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  • 1.
    Almokhtar, Mokhtar
    et al.
    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.
    Ubhayasekera, S. J. Kumari 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.
    Norlin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Motor neuron-like NSC-34 cells as a new model for the study of vitamin D metabolism in the brain.2016In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 158, p. 178-188Article in journal (Refereed)
    Abstract [en]

    Vitamin D-3 is a pro-hormone, which is sequentially activated by 25- and 1 alpha-hydroxylation to form 25-hydroxyvitamin D-3 [25(OH)D-3] and 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)2D(3)], respectively. Subsequent inactivation is performed by 24-hydroxylation. These reactions are carried out by a series of CYP450 enzymes. The 25-hydroxylation involves mainly CYP2R1 and CYP27A1, whereas 1 alpha-hydroxylation and 24-hydroxylation are catalyzed by CYP27B1 and CYP24A1, respectively, and are tightly regulated to maintain adequate levels of the active vitamin D hormone, 1 alpha,25(OH)(2)D-3. Altered circulating vitamin D levels, in particular 25(OH)D-3, have been linked to several disorders of the nervous system, e.g., schizophrenia and Parkinson disease. However, little is known about the mechanisms of vitamin D actions in the neurons. In this study, we examined vitamin D metabolism and its regulation in a murine motor neuron-like hybrid cell line, NSC-34. We found that these cells express mRNAs for the four major CYP450 enzymes involved in vitamin D activation and inactivation, and vitamin D receptor (VDR) that mediates vitamin D actions. We also found high levels of CYP24A1-dependent 24,25-dihydroxyvitamin D-3 [24,25(OH)(2)D-3] production, that was inhibited by the well-known CYP enzyme inhibitor ketoconazole and by several inhibitors that are more specific for CYP24A1. Furthermore, CYP24A1 mRNA levels in NSC-34 cells were up-regulated by 1 alpha,25(OH)(2)D-3 and its synthetic analogs, EB1089 and tacalcitol. Our results suggest that NSC-34 cells could be a novel model for the studies of neuronal vitamin D metabolism and its mechanism of actions.

  • 2.
    Asser, Andres
    et al.
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-51014 Tartu, Estonia.
    Koks, Sulev
    Univ Western Australia, Perron Inst Neurol & Translat Sci, Perth, WA, Australia.
    Soomets, Ursel
    Univ Tartu, Dept Biochem, Ravila 19, EE-50411 Tartu, Estonia.
    Terasmaa, Anton
    Univ Tartu, Dept Physiol, Ravila 19, EE-50411 Tartu, Estonia.
    Sauk, Martin
    Univ Tartu, Inst Mol & Cell Biol, Riia 23, EE-51010 Tartu, Estonia.
    Eltermaa, Mall
    Univ Tartu, Inst Biomed & Translat Med, Ravila 19, EE-50411 Tartu, Estonia.
    Piip, Piret
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-51014 Tartu, Estonia.
    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.
    Taba, Pille
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-51014 Tartu, Estonia.
    Acute effects of methcathinone and manganese in mice: A dose response study2019In: HELIYON, ISSN 2405-8440, Vol. 5, no 9, article id e02475Article in journal (Refereed)
    Abstract [en]

    An intravenously injectable illicit drug made by mixing pseudoephedrine, potassium permanganate, vinegar and water, yielding methcathinone (Mcat) and manganese (Mn), induces an extrapyramidal syndrome with parkinsonism, dystonia, gait and balance disorders similar to manganism. Although the cause of the syndrome is largely attributed to Mn, the interaction of the drug's individual components is not known and the role of Mcat is possibly underestimated. Aim of the present study was to analyze dose-dependent behavioral effects of the mixture and its two main active components Mcat and Mn in an acute setting and determine the lethal doses of each substance. Three groups of C57BL/6 mice were injected intraperitoneally with (1) the drug mixture containing 10, 25, 50, 100 or 150 mg of Mcat and respectively 1.6, 3.8, 6.9, 17.1 and 22.6 mg of Mn per kilogram of body weight; (2) 10, 25, 50, 100, 150, 200 or 300 mg of racemic Mcat/kg of body weight; (3) MnCl2 10, 25 or 50 mg/kg of body weight. Locomotor activity of the animals, various signs and time of death were recorded. Lower doses (10 and 25 mg/kg) of Mcat had a clear motor activity stimulating effect and this was clearly dose-dependent. High doses of Mcat produced epileptic seizures in 74% of the animals and became lethal with the highest doses. Similarly, the mixture had a clear dose-dependent stimulating effect and the higher doses became lethal. The LD50 of the pseudoephedrine mixture was 110.2 mg of Mcat/kg and for pure Mcat 201.7 mg/kg. Mn did not prove to be lethal in doses up to 50 mg/kg, but had a strong dose dependent inhibitory effect on the animals' behavior. Our data reveal that both Mn and Mcat have a significant role in the toxicity of the mixture.

  • 3.
    Berglund, Erik
    et al.
    Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet AND Department of Breast and Endocrine Surgery, Karolinska University Hospital.
    Ubhayasekera, Sarojini J.K.A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, Fredrik
    Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet AND Department of Breast and Endocrine Surgery, Karolinska University Hospital.
    Akcakaya, Pinar
    Department of Oncology-Pathology, Cancer Center Karolinska Institutet.
    Aluthgedara, Warunika
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ahlen, Jan
    Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet AND Department of Breast and Endocrine Surgery, Karolinska University Hospital.
    Fröbom, Robin
    Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet.
    Nilsson, Inga-Lena
    Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet AND Department of Breast and Endocrine Surgery, Karolinska University Hospital.
    Lui, Weng-Onn
    Department of Oncology-Pathology, Cancer Center Karolinska Institutet.
    Larsson, Catharina
    Department of Oncology-Pathology, Cancer Center Karolinska Institutet.
    Zedenius, Jan
    Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet AND Department of Breast and Endocrine Surgery, Karolinska University Hospital.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bränström, Robert
    Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet AND Department of Breast and Endocrine Surgery, Karolinska University Hospital.
    Intracellular concentration of the tyrosine kinase inhibitor imatinib in gastrointestinal stromal tumor cells.2014In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 25, no 4, p. 415-22Article in journal (Refereed)
    Abstract [en]

    Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract. In most GISTs, the underlying mechanism is a gain-of-function mutation in the KIT or the PDGFRA gene. Imatinib is a tyrosine kinase inhibitor that specifically blocks the intracellular ATP-binding sites of these receptors. A correlation exists between plasma levels of imatinib and progression-free survival, but it is not known whether the plasma concentration correlates with the intracellular drug concentration. We determined intracellular imatinib levels in two GIST cell lines: the imatinib-sensitive GIST882 and the imatinib-resistant GIST48. After exposing the GIST cells to imatinib, the intracellular concentrations were evaluated using LC-MS (TOF). The concentration of imatinib in clinical samples from three patients was also determined to assess the validity and reliability of the method in the clinical setting. Determination of imatinib uptake fits within detection levels and values are highly reproducible. The GIST48 cells showed significantly lower imatinib uptake compared with GIST882 in therapeutic doses, indicating a possible difference in uptake mechanisms. Furthermore, imatinib accumulated in the tumor tissues and showed intratumoral regional differences. These data show, for the first time, a feasible and reproducible technique to measure intracellular imatinib levels in experimental and clinical settings. The difference in the intracellular imatinib concentration between the cell lines and clinical samples indicates that drug transporters may contribute toward resistance mechanisms in GIST cells. This highlights the importance of further clinical studies to quantify drug transporter expression and measure intracellular imatinib levels in GIST patients.

