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Lundstedt, Torbjörn
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Publications (10 of 18) Show all publications
Dhillon, S. S., Torell, F., Donten, M., Lundstedt-Enkel, K., Bennett, K., Raennar, S., . . . Lundstedt, T. (2019). Metabolic profiling of zebrafish embryo development from blastula period to early larval stages. PLoS ONE, 14(5), Article ID e0213661.
Open this publication in new window or tab >>Metabolic profiling of zebrafish embryo development from blastula period to early larval stages
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0213661Article in journal (Refereed) Published
Abstract [en]

The zebrafish embryo is a popular model for drug screening, disease modelling and molecular genetics. In this study, samples were obtained from zebrafish at different developmental stages. The stages that were chosen were 3/4, 4/5, 24, 48, 72 and 96 hours post fertilization (hpf). Each sample included fifty embryos. The samples were analysed using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Principle component analysis (PCA) was applied to get an overview of the data and orthogonal projection to latent structure discriminant analysis (OPLS-DA) was utilised to discriminate between the developmental stages. In this way, changes in metabolite profiles during vertebrate development could be identified. Using a GC-TOF-MS metabolomics approach it was found that nucleotides and metabolic fuel (glucose) were elevated at early stages of embryogenesis, whereas at later stages amino acids and intermediates in the Krebs cycle were abundant. This agrees with zebrafish developmental biology, as organs such as the liver and pancreas develop at later stages. Thus, metabolomics of zebrafish embryos offers a unique opportunity to investigate large scale changes in metabolic processes during important developmental stages in vertebrate development. In terms of stability of the metabolic profile and viability of the embryos, it was concluded at 72 hpf was a suitable time point for the use of zebrafish as a model system in numerous scientific applications.

National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-387287 (URN)10.1371/journal.pone.0213661 (DOI)000467843000002 ()31086370 (PubMedID)
Funder
Swedish Research Council, 2011-6044Swedish Research Council, 2016-04376EU, FP7, Seventh Framework Programme, 238821
Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved
Torell, F., Bennet, K., Cereghini, S., Fabre, M., Rännar, S., Lundstedt-Enkel, K., . . . Lundstedt, T. (2018). Metabolic Profiling of Multiorgan Samples: Evaluation of MODY5/RCAD Mutant Mice. Journal of Proteome Research, 17(7), 2293-2306
Open this publication in new window or tab >>Metabolic Profiling of Multiorgan Samples: Evaluation of MODY5/RCAD Mutant Mice
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2018 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 17, no 7, p. 2293-2306Article in journal (Refereed) Published
Abstract [en]

In the present study, we performed a metabolomics analysis to evaluate a MODY5/RCAD mouse mutant line as a potential model for HNF1B-associated diseases. Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) of gut, kidney, liver, muscle, pancreas, and plasma samples uncovered the tissue specific metabolite distribution. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was used to identify the differences between MODY5/RCAD and wild-type mice in each of the tissues. The differences included, for example, increased levels of amino acids in the kidneys and reduced levels of fatty acids in the muscles of the MODY5/RCAD mice. Interestingly, campesterol was found in higher concentrations in the MODY5/RCAD mice, with a four-fold and three-fold increase in kidneys and pancreas, respectively. As expected, the MODY5/RCAD mice displayed signs of impaired renal function in addition to disturbed liver lipid metabolism, with increased lipid and fatty acid accumulation in the liver. From a metabolomics perspective, the MODY5/RCAD model was proven to display a metabolic pattern similar to what would be suspected in HNF1B-associated diseases. These findings were in line with the presumed outcome of the mutation based on the different anatomy and function of the tissues as well as the effect of the mutation on development.

