| 1. |
- Andersson, Lena, 1965-, et al.
(författare)
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Respiratory Health and Inflammatory Markers : Exposure to Cobalt in the Swedish Hard Metal Industry
- 2020
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Ingår i: Journal of Occupational and Environmental Medicine. - : Lippincott Williams & Wilkins. - 1076-2752 .- 1536-5948. ; 62:10, s. 820-829
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study the relationship between inhalable dust and cobalt and respiratory symptoms, lung function, exhaled nitric oxide in expired air and CC16 in the Swedish hard metal industry.METHODS: Personal sampling of inhalable dust and cobalt, medical examination including blood sampling was performed for 72 workers. Exposure-response relationships was determined using logistic, linear and mixed model analysis.RESULTS: The average inhalable dust and cobalt concentrations were 0.079 and 0.0017 mg/m, respectively. Statistically significant increased serum levels of CC16 were determined when the high and low cumulative exposures for cobalt were compared. Non-significant exposure-response relationships was observed between cross-shift inhalable dust or cobalt exposures and asthma, nose dripping and bronchitis.CONCLUSIONS: Our findings suggest an exposure-response relationship between inhalable cumulative cobalt exposure and CC16 levels in blood, which may reflect an injury or a reparation process in the lungs.
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| 2. |
- Lerm, Maria, 1973-, et al.
(författare)
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Leishmania donovani requires functional Cdc42 and Rac1 to prevent phagosomal maturation
- 2006
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 74:5, s. 2613-2618
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Tidskriftsartikel (refereegranskat)abstract
- Leishmania donovani promastigotes survive inside macrophage phagosomes by inhibiting phagosomal maturation. The main surface glycoconjugate on promastigotes, lipophosphoglycan (LPG), is crucial for survival and mediates the formation of a protective shell of F-actin around the phagosome. Previous studies have demonstrated that this effect involves inhibition of protein kinase Cα. The present study shows that functional Cdc42 and Rac1 are required for the formation of F-actin around L. donovani phagosomes. Moreover, we present data showing that phagosomes containing LPG-defective L. donovani, which is unable to induce F-actin accumulation, display both elevated levels of periphagosomal F-actin and impaired phagosomal maturation in macrophages with permanently active forms of Cdc42 and Rac1. We conclude that L. donovani engages Cdc42 and Rac1 to build up a protective coat of F-actin around its phagosome to prevent phagosomal maturation. Copyright © 2006, American Society for Microbiology. All Rights Reserved.
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| 3. |
- Westberg, Håkan, 1949-, et al.
(författare)
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Inflammatory and coagulatory markers and exposure to different size fractions of particle mass, number and surface area air concentrations in Swedish iron foundries, in particular respirable quartz
- 2019
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer Berlin/Heidelberg. - 0340-0131 .- 1432-1246. ; 92:8, s. 1087-1098
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To study the relationship between inhalation of airborne particles and quartz in Swedish iron foundries and markers of inflammation and coagulation in blood.METHODS: Personal sampling of respirable dust and quartz was performed for 85 subjects in three Swedish iron foundries. Stationary measurements were used to study the concentrations of respirable dust and quartz, inhalable and total dust, PM10 and PM2.5, as well as the particle surface area and the particle number concentrations. Markers of inflammation, namely interleukins (IL-1β, IL-6, IL-8, IL-10 and IL-12), C-reactive protein, and serum amyloid A (SAA) were measured in plasma or serum, together with markers of coagulation including fibrinogen, factor VIII (FVIII), von Willebrand factor and D-dimer. Complete sampling was performed on the second or third day of a working week after a work-free weekend, and follow-up samples were collected 2 days later. A mixed model analysis was performed including sex, age, smoking, infections, blood group, sampling day and BMI as covariates.RESULTS: The average 8-h time-weighted average air concentrations of respirable dust and quartz were 0.85 mg/m3 and 0.052 mg/m3, respectively. Participants in high-exposure groups with respect to some of the measured particle types exhibited significantly elevated levels of SAA, fibrinogen and FVIII.CONCLUSIONS: These observed relationships between particle exposure and inflammatory markers may indicate an increased risk of cardiovascular disease among foundry workers with high particulate exposure.