  • 4.
    Bowden, John A.
    et al.
    NIST, Marine Biochem Sci Grp, Div Chem Sci, Hollings Marine Lab, Charleston, SC 29412 USA..
    Heckert, Alan
    NIST, Stat Engn Div, Gaithersburg, MD 20899 USA..
    Ulmer, Candice Z.
    NIST, Marine Biochem Sci Grp, Div Chem Sci, Hollings Marine Lab, Charleston, SC 29412 USA..
    Jones, Christina M.
    NIST, Marine Biochem Sci Grp, Div Chem Sci, Hollings Marine Lab, Charleston, SC 29412 USA..
    Koelmel, Jeremy P.
    Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL USA..
    Abdullah, Laila
    Roskamp Inst, Sarasota, FL USA..
    Ahonen, Linda
    Steno Diabet Ctr Copenhagen, Gentofte, Denmark..
    Alnouti, Yazen
    Univ Nebraska, Med Ctr, Dept Pharmaceut Sci, Omaha, NE USA..
    Armando, Aaron M.
    Univ Calif San Diego, Sch Med, Dept Chem & Biochem, La Jolla, CA 92093 USA.;Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA..
    Asara, John M.
    Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Bamba, Takeshi
    Kyushu Univ, Med Inst Bioregulat, Res Ctr Trans Med, Div Metabol,Higashi Ku, Fukuoka, Japan..
    Barr, John R.
    Natl Ctr Environm Hlth, Ctr Dis Control & Prevent, Div Lab Sci, Atlanta, GA USA..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Borchers, Christoph H.
    Univ Victoria, Genome British Columbia Prote Ctr, Victoria, BC, Canada.;Univ Victoria, Dept Biochem & Microbiol, Victoria, BC, Canada.;McGill Univ, Jewish Gen Hosp, Gerald Bronfman Dept Oncol, Montreal, PQ, Canada.;McGill Univ, Jewish Gen Hosp, Prote Ctr, Segal Canc Ctr,Lady Davis Inst, Montreal, PQ, Canada..
    Brandsma, Joost
    Univ Southampton, Southampton Gen Hosp, Acad Unit Clin & Expt Sci, Fac Med, Southampton, Hants, England..
    Breitkopf, Susanne B.
    Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA..
    Cajka, Tomas
    Univ Calif Davis, Genome Ctr, Natl Inst Hlth West Coast Metabol Ctr, Davis, CA 95616 USA..
    Cazenave-Gassiot, Amaury
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore.;Singapore Lipidomic Incubator SLING, Inst Life Sci, Singapore, Singapore..
    Checa, Antonio
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Cinel, Michelle A.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia..
    Colas, Romain A.
    Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Cremers, Serge
    Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, Biomarker Core Lab, New York, NY USA..
    Dennis, Edward A.
    Univ Calif San Diego, Sch Med, Dept Chem & Biochem, La Jolla, CA 92093 USA.;Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA..
    Evans, James E.
    Roskamp Inst, Sarasota, FL USA..
    Fauland, Alexander
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Fiehn, Oliver
    Univ Calif Davis, Genome Ctr, Natl Inst Hlth West Coast Metabol Ctr, Davis, CA 95616 USA.;King Abdulaziz Univ, Biochem Dept, Jeddah, Saudi Arabia..
    Gardner, Michael S.
    Natl Ctr Environm Hlth, Ctr Dis Control & Prevent, Div Lab Sci, Atlanta, GA USA..
    Garrett, Timothy J.
    Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL USA..
    Gotlinger, Katherine H.
    New York Med Coll, Sch Med, Dept Pharmacol, Valhalla, NY 10595 USA..
    Han, Jun
    Univ Victoria, Genome British Columbia Prote Ctr, Victoria, BC, Canada..
    Huang, Yingying
    Thermo Fisher Sci, San Jose, CA USA..
    Neo, Aveline Huipeng
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore.;Singapore Lipidomic Incubator SLING, Inst Life Sci, Singapore, Singapore..
    Hyotylainen, Tuulia
    Orebro Univ, Dept Chem, Orebro, Sweden..
    Izumi, Yoshihiro
    Kyushu Univ, Med Inst Bioregulat, Res Ctr Trans Med, Div Metabol,Higashi Ku, Fukuoka, Japan..
    Jiang, Hongfeng
    Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, Biomarker Core Lab, New York, NY USA..
    Jiang, Houli
    New York Med Coll, Sch Med, Dept Pharmacol, Valhalla, NY 10595 USA..
    Jiang, Jiang
    Univ Calif San Diego, Sch Med, Dept Chem & Biochem, La Jolla, CA 92093 USA.;Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA..
    Kachman, Maureen
    Univ Michigan, BRCF, Metabol Core, Ann Arbor, MI 48109 USA..
    Kiyonami, Reiko
    Thermo Fisher Sci, San Jose, CA USA..
    Klavins, Kristaps
    Biocrates Life Sci AG, Innsbruck, Austria..
    Klose, Christian
    Lipotype GmbH, Dresden, Germany..
    Kofeler, Harald C.
    Med Univ Graz, Core Facil Mass Spectrometry, Graz, Austria..
    Kolmert, Johan
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Koal, Therese
    Biocrates Life Sci AG, Innsbruck, Austria..
    Koster, Grielof
    Univ Southampton, Southampton Gen Hosp, Acad Unit Clin & Expt Sci, Fac Med, Southampton, Hants, England..
    Kuklenyik, Zsuzsanna
    Natl Ctr Environm Hlth, Ctr Dis Control & Prevent, Div Lab Sci, Atlanta, GA USA..
    Kurland, Irwin J.
    Albert Einstein Coll Med, Diabet Res Ctr, Stable Isotope & Metabol Core Facil, Bronx, NY 10467 USA..
    Leadley, Michael
    Hosp Sick Children, Res Inst, Analyt Facil Bioact Mol, Toronto, ON, Canada..
    Lin, Karen
    Univ Victoria, Genome British Columbia Prote Ctr, Victoria, BC, Canada..
    Maddipati, Krishna Rao
    Wayne State Univ, Lipid Core Facil, Detroit, MI USA.;Wayne State Univ, Dept Pathol, Detroit, MI USA..
    McDougall, Danielle
    Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL USA..
    Meikle, Peter J.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia..
    Mellett, Natalie A.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia..
    Monnin, Cian
    Concordia Univ, Dept Chem & Biochem, Montreal, PQ, Canada..
    Moseley, M. Arthur
    Duke Univ, Sch Med, Levine Sci Res Ctr, Prote & Metabol Shared Resource, Durham, NC USA..
    Nandakumar, Renu
    Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, Biomarker Core Lab, New York, NY USA.;Lipotype GmbH, Dresden, Germany..
    Oresic, Matej
    Univ Turku, Turku Ctr Biotechnol, Turku, Finland.;Abo Akad Univ, Turku, Finland..
    Patterson, Rainey
    Peake, David
    Pierce, Jason S.
    Post, Martin
    Hosp Sick Children, Res Inst, Analyt Facil Bioact Mol, Toronto, ON, Canada..
    Postle, Anthony D.
    Pugh, Rebecca
    NIST, Chem Sci Div, Environm Specimen Bank Grp, Hollings Marine Lab, Charleston, SC USA..
    Qiu, Yunping
    Albert Einstein Coll Med, Diabet Res Ctr, Stable Isotope & Metabol Core Facil, Bronx, NY 10467 USA..
    Quehenberger, Oswald
    Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA.;Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA..
    Ramrup, Parsram
    Rees, Jon
    Natl Ctr Environm Hlth, Ctr Dis Control & Prevent, Div Lab Sci, Atlanta, GA USA..
    Rembiesa, Barbara
    Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC USA..
    Reynaud, Denis
    Hosp Sick Children, Res Inst, Analyt Facil Bioact Mol, Toronto, ON, Canada..
    Roth, Mary R.
    Kansas State Univ, Kansas Lipid Res Ctr, Div Biol, Manhattan, KS 66506 USA..
    Sales, Susanne
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Schuhmann, Kai
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Schwartzman, Michal Laniado
    New York Med Coll, Sch Med, Dept Pharmacol, Valhalla, NY 10595 USA..
    Serhan, Charles N.
    Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Shevchenko, Andrej
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Somerville, Stephen E.
    Med Univ South Carolina, Hollings Marine Lab, Charleston, SC USA..
    John-Williams, Lisa St.
    Duke Univ, Sch Med, Levine Sci Res Ctr, Prote & Metabol Shared Resource, Durham, NC USA..
    Surma, Michal A.
    Univ Michigan, BRCF, Metabol Core, Ann Arbor, MI 48109 USA..
    Takeda, Hiroaki
    Kyushu Univ, Med Inst Bioregulat, Res Ctr Trans Med, Div Metabol,Higashi Ku, Fukuoka, Japan..
    Thakare, Rhishikesh
    Univ Nebraska, Med Ctr, Dept Pharmaceut Sci, Omaha, NE USA..
    Thompson, J. Will
    Duke Univ, Sch Med, Levine Sci Res Ctr, Prote & Metabol Shared Resource, Durham, NC USA..
    Torta, Federico
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore.;Singapore Lipidomic Incubator SLING, Inst Life Sci, Singapore, Singapore..
    Triebl, Alexander
    Med Univ Graz, Core Facil Mass Spectrometry, Graz, Austria..
    Troetzmueller, Martin
    Med Univ Graz, Core Facil Mass Spectrometry, Graz, Austria..
    Ubhayasekera, S. J. Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Vuckovic, Dajana
    Weir, Jacquelyn M.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia..
    Welti, Ruth
    Kansas State Univ, Kansas Lipid Res Ctr, Div Biol, Manhattan, KS 66506 USA..
    Wenk, Markus R.
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore.;Singapore Lipidomic Incubator SLING, Inst Life Sci, Singapore, Singapore..
    Wheelock, Craig E.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Yao, Libin
    Kansas State Univ, Kansas Lipid Res Ctr, Div Biol, Manhattan, KS 66506 USA..
    Yuan, Min
    Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA..
    Zhao, Xueqing Heather
    Albert Einstein Coll Med, Diabet Res Ctr, Stable Isotope & Metabol Core Facil, Bronx, NY 10467 USA..
    Zhou, Senlin
    Wayne State Univ, Lipid Core Facil, Detroit, MI USA.;Wayne State Univ, Dept Pathol, Detroit, MI USA..
    Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma2017In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, no 12, p. 2275-2288Article in journal (Refereed)
    Abstract [en]

