42 results on '"Mathias Lundberg"'
Search Results
2. Aberrant default mode connectivity in adolescents with early-onset psychosis: A resting state fMRI study
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Eva Hilland, Cecilie Johannessen, Rune Jonassen, Dag Alnæs, Kjetil N. Jørgensen, Claudia Barth, Dimitrios Andreou, Stener Nerland, Laura A. Wortinger, Runar E. Smelror, Kirsten Wedervang-Resell, Hannes Bohman, Mathias Lundberg, Lars T. Westlye, Ole A. Andreassen, Erik G. Jönsson, and Ingrid Agartz
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Early-onset psychosis (EOP) ,Schizophrenia ,Affective psychosis ,Default mode network (DMN) ,Resting state fMRI (rsfMRI) ,Independent component analysis (ICA) ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abnormal default mode network (DMN) connectivity has been found in schizophrenia and other psychotic disorders. However, there are limited studies on early onset psychosis (EOP), and their results show lack of agreement. Here, we investigated within-network DMN connectivity in EOP compared to healthy controls (HC), and its relationship to clinical characteristics.A sample of 68 adolescent patients with EOP (mean age 16.53 ± 1.12 [SD] years, females 66%) and 95 HC (mean age 16.24 ± 1.50 [SD], females 60%) from two Scandinavian cohorts underwent resting state functional magnetic resonance imaging (rsfMRI). A group independent component analysis (ICA) was performed to identify the DMN across all participants. Dual regression was used to estimate spatial maps reflecting each participant’s DMN network, which were compared between EOP and HC using voxel-wise general linear models and permutation-based analyses. Subgroup analyses were performed within the patient group, to explore associations between diagnostic subcategories and current use of psychotropic medication in relation to connectivity strength.The analysis revealed significantly reduced DMN connectivity in EOP compared to HC in the posterior cingulate cortex, precuneus, fusiform cortex, putamen, pallidum, amygdala, and insula. The subgroup analysis in the EOP group showed strongest deviations for affective psychosis, followed by other psychotic disorders and schizophrenia. There was no association between DMN connectivity strength and the current use of psychotropic medication.In conclusion, the findings demonstrate weaker DMN connectivity in adolescent patients with EOP compared to healthy peers, and differential effects across diagnostic subcategories, which may inform our understanding of underlying disease mechanisms in EOP.
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- 2022
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3. Preclinical atherosclerosis in adolescents with psychotic or bipolar disorders investigated with carotid high‐frequency ultrasound
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Hannes Bohman, Ingrid Agartz, Shiva Mansouri, Tord Naessen, and Mathias Lundberg
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adolescents ,atherosclerosis ,bipolar disorder ,psychosis ,ultrasound ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Objective Early‐onset psychosis (EOP) and bipolar disorder (EOBP) (at
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- 2020
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4. Autoantibodies to the N-Methyl-D-Aspartate Receptor in Adolescents With Early Onset Psychosis and Healthy Controls
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Kristine Engen, Laura Anne Wortinger, Kjetil Nordbø Jørgensen, Mathias Lundberg, Hannes Bohman, Runar Elle Smelror, Anne Margrethe Myhre, Leslie Jacobson, Angela Vincent, and Ingrid Agartz
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early onset psychosis ,NMDAr antibodies ,adolescence ,psychosis ,MRI autoantibodies ,Psychiatry ,RC435-571 - Abstract
BackgroundAutoantibodies to the N-methyl-D-aspartate receptor (NMDAR-Abs) in autoimmune encephalitis have been associated with prominent psychiatric symptoms. The aims of the present study are to identify the prevalence of NMDAR-Abs in adolescents with early onset psychosis disorders (EOP) and healthy controls (HC) and examine its clinical significance.MethodPlasma samples were acquired from 46 adolescent EOP patients and 69 age- and sex matched HC, and assessed for the presence of immunoglobulin G NMDAR-Abs. All participants underwent psychiatric evaluation, neurological examination and head magnetic resonance imaging.ResultsNMDAR-Abs were detected in three of 46 (6.5%) EOP patients and in two of 69 (2.9%) HC. One NMDAR-Abs EOP patient presented with unusual psychopathology and minor T1 weighted lesions of vasculopathological origin located bi-frontally and in the basal ganglia, and had a recent diagnosis of a separate autoimmune disease. One NMDAR-Ab HC displayed a T2 weighted FLAIR hyperintensity lesion in the left frontal lobe. The remaining three NMDAR-Ab participants were two EOP patients without neurological or radiological findings, and one HC without any clinical findings.ConclusionsWe report that a small number of EOP patients and HC have NMDAR-Abs with a similar frequency in both groups. The presence of the antibodies was not associated with any distinctive clinical or radiological features. Detection of the antibodies had no diagnostic implication, and a positive NMDAR antibody test must be carefully interpreted and reviewed within the individual clinical context.
