| 1. |
- Adiels, Martin, 1976, et al.
(författare)
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Role of apolipoprotein C-III overproduction in diabetic dyslipidaemia
- 2019
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 21:8, s. 1861-1870
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Tidskriftsartikel (refereegranskat)abstract
- - Aims: To investigate how apolipoprotein C-III (apoC-III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC-III, and whether improvement of glycaemic control using the glucagon-like peptide-1 analogue liraglutide for 16 weeks modifies apoC-III dynamics. Materials and Methods: Postprandial apoC-III kinetics were assessed after a bolus injection of [5,5,5- 2 H 3 ]leucine using ultrasensitive mass spectrometry techniques. We compared apoC-III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non-diabetic subjects. Liver fat content, subcutaneous abdominal and intra-abdominal fat were determined using proton magnetic resonance spectroscopy. Results: Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC-III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC-III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC-III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC-III secretion rate was higher in subjects with type 2 diabetes compared with BMI-matched non-diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042). Conclusions: The results reveal that the secretion rate of apoC-III is associated with elevation of triglyceride-rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC-III. © 2019 John Wiley & Sons Ltd
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| 2. |
- Björnson, Elias, 1988, et al.
(författare)
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Apolipoprotein B48 metabolism in chylomicrons and very low-density lipoproteins and its role in triglyceride transport in normo- and hypertriglyceridemic human subjects
- 2020
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 288:4, s. 422-438
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Tidskriftsartikel (refereegranskat)abstract
- Background Renewed interest in triglyceride-rich lipoproteins as causative agents in cardiovascular disease mandates further exploration of the integrated metabolism of chylomicrons and very low-density lipoproteins (VLDL). Methods Novel tracer techniques and an integrated multi-compartmental model were used to determine the kinetics of apoB48- and apoB100-containing particles in the chylomicron and VLDL density intervals in 15 subjects with a wide range of plasma triglyceride levels. Results Following a fat-rich meal, apoB48 appeared in the chylomicron, VLDL1 and VLDL2 fractions in all subjects. Chylomicrons cleared rapidly from the circulation but apoB48-containing VLDL accumulated, and over the day were 3-fold higher in those with high versus low plasma triglyceride. ApoB48-containing particles were secreted directly into both the chylomicron and VLDL fractions at rates that were similar across the plasma triglyceride range studied. During fat absorption, whilst most triglyceride entered the circulation in chylomicrons, the majority of apoB48 particles were secreted into the VLDL density range. Conclusion The intestine secretes apoB48-containing particles not only as chylomicrons but also directly into the VLDL1 and VLDL2 density ranges both in the basal state and during dietary lipid absorption. Over the day, apoB48-containing particles appear to comprise about 20-25% of circulating VLDL and, especially in those with elevated triglycerides, form part of a slowly cleared 'remnant' particle population, thereby potentially increasing CHD risk. These findings provide a metabolic understanding of the potential consequences for increased CHD risk when slowed lipolysis leads to the accumulation of remnants, especially in individuals with hypertriglyceridemia.
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| 3. |
- Björnson, Elias, 1988, et al.
(författare)
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Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics
- 2019
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 285:5, s. 562-577
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundTriglyceride-rich lipoproteins and their remnants have emerged as major risk factors for cardiovascular disease. New experimental approaches are required that permit simultaneous investigation of the dynamics of chylomicrons (CM) and apoB48 metabolism and of apoB100 in very low-density lipoproteins (VLDL). MethodsMass spectrometric techniques were used to determine the masses and tracer enrichments of apoB48 in the CM, VLDL1 and VLDL2 density intervals. An integrated non-steady-state multicompartmental model was constructed to describe the metabolism of apoB48- and apoB100-containing lipoproteins following a fat-rich meal, as well as during prolonged fasting. ResultsThe kinetic model described the metabolism of apoB48 in CM, VLDL1 and VLDL2. It predicted a low level of basal apoB48 secretion and, during fat absorption, an increment in apoB48 release into not only CM but also directly into VLDL1 and VLDL2. ApoB48 particles with a long residence time were present in VLDL, and in subjects with high plasma triglycerides, these lipoproteins contributed to apoB48 measured during fasting conditions. Basal apoB48 secretion was about 50mgday(-1), and the increment during absorption was about 230mgday(-1). The fractional catabolic rates for apoB48 in VLDL1 and VLDL2 were substantially lower than for apoB48 in CM. DiscussionThis novel non-steady-state model integrates the metabolic properties of both apoB100 and apoB48 and the kinetics of triglyceride. The model is physiologically relevant and provides insight not only into apoB48 release in the basal and postabsorptive states but also into the contribution of the intestine to VLDL pool size and kinetics.
