scholarly journals Novel Antioxidant Therapy with the Immediate Precursor to Glutathione, γ-Glutamylcysteine (GGC), Ameliorates LPS-Induced Cellular Stress in In Vitro 3D-Differentiated Airway Model from Primary Cystic Fibrosis Human Bronchial Cells

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1204
Author(s):  
Chris K. Hewson ◽  
Alexander Capraro ◽  
Sharon L. Wong ◽  
Elvis Pandzic ◽  
Ling Zhong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cystic Fibrosis ◽  
Stress Responses ◽  
Therapeutic Potential ◽  
Membrane Integrity ◽  
The Body ◽  
Stress Granule ◽  
Cellular Respiration ◽  
Granule Formation ◽  
Lps Challenge

Systemic glutathione deficiency, inflammation, and oxidative stress are hallmarks of cystic fibrosis (CF), an inherited disease that causes persistent lung infections and severe damage to the respiratory system and many of the body organs. Improvements to current antioxidant therapeutic strategies are needed. The dietary supplement, γ-glutamylcysteine (GGC), which is the immediate precursor to glutathione, rapidly boosts cellular glutathione levels following a single dose in healthy individuals. Efficacy of GGC against oxidative stress induced by Pseudomonas aeruginosa, which is a common and chronic pathogen infecting lungs of CF patients, remains unassessed. Primary mucocilliary differentiated airway (bronchial and/or nasal) epithelial cells were created from four individuals with CF. Airway oxidative stress and inflammation was induced by P. aeruginosa lipopolysaccharide (LPS). Parameters including global proteomics alterations, cell redox state (glutathione, oxidative stress), pro-inflammatory mediators (IL-8, IDO-1), and cellular health (membrane integrity, stress granule formation, cell metabolic viability) were assayed under six experimental conditions: (1) Mock, (2) LPS-challenged (3) therapeutic, (4) prophylactic (5) therapeutic and prophylactic and (6) GGC alone. Proteomic analysis identified perturbation of several pathways related to cellular respiration and stress responses upon LPS challenge. Most of these were resolved when cells were treated with GGC. While GGC did not resolve LPS-induced IL-8 and IDO-1 activity, it effectively attenuated LPS-induced oxidative stress and stress granule formation, while significantly increasing total intracellular glutathione levels, metabolic viability and improving epithelial cell barrier integrity. Both therapeutic and prophylactic treatments were successful. Together, these findings indicate that GGC has therapeutic potential for treatment and prevention of oxidative stress-related damage to airways in cystic fibrosis.

Novel antioxidant therapy with the immediate precursor to glutathione, γ-glutamylcysteine (GGC), ameliorates LPS-induced cellular stress in an in vitro cystic fibrosis model

2020 ◽  
Author(s):  
Chris K Hewson ◽  
Alexander Capraro ◽  
Sharon L Wong ◽  
Elvis Pandzic ◽  
Bentotage S.M Fernando ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cystic Fibrosis ◽  
Cell Viability ◽  
Stress Responses ◽  
Therapeutic Potential ◽  
Membrane Integrity ◽  
Stress Granule ◽  
Cellular Respiration ◽  
Granule Formation ◽  
Lps Challenge

AbstractIntroductionGlutathione deficiency and chronic bacterial inflammation exacerbates the oxidative stress damage to airways in cystic fibrosis. Improvements to current antioxidant therapeutic strategies are needed. Dietary supplement, γ-glutamylcysteine (GGC), the immediate precursor to glutathione, rapidly boosts cellular glutathione levels following a single dose in healthy individuals. Efficacy of GGC against Pseudomonas aeruginosa derived lipopolysaccharide (LPS), a prominent factor in mediating both bacterial virulence and host responses, in CF remains unassessed.MethodsPrimary F508del/F508del mucociliary differentiated bronchial and nasal epithelial cells were created to model LPS-induced oxidative stress and inflammation of CF. The proteomic signature of GGC treated cells was resolved by qLC-MS/MS. Parameters including cell redox state (glutathione, ROS), anti-inflammatory mediators (IL-8, IDO-1) and cellular health (membrane integrity, stress granule formation and cell viability) were assayed.ResultsProteomic analysis identified perturbation of several pathways related to cellular respiration and stress responses upon LPS challenge. Most of these were resolved when cells were treated with GGC. While GGC did not resolve LPS-induced IL-8 and IDO-1 activity, it effectively attenuated LPS-induced ROS and stress granule formation, while significantly increasing intracellular glutathione levels and improving epithelial cell barrier integrity. Moreover, we compared the effect of GGC with thiols NAC and glutathione on cell viability. GGC was the only thiol that increased cell viability; protecting cells against LPS induced cell death. Both therapeutic and prophylactic treatments were successful.ConclusionTogether, these findings indicate that GGC has therapeutic potential for treatment and prevention of oxidative stress related damage to airways in Cystic Fibrosis.

