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  • 401.
    Undin, Torgny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Dahlin, Andreas P
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Wetterhall, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Competitive Protein Adsorption as Observed and Quantified by - Surface Enzymatic Digestion (oSED) and Mass Spectrometry2012In: 60th ASMS Conference on Mass Spectrometry and Allied Topics, May 20 - 24, Vancouver, Canada, 2012Conference paper (Refereed)
  • 402.
    Undin, Torgny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergström Lind, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Dahlin, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    A mass spectrometry based method for investigating time dependent protein adsorption on surfaces in contact with complex biological samplesArticle in journal (Other academic)
  • 403.
    Undin, Torgny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlin, Andreas P
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    MS for investigation of time-dependent protein adsorption on surfaces in complex biological samples2015In: Future Science OA, ISSN 2056-5623, article id 32Article in journal (Refereed)
    Abstract [en]

    Aim: This study aims at developing a nondestructive way for investigating proteinadsorption on surfaces such as biomaterials using mass spectrometry. Methods: Ventricular cerebrospinal fluid in contact with poly carbonate membranes were usedas adsorption templates and on-surface enzymatic digestion was applied to desorbproteins and cleave them into peptides. Mass spectrometric analysis provided bothprotein identification and determination of protein specific adsorption behavior. Results: In general, the adsorption increased with incubation time but also proteinspecifictime-resolved adsorption patterns from the complex protein solutionwere discovered. Conclusion: The method developed is a promising tool for thecharacterization of biofouling, which sometimes causes rejection and encapsulationof implants and can be used as complement to other surface analytical techniques.

    One problem associated with artificial materials in the body is that proteins in thebody interact with the surface, which sometimes causes rejection of the implant.In this study, a method for investigating the time-dependent protein adsorptionon a surface originating from a complex biological protein solution was developed.Compared with other surface analyses, this method can identify what proteins thatadsorbs on the surface. In addition, determination of protein-specific adsorptionbehavior in relation to incubation was possible

  • 404.
    Undin, Torgny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Dahlin, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Wetterhall, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Investigation of Time Dependent Competitive Protein Adsorption to Surfaces Using Mass Spectrometry2013Conference paper (Refereed)
    Abstract [en]

    Introduction

    Surfaces in a complex protein solution will adsorb proteins. This event is fast and dynamic and triggers a biological response against the inserted/implanted biomaterial that eventually will lead to biofouling and encapsulation. This affects the properties of the inserted devices, such as hampered membrane functions of microdialysis (MD) probes or distortion in response of biosensors.

    Methods

    Untreated and coated filtration membranes were used as adsorption templates for human ventricular cerebrospinal fluid (vCSF). After adsorption in an incubation chamber, the membranes were washed, dried and the proteins were reduced, alkylated and digested. The sample preparation procedure was conducted according to an on-surface enzymatic digestion (oSED) protocol previously described by our group. The oSED digests were analyzed by nanoLC ESI-MS/MS using a 7T hybrid LTQ FT and Velos pro orbitrap mass spectrometer.

    Preliminary Data

    In this study, we present a time resolved map of protein adsorption. Non-coated and tri-block polymer coated, polycarbonate membranes was used as templates. As expected, a time and surface property dependent protein adsorption relationship was observed. It is not surprising that the degree of protein binding onto modified and non-modified surfaces was dependent on the properties of the protein as well as the properties of the surface. The process of biofouling for in vivo inserted materials can be postponed and thereby increasing the lifetime and use of e.g. microdialysis probes for patient monitoring. The preliminary data are very promising making it possible to identify a spectra of adsorbed proteins on different surfaces in a time dependent way

  • 405.
    Undin, Torgny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlin, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Hörnaeus, Katarina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mechanistic investigation of the on surface enzymatic digestion (oSED) protein adsorption detection method using targeted mass spectrometry2016In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 141, no 5, p. 1714-1720Article in journal (Refereed)
    Abstract [en]

    This study describes our efforts to study some of the mechanistic aspects of the earlier established onsurface enzymatic digestion (oSED) method. In a multitude of application areas, it has become important to be able to fully characterize and understand selective protein adsorption to biomaterial surfaces for various applications, including biomedicine (implants), nanotechnology (microchip surfaces and sensors) and materials sciences. Herein, the investigation of the mechanistic aspects was based on microdialysis catheter tubes that were flushed with controlled protein solutions mimicking the extracellular fluid of the brain. The protein adsorption properties were monitored using high-resolution liquid chromatography tandem mass spectrometry (LC-MS/MS) with a targeted method. The temporally resolved results show that most proteins stay adsorbed onto the surface during the entire digestion process and are only cut away piece by piece, whereas smaller proteins and peptides seem to desorb rather easily from the surface. This information will simplify the interpretation of data generated using the oSED method and can also be used for the characterization of the physicochemical properties controlling the adsorption of individual proteins to specific surfaces.

  • 406.
    Undin, Torgny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Dahlin, Andreas P.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mass Spectrometric Determination of the Effect of Surface Deactivation on Membranes Used for In-Situ Sampling of Cerebrospinal Fluid (CSF)2018In: Separations, ISSN 2297-8739, Vol. 5, no 2, article id 27Article in journal (Refereed)
    Abstract [en]

    In this paper, a strategy for structured monitoring of surface modifications to control protein adsorption to membrane structures is presented. The already established on-surface enzymatic digestion (oSED) method combined with nano-liquid chromatography and tandem mass spectrometry (LC-MS/MS) analysis was employed for the analysis of proteins in ventricular cerebrospinal fluid (vCSF) from neurointensive care patients. Protein adsorption was studied by in-situ sampling in a temporally resolved manner on both immobilized native and Pluronic-deactivated membranes. Deactivation was significantly reducing the protein adsorption but it also induced novel selective properties of the surface. The proposed versatile strategy will facilitate protein-biomaterial, protein-polymer, protein-protein interaction studies in the future.

  • 407.
    Valdes, Alberto
    et al.
    CSIC, Inst Food Sci Res CIAL, Lab Food, Calle Nicolas Cabrera 9, Madrid 28049, Spain..
    Artemenko, Konstantin A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Garcia-Canas, Virginia
    CSIC, Inst Food Sci Res CIAL, Lab Food, Calle Nicolas Cabrera 9, Madrid 28049, Spain..
    Cifuentes, Alejandro
    CSIC, Inst Food Sci Res CIAL, Lab Food, Calle Nicolas Cabrera 9, Madrid 28049, Spain..
    Comprehensive Proteomic Study of the Antiproliferative Activity of a Polyphenol-Enriched Rosemary Extract on Colon Cancer Cells Using Nanoliquid Chromatography-Orbitrap MS/MS2016In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 15, no 6, p. 1971-1985Article in journal (Refereed)
    Abstract [en]

    In this work, a proteomics strategy based on nanoliquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) using an Orbitrap high-resolution mass spectrometer together with stable isotope dimethyl labeling (DML) is applied to quantitatively examine relative changes in the protein fraction of HT-29 human colon cancer cells treated with different concentrations of a polyphenol-enriched rosemary extract over the time. The major objective of this study was to gain insights into the antiproliferative mechanisms induced by rosemary polyphenols. Using this methodology, 1909 and 698 proteins were identified and quantified in cell extracts. The polyphenol-enriched rosemary extract treatment changed the expression of several proteins in a time- and concentration-dependent manner. Most of the altered proteins are implicated, in the activation of Nrf2 transcription factor and the unfolded protein response. In conclusion, rosemary polyphenols induced proteomic changes that were related to the attenuation of aggresome formation and activation of autophagy to alleviate cellular stress..

  • 408.
    Valdes, Alberto
    et al.
    CSIC, CIAL, Food Sci Res Inst, Lab Food, Calle Nicolas Cabrera 9, Madrid 28049, Spain..
    Garcia-Canas, Virginia
    CSIC, CIAL, Food Sci Res Inst, Lab Food, Calle Nicolas Cabrera 9, Madrid 28049, Spain..
    Artemenko, Konstantin A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Simo, Carolina
    CSIC, CIAL, Food Sci Res Inst, Lab Food, Calle Nicolas Cabrera 9, Madrid 28049, Spain..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cifuentes, Alejandro
    CSIC, CIAL, Food Sci Res Inst, Lab Food, Calle Nicolas Cabrera 9, Madrid 28049, Spain..
    Nano-liquid Chromatography-orbitrap MS-based Quantitative Proteomics Reveals Differences Between the Mechanisms of Action of Carnosic Acid and Carnosol in Colon Cancer Cells2017In: Molecular & cellular proteomics (online), ISSN 1535-9476, E-ISSN 1535-9484, Vol. 16, no 1, p. 8-22Article in journal (Refereed)
    Abstract [en]

    Carnosic acid (CA) and carnosol (CS) are two structurally related diterpenes present in rosemary herb (Rosmarinus officinalis). Although several studies have demonstrated that both diterpenes can scavenge free radicals and interfere in cellular processes such as cell proliferation, they may not necessarily exert the same effects at the molecular level. In this work, a shotgun proteomics study based on stable isotope dimethyl labeling (DML) and nano -liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) has been performed to identify the relative changes in proteins and to gain some light on the specific molecular targets and mechanisms of action of CA and CS in HT-29 colon cancer cells. Protein profiles revealed that CA and CS induce different Nrf2-mediated response. Furthermore, examination of our data revealed that each diterpene affects protein homeostasis by different mechanisms. CA treatment induces the expression of proteins involved in the unfolded protein response in a concentration dependent manner reflecting ER stress, whereas CS directly inhibits chymotrypsin-like activity of the 20S proteasome. In conclusion, the unbiased proteomics-wide method applied in the present study has demonstrated to be a powerful tool to reveal differences on the mechanisms of action of two related bioactive compounds in the same biological model.