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| 4. |
- Taskinen, Marja-Riitta, et al.
(författare)
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Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy
- 2023
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Ingår i: DIABETOLOGIA. - 0012-186X .- 1432-0428. ; 66:12, s. 2307-2319
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes on statin therapy. These abnormalities may contribute to residual CVD risk.Methods: To investigate the kinetics of ApoB-48- and ApoB-100-containing lipoproteins, we performed a secondary analysis of 11 overweight/obese individuals with type 2 diabetes who were treated with lifestyle counselling and on a stable dose of metformin who were from an earlier clinical study, and compared these with 11 control participants frequency-matched for age, BMI and sex. Participants in both groups were on a similar statin regimen during the study. Stable isotope tracers were used to determine the kinetics of the following in response to a standard fat-rich meal: (1) apolipoprotein (Apo)B-48 in chylomicrons and VLDL; (2) ApoB-100 in VLDL, intermediate-density lipoprotein (IDL) and LDL; and (3) triglyceride (TG) in VLDL.Results: The fasting lipid profile did not differ significantly between the two groups. Compared with control participants, in individuals with type 2 diabetes, chylomicron TG and ApoB-48 levels exhibited an approximately twofold higher response to the fat-rich meal, and a twofold higher increment was observed in ApoB-48 particles in the VLDL1 and VLDL2 density ranges (all p < 0.05). Again comparing control participants with individuals with type 2 diabetes, in the latter, total ApoB-48 production was 25% higher (556 +/- 57 vs 446 +/- 57 mg/day; p < 0.001), conversion (fractional transfer rate) of chylomicrons to VLDL was around 40% lower (35 +/- 25 vs 82 +/- 58 pools/day; p=0.034) and direct clearance of chylomicrons was 5.6-fold higher (5.6 +/- 2.2 vs 1.0 +/- 1.8 pools/day; p < 0.001). During the postprandial period, ApoB-48 particles accounted for a higher proportion of total VLDL in individuals with type 2 diabetes (44%) compared with control participants (25%), and these ApoB-48 VLDL particles exhibited a fivefold longer residence time in the circulation (p < 0.01). No between-group differences were seen in the kinetics of ApoB-100 and TG in VLDL, or in LDL ApoB-100 production, pool size and clearance rate. As compared with control participants, the IDL ApoB-100 pool in individuals with type 2 diabetes was higher due to increased conversion from VLDL2.Conclusions/interpretation: Abnormalities in the metabolism of intestinally derived ApoB-48-containing lipoproteins in individuals with type 2 diabetes on statins may help to explain the residual risk of CVD and may be suitable targets for interventions.
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| 5. |
- Taskinen, M. R., et al.
(författare)
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Role of endogenous incretins in the regulation of postprandial lipoprotein metabolism
- 2022
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 187:1, s. 75-84
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Incretins are known to influence lipid metabolism in the intestine when administered as pharmacologic agents. The aggregate influence of endogenous incretins on chylomicron production and clearance is less clear, particularly in light of opposing effects of co-secreted hormones. Here, we tested the hypothesis that physiological levels of incretins may impact on production or clearances rates of chylomicrons and VLDL. Design and methods: A group of 22 overweight/obese men was studied to determine associations between plasma levels of glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) after a fat-rich meal and the production and clearance rates of apoB48- and apoB100-containing triglyceride-rich lipoproteins. Subjects were stratified by above- and below-median incretin response (area under the curve). Results: Stratification yielded subgroups that differed about two-fold in incretin response. There were neither differences in apoB48 production rates in chylomicrons or VLDL fractions nor in apoB100 or triglyceride kinetics in VLDL between men with above- vs below-median incretin responses. The men with above-median GLP-1 and GLP-2 responses exhibited higher postprandial plasma and chylomicron triglyceride levels, but this could not be related to altered kinetic parameters. No differences were found between incretin response subgroups and particle clearance rates. Conclusion: We found no evidence for a regulatory effect of endogenous incretins on contemporaneous chylomicron or VLDL metabolism following a standardised fat-rich meal. The actions of incretins at pharmacological doses may not be reflected at physiological levels of these hormones.
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| 6. |
- Zettergren, Anna, 1978, et al.
