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  • 1.
    Boberg, Lena
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Szekeres, Ferenc L. M.
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Arner, Anders
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Signaling and metabolic properties of fast and slow smooth muscle types from mice2018In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 470, no 4, p. 681-691Article in journal (Refereed)
    Abstract [en]

    This study aims to improve the classification of smooth muscle types to better understand their normal and pathological functional phenotypes. Four different smooth muscle tissues (aorta, muscular arteries, intestine, urinary bladder) with a 5-fold difference in maximal shortening velocity were obtained from mice and classified according to expression of the inserted myosin heavy chain (SMHC-B). Western blotting and quantitative PCR analyses were used to determine 15 metabolic and 8 cell signaling key components in each tissue. The slow muscle type (aorta) with a 12 times lower SMHC-B had 6-fold lower expression of the phosphatase subunit MYPT1, a 7-fold higher expression of Rhokinase 1, and a 3-fold higher expression of the PKC target CPI17, compared to the faster (urinary bladder) smooth muscle. The slow muscle had higher expression of components involved in glucose uptake and glycolysis (type 1 glucose transporter, 3 times; hexokinase, 13 times) and in gluconeogenesis (phosphoenolpyruvate carboxykinase, 43 times), but lower expression of the metabolic sensing AMP-activated kinase, alpha 2 isoform (5 times). The slow type also had higher expression of enzymes involved in lipid metabolism (hormone-sensitive lipase, 10 times; lipoprotein lipase, 13 times; fatty acid synthase, 6 times; type 2 acetyl-coenzyme A carboxylase, 8 times). We present a refined division of smooth muscle into muscle types based on the analysis of contractile, metabolic, and signaling components. Slow compared to fast smooth muscle has a lower expression of the deactivating phosphatase and upregulated Ca2+ sensitizing pathways and is more adapted for sustained glucose and lipid metabolism. © 2018 The Author(s)

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  • 2.
    Diaz Cruz, Maria Araceli
    et al.
    Research School of Health and Welfare, School of Health and Welfare, University of Jönköping, Sweden.
    Karlsson, Sandra
    Department of Natural Science and Biomedicine, School of Health and Welfare, University of Jönköping, Sweden.
    Szekeres, Ferenc
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Faresjö, Maria
    Department of Natural Science and Biomedicine, School of Health and Welfare, University of Jönköping, Sweden.
    Lund, Dan
    Department of Natural Science and Biomedicine, School of Health and Welfare, University of Jönköping, Sweden.
    Larsson, Dennis
    Sahlgrenska University Hospital, Gothia Forum - for Clinical Research, Gothenburg, Sweden.
    Differential expression of protein disulfide-isomerase A3 isoforms, PDIA3 and PDIA3N, in human prostate cancer cell lines representing different stages of prostate cancer2021In: Molecular Biology Reports, ISSN 0301-4851, E-ISSN 1573-4978, Vol. 48, no 3, p. 2429-2436Article in journal (Refereed)
    Abstract [en]

    Prostate cancer (PCa) is a highly heterogeneous and unpredictable progressive disease. Sensitivity of PCa cells to androgens play a central role in tumor aggressiveness but biomarkers with high sensitivity and specificity that follow the progression of the disease has not yet been verified. The vitamin D endocrine system and its receptors, the Vitamin D Receptor (VDR) and the Protein Disulfide-Isomerase A3 (PDIA3), are related to anti-tumoral effects as well as carcinogenesis and have therefore been suggested as potential candidates for the prevention and therapy of several cancer forms, including PCa. In this study, we evaluated the mRNA expression of VDR and PDIA3 involved in vitamin D signaling in cell lines representing different stages of PCa (PNT2, P4E6, LNCaP, DU145 and PC3). This study further aimed to evaluate vitamin D receptors and their isoforms as potential markers for clinical diagnosis of PCa. A novel transcript isoform of PDIA3 (PDIA3N) was identified and found to be expressed in all PCa cell lines analyzed. Androgen-independent cell lines showed a higher mRNA expression ratio between PDIA3N/PDIA3 contrary to androgen-dependent cell lines that showed a lower mRNA expression ratio between PDIA3N/PDIA3. The structure of PDIA3N differed from PDIA3. PDIA3N was found to be a N-truncated isoform of PDIA3 and differences in protein structure suggests an altered protein function i.e. cell location, thioredoxin activity and affinity for 1,25(OH)2D3. Collectively, PDIA3 transcript isoforms, the ratio between PDIA3N/PDIA3 and especially PDIA3N, are proposed as candidate markers for future studies with different stages of PCa progression. 