  • 409.
    Valdes, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lewitt, Moira
    Univ West Scotland, Sch Hlth & Life Sci, Paisley PA1 2BE, Renfrew, Scotland.
    Wiss, Erica
    Albano Anim Hosp, S-18236 Stockholm, Sweden.
    Ramström, Margareta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Strage, Emma M.
    Swedish Univ Agr Sci, Univ Anim Hosp, Dept Clin Sci, S-75007 Uppsala, Sweden;Swedish Univ Agr Sci, Univ Anim Hosp, Clin Pathol Lab, S-75007 Uppsala, Sweden.
    Development of a Parallel Reaction Monitoring-MS Method To Quantify IGF Proteins in Dogs and a Case of Nonislet Cell Tumor Hypoglycemia2019In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 18, no 1, p. 18-29Article in journal (Refereed)
    Abstract [en]

    Nonislet-cell tumor hypoglycemia (NICTH) is a rare paraneoplastic phenomenon well described in dogs and humans. Tumors associated with NICTH secrete incompletely processed forms of insulin-like growth factor-II (IGF-II), commonly named big IGF-II. These forms have increased bioavailability and interact with the insulin and IGF-I receptor causing hypoglycemia and growth-promoting effects. Immunoassays designed for human samples have been used to measure canine IGF-I and -II, but they possess some limitations. In addition, there are no validated methods for measurement of big IGF-II in dogs. In the present study, a targeted parallel reaction monitoring MS-based method previously developed for cats has been optimized and applied to simultaneously quantify the serum levels of IGF-I, IGF-II, and IGFBP-3, and for the first time, the levels of big IGF-II in dogs. This method allows the absolute quantification of IGF proteins using a mixture of QPrEST proteins previously designed for humans. The method possesses good linearity and repeatability and has been used to evaluate the IGF-system in a dog with NICTH syndrome. In this dog, the levels of big IGF-II decreased by 80% and the levels of IGF-I and IGFBP-3 increased approximately 20- and 4-times, respectively, after removal of the tumor.

  • 410.
    Valdimarsdottir, Ragnheidur
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Valgeirsdóttir, Heiddis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics.
    Kallak, Theodora Kunovac
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Elenis, Evangelia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Piltonen, Terhi T
    Department of Obstetrics and Gynaecology, University of Oulu and Oulu University Hospital, Medical Research Center, PEDEGO Research Unit Oulu, Finland.
    Pigny, Pascal
    Laboratoire de Biochimie & Hormonologie, Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire, CHU de Lille, Lille, France;Jean-Pierre Aubert Research Center (JPArc), Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm, UMR-S 1172 Lille, France.
    Giacobini, Paolo
    Jean-Pierre Aubert Research Center (JPArc), Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm, UMR-S 1172 Lille, France;University of Lille, FHU 1,000 Days for Health, School of Medicine Lille, France.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Pregnancy and neonatal complications in women with polycystic ovary syndrome in relation to second-trimester anti-Müllerian hormone levels2019In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 39, no 1, p. 141-148Article in journal (Refereed)
    Abstract [en]

    RESEARCH QUESTION: An association has been found between high anti-Müllerian hormone (AMH) levels during pregnancy and the development of polycystic ovary syndrome (PCOS)-like phenotypic traits in mouse offspring. The aim of this study was to determine whether AMH levels are associated with maternal testosterone levels, and whether high AMH concentration influences the risk of developing PCOS-related adverse pregnancy outcomes.

    DESIGN: Maternal serum AMH, testosterone and sex hormone binding globulin levels were measured in blood samples taken in early second-trimester pregnancies from women with PCOS (n = 159) and healthy controls matched for body mass index (n = 320). Possible associations with preeclampsia, gestational hypertension, gestational diabetes, preterm birth and birthweight was explored by logistic and linear regression models.

    RESULTS: Women with PCOS had higher AMH, higher total testosterone levels and higher free androgen index than controls (P < 0.001 for all three parameters). Among women with PCOS, high testosterone levels (B = 2.7; β = 0.26; P = 0.001) and low first trimester body mass index (B = -0.5; β = -0.17; P = 0.043) remained independently associated with AMH. High AMH levels were associated with decreased risk of gestational hypertension (adjusted OR 0.55; 95% CI 0.34 to 0.87), but no association was found with other adverse pregnancy outcomes or birthweight.

    CONCLUSIONS: Women with PCOS had higher AMH levels during pregnancy compared with controls, but high AMH was not associated with increased risk of adverse pregnancy outcomes or birthweight.

  • 411.
    Valdés, Alberto
    et al.
    CSIC, CIAL, Inst Food Sci Res, Lab Food, Nicolas Cabrera 9, Madrid 28049, Spain..
    García-Cañas, Virginia
    CSIC, CIAL, Inst Food Sci Res, Mol Nutr & Metab, Nicolas Cabrera 9, Madrid 28049, Spain..
    Pérez-Sánchez, Almudena
    Miguel Herndndez Univ, Inst Mol & Cellular Biol, Avda Univ S-N, Elche 03202, Spain..
    Barrajón-Catalán, Enrique
    Miguel Herndndez Univ, Inst Mol & Cellular Biol, Avda Univ S-N, Elche 03202, Spain..
    Ruiz-Torres, Verónica
    Miguel Herndndez Univ, Inst Mol & Cellular Biol, Avda Univ S-N, Elche 03202, Spain..
    Artemenko, Konstantin A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Micol, Vicente
    Miguel Herndndez Univ, Inst Mol & Cellular Biol, Avda Univ S-N, Elche 03202, Spain.;Inst Salud Carlos III, CIBERobn, CIBER, Fisiopatol Obesidad & Nutr, CB12-03-30038, Madrid, Spain..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Cifuentes, Alejandro
    CSIC, CIAL, Inst Food Sci Res, Lab Food, Nicolas Cabrera 9, Madrid 28049, Spain..
    Shotgun proteomic analysis to study the decrease of xenograft tumor growth after rosemary extract treatment2017In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1499, p. 90-100Article in journal (Refereed)
    Abstract [en]

    The antiproliferative activity of Rosemary (Rosmarinus officinalis) has been widely studied in different in vitro and in vivo models, which demonstrate that rosemary extracts inhibit the cellular proliferation due to its ability to interact with a wide spectrum of molecular targets. However, a comprehensive proteomics study in vivo has not been carried out yet. In the present work, the effects of rosemary extract on xenograft tumor growth has been studied and, for the first time, a shotgun proteomic analysis based on nano-LC-MS/MS together with stable isotope dimethyl labeling (DML) has been applied to investigate the global protein changes in vivo. Our results show that the daily administration of a polyphenol-enriched rosemary extract reduces the progression of colorectal cancer in vivo with the subsequent deregulation of 74 proteins. The bioinformatic analysis of these proteins indicates that the rosemary extract mainly alters the RNA Post-Transcriptional Modification, the Protein Synthesis and the Amino Acid Metabolism functions and suggests the inactivation of the oncogene MYC. These results demonstrate the high utility of the proposed analytical methodology to determine, simultaneously, the expression levels of a large number of protein biomarkers and to generate new hypothesis about the molecular mechanisms of this extract in vivo.

  • 412.
    Valdés, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ström Holst, Bodil
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden.
    Lindersson, Sebastian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ramström, Margareta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Development of MS-based methods for identification and quantification of proteins altered during early pregnancy in dogs2019In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 192, p. 223-232Article in journal (Refereed)
    Abstract [en]

    Increased knowledge on serum protein profiles during early pregnancy in dogs would be valuable for several reasons, including animal welfare. Inflammatory changes during this period have been described. Today, mass spectrometry (MS) is a well-established technique to perform unbiased qualitative and quantitative studies of proteins in body fluids regardless of species. In the present study, a shotgun proteomic analysis based on nano-liquid chromatography-MS was performed to identify proteins of altered abundance during canine pregnancy, and, thereafter, a targeted parallel reaction monitoring (PRM)-method was developed and applied to absolutely quantify the concentrations of a selection of these proteins. Among the 32 proteins found altered between pregnant and non-pregnant dogs in the initial analysis, 12 were selected based on their changes in concentration and known biological importance, and these were analyzed using the PRM method. The PRM method showed good linearity, repeatability and sensitivity, and confirmed the higher concentration of Fibrinogen A, protein S alpha and C-reactive protein at early time points in pregnant bitches. In conclusion, the combination of both methods allowed the identification of several altered proteins, and the quantification and description of the concentration patterns for a selection of them during the early stage of dog pregnancy.