(författare)
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Proteomic analyses of limbic regions in neonatal male, female and androgen receptor knockout mice
- 2017
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Ingår i: Bmc Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is well-established that organizational effects of sex steroids during early development are fundamental for sex-typical displays of, for example, mating and aggressive behaviors in rodents and other species. Male and female brains are known to differ with respect to neuronal morphology in particular regions of the brain, including the number and size of neurons, and the density and length of dendrites in nuclei of hypothalamus and amygdala. The aim of the present study was to use global proteomics to identify proteins differentially expressed in hypothalamus/amygdala during early development (postnatal day 8) of male, female and conditional androgen receptor knockout (AR(NesDel)) male mice, lacking androgen receptors specifically in the brain. Furthermore, verification of selected sexually dimorphic proteins was performed using targeted proteomics. Results: Our proteomic approach, iTRAQ, allowed us to investigate expression differences in the 2998 most abundantly expressed proteins in our dissected tissues. Approximately 170 proteins differed between the sexes, and 38 proteins between AR(NesDel) and control males (p < 0.05). In line with previous explorative studies of sexually dimorphic gene expression we mainly detected subtle protein expression differences (fold changes < 1.3). The protein MARCKS (myristoylated alanine rich C kinase substrate), having the largest fold change of the proteins selected from the iTRAQ analyses and of known importance for synaptic transmission and dendritic branching, was confirmed by targeted proteomics as differentially expressed between the sexes. Conclusions: Overall, our results provide solid evidence that a large number of proteins show sex differences in their brain expression and could potentially be involved in brain sexual differentiation. Furthermore, our finding of a sexually dimorphic expression of MARCKS in the brain during development warrants further investigation on the involvement in sexual differentiation of this protein.
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| 7. |
- Crescitelli, Rossella, 1985, et al.
(författare)
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Subpopulations of extracellular vesicles from human metastatic melanoma tissue identified by quantitative proteomics after optimized isolation
- 2020
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The majority of extracellular vesicle (EV) studies conducted to date have been performed on cell lines with little knowledge on how well these represent the characteristics of EVs in vivo. The aim of this study was to establish a method to isolate and categorize subpopulations of EVs isolated directly from tumour tissue. First we established an isolation protocol for subpopulations of EVs from metastatic melanoma tissue, which included enzymatic treatment (collagenase D and DNase). Small and large EVs were isolated with differential ultracentrifugation, and these were further separated into high and low-density (HD and LD) fractions. All EV subpopulations were then analysed in depth using electron microscopy, Bioanalyzer (R), nanoparticle tracking analysis, and quantitative mass spectrometry analysis. Subpopulations of EVs with distinct size, morphology, and RNA and protein cargo could be isolated from the metastatic melanoma tissue. LD EVs showed an RNA profile with the presence of 18S and 28S ribosomal subunits. In contrast, HD EVs had RNA profiles with small or no peaks for ribosomal RNA subunits. Quantitative proteomics showed that several proteins such as flotillin-1 were enriched in both large and small LD EVs, while ADAM10 were exclusively enriched in small LD EVs. In contrast, mitofilin was enriched only in the large EVs. We conclude that enzymatic treatments improve EV isolation from dense fibrotic tissue without any apparent effect on molecular or morphological characteristics. By providing a detailed categorization of several subpopulations of EVs isolated directly from tumour tissues, we might better understand the function of EVs in tumour biology and their possible use in biomarker discovery.
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| 8. |
- Karlsson, Roger, 1975, et al.
(författare)
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Discovery of Species-unique Peptide Biomarkers of Bacterial Pathogens by Tandem Mass Spectrometry-based Proteotyping
- 2020
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 19:3, s. 518-528
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Tidskriftsartikel (refereegranskat)abstract
- Mass spectrometry (MS) and proteomics offer comprehensive characterization and identification of microorganisms and discovery of protein biomarkers that are applicable for diagnostics of infectious diseases. The use of biomarkers for diagnostics is widely applied in the clinic and the use of peptide biomarkers is increasingly being investigated for applications in the clinical laboratory. Respiratory-tract infections are a predominant cause for medical treatment, although, clinical assessments and standard clinical laboratory protocols are time-consuming and often inadequate for reliable diagnoses. Novel methods, preferably applied directly to clinical samples, excluding cultivation steps, are needed to improve diagnostics of infectious diseases, provide adequate treatment and reduce the use of antibiotics and associated development of antibiotic resistance. This study applied nano-liquid chromatography (LC) coupled with tandem MS, with a bioinformatics pipeline and an in-house database of curated high-quality reference genome sequences to identify species-unique peptides as potential biomarkers for four bacterial pathogens commonly found in respiratory tract infections (RTIs): Staphylococcus aureus; Moraxella catarrhalis; Haemophilus influenzae and Streptococcus pneumoniae. The species-unique peptides were initially identified in pure cultures of bacterial reference strains, reflecting the genomic variation in the four species and, furthermore, in clinical respiratory tract samples, without prior cultivation, elucidating proteins expressed in clinical conditions of infection. For each of the four bacterial pathogens, the peptide biomarker candidates most predominantly found in clinical samples, are presented. Data are available via ProteomeXchange with identifier PXD014522. As proof-of-principle, the most promising species-unique peptides were applied in targeted tandem MS-analyses of clinical samples and their relevance for identifications of the pathogens, i.e. proteotyping, was validated, thus demonstrating their potential as peptide biomarker candidates for diagnostics of infectious diseases.
