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  • 1.
    Ali, Neserin
    et al.
    Lund Univ, Sweden.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Wierzbicka, Aneta
    Lund Univ, Sweden.
    Pagels, Joakim
    Lund Univ, Sweden.
    Isaxon, Christina
    Lund Univ, Sweden.
    Gudmundsson, Anders
    Lund Univ, Sweden.
    Rissler, Jenny
    Lund Univ, Sweden.
    Nielsen, Jorn
    Lund Univ, Sweden.
    Lindh, Christian H.
    Lund Univ, Sweden.
    Karedal, Monica
    Lund Univ, Sweden.
    Comprehensive proteome analysis of nasal lavage samples after controlled exposure to welding nanoparticles shows an induced acute phase and a nuclear receptor, LXR/RXR, activation that influence the status of the extracellular matrix2018In: Clinical Proteomics, ISSN 1542-6416, E-ISSN 1559-0275, Vol. 15, article id 20Article in journal (Refereed)
    Abstract [en]

    Background: Epidemiological studies have shown that many welders experience respiratory symptoms. During the welding process a large number of airborne nanosized particles are generated, which might be inhaled and deposited in the respiratory tract. Knowledge of the underlying mechanisms behind observed symptoms is still partly lacking, although inflammation is suggested to play a central role. The aim of this study was to investigate the effects of welding fume particle exposure on the proteome expression level in welders suffering from respiratory symptoms, and changes in protein mediators in nasal lavage samples were analyzed. Such mediators will be helpful to clarify the pathomechanisms behind welding fume particle-induced effects. Methods: In an exposure chamber, 11 welders with work-related symptoms in the lower airways during the last month were exposed to mild-steel welding fume particles (1 mg/m(3)) and to filtered air, respectively, in a double-blind manner. Nasal lavage samples were collected before, immediately after, and the day after exposure. The proteins in the nasal lavage were analyzed with two different mass spectrometry approaches, label-free discovery shotgun LC-MS/MS and a targeted selected reaction monitoring LC-MS/MS analyzing 130 proteins and four in vivo peptide degradation products. Results: The analysis revealed 30 significantly changed proteins that were associated with two main pathways; activation of acute phase response signaling and activation of LXR/RXR, which is a nuclear receptor family involved in lipid signaling. Connective tissue proteins and proteins controlling the degradation of such tissues, including two different matrix metalloprotease proteins, MMP8 and MMP9, were among the significantly changed enzymes and were identified as important key players in the pathways. Conclusion: Exposure to mild-steel welding fume particles causes measurable changes on the proteome level in nasal lavage matrix in exposed welders, although no clinical symptoms were manifested. The results suggested that the exposure causes an immediate effect on the proteome level involving acute phase proteins and mediators regulating lipid signaling Proteases involved in maintaining the balance between the formation and degradation of extracellular matrix proteins are important key proteins in the induced effects.

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  • 2.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Exosomes in specific fractions of the boar ejaculate contain CD44: A marker for epididymosomes?2019In: Theriogenology, ISSN 0093-691X, E-ISSN 1879-3231, Vol. 140, p. 143-152Article in journal (Refereed)
    Abstract [en]

    Seminal plasma (SP) is a complex fluid containing proteins, peptides, enzymes, hormones as well as extracellular vesicles (EVs). The SP interacts with spermatozoa and the inner cell lining of the female genital tract, adsorbing proteins and exosomes that modulate sperm functions and female immune responsiveness. In the present study, boar sperm-free SP was studied using flow cytometry (FC) after membrane tetraspanins (CD9, CD63 and CD81) and membrane receptor CD44 marking of non-enriched (whole SP) or gradient fractions enriched through two-step discontinuous KBr-density-gradient ultracentrifugation, in whole ejaculate or in selected ejaculate fractions. The results, evaluated by transmission electron microscopy, confirmed the presence of exosomes in all fractions of the pig SP. Noteworthy, these pig SP-exosomes were CD44-bearing when analysed by FC, with bands detected by western blotting (WB) at the expected 85 kD size. The two-step discontinuous KBr-density-gradient ultracentrifugation enriched the population of exosomes in two specific gradient fractions, indicating exosomes (either prostasomes or epididymosomes) could be separated from low-density lipoprotein (LDL) but they co-sediment with the high-density lipoprotein (HDL)-bearing fraction. The findings pave for the selective isolation of exosomes in functional studies of their function when interacting with spermatozoa, the oocyte and/or the female genitalia, including hyaluronan-CD44 interplay. (C) 2019 Elsevier Inc. All rights reserved.

    The full text will be freely available from 2020-08-21 10:23
  • 3.
    Helmfrid, Ingela
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Nosratabadi, Ali Reza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Augustsson, Anna
    Linnaeus University, Kalmar, Sweden.
    Filipsson, Monika
    Linnaeus University, Kalmar, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Berglund, Marika
    Karolinska Institutet, Stockholm, Sweden.
    Exposure of metals and PAH through local foods and risk of cancer in a historically contaminated glasswork area2019In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 131, article id UNSP 104985Article in journal (Refereed)
    Abstract [en]

    Background

    Production of crystal glass and colored art glassware have been going on in the south-eastern part of Sweden since the 1700s, at over 100 glassworks and smaller glass blowing facilities, resulting in environmental contamination with mainly arsenic (As), cadmium (Cd), lead (Pb) and polycyclic hydrocarbons (PAH). High levels of metals have been found in soil, and moderately elevated levels in vegetables, mushrooms and berries collected around the glassworks sites compared with reference areas. Food in general, is the major exposure source to metals, such as Cd and Pb, and PAHs. Exposure to these toxic metals and PAH has been associated with a variety of adverse health effects in humans including cancer.

    Objective

    The aim of the present study was to evaluate the occurrence of cancer in a cohort from the contaminated glasswork area in relation to long-term dietary intake of locally produced foods, while taking into account residential, occupational and life styles factors.

    Methods

    The study population was extracted from a population cohort of 34,266 individuals who, at some time between the years 1979–2004, lived within a 2 km radius of a glassworks or glass landfill. Register information on cancer incidence and questionnaire information on consumption of local foods (reflecting 30 years general eating habits), life-time residence in the area, life style factors and occupational exposure was collected. Furthermore, blood (n = 660) and urine (n = 400) samples were collected in a subsample of the population to explore associations between local food consumption frequencies, biomarker concentrations in blood (Cd, Pb, As) and urine (PAH metabolite 1-OHPy) as well as environmental and lifestyle factors. The concurrent exposure to persistent organic pollutants (POPs) from food was also considered. A case-control study was performed for evaluation of associations between intakes of local food and risk of cancer.

