scholarly journals Genetic ablation of glutaredoxin-1 causes enhanced resolution of airways hyperresponsiveness and mucus metaplasia in mice with allergic airways disease

2012 ◽  
Vol 303 (6) ◽  
pp. L528-L538 ◽  
Author(s):  
Sidra M. Hoffman ◽  
Jane E. Tully ◽  
Karolyn G. Lahue ◽  
Vikas Anathy ◽  
James D. Nolin ◽  
...  
Keyword(s):  
Allergic Inflammation ◽  
Protein S ◽  
Redox Status ◽  
Oxidative Modification ◽  
Genetic Ablation ◽  
Proinflammatory Mediators ◽  
Enhanced Resolution ◽  
Important Player ◽  
The Impact ◽  
Mucus Metaplasia

Protein- S-glutathionylation (PSSG) is an oxidative modification of reactive cysteines that has emerged as an important player in pathophysiological processes. Under physiological conditions, the thiol transferase, glutaredoxin-1 (Glrx1) catalyses deglutathionylation. Although we previously demonstrated that Glrx1 expression is increased in mice with allergic inflammation, the impact of Glrx1/PSSG in the development of allergic airways disease remains unknown. In the present study we examined the impact of genetic ablation of Glrx1 in the pathogenesis of allergic inflammation and airway hyperresponsiveness (AHR) in mice. Glrx1 −/− or WT mice were subjected to the antigen, ovalbumin (OVA), and parameters of allergic airways disease were evaluated 48 h after three challenges, and 48 h or 7 days after six challenges with aerosolized antigen. Although no clear increases in PSSG were observed in WT mice in response to OVA, marked increases were detected in lung tissue of mice lacking Glrx1 48 h following six antigen challenges. Inflammation and expression of proinflammatory mediators were decreased in Glrx1 −/− mice, dependent on the time of analysis. WT and Glrx1 −/− mice demonstrated comparable increases in AHR 48 h after three or six challenges with OVA. However, 7 days postcessation of six challenges, parameters of AHR in Glrx1 −/− mice were resolved to control levels, accompanied by marked decreases in mucus metaplasia and expression of Muc5AC and GOB5. These results demonstrate that the Glrx1/ S-glutathionylation redox status in mice is a critical regulator of AHR, suggesting that avenues to increase S-glutathionylation of specific target proteins may be beneficial to attenuate AHR.

scholarly journals Loss of IL-10 signaling promotes IL-22 dependent host defenses against acute Clostridioides difficile infection

2021 ◽  
Author(s):  
Emily S. Cribas ◽  
Joshua E. Denny ◽  
Jeffrey R. Maslanka ◽  
Michael C. Abt
Keyword(s):  
Defense Mechanisms ◽  
Intestinal Inflammation ◽  
Bacterial Pathogen ◽  
Survival Advantage ◽  
Protective Mechanisms ◽  
Genetic Ablation ◽  
Proinflammatory Mediators ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
The Impact

Infection with the bacterial pathogen Clostridioides difficile causes severe damage to the intestinal epithelium that elicits a robust inflammatory response. Markers of intestinal inflammation accurately predict clinical disease severity. However, determining the extent to which host-derived proinflammatory mediators drive pathogenesis versus promote host protective mechanisms remains elusive. In this report, we employed Il10-/- mice as a model of spontaneous colitis to examine the impact of constitutive intestinal immune activation, independent of infection, on C. difficile disease pathogenesis. Upon C. difficile challenge, Il10-/- mice exhibited significantly decreased morbidity and mortality compared to littermate Il10 heterozygote (Il10HET) control mice, despite a comparable C. difficile burden, innate immune response, and microbiota composition following infection. Similarly, antibody-mediated blockade of IL-10 signaling in wild-type C57BL/6 mice conveyed a survival advantage if initiated three weeks prior to infection. In contrast, no advantage was observed if blockade was initiated on the day of infection, suggesting that constitutive activation of inflammatory defense pathways prior to infection mediated host protection. IL-22, a cytokine critical in mounting a protective response against C. difficile infection, was elevated in the intestine of uninfected, antibiotic-treated Il10-/- mice, and genetic ablation of the IL-22 signaling pathway in Il10-/- mice negated the survival advantage following C. difficile challenge. Collectively, these data demonstrate that constitutive loss of IL-10 signaling, via genetic ablation or antibody blockade, enhances IL-22 dependent host defense mechanisms to limit C. difficile pathogenesis.