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| 9. |
- Najar, Deman Hadi, et al.
(författare)
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Pharmacokinetic Properties of the Nephrotoxin Orellanine in Rats
- 2018
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Ingår i: Toxins. - : MDPI AG. - 2072-6651. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Orellanine is a nephrotoxin found in mushrooms of the Cortinarius family. Accidental intake of this substance may cause renal failure. Orellanine is specific for proximal tubular cells and could, therefore, potentially be used as treatment for metastatic renal cancer, which originates from these cells. However, more information is needed about the distribution and elimination of orellanine from the body to understand its potential use for therapy. In this study, 5 mg/kg orellanine (unlabeled and H-3-labeled) was injected intravenously in rats (Wistar and Sprague Dawley). Distribution was measured (Wistar rats, n = 10, n = 12) using radioluminography and the highest amount of orellanine was found in the kidney cortex and bladder at all time-points investigated. The pharmacokinetic properties of orellanine were investigated using LC-MS/MS and -scintillation to measure the amount of orellanine in plasma. Three groups of rats were investigated: control rats with intact kidneys (n = 10) and two groups with bilateral renal artery ligation (n = 7) where animals in one of these groups were treated with peritoneal dialysis (n = 8). Using LC-MS/MS, the half-life of orellanine was found to be 109 +/- 6 min in the controls. In the groups with ligated renal arteries, orellanine had a half-life of 756 +/- 98 min without and 238 +/- 28 min with dialysis. Thus, orellanine was almost exclusively eliminated by glomerular filtration as well as by peritoneal dialysis.
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| 10. |
- Norén, Åsa, et al.
(författare)
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Liver Graft Proteomics Reveals Potential Incipient Mechanisms behind Early Renal Dysfunction after Liver Transplantation
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 23:19
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Tidskriftsartikel (refereegranskat)abstract
- Acute kidney injury (AKI) is frequent after liver transplantation (LT) and correlates with later development of chronic kidney disease. Its etiology is multifactorial and combines pre-, intra-, and postoperative factors. Additionally, the liver graft itself seems an important element in the development of AKI, yet the detailed mechanisms remain unclear. We hypothesized that grafts of LT recipients developing significant early AKI may show distinct proteomic alterations, and we set out to identify proteome differences between LT recipients developing moderate or severe AKI (n = 7) and LT recipients without early renal injury (n = 7). Liver biopsies obtained one hour after reperfusion were assessed histologically and using quantitative proteomics. Several cytokines and serum amyloid A2 (SAA2) were analyzed in serum samples obtained preoperatively, 2-4 h, and 20-24 h after graft reperfusion, respectively. LT induced mild histological alterations without significant differences between groups but uniformly altered liver function tests peaking on postoperative day 1, with a trend towards more severe alterations in patients developing AKI. Global quantitative proteomic analysis revealed 136 proteins differing significantly in their expression levels (p < 0.05, FC 20%): 80 proteins had higher and 56 had lower levels in the AKI group. Most of these proteins were related to immune and inflammatory responses, host defense, and neutrophil degranulation. No differences between the studied pro- and anti-inflammatory cytokines or SAA2 between groups were found at any moment. Our results suggest that grafts of LT patients who develop early AKI reveal a distinct proteome dominated by an early yet prominent activation of the innate immunity. These findings support the hypothesis that AKI after LT may be favored by certain graft characteristics.
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| 11. |
- Oras, Jonatan, 1978, et al.
(författare)
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Anaesthetic-induced cardioprotection in an experimental model of the Takotsubo syndrome - isoflurane vs. propofol.
