| 1. |
- Mårtensson, Jonas, et al.
(författare)
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The Two Formyl Peptide Receptors Differently Regulate GPR84-Mediated Neutrophil NADPH Oxidase Activity
- 2021
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 13:4, s. 242-256
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils express the two formyl peptide receptors (FPR1 and FPR2) and the medium-chain fatty acid receptor GPR84. The FPRs are known to define a hierarchy among neutrophil G protein-coupled receptors (GPCRs), that is, the activated FPRs can either suppress or amplify GPCR responses. In this study, we investigated the position of GPR84 in the FPR-defined hierarchy regarding the activation of neutrophil nicotine adenine dinucleotide phosphate (NADPH) oxidase, an enzyme system designed to generate reactive oxygen species (ROS), which are important regulators in cell signaling and immune regulation. When resting neutrophils were activated by GPR84 agonists, a modest ROS release was induced. However, vast amounts of ROS were induced by these GPR84 agonists in FPR2-desensitized neutrophils, and the response was inhibited not only by a GPR84-specific antagonist but also by an FPR2-specific antagonist. This suggests that the amplified GPR84 agonist response is achieved through a reactivation of desensitized FPR2s. In addition, the GPR84-mediated FPR2 reactivation was independent of beta-arrestin recruitment and sensitive to a protein phosphatase inhibitor. In contrast to FPR2-desensitized cells, FPR1 desensitization primarily resulted in a suppressed GPR84 agonist-induced ROS response, indicating a receptor hierarchical desensitization of GPR84 by FPR1-generated signals. In summary, our data show that the two FPRs in human neutrophils control the NADPH oxidase activity with concomitant ROS production by communicating with GPR84 through different mechanisms. While FPR1 desensitizes GPR84 and by that suppresses the release of ROS induced by GPR84 agonists, amplified ROS release is achieved by GPR84 agonists through reactivation of the desensitized FPR2.
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| 2. |
- Bowers, Sarah M, et al.
(författare)
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Pathogenic variant c.1052T>A (p.Leu351Gln) in adenosine deaminase 2 impairs secretion and elevates type I IFN responsive gene expression.
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Adenosine deaminase 2 (ADA2) is a homodimeric, extracellular enzyme and putative growth factor that is produced by cells of the myeloid lineage and, catalytically, deaminates extracellular adenosine to inosine. Loss-of-(catalytic)-function variants in the ADA2 gene are associated with Deficiency of ADA2 (DADA2), an autosomal recessive disease associated with an unusually broad range of inflammatory manifestations including vasculitis, hematological defects and cytopenia. Previous work by our group led to the identification of ADA2 variants of novel association with DADA2, among which was a unique c.1052T>A (p.Leu351Gln; herein referred to as L351Q) variant located in the catalytic domain of the protein.Mammalian (Flp-IN CHO) cells were engineered to stably express wild-type ADA2 and ADA2 protein variants, including the pathogenic L351Q variant identified in DADA2 patients. An enzyme assay and immunoblotting were used to assess ADA2 catalytic activity and secretion, respectively, and the outcome of experimentally induced inhibition of protein processing (Golgi transport and N-linked glycosylation) was assessed. Reverse transcription quantitative real-time PCR (RT-qPCR) was applied to determine the relative expression of Type I Interferon stimulated genes (ISGs), IFIT3 and IRF7.In addition to abrogating catalytic activity, the L351Q variant impaired secretion of L351Q ADA2 resulting in an intracellular accumulation of L351Q ADA2 protein that was not observed in cells expressing wild-type ADA2 or other ADA2 protein variants. Retention of L351Q ADA2 was not attributable to impaired glycosylation on neighboring asparagine residues and did not impact cell growth or integrity. Constitutive expression of Type I ISGs IFIT3 and IRF7 was observed in cells expressing L351Q ADA2.The impaired secretion of L351Q ADA2 may be an important factor leading to the severe phenotype observed in patients with this variant further emphasizing the importance of assessing impacts beyond catalytic activity when evaluating genotype-phenotype relationships in DADA2.