scholarly journals Loss of IL-10 signaling promotes IL-22 dependent host defenses against acute Clostridioides difficile infection

2020 ◽  
Author(s):  
Emily S. Cribas ◽  
Joshua E. Denny ◽  
Jeffrey R. Maslanka ◽  
Michael C. Abt
Keyword(s):  
Defense Mechanisms ◽  
Intestinal Inflammation ◽  
Bacterial Pathogen ◽  
Survival Advantage ◽  
Protective Mechanisms ◽  
Genetic Ablation ◽  
Proinflammatory Mediators ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
The Impact

AbstractInfection with the bacterial pathogen Clostridioides difficile causes severe damage to the intestinal epithelium that elicits a robust inflammatory response. Markers of intestinal inflammation accurately predict clinical disease severity. However, determining the extent to which host-derived proinflammatory mediators drive pathogenesis versus promote host protective mechanisms remains elusive. In this report, we employed Il10-/- mice as a model of spontaneous colitis to examine the impact of constitutive intestinal immune activation, independent of infection, on C. difficile disease pathogenesis. Upon C. difficile challenge, Il10-/- mice exhibited significantly decreased morbidity and mortality compared to littermate Il10 heterozygote (Il10HET) control mice, despite a comparable C. difficile burden, innate immune response, and microbiota composition following infection. Similarly, antibody-mediated blockade of IL-10 signaling in wild-type C57BL/6 mice conveyed a survival advantage if initiated three weeks prior to infection. In contrast, no advantage was observed if blockade was initiated on the day of infection, suggesting that constitutive activation of inflammatory defense pathways prior to infection mediated host protection. IL-22, a cytokine critical in mounting a protective response against C. difficile infection, was elevated in the intestine of uninfected, antibiotic-treated Il10-/- mice, and genetic ablation of the IL-22 signaling pathway in Il10-/- mice negated the survival advantage following C. difficile challenge. Collectively, these data demonstrate that constitutive loss of IL-10 signaling, via genetic ablation or antibody blockade, enhances IL-22 dependent host defense mechanisms to limit C. difficile pathogenesis.

scholarly journals Effect of Bacillus spp. and Brevibacillus sp. on the Photosynthesis and Redox Status of Solanum lycopersicum

Horticulturae ◽  
2021 ◽  
Vol 7 (2) ◽  
pp. 24
Author(s):  
Marino Costa-Santos ◽  
Nuno Mariz-Ponte ◽  
Maria Celeste Dias ◽  
Luísa Moura ◽  
Guilhermina Marques ◽  
...  
Keyword(s):  
Solanum Lycopersicum ◽  
Intercellular Co2 Concentration ◽  
Redox Status ◽  
Antioxidant Defenses ◽  
Photosynthetic Parameters ◽  
Plant Growth Promoting Bacteria ◽  
Potted Plants ◽  
Chlorophylls A And B ◽  
Bacillus Spp ◽  
The Impact

Plant-growth-promoting bacteria (PGPB) are gaining attention as a sustainable alternative to current agrochemicals. This study evaluated the impact of three Bacillus spp. (5PB1, 1PB1, FV46) and one Brevibacillus sp. (C9F) on the important crop tomato (Solanum lycopersicum) using the model cv. ‘MicroTom’. The effects of these isolates were assessed on (a) seedlings’ growth and vigor, and (b) adult potted plants. In potted plants, several photosynthetic parameters (chlorophylls (a and b), carotenoids and anthocyanins contents, transpiration rate, stomatal conductance, net CO2 photosynthetic rate, and intercellular CO2 concentration, and on chlorophyll fluorescence yields of light- and dark-adapted leaves)), as well as soluble sugars and starch contents, were quantified. Additionally, the effects on redox status were evaluated. While the growth of seedlings was, overall, not influenced by the strains, some effects were observed on adult plants. The Bacillus safensis FV46 stimulated the content of pigments, compared to C9F. Bacillus zhangzhouensis 5PB1 increased starch levels and was positively correlated with some parameters of the photophosphorylation and the gas exchange phases. Interestingly, Bacillus megaterium 1PB1 decreased superoxide (O2−) content, and B. safensis FV46 promoted non-enzymatic antioxidant defenses, increasing total phenol content levels. These results, conducted on a model cultivar, support the theory that these isolates differently act on tomato plant physiology, and that their activity depends on the age of the plant, and may differently influence photosynthesis. It would now be interesting to analyze the influence of these bacteria using commercial cultivars.

