| 1. |
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| 2. |
- Andersson, Linnea, et al.
(author)
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Storage of Transfusion Platelet Concentrates is Associated with Complement Activation and Reduced Ability of Platelets to Respond to Protease-Activated Receptor-1 and Thromboxane A2 Receptor
- 2024
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:2
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Journal article (peer-reviewed)abstract
- Platelet activation and the complement system are mutually dependent. Here, we investigated the effects of storage time on complement activation and platelet function in routinely produced platelet concentrates. The platelet concentrates (n = 10) were stored at 22 degrees C for seven days and assessed daily for complement and platelet activation markers. Additionally, platelet function was analyzed in terms of their responsiveness to protease-activated receptor-1 (PAR-1) and thromboxane A2 receptor (TXA(2)R) activation and their capacity to adhere to collagen. Complement activation increased over the storage period for all analyzed markers, including the C1rs/C1-INH complex (fold change (FC) = 1.9; p < 0.001), MASP-1/C1-INH complex (FC = 2.0; p < 0.001), C4c (FC = 1.8, p < 0.001), C3bc (FC = 4.0; p < 0.01), and soluble C5b-9 (FC = 1.7, p < 0.001). Furthermore, the levels of soluble platelet activation markers increased in the concentrates over the seven-day period, including neutrophil-activating peptide-2 (FC = 2.5; p < 0.0001), transforming growth factor beta 1 (FC = 1.9; p < 0.001) and platelet factor 4 (FC = 2.1; p < 0.0001). The ability of platelets to respond to activation, as measured by surface expression of CD62P and CD63, decreased by 19% and 24% (p < 0.05) for PAR-1 and 69-72% (p < 0.05) for TXA(2)R activation, respectively, on Day 7 compared to Day 1. The extent of platelet binding to collagen was not significantly impaired during storage. In conclusion, we demonstrated that complement activation increased during the storage of platelets, and this correlated with increased platelet activation and a reduced ability of the platelets to respond to, primarily, TXA(2)R activation.
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| 3. |
- Baskaran, Karthikeyan, Senior Lecturer, 1983-, et al.
(author)
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Swedish version of the Massof activity inventory to measure vision-related activity difficulties among patients with nAMD
- 2024
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In: Acta Ophthalmol, vol 102, issue S279: Special Issue:Abstracts from the 2023 European Association for Vision and Eye Research Festival, 26‐28 October 2023, Valencia. - : John Wiley & Sons.
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Conference paper (peer-reviewed)abstract
- Aims/Purpose: The aim of this study was to assess vision-related activity difficulties among patients with neovascular AMD using a Swedish version of the mass of activity inventory (MAI). Methods: Participants were patients diagnosed with neovascular AMD receiving treatment for the disease in a hospital in southeast Sweden. Participants completed the Swedish version of the MAI questionnaire. MAI can be used to measure the overall visual ability and visual ability in 4 functional domains: reading, mobility, visual motor function and visual information processing. Best corrected distance and near visual acuity (VA) were also measured. Results: Among the 196 participants (mean age=78.5 years, SD=7.67, 66% female) the median VA in the better seeing eye was 0.18 logMAR (IQR=?0.34), and in the worse eye was 0.54 logMAR (IQR=0.98). The median visual ability for all participants was 1.92 logits (IQR=2.69). There was a significant negative correlation between distance VA in the better eye and visual ability (rho=0.4025, p<0.01). Using ROC curves, we tested the capacity of the MAI to detect cases of any vision impairment (VA worse than 0.3 logMAR in the better seeing eye), the area under the curve (AUC) was 0.717 (95% CI=0.643 - 0.791 p<0.001). When we tested for detection of moderate vision impairment (VA worse than 0.5 logMAR in the better seeing eye) the AUC was 0.738 (95% CI=0.648 - 0.829 p?<0.001). Conclusions: The results indicate that the Swedish version of the MAI produce measures of visual ability that are consistent with clinical measures among patients with nAMD. The Swedish version of the MAI can be used as outcome measure in interventions for people with nAMD.References1. Macedo, A.F. et al. Predictors of problems reported on the EQ-5D-3L dimensions among people with impaired vision in northern Portugal. Health Qual Life Outcomes 2022; 20: 132.
