidan extracted from EC exhibited prominent effects on peroxyl radical scavenging activity and 2, 2 0 -azobisdihydrochloride-induced oxidative stress in Vero cells and reduced ROS generation, lipid peroxidation, and cell death in a zebrafish model, proving its antioxidant capacities in vitro and in vivo despite being neither a polyphenol nor a flavonoid. Dieckol, isolated from the edible brown algae Ecklonia cava, induces apoptosis of ovarian cancer cells and inhibits tumor xenograft growth
cord-293319-oo0w6faj	2020	The antibacterial activities against Escherichia coli, Listeria innocua, and Pseudomonas syringae DC3000 in both the absence and presence of Ag(3)PO(4) under dark conditions and in the presence of Ag(3)PO(4) under red-light (625 nm) and blue-light (460 nm) irradiation were examined. The photoinduced enhancement of the Ag(3)PO(4) antibacterial activity under blue-light irradiation is explained by the formation of ROS during the antibacterial action of the Ag(3)PO(4). Moreover, the antiviral activity of Ag(3)PO(4) against amphotropic 10A1 murine leukemia virus enhanced under blue-light irradiation via ROS production. coli in the absence and presence of Ag 3 PO 4 under dark conditions and in the presence of Ag 3 PO 4 under red-light (625 nm) and blue-light (460 nm) irradiation. These data indicate that the antibacterial activity of Ag 3 PO 4 under blue-light irradiation corresponds to the amount of ROS in E. The photoinduced enhancement of the antibacterial and antiviral activities of Ag 3 PO 4 under blue-light irradiation was observed.
cord-295459-ffi1043k	2020	Small interfering RNA (siRNA)-mediated knockdown of the ubiquitous zinc uptake transporter ZIP1 suggests that labile zinc levels are increased due to the increased uptake by RSV-infected cells as an antiviral response. Our results suggest that zinc homeostasis plays a critical role in the host response to RSV infection by regulating oxidative stress and inhibiting virus replication. As with A549 cells, we observed a time-dependent increase in labile zinc levels in SAECs infected with RSV without any effect on cell viability ( Fig. 2A and B) . To further confirm the role of oxidative stress in RSV infection, cells infected with RSV were treated with 300 M H 2 O 2 (one of the ROS) and virus titers were measured at 24 h p.i. As observed in the case of zinc chelation, addition of H 2 O 2 led to a modest but significant increase in RSV titers at 24 h p.i.
cord-297469-26d8o1xk	2019	gondii effects of ursolic acid, and analyzed the production of nitric oxide (NO), reactive oxygen species (ROS), and cytokines through co-cultured immune cells, as well as the expression of intracellular organelles of T. Furthermore, ursolic acid effectively increased the production of NO, ROS, interleukin (IL)-10, IL-12, granulocyte macrophage colony stimulating factor (GM-CSF), and interferon-β, while reducing the expression of IL-1β, IL-6, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta 1 (TGF-β1) in T. gondii-infected cells were treated with different concentrations (12.5-200 µg/mL) of ursolic acid (UA) and sulfadiazine (SF) at 37 • C for 24 h, respectively; their survival rates were inhibited a dose-dependent manner. We evaluated the effect of ROS and NO production induced by ursolic acid in immune cells infected with T. We evaluated the effect of ROS and NO production induced by ursolic acid in immune cells infected with T.
cord-298265-elbnzgx6	2020	Studies have demonstrated that circulating neutrophils of RA patients are more easily stimulated to NETosis than those from healthy subjects [73, 74] , and as in other autoimmune conditions, NETs act as a source of extracellular autoantigens leading to excessive innate and adaptive immune responses in the joints and subsequent tissue injury [73, 75] . Inhibits ROS production, prevents thrombus formation [190] [191] [192] [193] [194] [195] Nucleases Recombinant human DNase DNA matrixes Reduces neutrophil infiltration, cleaves DNA matrixes [196] [197] [198] [199] [200] [201] [202] [203] [204] [205] [206] [207] Staphylokinase Plasminogen, alpha-defensins Converting NETs to deoxyadenosine mediating death of immune cells [208] [209] [210] [211] Notable compounds Probiotics PKC pathway run a study to evaluate the effect of inhibition of PAD4 in NETosis using an antagomiR-155, a pleiotropic microRNA important in the regulation of immune responses, demonstrating a decreased induction of PAD4 mRNA and subsequent reduced NETs in response to PMA challenge [13] .
cord-307148-k1uo3fxm	2020	R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. Others have also suggested that increasing systemic ketone levels may aid host defenses against respiratory viral infection, in part, by decreasing inflammation [1, 2] , including a recent comprehensive review [3] , while a clinical trial of the effects of a ketogenic diet on intubated SARS-CoV-2 patients has recently been registered (NCT04358835). Coronaviruses have been shown to increase the oxidation of phospholipids, which stimulate toll-like receptor 4 (TLR4) signaling on macrophages, leading to cytokine production and acute lung injury [163] , so HDAC inhibition with R-BHB appears to be a viable treatment to decrease cytokine levels and inflammation.
