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  • 1. Buentke, E
    et al.
    Nordström, Anders
    Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Lin, H
    Björklund, AC
    Laane, E
    Harada, M
    Lu, L
    Tegnebratt, T
    Stone-Elander, S
    Heyman, M
    Söderhäll, S
    Porwit, A
    Östenson, CG
    Shoshan, M
    Tamm, K Pokrovskaja
    Grandér, D
    Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells2011Ingår i: Blood Cancer Journal, E-ISSN 2044-5385, Vol. 1, nr e31, s. 9-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Malignant cells are known to have increased glucose uptake and accelerated glucose metabolism. Using liquid chromatography and mass spectrometry, we found that treatment of acute lymphoblastic leukemia (ALL) cells with the glucocorticoid (GC) dexamethasone (Dex) resulted in profound inhibition of glycolysis. We thus demonstrate that Dex reduced glucose consumption, glucose utilization and glucose uptake by leukemic cells. Furthermore, Dex treatment decreased the levels of the plasma membrane-associated glucose transporter GLUT1, thus revealing the mechanism for the inhibition of glucose uptake. Inhibition of glucose uptake correlated with induction of cell death in ALL cell lines and in leukemic blasts from ALL patients cultured ex vivo. Addition of di-methyl succinate could partially overcome cell death induced by Dex in RS4;11 cells, thereby further supporting the notion that inhibition of glycolysis contributes to the induction of apoptosis. Finally, Dex killed RS4;11 cells significantly more efficiently when cultured in lower glucose concentrations suggesting that modulation of glucose levels might influence the effectiveness of GC treatment in ALL. In summary, our data show that GC treatment blocks glucose uptake by leukemic cells leading to inhibition of glycolysis and that these effects play an important role in the induction of cell death by these drugs.

  • 2.
    Diamanti, Riccardo
    et al.
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Srinivas, Vivek
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Johansson, Annika I.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Swedish Metabolomics Centre.
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Griese, Julia J.
    Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
    Lebrette, Hugo
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Laboratoire de Microbiologie et Génétique Moléculaires (LMGM), Centre de Biologie Intégrative (CBI), CNRS, UPS, Université de Toulouse, Toulouse, France.
    Högbom, Martin
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Comparative structural analysis provides new insights into the function of R2-like ligand-binding oxidase2022Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 596, nr 12, s. 1600-1610Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    R2-like ligand-binding oxidase (R2lox) is a ferritin-like protein that harbours a heterodinuclear manganese–iron active site. Although R2lox function is yet to be established, the enzyme binds a fatty acid ligand coordinating the metal centre and catalyses the formation of a tyrosine–valine ether cross-link in the protein scaffold upon O2 activation. Here, we characterized the ligands copurified with R2lox by mass spectrometry-based metabolomics. Moreover, we present the crystal structures of two new homologs of R2lox, from Saccharopolyspora erythraea and Sulfolobus acidocaldarius, at 1.38 Å and 2.26 Å resolution, respectively, providing the highest resolution structure for R2lox, as well as new insights into putative mechanisms regulating the function of the enzyme.

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  • 3. Domingo-Almenara, Xavier
    et al.
    Montenegro-Burke, J. Rafael
    Ivanisevic, Julijana
    Thomas, Aurelien
    Sidibé, Jonathan
    Teav, Tony
    Guijas, Carlos
    Aisporna, Aries E.
    Rinehart, Duane
    Hoang, Linh
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Gómez-Romero, Maria
    Whiley, Luke
    Lewis, Matthew R.
    Nicholson, Jeremy K.
    Benton, H. Paul
    Siuzdak, Gary
    CMS-MRM and METLIN-MRM: a cloud library and public resource for targeted analysis of small molecules2018Ingår i: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 15, nr 9, s. 681-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report XCMS-MRM and METLIN-MRM (http://xcmsonline-mrm.scripps.edu/ and http://metlin.scripps.edu/), a cloud-based data-analysis platform and a public multiple-reaction monitoring (MRM) transition repository for small-molecule quantitative tandem mass spectrometry. This platform provides MRM transitions for more than 15,500 molecules and facilitates data sharing across different instruments and laboratories.

  • 4. Go, Eden P
    et al.
    Uritboonthai, Wilasinee
    Apon, Junefredo V
    Trauger, Sunia A
    Nordstrom, Anders
    The Scripps Research Institute.
    O'Maille, Grace
    Brittain, Scott M
    Peters, Eric C
    Siuzdak, Gary
    Selective metabolite and peptide capture/mass detection using fluorous affinity tags.2007Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 6, nr 4, s. 1492-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new and general methodology is described for the targeted enrichment and subsequent direct mass spectrometric characterization of sample subsets bearing various chemical functionalities from highly complex mixtures of biological origin. Specifically, sample components containing a chemical moiety of interest are first selectively labeled with perfluoroalkyl groups, and the entire sample is then applied to a perfluoroalkyl-silylated porous silicon (pSi) surface. Due to the unique hydrophobic and lipophobic nature of the perfluorinated tags, unlabeled sample components are readily removed using simple surface washes, and the enriched sample fraction can then directly be analyzed by desorption/ionization on silicon mass spectrometry (DIOS-MS). Importantly, this fluorous-based enrichment methodology provides a single platform that is equally applicable to both peptide as well as small molecule focused applications. The utility of this technique is demonstrated by the enrichment and mass spectrometric analysis of both various peptide subsets from protein digests as well as amino acids from serum.