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| 3. |
- Elling, Devy L., et al.
(författare)
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Effects of a multi-component alcohol prevention program in the workplace on hazardous alcohol use among employees
- 2023
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Ingår i: BMC Public Health. - : Springer Nature. - 1471-2458. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Background: The workplace can be affected negatively by hazardous alcohol use, and intervening at an early stage remains a challenge. Recently, a multi-component alcohol prevention program, Alcohol Policy and Managers’ skills Training (hereafter, ‘APMaT’), was delivered at the organizational level. In a previous outcome evaluation, APMaT appeared to be effective at the managerial level. The current study takes a step further by aiming to evaluate the effectiveness of APMaT in decreasing the alcohol risk level among employees.Methods: Data from 853 employees (control: n = 586; intervention: n = 267) were gathered through a cluster-randomized study. To analyze changes in the odds of hazardous alcohol use among employees, multilevel logistic regression was applied using group (control vs. intervention), time (baseline vs. 12-month follow-up), and the multiplicative interaction term (group × time) as the main predictors. The intervention effect was further adjusted for sociodemographic characteristics and policy awareness.Results: No statistically significant difference was observed in the odds of hazardous alcohol use, although employees in the intervention group showed a larger decrease compared to the control group. This remained even after adjusting for several factors, including the sociodemographic factors and policy awareness.Conclusions: The findings are insufficient to determine the effectiveness of APMaT at the employee level at the current stage of the evaluation. Future studies should strive to identify issues with implementation processes in workplace-based alcohol interventions.
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| 4. |
- Elling, Devy L., et al.
(författare)
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Evaluation of a workplace alcohol prevention program targeted on managers’ inclination to initiate early alcohol interventions
- 2022
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Ingår i: Work. - 1051-9815 .- 1875-9270. ; 73:2, s. 517-526
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alcohol interventions targeting the adult population are often conducted in healthcare settings, while preventive interventions often target adolescents or young adults. The general working population is often overlooked. A workplace-based intervention, consisting of development and implementation of an organizational alcohol policy, and skills development training for managers (APMaT) was carried out in order to prevent and reduce alcohol-related harms by identifying hazardous consumers at an early stage. Objective: This study aims to evaluate APMaT by focusing on managers’ inclination to initiate early alcohol intervention.Methods: In a cluster randomized design, data were obtained from 187 managers (control: n = 70; intervention: n = 117). Inclination to initiate early alcohol intervention was measured using three items on a 5-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree). Changes in managers’ inclination to intervene were analyzed by applying multilevel ordered logistic regression. Predictors included in the model were group (control vs. intervention), time (baseline vs. 12-month follow-up), and the multiplicative interaction term (group × time).Results: Significant increase in inclination to intervene against hazardous alcohol consumption among managers in the intervention group compared to managers in the control group was observed. Specifically, a 50% increase of confidence to initiate an intervention was observed among managers in the intervention group.Conclusions: APMaT seems effective to increase managers’ inclination to intervene early against hazardous consumption in the workplace. The effectiveness of APMaT at the employee level should be explored in prospective studies.
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| 5. |
- Elling, Devy L., et al.
(författare)
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Perceived barriers in the dissemination of an organisational alcohol policy as part of implementing an alcohol prevention programme among managers
- 2022
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Ingår i: Drugs, Habits and Social Policy. - 2752-6739. ; 23:2, s. 128-139
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Tidskriftsartikel (refereegranskat)abstract
- Purpose - An alcohol prevention programme, consisting of the implementation of an organisational alcohol policy and skills development training for managers, was delivered in Swedish workplaces. Previous findings revealed challenges in policy implementation because of the lack of dissemination amongst managers. This study aims to describe perceived dissemination barriers of the organisational alcohol policy by managers. Design/methodology/approach - A cross-sectional survey (n = 193 managers) was performed to identify common dissemination barriers in the workplace and complementary case illustrations derived from semi-structured interviews (n = 18 managers) were used to understand the dissemination barriers of the organisational alcohol policy. Frequency distributions were presented to describe common perceived barriers. Findings - Sixty-five per cent of managers reported that their workplace had not changed their approach to addressing alcohol-related issues compared to their usual practice before programme delivery. Various organisational factors, such as deprioritisation of programme dissemination, lack of communication and inadequate strategies were some of the common barriers perceived by managers. Moreover, managers reported uncertainties regarding any changes concerning the workplace's approach for addressing alcohol-related issues. Increased efforts in disseminating the organisational alcohol policy can reduce uncertainties among managers. Practical implications - A thorough process evaluation to understand processes in programme delivery and implementation is necessary to ensure the uptake of the intervention. Originality/value - This study highlighted the complexity of disseminating an alcohol policy in a dynamic setting, such as the workplace, and provided the importance of addressing organisational obstacles.