    Significance: MS is a powerful technique that allows the investigation of protein variations in samples from different origin, such as serum from dogs. The application of a shotgun proteomic analysis as a screening method has revealed the alteration of several proteins after fifteen days of pregnancy in dogs. The complementary development of a PRM MS-based method for several of these proteins has enabled the absolute quantification of their concentrations at five different time points during early pregnancy. With the MS technique, a combination of proteins can be studied with lower limits of detection than with immunoassays. Care should be taken not to interpret the observed changes in pregnant dogs as signs of disease.

  • 413.
    Valdés, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Zhao, Hongxing
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, Sara Bergström
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Time-resolved proteomics of adenovirus infected cells2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 9, article id e0204522Article in journal (Refereed)
    Abstract [en]

    Viral infections cause large problems in the world and deeper understanding of the disease mechanisms is needed. Here we present an analytical strategy to investigate the host cell protein changes during human adenovirus type 2 (HAdV-C2 or Ad2) infection of lung fibro-blasts by stable isotope labelling of amino acids in cell culture (SILAC) and nanoLC-MS/MS. This work focuses on early phase of infection (6 and 12 h post-infection (hpi)) but the data is combined with previously published late phase (24 and 36 hpi) proteomics data to produce a time series covering the complete infection. As many as 2169 proteins were quantitatively monitored from 6 to 36 hpi, while some proteins were time-specific. After applying different filter criteria, 2027 and 2150 proteins were quantified at 6 and 12 hpi and among them, 431 and 544 were significantly altered at the two time points. Pathway analysis showed that the De novo purine and pyrimidine biosynthesis, Glycolysis and Cytoskeletal regulation by Rho GTPase pathways were activated early during infection while inactivation of the Integrin signalling pathway started between 6 and 12 hpi. Moreover, upstream regulator analysis predicted MYC to be activated with time of infection and protein and RNA data for genes controlled by this transcription factor showed good correlation, which validated the use of protein data for this prediction. Among the identified phosphorylation sites, a group related to glycolysis and cytoskeletal reorganization were up-regulated during infection. The results show specific aspects on how the host cell proteins, the final products in the genetic information flow, are influenced by Ad2 infection, which would be overlooked if only knowledge derived from mRNA data is considered.

  • 414.
    Warnecke, Andreas
    et al.
    Karolinska Inst, Appl Immunol & Immunotherapy, Dept Clin Neurosci, Ctr Mol Med,Karolinska Univ Hosp Solna, S-17176 Solna, Sweden..
    Abele, Sonja
    Karolinska Inst, Appl Immunol & Immunotherapy, Dept Clin Neurosci, Ctr Mol Med,Karolinska Univ Hosp Solna, S-17176 Solna, Sweden..
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Harris, Robert A.
    Karolinska Inst, Appl Immunol & Immunotherapy, Dept Clin Neurosci, Ctr Mol Med,Karolinska Univ Hosp Solna, S-17176 Solna, Sweden..
    Scavenger Receptor A Mediates the Clearance and Immunological Screening of MDA-Modified Antigen by M2-Type Macrophages2017In: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 19, no 4, p. 463-479Article in journal (Refereed)
    Abstract [en]

    In this study, we investigated the uptake of malondialdehyde (MDA)-modified myelin oligodendrocyte glycoprotein (MOG) in the context of lipid peroxidation and its implications in CNS autoimmunity. The use of custom-produced fluorescently labeled versions of MOG or MDA-modified MOG enabled us to study and quantify the uptake by different macrophage populations and to identify the responsible receptor, namely SRA. The SRA-mediated uptake of MDA-modified MOG is roughly tenfold more efficient compared to that of the native form. Notably, this uptake is most strongly associated with anti-inflammatory M2-type macrophages. MDA-modified MOG was demonstrated to be resistant to degradation by lysine-dependent proteases in vitro, but the overall digestion fragments appeared to be similar in cell lysates, although their relative abundance appeared to be altered as a result of faster uptake. Accordingly, MDA-modified MOG is processed for presentation by APCs, allowing maximized recall proliferation of MOG(35-55)-specific 2D2 T cells in vitro due to higher uptake. However, MDA modification of MOG did not enhance immune priming or disease course in the in vivo MOG-EAE model, but did induce antibody responses to both MOG and MDA adducts. Taken together our results indicate that MDA adducts primarily constitute clearance signals for phagocytes and promote rapid removal of antigen, which is subjected to immunological screening by previously licensed T cells.

  • 415.
    Warnecke, Andreas
    et al.
    Karolinska Univ Hosp, Ctr Mol Med, Karolinska Inst, Dept Clin Neurosci Appl Immunol & Immunotherapy, S-17176 Stockholm, Sweden..
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    N'diaye, Marie
    Karolinska Univ Hosp, Ctr Mol Med, Karolinska Inst, Dept Clin Neurosci Appl Immunol & Immunotherapy, S-17176 Stockholm, Sweden..
    Sandalova, Tatyana
    Karolinska Univ Hosp, Karolinska Inst, Dept Infect Dis, Dept Med Solna,Sci Life Lab, SE-17176 Stockholm, Sweden..
    Achour, Adnane
    Karolinska Univ Hosp, Karolinska Inst, Dept Infect Dis, Dept Med Solna,Sci Life Lab, SE-17176 Stockholm, Sweden..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Harris, Robert A.
    Karolinska Univ Hosp, Ctr Mol Med, Karolinska Inst, Dept Clin Neurosci Appl Immunol & Immunotherapy, S-17176 Stockholm, Sweden..
    Nitration of MOG diminishes its encephalitogenicity depending on MHC haplotype2017In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 303, p. 1-12Article in journal (Refereed)
    Abstract [en]

    Post-translational modifications of autoantigens are hypothesized to affect their immunogenicity. We here report that nitration of tyrosine 40 in Myelin Oligodendrocyte Glycoprotein (MOG) abrogates its encephalitogenicity both at protein and peptide levels in the experimental autoimmune encephalomyelitis (EAE) model in H2(b) C57BL/6 mice. Furthermore, nitrated MOG displays inferior antigen-specific proliferation of 2D2 splenocytes in vitro. Conversely, H2(q) DBA1 mice remain fully susceptible to EAE induction using nitrated MOG as the dominant epitope of H2q mice is unaltered. Molecular modeling analysis of the MOG(35-55)/H2-lA(b) complex and bioinformatics peptide binding predictions indicate that the lack of T cell reactivity towards nitrated MOG can be attributed to the inability of murine H2-IA(b) to efficiently present the altered peptide ligand of MOG(35-55) because the nitrated tyrosine 40 cannot be accommodated in the p1 anchor pocket. In conclusion we demonstrate nitration as a relevant determinant affecting T cell recognition of carrier antigen depending on MHC haplotype. Our data have implications for understanding the role of post-translationally modified antigen in autoimmunity. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.

  • 416. Wehbe, Moe
    et al.
    Malhotra, Armaan
    Anantha, Malathi
    Roosendaal, Jeroen
    Leung, Ada W Y
    Plackett, David
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Gilabert-Oriol, Roger
    Bally, Marcel B
    A simple passive equilibration method for loading carboplatin into pre-formed liposomes incubated with ethanol as a temperature dependent permeability enhancer.2017In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 252, p. 50-61Article in journal (Refereed)
    Abstract [en]

    A passive equilibration method which relies on addition of candidate drugs to pre-formed liposomes is described as an alternative method for preparing liposome encapsulated drugs. The method is simple, rapid and applicable to liposomes prepared with high (45mol%) or low (<20mol%) levels of cholesterol. Passive equilibration is performed in 4-steps: (i) formation of liposomes, (ii) addition of the candidate drug to the liposomes in combination with a permeability enhancing agent, (iii) incubation at a temperature that facilitates diffusion of the added compound across the lipid bilayer, and (iv) quenching the enhanced membrane permeability by reduction in temperature and/or removal of the permeabilization enhancer. The method is fully exemplified here using ethanol as the permeabilization enhancer and carboplatin (CBDCA) as the drug candidate. It is demonstrated that ethanol can be added to liposomes prepared with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and Cholesterol (Chol) (55:45mol ratio) in amounts up to 30% (v/v) with no change in liposome size, even when incubated at temperatures>60°C. Super-saturated solutions of CBDCA (40mg/mL) can be prepared at 70°C and these are stable in the presence of ethanol even when the temperature is reduced to <30°C. maximum CBDCA encapsulation is achieved within 1h after the CBDCA solution is added to pre-formed DSPC/Chol liposomes in the presence of 30% (v/v) ethanol at 60°C. When the pre-formed liposomes are mixed with ethanol (30% v/v) at or below 40°C, the encapsulation efficiency is reduced by an order of magnitude. The method was also applied to liposomes prepared from other compositions include a cholesterol free formulations (containing 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG2000)) and a low Chol (<20mol%) formulations prepared with the distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol) DSPG)). The cytotoxic activity of CBDCA was unaffected when prepared in this manner and two of the resultant formulations exhibited good stability in vitro and in vivo. The cytotoxic activity of CBDCA was unaffected when prepared in this manner and the resultant formulations exhibited good stability in vitro and in vivo. Pharmacokinetics studies in CD-1 mice indicated that the resulting formulations increased the circulation half life of the associated CBDCA significantly (AUC0-24h of CBDCA=0.016μg·hr/mL; AUC0-24h of the DSPC/Chol CBDCA formulation=1014.0μg·hr/mL and AUC0-24h of the DSPC/DSPG/Chol CBDCA formulation=583.96μg·hr/mL). Preliminary efficacy studies in Rag-2M mice with established subcutaneous H1975 and U-251 tumors suggest that the therapeutic activity of CBDCA is improved when administered in liposomal formulations. The encapsulation method described here has not been disclosed previously and will have broad applications to drugs that would normally be encapsulated during liposome manufacturing.