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  • 3.
    Diaz Cruz, Maria Araceli
    et al.
    Research School of Health and Welfare, School of Health and Welfare, Jönköping University, Sweden.
    Lund, Dan
    Department of Natural Science and Biomedicine, School of Health and Welfare, Jönköping University, Sweden.
    Szekeres, Ferenc
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Karlsson, Sandra
    Department of Natural Science and Biomedicine, School of Health and Welfare, Jönköping University, Sweden.
    Faresjö, Maria
    Department of Natural Science and Biomedicine, School of Health and Welfare, Jönköping University, Sweden.
    Larsson, Dennis
    Sahlgrenska University Hospital, Gothia Forum for Clinical Research, Gothenburg, Sweden.
    Cis-regulatory elements in conserved non-coding sequences of nuclear receptor genes indicate for crosstalk between endocrine systems2021In: Open Medicine (Poland), ISSN 2391-5463, Vol. 16, no 1, p. 640-650Article in journal (Refereed)
    Abstract [en]

    Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression when bound to specific DNA sequences. Crosstalk between steroid NR systems has been studied for understanding the development of hormone-driven cancers but not to an extent at a genetic level. This study aimed to investigate crosstalk between steroid NRs in conserved intron and exon sequences, with a focus on steroid NRs involved in prostate cancer etiology. For this purpose, we evaluated conserved intron and exon sequences among all 49 members of the NR Superfamily (NRS) and their relevance as regulatory sequences and NR-binding sequences. Sequence conservation was found to be higher in the first intron (35%), when compared with downstream introns. Seventy-nine percent of the conserved regions in the NRS contained putative transcription factor binding sites (TFBS) and a large fraction of these sequences contained splicing sites (SS). Analysis of transcription factors binding to putative intronic and exonic TFBS revealed that 5 and 16%, respectively, were NRs. The present study suggests crosstalk between steroid NRs, e.g., vitamin D, estrogen, progesterone, and retinoic acid endocrine systems, through cis-regulatory elements in conserved sequences of introns and exons. This investigation gives evidence for crosstalk between steroid hormones and contributes to novel targets for steroid NR regulation. 

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  • 4.
    Fritz, T.
    et al.
    Center for Family and Community Medicine, Karolinska Institutet, Huddinge, Sweden.
    Caidahl, K.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Krook, A.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Lundström, P.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Mashili, F.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Osler, M.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Szekeres, Ferenc L. M.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Östenson, C. G.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Wändell, P.
    Center for Family and Community Medicine, Karolinska Institutet, Huddinge, Sweden.
    Zierath, J. R.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Effects of Nordic walking on cardiovascular risk factors in overweight individuals with type 2 diabetes, impaired or normal glucose tolerance2013In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 29, no 1, p. 25-32Article in journal (Refereed)
    Abstract [en]

    Background Physical activity remains a valuable prevention for metabolic disease. The effects of Nordic walking on cardiovascular risk factors were determined in overweight individuals with normal or disturbed glucose regulation. Methods We included 213 individuals, aged 60 +/- 5.3 years and with body mass index (BMI) of 30.2 +/- 3.8 kg/m(2); of these, 128 had normal glucose tolerance (NGT), 35 had impaired glucose tolerance (IGT) and 50 had type 2 diabetes mellitus (T2DM). Participants were randomized to unaltered physical activity or to 5 h per week of Nordic walking with poles, for a 4-month period. Dietary habits were unaltered. BMI, waist circumference, blood pressure, glucose tolerance, clinical chemistry, maximal oxygen uptake (peak VO2) and self-reported physical activity (questionnaire) were assessed at the time of inclusion and after 4 months. The participants in the exercise-intervention group kept a walking diary. Results In the NGT exercise group, self-reported physical activity increased markedly, and body weight (-2.0 +/- 3.8 kg), BMI (-0.8 +/- 1.4 kg/m(2)) and waist circumference (- 4.9 +/- 4.4 cm) (mean +/- SD) decreased. Exercise power output (12.9 +/- 9.9 W) and peak VO2 (2.7 +/- 2.8 mL/kg/min) increased in the IGT exercise group. More cardiovascular risk factors were improved after exercise intervention in people with NGT compared with those with IGT or T2DM. Exercise capacity improved significantly in all three groups of participants who reported at least 80% compliance with the scheduled exercise. Conclusions Nordic walking improved anthropometric measurements and exercise capacity. However, unsupervised Nordic walking may not provide a sufficient increase in exercise intensity to achieve ultimate health-promoting benefits on the cardiovascular parameters assessed in this study, particularly for those with disturbed glucose regulation. Copyright (C) 2012 John Wiley & Sons, Ltd.