    Results

    Despite high environmental levels of Cd, Pb and As at glasswork sites and landfills, current metal exposure in the population living in the surrounding areas was similar or only moderately higher in our study population compared to the general population. Reported high consumption of certain local foods was associated with higher Cd and Pb, but not As, concentrations in blood, and 1-OHPy in urine. An increased risk of cancer was associated with smoking, family history of cancer, obesity, and residence in glasswork area before age 5 years. Also, a long-term high consumption of local foods (reflecting 30 years general eating habits), i.e. fish and meat (game, chicken, lamb), was associated with increased risk of various cancer forms.

    Conclusions

    The associations between consumption of local food and different types of cancer may reflect a higher contaminant exposure in the past, and thus, if consumption of local food contributes to the risk of acquiring cancer, that contribution is probably lower today than before. Furthermore, it cannot be ruled out that other contaminants in the food contribute to the increased cancer risks observed.

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  • 4.
    Holleboom, Adriaan G
    et al.
    Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Occupational and Environmental Medicine Centre.
    Lin, Ruei-Shiuan
    Section on Biological Chemistry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
    Beres, Thomas M
    Section on Biological Chemistry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
    Sierts, Jeroen A
    Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Herman, Daniel S
    Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
    Stroes, Erik S G
    Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Aerts, Johannes M
    Department of Medical Biochemistry, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Kastelein, John J P
    Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Motazacker, Mohammad M
    Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Dallinga-Thie, Geesje M
    Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Levels, Johannes H M
    Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Zwinderman, Aeilko H
    Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Seidman, Jonathan G
    Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
    Seidman, Christine E
    Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Lefeber, Dirk J
    Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen 6525GA, The Netherlands.
    Morava, Eva
    Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, Nijmegen 6525GA, The Netherlands.
    Wevers, Ron A
    Department of Laboratory Medicine, Radboud University Nijmegen Medical Center, Nijmegen 6525GA, The Netherlands.
    Fritz, Timothy A
    Food and Drug Administration, Rockville, MD 20852, USA.
    Tabak, Lawrence A
    Section on Biological Chemistry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
    Lindahl, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Hovingh, G Kees
    Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Kuivenhoven, Jan Albert
    Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
    Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man2011In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 14, no 6, p. 811-8Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.

  • 5.
    Karlsson, Helen
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Work and Environmental Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ahrén, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Lindahl, Mats
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ljungman, Anders
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Two-dimensional gel electrophoresis and mass spectrometry in studies of nanoparticle-protein interactions2012In: Gel electrophoresis-Advanced Techniques / [ed] Sameh Magdeldin, Rijeka, Croatia: In Tech , 2012, p. 1-32Chapter in book (Other academic)
    Abstract [en]

    Over the years a number of epidemiological studies have shown that PM from combustion sources such as motor vehicles contributes to respiratory and cardiovascular morbidity and mortality.Especially so do the ultra-fine particles (UFPs) with a diameter less than 0.1 micrometer.UFPs from combustion engines are capable to translocate over the alveolar–capillary barrier.  When nano-sized PM (nanoparticles, NP), which are small enough to enter the blood stream, do so they are likely to interact with plasma proteins and this protein-NP interaction will probably affect the fate of and the effects caused by the NPs in the human body. Here, by using a proteomic approach, we present results showing that several proteins indeed are associated to NPs that have in vitro been introduced to human blood plasma.

  • 6.
    Kjellmo, Christian Abendstein
    et al.
    Nordland Hosp, Norway; Univ Tromso, Norway.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Nestvold, Torunn K.
    Nordland Hosp, Norway.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Cederbrant, Karin
    Swedish Toxicol Sci Res Ctr, Sweden.
    Marcusson-Stahl, Maritha
    Swedish Toxicol Sci Res Ctr, Sweden.
    Mathisen, Monica
    Nordland Hosp, Norway.
    Lappegard, Knut Tore
    Nordland Hosp, Norway; Univ Tromso, Norway.
    Hovland, Anders
    Nordland Hosp, Norway; Univ Tromso, Norway.
    Bariatric surgery improves lipoprotein profile in morbidly obese patients by reducing LDL cholesterol, apoB, and SAA/PON1 ratio, increasing HDL cholesterol, but has no effect on cholesterol efflux capacity2018In: Journal of Clinical Lipidology, ISSN 1933-2874, E-ISSN 1876-4789, Vol. 12, no 1, p. 193-202Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bariatric surgery has been shown to reduce cardiovascular events and cause specific mortality for coronary artery disease in obese patients. Lipoprotein biomarkers relating to low-density lipoprotein (LDL), high-density lipoprotein (HDL), their subfractions, and macrophage cholesterol efflux have all been hypothesized to be of value in cardiovascular risk assessment. OBJECTIVES: The objective of this study was to examine the effect of a lifestyle intervention followed by bariatric surgery on the lipid profile of morbidly obese patients. METHODS: Thirty-four morbidly obese patients were evaluated before and after lifestyle changes and then 1 year after bariatric surgery. They were compared with 17 lean subjects. Several lipoprotein metrics, serum amyloid A (SAA), serum paraoxonase-1 (PON1), and macrophage cholesterol efflux capacity (CEC) were assessed. RESULTS: Average weight loss after the lifestyle intervention was 10.5% and 1 year after bariatric surgery was 33.9%. The lifestyle intervention significantly decreased triglycerides (TGs; 28.7 mg/dL, P amp;lt; .05), LDL cholesterol (LDL-C; 32.3 mg/dL, P amp;lt; .0001), and apolipoprotein B (apoB; 62.9 mu g/mL, P amp;lt; .001). Bariatric surgery further reduced TGs (-36.7 mg/dL, P amp;lt; .05), increased HDL cholesterol (+12 mg/dL, P amp;lt; .0001), and reductions in LDL-C and apoB were sustained. Bariatric surgery reduced large, buoyant LDL (P amp;lt; .0001), but had no effect on the small, dense LDL.The large HDL subfractions increased (P amp;lt; .0001), but there was no effect on the smaller HDL sub fractions. The ratio for SAA/PON1 was reduced after the lifestyle intervention (P amp;lt; .01) and further reduced after bariatric surgery (P amp;lt; .0001). Neither the lifestyle intervention nor bariatric surgery had any effect on CEC. CONCLUSIONS: Lifestyle intervention followed by bariatric surgery in 34 morbidly obese patients showed favorable effects on TGs, LDL-C, and apoB. HDL cholesterol and apoA1 was increased, apoB/apoA1 ratio as well as SAA/PON1 ratio reduced, but bariatric surgery did not influence CEC. (C) 2017 National Lipid Association. All rights reserved.