  • 5. Go, Eden P
    et al.
    Wikoff, William R
    Shen, Zhouxin
    O'Maille, Grace
    Morita, Hirotoshi
    Conrads, Thomas P
    Nordstrom, Anders
    Department of Molecular Biology and The Center for Mass Spectrometry, The Scripps Research Institute.
    Trauger, Sunia A
    Uritboonthai, Wilasinee
    Lucas, David A
    Chan, King C
    Veenstra, Timothy D
    Lewicki, Hanna
    Oldstone, Michael B
    Schneemann, Anette
    Siuzdak, Gary
    Mass spectrometry reveals specific and global molecular transformations during viral infection.2006Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 5, nr 9, s. 2405-16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mass spectrometry analysis was used to target three different aspects of the viral infection process: the expression kinetics of viral proteins, changes in the expression levels of cellular proteins, and the changes in cellular metabolites in response to viral infection. The combination of these methods represents a new, more comprehensive approach to the study of viral infection revealing the complexity of these events within the infected cell. The proteins associated with measles virus (MV) infection of human HeLa cells were measured using a label-free approach. On the other hand, the regulation of cellular and Flock House Virus (FHV) proteins in response to FHV infection of Drosophila cells was monitored using stable isotope labeling. Three complementary techniques were used to monitor changes in viral protein expression in the cell and host protein expression. A total of 1500 host proteins was identified and quantified, of which over 200 proteins were either up- or down-regulated in response to viral infection, such as the up-regulation of the Drosophila apoptotic croquemort protein, and the down-regulation of proteins that inhibited cell death. These analyses also demonstrated the up-regulation of viral proteins functioning in replication, inhibition of RNA interference, viral assembly, and RNA encapsidation. Over 1000 unique metabolites were also observed with significant changes in over 30, such as the down-regulated cellular phospholipids possibly reflecting the initial events in cell death and viral release. Overall, the cellular transformation that occurs upon viral infection is a process involving hundreds of proteins and metabolites, many of which are structurally and functionally uncharacterized.

  • 6. Griese, Julia J
    et al.
    Kositzki, Ramona
    Schrapers, Peer
    Branca, Rui M M
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Lehtiö, Janne
    Haumann, Michael
    Högbom, Martin
    Structural Basis for Oxygen Activation at a Heterodinuclear Manganese/Iron Cofactor2015Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, nr 42, s. 25254-25272Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two recently discovered groups of prokaryotic di-metal carboxylate proteins harbor a heterodinuclear Mn/Fe cofactor. These are the class Ic ribonucleotide reductase R2 proteins and a group of oxidases that are found predominantly in pathogens and extremophiles, called R2-like ligand-binding oxidases (R2lox). We have recently shown that the Mn/Fe cofactor of R2lox self-assembles from Mn-II and Fe-II in vitro and catalyzes formation of a tyrosine-valine ether cross-link in the protein scaffold (Griese, J. J., Roos, K., Cox, N., Shafaat, H. S., Branca, R.M., Lehtio , J., Graslund, A., Lubitz, W., Siegbahn, P. E., and Hogbom, M. (2013) Proc. Natl. Acad. Sci. U.S.A. 110, 1718917194). Here, we present a detailed structural analysis of R2lox in the nonactivated, reduced, and oxidized resting Mn/Fe- and Fe/Fe-bound states, as well as the nonactivated Mn/Mn-bound state. X-ray crystallography and x-ray absorption spectroscopy demonstrate that the active site ligand configuration of R2lox is essentially the same regardless of cofactor composition. Both the Mn/Fe and the diiron cofactor activate oxygen and catalyze formation of the ether cross-link, whereas the dimanganese cluster does not. The structures delineate likely routes for gated oxygen and substrate access to the active site that are controlled by the redox state of the cofactor. These results suggest that oxygen activation proceeds via similar mechanisms at the Mn/Fe and Fe/Fe center and that R2lox proteins might utilize either cofactor in vivo based on metal availability.

  • 7.
    Gullberg, Jonas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Sjöström, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Moritz, Thomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Design of experiments: an efficient strategy to identify factors influencing extraction and derivatization of Arabidopsis thaliana samples in metabolomic studies with gas chromatography/mass spectrometry2004Ingår i: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 331, nr 2, s. 283-295Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The usual aim in metabolomic studies is to quantify the entire metabolome of each of a series of biological samples. To do this for complex biological matrices, e.g., plant tissues, efficient and reproducible extraction protocols must be developed. However, derivatization protocols must also be developed if GC/MS (one of the mostly widely used analytical methods for metabolomics) is involved. The aim of this study was to investigate how different chemical and physical factors (extraction solvent, derivatization reagents, and temperature) affect the extraction and derivatization of the metabolome from leaves of the plant Arabidopsis thaliana. Using design of experiment procedures, variation was systematically introduced, and the effects of this variation were analyzed using regression models. The results show that this approach allows a reliable protocol for metabolomic analysis of Arabidopsis to be determined with a relatively limited number of experiments. Following two different investigations an extraction and derivatization protocol was chosen. Further, the reproducibility of the analysis of 66 endogenous compounds was investigated, and it was shown that both hydrophilic and lipophilic compounds were detected with high reproducibility.

  • 8.
    Jonsson, Pär
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gullberg, Jonas
    Nordström, Anders
    Kusano, Miyako
    Kowalczyk, Mauriusz
    Sjöström, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Moritz, Thomas
    A strategy for identifying differences in large series of metabolomic samples analyzed by GC/MS2004Ingår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 76, nr 6, s. 1738-1745Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In metabolomics, the purpose is to identify and quantify all the metabolites in a biological system. Combined gas chromatography and mass spectrometry (GC/MS) is one of the most commonly used techniques in metabolomics together with 1H NMR, and it has been shown that more than 300 compounds can be distinguished with GC/MS after deconvolution of overlapping peaks. To avoid having to deconvolute all analyzed samples prior to multivariate analysis of the data, we have developed a strategy for rapid comparison of nonprocessed MS data files. The method includes baseline correction, alignment, time window determinations, alternating regression, PLS-DA, and identification of retention time windows in the chromatograms that explain the differences between the samples. Use of alternating regression also gives interpretable loadings, which retain the information provided by m/z values that vary between the samples in each retention time window. The method has been applied to plant extracts derived from leaves of different developmental stages and plants subjected to small changes in day length. The data show that the new method can detect differences between the samples and that it gives results comparable to those obtained when deconvolution is applied prior to the multivariate analysis. We suggest that this method can be used for rapid comparison of large sets of GC/MS data, thereby applying time-consuming deconvolution only to parts of the chromatograms that contribute to explain the differences between the samples.