  • 5.
    Huang-Doran, Isabel
    et al.
    Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
    Bicknell, Louise S.
    Medical Research Council Human Genetics Unit, Institute of Genetics and Mo- lecular Medicine, Western General Hospital, Edinburgh, UK.
    Finucane, Francis M.
    Metabolic Research Unit, St. James Hospital, Trinity College, Dublin, Ireland.
    Rocha, Nuno
    Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
    Porter, Keith M.
    Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
    Tung, Y. C. Loraine
    Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
    Szekeres, Ferenc
    Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Krook, Anna
    Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Nolan, John J.
    Metabolic Research Unit, St. James Hospital, Trinity College, Dublin, Ireland.
    O'Driscoll, Mark
    Human DNA Damage Response Disorders Group, University of Sussex, Brighton, UK.
    Bober, Michael
    Division of Genetics, Department of Pediatrics, Alfred I. DuPont Hospital for Children, Wilmington, Delaware.
    O'Rahilly, Stephen
    Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
    Jackson, Andrew P.
    Medical Research Council Human Genetics Unit, Institute of Genetics and Mo- lecular Medicine, Western General Hospital, Edinburgh, UK.
    Semple, Robert K.
    Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
    Genetic Defects in Human Pericentrin Are Associated With Severe Insulin Resistance and Diabetes2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 3, p. 925-935Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE-Genetic defects in human pericentrin (PCNT), encoding the centrosomal protein pericentrin, cause a form of osteodysplastic primordial dwarfism that is sometimes reported to be associated with diabetes. We thus set out to determine the prevalence of diabetes and insulin resistance among patients with PCNT defects and examined the effects of pericentrin depletion on insulin action using 3T3-L1 adipocytes as a model system. RESEARCH DESIGN AND METHODS-A cross-sectional metabolic assessment of 21 patients with PCNT mutations was undertaken. Pericentrin expression in human tissues was profiled using quantitative real-time PCR. The effect of pericentrin knockdown on insulin action and adipogenesis in 3T3-L1 adipocytes was determined using Oil red 0 staining, gene-expression analysis, irnmunoblotting, and glucose uptake assays. Pericentrin expression and localization also was determined in skeletal muscle. RESULTS-Of 21 patients with genetic defects in PCNT, 18 had insulin resistance, which was severe in the majority of subjects. Ten subjects had confirmed diabetes (mean age of onset 15 years [range 5-28]), and 13 had metabolic dyslipidemia. All patients without insulin resistance were younger than 4 years old. Knockdown of pericentrin in adipocytes had no effect on proximal insulin signaling but produced a twofold impairment in insulin-stimulated glucose uptake, approximately commensurate with an associated defect in cell proliferation and adipogenesis. Pericentrin was highly expressed in human skeletal muscle, where it showed a perinuclear distribution. CONCLUSIONS-Severe insulin resistance and premature diabetes are common features of PCNT deficiency but are not congenital. Partial failure of adipocyte differentiation may contribute to this, but pericentrin deficiency does not impair proximal insulin action in adipocytes. Diabetes 60:925-935, 2011

  • 6.
    Kulkarni, Sameer S.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Karlsson, Håkan K. R.
    Karolinska Institutet, Stockholm, Sweden.
    Szekeres, Ferenc
    Karolinska Institutet, Stockholm, Sweden.
    Chibalin, Alexander V.
    Karolinska Institutet, Stockholm, Sweden.
    Krook, Anna
    Karolinska Institutet, Stockholm, Sweden.
    Zierath, Juleen R.
    Karolinska Institutet, Stockholm, Sweden.
    Suppression of 5 '-Nucleotidase Enzymes Promotes AMP-activated Protein Kinase (AMPK) Phosphorylation and Metabolism in Human and Mouse Skeletal Muscle2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 40, p. 34567-34574Article in journal (Refereed)
    Abstract [en]

