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1.	Högstedt, Alexandra, et al. (författare) Investigation of proteins important for microcirculation using in vivo microdialysis after glucose provocation : a proteomic study 2021 Ingår i: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 11:1 Tidskriftsartikel (refereegranskat)abstract Insulin has metabolic and vascular effects in the human body. What mechanisms that orchestrate the effects in the microcirculation, and how the responds differ in different tissues, is however not fully understood. It is therefore of interest to search for markers in microdialysate that may be related to the microcirculation. This study aims to identify proteins related to microvascular changes in different tissue compartments after glucose provocation using in vivo microdialysis. Microdialysis was conducted in three different tissue compartments (intracutaneous, subcutaneous and intravenous) from healthy subjects. Microdialysate was collected during three time periods; recovery after catheter insertion, baseline and glucose provocation, and analyzed using proteomics. Altogether, 126 proteins were detected. Multivariate data analysis showed that the differences in protein expression levels during the three time periods, including comparison before and after glucose provocation, were most pronounced in the intracutaneous and subcutaneous compartments. Four proteins with vascular effects were identified (angiotensinogen, kininogen-1, alpha-2-HS-glycoprotein and hemoglobin subunit beta), all upregulated after glucose provocation compared to baseline in all three compartments. Glucose provocation is known to cause insulin-induced vasodilation through the nitric oxide pathway, and this study indicates that this is facilitated through the interactions of the RAS (angiotensinogen) and kallikrein-kinin (kininogen-1) systems.
2.	Högstedt, Alexandra, 1993- (författare) Microvascular effects of insulin in the skin 2021 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The microcirculation in the skin is essential for skin homeostasis. In instances of altered microvascular function, that may be the result of insulin resistance, tissue morbidity may ensue. The underlying mechanisms are however complex and not fully understood. By studying the physiological effects of insulin in the skin, the understanding of the complex interplay between glucose metabolism and skin microcirculation can be improved. The general aim of this thesis was to develop an experimental in vivo model to study metabolic and microvascular responses to insulin in the skin in healthy subjects. Microdialysis is a suiting technique as it allows for both local delivery of drugs and simultaneous monitoring of the local metabolic and vascular effects in the very same tissue compartment. The effects of local and systemic insulin provocation on skin blood flow and metabolism were investigated using microdialysis urea clearance and laser speckle contrast imaging (paper I). An insulin dependent increase in skin blood flow was observed, presumably induced through the nitric oxide pathway (paper II). Investigating the protein expression during an oral glucose provocation using proteomic approaches however indicates interactions with other pathways, such as the renin-angiotensin system and the kallikrein-kinin system (paper IV). Paper III also investigated methodological concerns regarding the sampling of insulin using microdialysis. This in vivo model can, in the future, be applied to assess the microvascular effects of insulin in the skin in different patient groups, including those with micro-vascular dysfunction due to, for instance, insulin resistance.
3.	Stensson, Niclas, 1974- (författare) Endocannabinoids and Related Lipids in Chronic Pain : Analytical and Clinical Aspects 2018 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract In Europe, approximately one in five adults experience chronic pain, pain that lasts more than three months. Chronic pain is a significant problem not only for those people suffering from chronic pain but also for society. The prevalence of chronic pain is higher in women and lower socioeconomic groups. Although chronic pain often originates in a specific site, it may eventually spread to several sites, transforming into chronic widespread pain (CWP), a condition evident in about 10% of the adult population. Approximately 1.2-5.4% are classified with fibromyalgia (FM). In addition to CWP, common symptoms of FM include, stiffness, fatigue, sleep disturbances, and cognitive dysfunction and common co-morbidities include depression and anxiety. Although FM/CWP has been reported to alter both central and peripheral nociceptive mechanisms, no objective biomarkers have been found that correlate with CWP/FM and no standard examinations such as blood test, X-ray or computed tomography can provide support for a diagnosis. Because there are no objective biomarkers that correlate with the pathophysiological processes associated with CWP/FM, this debilitating disease is difficult to diagnose and ultimately treat. However, there are some promising therapeutic targets for chronic pain with inter alia analgesic, anti-inflammatory, and stress modulating properties: the endocannabinoids (ECs) arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) and their related lipids oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA).This thesis investigates whether ECs and the related N-acylethanolamines (NAEs) can be used as potential biomarkers for CWP/FM. Specifically, the studies compared the peripheral and systemic levels of ECs and NAEs in 121 women with CWP/FM and in 137 healthy controls in two different cohorts. In addition, the correlation between lipid levels and common pain characteristics such as intensity, sensitivity, and duration were investigated. The EC and related lipid levels were measured using liquid chromatography in combination with tandem mass spectrometry. Multivariate data analysis was used for biomarker evaluation.Compared to the healthy controls, the CWP/FM patients had significantly higher concentrations of OEA, PEA, and SEA in muscle and plasma (p ≤ 0.05) and significantly higher 2-AG in plasma (p ≤ 0.01). These results may indicate that NAEs, are mobilized differently in painful muscles compared with pain free muscles. Moreover, increased systemic levels of NAEs and 2-AG in patients might be signs of ongoing low-grade inflammation inCWP/FM. These findings contribute to a better understanding of how peripheral and systemic factors maintain and activate chronic pain. Although the investigated lipids have statistically significant effects but biologically uncertain role in the clinical manifestations of CWP/FM. Thus plasma lipids are not a good biomarker for CWP/FM. Nevertheless, increased lipid levels indicate a metabolic asymmetry in CWP/FM, a finding that could serve as a basis for more research on pain management.