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| 6. |
- Elling, Devy L., et al.
(författare)
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Workplace alcohol prevention : are managers' individual characteristics associated with organisational alcohol policy knowledge and inclination to initiate early alcohol interventions?
- 2020
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Ingår i: International Journal of Workplace Health Management. - 1753-8351 .- 1753-836X. ; 13:5, s. 543-560
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Tidskriftsartikel (refereegranskat)abstract
- Purpose - Individual factors associated with managers' organisational alcohol policy knowledge and inclination to initiate early alcohol interventions have been understudied. This study aims to examine differences in managers' policy knowledge and inclination across a range of socio-demographic, work-related and health characteristics, and it aims to examine the association between policy knowledge and inclination to intervene, net of these characteristics.Design/methodology/approach - Questionnaire data were collected from 430 managers. Organisational alcohol policy knowledge and inclination to intervene were measured using a 5-point Likert scale ranging from 1 (very low) to 5 (very high). Socio-demographic, work-related and health characteristics included gender, age, education, managerial responsibility, years in current position, self-rated health and alcohol consumption. Associations were examined using multilevel ordinal regression analysis.Findings - Managers with a greater number of employees demonstrated the highest level of organisational alcohol policy knowledge and were more inclined to initiate early alcohol interventions. Alcohol policy knowledge was associated with inclination to intervene, net of individual characteristics.Practical implications - Considering how managers' characteristics might influence efforts to decrease hazardous alcohol consumption is potentially important when designing future workplace alcohol prevention programmes.Originality/value - Several individual factors related to managers' organisational alcohol policy knowledge and inclination to initiate early alcohol interventions were identified, particularly managerial responsibility. However, the association between policy knowledge and inclination to intervene remained strong after accounting for these individual factors. Future studies should explore alternative explanations at the individual and organisational levels.
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| 7. |
- Flockhart, Mikael, et al.
(författare)
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Glucosinolate-rich broccoli sprouts protect against oxidative stress and improve adaptations to intense exercise training.
- 2023
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Ingår i: Redox Biology. - : Elsevier. - 2213-2317. ; 67
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress plays a vital role for the adaptive responses to physical training. However, excessive oxidative stress can precipitate cellular damage, necessitating protective mechanisms to mitigate this effect. Glucosinolates, found predominantly in cruciferous vegetables, can be converted into isothiocyanates, known for their antioxidative properties. These compounds activate crucial antioxidant defence pathways and support mitochondrial function and protein integrity under oxidative stress, in both Nrf2-dependent and independent manners. We here administered glucosinolate-rich broccoli sprouts (GRS), in a randomized double-blinded cross-over fashion to 9 healthy subjects in combination with daily intense exercise training for 7 days. We found that exercise in combination with GRS significantly decreased the levels of carbonylated proteins in skeletal muscle and the release of myeloperoxidase into blood. Moreover, it lowered lactate accumulation during submaximal exercise, and attenuated the severe nocturnal hypoglycaemic episodes seen during the placebo condition. Furthermore, GRS in combination with exercise improved physical performance, which was unchanged in the placebo condition.
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| 8. |
- Forsman, Huamei, et al.
(författare)
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AZ2158 is a more potent formyl peptide receptor 1 inhibitor than the commonly used peptide antagonists in abolishing neutrophil chemotaxis.