scholarly journals THE TRANSCRIPTIONAL RESPONSE TO OXIDATIVE STRESS IS INDEPENDENT OF STRESS-GRANULE FORMATION

2021 ◽  
Author(s):  
Amanjot Singh ◽  
Arvind Reddy Kandi ◽  
Deepa Jayaprakashappa ◽  
Guillaume Thuery ◽  
Devam J Purohit ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Transcriptional Response ◽  
Stress Granules ◽  
Stress Granule ◽  
Cell Recovery ◽  
Granule Formation ◽  
Transcriptional Changes ◽  
Translational Arrest ◽  
Shock Proteins

ABSTRACTCells respond to stress with translational arrest, robust transcriptional changes, and transcription-independent formation of mRNP assemblies termed stress granules (SGs). Despite considerable interest in the role of SGs in oxidative, unfolded-protein, and viral stress responses, whether and how SGs contribute to stress-induced transcription has not been rigorously examined. To address this issue, we characterized transcriptional changes in Drosophila S2 cells induced by acute oxidative-stress and assessed how these were altered under conditions that disrupted SG assembly. Sodium-arsenite stress for 3 hours predominantly resulted in the induction or upregulation of stress-responsive mRNAs whose levels peaked during cell recovery after stress cessation. The stress-transcriptome is enriched in mRNAs coding for protein chaperones, including HSP70 and low molecular-weight heat shock proteins, glutathione transferases, and several non-coding RNAs. Oxidative stress also induced prominent cytoplasmic stress granules that disassembled 3-hours after stress cessation. As expected, RNAi-mediated knockdown of the conserved G3BP1/ Rasputin protein inhibited stress-granule assembly. However, this disruption had no significant effect on the stress-induced transcriptional response or stress-induced translational arrest. Thus, SG assembly and stress-induced effects on gene expression appear to be driven by distinctive signaling processes. We suggest that while SG assembly represents a fast, transient mechanism, the transcriptional response enables a slower, longer-lasting mechanism for adaptation to and recovery from cell stress.

scholarly journals Puumala and Andes Orthohantaviruses Cause Transient Protein Kinase R-Dependent Formation of Stress Granules

2019 ◽  
Vol 94 (3) ◽  
Author(s):  
Wanda Christ ◽  
Janne Tynell ◽  
Jonas Klingström
Keyword(s):  
Protein Kinase ◽  
Host Cell ◽  
Stress Responses ◽  
Stress Granules ◽  
Cell Stress ◽  
Stress Granule ◽  
Hantavirus Infection ◽  
Stress Signaling ◽  
Protein Kinase R ◽  
Granule Formation

ABSTRACT Virus infection frequently triggers host cell stress signaling resulting in translational arrest; as a consequence, many viruses employ means to modulate the host stress response. Hantaviruses are negative-sense, single-stranded RNA viruses known to inhibit host innate immune responses and apoptosis, but their impact on host cell stress signaling remains largely unknown. In this study, we investigated activation of host cell stress responses during hantavirus infection. We show that hantavirus infection causes transient formation of stress granules (SGs) but does so in only a limited proportion of infected cells. Our data indicate some cell type-specific and hantavirus species-specific variability in SG prevalence and show SG formation to be dependent on the activation of protein kinase R (PKR). Hantavirus infection inhibited PKR-dependent SG formation, which could account for the transient nature and low prevalence of SG formation observed during hantavirus infection. In addition, we report only limited colocalization of hantaviral proteins or RNA with SGs and show evidence indicating hantavirus-mediated inhibition of PKR-like endoplasmic reticulum (ER) kinase (PERK). IMPORTANCE Our work presents the first report on stress granule formation during hantavirus infection. We show that hantavirus infection actively inhibits stress granule formation, thereby escaping the detrimental effects on global translation imposed by host stress signaling. Our results highlight a previously uncharacterized aspect of hantavirus-host interactions with possible implications for how hantaviruses are able to cause persistent infection in natural hosts and for pathogenesis.