Keywords
HNF1B-associated diseases, metabolomics, OPLS-DA, multiorgan samples, MODY5, RCAD, mouse model
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-361549 (URN)10.1021/acs.jproteome.7b00821 (DOI)000438469900004 ()29873499 (PubMedID)
Funder
Swedish Research Council, 2011-6044Swedish Research Council, 2016-04376EU, FP7, Seventh Framework Programme
Available from: 2018-10-08 Created: 2018-10-08 Last updated: 2018-10-08Bibliographically approved
Torell, F., Bennett, K., Raennar, S., Lundstedt-Enkel, K., Lundstedt, T. & Trygg, J. (2017). The effects of thawing on the plasma metabolome: evaluating differences between thawed plasma and multi-organ samples. Metabolomics, 13(6), Article ID 66.
Open this publication in new window or tab >>The effects of thawing on the plasma metabolome: evaluating differences between thawed plasma and multi-organ samples
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2017 (English)In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 13, no 6, article id 66Article in journal (Refereed) Published
Abstract [en]

Introduction Post-collection handling, storage and transportation can affect the quality of blood samples. Pre-analytical biases can easily be introduced and can jeopardize accurate profiling of the plasma metabolome. Consequently, a mouse study must be carefully planned in order to avoid any kind of bias that can be introduced, in order not to compromise the outcome of the study. The storage and shipment of the samples should be made in such a way that the freeze-thaw cycles are kept to a minimum. In order to keep the latent effects on the stability of the blood metabolome to a minimum it is essential to study the effect that the post-collection and pre-analytical error have on the metabolome.

Objectives The aim of this study was to investigate the effects of thawing on the metabolic profiles of different sample types.

Methods In the present study, a metabolomics approach was utilized to obtain a thawing profile of plasma samples obtained on three different days of experiment. The plasma samples were collected from the tail on day 1 and 3, while retro-orbital sampling was used on day 5. The samples were analysed using gas chromatography time-of-flight mass spectrometry (GC TOF-MS).

Results The thawed plasma samples were found to be characterized by higher levels of amino acids, fatty acids, glycerol metabolites and purine and pyrimidine metabolites as a result of protein degradation, cell degradation and increased phospholipase activity. The consensus profile was thereafter compared to the previously published study comparing thawing profiles of tissue samples from gut, kidney, liver, muscle and pancreas.

Conclusions The comparison between thawed organ samples and thawed plasma samples indicate that the organ samples are more sensitive to thawing, however thawing still affected all investigated sample types.

Keywords
Mouse, Metabolomics, Plasma, Multi-organ, Freeze-thaw cycle, OPLS-DA
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-323768 (URN)10.1007/s11306-017-1196-9 (DOI)000401711400001 ()28473743 (PubMedID)
Funder
Swedish Research Council, 2011-6044EU, FP7, Seventh Framework Programme
Available from: 2017-06-09 Created: 2017-06-09 Last updated: 2017-06-09Bibliographically approved
Idborg, H., Rannar, S., Oliynyk, G., Forshed, J., Branca, R. M., Donten, M., . . . Jakobsson, P.-J. (2013). Stratification of sle Patients for Improved Diagnosis and Treatment. Annals of the Rheumatic Diseases, 72(S3), 466-466
Open this publication in new window or tab >>Stratification of sle Patients for Improved Diagnosis and Treatment
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2013 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S3, p. 466-466Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-221196 (URN)10.1136/annrheumdis-2013-eular.1398 (DOI)000331587903163 ()
Available from: 2014-03-26 Created: 2014-03-26 Last updated: 2017-12-05Bibliographically approved
Tian, Z. R., Sharma, A., Nozari, A., Subramaniam, R., Lundstedt, T. & Sharma, H. S. (2012). Nanowired Drug Delivery to Enhance Neuroprotection in Spinal Cord Injury. CNS & Neurological Disorders - Drug Targets, 11(1), 86-95
Open this publication in new window or tab >>Nanowired Drug Delivery to Enhance Neuroprotection in Spinal Cord Injury
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2012 (English)In: CNS & Neurological Disorders - Drug Targets, ISSN 1871-5273, Vol. 11, no 1, p. 86-95Article, review/survey (Refereed) Published
Abstract [en]