  • 9.
    Kolmert, Johan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå Plant Science Center, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå ; Global Safety Assessment, AstraZeneca R&D, Södertälje ; Department of Analytical Chemistry, Stockholm University.
    Forngren, B.
    Lindberg, J.
    Öhd, J.
    Åberg, K. M.
    Nilsson, G.
    Moritz, T.
    Nordström, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    A quantitative LC/MS method targeting urinary 1-methyl-4-imidazoleacetic acid for safety monitoring of the global histamine turnover in clinical studies2014Ingår i: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 406, nr 6, s. 1751-1762Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Anaphylaxis is a potentially life-threatening condition triggered mainly by the release of inflammatory mediators, notably histamine. In pharmaceutical research, drug discovery, and clinical evaluation, it may be necessary to accurately assess the potential of a compound, event, or disorder to promote the release of histamine. In contrast to the measurement of plasma histamine, determination of the stable metabolite 1-methyl-4-imidazoleacetic acid (tele-MIAA) in urine provides a noninvasive and more reliable methodology to monitor histamine release. This study presents a repeatable high-performance liquid chromatography coupled to electrospray mass spectrometry (LC-ESI-MS) method where tele-MIAA is baseline separated from its structural isomer 1-methyl-5-imidazoleacetic acid (pi-MIAA) and an unknown in human urine. The ion-pairing chromatography method, in reversed-phase mode, based on 0.5 mM tridecafluoroheptanoic acid demonstrated high repeatability and was applied in a clinical development program that comprised a large number of clinical samples from different cohorts. The inter- and intra-run precision of the method for tele-MIAA were 8.4 and 4.3 %, respectively, at the mean urinary concentration level, while method accuracy was between -16.2 and 8.0 % across the linear concentration range of 22-1,111 ng mL(-1). Overall, method precision was greater than that reported in previously published methods and enabled the identification of gender differences that were independent of age or demography. The median concentration measured in female subjects was 3.0 mu mol mmol(-1) of creatinine, and for male subjects, it was 2.1 mu mol mmol(-1) of creatinine. The results demonstrate that the method provides unprecedented accuracy, precision, and practicality for the measurement of tele-MIAA in large clinical settings.

  • 10. Lindahl, Anna
    et al.
    Forshed, Jenny
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
    Overlap in serum metabolic profiles between non-related diseases: implications for LC-MS metabolomics biomarker discovery2016Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 478, nr 3, s. 1472-1477Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Untargeted metabolic profiling has generated large activity in the field of clinical biomarker discovery. Yet, no clinically approved metabolite biomarkers have emerged with failure in validation phases often being a reason. To investigate why, we have applied untargeted metabolic profiling in a retrospective cohort of serum samples representing non-related diseases. Age and gender matched samples from patients diagnosed with pneumonia, congestive heart failure, lymphoma and healthy controls were subject to comprehensive metabolic profiling using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The metabolic profile of each diagnosis was compared to the healthy control group and significant metabolites were filtered out using t-test with FDR correction. Metabolites found to be significant between each disease and healthy controls were compared and analyzed for overlap. Results show that despite differences in etiology and clinical disease presentation, the fraction of metabolites with an overlap between two or more diseases was 61%. A majority of these metabolites can be associated with immune responses thus representing non-disease specific events. We show that metabolic serum profiles from patients representing non-related diseases display very similar metabolic differences when compared to healthy controls. Many of the metabolites discovered as disease specific in this study have further been associated with other diseases in the literature. Based on our findings we suggest non-related disease controls in metabolomics biomarker discovery studies to increase the chances of a successful validation and future clinical applications. 

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  • 11. Lindahl, Anna
    et al.
    Heuchel, Rainer
    Forshed, Jenny
    Lehtio, Janne
    Lohr, Matthias
    Nordström, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Discrimination of pancreatic cancer and pancreatitis by LC-MS metabolomics2017Ingår i: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 13, nr 5, artikel-id 61Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the fifth most common cause of cancer-related death in Europe with a 5-year survival rate of <5%. Chronic pancreatitis (CP) is a risk factor for PDAC development, but in the majority of cases malignancy is discovered too late for curative treatment. There is at present no reliable diagnostic marker for PDAC available.

    Objectives: The aim of the study was to identify single blood-based metabolites or a panel of metabolites discriminating PDAC and CP using liquid chromatography-mass spectrometry (LC-MS).

    Methods: A discovery cohort comprising PDAC (n = 44) and CP (n = 23) samples was analyzed by LC-MS followed by univariate (Student’s t test) and multivariate (orthogonal partial least squares-discriminant analysis (OPLS-DA)) statistics. Discriminative metabolite features were subject to raw data examination and identification to ensure high feature quality. Their discriminatory power was then confirmed in an independent validation cohort including PDAC (n = 20) and CP (n = 31) samples.

    Results: Glycocholic acid, N-palmitoyl glutamic acid and hexanoylcarnitine were identified as single markers discriminating PDAC and CP by univariate analysis. OPLS-DA resulted in a panel of five metabolites including the aforementioned three metabolites as well as phenylacetylglutamine (PAGN) and chenodeoxyglycocholate.

    Conclusion: Using LC-MS-based metabolomics we identified three single metabolites and a five-metabolite panel discriminating PDAC and CP in two independent cohorts. Although further study is needed in larger cohorts, the metabolites identified are potentially of use in PDAC diagnostics.

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  • 12. Lindahl, Anna
    et al.
    Saaf, Siv
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Lehtio, Janne
    Nordström, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, Stockholm, Sweden.
    Tuning Metabolome Coverage in Reversed Phase LC-MS Metabolomics of MeOH Extracted Samples Using the Reconstitution Solvent Composition2017Ingår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 89, nr 14, s. 7356-7364Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Considering the physicochemical diversity of the metabolome, untargeted metabolomics will inevitably discriminate against certain compound classes. Efforts are nevertheless made to maximize the metabolome coverage. Contrary to the main steps of a typical liquid chromatography-mass spectrometry (LC-MS) metabolomics workflow, such as metabolite extraction, the sample reconstitution step has not been optimized for maximal metabolome coverage. This sample concentration step typically occurs after metabolite extraction, when dried samples are reconstituted in a solvent for injection on column. The aim of this study was to evaluate the impact of the sample reconstitution solvent composition on metabolome coverage in untargeted LCMS metabolomics. Lysogeny Broth medium samples reconstituted in MeOH/H2O ratios ranging from 0 to 100% MeOH and analyzed with untargeted reversed phase LC-MS showed that the highest number of metabolite features (n = 1500) was detected in samples reconstituted in 100% H2O. As compared to a commonly used reconstitution solvent mixture of 50/50 MeOH/H2O, our results indicate that the small fraction of compounds increasing in peak area response by the addition of MeOH to H2O, 5%, is outweighed by the fraction of compounds with decreased response, 57%. We evaluated our results on human serum samples from lymphoma patients and healthy control subjects. Reconstitution in 100% H2O resulted in a higher number of significant metabolites discriminating between these two groups than both 50% and 100% MeOH. These findings show that the sample reconstitution step has a clear impact on the metabolome coverage of MeOH extracted biological samples, highlighting the importance of the reconstitution solvent composition for untargeted discovery metabolomics.