  • 417.
    Wehbe, Mohamed
    et al.
    British Columbia Canc Res Ctr, Expt Therapeut, Vancouver, BC V5Z 1L3, Canada.;Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada..
    Anantha, Malathi
    British Columbia Canc Res Ctr, Expt Therapeut, Vancouver, BC V5Z 1L3, Canada..
    Backstrom, Ian
    British Columbia Canc Res Ctr, Expt Therapeut, Vancouver, BC V5Z 1L3, Canada..
    Leung, Ada
    British Columbia Canc Res Ctr, Expt Therapeut, Vancouver, BC V5Z 1L3, Canada.;Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada..
    Chen, Kent
    British Columbia Canc Res Ctr, Expt Therapeut, Vancouver, BC V5Z 1L3, Canada..
    Malhotra, Armaan
    British Columbia Canc Res Ctr, Expt Therapeut, Vancouver, BC V5Z 1L3, Canada..
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala Univ, Dept Chem, 3 Husargatan B7, Uppsala, Sweden..
    Bally, Marcel B.
    British Columbia Canc Res Ctr, Expt Therapeut, Vancouver, BC V5Z 1L3, Canada.;Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada.;Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada.;Ctr Drug Res & Dev, Vancouver, BC, Canada..
    Nanoscale Reaction Vessels Designed for Synthesis of Copper-Drug Complexes Suitable for Preclinical Development2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0153416Article in journal (Refereed)
    Abstract [en]

    The development of copper-drug complexes (CDCs) is hindered due to their very poor aqueous solubility. Diethyldithiocarbamate (DDC) is the primary metabolite of disulfiram, an approved drug for alcoholism that is being repurposed for cancer. The anticancer activity of DDC is dependent on complexation with copper to form copper bis-diethyldithiocarbamate (Cu(DDC)(2)), a highly insoluble complex that has not been possible to develop for indications requiring parenteral administration. We have resolved this issue by synthesizing Cu(DDC)(2) inside liposomes. DDC crosses the liposomal lipid bilayer, reacting with the entrapped copper; a reaction that can be observed through a colour change as the solution goes from a light blue to dark brown. This method is successfully applied to other CDCs including the anti-parasitic drug clioquinol, the natural product quercetin and the novel targeted agent CX-5461. Our method provides a simple, transformative solution enabling, for the first time, the development of CDCs as viable candidate anticancer drugs; drugs that would represent a brand new class of therapeutics for cancer patients.

  • 418.
    Wei, Xiaodan
    et al.
    Binzhou Med Univ, Med & Pharmaceut Res Ctr, Yantai, Shandong, Peoples R China..
    Liu, Zhuang
    Binzhou Med Univ, Affiliated Hosp, Dept Clin Imaging, Binzhou, Shandong, Peoples R China..
    Li, Min
    Binzhou Med Univ, Med & Pharmaceut Res Ctr, Yantai, Shandong, Peoples R China..
    Yang, Chunhua
    Binzhou Med Univ, Med & Pharmaceut Res Ctr, Yantai, Shandong, Peoples R China..
    Wang, Wenming
    Binzhou Med Univ, Affiliated Hosp, Dept Clin Imaging, Binzhou, Shandong, Peoples R China..
    Li, Xianglin
    Binzhou Med Univ, Med & Pharmaceut Res Ctr, Yantai, Shandong, Peoples R China..
    Zhang, Shuping
    Binzhou Med Univ, Med & Pharmaceut Res Ctr, Yantai, Shandong, Peoples R China..
    Li, Xuri
    Binzhou Med Univ, Med & Pharmaceut Res Ctr, Yantai, Shandong, Peoples R China..
    Tian, Geng
    Binzhou Med Univ, Med & Pharmaceut Res Ctr, Yantai, Shandong, Peoples R China..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wang, Bin
    Binzhou Med Univ, Med & Pharmaceut Res Ctr, Yantai, Shandong, Peoples R China..
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. Binzhou Med Univ, Med & Pharmaceut Res Ctr, Yantai, Shandong, Peoples R China..
    The Number of Stenotic Intracranial Arteries Is Independently Associated with Ischemic Stroke Severity2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0163356Article in journal (Refereed)
    Abstract [en]

    Background The severity of ischemic stroke symptoms varies among patients and is a critical determinant of patient outcome. To date, the association between the number of stenotic intracranial arteries and stroke severity remains unclear. Aims We aimed to investigate the association between the number of stenotic major intracranial arteries (NSMIA) and ischemic stroke severity, as well as the degree of stenosis and common stroke risk factors. Methods We performed a retrospective analysis of patients with digital subtraction angiography (DSA)-confirmed ischemic stroke. Clinical stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). The number of stenotic vessels was counted from the internal carotid arteries and vertebral arteries, bilaterally. Results Eighty three patients were recruited from a single center and included in the study. NSMIA was significantly correlated with stroke severity (Pearson Correlation Coefficient = 0.485, P < 0.001), but not with the degree of stenosis (Pearson Correlation Coefficient = 0.01, P = 0.90). Multivariate regression analysis revealed that NSMIA was significantly associated with the NIHSS score after adjusting for stroke risk factors. The adjusted odds ratio (per lateral) was 2.092 (95% CI, 0.865 to 3.308, P = 0.001). The degree of stenosis was also significantly associated with the NIHSS score after adjusting for common risk factors. The odds ratio (per 10%) was 0.712 (95% CI, 0.202 to 1.223, P = 0.007). Conclusions The number of stenotic intracranial major arteries is associated with the severity of ischemic stroke independent of the degree of stenosis and other stroke risk factors. To the best of our knowledge, this has not been previosuly studied in great detail using DSA. Our data highlight the importance of examining all major arteries in stroke patients.

  • 419.
    Wei, Xiaodan
    et al.
    Chongqing Med Univ, Mol Med & Canc Res Ctr, 1 Med Rd, Chongqing 400016, Peoples R China;Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Zhang, Yuan
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Yu, Shoujun
    Binzhou Med Univ, Dept Radiol, Affiliated Hosp, 661 Second Huanghe Rd, Binzhou 256603, Shandong, Peoples R China.
    Li, Shasha
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Jiang, Wenguo
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Zhu, Yanping
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Xu, Yuxue
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Yang, Chunhua
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Tian, Geng
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Mi, Jia
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Chongqing Med Univ, Mol Med & Canc Res Ctr, 1 Med Rd, Chongqing 400016, Peoples R China.
    Zhao, Miaoqing
    Shandong Univ, Dept Pathol, Prov Hosp, 324 Jingwu Weiqi Rd, Jinan 250021, Shandong, Peoples R China.
    Song, Fangzhou
    Chongqing Med Univ, Mol Med & Canc Res Ctr, 1 Med Rd, Chongqing 400016, Peoples R China.
    PDLIM5 identified by label-free quantitative proteomics as a potential novel biomarker of papillary thyroid carcinoma2018In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 499, no 2, p. 338-344Article in journal (Refereed)
    Abstract [en]

    In order to better understand the mechanisms underlying the development of papillary thyroid carcinoma (PTC), and to identify new potential biomarkers, high-resolution label-free mass spectrometry was performed on PTC tissues and adjacent normal thyroid tissues from six patients. In this process, 2788 proteins were identified, out of which 49 proteins presented significant differences between PTC tissues and adjacent normal thyroid tissues. Gene ontology revealed that the majority of these proteins are involved in the catalytic activity and binding. We selected three proteins with differential expressions: PDZ and LIM domain 5 (PDLIM5), PDLIM1 and ALDH1A1; Protein expressions were further verified by RT-PCR and western blot. Among these, expression of PDLIM5 and PDLIM1 was up-regulated, while that of ALDH1A1 was down-regulated in PTC tissues. Next, we confirmed their expression through quantitative dot blot (QDB) technique. We found that knockdown of PDLIM5 expression in the B-CPAP cell line could inhibit the migration, invasion and proliferation of PTC cells. In addition, PDLIM5 knockdown reduced Ras and Phospho-ERK1/2 expression. Thus, we suggested that PDLIM5 promotes PTC via activation of the Ras-ERK pathway. Our research provides new molecular insight into the function of PDLIM5, which may assist in studying the mechanism of PTC. In addition, PDLIM5 could be further explored as a potential candidate for PTC treatment.