scholarly journals Imaging NAD(H) Redox Alterations in Cryopreserved Alveolar Macrophages from Ozone-Exposed Mice and the Impact of Nutrient Starvation during Long Lag Times

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 767
Author(s):  
He N. Xu ◽  
Joanna Floros ◽  
Lin Z. Li ◽  
Shaili Amatya
Keyword(s):  
Oxidative Stress ◽  
Alveolar Macrophages ◽  
Redox State ◽  
Redox Status ◽  
Nutrient Starvation ◽  
Ozone Exposure ◽  
Reduced Form ◽  
Time Period ◽  
Lag Times ◽  
The Impact

Employing the optical redox imaging technique, we previously identified a significant redox shift of nicotinamide adenine dinucleotide (NAD and the reduced form NADH) in freshly isolated alveolar macrophages (AM) from ozone-exposed mice. The goal here was twofold: (a) to determine the NAD(H) redox shift in cryopreserved AM isolated from ozone-exposed mice and (b) to investigate whether there is a difference in the redox status between cryopreserved and freshly isolated AM. We found: (i) AM from ozone-exposed mice were in a more oxidized redox state compared to that from filtered air (FA)-exposed mice, consistent with the results obtained from freshly isolated mouse AM; (ii) under FA exposure, there was no significant NAD(H) redox difference between fresh AM that had been placed on ice for 2.5 h and cryopreserved AM; however, under ozone exposure, fresh AM were more oxidized than cryopreserved AM; (iii) via the use of nutrient starvation and replenishment and H2O2-induced oxidative stress of an AM cell line, we showed that this redox difference between cryopreserved and freshly isolated AM is likely the result of the double “hit”, i.e., the ozone-induced oxidative stress plus nutrient starvation that prevented freshly isolated AM from a full recovery after being on ice for a prolonged time period. The cryopreservation technique we developed eliminates/minimizes the effects of oxidative stress and nutrient starvation on cells. This method can be adopted to preserve lung macrophages from animal models or clinical patients for further investigations.

scholarly journals AB1240 C4B BINDING PROTEIN AND WARFARIN IN THE ANTIPHOSPHOLIPID SYNDROME

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1911.2-1911
Author(s):  
G. Grosso ◽  
K. Sandholm ◽  
I. Gunnarsson ◽  
A. Zickert ◽  
A. Vikerfors ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Mediation Analysis ◽  
Binding Protein ◽  
Protein A ◽  
Protein S ◽  
Protein Isoforms ◽  
Type I ◽  
Complement Inhibitor ◽  
Warfarin Treatment ◽  
The Impact