    The 5'-nucleotidase (NT5) family of enzyme dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. We hypothesized that gene silencing of NT5 enzymes to increase the intracellular availability of AMP would increase AMP-activated protein kinase (AMPK) activity and metabolism. We determined the role of cytosolic NT5 in metabolic responses linked to the development of insulin resistance in obesity and type 2 diabetes. Using siRNA to silence NT5C2 expression in cultured human myotubes, we observed a 2-fold increase in the AMP/ATP ratio, a 2.4-fold increase in AMPK phosphorylation (Thr(172)), and a 2.8-fold increase in acetyl-CoA carboxylase phosphorylation (Ser(79)) (p<0.05). siRNA silencing of NT5C2 expression increased palmitate oxidation by 2-fold in the absence and by 8-fold in the presence of 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside. This was paralleled by an increase in glucose transport and a decrease in glucose oxidation, incorporation into glycogen, and lactate release from NT5C2-depleted myotubes. Gene silencing of NT5C1A by shRNA injection and electroporation in mouse tibialis anterior muscle reduced protein content (60%; p<0.05) and increased phosphorylation of AMPK (60%; p<0.05) and acetyl-CoA carboxylase (50%; p<0.05) and glucose uptake (20%; p<0.05). Endogenous expression of NT5C enzymes inhibited basal lipid oxidation and glucose transport in skeletal muscle. Reduction of 5'-nucleotidase expression or activity may promote metabolic flexibility in type 2 diabetes.

  • 7.
    Lindholm, Heléne
    et al.
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Ejeskär, Katarina
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Szekeres, Ferenc
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 15, p. 1-14, article id 8237Article in journal (Refereed)
    Abstract [en]

    Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1-100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.

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  • 8.
    Lindholm, Heléne
    et al.
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Ejeskär, Katarina
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Szekeres, Ferenc
    University of Skövde, Digital Health Research (DHEAR). University of Skövde, School of Health Sciences.
    Na+/K+‑ATPase subunit α3 expression is associated with the efficacy of digitoxin treatment in pancreatic cancer cells2022In: Medicine International, ISSN 2754-3242, Vol. 2, no 5, article id 27Article in journal (Refereed)
    Abstract [en]

    The alpha subunits (ATP1A1-3) of Na+/K+-ATPase binds digitoxin with varying affinity. The expression levels of these subunits dictate the anticancer effects of digitoxin. In the present study, three pancreatic cancer cell lines, AsPC-1, Panc-1 and CFPAC-1, were used to investigate the effects of digitoxin in relation to the expression of the subunits ATP1A1 and ATP1A3. Cell viability and intracellular calcium concentrations was measured in relation to the gene and protein expression of ATP1A1 and ATP1A3. Digitoxin was used to treat the cells at concentrations of 1-100 nM, and the intracellular calcium concentrations increased in a concentration-dependent manner in the Panc-1 and in the CFPAC-1 cells with treatment at 100 nM. In the AsPC-1 cells only the supraphysiological concentration of digitoxin (100 nM) resulted in a decrease in the number of viable cells (unviable cells increased to 22%), whereas it had no effect on intracellular calcium levels. The number of viable Panc-1 and CFPAC-1 cells decreased after digitoxin treatment at 25-100 nM (unviable Panc-1 cells increased to 33-59%; unviable CFPAC-1 cells increased to 22-56%). Digitoxin treatment also affected the transcriptional expression of the ATP1A1 and ATP1A3 subunits. In Panc-1 cells, ATP1A3 gene expression was negatively associated with the digitoxin concentration (25-100 nM). In the AsPC-1 and CFPAC-1 cells, the expression of the ATP1A1 gene increased in the cells treated with the 100 nM digitoxin concentration. The protein expression of ATP1A1 and ATP1A3 was not altered with digitoxin treatment. The basal protein expression of ATP1A1 was high in the AsPC-1 and CFPAC-1 cells, compared to the Panc-1 cells, in contrast to the basal expression of ATP1A3, which was higher in the Panc-1 cells, compared to the other pancreatic cancer cells used. On the whole, the present study demonstrates that the high expression of ATP1A3 renders pancreatic cancer cells more susceptible to digitoxin-induced cell death. The findings suggest that the expression of ATP1A3 may be used as a marker for tumor sensitivity to digitoxin treatment, where a high expression of ATP1A3 is favorable for the anticancer effects of digitoxin.