    As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950-Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra-and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium.jlr While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.

  • 5.
    de Kock, Neil
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Acharya, Santosh R.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ubhayasekera, S. J. Kumari 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. Uppsala Univ, Dept Chem, Biomed Ctr, Analyt Chem, Box 599, S-75124 Uppsala, Sweden.
    A Novel Targeted Analysis of Peripheral Steroids by Ultra-Performance Supercritical Fluid Chromatography Hyphenated to Tandem Mass Spectrometry2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 16993Article in journal (Refereed)
    Abstract [en]

    Ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS) is an alternative method for steroid analysis. Continuous development of analytical methodologies for steroid profiling is of major importance in the clinical environment to provide useful and more comprehensive data. The aim of this study was to identify and quantify a large number of endogenous steroids from the four major classes (estrogens, androgens, progestogens and corticosteroids) simultaneously within a short analytical time. This novel UPSFC-MS/MS method with electrospray in positive ionisation (ESI+) mode is robust, selective and present sufficiently high sensitivity to profile nineteen steroids in 50 mu L human plasma. Under optimised conditions, nineteen different steroids were separated with high efficiency in the multiple reaction monitoring (MRM) mode. The linearity of the method was good with correlation coefficients (R-2) in the range of 0.9983-0.9999 and with calibration range from 0.05-500 ng/mL in human plasma. The intraday and interday precision of the method, as RSD, was less than 15%. The accuracy of the nineteen analytes varied between 80 to 116%. Finally, the novel method was successfully applied for the determination of nineteen steroids within 5 minutes providing the possibility to use it for research as well as routine healthcare practice.

  • 6.
    Englund, Elias
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Pattanaik, Bagmi
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Ubhayasekera, Sarojini J.K.A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Stensjö, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lindberg, Pia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Production of Squalene in Synechocystis sp. PCC 68032014In: PLoS ONE, Vol. 9, no 3, p. e90270-Article in journal (Refereed)
    Abstract [en]

    In recent years, there has been an increased interest in the research and development of sustainable alternatives to fossil fuels. Using photosynthetic microorganisms to produce such alternatives is advantageous, since they can achieve direct conversion of carbon dioxide from the atmosphere into the desired product, using sunlight as the energy source. Squalene is a naturally occurring 30-carbon isoprenoid, which has commercial use in cosmetics and in vaccines. If it could be produced sustainably on a large scale, it could also be used instead of petroleum as a raw material for fuels and as feedstock for the chemical industry. The unicellular cyanobacterium Synechocystis PCC 6803 possesses a gene, slr2089, predicted to encode squalene hopene cyclase (Shc), an enzyme converting squalene into hopene, the substrate for forming hopanoids. Through inactivation of slr2089 (shc), we explored the possibility to produce squalene using cyanobacteria. The inactivation led to accumulation of squalene, to a level over 70 times higher than in wild type cells, reaching 0.67 mg OD750−1 L−1. We did not observe any significant growth deficiency in the Δshc strain compared to the wild type Synechocystis, even at high light conditions, suggesting that the observed squalene accumulation was not detrimental to growth, and that formation of hopene by Shc is not crucial for growth under normal conditions, nor for high-light stress tolerance. Effects of different light intensities and growth stages on squalene accumulation in the Δshc strain were investigated. We also identified a gene, sll0513, as a putative squalene synthase in Synechocystis, and verified its function by inactivation. In this work, we show that it is possible to use the cyanobacterium Synechocystis to generate squalene, a hydrocarbon of commercial interest and a potential biofuel. We also report the first identification of a squalene hopene cyclase, and the second identification of squalene synthase, in cyanobacteria.