- 2023
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Ingår i: Biochemical pharmacology. - : Elsevier BV. - 1873-2968 .- 0006-2952. ; 211
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Tidskriftsartikel (refereegranskat)abstract
- Formyl peptide receptor 1 (FPR1), a G protein-coupled receptor expressed in phagocytes, recognizes short N-formylated peptides originating from proteins synthesized by bacteria and mitochondria. Such FPR1 agonists are important regulators of neutrophil functions and by that, determinants of inflammatory reactions. As FPR1 is implicated in promoting both pro-inflammatory and pro-resolving responses associated with inflammatory diseases, characterization of ligands that potently and selectively modulate FPR1 induced functions might be of high relevance. Accordingly, a number of FPR1 specific antagonists have been identified and shown to inhibit agonist binding or receptor down-stream signaling as well as neutrophil functions such as granule secretion and NADPH oxidase activity. The inhibitory effect on neutrophil chemotaxis induced by FPR1 agonists has generally not been part of basic antagonist characterization. In this study we show that the inhibitory effects on neutrophil chemotaxis of established FPR1 antagonists (i.e., cyclosporin H, BOC1 and BOC2) are limited. Our data demonstrate that the recently described small molecule AZ2158 is a potent and selective FPR1 antagonist in human neutrophils. In contrast to the already established FPR1 antagonists, AZ2158 also potently inhibits chemotaxis. Whereas the cyclosporin H inhibition was agonist selective, AZ2158 inhibited the FPR1 response induced by both a balanced and a biased FPR1 agonist equally well. In accordance with the species specificity described for many FPR1 ligands, AZ2158 was not recognized by the mouse orthologue of FPR1. Our data demonstrate that AZ2158 may serve as an excellent tool compound for further mechanistic studies of human FPR1 mediated activities.
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| 9. |
- Göransson, J., et al.
(författare)
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Performance of a System for Rapid Phenotypic Antimicrobial Susceptibility Testing of Gram-Negative Bacteria Directly from Positive Blood Culture Bottles
- 2023
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Ingår i: Journal of Clinical Microbiology. - : American Society for Microbiology. - 0095-1137 .- 1098-660X. ; 61:3
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Tidskriftsartikel (refereegranskat)abstract
- The rapid administration of optimal antimicrobial treatment is paramount for the treatment of bloodstream infections (BSIs), and rapid antimicrobial susceptibility testing (AST) results are essential. Q-linea has developed the ASTar system, a rapid phenotypic AST device. Here, we report the performance of the ASTar BC G- (Gram-negative) kit when assessed according to the ISO 20776-2:2007 standard for performance evaluation of in vitro diagnostic AST devices. The evaluated ASTar BC G- kit uses a broad panel of 23 antimicrobials for the treatment of BSIs caused by Gram-negative fastidious and nonfastidious bacteria across a range of 6 to 14 2-fold dilutions, including cefoxitin as a screening agent for AmpC-producing Enterobacterales. The ASTar system processes blood culture samples to generate data on MICs and susceptible, intermediate, or resistant (SIR) category. The automated protocol includes concentration determination and concentration adjustment to enable a controlled inoculum, followed by broth microdilution (BMD) and microscopy performed continuously to generate MIC values within approximately 6 h once the test is run on the ASTar system. The performance of the ASTar system was assessed against the ISO 20776-2:2007 standard BMD reference method. Testing was performed across three sites, with results from 412 contrived blood cultures and 74 fresh clinical blood cultures. The ASTar system was also tested for reproducibility, with triplicate testing of 11 strains. The accuracy study comprised 8,650 data points of bacterium-antimicrobial tests. The ASTar system demonstrated an overall essential agreement (EA) of 95.8% (8,283/8,650) and a categorical agreement (CA) of 97.6% (8,433/8,639) compared to the reference BMD method. The overall rate of major discrepancies (MDs) was 0.9% (62/6,845), and that of very major discrepancies (VMDs) was 2.4% (30/1,239). This study shows that the ASTar system delivers reproducible results with overall EA and CA of >95%.
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