scholarly journals Stable Formation of Compositionally Unique Stress Granules in Virus-Infected Cells

2009 ◽  
Vol 84 (7) ◽  
pp. 3654-3665 ◽  
Author(s):  
Joanna Piotrowska ◽  
Spencer J. Hansen ◽  
Nogi Park ◽  
Katarzyna Jamka ◽  
Peter Sarnow ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heat Shock ◽  
Viral Infections ◽  
De Novo ◽  
Stress Granules ◽  
Stress Granule ◽  
Initiation Factor ◽  
Granule Formation ◽  
Infected Cells ◽  
Positive Strand Rna

ABSTRACT Stress granules are sites of mRNA storage formed in response to a variety of stresses, including viral infections. Here, the mechanisms and consequences of stress granule formation during poliovirus infection were examined. The results indicate that stress granules containing T-cell-restricted intracellular antigen 1 (TIA-1) and mRNA are stably constituted in infected cells despite lacking intact RasGAP SH3-domain binding protein 1 (G3BP) and eukaryotic initiation factor 4G. Fluorescent in situ hybridization revealed that stress granules in infected cells do not contain significant amounts of viral positive-strand RNA. Infection does not prevent stress granule formation in response to heat shock, indicating that poliovirus does not block de novo stress granule formation. A mutant TIA-1 protein that prevents stress granule formation during oxidative stress also prevents formation in infected cells. However, stress granule formation during infection is more dependent upon ongoing transcription than is formation during oxidative stress or heat shock. Furthermore, Sam68 is recruited to stress granules in infected cells but not to stress granules formed in response to oxidative stress or heat shock. These results demonstrate that stress granule formation in poliovirus-infected cells utilizes a transcription-dependent pathway that results in the appearance of stable, compositionally unique stress granules.

scholarly journals Physiological and Oxidative Stress Responses of Lettuce to Cleomside A: A Thiohydroximate, as a New Allelochemical from Cleome arabica L.

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4461
Author(s):  
Afef Ladhari ◽  
Anna Andolfi ◽  
Marina DellaGreca
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Membrane Integrity ◽  
Ethyl Acetate Fraction ◽  
The Other ◽  
Bioactive Metabolites ◽  
Natural Herbicides ◽  
Cleome Arabica ◽  
Oxidative Stress Responses ◽  
And Oxidative Stress

The inclination toward natural products have led the onset for the discovery of new bioactive metabolites that could be targeted for specific therapeutic or agronomic applications. This study aimed to isolate bioactive compounds from Cleome arabica L., and subsequently determine the unexplored mechanism of action of the newly identified compounds on Lactuca sativa L. Chemical investigation of the ethyl acetate fraction of methanolic silique extract of C. arabica afforded seven secondary metabolites belonging to different classes such as flavonoids, triterpene, and a new thiohydroximate derivative, named cleomside A. Among phytotoxic assays, the growth of lettuce was totally inhibited by cleomside A compared to the other identified compounds. This effect was associated with the increased levels of electrolyte leakage, malondialdehyde, and hydrogen peroxide indicating disruption of membrane integrity and induction of oxidative stress. Activities of the antioxidant enzymes SOD, CAT, and APX were also elevated, thereby demonstrating the enhanced generation of reactive oxygen species upon identified allelochemical exposure. Thus, the changes caused by cleomside A described herein can contribute to better understanding the allelochemical actions of thiohydroximate and the potential use of these substances in the production of natural herbicides compared to the other identified flavonoids and triterpene.