  • 7.
    Fallahsharoudi, Amir
    et al.
    Linkoping Univ, Dept Phys Chem & Biol, AVIAN Behav Genom & Physiol Grp, S-58183 Linkoping, Sweden..
    de Kock, Neil
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Johnsson, Martin
    Linkoping Univ, Dept Phys Chem & Biol, AVIAN Behav Genom & Physiol Grp, S-58183 Linkoping, Sweden..
    Bektic, Lejla
    Linkoping Univ, Dept Phys Chem & Biol, AVIAN Behav Genom & Physiol Grp, S-58183 Linkoping, Sweden..
    Ubhayasekera, S. J. Kumari 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.
    Wright, Dominic
    Linkoping Univ, Dept Phys Chem & Biol, AVIAN Behav Genom & Physiol Grp, S-58183 Linkoping, Sweden..
    Jensen, Per
    Linkoping Univ, Dept Phys Chem & Biol, AVIAN Behav Genom & Physiol Grp, S-58183 Linkoping, Sweden..
    Genetic and Targeted eQTL Mapping Reveals Strong Candidate Genes Modulating the Stress Response During Chicken Domestication2017In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 7, no 2, p. 497-504Article in journal (Refereed)
    Abstract [en]

    The stress response has been largely modified in all domesticated animals, offering a strong tool for genetic mapping. In chickens, ancestral Red Junglefowl react stronger both in terms of physiology and behavior to a brief restraint stress than domesticated White Leghorn, demonstrating modified functions of the hypothalamic-pituitary-adrenal (HPA) axis. We mapped quantitative trait loci (QTL) underlying variations in stress-induced hormone levels using 232 birds from the 12th generation of an advanced intercross between White Leghorn and Red Junglefowl, genotyped for 739 genetic markers. Plasma levels of corticosterone, dehydroepiandrosterone (DHEA), and pregnenolone (PREG) were measured using LC-MS/MS in all genotyped birds. Transcription levels of the candidate genes were measured in the adrenal glands or hypothalamus of 88 out of the 232 birds used for hormone assessment. Genes were targeted for expression analysis when they were located in a hormone QTL region and were differentially expressed in the pure breed birds. One genome-wide significant QTL on chromosome 5 and two suggestive QTL together explained 20% of the variance in corticosterone response. Two significant QTL for aldosterone on chromosome 2 and 5 (explaining 19% of the variance), and one QTL for DHEA on chromosome 4 (explaining 5% of the variance), were detected. Orthologous DNA regions to the significant corticosterone QTL have been previously associated with the physiological stress response in other species but, to our knowledge, the underlying gene(s) have not been identified. SERPINA10 had an expression QTL (eQTL) colocalized with the corticosterone QTL on chromosome 5 and PDE1C had an eQTL colocalized with the aldosterone QTL on chromosome 2. Furthermore, in both cases, the expression levels of the genes were correlated with the plasma levels of the hormones. Hence, both these genes are strong putative candidates for the domestication-induced modifications of the stress response in chickens. Improved understanding of the genes associated with HPA-axis reactivity can provide insights into the pathways and mechanisms causing stress-related pathologies.

  • 8.
    Fallahsharoudi, Amir
    et al.
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, S-58183 Linkoping, Sweden..
    de Kock, Neil
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Johnsson, Martin
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, S-58183 Linkoping, Sweden..
    Bektic, Lejla
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, S-58183 Linkoping, Sweden..
    Ubhayasekera, S. J. Kumari 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.
    Wright, Dominic
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, S-58183 Linkoping, Sweden..
    Jensen, Per
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, S-58183 Linkoping, Sweden..
    QTL mapping of stress related gene expression in a cross between domesticated chickens and ancestral red junglefowl2017In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 446, no C, p. 52-58Article in journal (Refereed)
    Abstract [en]

    Domestication of animals is associated with numerous alterations in physiology, morphology, and behavior. Lower reactivity of the hypothalamic-pituitary-adrenal (HPA) axis and reduced fearfulness is seen in most studied domesticates, including chickens. Previously we have shown that the physiological stress response as well as expression levels of hundreds of genes in the hypothalamus and adrenal glands are different between domesticated White Leghorn and the progenitor of modern chickens, the Red Junglefowl. To map genetic loci associated with the transcription levels of genes involved in the physiological stress response, we conducted an eQTL analysis in the F12 generation of an inter-cross between White Leghorn and Red Junglefowl. We selected genes for further studies based on their known function in the regulation of the HPA axis or sympathoadrenal (SA) system, and measured their expression levels in the hypothalamus and the adrenal glands after a brief stress exposure (physical restraint). The expression values were treated as quantitative traits for the eQTL mapping. The plasma levels of corticosterone were also assessed. We analyzed the correlation between gene expression and corticosterone levels and mapped eQTL and their potential effects on corticosterone levels. The effects on gene transcription of a previously found QTL for corticosterone response were also investigated. The expression levels of the glucocorticoid receptor (GR) in the hypothalamus and several genes in the adrenal glands were correlated with the post-stress levels of corticosterone in plasma. We found several cis- and transacting eQTL for stress-related genes in both hypothalamus and adrenal. In the hypothalamus, one eQTL for c-FOS and one QTL for expression of GR were found. In the adrenal tissue, we identified eQTL for the genes NROB1, RGS4, DBH, MAOA, GRIN1, GABRB2, GABRB3, and HSF1. None of the found eQTL were significant predictors of corticosterone levels. The previously found QTL for corticosterone was associated with GR expression in hypothalamus. Our data suggests that domestication related modification in the stress response is driven by changes in the transcription levels of several modulators of the HPA and SA systems in hypothalamus and adrenal glands and not by changes in the expression of the steroidogenic genes. The presence of eQTL for GR in hypothalamus combined with the negative correlation between GR expression and corticosterone response suggests GR as a candidate for further functional studies regarding modification of stress response during chicken domestication.

  • 9.
    Fallahsharoudi, Amir
    et al.
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    de Kock, Neil
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Johnsson, Martin
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    Ubhayasekera, Sarojini J.K.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.
    Wright, Dominic
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    Jensen, Per
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15345Article in journal (Refereed)
    Abstract [en]

    Understanding the genetic basis of phenotypic diversity is a challenge in contemporary biology. Domestication provides a model for unravelling aspects of the genetic basis of stress sensitivity. The ancestral Red Junglefowl (RJF) exhibits greater fear-related behaviour and a more pronounced HPA-axis reactivity than its domesticated counterpart, the White Leghorn (WL). By comparing hormones (plasmatic) and adrenal global gene transcription profiles between WL and RJF in response to an acute stress event, we investigated the molecular basis for the altered physiological stress responsiveness in domesticated chickens. Basal levels of pregnenolone and dehydroepiandrosterone as well as corticosterone response were lower in WL. Microarray analysis of gene expression in adrenal glands showed a significant breed effect in a large number of transcripts with over-representation of genes in the channel activity pathway. The expression of the best-known steroidogenesis genes were similar across the breeds used. Transcription levels of acute stress response genes such as StAR, CH25 and POMC were upregulated in response to acute stress. Dampened HPA reactivity in domesticated chickens was associated with changes in the expression of several genes that presents potentially minor regulatory effects rather than by means of change in expression of critical steroidogenic genes in the adrenal.