Spinal cord injury (SCI) is a serious clinical situation for which no suitable drug therapy exists. SCI often results in paraplegia or quadriplegia and, apart from the personal trauma leads to huge costs to society for rehabilitation or day-to-day life support. Sensory motor dysfunction following SCI is mainly a consequence of the slowly progressing cord pathology after primary injury that worsens over tine. Thus, almost all sensory and motor nerve control and pathways passing through spinal cord and reflexes are compromised in SCI patients. As a result their peripheral nervous system, autonomic nervous function and central nervous system regulations are adversely affected. Experiments carried out in our laboratory show that various therapeutic agents, if given within 10 to 30 minutes after primary SCI could correct morphological changes to a certain extent. In these rat models of SCI reduction in cord pathology, e.g., blood-spinal cord barrier (BSCB) breakdown, edema formation and cell injury by the neuroprotective agents that also limited sensory motor dysfunction and improved functional behavior. However, these drugs if given beyond 30 minutes after SCI showed a markedly reduced neuroprotective efficacy. Thus, new strategies are needed to enhance neuroprotection in SCI to prevent structural and functional changes over longer periods of time. To that end our laboratory has initiated a series of investigations in which nanowired delivery of various neurotherapeutic agents are applied after different time periods of SCI, that resulted in a much better outcome than with the parent compounds under identical conditions. The superior neuroprotective activity of nanowired compound delivery could be due to a reduced metabolism of active compounds in the central nervous system (CNS) or by sustained release of the drug for longer times. In addition, nanowired drugs may penetrate the CNS faster and could reach widespread areas once entering the spinal cord. Thus, nanowired drug delivery to treat SCI may have potential therapeutic value. These aspects of nanowired drug delivery to enhance neuroprotection in SCI are discussed in this review based on our own investigations.

Keywords
Nanowired drug delivery, spinal cord injury, blood-spinal cord barrier, spinal cord edema, TiO2 nanowires, silica nanowires, neuronal injury, stem cells, functional recovery, astrocytes, myelin, ultrastructure, nanoparticles
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-174981 (URN)000303449400010 ()
Available from: 2012-05-31 Created: 2012-05-30 Last updated: 2013-03-05Bibliographically approved
Idborg, H., Oliynyk, G., Rannar, S., Forshed, J., Branca, R. M., Donten, M., . . . Jakobsson, P.-J. (2012). Systems biology of SLE: biochemical characterisation of subgroups within sle for improved diagnosis and treatment. Paper presented at 32nd European Workshop for Rheumatology Research, FEB 23-25, 2012, Stockholm, SWEDEN. Annals of the Rheumatic Diseases, 71, A12
Open this publication in new window or tab >>Systems biology of SLE: biochemical characterisation of subgroups within sle for improved diagnosis and treatment
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2012 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, p. A12-Article in journal, Meeting abstract (Other academic) Published
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-173948 (URN)10.1136/annrheumdis-2011-201230.27 (DOI)000302323600028 ()
Conference
32nd European Workshop for Rheumatology Research, FEB 23-25, 2012, Stockholm, SWEDEN
Available from: 2012-05-10 Created: 2012-05-09 Last updated: 2017-12-07Bibliographically approved
Trygg, J., Holmes, E. & Lundstedt, T. (2007). Chemometrics in metabonomics. Journal of Proteome Research, 6(2), 469-479
Open this publication in new window or tab >>Chemometrics in metabonomics
2007 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 6, no 2, p. 469-479Article, review/survey (Refereed) Published
Abstract [en]

We provide an overview of how the underlying philosophy of chemometrics is integrated throughout metabonomic studies. Four steps are demonstrated: (1) definition of the aim, (2) selection of objects, (3) sample preparation and characterization, and (4) evaluation of the collected data. This includes the tools applied for linear modeling, for example, Statistical Experimental Design (SED), Principal Component Analysis (PCA), Partial least-squares (PLS), Orthogonal-PLS (OPLS), and dynamic extensions thereof. This is illustrated by examples from the literature.