scholarly journals Antidiabetic Potential of the Heme Oxygenase-1 Inducer Curcumin Analogues

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Yong Son ◽  
Ju Hwan Lee ◽  
Yong-Kwan Cheong ◽  
Hun-Taeg Chung ◽  
Hyun-Ock Pae
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Heme Oxygenase ◽  
Stress Responses ◽  
Therapeutic Potential ◽  
Heme Oxygenase 1 ◽  
Low Grade ◽  
Cellular Protection ◽  
Inflammatory Stress ◽  
Curcumin Analogues

Although there is a therapeutic treatment to combat diabetes, the identification of agents that may deal with its more serious aspects is an important medical field for research. Diabetes, which contributes to the risk of cardiovascular disease, is associated with a low-grade chronic inflammation (inflammatory stress), oxidative stress, and endoplasmic reticulum (ER) stress. Because the integration of these stresses is critical to the pathogenesis of diabetes, agents and cellular molecules that can modulate these stress responses are emerging as potential targets for intervention and treatment of diabetic diseases. It has been recognized that heme oxygenase-1 (HO-1) plays an important role in cellular protection. Because HO-1 can reduce oxidative stress, inflammatory stress, and ER stress, in part by exerting antioxidant, anti-inflammatory, and antiapoptotic effects, HO-1 has been suggested to play important roles in pathogenesis of diabetes. In the present review, we will explore our current understanding of the protective mechanisms of HO-1 in diabetes and present some emerging therapeutic options for HO-1 expression in treating diabetic diseases, together with the therapeutic potential of curcumin analogues that have their ability to induce HO-1 expression.

scholarly journals Oxidative stress in dogs

2016 ◽  
Vol 37 (3) ◽  
pp. 1431 ◽  
Author(s):  
Claudia Russo ◽  
Ana Paula F. Rodrigues Loureiro Bracarense
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Free Radicals ◽  
Cell Membrane ◽  
The Body ◽  
Antioxidant Defenses ◽  
Cellular Respiration ◽  
Bodily Fluids ◽  
Cellular Components ◽  
Harmful Effects

Reactive oxygen species (ROS), also known as free radicals, are generated during cellular respiration. Under normal conditions, the body has the ability to neutralize the effects of free radicals by using its antioxidant defenses. In the case of an imbalance between oxidants and antioxidants, free radical production exceeds the capacity of organic combustion, resulting in oxidative stress. Of all the cellular components compromised by the harmful effects of ROS, the cell membrane is the most severely affected owing to lipid peroxidation, which invariably leads to changes in the membrane structure and permeability. With lipid peroxidation of the cell membrane, some by-products can be detected and measured in tissues, blood, and other bodily fluids. The measurement of biomarkers of oxidative stress is commonly used to quantify lipid peroxidation of the cell membrane in humans, a species in which ROS can be considered as a cause or consequence of oxidative stress-related diseases. In dogs, few studies have demonstrated this correlation. The present review aims to identify current literature knowledge relating to oxidative stress diseases and their detection in dogs.

scholarly journals Internalization of Titanium Dioxide Nanoparticles Is Cytotoxic for H9c2 Rat Cardiomyoblasts

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1955 ◽  
Author(s):  
Elizabeth Huerta-García ◽  
Iván Zepeda-Quiroz ◽  
Helen Sánchez-Barrera ◽  
Zaira Colín-Val ◽  
Ernesto Alfaro-Moreno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Death ◽  
Titanium Dioxide ◽  
Titanium Dioxide Nanoparticles ◽  
Membrane Integrity ◽  
The Body ◽  
Potential Health ◽  
Tio2 Nps

Titanium dioxide nanoparticles (TiO2 NPs) are widely used in industry and daily life. TiO2 NPs can penetrate into the body, translocate from the lungs into the circulation and come into contact with cardiac cells. In this work, we evaluated the toxicity of TiO2 NPs on H9c2 rat cardiomyoblasts. Internalization of TiO2 NPs and their effect on cell proliferation, viability, oxidative stress and cell death were assessed, as well as cell cycle alterations. Cellular uptake of TiO2 NPs reduced metabolic activity and cell proliferation and increased oxidative stress by 19-fold measured as H2DCFDA oxidation. TiO2 NPs disrupted the plasmatic membrane integrity and decreased the mitochondrial membrane potential. These cytotoxic effects were related with changes in the distribution of cell cycle phases resulting in necrotic death and autophagy. These findings suggest that TiO2 NPs exposure represents a potential health risk, particularly in the development of cardiovascular diseases via oxidative stress and cell death.