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- 2020
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5. Somatic symptoms in adolescence as a predictor of severe mental illness in adulthood: a long-term community-based follow-up study
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Hannes Bohman, Sara B. Låftman, Neil Cleland, Mathias Lundberg, Aivar Päären, and Ulf Jonsson
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Pediatrics ,RJ1-570 ,Psychiatry ,RC435-571 - Abstract
Abstract Background Somatic symptoms are common and costly for society and correlate with suffering and low functioning. Nevertheless, little is known about the long-term implications of somatic symptoms. The objective of this study was to assess if somatic symptoms in adolescents with depression and in their matched controls predict severe mental illness in adulthood by investigating the use of hospital-based care consequent to different mental disorders. Methods The entire school population of 16–17-year-olds in the city of Uppsala, Sweden, was screened for depression in 1991–1993 (n = 2300). Adolescents with positive screenings (n = 307) and matched non-depressed controls (n = 302) participated in a semi-structured diagnostic interview for mental disorders. In addition, 21 different self-rated somatic symptoms were assessed. The adolescents with depression and the matched non-depressed controls were engaged in follow-up through the National Patient Register 17–19 years after the baseline study (n = 375). The outcome measures covered hospital-based mental health care for different mental disorders according to ICD-10 criteria between the participants’ ages of 18 and 35 years. Results Somatic symptoms were associated with an increased risk of later hospital-based mental health care in general in a dose–response relationship when adjusting for sex, adolescent depression, and adolescent anxiety (1 symptom: OR = 1.63, CI 0.55–4.85; 2–4 symptoms: OR = 2.77, 95% CI 1.04–7.39; ≥ 5 symptoms: OR = 5.75, 95% CI 1.98–16.72). With regards to specific diagnoses, somatic symptoms predicted hospital-based care for mood disorders when adjusting for sex, adolescent depression, and adolescent anxiety (p
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- 2018
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6. PACAP Protects Adult Neural Stem Cells from the Neurotoxic Effect of Ketamine Associated with Decreased Apoptosis, ER Stress and mTOR Pathway Activation.
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Shiva Mansouri, Ingrid Agartz, Sven-Ove Ögren, Cesare Patrone, and Mathias Lundberg
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Medicine ,Science - Abstract
Ketamine administration is a well-established approach to mimic experimentally some aspects of schizophrenia. Adult neurogenesis dysregulation is associated with psychiatric disorders, including schizophrenia. The potential role of neurogenesis in the ketamine-induced phenotype is largely unknown. Recent results from human genetic studies have shown the pituitary adenylate cyclase-activating polypeptide (PACAP) gene is a risk factor for schizophrenia. Its potential role on the regulation of neurogenesis in experimental model of schizophrenia remains to be investigated. We aimed to determine whether ketamine affects the viability of adult neural stem cells (NSC). We also investigated whether the detrimental effect mediated by ketamine could be counteracted by PACAP. NSCs were isolated from the subventricular zone of the mouse and exposed to ketamine with/without PACAP. After 24 hours, cell viability, potential involvement of apoptosis, endoplasmic reticulum (ER) stress, mTOR and AMPA pathway activation were assessed by quantitative RT-PCR and Western blot analysis. We show that ketamine impairs NSC viability in correlation with increased apoptosis, ER stress and mTOR activation. The results also suggest that the effect of ketamine occurs via AMPA receptor activation. Finally, we show that PACAP counteracted the decreased NSC viability induced by ketamine via the specific activation of the PAC-1 receptor subtype. Our study shows that the NSC viability may be negatively affected by ketamine with putative importance for the development of a schizophrenia phenotype in the ketamine induced animal model of schizophrenia. The neuroprotective effect via PAC-1 activation suggests a potentially novel pharmacological target for the treatment of schizophrenia, via neurogenesis normalization.