  • 13.
    Muthu, Magesh
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Kumar, Ranjeet
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Khaja, Azharuddin Sajid Syed
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Nordström, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism2019Ingår i: Cancers, ISSN 2072-6694, Vol. 11, nr 12, artikel-id 1945Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glutamate-ammonia ligase (GLUL) is important for acid-base homeostasis, ammonia detoxification, cell signaling, and proliferation. Here, we reported that GLUL ablation conferred resistance to several anticancer drugs in specific cancer cell lines while leaving other cell lines non-resistant to the same drugs. To understand the biochemical mechanics supporting this drug resistance, we compared drug-resistant GLUL knockout (KO) A549 non-small-cell lung carcinoma (NSCLC) cells with non-resistant GLUL KO H1299 NSCLC cells and found that the resistant A549 cells, to a larger extent, depended on exogenous glucose for proliferation. As GLUL activity is linked to the tricarboxylic acid (TCA) cycle via reversed glutaminolysis, we probed carbon flux through both glycolysis and TCA pathways by means of 13C5 glutamine, 13C5 glutamate, and 13C6 glucose tracing. We observed increased labeling of malate and aspartate in A549 GLUL KO cells, whereas the non-resistant GLUL KO H1299 cells displayed decreased 13C-labeling. The malate and aspartate shuttle supported cellular NADH production and was associated with cellular metabolic fitness. Inhibition of the malate-aspartate shuttle with aminooxyacetic acid significantly impacted upon cell viability with an IC50 of 11.5 μM in resistant GLUL KO A549 cells compared to 28 μM in control A549 cells, linking resistance to the malate-aspartate shuttle. Additionally, rescuing GLUL expression in A549 KO cells increased drug sensitivity. We proposed a novel metabolic mechanism in cancer drug resistance where the increased capacity of the malate-aspartate shuttle increased metabolic fitness, thereby facilitating cancer cells to escape drug pressure.

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  • 14.
    Muthu, Magesh
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Current Status and Future Prospects of Clinically Exploiting Cancer-specific Metabolism: Why Is Tumor Metabolism Not More Extensively Translated into Clinical Targets and Biomarkers?2019Ingår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 20, nr 6, artikel-id 1385Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Tumor cells exhibit a specialized metabolism supporting their superior ability for rapid proliferation, migration, and apoptotic evasion. It is reasonable to assume that the specific metabolic needs of the tumor cells can offer an array of therapeutic windows as pharmacological disturbance may derail the biochemical mechanisms necessary for maintaining the tumor characteristics, while being less important for normally proliferating cells. In addition, the specialized metabolism may leave a unique metabolic signature which could be used clinically for diagnostic or prognostic purposes. Quantitative global metabolic profiling (metabolomics) has evolved over the last two decades. However, despite the technology's present ability to measure 1000s of endogenous metabolites in various clinical or biological specimens, there are essentially no examples of metabolomics investigations being translated into actual utility in the cancer clinic. This review investigates the current efforts of using metabolomics as a tool for translation of tumor metabolism into the clinic and further seeks to outline paths for increasing the momentum of using tumor metabolism as a biomarker and drug target opportunity.

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  • 15.
    Nordström, Anders
    et al.
    Department of Molecular Biology, The Scripps Center for Mass Spectrometry, The Scripps Research Institute.
    Apon, Junefredo V
    Uritboonthai, Wilasinee
    Go, Eden P
    Siuzdak, Gary
    Surfactant-enhanced desorption/ionization on silicon mass spectrometry.2006Ingår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 78, nr 1, s. 272-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Perfluorinated surfactants are demonstrated to dramatically enhance desorption/ionization on fluorinated silicon (DIOS) mass spectrometry. Perfluorooctanesulfonic acid improved the signal-to-noise ratio of tryptic digests and gave a 3-fold increase in the number of peptides identified. Similar results were also obtained using perfluoroundecanoic acid; yet among the seven different surfactants tested, controls such as nonfluorinated sodium dodecyl sulfate or fluorinated molecules with minimal surfactant activity did not enhance the signal. The same surfactants also enhanced the DIOS-MS signal of amino acids, carbohydrates, and other small organic compounds. The signal enhancement may be facilitated by the high surface activity of the perfluorinated surfactants on the fluorinated silicon surfaces allowing for a higher concentration of analyte to be absorbed.

  • 16.
    Nordström, Anders
    et al.
    Department for Oncology–Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
    Lewensohn, Rolf
    Department for Oncology–Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
    Metabolomics: moving to the clinic.2010Ingår i: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, ISSN 1557-1904, Vol. 5, nr 1, s. 4-17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Assessment of a biological system by means of global and non-targeted metabolite profiling--metabolomics or metabonomics--provides the investigator with molecular information that is close to the phenotype in question in the sense that metabolites are an ultimate product of gene, mRNA, and protein activity. Over the last few years, there has been a rapidly growing number of metabolomics applications aimed at finding biomarkers which could assist diagnosis, provide therapy guidance, and evaluate response to therapy for particular diseases. Also, within the fields of drug discovery, drug toxicology, and personalized pharmacology, metabolomics is emerging as a powerful tool. This review seeks to update the reader on analytical strategies, biomarker findings, and implications of metabolomics for the clinic. Particular attention is paid to recent biomarkers found related to neurological, cardiovascular, and cancer diseases. Moreover, the impact of metabolomics in the drug discovery and development process is examined.