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  • 9.
    Monzur, Sadia
    et al.
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Hassan, Ghmkin
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Afify, Said M.
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan ; Chemistry Department, Division of Biochemistry, Faculty of Science, Menoufia University, Shebin El Kom-Menoufia, Egypt.
    Kumon, Kazuki
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Mansour, Hager
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Nawara, Hend M.
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Sheta, Mona
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan ; Department of Cancer Biology, National Cancer Institute, Cairo University, Egypt.
    Abu Quora, Hagar A.
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan ; Cytology, Histology and Histochemistry, Zoology Department, Faculty of Science, Menoufia University, Shebin El Kom-Menoufia, Egypt.
    Zahra, Maram H.
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Xu, Yanning
    Tianjin Key Laboratory of Human Development and Reproductive Regulation, Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Maternity Hospital, Tianjin, China.
    Fu, Xiaoyin
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan ; Department of Pathology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
    Seno, Akimasa
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan ; R&D Division, The Laboratory of Natural Food & Medicine Co., Ltd, Okayama University Incubator, Japan.
    Wikström, Per
    Glucox Biotech AB, Färentuna, Sweden.
    Szekeres, Ferenc L. M.
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Seno, Masaharu
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Diphenyleneiodonium efficiently inhibits the characteristics of a cancer stem cell model derived from induced pluripotent stem cells2022In: Cell Biochemistry and Function, ISSN 0263-6484, E-ISSN 1099-0844, Vol. 40, no 3, p. 310-320Article in journal (Refereed)
    Abstract [en]

    Diphenyleneiodonium (DPI) has long been evaluated as an anticancer drug inhibiting NADPH oxidase, the IC50 in several cancer cell lines was reported 10 µM, which is too high for efficacy. In this study, we employed miPS-Huh7cmP cells, which we previously established as a cancer stem cell (CSC) model from induced pluripotent stem cells, to reevaluate the efficacy of DPI because CSCs are currently one of the main foci of therapeutic strategy to treat cancer, but generally considered resistant to chemotherapy. As a result, the conventional assay for the cell growth inhibition by DPI accounted for an IC50 at 712 nM that was not enough to define the effectiveness as an anticancer drug. Simultaneously, the wound-healing assay revealed an IC50 of approximately 500 nM. Comparatively, the IC50 values shown on sphere formation, colony formation, and tube formation assays were 5.52, 12, and 8.7 nM, respectively. However, these inhibitory effects were not observed by VAS2780, also a reputed NADPH oxidase inhibitor. It is noteworthy that these three assays are evaluating the characteristic of CSCs and are designed in the three-dimensional (3D) culture methods. We concluded that DPI could be a suitable candidate to target mitochondrial respiration in CSCs. We propose that the 3D culture assays are more efficient to screen anti-CSC drug candidates and better mimic tumor microenvironment when compared to the adherent monolayer of 2D culture system used for a conventional assay, such as cell growth inhibition and wound-healing assays. © 2022 John Wiley & Sons Ltd.

  • 10.
    Mudry, Jonathan M.
    et al.
    Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Massart, Julie
    Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Szekeres, Ferenc L. M.
    Section for Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Krook, Anna
    Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden / Section for Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    TWIST1 and TWIST2 regulate glycogen storage and inflammatory genes in skeletal muscle2015In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 224, no 3, p. 303-313Article in journal (Refereed)
    Abstract [en]

    TWIST proteins are important for development of embryonic skeletal muscle and play a role in the metabolism of tumor and white adipose tissue. The impact of TWIST on metabolism in skeletal muscle is incompletely studied. Our aim was to assess the impact of TWIST1 and TWIST2 overexpression on glucose and lipid metabolism. In intact mouse muscle, overexpression of Twist reduced total glycogen content without altering glucose uptake. Expression of TWIST1 or TWIST2 reduced Pdk4 mRNA, while increasing mRNA levels of Il6, Tnf alpha, and Il1 beta. Phosphorylation of AKT was increased and protein abundance of acetyl CoA carboxylase ( ACC) was decreased in skeletal muscle overexpressing TWIST1 or TWIST2. Glycogen synthesis and fatty acid oxidation remained stable in C2C12 cells overexpressing TWIST1 or TWIST2. Finally, skeletal muscle mRNA levels remain unaltered in ob/ob mice, type 2 diabetic patients, or in healthy subjects before and after 3 months of exercise training. Collectively, our results indicate that TWIST1 and TWIST2 are expressed in skeletal muscle. Overexpression of these proteins impacts proteins in metabolic pathways and mRNA level of cytokines. However, skeletal muscle levels of TWIST transcripts are unaltered in metabolic diseases.