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| 4. |
- Ydrenius, Liselotte, et al.
(författare)
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Activation of cAMP-dependent protein kinase is necessary for actin rearrangements in human neutrophils during phagocytosis
- 2000
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Ingår i: Journal of Leukocyte Biology. - 0741-5400 .- 1938-3673. ; 67:4, s. 520-528
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the role of cAMP and cAMP-dependent protein kinase (cAPK) in neutrophil phagocytosis. Inhibition of cAPK with H-89 reduced complement- and IgG-dependent phagocytosis to 83 and 46%, respectively. Fluorescence intensity measurements of phalloidin-stained actin in neutrophils showed a reduced amount of filamentous actin (F-actin) in pseudopods and around the phagosome in cells treated with H-89 or cAMP-elevating agents (forskolin and rolipram). The amount of phosphotyrosine-containing proteins was also reduced in pseudopods and around the phagosome. Taken together, the data show that cAMP/cAPK regulates F-actin reorganization during receptor-mediated phagocytosis, particularly triggered by IgG-FcR interaction. Our results support the hypothesis that active subcortical reorganization of F-actin is a prerequisite for FcR-mediated phagocytosis, but is less important during CR3-mediated ingestion.
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| 5. |
- Alijagic, Andi, 1992-, et al.
(författare)
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A Novel Nanosafety Approach Using Cell Painting, Metabolomics, and Lipidomics Captures the Cellular and Molecular Phenotypes Induced by the Unintentionally Formed Metal-Based (Nano)Particles
- 2023
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Additive manufacturing (AM) or industrial 3D printing uses cutting-edge technologies and materials to produce a variety of complex products. However, the effects of the unintentionally emitted AM (nano)particles (AMPs) on human cells following inhalation, require further investigations. The physicochemical characterization of the AMPs, extracted from the filter of a Laser Powder Bed Fusion (L-PBF) 3D printer of iron-based materials, disclosed their complexity, in terms of size, shape, and chemistry. Cell Painting, a high-content screening (HCS) assay, was used to detect the subtle morphological changes elicited by the AMPs at the single cell resolution. The profiling of the cell morphological phenotypes, disclosed prominent concentration-dependent effects on the cytoskeleton, mitochondria, and the membranous structures of the cell. Furthermore, lipidomics confirmed that the AMPs induced the extensive membrane remodeling in the lung epithelial and macrophage co-culture cell model. To further elucidate the biological mechanisms of action, the targeted metabolomics unveiled several inflammation-related metabolites regulating the cell response to the AMP exposure. Overall, the AMP exposure led to the internalization, oxidative stress, cytoskeleton disruption, mitochondrial activation, membrane remodeling, and metabolic reprogramming of the lung epithelial cells and macrophages. We propose the approach of integrating Cell Painting with metabolomics and lipidomics, as an advanced nanosafety methodology, increasing the ability to capture the cellular and molecular phenotypes and the relevant biological mechanisms to the (nano)particle exposure.
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| 6. |
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| 7. |
- Alijagic, Andi, 1992-, et al.
(författare)
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Characteristics and health risks of the inhalable fraction of metal additive manufacturing powders
- 2024
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Ingår i: Nano Select. - : Wiley-VCH Verlagsgesellschaft. - 2688-4011. ; 5:4
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Tidskriftsartikel (refereegranskat)abstract
- Metal additive manufacturing (AM) is gaining traction but raises worker health concerns due to micron-sized powders, including fine inhalable particles. This study explored particle and surface characteristics, electrochemical properties, metal release in artificial lysosomal fluid (ALF), and potential toxicity of virgin and sieved virgin Fe-based powders, stainless steel (316L), Fe, and two tooling steels. Virgin particles ranged in size from 1 to 100μm, while sieved particles were within the respirable size range (<5–10μm). Surface oxide composition differed from bulk composition. The Fe powder showed low corrosion resistance and high metal release due to a lack of protective surface oxide. Sieved particles of 316L, Fe, and one tooling steel released more metals into ALF than virgin particles, with the opposite was observed for the other tooling steel. Sieved particles had no notable impact on cell viability or micronuclei formation in human bronchial epithelial cells. Inflammatory response in human macrophages was generally low, except for the Fe powder and one tooling steel, which induced increased interleukin-8 (IL-8/CXCL-8) and monocyte chemoattractant protein-1 (MCP-1/CCL-2) secretion. This study underscores distinctions between virgin and sieved Fe-based powders and suggests relatively low acute toxicity.