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  • 7.
    Lappegård, Knut Tore
    et al.
    Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.
    Kjellmo, Christian Abendstein
    Division of Internal Medicine, Nordland Hospital, Bodø, Norway.
    Ljunggren, Stefan A
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Cederbrant, Karin
    Swedish Toxicology Sciences Research Center, Södertälje, Sweden.
    Marcusson-Ståhl, Maritha
    Swedish Toxicology Sciences Research Center, Södertälje, Sweden.
    Mathisen, Monica
    Research Laboratory, Nordland Hospital, Bodø, Norway.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Hovland, Anders
    Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.
    Lipoprotein apheresis affects lipoprotein particle subclasses more efficiently compared to the PCSK9 inhibitor evolocumab, a pilot study.2018In: Transfusion and apheresis science, ISSN 1473-0502, E-ISSN 1878-1683, Vol. 57, no 1, p. 91-96Article in journal (Refereed)
    Abstract [en]

    Lipoprotein apheresis and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are last therapeutic resorts in patients with familial hypercholesterolemia (FH). We explored changes in lipoprotein subclasses and high-density lipoprotein (HDL) function when changing treatment from lipoprotein apheresis to PCSK9 inhibition. We measured the levels of low-density lipoprotein (LDL) and HDL particle subclasses, serum amyloid A1 (SAA1), paraoxonase-1 (PON1) activity and cholesterol efflux capacity (CEC) in three heterozygous FH patients. Concentrations of all LDL particle subclasses were reduced during apheresis (large 68.0 ± 17.5 to 16.3 ± 2.1 mg/dL, (p = 0.03), intermediate 38.3 ± 0.6 to 5.0 ± 3.5 mg/dL (p = 0.004) and small 5.0 ± 2.6 to 0.2 ± 0.1 mg/dL (p = 0.08)). There were non-significant reductions in the LDL subclasses during evolocumab treatment. There were non-significant reductions in subclasses of HDL particles during apheresis, and no changes during evolocumab treatment. CEC was unchanged throughout the study, while the SAA1/PON1 ratio was unchanged during apheresis but decreased during evolocumab treatment. In conclusion, there were significant reductions in large and intermediate size LDL particles during apheresis, and a non-significant reduction in small LDL particles. There were only non-significant reductions in the LDL subclasses during evolocumab treatment.

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  • 8.
    Levels, Johannes HM
    et al.
    Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
    Geurts, Pierre
    Department of Electrical Engineering and Computer Science & GIGA-research, University of Liège, Belgium.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Occupational and Environmental Medicine Centre.
    Marée, Raphaël
    GIGA Bioinformatics Platform, University of Liège, Belgium.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Fornander, Louise
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Wehenkel, Louis
    Department of Electrical Engineering and Computer Science & GIGA-research, University of Liège, Belgium.
    Lindahl, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Stroes, Erik SG
    Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
    Kuivenhoven, Jan A
    Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
    Meijers, Joost CM
    Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
    High-density Lipoprotein proteome dynamics in human endotoxemia2011In: Proteome Science, ISSN 1477-5956, E-ISSN 1477-5956, Vol. 9, no 34Article in journal (Refereed)
    Abstract [en]

    Background: A large variety of proteins involved in inflammation, coagulation, lipid-oxidation and lipid metabolism have been associated with high-density lipoprotein (HDL) and it is anticipated that changes in the HDL proteome have implications for the multiple functions of HDL. Here, SELDI-TOF mass spectrometry (MS) was used to study the dynamic changes of HDL protein composition in a human experimental low-dose endotoxemia model. Ten healthy men with low HDL cholesterol (0.7+/-0.1 mmol/L) and 10 men with high HDL cholesterol levels (1.9+/-0.4mmol/L) were challenged with endotoxin (LPS) intravenously (1ng/kg bodyweight). We previously showed that subjects with low HDL cholesterol are more susceptible to an inflammatory challenge. The current study tested the hypothesis that this discrepancy may be related to differences in the HDL proteome.

    Results: Plasma drawn at 7 time-points over a 24 hour time period after LPS challenge was used for direct capture of HDL using antibodies against apolipoprotein A-I followed by subsequent SELDI-TOF MS profiling. Upon LPS administration, profound changes in 21 markers (adjusted p-value<0.05) were observed in the proteome in both study groups. These changes were observed 1 hour after LPS infusion and sustained up to 24 hours, but unexpectedly were not different between the 2 study groups. Hierarchical clustering of the protein spectra at all time points of all individuals revealed 3 distinct clusters, which were largely independent of baseline HDL cholesterol levels but correlated with paraoxonase 1 activity. The acute phase protein serum amyloid A-1/2 (SAA-1/2) was clearly upregulated after LPS infusion in both groups and comprised both native and N-terminal truncated variants that were identified by two-dimensional gel electrophoresis and mass spectrometry. Individuals of one of the clusters were distinguished by a lower SAA-1/2 response after LPS challenge and a delayed time-response of the truncated variants.

    Conclusions: This study shows that the semi-quantitative differences in the HDL proteome as assessed by SELDI-TOF MS cannot explain why subjects with low HDL cholesterol are more susceptible to a challenge with LPS than those with high HDL cholesterol. Instead the results indicate that hierarchical clustering could be useful to predict HDL functionality in acute phase responses towards LPS.

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  • 9.
    Liang, Wenzhao
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Jilin University, Peoples R China.
    Ward, Liam
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Linköping University, Faculty of Medicine and Health Sciences.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Linköping University, Faculty of Medicine and Health Sciences.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Lindahl, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Linköping University, Faculty of Medicine and Health Sciences.
    Distinctive proteomic profiles among different regions of human carotid plaques in men and women2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 26231Article in journal (Refereed)
    Abstract [en]

    The heterogeneity of atherosclerotic tissue has limited comprehension in proteomic and metabolomic analyses. To elucidate the functional implications, and differences between genders, of atherosclerotic lesion formation we investigated protein profiles from different regions of human carotid atherosclerotic arteries; internal control, fatty streak, plaque shoulder, plaque centre, and fibrous cap. Proteomic analysis was performed using 2-DE with MALDI-TOF, with validation using nLC-MS/MS. Protein mapping of 2-DE identified 52 unique proteins, including 15 previously unmapped proteins, of which 41 proteins were confirmed by nLC-MS/MS analysis. Expression levels of 18 proteins were significantly altered in plaque regions compared to the internal control region. Nine proteins showed site-specific alterations, irrespective of gender, with clear associations to extracellular matrix remodelling. Five proteins display gender-specific alterations with 2-DE, with two alterations validated by nLC-MS/MS. Gender differences in ferritin light chain and transthyretin were validated using both techniques. Validation of immunohistochemistry confirmed significantly higher levels of ferritin in plaques from male patients. Proteomic analysis of different plaque regions has reduced the effects of plaque heterogeneity, and significant differences in protein expression are determined in specific regions and between genders. These proteomes have functional implications in plaque progression and are of importance in understanding gender differences in atherosclerosis.