  • 420.
    Werner, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Turner, Charlotta
    Investigation of different particle sizes on superhydrophobic surfaces made by rapid expansion of supercritical solution with in situ laser diffraction (RESS-LD)2012In: Journal of Supercritical Fluids, ISSN 0896-8446, E-ISSN 1872-8162, Vol. 67, p. 53-59Article in journal (Refereed)
    Abstract [en]

    In situ laser diffraction, scanning electron microscopy (SEM) imaging, and thermography have been used to investigate particle formation and particle size distribution of alkyl ketene dimer (AKD) produced by rapid expansion of supercritical solution (RESS). The investigated RESS process is based on an earlier reported method to prepare superhydrophobic coatings. Spray distance, pre-expansion temperature and pressure have been varied and the results from the methods have been compared. SEM images and light scattering data correlate well, and show that the mean particle size increased and the size distribution became significantly broader with increasing spray distance. Mean particle diameters of above 5 mu m were only observed for pre-expansion temperatures at 50 degrees C or below. Furthermore, results show that by placing the surface to be coated within the cold expansion zone of carbon dioxide (CO2), i.e. in this study at 55 mm or shorter for a pre-expansion temperature (T-pe) and pressure (P-pe) of 57 degrees C and 180 bar, respectively, will produce a surface evenly covered by 3-mu m crystalline AKD flake-like particles. Obtained results also indicated, but did not prove, that agglomerates of AKD particles were carried to the surface by liquid CO2 droplets in the jet.

  • 421.
    Wetterhall, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hjort, Klas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Dahlin, Andreas P
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Identification of human cerebrospinal fluid proteins and their distribution in an in vitro microdialysis sampling system2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, no SI, p. 34-40Article in journal (Refereed)
    Abstract [en]

    A qualitative study is presented on how proteins from a complex biological sample are distributed in a microdialysis sample system. A comparison between proteins identified in the human ventricular cerebrospinal fluid (CSF) sample, the collected dialysate and the proteins adsorbed onto the membrane was conducted. The microdialysis experiment was performed in vitro at 37 °C for the duration of 24h. Thereafter, the membranes were removed from the catheter and the adsorbed proteins were tryptically digested using the on-surface enzymatic digestion (oSED) protocol. The CSF samples and the dialysates were digested using a standard in-solution trypsin digestion protocol.  In the final phase, the samples were analysed using nano-liquid chromatography in combination with tandem mass spectrometry. In the four sample compartments analysed (CSF start, Membrane, Dialysate, CSF end) a total of 134 different proteins were found. However, most of the identified proteins(n=87) were uniquely found in one sample compartment only. Common CSF proteins such as albumin, apolipoproteins and cystatin C together with plasma proteins such as hemoglobin and fibrinogen were among the 11 proteins that were found in all samples. These proteins are present in high concentrations in CSF, which means that they effectively block out the detection signal of less abundant proteins.  Therefore, only 25 % of the proteins adsorbed onto the membrane were detected in the CSF compared with the dialysate that shared 44% of its proteins with the CSF. The proteins adsorbed onto the membrane were significantly more hydrophobic, had a lower instability index and more thermostable compared to the proteins in the CSF and the dialysate. The results suggest that proteins adsorbed onto the microdialysis membranes may escape detection because they are prevented from passing the membrane into the dialysate. Thus, the membrane needs to be examined after sample collection in order to better verify the protein content in the original sample. This is particularly important when searching for new protein biomarkers for neurodegenerative diseases.

  • 422.
    Wetterhall, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Sjödin, Marcus O D
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hjort, Klas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Dahlin, Andreas P
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Mapping the protein distribution within a microdialysis sampling system by on-surface enzymatic digestion in combination with mass spectrometry2012In: Monitoring Molecules in Neuroscience: 14th International Conference, September 16 – 20, London, U.K., 2012Conference paper (Refereed)
  • 423.
    Wintergerst, Mieke
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Detection of inositol phosphates with HPLC-ICP-AES: Method development2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Inositol phosphates (IPs) represent a major part of the organic phosphorus found in the environment, which makes their identification and quantification very important. The goal of this project was to explore the possibility of quantification of IPs with inductively coupled plasma - atomic emission spectrometry (ICP - AES). This paper deals with the creation of an in-house IP standard and the considerations for the successful linking of high performance liquid chromatography (HPLC) with ICP - AES. Experiments with different nebulizers, mobile phases, standard solutions and model substance were performed. The proposed optimal conditions for the ICP experiments are: the use of a modified Lichte nebulizer, mobile phase without methanol and the use of standards matched to the mobile phase. Adenosine monophosphate (AMP) was found to be a good model substance and showed that the band broadening from HPLC to ICP – AES was approximately a factor of 2. Limits of detection for AMP were 5 µM for HPLC and 20 µM for ICP – AES. The optimal way to create an in-house standard was using the potassium salt of IP6 and treating it for 90 minutes at a temperature of 120 ºC with 3.2 M acetic acid.

  • 424.
    Wånggren, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hanrieder, J.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Hambiliki, F.
    Gulen-Yaldir, F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hreinsson, Julius
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Supplementation with glycoprotein 130 to culture media improves human embryo development and blastocyst formation rate in-vitro2012In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 27, no Suppl. 2, p. P-214-Article in journal (Other academic)
  • 425.
    Xu, Xingxing
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Makaraviciute, Asta
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Pettersson, Jean
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Zhang, Shi-Li
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Nyholm, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Zhang, Zhen
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Revisiting the factors influencing gold electrodes prepared using cyclic voltammetry2019In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 283, p. 146-153Article in journal (Refereed)
    Abstract [en]

    Gold is widely used as the electrode material in different chemi- and biosensing applications while cyclic voltammetry (CV) in sulfuric acid solutions is a commonly employed method for gold surface preparation and characterization. However, as shown herein, chloride leakage from the Ag/AgCl/sat. KCl reference electrode and platinum dissolution from the platinum counter electrode can severely compromise the reproducibility and hence the reliability of the prepared gold electrodes. The aim of this work is to obtain a comprehensive understanding of the separate and interdependent effects of the aforementioned factors on the voltammetric behavior of microfabricated polycrystalline gold electrodes. It is shown that the leakage of chloride gives rise to etching of both the gold working and the platinum counter electrodes and that the chloride concentration has a strong influence on the ratio between the obtained gold and platinum concentrations in the electrolyte. The dissolved gold and platinum are then re-deposited on the gold electrode on the cathodic voltammetric scan, changing the structure and properties of the electrode. It is also demonstrated that the changes in the properties of the gold electrode are determined by the ratio between the co-deposited platinum and gold rather than the absolute amount of platinum deposited on the gold electrode. In addition, the chloride and sulfate adsorption behavior on the gold electrode is carefully investigated. It is proposed that redox peaks due to the formation ofthe corresponding Au(I) complexes can be seen in the double layer region of the voltammogram. The results show that the chloride leakage from the reference electrode needs to be carefully controlled and that platinum counter electrodes should be avoided when developing gold sensing electrodes. The present comprehensive understanding of the electrochemical performance of gold electrodes prepared using CV should be of significant importance in conjunction with both fundamental investigations and practical applications.

  • 426.
    Xu, Xingxing
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics. Uppsala University.
    Makaraviciute, Asta
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Pettersson, Jean
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Zhang, Shi-Li
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Zhang, Zhen
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Considerations for the Cyclic Voltammetry of Gold in Sulfuric Acid Solutions2018Conference paper (Other academic)
    Abstract [en]

    A comprehensive understanding of the cyclic voltammetry (CV) for gold surfaces is essential for advanced applications. In the present study, a series of experiments were designed to investigate CV for gold under different experimental conditions when using a conventional configuration of a Ag/AgCl/sat. KCl reference electrode and a platinum wire counter electrode. The interferences introduced by the configuration were reflected in the three fingerprint regions of the voltammograms. It was found that the shape of the voltammograms was less reproducible at a lower sample volume when the cycle number was increased. This observation could be explained by different concentrations of Cl- leaking from the reference electrode and platinum dissolved from the counter electrode. The reproducibility of the gold oxidation and reduction (Ox/Re) region in the voltammograms was improved when gold dissolution and re-deposition caused by Cl- leakage was eliminated by using a bridge. In the hydrogen evolution and oxidation reactions (HER/HOR) region the catalytic performance of the gold electrode could be minimized by replacing the platinum counter electrode with a graphite rod. Alternatively, it could be enhanced by increasing the surface ratio of the co-deposited platinum to gold. In the electric double layer (EDL) region, peaks dependent on the concentrations of Cl- and SO42- were observed. To account for the occurrence of these peaks, a new mechanism based on the formation of neutral gold (I) complexes at very low Au+ concentrations, was proposed. 