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| 8. |
- Alijagic, Andi, 1992-, et al.
(författare)
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Immunotoxic, genotoxic, and endocrine disrupting impacts of polyamide microplastic particles and chemicals
- 2024
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 183
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Tidskriftsartikel (refereegranskat)abstract
- Due to their exceptional properties and cost effectiveness, polyamides or nylons have emerged as widely used materials, revolutionizing diverse industries, including industrial 3D printing or additive manufacturing (AM). Powder-based AM technologies employ tonnes of polyamide microplastics to produce complex components every year. However, the lack of comprehensive toxicity assessment of particulate polyamides and polyamide-associated chemicals, especially in the light of the global microplastics crisis, calls for urgent action. This study investigated the physicochemical properties of polyamide-12 microplastics used in AM, and assessed a number of toxicity endpoints focusing on inflammation, immunometabolism, genotoxicity, aryl hydrocarbon receptor (AhR) activation, endocrine disruption, and cell morphology. Specifically, microplastics examination by means of field emission scanning electron microscopy revealed that work flow reuse of material created a fraction of smaller particles with an average size of 1-5 µm, a size range readily available for uptake by human cells. Moreover, chemical analysis by means of gas chromatography high-resolution mass spectrometry detected several polyamide-associated chemicals including starting material, plasticizer, thermal stabilizer/antioxidant, and migrating slip additive. Even if polyamide particles and chemicals did not induce an acute inflammatory response, repeated and prolonged exposure of human primary macrophages disclosed a steady increase in the levels of proinflammatory chemokine Interleukin-8 (IL-8/CXCL-8). Moreover, targeted metabolomics disclosed that polyamide particles modulated the kynurenine pathway and some of its key metabolites. The p53-responsive luciferase reporter gene assay showed that particles per se were able to activate p53, being indicative of a genotoxic stress. Polyamide-associated chemicals triggered moderate activation of AhR and elicited anti-androgenic activity. Finally, a high-throughput and non-targeted morphological profiling by Cell Painting assay outlined major sites of bioactivity of polyamide-associated chemicals and indicated putative mechanisms of toxicity in the cells. These findings reveal that the increasing use of polyamide microplastics may pose a potential health risk for the exposed individuals, and it merits more attention.
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| 9. |
- Alijagic, Andi, 1992-, et al.
(författare)
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NLRP3 inflammasome as a sensor of micro- and nanoplastics immunotoxicity
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
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Forskningsöversikt (refereegranskat)abstract
- Micro- and nanoplastics (MNPs) are emerging pollutants with scarcely investigated effects on human innate immunity. If they follow a similar course of action as other, more thoroughly investigated particulates, MNPs may penetrate epithelial barriers, potentially triggering a cascade of signaling events leading to cell damage and inflammation. Inflammasomes are intracellular multiprotein complexes and stimulus-induced sensors critical for mounting inflammatory responses upon recognition of pathogen- or damage-associated molecular patterns. Among these, the NLRP3 inflammasome is the most studied in terms of activation via particulates. However, studies delineating the ability of MNPs to affect NLRP3 inflammasome activation are still rare. In this review, we address the issue of MNPs source and fate, highlight the main concepts of inflammasome activation via particulates, and explore recent advances in using inflammasome activation for assessment of MNP immunotoxicity. We also discuss the impact of co-exposure and MNP complex chemistry in potential inflammasome activation. Development of robust biological sensors is crucial in order to maximize global efforts to effectively address and mitigate risks that MNPs pose for human health.
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| 10. |
- Alijagic, Andi, 1992-, et al.
(författare)
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Particle Safety Assessment in Additive Manufacturing : From Exposure Risks to Advanced Toxicology Testing.