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  • 10. Order onlineBuy this publication >>
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lipoproteomics: Environmental and Genetic Factors Affecting High-Density Lipoprotein (HDL)2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Lipoprotein particles act as lipid transporters in the blood stream, and measuring cholesterol content in specific subclasses of lipoprotein particles has long been, and still is, a frequently used tool to estimate the risk of cardiovascular disease (CVD). High-density lipoprotein (HDL) is a subclass of lipoproteins often regarded as providing protection against CVD via several functions including reverse cholesterol transport and anti-inflammatory capacities. However, the precise relationship between HDL cholesterol levels and health outcome is still unclear. Lately, new approaches to study HDL composition and function have therefore become more important.

    HDL function is to a large extent dependent on its proteome, containing more than 100 proteins. Investigating the proteome in individuals with altered gene expression for HDL-associated proteins or with known exposure to environmental contaminants may reveal new insights into how HDL metabolism is affected by various factors. This is of interest in order to better understand the role of HDL in CVD.

    Papers I and II focus on two different mutations in a structural HDL protein, apolipoprotein A-I (L202P and K131del), and one mutation in the scavenger receptor class B-1 (P297S), which is involved in selective lipid uptake of cholesterol mainly into hepatocytes and adrenal cells. The HDL proteome was analyzed using two-dimensional gel electrophoresis and mass spectrometry. The L202P mutation was identified in HDL of the heterozygote carriers together with a significant decrease of apolipoprotein E and increased zinc-alpha-2-glycoprotein. By contrast, the second apolipoprotein AI mutation (K131del) was associated with significantly elevated alpha-1-antitrypsin and transthyretin levels. Protein analyses of the scavenger receptor class B1 P297S heterozygotes showed a significant increase in HDL apoL-1 along with increased free apoE. The carriers showed no difference in antioxidative capability but a significant increase in apoA-I methionine oxidation.

    Papers III and IV focus on persistent organic pollutants that may influence HDL composition and function. These compounds accumulate in humans, and exposure has been linked to an increased risk of CVD. To provide a better understanding of the HDL system in relation to pollutants, a population living in a contaminated area was studied. Persistent organic pollutants in isolated HDL were quantified using high-resolution gas chromatography mass spectrometry and significantly increased levels were found in individuals with CVD as compared to healthy controls. Furthermore, there was a significant negative association between the pollutants and paraoxonase-1 anti-oxidant activity. Studying the proteome with nano-liquid chromatography tandem mass spectrometry led to the identification of 118 proteins in HDL, of which ten were significantly associated with the persistent organic pollutants.

    In summary, the present studies demonstrate protein pattern alterations in HDL associated with inherited genetic variants or pollutant exposure. The studies also provide a set of methods that are useful tools to further comprehend the complexity of lipoprotein metabolism and function. The results are important in order to improve our understanding of HDL in CVD and to explain an increased risk of CVD associated with exposure to organic pollutants.

    List of papers
    1. ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C
    Open this publication in new window or tab >>ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C
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    2014 (English)In: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 8, no 3-4, p. 241-250Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: Mutations in apolipoprotein A-I (apoA-I) may affect plasma high-density lipoprotein (HDL) cholesterol levels and the risk for cardiovascular disease but little is known about the presence and effects of circulating apoA-I variants. This study investigates whether the apoA-I mutations, apoA-I(L202P) and apoA-I(K131del) , are present on plasma HDL particles derived from heterozygote carriers and whether this is associated to changes in HDL protein composition.

    EXPERIMENTAL DESIGN: Plasma HDL of heterozygotes for either apoA-I(L202P) or apoA-I(K131del) and family controls was isolated using ultracentrifugation. HDL proteins were separated by 2DE and analyzed by MS.

    RESULTS: ApoA-I peptides containing apoA-I(L202P) or apoA-I(K131del) were identified in HDL from heterozygotes. The apoA-I(L202P) mutant peptide was less abundant than wild-type peptide while the apoA-I(K131del) mutant peptide was more abundant than wild-type peptide in the heterozygotes. Two-dimensional gel electrophoresis analyses indicated that, compared to controls, HDL in apoA-I(L202P) carriers contained less apoE and more zinc-α-2-glycoprotein while HDL from the apoA-I(K131del) heterozygotes contained more alpha-1-antitrypsin and transthyretin.

    CONCLUSIONS AND CLINICAL RELEVANCE: Both apoA-I(L202P) and apoA-I(K131del) were identified in HDL. In heterozygotes, these mutations have markedly differential effects on the concentration of wild-type apoA-I in the circulation, as well as the HDL proteome, both of which might affect the clinical phenotype encountered in the heterozygous carriers.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2014
    National Category
    Cell and Molecular Biology Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-105992 (URN)10.1002/prca.201300014 (DOI)000334251600013 ()24273187 (PubMedID)
    Available from: 2014-04-16 Created: 2014-04-16 Last updated: 2020-02-20
    2. Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
    Open this publication in new window or tab >>Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
    Show others...
    2015 (English)In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1851, no 12, p. 1587-1595Article in journal (Refereed) Published
    Abstract [en]

    The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1P297S mutation are characterized by increased HDL cholesterol levels, impaired cholesterol efflux from macrophages and attenuated adrenal function. Here, the composition and function of lipoproteins were studied in SR-B1P297S heterozygotes.

    Lipoproteins from six SR-B1P297S carriers and six family controls were investigated. HDL and LDL/VLDL were isolated by ultracentrifugation and proteins were separated by two-dimensional gel electrophoresis and identified by mass spectrometry. HDL antioxidant properties, paraoxonase 1 activities, apoA-I methionine oxidations and HDL cholesterol efflux capacity were assessed.

    Multivariate modeling separated carriers from controls based on lipoprotein composition. Protein analyses showed a significant enrichment of apoE in LDL/VLDL and of apoL-1 in HDL from heterozygotes compared to controls. The relative distribution of plasma apoE was increased in LDL and in lipid-free form. There were no significant differences in paraoxonase 1 activities, HDL antioxidant properties or HDL cholesterol efflux capacity but heterozygotes showed a significant increase of oxidized methionines in apoA-I.

    The SR-B1P297S mutation affects both HDL and LDL/VLDL protein compositions. The increase of apoE in carriers suggests a compensatory mechanism for attenuated SR-B1 mediated cholesterol uptake by HDL. Increased methionine oxidation may affect HDL function by reducing apoA-I binding to its targets. The results illustrate the complexity of lipoprotein metabolism that has to be taken into account in future therapeutic strategies aiming at targeting SR-B1.

