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1.
Melatonin interferes with COVID-19 at several distinct ROS-related steps.
Camp, OG, Bai, D, Gonullu, DC, Nayak, N, Abu-Soud, HM
Journal of inorganic biochemistry. 2021;:111546
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Abstract
Recent studies have shown a correlation between COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the distinct, exaggerated immune response titled "cytokine storm". This immune response leads to excessive production and accumulation of reactive oxygen species (ROS) that cause clinical signs characteristic of COVID-19 such as decreased oxygen saturation, alteration of hemoglobin properties, decreased nitric oxide (NO) bioavailability, vasoconstriction, elevated cytokines, cardiac and/or renal injury, enhanced D-dimer, leukocytosis, and an increased neutrophil to lymphocyte ratio. Particularly, neutrophil myeloperoxidase (MPO) is thought to be especially abundant and, as a result, contributes substantially to oxidative stress and the pathophysiology of COVID-19. Conversely, melatonin, a potent MPO inhibitor, has been noted for its anti-inflammatory, anti-oxidative, anti-apoptotic, and neuroprotective actions. Melatonin has been proposed as a safe therapeutic agent for COVID-19 recently, having been given with a US Food and Drug Administration emergency authorized cocktail, REGEN-COV2, for management of COVID-19 progression. This review distinctly highlights both how the destructive interactions of HOCl with tetrapyrrole rings may contribute to oxygen deficiency and hypoxia, vitamin B12 deficiency, NO deficiency, increased oxidative stress, and sleep disturbance, as well as how melatonin acts to prevent these events, thereby improving COVID-19 prognosis.
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A Multiple-Hit Hypothesis Involving Reactive Oxygen Species and Myeloperoxidase Explains Clinical Deterioration and Fatality in COVID-19.
Goud, PT, Bai, D, Abu-Soud, HM
International journal of biological sciences. 2021;(1):62-72
Abstract
Multi-system involvement and rapid clinical deterioration are hallmarks of coronavirus disease 2019 (COVID-19) related mortality. The unique clinical phenomena in severe COVID-19 can be perplexing, and they include disproportionately severe hypoxemia relative to lung alveolar-parenchymal pathology and rapid clinical deterioration, with poor response to O2 supplementation, despite preserved lung mechanics. Factors such as microvascular injury, thromboembolism, pulmonary hypertension, and alteration in hemoglobin structure and function could play important roles. Overwhelming immune response associated with "cytokine storms" could activate reactive oxygen species (ROS), which may result in consumption of nitric oxide (NO), a critical vasodilation regulator. In other inflammatory infections, activated neutrophils are known to release myeloperoxidase (MPO) in a natural immune response, which contributes to production of hypochlorous acid (HOCl). However, during overwhelming inflammation, HOCl competes with O2 at heme binding sites, decreasing O2 saturation. Moreover, HOCl contributes to several oxidative reactions, including hemoglobin-heme iron oxidation, heme destruction, and subsequent release of free iron, which mediates toxic tissue injury through additional generation of ROS and NO consumption. Connecting these reactions in a multi-hit model can explain generalized tissue damage, vasoconstriction, severe hypoxia, and precipitous clinical deterioration in critically ill COVID-19 patients. Understanding these mechanisms is critical to develop therapeutic strategies to combat COVID-19.
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3.
Neutrophil Extracellular Traps in Periodontitis.
Magán-Fernández, A, Rasheed Al-Bakri, SM, O'Valle, F, Benavides-Reyes, C, Abadía-Molina, F, Mesa, F
Cells. 2020;(6)
Abstract
Neutrophils are key cells of the immune system and have a decisive role in fighting foreign pathogens in infectious diseases. Neutrophil extracellular traps (NETs) consist of a mesh of DNA enclosing antimicrobial peptides and histones that are released into extracellular space following neutrophil response to a wide range of stimuli, such as pathogens, host-derived mediators and drugs. Neutrophils can remain functional after NET formation and are important for periodontal homeostasis. Periodontitis is an inflammatory multifactorial disease caused by a dysbiosis state between the gingival microbiome and the immune response of the host. The pathogenesis of periodontitis includes an immune-inflammatory component in which impaired NET formation and/or elimination can be involved, contributing to an exacerbated inflammatory reaction and to the destruction of gingival tissue. In this review, we summarize the current knowledge about the role of NETs in the pathogenesis of periodontitis.