- 2022
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Ingår i: Frontiers in Toxicology. - : Frontiers Media S.A.. - 2673-3080. ; 4
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Forskningsöversikt (refereegranskat)abstract
- Additive manufacturing (AM) or industrial three-dimensional (3D) printing drives a new spectrum of design and production possibilities; pushing the boundaries both in the application by production of sophisticated products as well as the development of next-generation materials. AM technologies apply a diversity of feedstocks, including plastic, metallic, and ceramic particle powders with distinct size, shape, and surface chemistry. In addition, powders are often reused, which may change the particles' physicochemical properties and by that alter their toxic potential. The AM production technology commonly relies on a laser or electron beam to selectively melt or sinter particle powders. Large energy input on feedstock powders generates several byproducts, including varying amounts of virgin microparticles, nanoparticles, spatter, and volatile chemicals that are emitted in the working environment; throughout the production and processing phases. The micro and nanoscale size may enable particles to interact with and to cross biological barriers, which could, in turn, give rise to unexpected adverse outcomes, including inflammation, oxidative stress, activation of signaling pathways, genotoxicity, and carcinogenicity. Another important aspect of AM-associated risks is emission/leakage of mono- and oligomers due to polymer breakdown and high temperature transformation of chemicals from polymeric particles, both during production, use, and in vivo, including in target cells. These chemicals are potential inducers of direct toxicity, genotoxicity, and endocrine disruption. Nevertheless, understanding whether AM particle powders and their byproducts may exert adverse effects in humans is largely lacking and urges comprehensive safety assessment across the entire AM lifecycle-spanning from virgin and reused to airborne particles. Therefore, this review will detail: 1) brief overview of the AM feedstock powders, impact of reuse on particle physicochemical properties, main exposure pathways and protective measures in AM industry, 2) role of particle biological identity and key toxicological endpoints in the particle safety assessment, and 3) next-generation toxicology approaches in nanosafety for safety assessment in AM. Altogether, the proposed testing approach will enable a deeper understanding of existing and emerging particle and chemical safety challenges and provide a strategy for the development of cutting-edge methodologies for hazard identification and risk assessment in the AM industry.
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| 11. |
- Alijagic, Andi, 1992-, et al.
(författare)
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The triple exposure nexus of microplastic particles, plastic-associated chemicals, and environmental pollutants from a human health perspective
- 2024
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 188
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Forskningsöversikt (refereegranskat)abstract
- The presence of microplastics (MPs) is increasing at a dramatic rate globally, posing risks for exposure and subsequent potential adverse effects on human health. Apart from being physical objects, MP particles contain thousands of plastic-associated chemicals (i.e., monomers, chemical additives, and non-intentionally added substances) captured within the polymer matrix. These chemicals are often migrating from MPs and can be found in various environmental matrices and human food chains; increasing the risks for exposure and health effects. In addition to the physical and chemical attributes of MPs, plastic surfaces effectively bind exogenous chemicals, including environmental pollutants (e.g., heavy metals, persistent organic pollutants). Therefore, MPs can act as vectors of environmental pollution across air, drinking water, and food, further amplifying health risks posed by MP exposure. Critically, fragmentation of plastics in the environment increases the risk for interactions with cells, increases the presence of available surfaces to leach plastic-associated chemicals, and adsorb and transfer environmental pollutants. Hence, this review proposes the so-called triple exposure nexus approach to comprehensively map existing knowledge on interconnected health effects of MP particles, plastic-associated chemicals, and environmental pollutants. Based on the available data, there is a large knowledge gap in regard to the interactions and cumulative health effects of the triple exposure nexus. Each component of the triple nexus is known to induce genotoxicity, inflammation, and endocrine disruption, but knowledge about long-term and inter-individual health effects is lacking. Furthermore, MPs are not readily excreted from organisms after ingestion and they have been found accumulated in human blood, cardiac tissue, placenta, etc. Even though the number of studies on MPs-associated health impacts is increasing rapidly, this review underscores that there is a pressing necessity to achieve an integrated assessment of MPs’ effects on human health in order to address existing and future knowledge gaps.
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| 12. |
- Andersson, Lena, 1965-, et al.