    Place, publisher, year, edition, pages
    Elsevier, 2015
    Keywords
    ApoE; ApoL-1; HDL; LDL/VLDL; P297S; SR-B1
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-122723 (URN)10.1016/j.bbalip.2015.09.006 (DOI)000364252800008 ()26454245 (PubMedID)
    Note

    Funding agencies: EUs Sixth Framework Program [037631]; European Union [FP7-603091-2]; CardioVascular Research Initiative [CVON2011-16]; Research Council of South East Sweden [FORSS-3755]; County Council of Ostergotland (C-ALF); Faculty of Health Sciences in Linkoping; Ven

    Available from: 2015-11-18 Created: 2015-11-18 Last updated: 2020-02-20
    3. Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.
    Open this publication in new window or tab >>Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.
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    2014 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 65, p. 93-9Article in journal (Refereed) Published
    Abstract [en]

    Persistent organic pollutants (POPs) are lipophilic environmental toxins that have been associated with cardiovascular disease (CVD) and cancer. The aim of this study was to investigate the concentrations of POPs in human high and low/very low-density lipoproteins (HDL and LDL/VLDL) and the possible association with CVD and cancer occurrence in individuals living in a contaminated area. Lipoproteins from 28 individuals (7 healthy controls, 8 subjects with cancer, 13 subjects with CVD) were isolated and the fraction-specific concentration of 20 different POPs was analyzed by high resolution gas chromatography/high resolution mass spectrometry. The activity of Paraoxonase 1 (PON1), an anti-oxidant in HDL, was determined in plasma of these 28 subjects and additional 50 subjects from the same area excluding diseases other than cancer or CVD. Fourteen polychlorinated biphenyls (PCBs) and three organochlorine pesticides were detected, and especially highly chlorinated PCBs were enriched in lipoproteins. Significantly higher concentrations of POPs were found among individuals with CVD or cancer compared to controls. Principal component analyses showed that POP concentrations in HDL were more associated with CVD, while POP concentrations in LDL/VLDL were more associated with cancer. PON1 activity was negatively correlated to sumPCB and a co-variation between decreased arylesterase-activity, increased PCB concentrations and CVD was found. This study shows that POPs are present in lipoproteins and were more abundant in individuals with CVD or cancer compared to healthy controls. The results also indicate that PCB exposure is accompanied by reduced PON1 activity that could impair the HDL function to protect against oxidation.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    National Category
    Clinical Medicine Other Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-104755 (URN)10.1016/j.envint.2013.12.017 (DOI)000334728500010 ()24472825 (PubMedID)
    Available from: 2014-02-25 Created: 2014-02-25 Last updated: 2020-02-20
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    Lipoproteomics Environmental and Genetic Factors Affecting High-Density Lipoprotein (HDL)
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  • 11.
    Ljunggren, Stefan A
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Linköping University, Faculty of Medicine and Health Sciences.
    Iggland, Madeleine
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rönn, Monika
    Uppsala University, Uppsala, Sweden.
    Lind, Lars
    Uppsala University, Uppsala, Sweden.
    Lind, P M
    Uppsala University, Uppsala, Sweden.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Linköping University, Faculty of Medicine and Health Sciences.
    Altered heart proteome in fructose-fed Fisher 344 rats exposed to bisphenol A.2016In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 347-349, p. 6-16Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA), is an artificial estrogen initially produced for medical purposes but is today widely used in polycarbonate plastics and epoxy resins. Exposure-related reproductive disorders have been found, but recently it has also been suggested that BPA may be involved in obesity, diabetes, myocardial hypertrophy and myocardial infarction in humans. To mimic a modern lifestyle, female rats were fed with fructose or fructose plus BPA (0.25mg/L drinking water). The myocardial left ventricle proteome of water controls, fructose-fed and fructose-fed plus BPA supplemented rats was explored. The proteome was investigated using nano-liquid chromatography tandem mass spectrometry and two-dimensional gel electrophoresis followed by matrix assisted laser desorption/ionization mass spectrometry identification. In total, 41 proteins were significantly altered by BPA exposure compared to water or fructose controls. Principal component analysis and cellular process enrichment analysis of altered proteins suggested increased fatty acid transport and oxidation, increased ROS generation and altered structural integrity of the myocardial left ventricle in the fructose-fed BPA-exposed rats, indicating unfavorable effects on the myocardium. In conclusion, BPA exposure in the rats induces major alterations in the myocardial proteome.

  • 12.
    Ljunggren, Stefan A
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Helmfrid, Ingela
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Salihovic, Samira
    Örebro University, Sweden.
    van Bavel, Bert
    Örebro University, Sweden.
    Wingren, Gun
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Lindahl, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.2014In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 65, p. 93-9Article in journal (Refereed)
    Abstract [en]

    Persistent organic pollutants (POPs) are lipophilic environmental toxins that have been associated with cardiovascular disease (CVD) and cancer. The aim of this study was to investigate the concentrations of POPs in human high and low/very low-density lipoproteins (HDL and LDL/VLDL) and the possible association with CVD and cancer occurrence in individuals living in a contaminated area. Lipoproteins from 28 individuals (7 healthy controls, 8 subjects with cancer, 13 subjects with CVD) were isolated and the fraction-specific concentration of 20 different POPs was analyzed by high resolution gas chromatography/high resolution mass spectrometry. The activity of Paraoxonase 1 (PON1), an anti-oxidant in HDL, was determined in plasma of these 28 subjects and additional 50 subjects from the same area excluding diseases other than cancer or CVD. Fourteen polychlorinated biphenyls (PCBs) and three organochlorine pesticides were detected, and especially highly chlorinated PCBs were enriched in lipoproteins. Significantly higher concentrations of POPs were found among individuals with CVD or cancer compared to controls. Principal component analyses showed that POP concentrations in HDL were more associated with CVD, while POP concentrations in LDL/VLDL were more associated with cancer. PON1 activity was negatively correlated to sumPCB and a co-variation between decreased arylesterase-activity, increased PCB concentrations and CVD was found. This study shows that POPs are present in lipoproteins and were more abundant in individuals with CVD or cancer compared to healthy controls. The results also indicate that PCB exposure is accompanied by reduced PON1 activity that could impair the HDL function to protect against oxidation.

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  • 13.
    Ljunggren, Stefan A
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Levels, Johannes H M
    Academic Medical Centre, Amsterdam, the Netherlands.
    Hovingh, Kees
    Academic Medical Centre, Amsterdam, the Netherlands.
    Holleboom, Adriaan G
    Academic Medical Centre, Amsterdam, the Netherlands.
    Vergeer, Menno
    Academic Medical Centre, Amsterdam, the Netherlands.
    Argyri, Letta
    National Center for Scientific Research "Demokritos", Athens, Greece.
    Gkolfinopoulou, Christina
    National Center for Scientific Research "Demokritos", Athens, Greece.
    Chroni, Angeliki
    National Center for Scientific Research "Demokritos", Athens, Greece.
    Sierts, Jeroen A
    Academic Medical Centre, Amsterdam, the Netherlands.
    Kastelein, John J
    Academic Medical Centre, Amsterdam, the Netherlands.
    Kuivenhoven, Jan Albert
    University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
    Lindahl, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.2015In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1851, no 12, p. 1587-1595Article in journal (Refereed)
    Abstract [en]

    The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1P297S mutation are characterized by increased HDL cholesterol levels, impaired cholesterol efflux from macrophages and attenuated adrenal function. Here, the composition and function of lipoproteins were studied in SR-B1P297S heterozygotes.