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| 4. |
- Biglarnia, Ali Reza, et al.
(author)
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The multifaceted role of complement in kidney transplantation
- 2018
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In: Nature Reviews Nephrology. - : Nature Publishing Group. - 1759-5061 .- 1759-507X. ; 14:12, s. 767-781
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Research review (peer-reviewed)abstract
- Increasing evidence indicates an integral role for the complement system in the deleterious inflammatory reactions that occur during critical phases of the transplantation process, such as brain or cardiac death of the donor, surgical trauma, organ preservation and ischaemia-reperfusion injury, as well as in humoral and cellular immune responses to the allograft. Ischaemia is the most common cause of complement activation in kidney transplantation and in combination with reperfusion is a major cause of inflammation and graft damage. Complement also has a prominent role in antibody-mediated rejection (ABMR) owing to ABO and HL A incompatibility, which leads to devastating damage to the transplanted kidney. Emerging drugs and treatment modalities that inhibit complement activation at various stages in the complement cascade are being developed to ameliorate the damage caused by complement activation in transplantation. These promising new therapies have various potential applications at different stages in the process of transplantation, including inhibiting the destructive effects of ischaemia and/or reperfusion injury, treating ABMR, inducing accommodation and modulating the adaptive immune response.
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| 5. |
- Demirel, Isak, 1987-, et al.
(author)
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Nitric oxide activates IL-6 production and expression in human renal epithelial cells
- 2012
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In: American Journal of Nephrology. - Basel, Switzerland : S. Karger. - 0250-8095 .- 1421-9670. ; 36:6, s. 524-530
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Journal article (peer-reviewed)abstract
- Background/Aims: Increased nitric oxide (NO) production or inducible form of NO synthase activity have been documented in patients suffering from urinary tract infection (UTI), but the role of NO in this infection is unclear. We investigated whether NO can affect the host response in human renal epithelial cells by modulating IL-6 production and mRNA expression. Methods: The human renal epithelial cell line A498 was infected with a uropathogenic Escherichia coli (UPEC) strain and/or the NO donor DETA/NO. The IL-6 production and mRNA expression were evaluated by ELISA and real-time RT-PCR. IL-6 mRNA stability was evaluated by analyzing mRNA degradation by real-time RT-PCR.Results: DETA/NO caused a significant (p < 0.05) increase in IL-6 production. Inhibitors of p38 MAPK and ERK1/2 signaling, but not JNK, were shown to significantly suppress DETA/NO-induced IL-6 production. UPEC-induced IL-6 production was further increased (by 73 ± 23%, p < 0.05) in the presence of DETA/NO. The IL-6 mRNA expression increased 2.1 ± 0.17-fold in response to DETA/NO, while the UPEC-evoked increase was pronounced (20 ± 4.5-fold). A synergistic effect of DETA/NO on UPEC-induced IL-6 expression was found (33 ± 7.2-fold increase). The IL-6 mRNA stability studies showed that DETA/NO partially attenuated UPEC-induced degradation of IL-6 mRNA.Conclusions: NO was found to stimulate IL-6 in renal epithelial cells through p38 MAPK and ERK1/2 signaling pathways and also to increase IL-6 mRNA stability in UPEC-infected cells. This study proposes a new role for NO in the host response during UTI by modulating the transcription and production of the cytokine IL-6.
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| 6. |
- Englund Johansson, Ulrica, et al.