scholarly journals POTENTIAL USE OF SULFORAPHANE AS A NEUROPROTECTOR

2021 ◽  
pp. 125-136
Author(s):  
S. A. Tsiumpala ◽  
K. M. Starchevska ◽  
V. I. Lushchak
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Old Age ◽  
Neurodegenerative Disorders ◽  
Therapeutic Potential ◽  
The Body ◽  
Biologically Active ◽  
Inflammatory Processes ◽  
The Brain ◽  
Potential Use

Introduction. Under normal conditions, oxidative stress and proinflammatory processes are tightly controlled. However, during neuroinflammation and overproduction of reactive oxygen species (ROS), homeostasis is disrup­ted, which may lead to development of Alzheimer’s disease, Parkinson’s disease and other neurodegenerative disorders. Inflammatory processes may result in neurodegenerative disorders. Sulforaphane is an isothiocyanate compound which has potential for treatment of neurodegenerative disorders. Its therapeutic potential is based on the ability to activate transcription of genes, that regulate protective cellular mechanisms. The importance of stu­dying sulforaphane as a neuroprotector is based on the fact, that dementias are the seventh leading cause of death glo­bally and actively progress due to aging of human population. In this review, the anti-inflammatory effects of sulforaphane in the brain and its use as a potential neuroprotector in the treatment of neurodegenerative diseases are discussed. The aim of the study – to review available literature sources on the potential use of sulforaphane to prevent or mitigate neuroinflammation. Conclusions. Economic and technological development of mankind and the improvement of the general qua­lity of life leads to prolongation of human life. But, achievements of longevity give new challenges to humanity. In young age and early adulthood, the organisms can relatively easily maintain homeostasis, then in old age intensification of oxidative stress and inflammatory processes can lead to the development of dementias and mental disorders. What should we do now to save clear mind in old age? In this review, sulforaphane is considered to be a potential neuroprotector. Biologically active supplements and drugs containing sulforaphane can weaken up inflammatory processes in the brain and in the body in general, and therefore they can be used for prevention and treatment of neurodegenerative diseases.

DIBI, a novel polymeric iron chelator modulates IL-6 and IL-8 secretion from Cystic Fibrosis airway epithelial cells in response to endotoxin induction

2020 ◽  
pp. 1-10
Author(s):  
Maral Aali ◽  
Alexa Caldwell ◽  
Audrey Li ◽  
Bruce Holbein ◽  
Valerie Chappe ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Chronic Inflammation ◽  
Therapeutic Potential ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Airway Epithelial Cells ◽  
High Dose ◽  
Dependent Manner ◽  
Lps Challenge

Iron chelators have been utilized clinically to treat patients with iron overload conditions. There is a growing body of evidence linking iron dysregulation and reactive oxygen species (ROS) overproduction as underlying factors in Cystic Fibrosis (CF) disease. The chronic inflammation can lead to progressive airway destruction. Alleviation of this chronic inflammation is a potential target for CF treatment and thus, this research investigated the dose-response effects of DIBI, a novel iron chelator, on inflammation in CF nasal epithelial cells. Polarized CF cells were stimulated with, lipopolysaccharide (LPS), co-treated with DIBI (LPS+DIBI), or DIBI alone (DIBI). We demonstrated that DIBI modulated the release of IL-6 and IL-8 in CF cells in a dose-dependent manner. Reduction of extracellular iron with the lower doses of DIBI (25 and 50μM), increased IL-6 secretion in non-induced cells. LPS challenge increased IL-6 and IL-8 secretion which was suppressed by high dose (200μM) DIBI administration. This study demonstrates the therapeutic potential of iron chelation therapy to treat the dysregulation of the immune response in CF patients.

Sign in / Sign up

Export Citation Format

Share Document