  • 10.
    Hellgren, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Edvinsson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olivier, Jocelien D.
    Univ Groningen, Groningen Inst Evolutionary Life Sci, Dept Neurobiol, Unit Behav Neurosci, NL-9700 AB Groningen, Netherlands..
    Fornes, Romina
    Karolinska Inst, Dept Physiol & Pharmacol, S-10401 Stockholm, Sweden..
    Stener-Victorin, Elisabet
    Karolinska Inst, Dept Physiol & Pharmacol, S-10401 Stockholm, Sweden..
    Ubhayasekera, S. J. Kumari A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Tandem mass spectrometry determined maternal cortisone to cortisol ratio and psychiatric morbidity during pregnancy-interaction with birth weight2016In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 69, p. 142-149Article in journal (Refereed)
    Abstract [en]

    Maternal serum cortisol has been suggested to be influenced by psychiatric morbidity, and may also influence fetal growth. However, several studies found equal cortisol levels in depressed and healthy pregnant women. Placental 11-beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) shields the fetus from maternal cortisol by conversion to cortisone, a function that may be compromised by maternal stress. We aimed to compare the serum ratio of cortisone to cortisol, in women with and without psychiatric morbidity during pregnancy. A secondary aim was to investigate whether fetal growth, approximated by infant birth weight, was associated with the cortisone to cortisol ratio. We performed tandem mass spectrometry analysis of serum cortisol and cortisone in late pregnancy in 94 women with antenatal psychiatric morbidity and 122 controls (cohort 1). We also compared the placental gene expression of HSD11B1 and 2 in another group of 69 women with psychiatric morbidity and 47 controls (cohort 2). There were no group differences in cortisol to cortisone ratio, absolute levels of cortisone and cortisol (cohort 1), or expression of HSD11B1 or 2 (cohort 2). However, cortisone to cortisol ratio was positively associated with birth weight in women with psychiatric morbidity, also after adjustment for gestational length, fetal sex, maternal height, smoking, SSRI use, and time of blood sampling (standardized beta = 0.35, p < 0.001), with no association in the healthy controls Thus, the maternal serum cortisone to cortisol ratio does not seem to be affected by psychiatric morbidity, but psychiatric morbidity may increase fetal exposure to cortisol or other metabolic factors influencing fetal growth.

  • 11.
    Hompland, Ivar
    et al.
    Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, POB 4953, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Bruland, Oyvind Sverre
    Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, POB 4953, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Ubhayasekhera, 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.
    Boye, Kjetil
    Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, POB 4953, N-0424 Oslo, Norway.;Oslo Univ Hosp, Norwegian Radium Hosp, Dept Tumor Biol, Oslo, Norway..
    Clinical implications of repeated drug monitoring of imatinib in patients with metastatic gastrointestinal stromal tumour2016In: Clinical Sarcoma Research, ISSN 2045-3329, Vol. 6, article id 21Article in journal (Refereed)
    Abstract [en]

    Background: Imatinib mesylate (IM) is the preferred treatment for the majority of patients with metastatic gastrointestinal stromal tumour (GIST). Low trough IM concentration (C-min) values have been associated with poor clinical outcomes in GIST patients. However, there are few studies of repeated measurements of IM levels, and therapeutic drug monitoring is not yet a part of routine clinical practice. This study was conducted to reveal clinical scenarios where plasma concentration measurement of IM trough level (Cmin) is advantageous. Methods: Patients with advanced GIST receiving IM were included from January 2011 to April 2015. Heparin plasma was collected at each follow-up visit. Ninety-six samples from 24 patients were selected for IM concentration measurement. Associations between IM plasma concentration and clinical variables were analyzed by Students't test, univariate and multivariate linear regression analyses. Results: The mean IM Cmin plasma concentrations for patients taking < 400, 400 and > 400 mg daily were 782, 1132 and 1665 ng/mL, respectively (p = 0.010). High IM C-min levels were correlated with age, low body surface area, low haemoglobin concentration, low creatinine clearance, absence of liver metastasis and no prior gastric resection in univariate analysis. In multivariate analysis age, gastric resection and liver metastasis were included in the final model. Eight patients had disease progression during the study, and mean IM levels were significantly lower at time of progression compared to the previous measurement for the same patients (770 and 1223 ng/mL, respectively; p = 0.020). Conclusions: Our results do not support repeated monitoring of IM levels on a routine basis in all patients. However, we have revealed clinical scenarios where drug measurement could be beneficial, such as for patients who have undergone gastric resection, suspicion of non-compliance, subjectively reported side effects, in elderly patients and at the time of disease progression.

  • 12.
    Kallak, Theodora Kunovac
    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.
    Hellgren, Charlotte
    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.
    Skalkidou, Alkistis
    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.
    Sandelin-Francke, Lotta
    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.
    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.
    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.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Campbell, Rebecca E
    Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Medical Sciences, Dunedin, New Zealand.
    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.
    Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain2017In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 177, no 4, p. 379-388Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Prenatal androgen exposure has been suggested to play a role in polycystic ovary syndrome. Given the limited information on what maternal characteristics influence maternal testosterone levels, and the even less explored routes by which female fetus androgen exposure would occur, the aim of this study was to investigate the impact of maternal age, BMI, weight gain, depressed mood and aromatase SNPs on testosterone levels in maternal serum and amniotic fluid of female fetuses.

    METHODS: Blood samples from pregnant women (n = 216) obtained in gestational weeks 35-39, and pre-labor amniotic fluid samples from female fetuses (n = 56), taken at planned Caesarean section or in conjunction with amniotomy for induction of labor, were analyzed. Maternal serum testosterone and amniotic fluid testosterone and cortisol were measured by tandem mass spectrometry.

    RESULTS: Multiparity (β = -0.28, P < 0.001), self-rated depression (β = 0.26, P < 0.001) and weight gain (β = 0.18, P < 0.05) were independent explanatory factors for the maternal total testosterone levels. Maternal age (β = -0.34, P < 0.001), weight gain (β = 0.19, P < 0.05) and amniotic fluid cortisol levels (β = 0.44, P < 0.001) were independent explanatory factors of amniotic fluid testosterone in female fetuses, explaining 64.3% of the variability in amniotic fluid testosterone.

    WIDER IMPLICATIONS OF THE FINDINGS: Young maternal age and excessive maternal weight gain may increase the prenatal androgen exposure of female fetuses. Further studies are needed to explore this finding.

  • 13.
    Manell, Hannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ubhayasekera, Sarojini Jayantha Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mörwald, Katharina
    Paracelsus Medical University.
    Staaf, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Cadamuro, Janne
    Paracelsus Medical University.
    Zsoldos, Fanni
    Paracelsus Medical University.
    Göpel, Sven
    AstraZeneca.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Weghuber, Daniel
    Paracelsus Medical University.
    Forslund, Anders
    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), Paediatric Inflammation Research.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. 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), Paediatric Inflammation Research.
    Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity and impaired glucose tolerance2019In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 20, no 7, p. 880-891Article in journal (Refereed)
    Abstract [en]

    Objective: To delineate mechanisms for fasting hyperglucagonemia in childhood obesity bystudying the associations between fasting plasma glucagon concentrations and plasmalipid parameters and fat compartments.

    Methods: Cross-sectional study of children and adolescents with obesity (n=147) and leancontrols (n=43). Differences in free fatty acids (FFA), triglycerides, insulin and fatcompartments (quantified by magnetic resonance imaging) across quartiles of fastingplasma glucagon concentration were analysed. Differences in OGTT glucagonresponse was tested in high vs low FFAs, triglycerides and insulin. Human islets ofLangerhans were cultured at 5.5 mmol/l glucose and in the absence or presence of aFFA mixture with total FFA concentration of 0.5 mmol/l and glucagon secretionquantified.

    Results: In children with obesity, the quartile with the highest fasting glucagon had higherinsulin (201±174 vs 83±39 pmol/l, p<0.01), FFAs (383±52 vs 338±109 μmol/l,p=0.02), triglycerides (1.5±0.9 vs 1.0±0.7 mmol/l, p<0.01), visceral adipose tissuevolume (1.9±0.8 vs 1.2±0.3 dm3, p<0.001) and a higher prevalence of impairedglucose tolerance (41% vs 8%, p=0.01) than the lowest quartile. During OGTT,children with obesity and high insulin had a worse suppression of glucagon during thefirst 10 minutes after glucose intake. Glucagon secretion was 2.6-fold higher in isletstreated with FFAs than in those not treated with FFAs.4

    Conclusion: Hyperglucagonemia in childhood obesity is associated with hyperinsulinemia, highplasma FFAs, high plasma triglycerides, visceral adiposity and impaired glucosetolerance. The glucagonotropic effect of FFAs on isolated human islets provides apotential mechanism linking high fasting plasma FFAs and glucagon levels.