    Lipoproteins from six SR-B1P297S carriers and six family controls were investigated. HDL and LDL/VLDL were isolated by ultracentrifugation and proteins were separated by two-dimensional gel electrophoresis and identified by mass spectrometry. HDL antioxidant properties, paraoxonase 1 activities, apoA-I methionine oxidations and HDL cholesterol efflux capacity were assessed.

    Multivariate modeling separated carriers from controls based on lipoprotein composition. Protein analyses showed a significant enrichment of apoE in LDL/VLDL and of apoL-1 in HDL from heterozygotes compared to controls. The relative distribution of plasma apoE was increased in LDL and in lipid-free form. There were no significant differences in paraoxonase 1 activities, HDL antioxidant properties or HDL cholesterol efflux capacity but heterozygotes showed a significant increase of oxidized methionines in apoA-I.

    The SR-B1P297S mutation affects both HDL and LDL/VLDL protein compositions. The increase of apoE in carriers suggests a compensatory mechanism for attenuated SR-B1 mediated cholesterol uptake by HDL. Increased methionine oxidation may affect HDL function by reducing apoA-I binding to its targets. The results illustrate the complexity of lipoprotein metabolism that has to be taken into account in future therapeutic strategies aiming at targeting SR-B1.

    Download full text (pdf)
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  • 14.
    Ljunggren, Stefan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Bengtsson, Torbjorn
    Orebro Univ, Sweden.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Linköping University, Faculty of Medicine and Health Sciences.
    Starkhammar Johansson, Carin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Public Dental Health Care, Center for Oral Rehabilitation Linköping.
    Palm, Eleonor
    Orebro Univ, Sweden.
    Nayeri, Fariba
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Davies, Julia
    Malmo Univ, Sweden.
    Svensater, Gunnel
    Malmo Univ, Sweden.
    Lönn, Johanna
    Orebro Univ, Sweden; Malmo Univ, Sweden; PEAS Research Institute, Sweden.
    Modified lipoproteins in periodontitis: a link to cardiovascular disease?2019In: Bioscience Reports, ISSN 0144-8463, E-ISSN 1573-4935, Vol. 39, no 3, article id BSR20181665Article in journal (Refereed)
    Abstract [en]

    There is a strong association between periodontal disease and atherosclerotic cardiovascular disorders. A key event in the development of atherosclerosis is accumulation of modified lipoproteins within the arterial wall. We hypothesise that patients with periodontitis have an altered lipoprotein profile towards an atherogenic form. Therefore, the present study aims at identifying modifications of plasma lipoproteins in periodontitis. Lipoproteins from ten female patients with periodontitis and gender- and age-matched healthy controls were isolated by density-gradient ultracentrifugation. Proteins were separated by 2D gel-electrophoresis and identified by map-matching or by nano-LC followed by MS. Apolipoprotein (Apo) A-I (ApoA-I) methionine oxidation, Oxyblot, total antioxidant capacity and a multiplex of 71 inflammation-related plasma proteins were assessed. Reduced levels of apoJ, phospholipid transfer protein, apoF, complement C3, paraoxonase 3 and increased levels of alpha-1-antichymotrypsin, apoA-II, apoC-III were found in high-density lipoprotein (HDL) from the patients. In low-density lipoprotein (LDL)/very LDL (VLDL), the levels of apoL-1 and platelet-activating factor acetylhydrolase (PAF-AH) as well as apo-B fragments were increased. Methionine oxidation of apoA-I was increased in HDL and showed a relationship with periodontal parameters. alpha-1 antitrypsin and alpha-2-HS glycoprotein were oxidised in LDL/VLDL and antioxidant capacity was increased in the patient group. A total of 17 inflammation-related proteins were important for group separation with the highest discriminating proteins identified as IL-21, Fractalkine, IL-17F, IL-7, IL-1RA and IL-2. Patients with periodontitis have an altered plasma lipoprotein profile, defined by altered protein levels as well as post-translational and other structural modifications towards an atherogenic form, which supports a role of modified plasma lipoproteins as central in the link between periodontal and cardiovascular disease (CVD).

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  • 15.
    Ljunggren, Stefan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Helmfrid, Ingela
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Norinder, Ulf
    Swedish Toxicol Science Research Centre, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Wingren, Gun
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Lindahl, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Alterations in high-density lipoprotein proteome and function associated with persistent organic pollutants2017In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 98, p. 204-211Article in journal (Refereed)
    Abstract [en]

    There is a growing body of evidence that persistent organic pollutants (POPs) may increase the risk for cardiovascular disease (CVD), but the mechanisms remain unclear. High- density lipoprotein (HDL) acts protective against CVD by different processes, andwe have earlier found that HDL from subjects with CVD contains higher levels of POPs than healthy controls. In the present study, we have expanded analyses on the same individuals living in a contaminated community and investigated the relationship between the HDL POP levels and protein composition/ function. HDL from17 subjectswas isolated by ultracentrifugation. HDL protein composition, using nanoliquid chromatography tandemmass spectrometry, and antioxidant activity were analyzed. The associations of 16 POPs, including polychlorinated biphenyls (PCBs) and organochlorine pesticides, with HDL proteins/functionswere investigated by partial least square and multiple linear regression analysis. Proteomic analyses identified 118 HDL proteins, of which ten were significantly (p b 0.05) and positively associated with the combined level of POPs or with highly chlorinated PCB congeners. Among these, cholesteryl ester transfer protein and phospholipid transfer protein, as well as the inflammatory marker serum amyloid A, were found. The serum paraoxonase/arylesterase 1 activity was inversely associated with POPs. Pathway analysis demonstrated that up- regulated proteinswere associatedwith biological processes involving lipoproteinmetabolism, while down- regulated proteinswere associatedwith processes such as negative regulation of proteinases, acute phase response, platelet degranulation, and complement activation. These results indicate an association between POP levels, especially highly chlorinated PCBs, and HDL protein alterations that may result in a less functional particle. Further studies are needed to determine causality and the importance of other environmental factors. Nevertheless, this study provides a first insight into a possible link between exposure to POPs and risk of CVD. (C) 2016 Elsevier Ltd. All rights reserved.