  • 17.
    Nordström, Anders
    et al.
    Department of Molecular Biology, Scripps Center for Mass Spectrometry, The Scripps Research Institute.
    O'Maille, Grace
    Qin, Chuan
    Siuzdak, Gary
    Nonlinear data alignment for UPLC-MS and HPLC-MS based metabolomics: quantitative analysis of endogenous and exogenous metabolites in human serum.2006Ingår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 78, nr 10, s. 3289-95Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A nonlinear alignment strategy was examined for the quantitative analysis of serum metabolites. Two small-molecule mixtures with a difference in relative concentration of 20-100% for 10 of the compounds were added to human serum. The metabolomics protocol using UPLC and XCMS for LC-MS data alignment could readily identify 8 of 10 spiked differences among more than 2700 features detected. Normalization of data against a single factor obtained through averaging the XCMS integrated response areas of spiked standards increased the number of identified differences. The original data structure was well preserved using XCMS, but reintegration of identified differences in the original data reduced the number of false positives. Using UPLC for separation resulted in 20% more detected components compared to HPLC. The length of the chromatographic separation also proved to be a crucial parameter for a number of detected features. Moreover, UPLC displayed better retention time reproducibility and signal-to-noise ratios for spiked compounds over HPLC, making this technology more suitable for nontargeted metabolomics applications.

  • 18.
    Nordström, Anders
    et al.
    Swedish University of Agricultural Sciences.
    Tarkowski, Petr
    Tarkowska, Danuse
    Dolezal, Karel
    Astot, Crister
    Sandberg, Göran
    Moritz, Thomas
    Derivatization for LC-electrospray ionization-MS: a tool for improving reversed-phase separation and ESI responses of bases, ribosides, and intact nucleotides.2004Ingår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 76, nr 10, s. 2869-77Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have developed a method for analyzing polar compounds by reversed-phase LC-ESI-MS following esterification of the analytes' free hydroxyl groups with propionyl or benzoyl acid anhydride. The method was applied to members of the plant hormone group cytokinins, which includes adenine bases, ribosides/glycosides, and nucleotides substituted at N-6 with an isoprenoid side chain, spanning a wide range of polarity. It was also used to analyze other compounds of biological importance, e.g., the nucleotides AMP, ADP, and ATP. The formation of more hydrophobic derivatives had a significant impact on two aspects of the analysis. The retention on a reversed-phase material was greatly increased without the use of any acetate/formate buffer or ion pairing reagent, and the ESI response was enhanced, due to the higher surface activities of the derivatives. Detection limits of propionylated cytokinins were in the high-attomole to low-femtomole range, an improvement by factors of 10-100 compared to previously reported figures. Using an automated SPE-based purification method, 12 endogenous cytokinins were quantified in extracts from 20- to 100-mg samples of leaves (from the plant Arabidopsis thaliana) with high accuracy and precision. Furthermore, the chromatographic properties of the benzoylated AMP, ADP, and ATP in the reversed-phase LC-MS system were much better in terms of retention, separation, and sensitivity than those of their underivatized counterparts, even without the use of any ion pairing reagent. Our data show that derivatization followed by LC-ESI-MS is an effective strategy for analyzing low molecular weight compounds, enabling compounds with a wide range of polarity to be determined in a single-injection LC-MS analysis.

  • 19.
    Nordström, Anders
    et al.
    Umeå Plant Science Centre, Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences.
    Tarkowski, Petr
    Tarkowska, Danuse
    Norbaek, Rikke
    Astot, Crister
    Dolezal, Karel
    Sandberg, Göran
    Auxin regulation of cytokinin biosynthesis in Arabidopsis thaliana: a factor of potential importance for auxin-cytokinin-regulated development.2004Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, nr 21, s. 8039-44Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One of the most long-lived models in plant science is the belief that the long-distance transport and ratio of two plant hormones, auxin and cytokinin, at the site of action control major developmental events such as apical dominance. We have used in vivo deuterium labeling and mass spectrometry to investigate the dynamics of homeostatic cross talk between the two plant hormones. Interestingly, auxin mediates a very rapid negative control of the cytokinin pool by mainly suppressing the biosynthesis via the isopentenyladenosine-5'-monophosphate-independent pathway. In contrast, the effect of cytokinin overproduction on the entire auxin pool in the plant was slower, indicating that this most likely is mediated through altered development. In addition, we were able to confirm that the lateral root meristems are likely to be the main sites of isopentenyladenosine-5'-monophosphate-dependent cytokinin synthesis, and that the aerial tissue of the plant surprisingly also was a significant source of cytokinin biosynthesis. Our demonstration of shoot-localized synthesis, together with data demonstrating that auxin imposes a very rapid regulation of cytokinin biosynthesis, illustrates that the two hormones can interact also on the metabolic level in controlling plant development, and that the aerial part of the plant has the capacity to synthesize its own cytokinin independent of long-range transport from the root system.

  • 20.
    Nordström, Anders
    et al.
    The Scripps Research Institute; Karolinska Institutet and Karolinska University Hospital.
    Want, Elizabeth
    Northen, Trent
    Lehtiö, Janne
    Siuzdak, Gary
    Multiple ionization mass spectrometry strategy used to reveal the complexity of metabolomics.2008Ingår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 80, nr 2, s. 421-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A multiple ionization mass spectrometry strategy is presented based on the analysis of human serum extracts. Chromatographic separation was interfaced inline with the atmospheric pressure ionization techniques electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) in both positive (+) and negative (-) ionization modes. Furthermore, surface-based matrix-assisted laser desorption/ionization (MALDI) and desorption ionization on silicon (DIOS) mass spectrometry were also integrated with the separation through fraction collection and offline mass spectrometry. Processing of raw data using the XCMS software resulted in time-aligned ion features, which are defined as a unique m/z at a unique retention time. The ion feature lists obtained through LC-MS with ESI and APCI interfaces in both +/- ionization modes were compared, and unique ion tables were generated. Nonredundant, unique ion features, were defined as mass numbers for which no mass numbers corresponding to [M + H](+), [M - H](-), or [M + Na](+) were observed in the other ionization methods at the same retention time. Analysis of the extracted serum using ESI for both (+) and (-) ions resulted in >90% additional unique ions being detected in the (-) ESI mode. Complementing the ESI analysis with APCI resulted in an additional approximately 20% increase in unique ions. Finally, ESI/APCI ionization was combined with fraction collection and offline-MALDI and DIOS mass spectrometry. The parts of the total ion current chromatograms in the LC-MS acquired data corresponding to collected fractions were summed, and m/z lists were compiled and compared to the m/z lists obtained from the DIOS/MALDI spectra. It was observed that, for each fraction, DIOS accounted for approximately 50% of the unique ions detected. These results suggest that true global metabolomics will require multiple ionization technologies to address the inherent metabolite diversity and therefore the complexity in and of metabolomics studies.