(author)
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Human neural progenitor cells promote photoreceptor survival in retinal explants
- 2010
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In: Experimental Eye Research. - : Elsevier BV. - 0014-4835 .- 1096-0007. ; 90:2, s. 292-299
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Journal article (peer-reviewed)abstract
- Different types of progenitor and stem cells have been shown to provide neuroprotection in animal models of photoreceptor degeneration. The present study was conducted to investigate whether human neural progenitor cells (HNPCs) have neuroprotective properties on retinal explants models with calpain- and caspase-3-dependent photoreceptor cell death. In the first experiments, HNPCs in a feeder layer were co-cultured for 6 days either with postnatal rd1 mouse or normal rat retinas. Retinal histological sections were used to determine outer nuclear layer (ONL) thickness, and to detect the number of photoreceptors with labeling for calpain activity, cleaved caspase-3 and TUNEL The ONL thickness of co-cultured rat and rd1 retinas was found to be almost 10% and 40% thicker, respectively, compared to controls. Cell counts of calpain activity, cleaved caspase-3 and TUNEL labeled photoreceptors in both models revealed a 30-50% decrease when co-cultured with HNPCs. The results represent significant increases of photoreceptor survival in the co-cultured retinas. In the second experiments, for an identification of putative survival factors, or a combination of them, a growth factor profile was performed on conditioned medium. The relative levels of various growth factors were analyzed by densitometric measurements of growth factor array membranes. Following growth factors were identified as most potential survival factors: granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GMCSF), insulin-like growth factor 11 (IGF-II), neurotrophic factor 3 (NT-3), placental growth factor (PIGF), transforming growth factors (TGF-beta 1 and TGF-beta 2) and vascular endothelial growth factor (VEGF-D). HNPCs protect both against calpain- and caspase-3-dependent photoreceptor cell death in the rd1 mouse and against caspase-3-dependent photoreceptor cell death in normal rat retinas in vitro. The protective effect is possibly achieved by a variety of growth factors secreted from the HNPCs. (C) 2009 Elsevier Ltd. All rights reserved.
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| 7. |
- Eriksson, Oskar, 1984-, et al.
(author)
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The Human Platelet as an Innate Immune Cell : Interactions Between Activated Platelets and the Complement System
- 2019
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In: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 10, s. 1-16
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Research review (peer-reviewed)abstract
- Platelets play an essential role in maintaining homeostasis in the circulatory system after an injury by forming a platelet thrombus, but they also occupy a central node in the intravascular innate immune system. This concept is supported by their extensive interactions with immune cells and the cascade systems of the blood. In this review we discuss the close relationship between platelets and the complement system and the role of these interactions during thromboinflammation. Platelets are protected from complement-mediated damage by soluble and membrane-expressed complement regulators, but they bind several complement components on their surfaces and trigger complement activation in the fluid phase. Furthermore, localized complement activation may enhance the procoagulant responses of platelets through the generation of procoagulant microparticles by insertion of sublytic amounts of C5b9 into the platelet membrane. We also highlight the role of post-translational protein modifications in regulating the complement system and the critical role of platelets in driving these reactions. In particular, modification of disulfide bonds by thiol isomerases and protein phosphorylation by extracellular kinases have emerged as important mechanisms to fine-tune complement activity in the platelet microenvironment. Lastly, we describe disorders with perturbed complement activation where part of the clinical presentation includes uncontrolled platelet activation that results in thrombocytopenia, and illustrate how complement-targeting drugs are alleviating the prothrombotic phenotype in these patients. Based on these clinical observations, we discuss the role of limited complement activation in enhancing platelet activation and consider how these drugs may provide opportunities for further dissecting the complex interactions between complement and platelets.
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| 8. |
- Gerogianni, Alexandra, et al.
(author)
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Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation
- 2022
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In: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 13
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Journal article (peer-reviewed)abstract
- Hemolysis, as a result of disease or exposure to biomaterials, is characterized by excess amounts of cell-free heme intravascularly and consumption of the protective heme-scavenger proteins in plasma. The liberation of heme has been linked to the activation of inflammatory systems, including the complement system, through alternative pathway activation. Here, we investigated the impact of heme on the regulatory function of the complement system. Heme dose-dependently inhibited factor I-mediated degradation of soluble and surface-bound C3b, when incubated in plasma or buffer with complement regulatory proteins. Inhibition occurred with factor H and soluble complement receptor 1 as co-factors, and the mechanism was linked to the direct heme-interaction with factor I. The heme-scavenger protein hemopexin was the main contaminant in purified factor I preparations. This led us to identify that hemopexin formed a complex with factor I in normal human plasma. These complexes were significantly reduced during acute vasoocclusive pain crisis in patients with sickle cell disease, but the complexes were normalized at their baseline outpatient clinic visit. Hemopexin exposed a protective function of factor I activity in vitro, but only when it was present before the addition of heme. In conclusion, we present a mechanistic explanation of how heme promotes uncontrolled complement alternative pathway amplification by interfering with the regulatory capacity of factor I. Reduced levels of hemopexin and hemopexin-factor I complexes during an acute hemolytic crisis is a risk factor for heme-mediated factor I inhibition.