Background:Complement plays a role in the Antiphospholipid Syndrome (APS). C4b Binding Protein (C4BP) is a complement inhibitor with anticoagulant function (1). It belongs to the same protein family as β2GPI, the main antigen in APS. Its main isoform is bound to protein S in the circulation. Levels of both protein S and C4BP are known to be reduced by warfarin treatment (2) as well as by aPL, directly and indirectly.Objectives:To investigate the levels of C4BP in primary (p) and secondary (s) APS, also considering warfarin treatment.Methods:The total amount of C4BP (C4BPt) was measured by using magnetic carboxylated microspheres which were coupled with a monoclonal antibody against the α-chain of human-C4BP to capture the antigen. To detect C4BPt the same antibody was used, biotinylated. The binding of biotinylated antibodies was detected by streptavidin-phycoerythrin and data were collected using a MAGPIX Multiplex Reader. Using independent t-test, we compared C4BP in 118 SLE patients with repeated positivity for Antiphospholipid antibodies (aPL) (39/118 on warfarin), 291 aPL negative SLE patients (16/291 on warfarin), 67 pAPS (33/67 on warfarin), and 322 controls (none on warfarin). We then performed an interaction and a mediation analysis (3) in the SLE group to study the impact of warfarin on C4BP levels: since warfarin is mostly prescribed to aPL+ patients, it is considered a mediator in the reducing effect of aPL on C4BP. Therefore we compared individuals exposed and non-exposed to the presence of aPL with or without the mediator warfarin and calculated the percentage of reduction in C4BP that could be attributed to aPL or warfarin.Results:Overall C4BP is 20% reduced in aPL+ patients (fig 1), independently of SLE, past thrombotic events and nephritis. Warfarin treated patients have lower levels of C4BP (fig 2). According to mediation analysis 11% of C4BP reduction is due to aPL and 9% to warfarin.Figure 1.C4BP in different subgroups (67 pAPS, 118 SLEaPL+, 291 SLEaPL-, 322 controls)Figure 2.C4BP in 67 pAPS patients, 33/67 on warfarinConclusion:Both aPL and warfarin decrease levels of C4BP, a complement and coagulation regulator. Reduction of this complement inhibitor could contribute to complement activation and thrombosis in APS. Our results raise new questions regarding the effects of warfarin treatment on complement and coagulation in APS.References:[1]Dahlbäck B. C4b-binding protein: a forgotten factor in thrombosis and hemostasis. Seminars in thrombosis and hemostasis 2011; 37(4): 355.[2]Zöller B, García de Frutos P, Dahlbäck B. Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995; 85(12): 3524.[3]Vanderweele TJ, Vansteelandt S. Conceptual issues concerning mediation, interventions and composition. Statistics and Its Interface 2009; 2(4): 457-68.Disclaimer:AV is employed at the Swedish Medical Products Agency, the views expressed in this paper are the personal views of the authors and not necessarily the views of the Governement AgencyAcknowledgments:Thanks to the Biostatistics Core Facility, Karolinska UniversityDisclosure of Interests:None declared

scholarly journals Human IFITM3 restricts Chikungunya virus and Mayaro virus infection and is susceptible to virus-mediated counteraction

2020 ◽  
Author(s):  
Sergej Franz ◽  
Thomas Zillinger ◽  
Fabian Pott ◽  
Christiane Schüler ◽  
Sandra Dapa ◽  
...  
Keyword(s):  
Virus Infection ◽  
Influenza A ◽  
Chikungunya Virus ◽  
Protein S ◽  
Human Cells ◽  
Structural Protein ◽  
Infected Cells ◽  
Mayaro Virus ◽  
The Impact

AbstractInterferon-induced transmembrane (IFITM) proteins restrict infection by enveloped viruses through interfering with membrane fusion and virion internalisation. The role of IFITM proteins during alphaviral infection of human cells and viral counteraction strategies remain largely unexplored. Here, we characterized the impact of IFITM proteins and variants on entry and spread of Chikungunya virus (CHIKV) and Mayaro virus (MAYV) in human cells, and provide first evidence for a CHIKV-mediated antagonism of IFITM proteins. IFITM1, 2 and 3 restricted infection at the level of alphavirus glycoprotein-mediated entry, both in the context of direct infection and during cell-to-cell transmission. Relocalization of normally endosomal IFITM3 to the plasma membrane resulted in the loss of its antiviral activity. rs12252-C, a naturally occurring variant of IFITM3 that has been proposed to associate with severe influenza in humans, restricted CHIKV, MAYV and influenza A virus infection as efficiently as wild-type IFITM3. Finally, all antivirally active IFITM variants displayed reduced cell surface levels in CHIKV-infected cells involving a posttranscriptional process mediated by one or several non-structural protein(s) of CHIKV.

scholarly journals Mineral Micronutrients in Asthma

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 4001
Author(s):  
Dominika Zajac
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Air Pollution ◽  
Defense Mechanisms ◽  
Redox Status ◽  
Chronic Inflammatory Disease ◽  
Modern World ◽  
Medical Issues ◽  
Persistent Inflammation ◽  
The Impact

Asthma represents one of the most common medical issues in the modern world. It is a chronic inflammatory disease characterized by persistent inflammation of the airways and disturbances in redox status, leading to hyperresponsiveness of bronchi and airway obstruction. Apart from classical risk factors such as air pollution, family history, allergies, or obesity, disturbances of the levels of micronutrients lead to impairments in the defense mechanisms of the affected organism against oxidative stress and proinflammatory stimuli. In the present review, the impact of micronutrients on the prevalence, severity, and possible risk factors of asthma is discussed. Although the influence of classical micronutrients such as selenium, copper, or zinc are well known, the effects of those such as iodine or manganese are only rarely mentioned. As a consequence, the aim of this paper is to demonstrate how disturbances in the levels of micronutrients and their supplementation might affect the course of asthma.