  • 11.
    Olofsson, Peder S.
    et al.
    Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden / Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Steinberg, Benjamin E.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA / The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
    Sobbi, Roozbeh
    Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
    Cox, Maureen A.
    The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
    Ahmed, Mohamed N.
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Oswald, Michaela
    Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Szekeres, Ferenc
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Hanes, William M.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Introini, Andrea
    Department of Medicine, Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Liu, Shu Fang
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Holodick, Nichol E.
    Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Rothstein, Thomas L.
    Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Lövdahl, Cecilia
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Chavan, Sangeeta S.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Yang, Huan
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Pavlov, Valentin A.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Broliden, Kristina
    Department of Medicine, Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Andersson, Ulf
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Diamond, Betty
    The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Miller, Edmund J.
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Arner, Anders
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Gregersen, Peter K.
    Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Backx, Peter H.
    Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada / Department of Biology, York University, Toronto, Ontario, Canada.
    Mak, Tak W.
    The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
    Tracey, Kevin J.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Blood pressure regulation by CD4lymphocytes expressing choline acetyltransferase2016In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 34, no 10, p. 1066-1071Article in journal (Refereed)
    Abstract [en]

    Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4(+) T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals(1). Here we show that these CD4(+)CD44(hi)CD62L(Io) T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 T-ChAT). Mice lacking ChAT expression in CD4(+) cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JT(ChAT)) decreased blood pressure when infused into mice. Co-incubation of JT(ChAT) and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide. The isolation and characterization of CD4 T-ChAT cells will enable analysis of the role of these cells in hypotension and hypertension, and may suggest novel therapeutic strategies by targeting cell-mediated vasorelaxation.

  • 12.
    Rune, A.
    et al.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Salehzadeh, F.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Szekeres, F.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Kuhn, I.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Osler, M. E.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Al-Khalili, L.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Evidence against a sexual dimorphism in glucose and fatty acid metabolism in skeletal muscle cultures from age-matched men and post-menopausal women2009In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 197, no 3, p. 207-215Article in journal (Refereed)
    Abstract [en]

    Aim: In vivo whole body differences in glucose/lipid metabolism exist between men and women. Thus, we tested the hypothesis that intrinsic sex differences exist in skeletal muscle gene expression and glucose/lipid metabolism using cultured myotubes. Methods: Myotube cultures were prepared for gene expression and metabolic studies from vastus lateralis skeletal muscle biopsies obtained from age-matched men (n = 11; 59 +/- 2 years) and post-menopausal women (n = 10; 60 +/- 1 years). Results: mRNA expression of several genes involved in glucose and lipid metabolism was higher in skeletal muscle biopsies from female vs. male donors, but unaltered between the sexes in cultured myotubes. Basal and insulin-stimulated glucose uptake, as well as glucose incorporation into glycogen, was similar in myotube cultures derived from male vs. female donors. In males vs. females, insulin increased glucose uptake (1.3 +/- 0.1 vs. 1.5 +/- 0.1-fold respectively) and incorporation into glycogen (2.3 +/- 0.3 vs. 2.0 +/- 0.3-fold respectively) to the same extent. Basal fatty acid oxidation and rate of uptake/accumulation was similar between sexes. In response to the 5'AMP-activated protein kinase activator AICAR, lipid oxidation was increased to the same extent in myotubes established from male vs. female donors (1.6 +/- 0.6 vs. 2.0 +/- 0.3-fold respectively). Moreover, the AICAR-induced rate of uptake/accumulation was similar between sexes. Conclusion: Differences in metabolic parameters and gene expression profiles between age-matched men and post-menopausal women noted in vivo are not observed in cultured human skeletal muscle cells. Thus, the sexual dimorphism in glucose and lipid metabolism is likely a consequence of systemic whole body factors, rather than intrinsic differences in the skeletal muscle proper.

  • 13.
    Sogaard, Peter
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Szekeres, Ferenc
    Karolinska Institutet.
    Garcia-Roves, Pablo M.
    Karolinska Institutet.
    Larsson, Dennis
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Chibalin, Alexander V.
    Karolinska Institutet.
    Zierath, Juleen R.
    Karolinska Institutet.
    Spatial Insulin Signalling in Isolated Skeletal Muscle Preparations2010In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 109, no 5, p. 943-949Article in journal (Refereed)
    Abstract [en]

    During in vitro incubation in the absence or presence of insulin, glycogen depletion occurs in the inner core of the muscle specimen, concomitant with increased staining of hypoxia-induced-factor-1-alpha and caspase-3, markers of hypoxia and apoptosis, respectively. The aim of this study was to determine whether insulin is able to diffuse across the entire muscle specimen in sufficient amounts to activate signalling cascades to promote glucose uptake and glycogenesis within isolated mouse skeletal muscle. Phosphoprotein multiplex assay on lysates from muscle preparation was performed to detect phosphorylation of insulin-receptor on Tyr1146, Akt on Ser473 and glycogen-synthases-kinase-3 on Ser21/Ser9. To address the spatial resolution of insulin signalling, immunohistochemistry studies on cryosections were performed. Our results provide evidence to suggest that during the in vitro incubation, insulin sufficiently diffuses into the centre of tubular mouse muscles to promote phosphorylation of these signalling events. Interestingly, increased insulin signalling was observed in the core of the incubated muscle specimens, correlating with the location of oxidative fibres. In conclusion, insulin action was not restricted due to insufficient diffusion of the hormone during in vitro incubation in either extensor digitorum longus or soleus muscles from mouse under the specific experimental settings employed in this study. Hence, we suggest that the glycogen depleted core as earlier observed is not due to insufficient insulin action.