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4.
NPR1 and Redox Rhythmx: Connections, between Circadian Clock and Plant Immunity.
Zhang, J, Ren, Z, Zhou, Y, Ma, Z, Ma, Y, Hou, D, Xu, Z, Huang, X
International journal of molecular sciences. 2019;(5)
Abstract
The circadian clock in plants synchronizes biological processes that display cyclic 24-h oscillation based on metabolic and physiological reactions. This clock is a precise timekeeping system, that helps anticipate diurnal changes; e.g., expression levels of clock-related genes move in synchrony with changes in pathogen infection and help prepare appropriate defense responses in advance. Salicylic acid (SA) is a plant hormone and immune signal involved in systemic acquired resistance (SAR)-mediated defense responses. SA signaling induces cellular redox changes, and degradation and rhythmic nuclear translocation of the non-expresser of PR genes 1 (NPR1) protein. Recent studies demonstrate the ability of the circadian clock to predict various potential attackers, and of redox signaling to determine appropriate defense against pathogen infection. Interaction of the circadian clock with redox rhythm promotes the balance between immunity and growth. We review here a variety of recent evidence for the intricate relationship between circadian clock and plant immune response, with a focus on the roles of redox rhythm and NPR1 in the circadian clock and plant immunity.
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5.
A thermodynamically-constrained mathematical model for the kinetics and regulation of NADPH oxidase 2 complex-mediated electron transfer and superoxide production.
Tomar, N, Sadri, S, Cowley, AW, Yang, C, Quryshi, N, Pannala, VR, Audi, SH, Dash, RK
Free radical biology & medicine. 2019;:581-597
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Abstract
Reactive oxygen species (ROS) play an important role in cell signaling, growth, and immunity. However, when produced in excess, they are toxic to the cell and lead to premature aging and a myriad of pathologies, including cardiovascular and renal diseases. A major source of ROS in many cells is the family of NADPH oxidase (NOX), comprising of membrane and cytosolic components. NOX2 is among the most widely expressed and well-studied NOX isoform. Although details on the NOX2 structure, its assembly and activation, and ROS production are well elucidated experimentally, there is a lack of a quantitative and integrative understanding of the kinetics of NOX2 complex, and the various factors such as pH, inhibitory drugs, and temperature that regulate the activity of this oxidase. To this end, we have developed here a thermodynamically-constrained mathematical model for the kinetics and regulation of NOX2 complex based on diverse published experimental data on the NOX2 complex function in cell-free and cell-based assay systems. The model incorporates (i) thermodynamics of electron transfer from NADPH to O2 through different redox centers of the NOX2 complex, (ii) dependence of the NOX2 complex activity upon pH and temperature variations, and (iii) distinct inhibitory effects of different drugs on the NOX2 complex activity. The model provides the first quantitative and integrated understanding of the kinetics and regulation of NOX2 complex, enabling simulation of diverse experimental data. The model also provides several novel insights into the NOX2 complex function, including alkaline pH-dependent inhibition of the NOX2 complex activity by its reaction product NADP+. The model provides a mechanistic framework for investigating the critical role of NOX2 complex in ROS production and its regulation of diverse cellular functions in health and disease. Specifically, the model enables examining the effects of specific targeting of various enzymatic sources of pathological ROS which could overcome the limitations of pharmacological efforts aimed at scavenging ROS which has resulted in poor outcomes of antioxidant therapies in clinical studies.
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Mutual interplay of Ca2+ and ROS signaling in plant immune response.