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| 9. |
- Gerogianni, Alexandra, et al.
(author)
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In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model
- 2023
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In: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
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Journal article (peer-reviewed)abstract
- Iron oxide nanoparticles (IONPs) are widely used in diagnostic and therapeutic settings. Upon systemic administration, however, they are rapidly recognized by components of innate immunity, which limit their therapeutic capacity and can potentially lead to adverse side effects. IONPs were previously found to induce the inflammatory response in human whole blood, including activation of the complement system and increased secretion of cytokines. Here, we investigated the thromboinflammatory response of 10-30 nm IONPs in lepirudin anticoagulated whole blood in interplay with endothelial cells and evaluated the therapeutic effect of applying complement inhibitors to limit adverse effects related to thromboinflammation. We found that IONPs induced complement activation, primarily at the C3-level, in whole blood incubated for up to four hours at 37°C with and without human microvascular endothelial cells. Furthermore, IONPs mediated a strong thromboinflammatory response, as seen by the significantly increased release of 21 of the 27 analyzed cytokines (p<0.05). IONPs also significantly increased cell-activation markers of endothelial cells [ICAM-1 (p<0.0001), P/E-selectin (p<0.05)], monocytes, and granulocytes [CD11b (p<0.001)], and platelets [CD62P (p<0.05), CD63 (p<0.05), NAP-2 (p<0.01), PF4 (p<0.05)], and showed cytotoxic effects, as seen by increased LDH (p<0.001) and heme (p<0.0001) levels. We found that inflammation and endothelial cell activation were partly complement-dependent and inhibition of complement at the level of C3 by compstatin Cp40 significantly attenuated expression of ICAM-1 (p<0.01) and selectins (p<0.05). We show that complement activation plays an important role in the IONPs-induced thromboinflammatory response and that complement inhibition is promising in improving IONPs biocompatibility.
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| 10. |
- Gerogianni, Alexandra, 1993-
(author)
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The role of the thromboinflammatory response under hemolytic conditions : pathophysiological mechanisms and therapeutic inhibition
- 2023
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Doctoral thesis (other academic/artistic)abstract
- In blood circulation, the complement and the coagulation cascades, together with platelets and endothelial cells form a complex network of crosstalk. When dysregulated, these interactions can lead to inflammation in combination with thrombosis (thromboinflammation) and the manifestation of pathophysiological complications. As complement activation and thromboinflammation are often associated with intravascular hemolysis, e.g., sickle cell disease (SCD), we aimed to study these reactions in relation to heme, a product of hemolysis. Furthermore, our goal was to evaluate whether exposure to biomaterials results in hemolysis-induced thromboinflammation, and to examine the potential of complement inhibition.Our findings show that heme could lead to a significant thromboinflammatory response in our in vitro whole blood model, as seen by complement-, cell- and coagulation- activation, as well as increased cytokine secretion. Inflammation, including complement activation, was also linked with increased heme concentrations in vivo in hemolytic disease in SCD patients. The mechanism of action was attributed to uncontrolled alternative pathway (AP) activation, as heme was shown to bind and inhibit the main AP regulator, factor I, resulting in increased concentrations of fluid phase and surface-bound C3b.Moreover, administration of iron oxide nanoparticles (IONPs) in vitro and implantation of left ventricular assist device (LVAD) in vivo were monitored and correlated with increased hemolytic, e.g., heme, and thromboinflammatory markers, e.g., complement-, endothelial cell- and platelet- activation. Targeting complement components C5 and C3 in vitro was shown overall beneficial in the presence of heme or IONPs respectively. In our settings, the majority of the thromboinflammatory markers measured were successfully attenuated, indicating that complement fuels this response.In conclusion, the results in this thesis stress that heme-induced complement activation is an important player in thromboinflammation. In addition, we propose that complement inhibition can be used as a therapeutic approach in hemolytic conditions and as a strategy to enhance biomaterials’ biocompatibility.
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