(författare)
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Inflammatory and coagulatory markers and exposure to different size fractions of particle mass, number and surface area air concentrations in the Swedish hard metal industry, in particular to cobalt
- 2021
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Ingår i: Biomarkers. - : Taylor & Francis. - 1354-750X .- 1366-5804. ; 26:6, s. 557-569
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To study the relationship between inhalation of airborne particles and cobalt in the Swedish hard metal industry and markers of inflammation and coagulation in blood.Methods: Personal sampling of inhalable cobalt and dust were performed for subjects in two Swedish hard metal plants. Stationary measurements were used to study concentrations of inhalable, respirable, and total dust and cobalt, PM10 and PM2.5, the particle surface area and the particle number concentrations. The inflammatory markers CC16, TNF, IL-6, IL-8, IL-10, SAA and CRP, and the coagulatory markers FVIII, vWF, fibrinogen, PAI-1 and D-dimer were measured. A complete sampling was performed on the second or third day of a working week following a work-free weekend, and additional sampling was taken on the fourth or fifth day. The mixed model analysis was used, including covariates.Results: The average air concentration of inhalable dust and cobalt were 0.11 mg/m3 and 0.003 mg/m3, respectively. For some mass-based exposure measures of cobalt and total dust, statistically significant increased levels of FVIII, vWF and CC16 were found.Conclusions: The observed relationships between particle exposure and coagulatory biomarkers may indicate an increased risk of cardiovascular disease.
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| 13. |
- Andersson, Lena, 1965-, et al.
(författare)
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Respiratory health and inflammatory markers : Exposure to respirable dust and quartz and chemical binders in Swedish iron foundries
- 2019
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Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To study the relationship between respirable dust, quartz and chemical binders in Swedish iron foundries and respiratory symptoms, lung function (as forced expiratory volume FEV1 and vital capacity FVC), fraction of exhaled nitric oxide (FENO) and levels of club cell secretory protein 16 (CC16) and CRP.METHODS: Personal sampling of respirable dust and quartz was performed for 85 subjects in three Swedish iron foundries. Full shift sampling and examination were performed on the second or third day of a working week after a work free weekend, with additional sampling on the fourth or fifth day. Logistic, linear and mixed model analyses were performed including, gender, age, smoking, infections, sampling day, body mass index (BMI) and chemical binders as covariates.RESULTS: The adjusted average respirable quartz and dust concentrations were 0.038 and 0.66 mg/m3, respectively. Statistically significant increases in levels of CC16 were associated with exposure to chemical binders (p = 0.05; p = 0.01) in the regression analysis of quartz and respirable dust, respectively. Non-significant exposure-responses were identified for cumulative quartz and the symptoms asthma and breathlessness. For cumulative chemical years, non-significant exposure-response were observed for all but two symptoms. FENO also exhibited a non significant exposure-response for both quartz and respirable dust. No exposure-response was determined for FEV1 or FVC, CRP and respirable dust and quartz.CONCLUSIONS: Our findings suggest that early markers of pulmonary effect, such as increased levels of CC16 and FENO, are more strongly associated with chemical binder exposure than respirable quartz and dust in foundry environments.
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| 14. |
- Andersson, Lena, 1965-, et al.
(författare)
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Silica Exposure and Cardiovascular, Cerebrovascular, and Respiratory Morbidity in a Cohort of Male Swedish Iron Foundry Workers
- 2023
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Ingår i: Journal of Occupational and Environmental Medicine. - : Lippincott Williams & Wilkins. - 1076-2752 .- 1536-5948. ; 65:9, s. 731-739
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we present quantitative exposure-response data on silica exposure in male Swedish iron foundry workers receiving inpatient care for cardiovascular, cerebrovascular, and respiratory morbidity. The study show a significantly increased COPD risk at cumulative silica exposures that correspond to TWA silica below the Swedish OEL of 0.1 mg/m3. ObjectiveWe present quantitative exposure-response data on silica exposure in male Swedish iron foundry workers for cardiovascular, cerebrovascular, and respiratory morbidity.MethodsThis research is a cohort study of 2063 male Swedish iron foundry workers. From the Swedish National Patient Registers, data on morbidity incidence were retrieved. A historical measurement database of 1667 respirable silica exposure measurements from 10 Swedish iron foundries was used to calculate the cumulative exposure dose for each worker.ResultsIncreased morbidity risk for the whole group of foundry workers was determined for ischemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), bronchitis, and pneumonia. In addition, an increased risk for COPD at cumulative silica exposures ranging from 0.11 to 0.84 mg/m3 year is presented.ConclusionsThe study presents a significantly increased COPD risk at cumulative silica exposures below the Swedish occupational exposure limit.