  • 16.
    Ljunggren, Stefan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Mörtstedt, Harriet
    Occupational and Environmental Medicine, Lund University Hospital, Lund.
    Hellström, L.
    Internal Medicine and Environmental Medicine and Public Health, Oskarshamn Hospital, Oskarshamn, Sweden.
    Perk, J.
    Internal Medicine and Environmental Medicine and Public Health, Oskarshamn Hospital, Oskarshamn, Sweden.
    Besler, C.
    Cardiovascular Center, Zurich University Hospital, Switzerland.
    Landmesser, U.
    Cardiovascular Center, Zurich University Hospital, Switzerland.
    von Eckardstein, A.
    Institute for Clinical Chemistry, Zurich University Hospital, Zurich, Switzerland.
    Lindahl, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Changes in Human Liportein Composition in Patients with Acute Coronary Syndrome2011In: Atherosclerosis Supplements, ISSN 1567-5688, E-ISSN 1878-5050, Vol. 12, no 1, p. 14-14Article in journal (Other academic)
    Abstract [en]

    The protein composition of lipoproteins may serve as biomarkers or reveal underlying mechanisms during different states of disease. Here we have analysed the protein composition of LDL and HDL from patients with acute coronary syndrome (ACS) and patients receiving statins after previous ACS. Plasma samples were obtained from males, namely 12 healthy donors, 9 patients with ACS and 7 stable patients receiving statin treatment after previous ACS. LDL and HDL were isolated by two-step density ultracentrifugation. LDL proteins were analysed with two-dimensional gel electrophoresis and mass spectrometry. Paraoxonase 1 (PON-1) in HDL was analyzed with  SDSPAGE/Western Blot.

    Concentrations of apo A-IV, a1-antitrypsin and transthyretin were significantly increased (P < 0.05) in LDL from patients with ACS compared to healthy controls. In patients receiving statins, a1-antitrypsin remained increased while serum amyloid A4 was decreased. By western blot analysis, a non-significant increase in PON-1 was found in HDL from patients with ACS. Interestingly, a truncated form of PON-1 was detected in all patients with ACS but not in any of the controls.

    In conclusion, we confirm previous findings that LDL-associated transthyretin is a possible biomarker of myocardial infarction. Moreover, the increased concentration of the inflammatory marker a1-antitrypsin in LDL from both ACS patients and stable patients after ACS indicate that the enrichment does not only reflect an acute phase response. The presence of a truncated form of the antioxidant protein PON-1 in HDL may explain previous findings showing increased amounts but lower activity of PON-1 in patients with ACS.

  • 17.
    Ljunggren, Stefan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Ståhlbom, Bengt
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Krapi, Blerim
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Fornander, Louise
    Orebro Univ, Sweden.
    Karlsson, Lovisa E.
    Orebro Univ Hosp, Sweden.
    Bergstrom, Bernt
    Orebro Univ Hosp, Sweden.
    Nordenberg, Eva
    Siemens Ind Turbomachinery, Sweden.
    Ervik, Torunn K.
    Natl Inst Occupat Hlth, Norway.
    Graff, Pal
    Natl Inst Occupat Hlth, Norway.
    Biomonitoring of Metal Exposure During Additive Manufacturing (3D Printing)2019In: SH@W Safety and Health at Work, ISSN 2093-7911, E-ISSN 2093-7997, Vol. 10, no 4, p. 518-526Article in journal (Refereed)
    Abstract [en]

    Background: Additive manufacturing (AM) is a rapidly expanding new technology involving challenges to occupational health. Here, metal exposure in an AM facility with large-scale metallic component production was investigated during two consecutive years with preventive actions in between. Methods: Gravimetric analyzes measured airborne particle concentrations, and filters were analyzed for metal content. In addition, concentrations of airborne particles amp;lt;300 nm were investigated. Particles from recycled powder were characterized. Biomonitoring of urine and dermal contamination among AM operators, office personnel, and welders was performed. Results: Total and inhalable dust levels were almost all below occupational exposure limits, but inductively coupled plasma mass spectrometry showed that AM operators had a significant increase in cobalt exposure compared with welders. Airborne particle concentrations (amp;lt;300 nm) showed transient peaks in the AM facility but were lower than those of the welding facility. Particle characterization of recycled powder showed fragmentation and condensates enriched in volatile metals. Biomonitoring showed a nonsignificant increase in the level of metals in urine in AM operators. Dermal cobalt and a trend for increasing urine metals during Workweek Year 1, but not in Year 2, indicated reduced exposure after preventive actions. Conclusion: Gravimetric analyses showed low total and inhalable dust exposure in AM operators. However, transient emission of smaller particles constitutes exposure risks. Preventive actions implemented by the company reduced the workers metal exposure despite unchanged emissions of particles, indicating a need for careful design and regulation of the AM environments. It also emphasizes the need for relevant exposure markers and biomonitoring of health risks. (C) 2019 Occupational Safety and Health Research Institute, Published by Elsevier Korea LLC.

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  • 18.
    Ljunggren, Stefan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Levels, Johannes H M
    Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
    Turkina, Maria V
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Sundberg, Sofie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Bochem, Andrea E
    Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
    Hovingh, Kees
    Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
    Holleboom, Adriaan G
    Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
    Lindahl, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Kuivenhoven, Jan Albert
    University of Groningen, Groningen, The Netherlands.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C2014In: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 8, no 3-4, p. 241-250Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Mutations in apolipoprotein A-I (apoA-I) may affect plasma high-density lipoprotein (HDL) cholesterol levels and the risk for cardiovascular disease but little is known about the presence and effects of circulating apoA-I variants. This study investigates whether the apoA-I mutations, apoA-I(L202P) and apoA-I(K131del) , are present on plasma HDL particles derived from heterozygote carriers and whether this is associated to changes in HDL protein composition.

    EXPERIMENTAL DESIGN: Plasma HDL of heterozygotes for either apoA-I(L202P) or apoA-I(K131del) and family controls was isolated using ultracentrifugation. HDL proteins were separated by 2DE and analyzed by MS.

    RESULTS: ApoA-I peptides containing apoA-I(L202P) or apoA-I(K131del) were identified in HDL from heterozygotes. The apoA-I(L202P) mutant peptide was less abundant than wild-type peptide while the apoA-I(K131del) mutant peptide was more abundant than wild-type peptide in the heterozygotes. Two-dimensional gel electrophoresis analyses indicated that, compared to controls, HDL in apoA-I(L202P) carriers contained less apoE and more zinc-α-2-glycoprotein while HDL from the apoA-I(K131del) heterozygotes contained more alpha-1-antitrypsin and transthyretin.

    CONCLUSIONS AND CLINICAL RELEVANCE: Both apoA-I(L202P) and apoA-I(K131del) were identified in HDL. In heterozygotes, these mutations have markedly differential effects on the concentration of wild-type apoA-I in the circulation, as well as the HDL proteome, both of which might affect the clinical phenotype encountered in the heterozygous carriers.