cord-310723-ogo9mvi5	2020	Therefore, the correct extrapolation of in vivo results obtained in rats to a human organism requires the identification of amino acids involved in protein-ligand interaction, determination of all structural and conformational features of the binding sites and comparison of the obtained characteristics in HSA vs. Therefore, the correct extrapolation of in vivo results obtained in rats to a human organism requires the identification of amino acids involved in protein-ligand interaction, determination of all structural and conformational features of the binding sites and comparison of the obtained characteristics in HSA vs. It was demonstrated by the method of electron paramagnetic resonance (EPR) that oxidation of albumin of the healthy subjects with hydrogen peroxide and tert-butyl hydroperoxide led to conformational changes in the microenvironment of the binding sites of maleimide and iodoacetamide spin labels, which interact predominantly with the thiol group of Cys34.
cord-313825-bbjxd86y	2016	The lung is the first target organ for air pollution and PM exposure is associated with reduced lung function, increased lung inflammation, asthma, respiratory infections, lung cancer and exacerbation of COPD, which lead to systemic inflammation and oxidative stress affecting blood, vasculature, heart and brain, ultimately contribute to the premature mortality ( Fig. 2) [3, 8, 14, 16] . These specific features of UFPs can significantly contribute to the adverse effects through ROS over-production by the redox-active organic chemicals and metals on particle surface, resulting in cellular oxidative stress [18, 19, 21, 44, 48] . These include: (i) carbon core of PM and UFPs could induce ROS generation and oxidative stress; (ii) catalytic conversion of PAHs to quinones by cytochrome P450 in the endoplasmic reticulum; (iii) quinone redox cycling by NADPH-dependent P450 reductase in microsomes; (iv) mitochondrial perturbation leading to electron leakage in the inner membrane; and (v) NADPH oxidase activity in the macrophage surface membrane and associated phagosomes.
cord-313918-uv9xdp5f	2020	Abbreviations 2-oxoglutarate carrier (OGC; SLC25A11); adenine nucleotide translocator (ANT); alcoholic liver disease (ALD); alcoholic steatohepatitis (ASH); Alzheimer''s disease (AD); amyloid beta peptides (Aβ); amyloid precursor protein/presenilin 1 (APP/PS1); amyotrophic lateral sclerosis (ALS); Cu/Zn-superoxide dismutase (SOD1); diabetic nephropathy (DN); electron transport chain (ETC); endoplasmic reticulum (ER); free cholesterol (FC); glyoxalase II (GLO2); Glutathione (GSH); glutathione disulfide (GSSG); glutathione reductase (GR); glutathione S-transferase (GST); GSH ethyl ester (GEE); GSH peroxidases (GPx); hepatic steatosis (HS); metabolic associated fatty liver disease (MAFLD); mitochondrial dicarboxylate carrier (DIC; SLC25A10); mitochondrial glutathione (mGSH); mitochondrial NADP+-dependent isocitrate dehydrogenase (IDPm); mitochondrial permeability transition (MPT); non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); Parkinson''s disease (PD); peroxiredoxins (Prx); protein disulfide isomerase (PDI); reactive oxygen species (ROS); S-adenosyl-l-methionine (SAM); S-d-lactoylglutathione (SLG); sterol regulatory element binding protein 2 (SREBP-2); thioredoxin 2/thioredoxin reductase 2 (Trx2/TrxR2); tumor necrosis factor (TNF).
cord-316244-s5ua0re3	2016	PRDX6 is an oxidative stress inducible protein regulated by Nrf2 and activation of the gene expression was observed in mouse lungs by hyperoxia and in cultured lung epithelial cells following treatment with H 2 O 2 or paraquat . One previous study reported that hypoxia increases AR activity in prostate cancer cells, and that PRDX1, which is upregulated by hypoxia, interacts with AR to enhance the expression of androgen-regulated genes (Chhipa, Lee, Onate, Wu, & Ip, 2009; Park et al., 2006) . PRDX2 is overexpressed in colorectal carcinoma tissues compared with the matched non-cancer colorectal mucosa tissues and that expression is positively associated with tumor metastasis and the TNM stage by regulation of oxidation induced apoptosis (Lu et al., 2014a) . Other researchers also demonstrated that PRDX2 knockdown using a lentiviral vector-mediated specific shRNA inhibited cell growth, stimulated apoptosis, and augmented the production of endogenous ROS that led to an altered expression of proteins associated with the Wnt signaling pathway (Lu et al., 2014b) .
cord-319614-4qi59pbz	2019	Experimental data indicate that during persistent infection, lymphocytic choriomeningitis virus (LCMV) may both directly or indirectly modulate regulatory cellular processes and alter cellular functions that are not critical for survival, but are essential for cell homeostasis. Increased levels of ROS were accompanied by changes in the pattern of telomere restriction fragments (TRFs) in infected cells and mediated activation of hypoxia-inducible transcription factor-1 (HIF-1) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways. These data suggest that LCMV maintains its replication in persistently infected cells by regulating redox signaling through modulation of local levels of H 2 O 2 and subsequent activation of cellular processes that it uses for its own benefit. Notably, the treatment with antioxidants also resulted in reduced levels of viral NP in HeLa, as well as in A549 LCMV-infected cells, suggesting a link between ROS-dependent signaling and virus replication (Figures 7B,D and Supplementary Figure S2B ).