  • 14.
    Manukyan, Levon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ubhayasekera, Sarojini J.K.A.
    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.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palmitate-induced impairments of beta-cell function are linked with generation of specific ceramide species via acylation of sphingosine2015In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 156, no 3, p. 802-812Article in journal (Refereed)
    Abstract [en]

    Prolonged exposure to palmitate impairs beta-cell function and mass. One of the proposed mechanisms is alteration in ceramide generation. In the present study, exposure to palmitate induced the level of palmitoyl transferase and ceramide synthases, enzymes of the ceramide de novo and salvage pathways, and doubled total ceramide levels, which was associated with decreased insulin secretion and augmented apoptosis in MIN6 cells and human islets. By inhibiting enzymes of the pathways pharmacologically with ISP-1 or fumonisin B1 or by siRNA we showed that Cer(14:0), Cer(16:0), Cer(20:1) and Cer(24:0) species, generated by the salvage pathway, are linked to the harmful effect of palmitate on beta-cells. Oleate attenuates negative effects of palmitate on beta-cells. When oleate was included during culture of MIN6 cells with palmitate the palmitate-induced up-regulation of the enzymes of the de novo and salvage pathways was prevented resulting in normalized levels of all ceramide species except Cer(20:1). Our data suggest that enhanced ceramide generation in response to elevated palmitate levels involves both de novo and salvage pathways. However, the negative effects of palmitate on beta-cells are attributed to generation of ceramide species Cer(14:0), Cer(16:0) and Cer(24:0) via acylation of sphingosine.

  • 15.
    Roomp, Kirsten
    et al.
    Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Belval, Luxembourg..
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Schvartz, Domitille
    Univ Geneva, Human Prot Sci Dept, Ctr Med Univ, Geneva, Switzerland..
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Manukyan, Levon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Chowdhury, Azazul Islam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Manell, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Satagopam, Venkata
    Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Belval, Luxembourg..
    Groebe, Karlfried
    Pivot Biomed Sci GmbH, Trier, Germany..
    Schneider, Reinhard
    Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Belval, Luxembourg..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sanchez, Jean-Charles
    Univ Geneva, Human Prot Sci Dept, Ctr Med Univ, Geneva, Switzerland..
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0176391Article in journal (Refereed)
    Abstract [en]

    Studies on the pathophysiology of type 2 diabetes mellitus (T2DM) have linked the accumulation of lipid metabolites to the development of beta-cell dysfunction and impaired insulin secretion. In most in vitro models of T2DM, rodent islets or beta-cell lines are used and typically focus is on specific cellular pathways or organs. Our aim was to, firstly, develop a combined lipidomics and proteomics approach for lipotoxicity in isolated human islets and, secondly, investigate if the approach could delineate novel and/or confirm reported mechanisms of lipotoxicity. To this end isolated human pancreatic islets, exposed to chronically elevated palmitate concentrations for 0, 2 and 7 days, were functionally characterized and their levels of multiple targeted lipid and untargeted protein species determined. Glucosestimulated insulin secretion from the islets increased on day 2 and decreased on day 7. At day 7 islet insulin content decreased and the proinsulin to insulin content ratio doubled. Amounts of cholesterol, stearic acid, C16 dihydroceramide and C24: 1 sphingomyelin, obtained from the lipidomic screen, increased time-dependently in the palmitate-exposed islets. The proteomic screen identified matching changes in proteins involved in lipid biosynthesis indicating up-regulated cholesterol and lipid biosynthesis in the islets. Furthermore, proteins associated with immature secretory granules were decreased when palmitate exposure time was increased despite their high affinity for cholesterol. Proteins associated with mature secretory granules remained unchanged. Pathway analysis based on the protein and lipid expression profiles implicated autocrine effects of insulin in lipotoxicity. Taken together the study demonstrates that combining different omics approaches has potential in mapping of multiple simultaneous cellular events. However, it also shows that challenges exist for effectively combining lipidomics and proteomics in primary cells. Our findings provide insight into how saturated fatty acids contribute to islet cell dysfunction by affecting the granule maturation process and confirmation in human islets of some previous findings from rodent islet and cell-line studies.

  • 16. Skoglund, Karin
    et al.
    Richter, Johan
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Aluthgedara, Warunika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ubhayasekera, S J Kumari A
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Vikingsson, Svante
    Svedberg, Anna
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sandstedt, Anna
    Johnsson, Anders
    Aagesen, Jesper
    Alsenhed, Jonas
    Hägg, Staffan
    Peterson, Curt
    Lotfi, Kourosh
    Gréen, Henrik
    In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients2016In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, p. 230-238Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: CYP3A metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in chronic myeloid leukemia (CML) patients. The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in CML patients.

    METHODS: Forty-three CML patients were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry.

    RESULTS: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to non-optimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P=0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity.

    CONCLUSIONS: CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

  • 17.
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Does Feed Containing Trans Fatty Acids Influence the Cholesterol and Oxycholesterols Levels in Chicken?2011In: Nutrition Focus Newsletter, Nutrition Society of Sri Lanka, no 3, p. 5-Article in journal (Other (popular science, discussion, etc.))
  • 18.
    Ubhayasekera, Kumari
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Acharya, Santosh R.
    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.
    A novel, fast and sensitive supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) method for analysis of arachidonic acid metabolites2018In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 143, no 15, p. 3661-3669Article in journal (Refereed)
    Abstract [en]

    The development of a rapid, sensitive and reliable method for the quantification of bioactive arachidonic acid metabolites (AA-metabolites) in biological samples is quite challenging due to the minute concentration, short half-life and their structural complexity arising from different isomers. In this study, a simple, fast and environmentally friendly supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) method was developed and validated for simultaneous measurement of five (PGD(2), PGE(2), PGF(2), 6KetoPGF(1) and LTB4) AA-metabolites in biological samples. These analytes were extracted by protein precipitation followed by separation and quantification. The analysis was completed within 3 minutes. The matrix matched linear calibration ranged from 0.5-100 ng mL(-1) (r(2) 0.995), whilst, the limit of quantification of PGD(2), PGE(2), PGF(2), and LTB4 was 0.5 ng mL(-1) and was 2.5 ng mL(-1) for 6KetoPGF(1). The interday and intraday precisions of the method were less than 15% while the accuracy of most of the analytes varied between 83 and 109%. Finally, as a proof of concept, the method was successfully applied for the determination of eicosanoids in human samples, which expands the possibility to explore physiological states, disease phenotypes, and novel biomarkers.