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| 15. |
- Asfaw Idosa, Berhane, 1977-, et al.
(författare)
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C10X polymorphism in the CARD8 gene is associated with bacteraemia
- 2014
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Ingår i: Immunity, inflammation and disease. - West Sussex, UK : John Wiley & Sons. - 2050-4527. ; 2:1, s. 13-20
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Tidskriftsartikel (refereegranskat)abstract
- The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase-1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection. Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures. The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in either group of patients. Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.
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| 16. |
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| 17. |
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| 18. |
- Asfaw Idosa, Berhane, PhD, 1977-, et al.
(författare)
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Neisseria meningitidis-Induced Caspase-1 Activation in Human Innate Immune Cells Is LOS-Dependent
- 2019
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Ingår i: Journal of Immunology Research. - : Hindawi Publishing Corporation. - 2314-8861 .- 2314-7156.
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Tidskriftsartikel (refereegranskat)abstract
- Meningococcal disease such as sepsis and meningitidis is hallmarked by an excessive inflammatory response. The causative agent, Neisseria meningitidis, expresses the endotoxin lipooligosaccharide (LOS) that is responsible for activation of immune cells and the release of proinflammatory cytokines. One of the most potent proinflammatory cytokines, interleukin-1 (IL-1), is activated following caspase-1 activity in the intracellular multiprotein complex called inflammasome. Inflammasomes are activated by a number of microbial factors as well as danger molecules by a two-step mechanismpriming and licensing of inflammasome activationbut there are no data available regarding a role for inflammasome activation in meningococcal disease. The aim of this study was to investigate if N. meningitidis activates the inflammasome and, if so, the role of bacterial LOS in this activation. Cells were subjected to N. meningitidis, both wild-type (FAM20) and its LOS-deficient mutant (lpxA), and priming as well as licensing of inflammasome activation was investigated. The wild-type LOS-expressing parental FAM20 serogroup C N. meningitidis (FAM20) strain significantly enhanced the caspase-1 activity in human neutrophils and monocytes, whereas lpxA was unable to induce caspase-1 activity as well as to induce IL-1 release. While the lpxA mutant induced a priming response, measured as increased expression of NLRP3 and IL1B, the LOS-expressing FAM20 further increased this priming. We conclude that although non-LOS components of N. meningitidis contribute to the priming of the inflammasome activity, LOS per se is to be considered as the central component of N. meningitidis virulence, responsible for both priming and licensing of inflammasome activation.
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| 19. |
- Baban, Bayar, 1973-, et al.
(författare)
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Altered insulin sensitivity and immune function in patients with colorectal cancer
- 2023
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Ingår i: Clinical Nutrition ESPEN. - : Elsevier. - 2405-4577. ; 58, s. 193-200
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Tidskriftsartikel (refereegranskat)abstract
- Background & aims: Insulin resistance and chronic inflammation have been reported in patients with cancer. However, many of the underlying mechanisms and associations are yet to be unveiled. We examined both the level of insulin sensitivity and markers of inflammation in patients with colorectal cancer for comparison to controls.Methods: Clinical exploratory study of patients with colorectal cancer (n = 20) and matched controls (n = 10). Insulin sensitivity was quantified using the hyperinsulinemic normoglycemic clamp and blood samples were taken for quantification of several key, both intra- and extracellular, inflammatory markers. We analysed the differences in these parameters between the two groups.Results: Patients exhibited both insulin resistance (M-value, patients median (Mdn) 4.57 interquartile range (IQR) 3.49-5.75; controls Mdn 5.79 (IQR 5.20-6.81), p = 0.049), as well as increased plasma levels of the pro-inflammatory cytokines IL-1b(patients Mdn 0.48 (IQR 0.33-0.58); controls Mdn 0.36 (IQR 0.29-0.42), p = 0.02) and IL-6 (patients Mdn 3.21 (IQR 2.31-4.93); controls Mdn 2.16 (IQR 1.50-2.65), p = 0.02). The latter is present despite an almost two to three fold decrease (p < 0.01) in caspase-1 activity, a facilitating enzyme of IL-1b production, within circulating immune cells.Conclusion: Patients with colorectal cancer displayed insulin resistance and higher levels of plasma IL-1b and IL-6, in comparison to matched healthy controls. The finding of a seemingly disconnect between inflammasome (caspase-1) activity and plasma levels of key pro-inflammatory cytokines in cancer patients may suggest that, in parallel to dysregulated immune cells, tumour-driven inflammatory pathways also are in effect.