Keywords
Kinetics, Least-Squares Analysis, Metabolism, Models; Statistical, Multivariate Analysis, Proteins/*chemistry/*metabolism
National Category
Pharmaceutical Sciences Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-17094 (URN)10.1021/pr060594q (DOI)000243927900003 ()17269704 (PubMedID)
Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2018-01-12Bibliographically approved
Nurbo, J., Roos, A. K., Muthas, D., Wahlström, E., Ericsson, D. J., Lundstedt, T., . . . Karlén, A. (2007). Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase. Journal of Peptide Science, 13(12), 822-832
Open this publication in new window or tab >>Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase
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2007 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, no 12, p. 822-832Article in journal (Refereed) Published
Abstract [en]

Mycobacterium tuberculosis ribonucleotide reductase (RNR) is a potential target for new antitubercular drugs. Herein we describe the synthesis and evaluation of peptide inhibitors of RNR derived from the C-terminus of the small subunit of M. tuberculosis RNR. An N-terminal truncation, an alanine scan and a novel statistical molecular design (SMD) approach based on the heptapeptide Ac-Glu-Asp-Asp-Asp-Trp-Asp-Phe-OH were applied in this study. The alanine scan showed that TrP5 and Phe7 were important for inhibitory potency. A quantitative structure relationship (QSAR) model was developed based on the synthesized peptides which showed that a negative charge in positions 2, 3, and 6 is beneficial for inhibitory potency. Finally, in position 5 the model coefficients indicate that there is room for a larger side chain., as compared to Trp5.

Keywords
mycobacterium tuberculosis, ribonucleotide reductase, peptide inhibitors, alanine scan, statistical molecular design, structure activity relationships, FHDoE
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-14261 (URN)10.1002/psc.906 (DOI)000252000600007 ()17918768 (PubMedID)
Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-01-12Bibliographically approved
Muthas, D., Lek, P. M., Nurbo, J., Karlén, A. & Lundstedt, T. (2007). Focused hierarchical design of peptide libraries - follow the lead. Journal of Chemometrics, 21(10-11), 486-495
Open this publication in new window or tab >>Focused hierarchical design of peptide libraries - follow the lead
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2007 (English)In: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 21, no 10-11, p. 486-495Article in journal (Refereed) Published
Abstract [en]

A novel design strategy based on the hierarchical design of experiments (HDoE) method named focused hierarchical design of experiments (FHDoE) is presented. FHDoE combine two design layers and use focused substitutions to increase the probability of obtaining active peptides when designing libraries through a selection of compounds biased towards a lead structure. Increasing the number of peptides with measurable activity will increase the information gained and the likelihood of constructing good quantitative structure-activity relationship (QSAR) models. The utility of the novel design method is verified using two different approaches. First, a library designed with the novel FHDoE method was compared with libraries generated from classical positional scanning techniques (e.g., alanine scan) as well as with general and centered minimum analog peptide sets (MAPS) libraries by using an example found in the literature. Secondly, the same design strategies were applied to a dataset of 58 angiotensin converting enzyme (ACE) dipeptide inhibitors. QSAR models were generated from designed sublibraries and the activities of the remaining compounds were predicted. These two examples show that the use of FHDoE renders peptide libraries close in physicochemical space to the native ligand, yielding a more thorough screening of the area of interest as compared to the classical positional scans and fractional factorial design (FFD). It is also shown that an FHDoE library of six dipeptides could produce a QSAR model that better described the requisites of high activity ACE inhibitors than could QSAR models built from either a nine-dipeptide library designed with MAPS or a 58-dipeptide library.

Keywords
design of experiments, peptide library design, hierarchical design, amino acid z-scales, PCA
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-17025 (URN)10.1002/cem.1069 (DOI)000250873300009 ()
Available from: 2008-06-15 Created: 2008-06-15 Last updated: 2018-01-12Bibliographically approved
Lundstedt-Enkel, K., Lek, P. M., Lundstedt, T. & Örberg, J. (2007). Relationships between physicochemical and structural descriptors and biomagnification of organochlorines and brominated flame retardants. In: BFR2007, The Fourth International Workshop on Brominated Flame Retardants: Amsterdam, the Netherlands from 24 to 27 April 2007.
Open this publication in new window or tab >>Relationships between physicochemical and structural descriptors and biomagnification of organochlorines and brominated flame retardants
2007 (English)In: BFR2007, The Fourth International Workshop on Brominated Flame Retardants: Amsterdam, the Netherlands from 24 to 27 April 2007, 2007Conference paper, Published paper (Refereed)
Identifiers
urn:nbn:se:uu:diva-16336 (URN)
Available from: 2008-05-21 Created: 2008-05-21
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