  • 427. Ye, Weihua
    et al.
    Lind, Jesper
    Eriksson, Jonny
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Maler, Lena
    Characterization of the Morphology of Fast-Tumbling Bicelles with Varying Composition2014In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 30, no 19, p. 5488-5496Article in journal (Refereed)
    Abstract [en]

    Small, fast-tumbling bicelles are frequently used in solution NMR studies of protein lipid interactions. For this purpose it is critical to have information about the organization of the lipids within the bicelle structure. We have studied the morphology of small, fast-tumbling bicelles containing DMPC and DHPC as a function of temperature, lipid concentration, and the relative ratio (q value) of lipid (DMPC) to detergent (DHPC) amounts. Dynamic light scattering and cryo-transmission electron microscopy techniques were used to measure the size of the bicelles and to monitor the shape and dispersity of the particles in the samples. The stability and size of DMPC-containing bicelle mixtures were found to be highly dependent on temperature and the total lipid concentration for mixtures with q = 1 and q = 1.5. Stable DMPC/DHPC bicelles are only formed at low q values (0.5). Bicelle mixtures with q > 0.5 appear to be multidisperse containing more than one component, one with r(H) around 2.5 nm and one with r(H) of 6-8 nm. This is interpreted as a coexistence of small (possibly mixed micelles) bicelles and much larger bicelles. Incubating the sample at 37 degrees C increases the phase separation. Moreover, low total amphiphile concentrations and low q values lead to the formation of a temperature-independent morphology, interpreted as the formation of small particles in which the DHPC and DMPC are more mixed. On the basis of these results, we propose the existence of a critical bicelle concentration, a parameter that determines the existence of bilayered bicelles, which varies with q value. This polymorphism was not observed at any concentrations for q = 0.5 bicelles, for which a small but detectable temperature dependence was observed at high concentrations. The results demonstrate that q = 0.5 mixtures predominantly form "classical" bicelles, but that caution is needed when using fast-tumbling mixtures with q values higher than 0.5.

  • 428.
    Yu, Hans
    et al.
    Univ Bodenkultur Wien, Interuniv Dept Agrobiotechnol IFA Tulln, Inst Biotechnol Anim Prod, Tulln, Austria.;Univ Vet Med Vienna, Dept Biomed Sci, Inst Anim Breeding & Genet, Vienna, Austria..
    Reiser, Judith
    Ludwig Maximilians Univ Munchen, Inst Mol Anim Breeding & Biotechnol, Munich, Germany..
    Besenfelder, Urban
    Univ Bodenkultur Wien, Interuniv Dept Agrobiotechnol IFA Tulln, Inst Biotechnol Anim Prod, Tulln, Austria.;Univ Vet Med Vienna, Reprod Ctr Wieselburg, Vienna, Austria..
    Razzazi-Fazeli, Ebrahim
    Univ Vet Med Vienna, VetCore Facil Res, Vienna, Austria..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Brem, Gottfried
    Univ Bodenkultur Wien, Interuniv Dept Agrobiotechnol IFA Tulln, Inst Biotechnol Anim Prod, Tulln, Austria.;Univ Vet Med Vienna, Dept Biomed Sci, Inst Anim Breeding & Genet, Vienna, Austria..
    Artemenko, Konstantin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mayrhofer, Corina
    Univ Bodenkultur Wien, Interuniv Dept Agrobiotechnol IFA Tulln, Inst Biotechnol Anim Prod, Tulln, Austria.;Univ Vet Med Vienna, Dept Biomed Sci, Inst Anim Breeding & Genet, Vienna, Austria..
    Exploring the oviductal fluid proteome by a lectin-based affinity approach2016In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 16, no 23, p. 2962-2966Article in journal (Refereed)
    Abstract [en]

    The analysis of glycoproteins in body fluids represents a central task in the study of vital processes. Herein, we assessed the combined use of Concanavalin A and Wheat Germ Agglutinin as ligands to fractionate and enrich glycoproteins from oviductal fluid (OF), which is a source of molecules involved in fertilization. First, the selectivity was corroborated by a gel-based approach using glycoprotein staining and enzymatic deglycosylation. Nanoliquid chromatography-tandem mass spectrometry (nLC-ESI-MS/MS) further allowed the reliable identification of 134 nonbound as well as 130 lectin-bound OF proteins. Enrichment analysis revealed that 77% of the annotated proteins in the lectin-bound fraction were known glycoproteins (p-value [FDR] = 1.45E-31). The low variance of the number of peptide spectrum matches for each protein within replicates indicated a consistent reproducibility of the whole workflow (median CV 17.3% for technical replicates and 20.7% for biological replicates). Taken together, this study highlights the applicability of a lectin-based workflow for the comprehensive analysis of OF proteins and gives for the first time an insight into the broad glycoprotein content of OF.

  • 429.
    Zanni, Giulia
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Ctr Brain Repair & Rehabil, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Michno, Wojciech
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden..
    Di Martino, Elena
    Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Tjärnlund-Wolf, Anna
    Univ Gothenburg, Sahlgrenska Acad, Ctr Brain Repair & Rehabil, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Pettersson, Jean
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mason, Charlotte Elizabeth
    Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Hellspong, Gustaf
    Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Blomgren, Klas
    Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Pediat Oncol, Stockholm, Sweden..
    Hanrieder, Jorg
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden.;Chalmers, Dept Chem & Chem Engn, Gothenburg, Sweden.;UCL, Inst Neurol, Dept Mol Neurosci, London WC1E 6BT, England..
    Lithium Accumulates in Neurogenic Brain Regions as Revealed by High Resolution Ion Imaging2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 40726Article in journal (Refereed)
    Abstract [en]

    Lithium (Li) is a potent mood stabilizer and displays neuroprotective and neurogenic properties. Despite extensive investigations, the mechanisms of action have not been fully elucidated, especially in the juvenile, developing brain. Here we characterized lithium distribution in the juvenile mouse brain during 28 days of continuous treatment that result in clinically relevant serum concentrations. By using Time-of-Flight Secondary Ion Mass Spectrometry-(ToF-SIMS) based imaging we were able to delineate temporospatial lithium profile throughout the brain and concurrent distribution of endogenous lipids with high chemical specificity and spatial resolution. We found that Li accumulated in neurogenic regions and investigated the effects on hippocampal neurogenesis. Lithium increased proliferation, as judged by Ki67-immunoreactivity, but did not alter the number of doublecortin-positive neuroblasts at the end of the treatment period. Moreover, ToF-SIMS revealed a steady depletion of sphingomyelin in white matter regions during 28d Li-treatment, particularly in the olfactory bulb. In contrast, cortical levels of cholesterol and choline increased over time in Li-treated mice. This is the first study describing ToF-SIMS imaging for probing the brain-wide accumulation of supplemented Li in situ. The findings demonstrate that this technique is a powerful approach for investigating the distribution and effects of neuroprotective agents in the brain.

  • 430.
    Zayny, Ahmad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Almokhtar, Mokhtar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wikvall, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Kibar, Pinar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Norlin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of glucocorticoids on vitamin D3-metabolizing 24-hydroxylase (CYP24A1) in Saos-2 cells and primary human osteoblasts2019In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 496, article id 110525Article in journal (Refereed)
    Abstract [en]

    Vitamin D is essential for bone function and deficiency in active vitamin D hormone can lead to bone disorders. Long-term treatment with glucocorticoids results in osteoporosis and increased risk of fractures. Much remains unclear regarding the effects of these compounds in bone cells. In the current study, human osteosarcoma Saos-2 cells and primary human osteoblasts were found to express mRNA for the vitamin D receptor as well as activating and deactivating enzymes in vitamin D-3 metabolism. These bone cells exhibited CYP24A1-mediated 24-hydroxylation which is essential for deactivation of the active vitamin form. However, bioactivating vitamin D-3 hydroxylase activities could not be detected in either of these cells. Several glucocorticoids, including prednisolone, down regulated CYP24A1 mRNA and CYP24A1-mediated 24-hydroxylase activity in both Saos-2 and primary human osteoblasts. Also, prednisolone significantly suppressed a human CYP24A1 promoter-luciferase reporter gene in Saos-2 cells co-transfected with the glucocorticoid receptor. Thus, the results of the present study show suppression by glucocorticoids on CYP24A1 mRNA, CYP24A1-mediated metabolism and CYP24A1 promoter activity in human osteoblast-like cells. As part of this study we examined if glucocorticoids are formed locally in Saos-2 cells. The experiments indicate formation of 11-deoxycortisol, a steroid with glucocorticoid activity, which can bind the glucocorticoid receptor. Our data showing suppression by glucocorticoids on CYP24A1 expression in human osteoblasts suggest a previously unknown mechanism for effects of glucocorticoids in human bone, where these compounds may interfere with regulation of active vitamin D levels.

