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Coordination of frontline defense mechanisms under severe oxidative stress.

ABSTRACT: Complexity of cellular response to oxidative stress (OS) stems from its wide-ranging damage to nucleic acids, proteins, carbohydrates, and lipids. We have constructed a systems model of OS response (OSR) for Halobacterium salinarum NRC-1 in an attempt to understand the architecture of its regulatory network that coordinates this complex response. This has revealed a multi-tiered OS-management program to transcriptionally coordinate three peroxidase/catalase enzymes, two superoxide dismutases, production of rhodopsins, carotenoids and gas vesicles, metal trafficking, and various other aspects of metabolism. Through experimental validation of interactions within the OSR regulatory network, we show that despite their inability to directly sense reactive oxygen species, general transcription factors have an important function in coordinating this response. Remarkably, a significant fraction of this OSR was accurately recapitulated by a model that was earlier constructed from cellular responses to diverse environmental perturbations--this constitutes the general stress response component. Notwithstanding this observation, comparison of the two models has identified the coordination of frontline defense and repair systems by regulatory mechanisms that are triggered uniquely by severe OS and not by other environmental stressors, including sub-inhibitory levels of redox-active metals, extreme changes in oxygen tension, and a sub-lethal dose of gamma rays.

SUBMITTER: Kaur A

PROVIDER: S-EPMC2925529 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Coordination of frontline defense mechanisms under severe oxidative stress.

Kaur Amardeep A Van Phu T PT Busch Courtney R CR Robinson Courtney K CK Pan Min M Pang Wyming Lee WL Reiss David J DJ DiRuggiero Jocelyne J Baliga Nitin S NS

Molecular systems biology 20100701

Complexity of cellular response to oxidative stress (OS) stems from its wide-ranging damage to nucleic acids, proteins, carbohydrates, and lipids. We have constructed a systems model of OS response (OSR) for Halobacterium salinarum NRC-1 in an attempt to understand the architecture of its regulatory network that coordinates this complex response. This has revealed a multi-tiered OS-management program to transcriptionally coordinate three peroxidase/catalase enzymes, two superoxide dismutases, pr ...[more]

PMID: 20664639

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Project description:Oxidative stress (OS) results from genetic defects or stressful environmental challenges that cause unchecked production of reactive oxygen species (ROS). OS has been implicated in many diseases due to its wide ranging damage to nucleic acids, proteins and lipids. Using Halobacterium salinarum NRC-1, an extremophile that thrives under conditions of excessive OS, we have constructed a systems model for oxidative stress response (OSR) by integrating transcriptional changes induced by treatments with H2O2 and paraquat, functional associations inferred through comparative genomics, and de novo discovered cis-regulatory motifs. Together with phenotypic analysis of mutant strains this has revealed a multi-tiered OS management program to transcriptionally coordinate three peroxidase/catalase enzymes, two superoxide dismutases, production of rhodopsins, carotenoids, and gas vesicles, metal trafficking, and various other aspects of metabolism. Remarkably, a significant fraction of this OSR was accurately recapitulated by a model that was previously constructed from cellular responses to diverse environmental perturbations –this constitutes the general stress response component. Notwithstanding this observation, comparison of the two models has identified the coordination of frontline defense and repair systems by regulatory mechanisms that are triggered uniquely by severe OS and not by other environmental stressors, including sub-inhibitory levels of redox-active metals, extreme changes in oxygen tension, and a sub-lethal dose of g rays. Mid-log phase cultures of H. salinarum NRC-1 (2 biological replicates) grown in flasks were treated with either sub-lethal concentrations of 25mM H2O2 or 4mM PQ and incubated with shaking for up to 240 min. For each treatment, two time courses were run to determine the transcriptional responses to (1) constant stress and (2) recovery of H. salinarum NRC-1 to H2O2 and PQ. During constant stress, culture aliquots (~4ml) were collected over a time course (-1, 5, 10, 20, 40, 80 and 160 minutes), centrifuged (16000g, 90 seconds) and flash frozen. For recovery, cells were first treated for 2-hours with either 25 mM H2O2 or 4mM PQ, recovered by centrifugation, washed and re-suspended in CM. Cultures were returned to the incubator with shaking and samples were taken at 0, 10, 20, 30, 40, 50, 60, 120, and 240 minutes and processed as described previously. Analysis of temporal transcriptional changes (-1, 0, 5, 10, 20, 40, 80, 160 and 320m) to sub-inhibitory concentrations of PQ (0.25mM) was also characterized. Total RNA was prepared and labeled with Alexa547 and Alexa647 dyes. Intensities were normalized between the Alexa 546 and Alexa 647 channels by scaling all intensities in one channel such that the 75th percentile in each channel was made equal.