  • 14.
    Szekeres, Ferenc
    et al.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Chadt, Alexandra
    German Institute of Human Nutrition, Potsdam-Rehbruecke, Department of Pharmacology, Nuthetal, Germany.
    Tom, Robby Z.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Deshmukh, Atul S.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Chibalin, Alexander V.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Björnholm, Marie
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Al-Hasani, Hadi
    German Institute of Human Nutrition, Potsdam-Rehbruecke, Department of Pharmacology, Nuthetal, Germany.
    Zierath, Juleen R.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden / Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism2012In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 303, no 4, p. E524-E533Article in journal (Refereed)
    Abstract [en]

    Szekeres F, Chadt A, Tom RZ, Deshmukh AS, Chibalin AV, Bjornholm M, Al-Hasani H, Zierath JR. The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism. Am J Physiol Endocrinol Metab 303: E524-E533, 2012. First published June 12, 2012; doi:10.1152/ajpendo.00605.2011.-The Rab-GTPase-activating protein TBC1D1 has emerged as a novel candidate involved in metabolic regulation. Our aim was to determine whether TBC1D1 is involved in insulin as well as energy-sensing signals controlling skeletal muscle metabolism. TBC1D1-deficient congenic B6.SJL-Nob1.10 (Nob1.10(SJL)) and wild-type littermates were studied. Glucose and insulin tolerance, glucose utilization, hepatic glucose production, and tissue-specific insulin-mediated glucose uptake were determined. The effect of insulin, AICAR, or contraction on glucose transport was studied in isolated skeletal muscle. Glucose and insulin tolerance tests were normal in TBC1D1-deficient Nob1.10(SJL) mice, yet the 4-h-fasted insulin concentration was increased. Insulin-stimulated peripheral glucose utilization during a euglycemic hyperinsulinemic clamp was similar between genotypes, whereas the suppression of hepatic glucose production was increased in TBC1D1-deficient mice. In isolated extensor digitorum longus (EDL) but not soleus muscle, glucose transport in response to insulin, AICAR, or contraction was impaired by TBC1D1 deficiency. The reduction in glucose transport in EDL muscle from TBC1D1-deficient Nob1.10(SJL) mice may be explained partly by a 50% reduction in GLUT4 protein, since proximal signaling at the level of Akt, AMPK, and acetyl-CoA carboxylase (ACC) was unaltered. Paradoxically, in vivo insulin-stimulated 2-deoxyglucose uptake was increased in EDL and tibialis anterior muscle from TBC1D1-deficient mice. In conclusion, TBC1D1 plays a role in regulation of glucose metabolism in skeletal muscle. Moreover, functional TBC1D1 is required for AICAR- or contraction-induced metabolic responses, implicating a role in energy-sensing signals.

  • 15.
    Szekeres, Ferenc L. M.
    et al.
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). Division of Genetic Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Walum, Erik
    Glucox Biotech AB, Färentuna, Sweden.
    Wikström, Per
    Glucox Biotech AB, Färentuna, Sweden.
    Arner, Anders
    Division of Genetic Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockhom, Sweden ; Department of Clinical Sciences Lund, Thoracic Surgery, Lund University, c/o Igelösa Life Science AB, Lund, Sweden.
    A small molecule inhibitor of Nox2 and Nox4 improves contractile function after ischemia–reperfusion in the mouse heart2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 11970Article in journal (Refereed)
    Abstract [en]

    The NADPH oxidase enzymes Nox2 and 4, are important generators of Reactive oxygen species (ROS). These enzymes are abundantly expressed in cardiomyocytes and have been implicated in ischemia–reperfusion injury. Previous attempts with full inhibition of their activity using genetically modified animals have shown variable results, suggesting that a selective and graded inhibition could be a more relevant approach. We have, using chemical library screening, identified a new compound (GLX481304) which inhibits Nox 2 and 4 (with IC50 values of 1.25 µM) without general antioxidant effects or inhibitory effects on Nox 1. The compound inhibits ROS production in isolated mouse cardiomyocytes and improves cardiomyocyte contractility and contraction of whole retrogradely (Langendorff) perfused hearts after a global ischemia period. We conclude that a pharmacological and partial inhibition of ROS production by inhibition of Nox 2 and 4 is beneficial for recovery after ischemia reperfusion and might be a promising venue for treatment of ischemic injury to the heart. 