Platelet-mediated proteolytic down regulation of the anticoagulant activity of protein S in individuals with haematological malignancies

2012 ◽  
Vol 107 (03) ◽  
pp. 468-476 ◽  
Author(s):  
Ilze Dienava-Verdoold ◽  
Marina R. Marchetti ◽  
Liane C. J. te Boome ◽  
Laura Russo ◽  
Anna Falanga ◽  
...  
Keyword(s):  
Protein C ◽  
Normal Values ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Protein S ◽  
Intact Protein ◽  
The Impact ◽  
Independent Protein

SummaryThe natural anticoagulant protein S contains a so-called thrombin-sensitive region (TSR), which is susceptible to proteolytic cleavage. We have previously shown that a platelet-associated protease is able to cleave protein S under physiological plasma conditions in vitro. The aim of the present study was to investigate the relation between platelet-associated protein S cleaving activity and in vivo protein S cleavage, and to evaluate the impact of in vivo protein S cleavage on its anticoagulant activity. Protein S cleavage in healthy subjects and in thrombocytopenic and thrombocythaemic patients was evaluated by immunological techniques. Concentration of cleaved and intact protein S was correlated to levels of activated protein C (APC)-dependent and APC-independent protein S anticoagulant activity. In plasma from healthy volunteers 25% of protein S is cleaved in the TSR. While in plasma there was a clear positive correlation between levels of intact protein S and both APC-dependent and APC-independent protein S anticoagulant activities, these correlations were absent for cleaved protein S. Protein S cleavage was significantly increased in patients with essential thrombocythaemia (ET) and significantly reduced in patients with chemotherapy-induced thrombocytopenia. In ET patients on cytoreductive therapy, both platelet count and protein S cleavage returned to normal values. Accordingly, platelet transfusion restored cleavage of protein S to normal values in patients with chemotherapy-induced thrombocytopenia. In conclusion, proteases from platelets seem to contribute to the presence of cleaved protein S in the circulation and may enhance the coagulation response in vivo by down regulating the anticoagulant activity of protein S.

The impact of early gut microbiota modulation on the risk of child disease: alert to accuracy in probiotic studies

2015 ◽  
Vol 6 (2) ◽  
pp. 167-171 ◽  
Author(s):  
E. Isolauri ◽  
S. Salminen
Keyword(s):  
Gut Microbiota ◽  
Allergic Inflammation ◽  
Clinical Intervention ◽  
Probiotic Potential ◽  
Inflammatory State ◽  
Probiotic Strains ◽  
Risk Of Disease ◽  
Different Populations ◽  
The Impact ◽  
And Storage

The composition of the gut microbiota, and thus also the modification of the gut microbiota by specific probiotics or prebiotics early in life, may have an impact on the risk of disease in the child. Above the impact on gut microecology, probiotic effects have been attributed to restoration to normal of increased intestinal permeability, improvement of the intestine's immunological barrier functions, alleviation of the intestinal inflammatory response, and reduced generation of proinflammatory cytokines characteristic of local and systemic allergic inflammation. Recent demonstrations from experimental and clinical studies suggest that the gut microbiota is also involved in the control of body weight and energy metabolism, affecting the two main causes of obesity: energy acquisition and storage, and contributing to insulin resistance and the inflammatory state characterising obesity. Current research focuses both on characterising specific probiotic strains and on how the food matrix and the dietary content interacts with the most efficient probiotic strains. It is important to characterise each probiotic to species and strain level and to select strains with documented properties, the probiotic potential being strain-specific. As any proof of causality requires clinical intervention studies in humans in different populations, rigorous and detailed documentation will enhance reproducibility and circumvent confusion.

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