4.	Bäckryd, Emmanuel, et al. (författare) Cerebrospinal Fluid Metabolomics Identified Ongoing Analgesic Medication in Neuropathic Pain Patients 2023 Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:9 Tidskriftsartikel (refereegranskat)abstract Background: Cerebrospinal fluid (CSF) can reasonably be hypothesized to mirror central nervous system pathophysiology in chronic pain conditions. Metabolites are small organic molecules with a low molecular weight. They are the downstream products of genes, transcripts and enzyme functions, and their levels can mirror diseased metabolic pathways. The aim of this metabolomic study was to compare the CSF of patients with chronic neuropathic pain (n = 16) to healthy controls (n = 12). Methods: Nuclear magnetic resonance spectroscopy was used for analysis of the CSF metabolome. Multivariate data analysis by projection discriminant analysis (OPLS-DA) was used to separate information from noise and minimize the multiple testing problem. Results: The significant OPLS-DA model identified 26 features out of 215 as important for group separation (R2 = 0.70, Q2 = 0.42, p = 0.017 by CV-ANOVA; 2 components). Twenty-one out of twenty-six features were statistically significant when comparing the two groups by univariate statistics and remained significant at a false discovery rate of 10%. For six out of the top ten metabolite features, the features were absent in all healthy controls. However, these features were related to medication, mainly acetaminophen (=paracetamol), and not to pathophysiological processes. Conclusion: CSF metabolomics was a sensitive method to detect ongoing analgesic medication, especially acetaminophen.
5.	Farnebo, Simon, et al. (författare) Differentially Expressed Proteins in Intra Synovial Compared to Extra Synovial Flexor Tendon Grafts in a Rabbit Tendon Transplantation Model 2020 Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 8:10 Tidskriftsartikel (refereegranskat)abstract Uncomplicated healing of grafts for tendon reconstruction remains an unsolved problem in hand surgery. Results are limited by adhesion formation and decreased strength properties, especially within the tight fibro-osseous sheath of the digits. This is especially problematic when an extra synovial tendon graft is used to replace an intra synovial flexor tendon. Compositional differences are likely to play an important role in these processes. The aim of this study was, therefore, to compare protein expression in pair-matched intra synovial tendon grafts with extra synovial tendon grafts, using a rabbit tendon injury model. We hypothesized that there would be significant differences in proteins critical for response to tensile loading and adhesion formation between the two groups. Using mass spectrometry and multivariate statistical data analysis, we found tissue-specific differences in 22 proteins, where 7 explained 93% (R2) of the variation, with a prediction of 81% (Q2). Among the highest discriminating proteins were Galectin, Histone H2A, and Periostin, which were found in a substantially larger amount in the extra synovial tendons compared to the intra synovial tendons. These findings may contribute to improved understanding of the differences in outcome seen after tendon reconstruction using tendon grafts with intra synovial and extra synovial grafts.