  • 19.
    Ubhayasekera, Sarojini J. K. A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Dutta, Paresh
    Division of Food Chemistry, Department of Food Science, Swedish University of Agricultural Sciences, Uppsala.
    Assessment of Sterol Oxidation in Oils Recovered from Exhausted Bleaching Earth by Coupled Capillary Column GC and GC–MS Methods2012In: Journal of the American Oil Chemists Society, ISSN 0003-021X, E-ISSN 1558-9331, Vol. 89, no 8, p. 1427-1433Article in journal (Refereed)
    Abstract [en]

    Cholesterol and phytosterols are generally present in foods at ppm levels and they can generate many oxidation products, i.e. oxysterols. The oxysterols comprise only a small percentage of unoxidized sterols. Reliable quantitative data on these compounds requires reasonably good separation by capillary column GC. The present study attempts to overcome the difficulties involved in separating many common oxysterols generated from cholesterol, brassicasterol, campesterol, stigmasterol, and sitosterol by coupling two high-resolution GC capillary columns. The columns, DB-17MS and DB-35MS, were coupled separately to a DB-5MS column. Total separation time of the authentic samples of oxysterols was 41 min for the DB-35MS/DB-5MS and 44 min for the DB-17MS/DB-5MS coupled columns. Two oil samples EBE1 and EBE2 extracted from exhausted bleaching earth collected from Europe were analyzed for oxysterol content by using these column combination systems. Both systems showed similar quantitative results; the total levels of oxysterols in these samples ranged from 2 to 3 mg/100 g. The prominent oxysterols were as follows: 7α-hydroxysterols (0.29–0.49 mg/100 g), 7β-hydroxysterols (0.13–0.68 mg/100 g) and 7-ketosterols (0.63–0.69 mg/100 g).

  • 20.
    Ubhayasekera, Sarojini J. K. A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Jayasinghe, Pradeepa
    Ekanayake, Sagarika
    Dutta, Paresh C.
    High cholesterol oxidation in pickled mackerel (Rastrelliger kanagurta) from Sri Lanka2012In: European Journal of Lipid Science and Technology, ISSN 1438-7697, E-ISSN 1438-9312, Vol. 114, no 6, p. 695-700Article in journal (Refereed)
    Abstract [en]

    Traditional mode of preservation of fatty fish in most countries is either by smoking or pickling. Mackerel is a commonly used fatty fish in the preparation of jaadi, a locally prepared pickled fish product in Sri Lanka produced especially in the glut season. The aim of this study was to assess the formation of cholesterol oxidation products (COPs) during storage time during 18?wk in traditionally preserved mackerel. The most common COPs were quantified and identified by GC and GC-MS, respectively. Total cholesterol and COPs ranged from 20 to 113?mg/100?g sample and from 0.2 to 3.8?mg/100?g sample, respectively. The content of COPs increased up to 6?wk and gradually decreased during the storage. The formation of COPs is low until week 4 of storage of jaadi. Between week 4 and 6 of storage the formation of COPs reaches its maximum level and then decreases during storage. Regular consumption of this pickled fish can be a source of considerable amounts of COPs in the diet of the local population in Sri Lanka. Practical applications: Cleaned mackerel (Rastrelliger kanagurta) covered with sun-dried salt powder and a paste of sun-dried Garcinia (Garcinia cambogia) fruit locally known as goraka is used to produce jaadi in Sri Lanka. Garcinia is a traditional commodity used for fish preservation and cooking, probably due to its antioxidant and antimicrobial properties. The results of this preliminary study could be useful in the future to increase the stability of preserved mackerel.

  • 21.
    Ubhayasekera, Sarojini J.K.A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Effects of Oxidized Lipids on Cholesterol and Cholesterol Oxidation in the Tissues of Chicken and Rabbit2008Conference paper (Refereed)
  • 22.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    Swedish University of Agricultural Sciences Division of Food Chemistry, Department of Food Science, Uppsala Sweden.
    Dutta, P. C.
    1.Swedish University of Agricultural Sciences Division of Food Chemistry, Department of Food Science, Uppsala Sweden.
    Analysis of oxidized sterols in frying oils2010In: FRYING OILS – ANALYSIS (on-line chapter) / [ed] W. W. Christie, The American Oil Chemists' Society , 2010Chapter in book (Other academic)
  • 23.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    1.Swedish University of Agricultural Sciences Division of Food Chemistry, Department of Food Science, Sweden.
    Dutta, P. C.
    1.Swedish University of Agricultural Sciences Division of Food Chemistry, Department of Food Science, Sweden.
    High levels of sterols and sterol oxidation products in some feeding fats obtained from co- and by-products from the food chain in Europe2008Conference paper (Refereed)
  • 24.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Dutta, P. C.
    Department of Food Science, SLU, Sweden.
    Oxidation of Plant Sterols in the Industrial By-products of Edible Fats and Oils2010In: 101st AOCS Annual Meeting & Expo, Phoenix, Arizona, USA, May 16-19, 2010, AOCS Abstract, Urbana: AOCS Press , 2010, p. 17-Conference paper (Refereed)
  • 25.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    1.Swedish University of Agricultural Sciences Division of Food Chemistry, Department of Food Science, Sweden.
    Dutta, P. C.
    1.Swedish University of Agricultural Sciences Division of Food Chemistry, Department of Food Science, Sweden.
    Sterol oxidation products in feeding fat samples obtained from various sources in Europe2006In:  De nationella Livsmedelsforskardagarna 2006, Svensk livsmedelsforskning bär frukt: Program och sammanfattningar, 2006Conference paper (Other academic)
  • 26.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    1.Swedish University of Agricultural Sciences Division of Food Chemistry, Department of Food Science Box 7051 75007 Uppsala Sweden.
    Dutta, P. C.
    1.Swedish University of Agricultural Sciences Division of Food Chemistry, Department of Food Science Box 7051 75007 Uppsala Sweden.
    Sterols and sterol oxidation in feeding fats obtained from co- and by-products from the food chain in Europe2007In: Book of Abstracts: 5th Euro Fed Lipid Congress and 24th Nordic Lipid Symposium Oils, Fats and Lipids: From Science to Applications - Innovations for a better World -16-19 September 2007, Gothenburg, Sweden, 2007, p. 298-Conference paper (Refereed)
  • 27.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    1.Swedish University of Agricultural Sciences Division of Food Chemistry, Sweden.
    Dutta, Paresh
    1.Swedish University of Agricultural Sciences Division of Food Chemistry, Sweden.
    Sterols and Oxidized Sterols in Feed Ingredients Obtained from Chemical and Physical Refining Processes of Fats and Oils2009In: Journal of the American Oil Chemists Society, ISSN 0003-021X, E-ISSN 1558-9331, Vol. 86, no 6, p. 595-604Article in journal (Refereed)
    Abstract [en]

    The by-products obtained from conventional chemical and physical refining processes for edible fats and oils are important sources of valuable fatty components such as sterols, tocopherols, fatty acids, etc., and are also used as ingredients in animal feed formulations. Reports on sterol composition and content are limited, and the levels of oxidized sterols in these valuable by-products are unknown. This study analyzed by-product fractions from European refineries intended for use as ingredients in animal feeds for their content and composition of sterols and sterol oxidation products. The complex mixtures of sterol oxidation products were separated and quantified by multidimensional capillary columns, a medium polar DB-17MS and an apolar DB-5MS, in GC and GC–MS. Sterol content ranged from 0.l to 3.4 and 0.03 to 5.0 g/100 g in the by-product fractions collected from chemical and physical refining processes, respectively, while the corresponding ranges for sterol oxidation products were 0.02–17 and 0.02–1.5 mg/100 g.