cord-320591-re99v1qt	2020	Particularly, these studies mostly focused on the antioxidant and anticancer activities of broccoli sprouts and microgreens owing to the functions of glucosinolates and phenolic compounds (Tables 4 and 5 ). Particularly, these studies mostly focused on the antioxidant and anticancer activities of broccoli sprouts and microgreens owing to the functions of glucosinolates and phenolic compounds (Tables 4 and 5 ). In summary, previous studies showed that broccoli sprout extracts rich in vitamins, carotenoids, and phenolic compounds showed very high antioxidant activity in both in vitro and in vivo tests (Table 4) . Moreover, the previous studies have focused on several biological activities of broccoli seedlings, such as antioxidant, anticancer, antimicrobial, and anti-inflammatory, as well as the potentially beneficial effects for patients with cancers, diabetes, and obesity.
cord-323730-5iawbnua	2016	Whatever the trigger factors for lesion Experimental Neurology 277 (2016) [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] Abbreviations: APCs, antigen-presenting cells; ARE, antioxidant response element; DMF, dimethyl fumarate; FAEs, fumaric acid esters; GSH, glutathione; HO, heme oxygenase; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; Keap1, Kelch ECH associating protein 1; MDSC, myeloid-derived suppressor cells; MMF, monomethyl fumarate; NQO1, NAD(P)H: quinone oxidoreductase 1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; RNS, reactive nitrogen species; ROS, reactive oxygen species; S1P, sphingosine 1-phosphate; TGF, transforming growth factor; T h , T helper cell; T reg , regulatory T cell; Trx, thioredoxin. Furthermore, redox stress is important for the functional outcome during experimentally-induced adaptive-immunity responses; e.g. in a graft-versus-host disease mouse model, free radical scavenger therapy with NecroX-7 attenuates disease severity, probably via the induction of T reg cells (Im et al., 2015) and oxidative damage regulates antigen-specific T cell responses in agerelated macular degeneration (Cruz-Guilloty et al., 2014) .
cord-331673-xv1tcugl	2020	For instance, in the case of Herpesviridae and Paramyxoviridae viruses (both enveloped viruses with embedded viral-encoded glycoproteins), AgNPs can effectively reduce their infectivity, by blocking the interaction between the viral particles and the host cells with an antiviral activity strictly dependent on the size and ζ potential of the AgNPs. As a general observation, it was reported that smaller nanoparticles have better antiviral effect. cAgNPs could reduce cytopathic effects induced by RSV and showed efficient antiviral activity against infection by directly inactivating the virus prior to entry into the host cells. have reported that porous AuNPs are able to inhibit influenza A infection more efficiently than nonporous AuNPs. 39 This effect has been associated with the higher surface area of the porous material that favors their interaction with capsids and thus increases their antiviral activity ( Figure 4 ).
cord-335676-7ak53hto	2020	It seems that "cytokine storm" phenomenon in elderly patients with severe COVID-19 infection, is associated with many age-related pathophysiologic processes, including alteration of angiotensin-converting enzyme 2 (ACE2) receptor expression [9] , excess ROS production [10] , alteration of autophagy [11] , the inflammatory phenotype of senescent cell activity, particularly adipose tissue [12] , and immune-senescence [13] , as well as lack of vitamin D content [14] . As shown in Fig. 2 , several factors, including alteration of ACE2 receptor expression, excess reactive oxygen species (ROS) production, senescent adipocytes activity, alteration of autophagy and mitophagy, immune-senescent, as well as vitamin D (VD) deficiency, may associate "inflame-aging" to cytokine storm in elderly patients of COVID-19. Furthermore, the lack of VD in aged subjects is associated with the pro-inflammatory phenotype of immune cells, leading to likely increasing the risk of elderly adults with chronic mild inflammation condition [122] .
cord-336201-fl606l3b	2020	Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. T2DM, the most common form of diabetes (∼90%), is characterized by a systemic inflammatory disease accompanied by insulin resistance (IR) or decreased metabolic response to insulin in several tissues, including the adipose tissue, liver, and skeletal muscle, as well as by reduced insulin synthesis by pancreatic beta cells (4, 5) . During the progression of diabetes, hyperglycemia promotes mitochondrial dysfunction and induces the formation of reactive oxygen species (ROS) that cause oxidative stress in several tissues such as blood vessels and pancreatic beta cells (7) (8) (9) . In addition, the attachment of AGEs to their receptors [e.g., CD36, galectin-3, scavenger receptors types I (SR-A1), and II (SR-A2)] on the surfaces of immune cells in the circulation and tissues activates the expression of pro-inflammatory cytokines and increases free radical generation (18) .