6.	Gerdle, Björn, 1953-, et al. (författare) Changes in inflammatory plasma proteins from patients with chronic pain associated with treatment in an interdisciplinary multimodal rehabilitation program - an explorative multivariate pilot study. 2020 Ingår i: Scandinavian Journal of Pain. - : Walter de Gruyter. - 1877-8860 .- 1877-8879. ; 20:1, s. 125-138 Tidskriftsartikel (refereegranskat)abstract It has been suggested that alterations in inflammation molecules maintain chronic pain although little is known about how these factors influence homeostatic and inflammatory events in common chronic pain conditions. Nonpharmacological interventions might be associated with alterations in inflammation markers in blood. This study of patients with chronic pain investigates whether an interdisciplinary multimodal rehabilitation program (IMMRP) was associated with significant alterations in the plasma pattern of 68 cytokines/chemokines 1 year after rehabilitation and whether such changes were associated with clinical changes. Blood samples and self-reports of pain, psychological distress, and physical activity of 25 complex chronic pain patients were collected pre-IMMRP and at 12-month follow-up. Analyses of inflammatory proteins (cytokines/chemokines/growth factors) were performed directly in plasma using the multiplex immunoassay technology Meso Scale Discovery. This explorative pilot study found that 12 substances, mainly pro-inflammatory, decreased after IMMRP. In two other relatively small IMMRP studies, four of these proinflammatory markers were also associated with decreases. The pattern of cytokines/chemokines pre-IMMRP was associated with changes in psychological distress but not with pain or physical activity. The present study cannot impute cause and effect. These results together with the results of the two previous IMMRP studies suggest that there is a need for larger and more strictly controlled studies of IMMRP with respect to inflammatory markers in blood. Such studies need to consider responders/non-responders, additional therapies, involved pain mechanisms and diagnoses. This and the two other studies open up for developing biologically measurable outcomes from plasma. Such biomarkers will be an important tool for further development of IMMRP and possibly other treatments for patients w ith chronic pain.
7.	Gerdle, Björn, 1953-, et al. (författare) Proteomic studies of common chronic pain conditions-a systematic review and associated network analyses 2020 Ingår i: Expert Review of Proteomics. - : TAYLOR & FRANCIS LTD. - 1478-9450 .- 1744-8387. ; 17:6, s. 483-505 Forskningsöversikt (refereegranskat)abstract Introduction The lack of biomarkers indicating involved nociceptive and/or pain mechanisms makes diagnostic procedures problematic. Clinical pain research has begun to use proteomics. Areas covered This systematic review covers proteomic studies of chronic pain cohorts and in relation to clinical variables. Searches in three databases identified 96 studies from PubMed, 161 from Scopus and 155 from Web of Science database. Finally, 27 relevant articles were included. Network analyses based on the identified proteins were performed. Expert opinion Small pain cohorts were investigated and the number of studies per diagnosis and tissue is small. The use of proteomics in chronic pain research is exploratory and larger proteomic studies are needed. It will be necessary to standardize the descriptions of the pain cohorts investigated. There is a need to identify the mechanisms underlying the whole clinical presentation of specific chronic pain conditions. Multivariate methods capable of handling and identifying intercorrelated protein patterns must be applied. Rather than focusing on a few proteins, future studies should use network analyses to investigate interactions and biological processes. Proteomics in combination with bioinformatics have a huge potential to identify previously unknown panels of proteins involved in chronic pain and relevant when devising new pain control strategies.
8.	Ghafouri, Bijar, 1972-, et al. (författare) An investigation of metabolome in blood in patients with chronic peripheral, posttraumatic/postsurgical neuropathic pain. 2022 Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12 Tidskriftsartikel (refereegranskat)abstract Neuropathic pain (NP) is a chronic pain condition resulting from a lesion or disease in the somatosensory nervous system. The aim of this study was to investigate the metabolome in plasma from patients with chronic peripheral, posttraumatic/postsurgical NP compared to healthy controls. Further, we aimed to investigate the correlation between pain intensity and the metabolome in plasma. The metabolic profile in plasma samples from 16 patients with chronic NP and 12 healthy controls was analyzed using a nuclear magnetic resonance spectroscopy method. Information about pain intensity, pain duration, body mass index (BMI), age, sex, and blood pressure were obtained through a questionnaire and clinical examination. Multivariate data analysis was used to identify metabolites significant for group separation and their correlation with pain intensity and duration, BMI, and age. We found 50 out of 326 features in plasma significantly contributing to group discrimination between NP and controls. Several of the metabolites that significantly differed were involved in inflammatory processes, while others were important for central nervous system functioning and neural signaling. There was no correlation between pain intensity and levels of metabolite in NP. These findings indicate that there seems to be peripheral/systemic differences in the metabolic profile between patients with chronic NP and healthy individuals.