  • 431.
    Zayny, Ahmad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Almokhtar, Mokhtar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wikvall, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ubhayasekera, S. J. Kumari A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergqvist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Norlin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of glucocorticoids on vitamin D3 24-hydroxylase (CYP24A1) in Saos-2 cells and primary human osteoblastsManuscript (preprint) (Other academic)
    Abstract [en]

    Vitamin D is essential for bone function and deficiency in active vitamin D hormone can lead to rickets, osteomalacia or osteoporosis. Long-term treatment with glucocorticoids is known to result in osteoporosis and a substantially increased risk of fractures. Although the actions of vitamin D and glucocorticoids play important roles for bone function and in the development of osteoporosis, much remains unclear regarding the effects of these compounds in cells of the bone. In the current study, the human osteosarcoma Saos-2 cell line and primary human osteoblast-like cells were found to express mRNA for the vitamin D receptor as well as both activating and deactivating enzymes in vitamin D3 metabolism. These bone cells exhibited the CYP24A1-mediated 24-hydroxylation, involved in deactivation of the active vitamin D3 form. However, bioactivating vitamin D3 hydroxylase activities could not be detected in either of these cells. Several commonly used therapeutic glucocorticoids, including prednisolone, down regulated mRNA expression for the CYP24A1 gene as well as the CYP24A1-mediated 24-hydroxylase activity in both Saos-2 and primary human osteoblast-like cells. Prednisolone had the strongest suppressive effect on CYP24A1 expression. Results from experiments with a human CYP24A1 promoter-luciferase reporter gene in Saos-2 cells, co-transfected with the glucocorticoid receptor, showed that treatment with prednisolone significantly suppresses the CYP24A1 promoter activity. Thus, the results of the present study showed suppression by glucocorticoids on expression of CYP24A1 mRNA, CYP24A1-mediated metabolism and CYP24A1 promoter activity in human osteoblast-like cells. As part of the present investigation we examined if glucocorticoids are formed locally in Saos-2 cells. The experiments indicate formation of 11-deoxycortisol, a steroid that has glucocorticoid activity and is able to bind to the glucocorticoid receptor.

    Our data showing suppression by glucocorticoids on CYP24A1 expression in human osteoblast-like cells suggest a previously unknown mechanism for effects of glucocorticoids in human bone, where these compounds may act by increasing the normal levels of active vitamin D.

  • 432.
    Zhang, Jinbao
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Ellis, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Yang, Lei
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Johansson, Erik M. J.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Boschloo, Gerrit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Vlachopoulos, Nick
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Hagfeldt, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Shevchenko, Denys
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Matrix-Assisted Laser Desorption/Ionization Mass Spectrometric Analysis of Poly(3,4-ethylenedioxythiophene) in Solid-State Dye-Sensitized Solar Cells: Comparison of In Situ Photoelectrochemical Polymerization in Aqueous Micellar and Organic Media2015In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 87, no 7, p. 3942-3948Article in journal (Refereed)
    Abstract [en]

    Solid-state dye-sensitized solar cells (sDSCs) are devoid of such issues as electrolyte evaporation or leakage and electrode corrosion, which are typical for traditional liquid electrolyte-based DSCs. Poly(3,4-ethylenedioxythiophene) (PEDOT) is one of the most popular and efficient p-type conducting polymers that are used in sDSCs as a solid-state hole-transporting material. The most convenient way to deposit this insoluble polymer into the dye-sensitized mesoporous working electrode is in situ photoelectrochemical polymerization. Apparently, the structure and the physicochemical properties of the generated conducting polymer, which determine the photovoltaic performance of the corresponding solar cell, can be significantly affected by the preparation conditions. Therefore, a simple and fast analytical method that can reveal information on polymer chain length, possible chemical modifications, and impurities is strongly required for the rapid development of efficient solar energy-converting devices. In this contribution, we applied matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) for the analysis of PEDOT directly on sDSCs. It was found that the PEDOT generated in aqueous micellar medium possesses relatively shorter polymeric chains than the PEDOT deposited from an organic medium. Furthermore, the micellar electrolyte promotes a transformation of one of the thiophene terminal units to thiophenone. The introduction of a carbonyl group into the PEDOT molecule impedes the growth of the polymer chain and reduces the conductivity of the final polymer film. Both the simplicity of sample preparation (only application of the organic matrix onto the solar cell is needed) and the rapidity of analysis hold the promise of making MALDI MS an essential tool for the physicochemical characterization of conducting polymer-based sDSCs.

  • 433.
    Zhang, Yuan
    et al.
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Wang, Dan
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China;Binzhou Med Univ, Affiliated Hosp, Dept Radiol, 661 Second Huanghe Rd, Binzhou 256603, Shandong, Peoples R China.
    Li, Min
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Wei, Xiaodan
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Liu, Shuang
    Binzhou Med Univ, Coll Enol, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Zhao, Miaoqing
    Shandong Univ, Prov Hosp, Dept Pathol, 324 Jingwu Weiqi Rd, Jinan 250021, Shandong, Peoples R China.
    Liu, Chu
    Yantai Yuhuangding Hosp, Dept Urol, 20 Yuhuangding East Rd, Yantai 264000, Shandong, Peoples R China.
    Wang, Xizhen
    Weifang Med Univ, Affiliated Hosp, Imaging Ctr, 465 Yuhe Rd, Weifang 256603, Shandong, Peoples R China.
    Jiang, Xingyue
    Binzhou Med Univ, Affiliated Hosp, Dept Radiol, 661 Second Huanghe Rd, Binzhou 256603, Shandong, Peoples R China.
    Li, Xuri
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Zhang, Shuping
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Bergquist, Jonas
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Wang, Bin
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Yang, Chunhua
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Tian, Geng
    Binzhou Med Univ, Med & Pharm Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Quantitative Proteomics of TRAMP Mice Combined with Bioinformatics Analysis Reveals That PDGF-B Regulatory Network Plays a Key Role in Prostate Cancer Progression2018In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 17, no 7, p. 2401-2411Article in journal (Refereed)
    Abstract [en]

    Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice is a widely used transgenic animal model of prostate cancer (PCa). We performed a label-free quantitative proteomics analysis combined with a bioinformatics analysis on the entire prostate protein extraction from TRAMP mice and compared it with WT littermates. From 2379 total identified proteins, we presented a modest mice prostate reference proteome containing 919 proteins. 61 proteins presented a significant expression difference between two groups. The integrative bioinformatics analysis predicted the overexpression of platelet-derived growth factor B (PDGF-B) in tumor tissues and supports the hypothesis of the PDGF-B signaling network as a key upstream regulator in PCa progression. Furthermore, we demonstrated that Crenolanib, a novel PDGF receptor inhibitor, inhibited PCa cell proliferation in a dose-dependent manner. Finally, we revealed the importance of PDGF-B regulatory network in PCa progression, which will assist us in understanding the role and mechanisms of PDGF-B in promoting cancer growth and provide valuable knowledge for future research on anti-PDGF therapy.

  • 434.
    Zhao, Hongxing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Chen, Maoshan
    Monash Univ, Cent Clin Sch, Australian Ctr Blood Dis, Clayton, Vic, Australia.
    Valdes, Alberto
    Univ Alcala De Henares, Dept Analyt Chem Phys Chem & Chem Engn, Madrid, Spain.
    Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Transcriptomic and proteomic analyses reveal new insights into the regulation of immune pathways during adenovirus type 2 infection2019In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 19, article id 15Article in journal (Refereed)
    Abstract [en]

    Background: Human adenovirus (Ad) infection leads to the changes of host cell gene expression and biosynthetic processes. Transcriptomics in adenovirus type 2 (Ad2)-infected lung fibroblasts (IMR-90) cells has previously been studied using RNA sequencing. However, this study included only two time points (12 and 24 hpi) using constrained 76bp long sequencing reads. Therefore, a more detailed study of transcription at different phases of infection using an up-graded sequencing technique is recalled. Furthermore, the correlation between transcription and protein expression needs to be addressed.

    Results: In total, 3556 unique cellular genes were identified as differentially expressed at the transcriptional level with more than 2-fold changes in Ad2-infected cells as compared to non-infected cells by using paired-end sequencing. Based on the kinetics of the gene expression changes at different times after infection, these RNAs fell into 20 clusters. Among them, cellular genes involved in immune response were highly up-regulated in the early phase before becoming down-regulated in the late phase. Comparison of differentially expressed genes at transcriptional and posttranscriptional levels revealed low correlation. Particularly genes involved in cellular immune pathways showed a negative correlation. Here, we highlight the genes which expose inconsistent expression profiles with an emphasis on key factors in cellular immune pathways including NFB, JAK/STAT, caspases and MAVS. Different from their transcriptional profiles with up- and down-regulation in the early and late phase, respectively, these proteins were up-regulated in the early phase and were sustained in the late phase. A surprising finding was that the target genes of the sustained activators failed to show response.

    Conclusion: There were features common to genes which play important roles in cellular immune pathways. Their expression was stimulated at both RNA and protein levels during the early phase. In the late phase however, their transcription was suppressed while protein levels remained stable. These results indicate that Ad2 and the host cell use different strategies to regulate cellular immune pathways. A control mechanism at the post-translational level must thus exist which is under the control of Ad2.

  • 435.
    Zhao, Hongxing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Chen, Moashan
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Distinct temporal changes in host cell lncRNA expression during the course of an adenovirus infection2016In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 492, p. 242-250Article in journal (Refereed)
    Abstract [en]

    The deregulation of cellular long non-coding RNA (lncRNA) expression during a human adenovirus infection was studied by deep sequencing. Expression of lncRNAs increased substantially following the progression of the infection. Among 645 significantly expressed lncRNAs, the expression of 398 was changed more than 2-fold. More than 80% of them were up-regulated and 80% of them were detected during the late phase. Eased on the genomic locations of the deregulated lncRNAs in relation to known mRNAs and miRNAs, they were predicted to be involved in growth, structure, apoptosis and wound healing in the early phase, cell proliferation in the intermediate phase and protein synthesis, modification and transport in the late phase. The most significant functions of cellular RNA-binding proteins, previously shown to interact with the deregulated lncRNAs identified here, are involved in RNA splicing, nuclear export and translation events. We hypothesize that adenoviruses exploit the lncRNA network to optimize their reproduction.