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- 2017
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7. Pituitary Adenlylate Cyclase Activating Peptide Protects Adult Neural Stem Cells from a Hypoglycaemic milieu.
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Shiva Mansouri, Grazyna Lietzau, Mathias Lundberg, David Nathanson, Thomas Nyström, and Cesare Patrone
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Medicine ,Science - Abstract
Hypoglycaemia is a common side-effect of glucose-lowering therapies for type-2 diabetic patients, which may cause cognitive/neurological impairment. Although the effects of hypoglycaemia in the brain have been extensively studied in neurons, how hypoglycaemia impacts the viability of adult neural stem cells (NSCs) has been poorly investigated. In addition, the cellular and molecular mechanisms of how hypoglycaemia regulates NSCs survival have not been characterized. Recent work others and us have shown that the pituitary adenylate cyclase-activating polypeptide (PACAP) and the glucagon-like peptide-1 receptor (GLP-1R) agonist Exendin-4 stimulate NSCs survival against glucolipoapoptosis. The aim of this study was to establish an in vitro system where to study the effects of hypoglycaemia on NSC survival. Furthermore, we determine the potential role of PACAP and Exendin-4 in counteracting the effect of hypoglycaemia. A hypoglycaemic in vitro milieu was mimicked by exposing subventricular zone-derived NSC to low levels of glucose. Moreover, we studied the potential involvement of apoptosis and endoplasmic reticulum stress by quantifying protein levels of Bcl-2, cleaved caspase-3 and mRNA levels of CHOP. We show that PACAP via PAC-1 receptor and PKA activation counteracts impaired NSC viability induced by hypoglycaemia. The protective effect induced by PACAP correlated with endoplasmic reticulum stress, Exendin-4 was ineffective. The results show that hypoglycaemia decreases NSC viability and that this effect can be substantially counteracted by PACAP via PAC-1 receptor activation. The data supports a potential therapeutic role of PAC-1 receptor agonists for the treatment of neurological complications, based on neurogenesis impairment by hypoglycaemia.
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- 2016
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8. The Cellular Thioredoxin-1/Thioredoxin Reductase-1 Driven Oxidoreduction Represents a Chemotherapeutic Target for HIV-1 Entry Inhibition.
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Kathrin Reiser, Leen Mathys, Sophie Curbo, Christophe Pannecouque, Sam Noppen, Sandra Liekens, Lars Engman, Mathias Lundberg, Jan Balzarini, and Anna Karlsson
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Medicine ,Science - Abstract
BACKGROUND:The entry of HIV into its host cell is an interesting target for chemotherapeutic intervention in the life-cycle of the virus. During entry, reduction of disulfide bridges in the viral envelope glycoprotein gp120 by cellular oxidoreductases is crucial. The cellular thioredoxin reductase-1 plays an important role in this oxidoreduction process by recycling electrons to thioredoxin-1. Therefore, thioredoxin reductase-1 inhibitors may inhibit gp120 reduction during HIV-1 entry. In this present study, tellurium-based thioredoxin reductase-1 inhibitors were investigated as potential inhibitors of HIV entry. RESULTS:The organotellurium compounds inhibited HIV-1 and HIV-2 replication in cell culture at low micromolar concentrations by targeting an early event in the viral infection cycle. Time-of-drug-addition studies pointed to virus entry as the drug target, more specifically: the organotellurium compound TE-2 showed a profile similar or close to that of the fusion inhibitor enfuvirtide (T-20). Surface plasmon resonance-based interaction studies revealed that the compounds do not directly interact with the HIV envelope glycoproteins gp120 and gp41, nor with soluble CD4, but instead, dose-dependently bind to thioredoxin reductase-1. By inhibiting the thioredoxin-1/thioredoxin reductase-1-directed oxidoreduction of gp120, the organotellurium compounds prevent conformational changes in the viral glycoprotein which are necessary during viral entry. CONCLUSION:Our findings revealed that thioredoxin-1/thioredoxin reductase-1 acts as a cellular target for the inhibition of HIV entry.