9.	Ghafouri, Bijar, 1972-, et al. (författare) Comparative proteomics of nasal fluid in seasonal allergic rhinitis 2006 Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 5:2, s. 330-338 Tidskriftsartikel (refereegranskat)abstract A comparative proteomic approach was applied to examine nasal lavage fluid (NLF) from patients with seasonal allergic rhinitis (SAR, n = 6) and healthy subjects (controls, n = 5). NLF samples were taken both before allergy (pollen) season and during season, and proteins were analyzed by two-dimensional gel electrophoresis (2-DE) and matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) after tryptic cleavage. Twenty proteins were selected and quantified. During allergy season, the levels of six sialylated isoforms of PLUNC (palate lung nasal epithelial clone) were lower in SAR patients than controls, as were the levels of six isoforms of von Ebner's gland protein (VEGP), including a previously undescribed form with N-linked glycosylation, and of cystatin S. PLUNC is a new innate immunity protein and VEGP and cystatin S are two endogenous proteinase inhibitors. By contrast, the levels of an acidic form of alpha-1-antitrypsin were higher in SAR patients than controls. One previously unidentified NLF protein was found in all samples from the SAR patients during allergy season but not in any sample before allergy season: this protein was identified as eosinophil lysophospholipase (Charcot-Leyden crystal protein/galactin 10). MS/MS analysis of the N-terminus of the protein showed removal of Met and acetylation of Ser. Altogether, these findings illustrate the potential use of proteomics for identifying protein changes associated with allergic rhinitis and for revealing post-translational modifications of such new potential markers of allergic inflammation.
10.	Ghafouri, Bijar, 1972-, et al. (författare) Mapping of proteins in human saliva using two-dimensional gel electrophoresis and peptide mass fingerprinting 2003 Ingår i: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 3:6, s. 1003-1015 Tidskriftsartikel (refereegranskat)abstract Human saliva contains a large number of proteins that can be used for diagnosis and are of great potential in clinical and epidemiological research. The aim of this work was to map the proteins in saliva by two-dimensional gel electrophoresis (2-DE), and to identify abundant proteins by peptide mass fingerprinting using trypsin cleavage and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry analysis. One hundred proteins were identified representing 20 different identities according to accession numbers. Abundant proteins expressed in different forms were: α-amylase, immunoglobulin A, prolactin-inducible protein, zinc-α2-glycoprotein and cystatins (S, SA, D and SN). Other proteins found were interleukin-1 receptor antagonist, von Ebner’s gland protein (lipocalin-1) and calgranulin A and B (S100A8 and A9). Furthermore, apolipoprotein A-I, β2-microglobulin, glutathione S-transferase P and fatty acid-binding protein were also identified. Our results show that human saliva contains a large number of proteins that are involved in inflammatory and immune responses. The 2-DE protein map constructed opens the possibility to investigate protein changes associated with disease processes.
11.	Ghafouri, Bijar, 1972-, et al. (författare) Note: 2,5-Dihydroxybenzoic acid instead of α-cyano-4-hydroxycinnamic acid as matrix in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for analyses of in-gel digests of silver-stained proteins : in Analytical Biochemistry(ISSN 0003-2697), vol 371, issue 1, pp 121-123 2007 Ingår i: Analytical Biochemistry. - : Elsevier. - 0003-2697 .- 1096-0309. ; 371:1, s. 121-123 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
12.	Ghafouri, Bijar, 1972-, et al. (författare) PLUNC in human nasal lavage fluid : multiple isoforms that bind to lipopolysaccharide 2004 Ingår i: Biochimica et Biophysica Acta - Proteins and Proteomics. - 1570-9639 .- 1878-1454. ; 1699:1-2, s. 57-63 Tidskriftsartikel (refereegranskat)abstract Here, we demonstrate the presence of multiple isoforms of palate lung nasal epithelial clone (PLUNC) in human nasal lavage fluid (NLF). Eight isoforms were separated by two-dimensional gel electrophoresis (2-DE), and peptide mapping of the proteins was performed using MALDI-TOF MS (matrix assisted laser desorption/ionization time of flight mass spectrometry) of tryptic and asparginase cleavages. The identification was verified by amino acid sequencing after analysis of collision-induced dissociation (CID) fragmentation spectra with nanoelectrospray MS/MS. One isoform showed an electrophoretic mobility shift after N-glycosidase treatment, indicating that at least one of the PLUNC isoforms is glycosylated. We also demonstrate that PLUNC in NLF binds to lipopolysaccharide (LPS) in vitro; indeed, out of all proteins present in NLF only the PLUNC isoforms were found to adsorb to an LPS-coated surface. These results show that PLUNC is expressed as multiple LPS-binding isoforms in human NLF. The possibility that PLUNC may play a role in the innate immune response of the upper airways is inferred.