  • 28.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    Swedish University of Agricultural Sciences Division of Food Chemistry, Department of Food Science Box 7051 75007 Uppsala Sweden.
    Jayasinghe, Pradeepa
    Ekanayaka, S.
    Putta, P. C.
    Swedish University of Agricultural Sciences Division of Food Chemistry, Department of Food Science Box 7051 75007 Uppsala Sweden.
    Changes in fatty acid cholesterol content of jaadi made from Indian Mackerel (rastreliger kanagurata) during curing2005Conference paper (Refereed)
  • 29.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    Department of Food Science, Division of Food Chemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Kochhar, Sri P.
    Sonning, Reading, Berkshire, UK.
    Dutta, Paresh C.
    Department of Food Science, Division of Food Chemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Lipids and lipid oxidation with emphasis on cholesterol oxides in some Indian sweets available in London2006In: International Journal of Food Sciences and Nutrition, Vol. 57, p. 451-458Article in journal (Refereed)
  • 30.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Staaf, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Free fatty acid determination in plasma by GC-MS after conversion to Weinreb amides2013In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 405, no 6, p. 1929-1935Article in journal (Refereed)
    Abstract [en]

    Circulating free fatty acids (FFAs) play important physiological roles as contributing components in cellular structure as well as energy utilization. Elevated levels of circulating FFAs are associated with metabolic aberrations in humans. FFAs differ in chain length and saturation and may be altered in metabolically dysregulated conditions, such as type 2 diabetes mellitus. Potentially, alterations in circulating levels of specific FFAs could also be important in terms of prognostic value. Various methods have been used to analyze FFAs. In this study, a straightforward and accurate method for the determination of FFAs in plasma has been established and evaluated, through conversion of plasma FFAs into acid fluorides followed by conversion to Weinreb amides (dimethylamide). The method is mild, efficient, selective, and quantitative for FFAs, when analyzed with capillary gas chromatography tandem mass spectrometry. Standard curves were linear over the range of 1,000–20,000 ng/mL with a correlation coefficient (r2) of 0.998, and coefficient of variation of triplicate analysis was <10 %. The gas chromatography–mass spectrometry (GC-MS) technique was reproducible and repeatable, and recoveries were above 90 %. From the generated MS spectra, five specific FFAs were identified. An explicit interest was the quantification of palmitate (C16:0) and palmitoleate (C16:1), which have been connected with detrimental and positive effects on the insulin-producing beta cells, respectively. The results demonstrate the suitability of Weinreb amides for efficient and rapid isolation of FFAs in plasma, prior to quantitative GC-MS analysis. We suggest that the method can be used as a routine standardized way of quantifying FFAs.

  • 31.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    1.Swedish University of Agricultural Sciences (SLU) Division of Food Chemistry.
    Tres, Alba
    2.University of Barcelona Nutrition and Food Science Department, XaRTA, INSA, Barcelona Spain.
    Codony, Rafael
    2.University of Barcelona Nutrition and Food Science Department, XaRTA, INSA, Barcelona Spain.
    Dutta, Paresh
    1.Swedish University of Agricultural Sciences (SLU) Division of Food Chemistry.
    Effect of Feed Fat By-Products with Trans Fatty Acids and Heated Oil on Cholesterol and Oxycholesterols in Chicken2010In: Journal of the American Oil Chemists Society, ISSN 0003-021X, E-ISSN 1558-9331, Vol. 87, no 2, p. 173-184Article in journal (Refereed)
    Abstract [en]

    Chicken is the most widely consumed meat all over the world due to chickens being easy to rear, their fast growth rate and the meat having good nutritional characteristics. The main objective of this paper was to study the effects of dietary fatty by-products in low, medium and high levels of oxidized lipids and trans fatty acids (TFAs) on the contents of cholesterol and oxycholesterols in meat, liver, and plasma of chickens. A palm fatty acid distillate, before and after hydrogenation, and a sunflower–olive oil blend (70/30, v/v) before and after use in a commercial frying process were used in feeding trials after adding 6% of the fats to the feeds. Highly oxidized lipid and TFA feeds significantly increased the contents of cholesterol and oxycholesterols in all tissues of chicken (0.01 < p ≤ 0.05). The contents of oxycholesterols in chicken meat, liver and plasma obtained from TFA feeding trials varied between 17 and 48 μg/100 g in meat, 19–42 μg/100 g in liver and 105–126 μg/dL in plasma. In contrast, in the oxidized lipid feeding trials, oxycholesterols varied between 13 and 75 μg/100 g in meat, 30–58 μg/100 g in liver and 66–209 μg/dL in plasma. Meat from chickens fed with feeds containing high levels of TFAs or oxidized lipids may contribute to higher ingestion of cholesterol and oxycholesterols by humans.

  • 32.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    Division of Food Chemistry, Department of Food Science, Swedish University of Agricultural Sciences.
    Tres, Alba
    Nutrition and Food Science Department-XaRTA, University of Barcelona, Spain.
    Codony, Rafael
    Nutrition and Food Science Department-XaRTA, University of Barcelona, Spain.
    Dutta, Paresh C.
    Division of Food Chemistry, Department of Food Science, Swedish University of Agricultural Sciences.
    Effects of different levels of trans fatty acids and oxidised lipids in diet on cholesterol and cholesterol oxidation products formation in rabbit2010In: Food Chemistry, ISSN 0308-8146, E-ISSN 1873-7072, Vol. 121, p. 1198-1202Article in journal (Refereed)
    Abstract [en]

    The objective was to assess the effects of trans fatty acids and oxidised lipids, present in dietary fat by-products used in feeds, on cholesterol and oxycholesterols in meat, liver and plasma of rabbits. A palm fatty acid distillate, before and after hydrogenation (trans fatty acid trial), and a sunflower–olive oil blend (70/30, v/v), before and after use in a commercial frying process (oxidised lipid trial), were used in experimental feeds (at 3%, w/w). High trans fatty acid and oxidised lipid diets caused significantly higher cholesterol and oxycholesterol levels in all tissues of rabbit (0.01 <  0.05). The content of oxycholesterols in rabbit meat, liver and plasma obtained from trans fatty acid experiments varied from 9 to 34 μg/100 g, 24 to 61 μg/100 g and 60 to 138 μg/dl, respectively, from low to high levels. In the oxidised lipid experiments, content of oxycholesterols varied from 16 to 52 μg/100 g, 14 to 108 μg/100 g and 52 to 269 μg/dl in meat, liver and plasma, respectively. As a consequence, meat products from rabbits fed a diet containing higher levels of trans fatty acids or oxidised lipids may result in higher intakes of cholesterol and oxycholesterols by humans.

  • 33.
    Ubhayasekera, Sarojini J.K.A.
    et al.
    Department of Food Science, Division of Food Chemistry, Swedish University of Agricultural Sciences, Sweden.
    Verleyen, T.
    Department of Organic Chemistry, Coupure Links 653, 9000, Gent, Belgium.
    Dutta, P. C.
    Department of Food Science, Division of Food Chemistry, Swedish University of Agricultural Sciences, Sweden.
    Evaluation of GC and GC-MS methods for the analysis of cholesterol oxidation products2004In: Food Chemistry, ISSN 0308-8146, E-ISSN 1873-7072, Vol. 84, p. 149-157Article in journal (Refereed)
    Abstract [en]

    Various methods are used to analyse cholesterol oxidation products (COP) due to the unavailability of a standard method. In order to select a suitable method for the enrichment of COP, three methods of saponification (A-C), and transesterification (D) of tallow with three levels (5, 10 and 20 [mu]g) of spiked COP, were evaluated. Further enrichment of COP was done by solid phase extraction, quantified by GC, and confirmed by GC-MS. The in-house method A, and method D showed,the best results among the four methods evaluated. The recoveries at all levels of spiked COP were generally higher than 60% in method A. The recoveries of all spiked COP at 5 [mu]g level were consistently lower in method D compared with method A. From the results of this study it can be concluded that method A may be more suitable for the analysis of very low levels of COP in foods.

  • 34.
    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.

  • 35.
    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.

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