- 2017
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Ingår i: Acta anaesthesiologica Scandinavica. - : Wiley. - 1399-6576 .- 0001-5172. ; 61:3, s. 309-321
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Tidskriftsartikel (refereegranskat)abstract
- Takotsubo syndrome (TS) is an acute cardiac condition with a substantial mortality for which no specific treatment is available. We have previously shown that isoflurane attenuates the development of left ventricular (LV) dysfunction in an experimental TS-model. We compared the effects of equi-anaesthetic doses of isoflurane, propofol and ketamine+midazolam on haemodynamics, global and regional LV systolic function and the activation of intracellular metabolic pathways in experimental TS. We hypothesized that cardioprotection in experimental TS is specific for isoflurane.Forty-five rats were randomized to isoflurane (0.6 MAC, n=15), propofol (bolus 200mg/kg+360mg/kg/h, n=15) or ketamine (100mg/kg)+midazolam (10mg/kg, n=15) anaesthesia. Arterial pressure, heart rate and body temperature were continuously measured and arterial blood gas analysis was performed intermittently. TS was induced by intraperitoneal injection of isoprenaline, 50mg/kg. LV echocardiography was performed 90min after isoprenaline injection. Apical cardiac tissue was analysed by global discovery proteomics and pathway analysis.Isoprenaline-induced changes in arterial blood pressure, heart rate or body temperature did not differ between groups. LV ejection fraction was higher and extent of LV akinesia was lower with isoflurane, when compared with the propofol and the ketamine+midazolam groups. In this TS-model, the proteomic analysis revealed an up-regulation of pathways involved in inflammation, coagulation, endocytosis and lipid metabolism. This up-regulation was clearly attenuated with isoflurane compared to propofol.In an experimental model of TS, isoflurane, but not propofol, exerts a cardioprotective effect. The proteomic analysis suggests that inflammation might be involved in pathogenesis of TS.
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| 12. |
- Taskinen, Marja-Riitta, et al.
(författare)
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Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes.
- 2021
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Ingår i: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636.
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Tidskriftsartikel (refereegranskat)abstract
- Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL1 (very low-density lipoprotein) and VLDL2; and apoB100 in VLDL1, VLDL2, IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL1. In contrast, the fractional catabolic rates of VLDL2-apoB100 and VLDL2-triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL2- and IDL-apoB100 concentrations.Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL1) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL2, IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.
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| 13. |
- Taskinen, M. R., et al.
(författare)
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Effects of liraglutide on the metabolism of triglyceride-rich lipoproteins in type 2 diabetes
- 2021
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 23:5, s. 1191-1201
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo) B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat-rich meal. Materials and Methods: Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on 1.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal. Results: Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p < .0001) and increased the triglyceride/apoB48 ratio (i.e. the size) of chylomicrons (p < .001). Direct clearance of chylomicrons, a quantitatively significant pathway pretreatment, decreased by 90% on liraglutide (p < .001). Liraglutide also reduced VLDL1-triglyceride secretion (p = .017) in parallel with reduced liver fat. Chylomicron-apoB48 production and particle size were related to insulin sensitivity (p = .015 and p < .001, respectively), but these associations were perturbed by liraglutide. Conclusions: In a physiologically relevant setting that mirrored regular feeding in subjects with T2D, liraglutide promoted potentially beneficial changes on postprandial apoB48 metabolism. Using our data in an integrated metabolic model, we describe how the action of liraglutide in T2D on chylomicron and VLDL kinetics could lead to decreased generation of remnant lipoproteins.
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| 14. |
- Thorsell, Annika, 1973, et al.
(författare)
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Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer's disease
- 2010
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Ingår i: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1362, s. 13-22
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic pathology occurs early in Alzheimer's disease (AD) development, and cerebrospinal fluid biomarkers for synaptic damage may be altered early in the disease process. In the present study we examined cerebrospinal fluid levels of the postsynaptic protein neurogranin in patients with mild cognitive impairment (MCI) or AD and controls. The low neurogranin level in cerebrospinal fluid required enrichment by immunoprecipitation prior to mass spectrometric identification and semi-quantitative immunoblot analysis. Relative quantification revealed a significant increase of neurogranin in the AD group compared with controls, while the MCI group was not statistically different from either controls or the AD group. The concentrations of the AD biomarkers T-tau, P-tau(181) and A beta(42) were significantly changed in the control and MCI groups compared with the AD group, but no significant differences were found between the MCI group and controls for the three biomarkers. Nevertheless, a trend towards increasing levels of neurogranin, T-tau and P-tau(181) was found in cerebrospinal fluid from MCI patients compared with controls. The elevated neurogranin levels in the MCI and AD groups might reflect synaptic degeneration. These results together suggest that cerebrospinal fluid neurogranin might be valuable together with the established AD biomarkers in the early diagnosis of AD and warrants further studies to determine the diagnostic value of neuroganin. (C) 2010 Elsevier B.V. All rights reserved.
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| 15. |
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| 16. |
- Bram Ednersson, Susanne, et al.