13.	Ghafouri, Bijar, 1972-, et al. (författare) PLUNC (palate, lung and nasal epithelial clone) proteins in human nasal lavage fluid 2003 Ingår i: Biochemical Society Transactions. - 0300-5127 .- 1470-8752. ; 31:4, s. 810-814 Tidskriftsartikel (refereegranskat)abstract PLUNC (palate, lung and nasal epithelial clone) is a newly discovered gene that is expressed in the upper respiratory tract and is suggested to be of importance in host defence against bacteria. We have identified two forms of the PLUNC protein in human nasal lavage fluid (NLF) using two-dimensional gel electrophoresis (2-DE) and MS. The apparent molecular masses and isoelectric points of these forms are 24.8 kDa/pI 5.4 and 25.1 kDa/pI 5.5. Notably, the 24.8 kDa/pI 5.4 form of PLUNC is an abundant protein in the 2-DE protein patterns of NLF from healthy subjects. Decreased levels of PLUNC were found in NLF from smokers and workers exposed to reactive epoxy chemicals, indicating that long-term exposure to airway irritants impairs the production of PLUNC in the upper respiratory tract. We have also investigated the presence of lipopolysaccharide (LPS)-binding proteins in NLF. Five proteins were found to adsorb to a LPS-coated surface; two of these proteins correspond to the two PLUNC forms, as judged by 2-DE pattern matching. For comparison, human saliva was found to contain a set of LPS-binding proteins with similar 2-DE spot positions (the same pIs but somewhat lower apparent molecular masses of 20 kDa). These results indicate that PLUNC may be a new marker of airway inflammation and may play a part in the innate immune response, and that human saliva contains yet other members of the family of LPS-binding proteins.
14.	Ghafouri, Bijar, 1972- (författare) Proteomics of the upper airways : studies on a new lipopolysaccharide-binding protein, PLUNC 2005 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract There is now significant interest in identifying, quantifying and characterizing the human proteome, and new powerful techniques (proteomics) have evolved to deal with this giant task. In the present study, proteomics have been applied for the first time to map the proteins of the upper airways. The protein contents of human nasal fluid (NLF) and saliva were analysed using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and the proteins were identified by peptide mass fingerprinting using matrix assisted laser desorptioniionization time of night mass spectrometry (MALDI-TOF MS) or by amino acid sequencing using electrospray ionization tandem mass spectrometry (ESI- MS/MS). More than 100 proteins were identified and protein maps of nasal fluid and saliva were thus established. Of particular interest was the identification of a new lipopolysaccharide (LPS)-binding protein, PLUNC (palate lung and nasal epithelial clone), which was shown to be the only protein in NLF that binds to LPS. PLUNC was characterized as multiple isoforms (Mr/p1: 27/5.1, 26/5.2, 25/5.3, 27.5/5.1, 27/5.2, 26/5.3, 25.1/5.5 and 24.8/5.4), and several of these isoforms were demonstrated to be sialylated. Notably, decreased levels of PLUNC were found in NLF of (i) smokers, (ii) epoxy workers with airway irritation, and (iii) patients with seasonal allergic rhinitis (SAR) during allergy season. In addition, the levels of von Ebner's gland protein, α1-antitrypsin, cystatin S, Clara cell protein 16 and lipocortin-1 were altered, either in smokers or SAR patients or both. One previously unidentified NLF protein was found in SAR patients during allergy season but not before season: this protein was identified as eosinophil lysophospholipase. Many of these proteins were post-translationally modified by glycosylation (PLUNC, α1-antitrypsin, von Ebner's gland protein), phosphorylation (cystatin S), acetylation (eosinophil lysophospholipase), or truncation (lipocortin-1). Altogether, these findings illustrate the potential use of proteomics for identifying new markers of upper airway inflammation and for revealing structural details of such markers. The findings also indicate that allergic inflammation in the nasal mucosa is associated with decreased nasal fluid levels of the endogenous proteinase inhibitors, cystatin S and von Ebner's gland protein, and of the new irritation marker, PLUNC. Further studies are required to explore the possibility that PLUNC plays an important part in microbial recognition and that this function is impaired after exposure to airway irritants and during upper airway inflammation.