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| 20. |
- Baban, Bayar, 1973-
(författare)
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Colorectal cancer and surgery : Insights into insulin resistance and inflammatory markers
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The art of surgery has progressively extended from the realm of anatomy to encompass physiology and beyond, in search of further refinement and optimal recovery. Integral to this is a deeper understanding of the body’s essential metabolic and inflammatory responses to surgical trauma.This thesis aims to provide insights into the intricate interplay between insulin resistance, inflammation and surgical interventions in colorectal cancer patients, as each has an influence on postoperative recovery. Particular emphasis is placed on the role of inflammasomes – central mediators of the innate immune response, adept at detecting and responding to a diverse range of triggers, yet insufficiently explored in these specific contexts.Study I is a comparative analysis of the hyperinsulinemic–euglycaemic clamp and homeostatic model assessment (HOMA) in determining postoperative insulin resistance in 113 patients undergoing various elective surgeries. The findings establish the clamp as the accurate method, detecting key physiological distinctions missed by HOMA.Study II, an exploratory case–control study, assesses insulin sensitivity and inflammatory markers in 20 colorectal cancer patients compared to 10 matched healthy controls. Results indicate insulin resistance, reduced inflammasome activity in circulating immune cells and elevated systemic IL-1β and IL-6 levels in patients.Study III, a pilot exploratory study of 17 patients from Study II, assesses the impact of surgical technique, open versus minimally invasive surgery, on postoperative insulin resistance and inflammation in colorectal cancer resections. It indicates a differential inflammatory response with higher levels in open surgeries, yet a consistent degree of insulin resistance across both surgical techniques.Study IV explores the perioperative temporal sequencing of inflammation and inflammasome action in 18 patients from Study II undergoing elective colorectal cancer resections. It points to a more immediate and pronounced inflammatory response in open surgery compared to minimally invasive surgery, though both techniques show reduced intraoperative caspase-1 activity.In conclusion, the hyperinsulinemic euglycaemic clamp is the accurate method in determinations of postoperative insulin resistance. Patients with colorectal cancer, in comparison to matched healthy controls, exhibit insulin resistance and higher levels of inflammation, but decreased inflammasome (caspase-1) activity in circulating immune cells. Finally, colorectal cancer resections induce both insulin resistance and inflammation; however, the surgical technique utilized only significantly affects the latter, with generally higher inflammatory / inflammasome responses in open surgery.
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| 21. |
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| 22. |
- Baban, Bayar, 1973-, et al.
(författare)
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Inflammasome activation, colonic cancer and glucose metabolism
- 2016
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Ingår i: Clinical Nutrition ESPEN. - : Elsevier. - 2405-4577. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To study the association between inflammasome activation (a potent initiator of inflammation acting via caspase-1 and maturation of interleukin-1β), colonic cancer and glucose metabolism.Methods: Five patients with colon cancer and ten matched controls without cancer were measured for insulin sensitivity using the hyperinsulinemic euglycemic clamp. For detection of inflammasome activation the caspase-1 activity, determined by detecting FLICA using flow cytometry, was measured in both monocytes and granulocytes at the start of, and at 120 minutes into the clamp. Descriptive and analytical statistics were performed using nonparametric methods by SPSS.Results: There was no difference in levels of insulin sensitivity between the two groups (p=0.09). The cancer patients had significantly lower levels of caspase-1 both in monocytes (p<0.05) and granulocytes (p<0.05) compared with the controls. However both patients and controls had significantly higher levels of both mono- and granulocyte caspase-1 activity at 120 minutes into the clamp as compared to at start (p<0.05). Patients showed an overall higher relative increase in caspase-1 during the clamp, however this finding did not reach statistical significance (monocytes; p=0.27, granulocytes; p=0.22).