(författare)
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Proteomic analysis in diffuse large B-cell lymphoma identifies dysregulated tumor microenvironment proteins in non-GCB/ABC subtype patients
- 2021
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Ingår i: Leukemia & Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 62:10, s. 2360-2373
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Tidskriftsartikel (refereegranskat)abstract
- The complexity of the activated B-cell like (ABC) diffuse large B-cell lymphoma (DLBCL) subtype is probably not only explained by genetic alterations and methods to measure global protein expression could bring new knowledge regarding the pathophysiology. We used quantitative proteomics to analyze the global protein expression of formalin-fixed paraffin-embedded (FFPE) tumor tissues from 202 DLBCL patients. We identified 6430 proteins and 498 were significantly regulated between the germinal center B-cell like (GCB) and non-GCB groups. A number of proteins previously not described to be upregulated in non-GCB or ABC DLBCL was found, e.g. CD64, CD85A, guanylate-binding protein 1 (GBP1), interferon-induced proteins with tetratricopeptide repeat (IFIT)2, and mixed lineage kinase domain-like protein (MLKL) and immunohistochemical staining showed higher expression of GBP1 and MLKL. A cluster analysis revealed that the most prominent cluster contained proteins involved in the tumor microenvironment and regulation of the immune system. Our data suggest that the therapeutic focus should be expanded toward the tumor microenvironment in non-GCB/ABC subtype patients.
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| 17. |
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| 18. |
- Devarakonda, Sravani, et al.
(författare)
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Low-grade intestinal inflammation two decades after pelvic radiotherapy.
- 2023
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Ingår i: EBioMedicine. - 2352-3964. ; 94
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Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors.We biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag (TMT) mass spectrometry and mRNA sequencing (mRNA-seq), we charted proteomic and transcriptomic profiles of the mucosal tissue previously exposed to a high or a low/no dose of radiation. Changes in the immune cell populations were determined with flow cytometry. The integrity of the protective mucus layers were determined by permeability analysis and 16S rRNA bacterial detection.942 proteins were differentially expressed in mucosa previously exposed to a high radiation dose compared to a low radiation dose. The data suggested a chronic low-grade inflammation with neutrophil activity, which was confirmed by mRNA-seq and flow cytometry and further supported by findings of a weakened mucus barrier with bacterial infiltration.Our results challenge the idea that pelvic radiotherapy causes an acute intestinal inflammation that either heals or turns fibrotic without progression to chronic inflammation. This provides a rationale for exploring novel strategies to mitigate chronic bowel symptoms in pelvic cancer survivors.This study was supported by the King Gustav V Jubilee Clinic Cancer Foundation (CB), The Adlerbertska Research Foundation (CB), The Swedish Cancer Society (GS), The Swedish State under the ALF agreement (GS and CB), Mary von Sydow's foundation (MA and VP).
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| 19. |
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| 20. |
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| 21. |
- Faijerson, Jonas, 1977, et al.
(författare)
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Adult neural stem/progenitor cells reduce NMDA-induced excitotoxicity via the novel neuroprotective peptide pentinin.
- 2009
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Ingår i: Journal of neurochemistry. - 1471-4159. ; 109:3, s. 858-66
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Tidskriftsartikel (refereegranskat)abstract
- Although the potential of adult neural stem cells to repair damage via cell replacement has been widely reported, the ability of endogenous stem cells to positively modulate damage is less well studied. We investigated whether medium conditioned by adult hippocampal stem/progenitor cells altered the extent of excitotoxic cell death in hippocampal slice cultures. Conditioned medium significantly reduced cell death following 24 h of exposure to 10 microM NMDA. Neuroprotection was greater in the dentate gyrus, a region neighboring the subgranular zone where stem/progenitor cells reside compared with pyramidal cells of the cornis ammonis. Using mass spectrometric analysis of the conditioned medium, we identified a pentameric peptide fragment that corresponded to residues 26-30 of the insulin B chain which we termed 'pentinin'. The peptide is a putative breakdown product of insulin, a constituent of the culture medium, and may be produced by insulin-degrading enzyme, an enzyme expressed by the stem/progenitor cells. In the presence of 100 pM of synthetic pentinin, the number of mature and immature neurons killed by NMDA-induced toxicity was significantly reduced in the dentate gyrus. These data suggest that progenitors in the subgranular zone may convert exogenous insulin into a peptide capable of protecting neighboring neurons from excitotoxic injury.
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| 22. |
- Faijerson, Jonas, 1977, et al.
(författare)
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Reactive astrogliosis induces astrocytic differentiation of adult neural stem/progenitor cells in vitro.