15.	Jasim, Hajer, et al. (författare) Diurnal variation of inflammatory plasma proteins involved in pain 2019 Ingår i: Pain Reports. - : Wolters Kluwer. - 2471-2531. ; 4:5 Tidskriftsartikel (refereegranskat)abstract Introduction: Proteomics is a powerful approach for biochemical research because it directly studies the main functional components of biochemical systems. The understanding of the normal fluctuations of the proteome in health is essential to identify pain-specific biomarkers.Objective: To investigate fluctuations of the plasma proteome in healthy pain-free individuals.Methods: Blood samples were structurally collected in the early morning and evening from 10 clinically healthy individuals (26.3 ± 3.3 years). High abundant proteins were removed from plasma, and proteins were then analysed by nanoliquid chromatography combined with mass spectrometry. In addition, an assay of 71 cytokines/chemokines/growth factors was analysed.Results: Multivariate statistical analysis displayed that there were up to 64 proteins whose expression levels were significantly altered between the plasma samples collected during the morning and evening; no changes existed for the assay. The levels of 34 proteins were increased and 30 proteins were decreased during the evening compared with the morning sample. The increased proteins were involved in the biological processes such as protein activation cascade, complement activation, and stress response. The decreased proteins were involved in regulation of endopeptidase activity, inflammatory response, and protein metabolic processes.Conclusion: The circadian variations in the plasma proteome stress the need to collect blood samples of both patients and controls at a fixed time of the day. The results in this study might be useful for better understanding of the complexity of individual variation in the human plasma proteome over time and provide a baseline for improved pain biomarker discovery.
16.	Kallman, Thomas F., et al. (författare) Salivary beta-endorphin and substance P are not biomarkers of neuropathic chronic pain propensity 2018 Ingår i: Heliyon. - : Elsevier. - 2405-8440. ; 4:8 Tidskriftsartikel (refereegranskat)abstract ObjectiveThe pathophysiology of chronic pain is complex, with most of our knowledge being derived from preclinical studies. The search for biomarkers mirroring the pathophysiology of chronic pain is ongoing, and there is an increasing interest in saliva as a diagnostic tool. Given what is known about salivary substance Pand salivary gland innervation, we hypothesized that salivary substance P and/or beta-endorphin might reflect the basal activity of these neuropeptides in the central nervous system, thereby perhaps mirroring a general propensity to chronic pain. Based on this overall hypothesis, our aim was to compare salivary levels of these neuropeptides in chronic neuropathic pain patients with healthy controls. An additional aim was to relate salivary levels to plasma levels.Materials and methodsWe compared salivary concentrations of beta-endorphin and substance P in 14 chronic neuropathic pain patients with concentrations in 18 healthy controls using a Luminex technology kit. Salivary-to-plasma quotients were also calculated.ResultsWe found no significant difference between the groups' salivary concentrations of substance P and beta-endorphin. No correlation was found between salivary and plasma concentrations of each neuropeptide, which we hypothesize might point to local production of beta-endorphin and/or substance P in the salivary glands. Given high substance P salivary-to-plasma quotients, such a local production seems more likely for substance P than for beta-endorphin.ConclusionsPropensity to neuropathic chronic pain was not substantiated by our analysis of salivary levels of substance P and/or beta-endorphin. However, we report salivary-to-plasma quotients that give potentially important physiological insight about these neuropeptides.
17.	Karlsson, Helen, 1961-, et al. (författare) Kartläggning av proteiner i LDL och HDL med två-dimensionell gelelektrofores samt masspektrometri. 2003 Ingår i: Svenska Läkaresällskapets Handlingar,2003. ; , s. 11-26 Konferensbidrag (refereegranskat)
18.	Ljunggren, Stefan, 1988-, et al. (författare) Modified lipoproteins in periodontitis : a link to cardiovascular disease? 2019 Ingår i: Bioscience Reports. - : Portland Press. - 0144-8463 .- 1573-4935. ; 39:3 Tidskriftsartikel (refereegranskat)abstract 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 hypothesize that patients with periodontitis have an altered lipoprotein profile towards an atherogenic form. Therefore, this 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 two-dimensional gel-electrophoresis and identified by map-matching or by nano-liquid chromatography followed by mass spectrometry. 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 HDL from the patients. In LDL/VLDL, the levels of apoL-1 and platelet-activating factor acetylhydrolase 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. 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 posttranslational 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).
19.	Mayo, Leah M., 1987-, et al. (författare) Protective effects of elevated anandamide on stress and fear-related behaviors : translational evidence from humans and mice 2020 Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:5, s. 993-1005 Tidskriftsartikel (refereegranskat)abstract Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C-greater thanA substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.