  • 436.
    Zhao, Hongxing
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Konzer, Anne
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Chen, Moashan
    La Trobe University.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lind, Sara Bergström
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Posttranscriptional regulation in adenovirus infected cells2017In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 16, no 2, p. 872-888Article in journal (Refereed)
    Abstract [en]

    A deeper understanding of how viruses reprogramtheir hosts for production of progeny is needed to combatinfections. Most knowledge on the regulation of cellular geneexpression during adenovirus infection is derived from mRNAstudies. Here, we investigated the changes in protein expressionduring the late phase of adenovirus type 2 (Ad2) infection of theIMR-90 cell line by stable isotope labeling in cell culture withsubsequent liquid chromatography−high resolution tandemmass spectrometric analysis. Two biological replicates of samplescollected at 24 and 36 h post-infection (hpi) were investigated using swapped labeling. In total, 2648 and 2394 proteins werequantified at 24 and 36 hpi, respectively. Among them, 659 and 645 were deregulated >1.6-fold at the two time points. Theprotein expression was compared with RNA expression using cDNA sequencing data. The correlation was surprisingly low(r = 0.3), and several examples of posttranscriptional regulation were observed; e.g., proteins related to carbohydrate metabolismwere up-regulated at the protein level but unchanged at the RNA level, whereas histone proteins were down-regulated at theprotein level but up-regulated at the RNA level. The deregulation of cellular gene expression by adenovirus is mediated atmultiple levels and more complex than hitherto believed.

  • 437.
    ZHAO, WENJUN
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Analysis of most common endogenous steroids in plasma2014Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
  • 438. Zhao, Xi
    et al.
    Wu, Jie
    Gong, Fang-Ling
    Cui, Jin-Mei
    Janson, Jan-Christer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ma, Guang-Hui
    Su, Zhi-Guo
    Preparation of uniform and large sized agarose microspheres by an improved membrane emulsification technique2014In: Powder Technology, ISSN 0032-5910, E-ISSN 1873-328X, Vol. 253, p. 444-452Article in journal (Refereed)
    Abstract [en]

    The SPG (Shirasu porous-glass) membrane emulsification technique has been subject to much attention for the preparation of uniform emulsions. However, so far primarily used for the production of droplets with sizes below approximately 60 mu m. A production bottleneck occurred if the desired size was further increased, especially when highly viscous dispersed phases were involved. To this end, an improved membrane emulsification technique was proposed and has been applied to the preparation of large agarose microspheres, with a size of around 90 mu m and with a narrow size distribution. The effects of important emulsification parameters, including the pore size of the SPG membrane, the operating pressure, the stirring rate of the continuous phase, the composition of the continuous oil phase, and the concentration of agarose in the dispersed water phase, have been extensively studied. Under optimum conditions, uniform-size agarose microspheres with an average diameter of 93 pm and a size distribution index of 0.65 were successfully prepared. The average particle size of the home-made agarose microspheres was almost identical to that of the commercial product Sepharose 4 Fast Flow (4FF), which is produced by mechanical stirring and an additional sieving process. However, the size distribution of the former was much narrower than that of the latter. Therefore, the improved membrane emulsification technique presented here is promising for the application of high viscosity systems such as agarose solutions, and the production scale can be further enhanced by increasing the number of membrane units attached to the experimental apparatus. (C) 2013 Elsevier B.V. All rights reserved.

  • 439.
    Zhou, Y.
    et al.
    Royal Inst Technol, Sch Elect Engn, Dept Fus Plasma Phys, S-10405 Stockholm, Sweden..
    Bergsaker, H.
    Royal Inst Technol, Sch Elect Engn, Dept Fus Plasma Phys, S-10405 Stockholm, Sweden..
    Bykov, I.
    Royal Inst Technol, Sch Elect Engn, Dept Fus Plasma Phys, S-10405 Stockholm, Sweden..
    Petersson, P.
    Royal Inst Technol, Sch Elect Engn, Dept Fus Plasma Phys, S-10405 Stockholm, Sweden..
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Likonen, J.
    VTT Tech Res Ctr Finland, POB 1000, FIN-02044 Espoo, Finland..
    Pettersson, Jean
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Culham Sci Ctr, CCFE, Abingdon OX14 3DB, Oxon, England..
    Koivuranta, S.
    VTT Tech Res Ctr Finland, POB 1000, FIN-02044 Espoo, Finland..
    Widdowson, A. M.
    Proceedings 25th IAEA Fus Energy Conf 2014, St Petersburg, Russia..
    Microanalysis of deposited layers in the inner divertor of JET with ITER-like wall2017In: NUCLEAR MATERIALS AND ENERGY, ISSN 2352-1791, Vol. 12, no SI, p. 412-417Article in journal (Refereed)
    Abstract [en]

    In JET with ITER-like wall, beryllium eroded in the main chamber is transported to the divertor and deposited mainly at the horizontal surfaces of tiles 1 and 0 (high field gap closure, HFGC). These surfaces are tungsten coated carbon fibre composite (CFC). Surface sampleswere collected following the plasma operations in 2011-2012 and 2013-2014 respectively. The surfaces, as well as polished cross sections of the deposited layers at the surfaces have been studied with micro ion beam analysis methods (mu-IBA). Deposition of Beand other impurities, and retention of D is microscopically inhomogeneous. Impurities and trapped deuterium accumulate preferentially in cracks, pits and depressed regions, and at the sides of large pits in the substrate (e.g. arc tracks where the W coating has been removed). With careful overlaying of mu-NRA elemental maps with optical microscopy images, it is possible to separate surface roughness effects from depth profiles at microscopically flat surface regions.

  • 440.
    Zhu, Yanping
    et al.
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Qi, Xiaoying
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Yu, Cuicui
    Qing Dao Univ, Affiliated Yantai Yuhuangding Hosp, Dept Anesthesiol, 20 Yudong Rd, Yantai S264009, Shandong, Peoples R China.
    Yu, Shoujun
    Binzhou Med Univ, Yantai Affiliated Hosp, Dept Ultrasound, 717 Jinfu Rd, Binzhou 264100, Shandong, Peoples R China.
    Zhang, Chao
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Zhang, Yuan
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Liu, Xiuxiu
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Xu, Yuxue
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Yang, Chunhua
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Jiang, Wenguo
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Tian, Geng
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Li, Xuri
    Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Zhang, Jiandi
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China;Yantai Zestern Biotech Co LTD, 39 Keji Ave Bioasis, Yantai, Peoples R China.
    Wang, Lei
    Harbin Med Univ, Affiliated Hosp 1, Dept Thorac Surg, 23 Youzheng St, Harbin 150000, Heilongjiang, Peoples R China.
    Mi, Jia
    Binzhou Med Univ, Precis Med Res Ctr, 346 Guanhai Rd, Yantai 264003, Shandong, Peoples R China.
    Identification of prothymosin alpha (PTMA) as a biomarker for esophageal squamous cell carcinoma (ESCC) by label-free quantitative proteomics and Quantitative Dot Blot (QDB)2019In: Clinical Proteomics, ISSN 1542-6416, E-ISSN 1559-0275, Vol. 16, article id 12Article in journal (Refereed)
    Abstract [en]

    Background: Esophageal cancer (EC) is one of the malignant tumors with a poor prognosis. The early stage of EC is asymptomatic, so identification of cancer biomarkers is important for early detection and clinical practice.

    Methods: In this study, we compared the protein expression profiles in esophageal squamous cell carcinoma (ESCC) tissues and adjacent normal esophageal tissues from five patients through high-resolution label-free mass spectrometry. Through bioinformatics analysis, we found the differentially expressed proteins of ESCC. To perform the rapid identification of biomarkers, we adopted a high-throughput protein identification technique of Quantitative Dot Blot (QDB). Meanwhile, the QDB results were verified by classical immunohistochemistry.

    Results: In total 2297 proteins were identified, out of which 308 proteins were differentially expressed between ESCC tissues and normal tissues. By bioinformatics analysis, the four up-regulated proteins (PTMA, PAK2, PPP1CA, HMGB2) and the five down-regulated proteins (Caveolin, Integrin beta-1, Collagen alpha-2(VI), Leiomodin-1 and Vinculin) were selected and validated in ESCC by Western Blot. Furthermore, we performed the QDB and IHC analysis in 64 patients and 117 patients, respectively. The PTMA expression was up-regulated gradually along the progression of ESCC, and the PTMA expression ratio between tumor and adjacent normal tissue was significantly increased along with the progression. Therefore, we suggest that PTMA might be a potential candidate biomarker for ESCC.

    Conclusion: In this study, label-free quantitative proteomics combined with QDB revealed that PTMA expression was up-regulated in ESCC tissues, and PTMA might be a potential candidate for ESCC. Since Western Blot cannot achieve rapid and high-throughput screening of mass spectrometry results, the emergence of QDB meets this demand and provides an effective method for the identification of biomarkers.

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