Marcec, MJ, Gilroy, S, Poovaiah, BW, Tanaka, K
Plant science : an international journal of experimental plant biology. 2019;:343-354
Abstract
Second messengers are cellular chemicals that act as "language codes", allowing cells to pass outside information to the cell interior. The cells then respond through triggering downstream reactions, including transcriptional reprograming to affect appropriate adaptive responses. The spatiotemporal patterning of these stimuli-induced signal changes has been referred to as a "signature", which is detected, decoded, and transmitted to elicit these downstream cellular responses. Recent studies have suggested that dynamic changes in second messengers, such as calcium (Ca2+), reactive oxygen species (ROS), and nitric oxide (NO), serve as signatures for both intracellular signaling and cell-to-cell communications. These second messenger signatures work in concert with physical signal signatures (such as electrical and hydraulic waves) to create a "lock and key" mechanism that triggers appropriate response to highly varied stresses. In plants, detailed information of how these signatures deploy their downstream signaling networks remains to be elucidated. Recent evidence suggests a mutual interplay between Ca2+ and ROS signaling has important implications for fine-tuning cellular signaling networks in plant immunity. These two signaling mechanisms amplify each other and this interaction may be a critical element of their roles in information processing for plant defense responses.
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EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation.
Gilardini Montani, MS, Santarelli, R, Granato, M, Gonnella, R, Torrisi, MR, Faggioni, A, Cirone, M
Autophagy. 2019;(4):652-667
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Abstract
EBV has been reported to impair monocyte in vitro differentiation into dendritic cells (DCs) and reduce cell survival. In this study, we added another layer of knowledge to this topic and showed that these effects correlated with macroautophagy/autophagy, ROS and mitochondrial biogenesis reduction. Of note, autophagy and ROS, although strongly interconnected, have been separately reported to be induced by CSF2/GM-CSF (colony stimulating factor 2) and required for CSF2-IL4-driven monocyte in vitro differentiation into DCs. We show that EBV infects monocytes and initiates a feedback loop in which, by inhibiting autophagy, reduces ROS and through ROS reduction negatively influences autophagy. Mechanistically, autophagy reduction correlated with the downregulation of RAB7 and ATG5 expression and STAT3 activation, leading to the accumulation of SQSTM1/p62. The latter activated the SQSTM1-KEAP1- NFE2L2 axis and upregulated the anti-oxidant response, reducing ROS and further inhibiting autophagy. ROS decrease correlated also with the reduction of mitochondria, the main source of intracellular ROS, achieved by the downregulation of NRF1 and TFAM, mitochondrial biogenesis transcription factors. Interestingly, mitochondria supply membranes and ATP required for autophagy execution, thus their reduction may further reduce autophagy in EBV-infected monocytes. In conclusion, this study shows for the first time that the interconnected reduction of autophagy, intracellular ROS and mitochondria mediated by EBV switches monocyte differentiation into apoptosis, giving new insights into the mechanisms through which this virus reduces immune surveillance. Abbreviations: ACTB actin beta; ATG5: autophagy related 5; BAF: bafilomycin A1; BECN1: beclin 1; CAT: catalase; CSF2: colony stimulating factor 2; CT: control; CYCS (cytochrome C: somatic); DCs: dendritic cells; EBV: Epstein-Barr virus; GSR: glutathione-disulfide reductase; KEAP1: kelch like ECH associated protein 1; IL4: interleukin 4; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MET: metformin; NAC: N-acetylcysteine; NFE2L2/NRF2 nuclear factor: erythroid 2 like 2; NRF1 (nuclear respiratory factor 1); clPARP1: cleaved poly(ADP-ribose) polymerase; Rapa: Rapamycin; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TFAM (transcription factor A: mitochondrial); TUBA1A: tubulin alpha 1a.
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Chemistry and biochemistry of cold physical plasma derived reactive species in liquids.