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  • 19.
    Ljunggren, Stefan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Nosratabadi, Ali Reza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Graff, Pål
    National Institute of Occupational Health, Norway.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Monthly variation in masses, metals and endotoxin content as well as pro-inflammatory response of airborne particles collected by TEOM monitors2019In: Air quality, atmosphere and health, ISSN 1873-9318, E-ISSN 1873-9326, Vol. 12, no 12, p. 1441-1448Article in journal (Refereed)
    Abstract [en]

    Particle exposure has been linked to an increased incidence of cardiovascular disease. Furthermore, particle exposure has been shown to have a chronic inhibitory effect on lung development in young people and may result in increased respiratory problems in adults or children with respiratory-related diseases. In today’s urban environments, particle levels are mainly monitored gravimetrically; however, other factors such as particle size, shape and surface reactivity have recently been noted as highly important in relation to possible health outcomes. Here, particles from TEOM monitor filters placed in three different cities were studied. The purpose of the study was to investigate whether there are variations in particle masses, cadmium and lead contents, as well as endotoxin levels between locations and time points over the year and if this can be correlated to the particles ability to induce a pro-inflammatory response in vitro. Results showed that it is possible to detect variations at different locations and at different time points over the year and that cadmium, lead and endotoxin levels did not coincide with the increased total particle masses while endotoxin levels coincided with pro-inflammatory responses in vitro. The present study shows that filter analysis is a useful complement to gravimetric or particle-counting measurements in studies of particle-related health effects and will give useful information regarding future air quality measurements.

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  • 20.
    Lönn, J.
    et al.
    Malmo Univ, Sweden; PEAS Inst AB, Linkoping, Sweden.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Klarstrom-Engstrom, K.
    Orebro Univ, Sweden.
    Demirel, I.
    Orebro Univ, Sweden.
    Bengtsson, T.
    Orebro Univ, Sweden.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Lipoprotein modifications by gingipains of Porphyromonas gingivalis2018In: Journal of Periodontal Research, ISSN 0022-3484, E-ISSN 1600-0765, Vol. 53, no 3, p. 403-413Article in journal (Refereed)
    Abstract [en]

    Background and Objective: Several studies have shown an association between periodontitis and cardiovascular disease (CVD). Atherosclerosis is the major cause of CVD, and a key event in the development of atherosclerosis is accumulation of lipoproteins within the arterial wall. Bacteria are the primary etiologic agents in periodontitis and Porphyromonas gingivalis is the major pathogen in the disease. Several studies support a role of modified low-density lipoprotein (LDL) in atherogenesis; however, the pathogenic stimuli that induce the changes and the mechanisms by which this occur are unknown. This study aims to identify alterations in plasma lipoproteins induced by the periodontopathic species of bacterium, P.gingivalis, in vitro. Material and Methods: Plasma lipoproteins were isolated from whole blood treated with wild-type and gingipain-mutant (lacking either the Rgp- or Kgp gingipains) P.gingivalis by density/gradient-ultracentrifugation and were studied using 2-dimensional gel electrophoresis followed by matrix-assisted laser desorption/ionization mass spectrometry. Porphyromonasgingivalis-induced lipid peroxidation and antioxidant levels were measured by thiobarbituric acid-reactive substances and antioxidant assay kits, respectively, and lumiaggregometry was used for measurement of reactive oxygen species (ROS) and aggregation. Results: Porphyromonas gingivalis exerted substantial proteolytic effects on the lipoproteins. The Rgp gingipains were responsible for producing 2 apoE fragments, as well as 2 apoB-100 fragments, in LDL, and the Kgp gingipain produced an unidentified fragment in high-density lipoproteins. Porphyromonasgingivalis and its different gingipain variants induced ROS and consumed antioxidants. Both the Rgp and Kgp gingipains were involved in inducing lipid peroxidation. Conclusion: Porphyromonas gingivalis has the potential to change the expression of lipoproteins in blood, which may represent a crucial link between periodontitis and CVD.

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  • 21.
    Ward, Liam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Exposure to atheroma-relevant 7-oxysterols causes proteomic alterations in cell death, cellular longevity, and lipid metabolism in THP-1 macrophages2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0174475Article in journal (Refereed)
    Abstract [en]

    The 7-oxysterols are recognised as strong enhancers of inflammatory processes in foamy macrophages. Atheroma-relevant 7-oxysterol mixtures induce a mixed type of cell death in macrophages, and trigger cellular oxidative stress responses, which mimic oxidative exposures observed in atherosclerotic lesions. However, the macrophage proteome has not previously been determined in the 7-oxysterol treated cell model. The aim of the present study was to determine the specific effects of an atheroma-relevant 7-oxysterol mixture on human macrophage proteome. Human THP-1 macrophages were exposed to an atheroma-relevant mixture of 7 beta-hydroxycholesterol and 7-ketocholesterol. Two-dimensional gel electrophoresis and mass spectrometry techniques were used to analyse the alterations in macrophage proteome, which resulted in the identification of 19 proteins with significant differential expression upon oxysterol loading; 8 increased and 11 decreased. The expression patterns of 11 out of 19 identified significant proteins were further confirmed by tandemmass spectrometry, including further validation of increased histone deacetylase 2 and macrophage scavenger receptor types I and II expressions by western blot analysis. Identified proteins with differential expression in the cell model have been associated with i) signalling imbalance in cell death and cellular longevity; ii) lipid uptake and metabolism in foam cells; and iii) inflammatory proteins. The presented findings highlight a new proteomic platform for further studies into the functional roles of macrophages in atherosclerosis, and present a cell model for future studies to modulate the macrophage proteome by potential anti-atherosclerotic agents.

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  • 22.
    Zsigmond, Peter
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Proteomic Analysis of the Cerebrospinal Fluid in Patients With Essential Tremor Before and After Deep Brain Stimulation Surgery: A Pilot Study2019In: Neuromodulation (Malden, Mass.), ISSN 1094-7159, E-ISSN 1525-1403Article in journal (Refereed)
    Abstract [en]

    Objective Electrical neuromodulation by deep brain stimulation (DBS) is a well-established method for treatment of severe essential tremor (ET). The mechanism behind the tremor relieving effect remains largely unknown. Our aim of this study was to evaluate alterations in proteomics pre- and post-DBS in patients diagnosed with severe ET. Materials and Methods Ten right-handed ET patients were included in this study. Cerebrospinal fluid (CSF) was obtained by lumbar puncture preoperatively (N = 10) and six months postoperatively (N = 7). The samples were analyzed by high sensitive liquid chromatography tandem mass spectrometry. Results Twenty-two proteins were statistically significantly altered in the CSF of ET patients before and after DBS treatment. Downregulated proteins were involved in regulatory processes of protein activation, complement activation, humoral immune response as well as acute inflammatory response. The upregulated proteins were involved in pathways for cell secretion, adhesion as well as response to axon injury. Conclusions DBS in ET patients effects the neurochemical environment in the CSF. These findings further elucidate the mechanisms of DBS and may lead to new biomarkers for evaluating the effect of DBS treatment.

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