- 2006
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Ingår i: Journal of neuroscience research. - : Wiley. - 0360-4012 .- 1097-4547. ; 84:7, s. 1415-24
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Tidskriftsartikel (refereegranskat)abstract
- Neural stem cells reside in defined areas of the adult mammalian brain, including the dentate gyrus of the hippocampus. Rat neural stem/progenitor cells (NSPCs) isolated from this region retain their multipotency in vitro and in vivo after grafting into the adult brain. Recent studies have shown that endogenous or grafted NSPCs are activated after an injury and migrate toward lesioned areas. In these areas, reactive astrocytes are present and secrete numerous molecules and growth factors; however, it is not currently known whether reactive astrocytes can influence the lineage selection of NSPCs. We investigated whether reactive astrocytes could affect the differentiation, proliferation, and survival of adult NSPCs by modelling astrogliosis in vitro, using mechanical lesion of primary astrocytes. Initially, it was found that conditioned medium from lesioned astrocytes induced astrocytic differentiation of NSPCs without affecting neuronal or oligodendrocytic differentiation. In addition, NSPCs in coculture with lesioned astrocytes also displayed increased astrocytic differentiation and some of these NSPC-derived astrocytes participated in glial scar formation in vitro. When proliferation and survival of NSPCs were analyzed, no differential effects were observed between lesioned and nonlesioned astrocytes. To investigate the molecular mechanisms of the astrocyte-inducing activity, the expression of two potent inducers of astroglial differentiation, ciliary neurotrophic factor and leukemia inhibitory factor, was analyzed by Western blot and shown to be up-regulated in conditioned medium from lesioned astrocytes. These results demonstrate that lesioned astrocytes can induce astroglial differentiation of NSPCs and provide a mechanism for astroglial differentiation of these cells following brain injury.
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| 23. |
- Futo, M., et al.
(författare)
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Embryo-Like Features in Developing Bacillus subtilis Biofilms
- 2021
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Ingår i: Molecular Biology and Evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 38:1, s. 31-47
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Tidskriftsartikel (refereegranskat)abstract
- Correspondence between evolution and development has been discussed for more than two centuries. Recent work reveals that phylogeny-ontogeny correlations are indeed present in developmental transcriptomes of eukaryotic clades with complex multicellularity. Nevertheless, it has been largely ignored that the pervasive presence of phylogeny-ontogeny correlations is a hallmark of development in eukaryotes. This perspective opens a possibility to look for similar parallelisms in biological settings where developmental logic and multicellular complexity are more obscure. For instance, it has been increasingly recognized that multicellular behavior underlies biofilm formation in bacteria. However, it remains unclear whether bacterial biofilm growth shares some basic principles with development in complex eukaryotes. Here we show that the ontogeny of growing Bacillus subtilis biofilms recapitulates phylogeny at the expression level. Using time-resolved transcriptome and proteome profiles, we found that biofilm ontogeny correlates with the evolutionary measures, in a way that evolutionary younger and more diverged genes were increasingly expressed toward later timepoints of biofilm growth. Molecular and morphological signatures also revealed that biofilm growth is highly regulated and organized into discrete ontogenetic stages, analogous to those of eukaryotic embryos. Together, this suggests that biofilm formation in Bacillus is a bona fide developmental process comparable to organismal development in animals, plants, and fungi. Given that most cells on Earth reside in the form of biofilms and that biofilms represent the oldest known fossils, we anticipate that the widely adopted vision of the first life as a single-cell and free-living organism needs rethinking.
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| 24. |
- Kondori, Nahid, 1967, et al.
(författare)
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Mass Spectrometry Proteotyping-Based Detection and Identification of Staphylococcus aureus, Escherichia coli, and Candida albicans in Blood
- 2021
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Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media SA. - 2235-2988. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Bloodstream infections (BSIs), the presence of microorganisms in blood, are potentially serious conditions that can quickly develop into sepsis and life-threatening situations. When assessing proper treatment, rapid diagnosis is the key; besides clinical judgement performed by attending physicians, supporting microbiological tests typically are performed, often requiring microbial isolation and culturing steps, which increases the time required for confirming positive cases of BSI. The additional waiting time forces physicians to prescribe broad-spectrum antibiotics and empirically based treatments, before determining the precise cause of the disease. Thus, alternative and more rapid cultivation-independent methods are needed to improve clinical diagnostics, supporting prompt and accurate treatment and reducing the development of antibiotic resistance. In this study, a culture-independent workflow for pathogen detection and identification in blood samples was developed, using peptide biomarkers and applying bottom-up proteomics analyses, i.e., so-called "proteotyping". To demonstrate the feasibility of detection of blood infectious pathogens, using proteotyping, Escherichia coli and Staphylococcus aureus were included in the study, as the most prominent bacterial causes of bacteremia and sepsis, as well as Candida albicans, one of the most prominent causes of fungemia. Model systems including spiked negative blood samples, as well as positive blood cultures, without further culturing steps, were investigated. Furthermore, an experiment designed to determine the incubation time needed for correct identification of the infectious pathogens in blood cultures was performed. The results for the spiked negative blood samples showed that proteotyping was 100- to 1,000-fold more sensitive, in comparison with the MALDI-TOF MS-based approach. Furthermore, in the analyses of ten positive blood cultures each of E. coli and S. aureus, both the MALDI-TOF MS-based and proteotyping approaches were successful in the identification of E. coli, although only proteotyping could identify S. aureus correctly in all samples. Compared with the MALDI-TOF MS-based approaches, shotgun proteotyping demonstrated higher sensitivity and accuracy, and required significantly shorter incubation time before detection and identification of the correct pathogen could be accomplished.