Wende, K, von Woedtke, T, Weltmann, KD, Bekeschus, S
Biological chemistry. 2018;(1):19-38
Abstract
Reactive oxygen and nitrogen species deposited by cold physical plasma are proposed as predominant effectors in the interaction between discharge and biomedical application. Most reactive species found in plasma sources are known in biology for inter- and intracellular communication (redox signaling) and mammalian cells are equipped to interpret the plasma derived redox signal. As such, considerable effort has been put into the investigation of potential clinical applications and the underlying mechanism, with a special emphasis on conditions orchestrated significantly via redox signaling. Among these, immune system control in wound healing and cancer control stands out with promising in vitro and in vivo effects. From the fundamental point of view, further insight in the interaction of the plasma-derived species with biological systems is desired to (a) optimize treatment conditions, (b) identify new fields of application, (c) to improve plasma source design, and (d) to identify the trajectories of reactive species. Knowledge on the biochemical reactivity of non-thermal plasmas is compiled and discussed. While there is considerable knowledge on proteins, lipids and carbohydrates have not received the attention deserved. Nucleic acids have been profoundly investigated yet focusing on molecule functionality rather than chemistry. The data collected underline the efforts taken to understand the fundamentals of plasma medicine but also indicate 'no man's lands' waiting to be discovered.
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The role of reactive oxygen species in the integration of temperature and light signals.
Krasensky-Wrzaczek, J, Kangasjärvi, J
Journal of experimental botany. 2018;(14):3347-3358
Abstract
The remarkable plasticity of the biochemical machinery in plants allows the integration of a multitude of stimuli, enabling acclimation to a wide range of growth conditions. The integration of information on light and temperature enables plants to sense seasonal changes and adjust growth, defense, and transition to flowering according to the prevailing conditions. By now, the role of reactive oxygen species (ROS) as important signaling molecules has been established. Here, we review recent data on ROS as important components in the integration of light and temperature signaling by crosstalk with the circadian clock and calcium signaling. Furthermore, we highlight that different environmental conditions critically affect the interpretation of stress stimuli, and consequently defense mechanisms and stress outcome. For example, day length plays an important role in whether enhanced ROS production under stress conditions is directed towards activation of redox poising mechanisms or triggering programmed cell death (PCD). Furthermore, a mild increase in temperature can cause down-regulation of immunity and render plants more sensitive to biotrophic pathogens. Taken together, the evidence presented here demonstrates the complexity of signaling pathways and outline the importance of their correct interpretation in context with the given environmental conditions.
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Plasmodesmal regulation during plant-pathogen interactions.
Cheval, C, Faulkner, C
The New phytologist. 2018;(1):62-67
Abstract
Contents Summary 62 I. Introduction 62 II. Plasmodesmal regulation is an innate defence response 63 III. Reactive oxygen species regulate plasmodesmal function 63 IV. Plasmodesmal regulation by and of defence-associated small molecules 64 V. Plasmodesmata facilitate systemic defence signalling 64 VI. Virulent pathogens exploit plasmodesmata 66 VII. Outlook 66 Acknowledgements 66 References 66 SUMMARY Plasmodesmata (PD) are plasma membrane-lined pores that connect neighbouring plant cells, bridging the cell wall and establishing cytoplasmic and membrane continuity between cells. PD are dynamic structures regulated by callose deposition in a variety of stress and developmental contexts. This process crudely controls the aperture of the pore and thus the flux of molecules between cells. During pathogen infection, plant cells initiate a range of immune responses and it was recently identified that, following perception of fungal and bacterial pathogens, plant cells initially close their PD. Systemic defence responses depend on the spread of signals between cells, raising questions about whether PD are in different functional states during different immune responses. It is well established that viral pathogens exploit PD to spread between cells, but it has more recently been identified that protein effectors secreted by fungal pathogens can spread between host cells via PD. It is possible that many classes of pathogens specifically target PD to aid infection, which would infer antagonistic regulation of PD by host and pathogen. How PD regulation benefits both host immune responses and pathogen infection is an important question and demands that we examine the multicellular nature of plant-pathogen interactions.