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| 23. |
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| 24. |
- Bergström, Ida, et al.
(författare)
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Annexin A1 in blood mononuclear cells from patients with coronary artery disease : Its association with inflammatory status and glucocorticoid sensitivity
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of glucocorticoid actions. In atherosclerotic tissue, increased expression of AnxA1 has been associated with protective plaque-stabilizing effects. Here, we investigated the expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Blood was collected from 57 patients with stable CAD (SCAD) and 41 healthy controls. We also included a minor group (n = 10) with acute coronary syndrome (ACS). AnxA1 mRNA was measured in PBMCs. Expression of AnxA1 protein (total and surface-bound) and glucocorticoid receptors (GR) were detected in PBMC subsets by flow cytometry. Also, salivary cortisol, interleukin(IL)-6 and IL-10 in plasma, and LPS-induced cytokine secretion from PBMCs, with or without dexamethasone, were assessed. AnxA1 mRNA was found to be slightly increased in PBMCs from SCAD patients compared with controls. However, protein expression of AnxA1 or GRs in PBMC subsets did not differ between SCAD patients and controls, despite SCAD patients showing a more proinflammatory cytokine profile ex vivo. Only surface expression of AnxA1 on monocytes correlated with dexamethasone-mediated suppression of cytokines. In ACS patients, a marked activation of AnxA1 was seen involving both gene expression and translocation of protein to cell surface probably reflecting a rapid glucocorticoid action modulating the acute inflammatory response in ACS. To conclude, surface expression of AnxA1 on monocytes may reflect the degree of glucocorticoid sensitivity. Speculatively, "normal" surface expression of AnxA1 indicates that anti-inflammatory capacity is impaired in SCAD patients.
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- Blomgran, Robert, et al.
(författare)
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Common Genetic Variations in the NALP3 Inflammasome Are Associated with Delayed Apoptosis of Human Neutrophils
- 2012
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Ingår i: PLOS ONE. - San Francisco, USA : Public Library of Science. - 1932-6203. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neutrophils are key-players in the innate host defense and their programmed cell death and removal are essential for efficient resolution of inflammation. These cells recognize a variety of pathogens, and the NOD-like receptors (NLRs) have been suggested as intracellular sensors of microbial components and cell injury/stress. Some NLR will upon activation form multi-protein complexes termed inflammasomes that result in IL-1 beta production. NLR mutations are associated with auto-inflammatory syndromes, and our previous data propose NLRP3 (Q705K)/CARD-8 (C10X) polymorphisms to contribute to increased risk and severity of inflammatory disease by acting as genetic susceptibility factors. These gene products are components of the NALP3 inflammasome, and approximately 6.5% of the Swedish population are heterozygote carriers of these combined gene variants. Since patients carrying the Q705K/C10X polymorphisms display leukocytosis, the aim of the present study was to find out whether the inflammatory phenotype was related to dysfunctional apoptosis and impaired clearance of neutrophils by macrophages. less thanbrgreater than less thanbrgreater thanMethods and Findings: Patients carrying the Q705K/C10X polymorphisms displayed significantly delayed spontaneous as well as microbe-induced apoptosis compared to matched controls. Western blotting revealed increased levels and phosphorylation of Akt and Mcl-1 in the patients neutrophils. In contrast to macrophages from healthy controls, macrophages from the patients produced lower amounts of TNF; suggesting impaired macrophage clearance response. less thanbrgreater than less thanbrgreater thanConclusions: The Q705K/C10X polymorphisms are associated with delayed apoptosis of neutrophils. These findings are explained by altered involvement of different regulators of apoptosis, resulting in an anti-apoptotic profile. Moreover, the macrophage response to ingestion of microbe-induced apoptotic neutrophils is altered in the patients. Taken together, the patients display impaired turnover and clearance of apoptotic neutrophils, pointing towards a dysregulated innate immune response that influences the resolution of inflammation. The future challenge is to understand how microbes affect the activation of inflammasomes, and why this interaction will develop into severe inflammatory disease in certain individuals.
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