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  • 16.
    Szekeres, Ferenc
    et al.
    Karolinska Institutet, Department of physiology and pharmacology, Division of genetic physiology, Stockholm, Sweden.
    Walum, Erik
    Glucox Biotech AB, Stockholm, Sweden.
    Wikström, P.
    Glucox Biotech AB, Stockholm, Sweden.
    Arner, A.
    Karolinska Institutet, Department of physiology and pharmacology, Division of genetic physiology, Stockholm, Sweden.
    A small molecule inhibitor of Nox2 and Nox4 improves cardiac contractility after ischemia-reperfusion in the mouse heart2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no s696, p. 93-93Article in journal (Refereed)
  • 17.
    Sögaard, Peter
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Szekeres, Ferenc
    Department of Molecular Medicine and Surgery, Section og Integrative Physiology, Karolinska Institutet.
    Holmström, Maria
    Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet.
    Larsson, Dennis
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Harlén, Mikael
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Garcia-Roves, Pablo
    Section of Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet.
    Chibalin, Alexander V.
    Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet.
    Effects of fibre type and diffusion distance on mouse skeletal muscle glycogen content in vitro2009In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 107, no 6, p. 1189-1197Article in journal (Refereed)
    Abstract [en]

    In vitro incubation of isolated rodent skeletal muscle is a widely used procedure in metabolic research. One concern with this method is the development of an anoxic state during the incubation period that can cause muscle glycogen depletion. Our aim was to investigate whether in vitro incubation conditions influence glycogen concentration in glycolytic extensor digitorum longus (EDL) and oxidative soleus mouse muscle. Quantitative immunohistochemistry was applied to assess glycogen content in incubated skeletal muscle. Glycogen concentration was depleted, independent of insulin-stimulation in the incubated skeletal muscle. The extent of glycogen depletion was correlated with the oxidative fibre distribution and with the induction of hypoxia-induced-factor-1-alpha. Insulin exposure partially prevented glycogen depletion in soleus, but not in EDL muscle, providing evidence that glucose diffusion is not a limiting step to maintain glycogen content. Our results provide evidence to suggest that the anoxic milieu and the intrinsic characteristics of the skeletal muscle fibre type play a major role in inducing glycogen depletion in during in vitro incubations.

  • 18.
    Sögård, Peter
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences. Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Harlén, Mikael
    University of Skövde, School of Life Sciences.
    Long, Yun Chau
    Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Szekeres, Ferenc
    Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Barnes, Brian R.
    Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Chibalin, Alexander V.
    Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Zierath, Juleen R.
    Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Validation of the in vitro incubation of extensor digitorum longus muscle from mice with a mathematical model2010In: Journal of biological systems, ISSN 0218-3390, Vol. 18, no 3, p. 687-707Article in journal (Refereed)
    Abstract [en]

    In vitro incubation of tissues; in particular, skeletal muscles from rodents, is a widely-used experimental method in diabetes research. This experimental method has previously been validated, both experimentally and theoretically. However, much of the method's experimental data remains unclear, including the high-rate of lactate production and the lack of an observable increase in glycogen content, within a given time. The predominant hypothesis explaining the high-rate of lactate production is that this phenomenon is dependent on a mechanism in glycolysis that works as a safety valve, producing lactate when glucose uptake is super-physiological. Another hypothesis is that existing anoxia forces more ATP to be produced from glycolysis, leading to an increased lactate concentration. The lack of an observable increase in glycogen content is assumed to be dependent on limitations in sensitivity of the measuring method used. We derived a mathematical model to investigate which of these hypotheses is most likely to be correct. Using our model, data analysis indicates that the in vitro incubated muscle specimens, most likely are sensing the presence of existing anoxia, rather than an overflow in glycolysis. The anoxic milieu causes the high lactate production. The model also predicts an increased glycogenolysis. After mathematical analyses, an estimation of the glycogen concentration could be made with a reduced model. In conclusion, central anoxia is likely to cause spatial differences in glycogen concentrations throughout the entire muscle. Thus, data regarding total glycogen levels in the incubated muscle do not accurately represent the entire organ. The presented model allows for an estimation of total glycogen, despite spatial differences present in the muscle specimen.

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