Project description:Stroke remains a debilitating cerebrovascular condition associated with oxidative stress, while COVID-19 has emerged as a global health crisis with multifaceted systemic implications. This study investigates the hypothesis that patients experiencing acute ischemic stroke alongside COVID-19 exhibit elevated oxidative stress markers and altered antioxidant defense mechanisms compared to those with acute ischemic stroke. We conducted a single-center prospective cross-sectional study to investigate oxidative stress balance through oxidative damage markers: TBARS (thiobarbituric acid reactive substances level) and PCARB (protein carbonyls); antioxidant defense mechanisms: TAC (total antioxidant capacity), GPx (glutathione peroxidase), GSH (reduced glutathione), CAT (catalase), and SOD (superoxide dismutase); as well as inflammatory response markers: NLR (neutrophil-to-lymphocyte ratio), CRP (C-reactive protein), and ESR (erythrocyte sedimentation rate). Statistical analyses and correlation models were employed to elucidate potential associations and predictive factors. Our results revealed increased oxidative stress, predominantly indicated by elevated levels of TBARS in individuals experiencing ischemic stroke alongside a concurrent COVID-19 infection (p < 0.0001). The Stroke-COVID group displayed notably elevated levels of GSH (p = 0.0139 *), GPx (p < 0.0001 ****), SOD (p = 0.0363 *), and CAT (p = 0.0237 *) activities. Multivariate analysis found a significant association for TBARS (p < 0.0001 ****), PCARB (p = 0.0259 *), and GPx activity (p < 0.0001 ****), together with NLR (p = 0.0220 *) and CRP (p = 0.0008 ***). Notably, the interplay between stroke and COVID-19 infection appears to amplify oxidative damage, potentially contributing to exacerbated neurological deficits and poorer outcomes. This study highlights the intricate relationship between oxidative stress, inflammation, and concurrent health conditions. Understanding these interactions may open avenues for novel therapeutic strategies aimed at ameliorating oxidative damage in patients with acute ischemic stroke and COVID-19, ultimately improving their prognosis and quality of life.

Project description:Salinity is a global conundrum that negatively affects various biometrics of agricultural crops. Jasmonic acid (JA) is a phytohormone that reinforces multilayered defense strategies against abiotic stress, including salinity. This study investigated the effect of JA (60 μM) on two wheat cultivars, namely ZM9 and YM25, exposed to NaCl (14.50 dSm-1) during two consecutive growing seasons. Morphologically, plants primed with JA enhanced the vegetative growth and yield components. The improvement of growth by JA priming is associated with increased photosynthetic pigments, stomatal conductance, intercellular CO2, maximal photosystem II efficiency, and transpiration rate of the stressed plants. Furthermore, wheat cultivars primed with JA showed a reduction in the swelling of the chloroplast, recovery of the disintegrated thylakoids grana, and increased plastoglobuli numbers compared to saline-treated plants. JA prevented dehydration of leaves by increasing relative water content and water use efficiency via reducing water and osmotic potential using proline as an osmoticum. There was a reduction in sodium (Na+) and increased potassium (K+) contents, indicating a significant role of JA priming in ionic homeostasis, which was associated with induction of the transporters, viz., SOS1, NHX2, and HVP1. Exogenously applied JA mitigated the inhibitory effect of salt stress in plants by increasing the endogenous levels of cytokinins and indole acetic acid, and reducing the abscisic acid (ABA) contents. In addition, the oxidative stress caused by increasing hydrogen peroxide in salt-stressed plants was restrained by JA, which was associated with increased α-tocopherol, phenolics, and flavonoids levels and triggered the activities of superoxide dismutase and ascorbate peroxidase activity. This increase in phenolics and flavonoids could be explained by the induction of phenylalanine ammonia-lyase activity. The results suggest that JA plays a key role at the morphological, biochemical, and genetic levels of stressed and non-stressed wheat plants which is reflected in yield attributes. Hierarchical cluster analysis and principal component analyses showed that salt sensitivity was associated with the increments of Na+, hydrogen peroxide, and ABA contents. The regulatory role of JA under salinity stress was interlinked with increased JA level which consequentially improved ion transporting, osmoregulation, and antioxidant defense.

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Coordination of frontline defense mechanisms under severe oxidative stress.

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Coordination of frontline defense mechanisms under severe oxidative stress.

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