20.	Nyman, Erika, 1976-, et al. (författare) Hyaluronic Acid Accelerates Re-epithelialization and Alters Protein Expression in a Human Wound Model 2019 Ingår i: Plastic and Reconstructive Surgery - Global Open. - : Lippincott Williams & Wilkins. - 2169-7574. ; 7:5 Tidskriftsartikel (refereegranskat)abstract Background: Hyaluronic acid (HA), a large glycosaminoglycan involved in proliferation, migration, and tissue repair, is suggested to be an important factor for keratinocyte activation and re-epithelialization. The experimental hypothesis of this study was that HA accelerates re-epithelialization, and we aimed to investigate the effect of exogenous intradermal HA during deep dermal, incisional wound healing in vivo in humans, the primary endpoint being re-epithelialization. Methods: A total of 8 standardized deep dermal incisional wounds (depth 1.6mm, width 1.8mm) per subject were induced in 10 healthy volunteers. Two of the wound sites per subject were pretreated with injections of HA and 2 with saline solution. At 2 time points (24 hours and 14 days), 2 biopsies for each treatment group (one for histology and one for proteomics) were taken. Skin erythema was measured at 24-hour intervals for 14 days as a surrogate measurement of inflammation. Results: At 24 hours, 8 of 9 wounds pretreated with HA showed complete re-epithelization, whereas none of the wounds pretreated with saline had re-epithelized. Wounds pretreated with HA also showed a 10-fold regulation of 8 identified proteins involved in wound healing compared to wounds treated with saline solution. No difference in inflammation, as measured as erythema, could be seen between any of the groups. Conclusions: We conclude that HA accelerates re-epithelialization and stimulates an altered protein expression in vivo in human deep dermal incisional skin wounds, but has no effect on the inflammation process as measured by erythema.
21.	Perini, Irene, 1983-, et al. (författare) Resilience to substance use disorder following childhood maltreatment: association with peripheral biomarkers of endocannabinoid function and neural indices of emotion regulation 2023 Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; :6, s. 2563-2571 Tidskriftsartikel (refereegranskat)abstract Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure.
22.	Tobieson, Lovisa (författare) Surgically Treated Intracerebral Haemorrhage : Pathophysiology and Clinical Aspects 2019 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Mortality and morbidity of intracerebral haemorrhage (ICH) is excessively high, and the case fatality rate has not improved in the last decades. Although surgery for ICH can be life-saving, no positive effect on functional outcome has been found in large cohorts of ICH patients. Increased understanding of the pathophysiology of ICH is needed to develop improved treatment strategies.In 17 ICH patients, paired cerebral microdialysis (CMD) catheters were inserted in the perihaemorrhagic zone (PHZ) and in normal uninjured cortex at time of surgery. Despite normalisation of cerebral blood flow, a persistent metabolic crisis indicative of mitochondrial dysfunction was detected in the PHZ. This metabolic pattern was not observed in the uninjured cortex.CMD was also used to sample proteins for proteomic analysis. A distinct proteome profile that changed over time was found in the PHZ when compared to the seemingly normal, uninjured cortex. However, protein adsorption to CMD membranes, which may interfere with concentration measurements, was substantial.Surgical treatment of 578 ICH patients was analysed in a nation-wide retrospective multi-centre study in Sweden over five years. Patients selected for surgery had similar age, pre-operative level of consciousness and co-morbidity profiles, but ICH volume and the proportion of deep-seated ICH differed among the six neurosurgical centres. Furthermore, there was variability in the post-operative care, including the use and duration of intracranial pressure monitoring, cerebrospinal fluid drainage and mechanical ventilation.In conclusion, the results of this thesis show that:(i) Despite surgical removal of an ICH a metabolic crisis caused by mitochondrial dysfunction, a potential future therapeutic target, persists in the perihaemorrhagic zone.(ii-iii) CMD is a valuable tool in ICH research for sampling novel biomarkers using proteomics, which may aid in the development of improved therapeutic interventions. However, caveats of the technique, such as protein adsorption to the CMD membrane, must be considered.(iv) The nation-wide study illustrates similar clinical features in patients selected for ICH surgery, but substantial variability in ICH volume and location as well as neurocritical care strategies among Swedish neurosurgical centres. Development of refined clinical guidelines may reduce such intercentre variability and lead to improved functional outcome for ICH patients.