  • 21. Northen, Trent R
    et al.
    Woo, Hin-Koon
    Northen, Michael T
    Nordström, Anders
    Center for Mass Spectrometry, The Scripps Research Institute.
    Uritboonthail, Winnie
    Turner, Kimberly L
    Siuzdak, Gary
    High surface area of porous silicon drives desorption of intact molecules.2007Ingår i: Journal of the American Society for Mass Spectrometry, ISSN 1044-0305, E-ISSN 1879-1123, Vol. 18, nr 11, s. 1945-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The surface structure of porous silicon used in desorption/ionization on porous silicon (DIOS) mass analysis is known to play a primary role in the desorption/ionization (D/I) process. In this study, mass spectrometry and scanning electron microscopy (SEM) are used to examine the correlation between intact ion generation with surface ablation and surface morphology. The DIOS process is found to be highly laser energy dependent and correlates directly with the appearance of surface ions (Si(n)(+) and OSiH(+)). A threshold laser energy for DIOS is observed (10 mJ/cm(2)), which supports that DIOS is driven by surface restructuring and is not a strictly thermal process. In addition, three DIOS regimes are observed that correspond to surface restructuring and melting. These results suggest that higher surface area silicon substrates may enhance DIOS performance. A recent example that fits into this mechanism is the surface of silicon nanowires, which has a high surface energy and concomitantly requires lower laser energy for analyte desorption.

  • 22. Northen, Trent R
    et al.
    Yanes, Oscar
    Northen, Michael T
    Marrinucci, Dena
    Uritboonthai, Winnie
    Apon, Junefredo
    Golledge, Stephen L
    Nordström, Anders
    Department of Molecular Biology, Scripps Center for Mass Spectrometry.
    Siuzdak, Gary
    Clathrate nanostructures for mass spectrometry.2007Ingår i: Nature, ISSN 1476-4687, Vol. 449, nr 7165, s. 1033-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The ability of mass spectrometry to generate intact biomolecular ions efficiently in the gas phase has led to its widespread application in metabolomics, proteomics, biological imaging, biomarker discovery and clinical assays (namely neonatal screens). Matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization have been at the forefront of these developments. However, matrix application complicates the use of MALDI for cellular, tissue, biofluid and microarray analysis and can limit the spatial resolution because of the matrix crystal size (typically more than 10 mum), sensitivity and detection of small compounds (less than 500 Da). Secondary-ion mass spectrometry has extremely high lateral resolution (100 nm) and has found biological applications although the energetic desorption/ionization is a limitation owing to molecular fragmentation. Here we introduce nanostructure-initiator mass spectrometry (NIMS), a tool for spatially defined mass analysis. NIMS uses 'initiator' molecules trapped in nanostructured surfaces or 'clathrates' to release and ionize intact molecules adsorbed on the surface. This surface responds to both ion and laser irradiation. The lateral resolution (ion-NIMS about 150 nm), sensitivity, matrix-free and reduced fragmentation of NIMS allows direct characterization of peptide microarrays, direct mass analysis of single cells, tissue imaging, and direct characterization of blood and urine.

  • 23.
    Pateras, Ioannis S.
    et al.
    2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Williams, Chloe
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Gianniou, Despoina D.
    Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
    Margetis, Aggelos T.
    2nd Department of Internal Medicine, Athens Naval and Veterans Hospital, Athens, Greece.
    Avgeris, Margaritis
    Laboratory of Clinical Biochemistry-Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, “P. & A. Kyriakou” Children’s Hospital, Athens, Greece; Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
    Rousakis, Pantelis
    Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece.
    Legaki, Aigli-Ioanna
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Mirtschink, Peter
    Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
    Zhang, Wei
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Swedish Metabolomics Centre, Umeå University, Umeå, Sweden.
    Panoutsopoulou, Konstantina
    Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
    Delis, Anastasios D.
    Centre for Basic Research, Bioimaging Unit, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
    Pagakis, Stamatis N.
    Centre for Basic Research, Bioimaging Unit, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
    Tang, Wei
    Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), NCI, NIH, MD, Bethesda, United States; Data Science & Artificial Intelligence, R&D, AstraZeneca, MD, Gaithersburg, United States.
    Ambs, Stefan
    Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), NCI, NIH, MD, Bethesda, United States.
    Warpman Berglund, Ulrika
    Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Helleday, Thomas
    Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
    Varvarigou, Anastasia
    Department of Paediatrics, University of Patras Medical School, General University Hospital, Patras, Greece.
    Chatzigeorgiou, Antonios
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Swedish Metabolomics Centre, Umeå University, Umeå, Sweden.
    Tsitsilonis, Ourania E.
    Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece.
    Trougakos, Ioannis P.
    Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Frisan, Teresa
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming2023Ingår i: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 21, nr 1, artikel-id 169Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.

    Methods: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model.

    Results: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model.

    Conclusions: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.