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| 25. |
- Koppner, Jenny, 1973-
(författare)
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Stress and mental health in populations of societies exposed to extraordinary circumstances : with focus on perceived and biological stress, perceived health, psychosocial factors, and sense of coherence
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As our societies have grown larger, and communications have become global and fast-paced, our bodies and minds have been subjected to a mental stress different from the "fight or flight" situations we have adapted to through evolution. Furthermore, mental health issues are now seen to be on the rise all over the world. Globalisation has enabled social crises of different origins, e.g. financial or biological, to influence nations worldwide and spread faster than ever before. This thesis aims to investigate how populations are affected in regard to stress and mental health by the extraordinary circumstances of the global financial crisis of 2008 and the COVID-19 pandemic of 2020-2023.The first two studies in this thesis focus on the effects of the financial crisis on young adults (Paper I) and adults in working ages (Paper II). Greece was severely affected by the global financial crisis of 2008 and went into a decade long recession, whereas Scandinavian countries were less affected. University students were recruited from the psychology and medicine programs in Athens, Greece and Linköping, Sweden. Primary care visitors were recruited consecutively at primary health care centres (PHCC) in Greece, Sweden, and Norway. Data was collected in connection to recruitment. All participants filled out the same short questionnaire and gave hair samples that were analysed for cortisol concentrations (HCC) as a biological measure of stress.Papers III and IV are based on the Healthy OLD-study and investigate mental health, stress, and coping in older adults (70-80 years) during the COVID-19 pandemic. This age group was particularly vulnerable to the virus and therefore subjected to protective restrictions like social isolation. Participants were randomly recruited from five PHCC in south-east Sweden. Data was collected during one visit at the participant’s own PHCC and consisted of a comprehensive questionnaire, biometrics, and samples of blood, hair, and saliva. In Paper III only the questionnaire was used, and in Paper IV both the questionnaire and hair samples (analysed for HCC) were used.In Papers I and II the Greek participants reported a significantly higher occurrence of self-reported stress, anxiety, and depressive symptoms than their Swedish/Scandinavian peers. They also experienced more serious life events, and less hope for the future. In Paper I, cortisol levels were significantly lower for the Greek participants than the Swedish, which could indicate a fatigued Hypothalamic-Pituitary-Adrenal (HPA) axis due to longterm stress exposure, and/or genetic differences, and/or cultural differences. However, there was no significant difference in cortisol values between adults in working ages for Greeks and Scandinavians in Paper II, although significantly poorer overall health was reported in the Greek population compared to the Scandinavian population in Paper II. The strongest predictors explaining self-reported poor health were being Greek and feeling hopeless about the future. The strongest predictors for high perceived stress were moderate and high anxiety, and moderate depression.In Paper III social distancing was the factor most participants found had affected them the most during the COVID-19 pandemic. The participants who stated they had suffered a decline in mental health due to the COVID-19 pandemic reported more anxiety, depression, and stress than the participants who stated they had not been affected mentally. Risk factors for experiencing deteriorating mental health due to the pandemic were found to be a negative change in social life, experiencing a bad family situation, a change in physical activity, anxiety, and being a woman.In Paper IV, a low sense of coherence was significantly associated with anxiety, self-reported poor financial status, little belief in the future, and perceived negative mental effect from the COVID-19 pandemic. Anxiety was found to be a possible mediator between being mentally affected and sense of coherence. No association was found between sense of coherence and hair cortisol levels in this study. In general, women reported poorer mental health and quality of life than men, but there was no significant difference in hair cortisol levels.To conclude, the findings of this thesis show a high occurrence of stress, anxiety, and depression in adults living in societies exposed to financial crisis or the COVID-19 pandemic. Symptoms of anxiety and depression were shown to be predictors of high levels of perceived stress in young adults. Anxiety was especially prominent in older adults during the pandemic and is suggested to be a mediator in the association between sense of coherence (SoC) and participants who reported a decline in mental health due to the pandemic. A multitude of psychosocial factors were strongly correlated with SoC, respectively those mentally affected by the pandemic. Young Greek adults presented with lower HCC than their Swedish peers, which could be caused by fatigue of the HPA axis due to long-term stress exposure.The aim of this thesis does not have a direct clinical application, but the high occurrence of mental health issues, especially anxiety, found among adults living in societies exposed to extreme events emphasizes the importance of actively asking a patient how he/she is affected by a difficult life event, not least older women.
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