23.	Wåhlén, Karin, 1986-, et al. (författare) Proteomic Investigation in Plasma from Women with Fibromyalgia in Response to a 15-wk Resistance Exercise Intervention 2022 Ingår i: Medicine & Science in Sports & Exercise. - Philadelphia, PA, United States : Ovid Technologies (Wolters Kluwer Health). - 0195-9131 .- 1530-0315. ; 54:2, s. 232-246 Tidskriftsartikel (refereegranskat)abstract PurposeFibromyalgia (FM) is a complex pain condition, and exercise is considered the first option of treatment. Few studies have examined the effect of exercise on molecular mechanisms in FM. The aim of this study was to analyze the plasma proteome in women with FM and healthy controls (CON) before and after 15 wk of resistance exercise. This study further investigated whether clinical and exercises-related outcomes correlated with identified plasma proteins in FM.MethodsPlasma samples from 40 FM/25 CON (baseline) and 21 FM/24 CON (postexercise) were analyzed using shotgun proteomics. Clinical/background data were retrieved through questionnaires. Exercise-related variables and pressure pain thresholds were assessed using standardized instruments. Multivariate statistics were applied to analyze the proteomic profile at baseline and postexercise, and correlation with clinical/exercise-related data.ResultsFifteen weeks of resistance exercises improved clinical symptoms and muscle strength, and affected circulating proteins related to immunity, stress, mRNA stability, metabolic processes, and muscle structure development in FM. Pressure pain threshold was related to a specific protein profile, with proteins involved in metabolic and immune response. Subgroups of FM based on plasma proteins, FM duration, and improved muscle strength were identified.ConclusionsExercise seems to affect circulating proteins, clinical characteristics, and muscle strength in FM. This study contributes to better understanding of systemic protein changes in FM compared with CON and how resistance exercise affects such changes.
24.	Wåhlén, Karin, 1986- (författare) The pain profile in fibromyalgia : Painomic studies of pain characteristics and proteins in blood 2020 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Chronic widespread pain (CWP), including fibromyalgia (FM), is a complex pain condition, where little is known about the molecular mechanisms contributing to its pathophysiology. To date, there are no established biomarkers for CWP/FM. This thesis has investigated potential molecular mechanisms and biomarkers in blood for chronic pain in women with CWP/FM. Furthermore, investigations are made to evaluate whether common pain characteristics such as pain intensity, sensitivity, and psychological distress in CWP/FM are correlated with specific proteins in blood.The pain profile of CWP/FM, which includes the plasma proteome and clinical characteristics, is analyzed using proteomics, advanced multivariate statistics, and bioinformatics. The results from paper I, III, and IV indicate that there are prominent systemic changes related to immunity, inflammation, and metabolic processes in women with CWP/FM compared to healthy controls. Furthermore, paper II and III show that in CWP/FM, pain intensity is related to protein profiles involved in immunity processes, psychological distress with metabolic and immunity processes, and pain sensitivity with inflammatory processes.In paper IV, the plasma proteome is investigated before and after a 15 weeks resistance exercise intervention in FM and healthy controls. Both at baseline and post exercise in FM and controls, prominent protein alterations are found that are involved in immunity, stress, mRNA stability, and muscle structure development. Exercise seems to influence clinical characteristics and circulating proteins in FM. Furthermore, specific plasma proteome profile is found related to grade of chronification, pain sensitivity, and improved muscle force of the quadriceps muscle.To summarize, the results from this thesis suggest that in CWP/FM there might be a dysregulation in the biological processes involved in the immune system and metabolic processes, which are tightly linked to several proteins in the complement system and blood coagulation cascade. These results shed light on potential ongoing mechanisms involved in the pathophysiology of the complex pain condition CWP/FM. This type of biomarker research has a large potential in increasing knowledge about mechanisms involved in CWP/FM and can hereby open for better clinical understanding and management of this and other chronic pain states. The clinical value of collecting a blood sample and measuring stable pain mechanism markers in combination with evaluation of anamnesis and clinical examination would in the future help clinicians and patients receive a faster and more precise diagnosis and ultimately better treatment strategies.
25.	Ydrefors, Johannes, et al. (författare) Automated Nociceptive Withdrawal Reflex Measurements Reveal Normal Reflex Thresholds and Augmented Pain Ratings in Patients with Fibromyalgia. 2020 Ingår i: Journal of clinical medicine. - Switzerland : MDPI AG. - 2077-0383. ; 9:6 Tidskriftsartikel (refereegranskat)abstract The nociceptive withdrawal reflex (NWR) is used to probe spinal cord excitability in chronic pain states. Here, we used an automated and unbiased procedure for determining the NWR threshold and compared the reflex thresholds and corresponding pain ratings in a well-characterized cohort of fibromyalgia (n = 29) and matched healthy controls (n = 21). Surface electrical stimuli were delivered to the foot in a stepwise incremental and decremental manner. The surface electromyographic activity was recorded from the ipsilateral tibialis anterior muscle. Fibromyalgia patients reported significantly higher scores for psychological distress and pain-related disability and a significantly lower score for perceived state of health compared to the matched controls. The subjective pain ratings were significantly higher in patients. The NWR thresholds were similar to the controls. In the patients, but not in controls, the NWR thresholds and subjective pain ratings were significantly correlated. Our results showed an increased subjective pain sensitivity in fibromyalgia, but we found no evidence for spinal sensitization based on the reflex measures.

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