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  • 24.
    Silverstein, Arthur
    et al.
    Department of the History of Medicine, Johns Hopkins University, MD, Baltimore, United States.
    Dudaev, Anton
    MGUPP, Moscow, Russian Federation.
    Studneva, Maria
    MGUPP, Moscow, Russian Federation; EPMA (European Association for Predictive, Preventive and Personalized Medicine), Brussels, Belgium.
    Aitken, John
    Otakaro Pathways, Christchurch, New Zealand.
    Blokh, Sofya
    Filatov's Moscow Clinical Pediatric Hospital, Moscow, Russian Federation.
    Miller, Andrew David
    Mendel University and Veterinary Research Institute, Brno, Czech Republic.
    Tanasova, Sofia
    A.I. Evdokimov Moscow State University of Medicine & Dentistry, Moscow, Russian Federation.
    Rose, Noel
    Johns Hopkins Bloomberg School of Public Health, MD, Baltimore, United States.
    Ryals, John
    Mathematics Department at Central Georgia Technical College, GA, Warner Robins, United States.
    Borchers, Christoph
    Lady Davis Institute, Segal Cancer Proteomics Centre, McGill University, QC, Montreal, Canada.
    Nordström, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Moiseyakh, Marina
    MGUPP, Moscow, Russian Federation.
    Herrera, Arturo Solís
    University of Florida, FL, Gainesville, United States.
    Skomorohov, Nikita
    MGUPP, Moscow, Russian Federation.
    Marshall, Trevor
    University of Adelaide, SA, Adelaide, Australia; Murdoch University, WA, Murdoch, Australia; The Autoimmunity Research Foundation, CA, Thousand Oaks, United States.
    Wu, Alan
    San Francisco General Hospital, CA, San Francisco, United States; UCSF, CA, San Francisco, United States.
    Cheng, R. Holland
    College of Biological Sciences, UC Davis, CA, Davis, United States.
    Syzko, Ksenia
    MGUPP, Moscow, Russian Federation.
    Cotter, Philip D.
    UCSF, CA, San Francisco, United States; ResearchDx and PacificDx, CA, Irvine, United States.
    Podzyuban, Marianna
    MGUPP, Moscow, Russian Federation.
    Thilly, William
    Massachusetts Institute of Technology, MIT, MA, Cambridge, United States.
    Smith, Paul David
    Newberry College, SC, Newberry, United States.
    Barach, Paul
    Wayne State University, IL, Detroit, United States.
    Bouri, Khaled
    Georgetown University, DC, Washington, United States.
    Schoenfeld, Yehuda
    Sheba Medical Center in Tel Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
    Matsuura, Eiji
    Neutron Therapy Research, Center Collaborative Research Center for OMIC & Department of Cell Chemistry, Okayama University, Okayama, Japan.
    Medvedeva, Veronika
    I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation.
    Shmulevich, Ilya
    Institute of Systems Biology (ISB), WA, Seattle, United States.
    Cheng, Liang
    Genitourinary Pathology Service, The Urologic Pathology Fellowship, and Molecular Diagnostics and Molecular Pathology Laboratories, Indiana University School of Medicine, IN, Indianapolis, United States.
    Seegers, Paul
    Stichting PALGA (Pathologisch Anatomisch Landelijk Geautomatiseerd Archief), Houten, Netherlands.
    Khotskaya, Yekaterina
    Clinical Decision Support Management, The Curematch, Inc, CA, San Diego, United States.
    Flaherty, Keith
    Harvard Medical School, MA, Boston, United States; Mass General Cancer Center, Massachusetts General Hospital, MA, Boston, United States.
    Dooley, Steven
    Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
    Sorenson, Eric J.
    Mayo Clinic, MN, Rochester, United States.
    Ross, Michael
    UCLA Medical Center Obstetrics & Gynecology, CA, Los Angeles, United States.
    Suchkov, Sergey
    MGUPP, Moscow, Russian Federation; EPMA (European Association for Predictive, Preventive and Personalized Medicine), Brussels, Belgium; A.I. Evdokimov Moscow State University of Medicine & Dentistry, Moscow, Russian Federation; ISPM (International Society for Personalized Medicine), Tokyo, Japan; PMC (Personalized Medicine Coalition), DC, Washington, United States; New York Academy of Sciences, NY, New York, United States; Association for Medical Education in Europe (AMEE), Dundee, United Kingdom.
    Evolution of biomarker research in autoimmunity conditions for health professionals and clinical practice2022Ingår i: Precision medicine / [ed] David B. Teplow, Elsevier, 2022, s. 219-276Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Medical abzymology has made a great contribution to the development of general autoimmunity theory: it has put the autoantibodies (Ab) as the key brick of the theory to the level of physiological functionality by providing such Ab with the ability to catalyze and mediate direct and independent cytotoxic effect on cellular and molecular targets. Natural catalytic autoantibodies (abzymes) while being a pool of canonical Abs and possessing catalytic activity belong to the new group of physiologically active substances whose features and properties are evolutionary consolidated in one functionally active biomolecule. Therefore, further studies on Ab-mediated autoAg degradation and other targeted Ab-mediated proteolysis may provide biomarkers of newer generations and thus a supplementary tool for assessing the disease progression and predicting disability of the patients and persons at risks. This chapter is a summary of current knowledge and prognostic perspectives toward catalytic Abs in autoimmunity and thus some autoimmune clinical cases, their role in pathogenesis, and the exploitation of both whole molecules and their constituent parts in developing highly effective targeted drugs of the future to come, and thus the therapeutic protocols being individualized.

  • 25.
    Stäubert, Claudia
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, S-90183 Umea, Sweden; Univ Leipzig, Inst Biochem, Fac Med, D-04103 Leipzig, Germany.
    Bhuiyan, Hasanuzzaman
    Lindahl, Anna
    Broom, Oliver Jay
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Zhu, Yafeng
    Islam, Saiful
    Linnarsson, Sten
    Lehtio, Janne
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, S-90183 Umea, Sweden; Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17177 Stockholm, Sweden.
    Rewired metabolism in drug-resistant leukemia cells: a metabolic switch hallmarked by reduced dependence on exogenous glutamine2015Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, nr 13, s. 8348-8359Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate-ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid beta-xidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics andRNAexpression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies.

  • 26.
    Stäubert, Claudia
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
    Broom, Oliver Jay
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Hydroxycarboxylic acid receptors are essential for breast cancer cells to control their lipid/fatty acid metabolism2015Ingår i: Oncotarget, E-ISSN 1949-2553, Vol. 6, nr 23, s. 19706-19720Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cancer cells exhibit characteristic changes in their metabolism with efforts being made to address them therapeutically. However, targeting metabolic enzymes as such is a major challenge due to their essentiality for normal proliferating cells. The most successful pharmaceutical targets are G protein-coupled receptors (GPCRs), with more than 40% of all currently available drugs acting through them. We show that, a family of metabolite-sensing GPCRs, the Hydroxycarboxylic acid receptor family (HCAs), is crucial for breast cancer cells to control their metabolism and proliferation. We found HCA(1) and HCA(3) mRNA expression were significantly increased in breast cancer patient samples and detectable in primary human breast cancer patient cells. Furthermore, siRNA mediated knock-down of HCA3 induced considerable breast cancer cell death as did knock-down of HCA1, although to a lesser extent. Liquid Chromatography Mass Spectrometry based analyses of breast cancer cell medium revealed a role for HCA3 in controlling intracellular lipid/fatty acid metabolism. The presence of etomoxir or perhexiline, both inhibitors of fatty acid beta-oxidation rescues breast cancer cells with knocked-down HCA3 from cell death. Our data encourages the development of drugs acting on cancer-specific metabolite-sensing GPCRs as novel anti-proliferative agents for cancer therapy.

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  • 27.
    Stäubert, Claudia
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Department of Forest Genetics and Plant Physiology, Swedish Metabolomics Centre, Swedish University of Agricultural Sciences, Umeå; Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Germany.
    Krakowsky, Rosanna
    Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany .
    Bhuiyan, Hasanuzzaman
    Doping Laboratory, Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
    Witek, Barbara
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Lindahl, Anna
    Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
    Broom, Oliver
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Department of Forest Genetics and Plant Physiology, Swedish Metabolomics Centre, Swedish University of Agricultural Sciences, Umeå; Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet.
    Increased lanosterol turnover: a metabolic burden for daunorubicin-resistant leukemia cells2016Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 33, nr 1, artikel-id 6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cholesterol metabolism is essential for cancer cell proliferation. We found the expression of genes involved in the cholesterol biosynthesis pathway up-regulated in the daunorubicin-resistant leukemia cell line CEM/R2, which is a daughter cell line to the leukemia cell line CCRF-CEM (CEM). Cellular (H2O)-H-2 labelling, mass spectrometry, and isotopomer analysis revealed an increase in lanosterol synthesis which was not accompanied by an increase in cholesterol flux or pool size in CEM/R2 cells. Exogenous addition of lanosterol had a negative effect on CEM/R2 and a positive effect on sensitive CEM cell viability. Treatment of CEM and CEM/R2 cells with cholesterol biosynthesis inhibitors acting on the enzymes squalene epoxidase and lanosterol synthase, both also involved in the 24,25-epoxycholesterol shunt pathway, revealed a connection of this pathway to lanosterol turnover. Our data highlight that an increased lanosterol flux poses a metabolic weakness of resistant cells that potentially could be therapeutically exploited.

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  • 28. Tarkowski, Petr
    et al.
    Floková, Kristýna
    Václavíková, Kateřina
    Jaworek, Pavel
    Raus, Martin
    Nordström, Anders
    Department for Oncology–Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden .
    Novák, Ondřej
    Doležal, Karel
    Sebela, Marek
    Frébortová, Jitka
    An improved in vivo deuterium labeling method for measuring the biosynthetic rate of cytokinins.2010Ingår i: Molecules (Basel, Switzerland), ISSN 1420-3049, Vol. 15, nr 12, s. 9214-29Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An improved method for determining the relative biosynthetic rate of isoprenoid cytokinins has been developed. A set of 11 relevant isoprenoid cytokinins, including zeatin isomers, was separated by ultra performance liquid chromatography in less than 6 min. The iP-type cytokinins were observed to give rise to a previously-unknown fragment at m/z 69; we suggest that the diagnostic (204-69) transition can be used to monitor the biosynthetic rate of isopentenyladenine. Furthermore, we found that by treating the cytokinin nucleotides with alkaline phosphatase prior to analysis, the sensitivity of the detection process could be increased. In addition, derivatization (propionylation) improved the ESI-MS response by increasing the analytes' hydrophobicity. Indeed, the ESI-MS response of propionylated isopentenyladenosine was about 34% higher than that of its underivatized counterpart. Moreover, the response of the derivatized zeatin ribosides was about 75% higher than that of underivatized zeatin ribosides. Finally, we created a web-based calculator (IZOTOP) that facilitates MS/MS data processing and offer it freely to the research community.

  • 29.
    Viklund, Camilla
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nordström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Irgum, Knut
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Svec, Frantisek
    Frechet, Jean M J
    Preparation of Porous Poly(styrene-co-divinylbenzene) Monoliths with Controlled Pore Size Distributions Initiated by Stable Free Radicals and Their Pore Surface Functionalization by Grafting2001Ingår i: Macromolecules, Vol. 34, nr 13, s. 4361-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A stable free radical (SFR) mediated preparation of porous poly(styrene-co-divinylbenzene) monoliths using new types of SFRs and a novel binary porogenic solvent consisting of poly(ethylene glycol) and 1-decanol has been studied. Polymerizations carried out in the presence of 3-carboxy-2,2,5,5-tetramethylpyrrolidinyl-1-oxy (3-carboxy-PROXYL) or 4-carboxy-2,2,6,6-tetramethylpiperidinyl-1-oxy (4-carboxy-TEMPO) were faster, and higher degrees of monomer conversions were achieved in a shorter period of time compared to the corresponding reactions mediated by 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO). The effect of the type of SFR (TEMPO, 3-carboxy-PROXYL, 4-carboxy-TEMPO, 4-amino-TEMPO, 4-acetamido-TEMPO, and 4-trimethylammonio-TEMPO iodide) on the pore size distribution was also investigated. The use of carboxy functional SFRs simultaneously accelerated the reaction kinetics, improved the permeability of the prepared monoliths, and enabled control of the porous properties of the monolithic polymers over a wide range simply by modifying the ratio of poly(ethylene glycol) 400 and 1-decanol in the porogenic mixture. The reinitiation capability of poly(styrene-co-divinylbenzene) monoliths capped with 3-carboxy-PROXYL or 4-carboxy-TEMPO moieties was utilized to perform in situ grafting of 2-hydroxyethyl methacrylate and 3-sulfopropyl methacrylate, resulting in monoliths with altered surface polarities.

  • 30. Want, Elizabeth J
    et al.
    Nordström, Anders
    Department of Molecular Biology, The Scripps Center for Mass Spectrometry.
    Morita, Hirotoshi
    Siuzdak, Gary
    From exogenous to endogenous: the inevitable imprint of mass spectrometry in metabolomics.2007Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 6, nr 2, s. 459-68Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mass spectrometry (MS) is an established technology in drug metabolite analysis and is now expanding into endogenous metabolite research. Its utility derives from its wide dynamic range, reproducible quantitative analysis, and the ability to analyze biofluids with extreme molecular complexity. The aims of developing mass spectrometry for metabolomics range from understanding basic biochemistry to biomarker discovery and the structural characterization of physiologically important metabolites. In this review, we will discuss the techniques involved in this exciting area and the current and future applications of this field.

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