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- 2016
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9. Methodological aspects of ELISA analysis of thioredoxin 1 in human plasma and cerebrospinal fluid.
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Mathias Lundberg, Sophie Curbo, Kathrin Reiser, Thomas Masterman, Sten Braesch-Andersen, Irene Areström, and Niklas Ahlborg
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Medicine ,Science - Abstract
Thioredoxin-1 (Trx1) is a protein antioxidant involved in major cellular processes. Increased plasma levels of Trx1 have been associated with human diseases suggesting that Trx1 is a marker for oxidative stress with putative clinical use. However, the reported mean levels of Trx1 in the control cohorts vary a hundred-fold between studies (0.8-87 ng/ml), possibly due to methodological differences between the capture ELISA used in the different studies. The aim of this study was to investigate methodological aspects related to the ELISA measurement of Trx1. ELISAs utilizing different capture and detection combinations of antibodies to Trx1 and as well as recombinant human (rh) Trx1 standards from two sources were characterized. The different ELISAs were subsequently used to measure Trx1 in human plasma and cerebrospinal fluid samples (CSF) from healthy donors and from patients with various neurological diagnoses. The Trx1 standards differed in their content of monomeric and oligomeric Trx1, which affected the ELISAs composed of different antibody combinations. Thus, the levels of Trx1 determined in human plasma and CSF samples varied depending on the antibody used in the ELISAs and on the rhTrx1 standard. Furthermore, the relevance of preventing interference by heterophilic antibodies (HA) in human plasma and CSF was investigated. The addition of a HA blocking buffer to human samples drastically reduced the ELISA signals in many samples showing that HA are likely to cause false positive results unless they are blocked. In conclusion, the study shows that the design of a Trx1 ELISA in regards to antibodies and standards used has an impact on the measured Trx1 levels. Importantly, analyses of human plasma and CSF without preventing HA interference may obscure the obtained data. Overall, the results of this study are crucial for the improvement of future studies on the association of Trx1 levels with various diseases.
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- 2014
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10. In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis
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Claudia Barth, Sinead Kelly, Stener Nerland, Neda Jahanshad, Clara Alloza, Sonia Ambrogi, Ole A. Andreassen, Dimitrios Andreou, Celso Arango, Inmaculada Baeza, Nerisa Banaj, Carrie E. Bearden, Michael Berk, Hannes Bohman, Josefina Castro-Fornieles, Yann Chye, Benedicto Crespo-Facorro, Elena de la Serna, Covadonga M. Díaz-Caneja, Tiril P. Gurholt, Catherine E. Hegarty, Anthony James, Joost Janssen, Cecilie Johannessen, Erik G. Jönsson, Katherine H. Karlsgodt, Peter Kochunov, Noemi G. Lois, Mathias Lundberg, Anne M. Myhre, Saül Pascual-Diaz, Fabrizio Piras, Runar E. Smelror, Gianfranco Spalletta, Therese S. Stokkan, Gisela Sugranyes, Chao Suo, Sophia I. Thomopoulos, Diana Tordesillas-Gutiérrez, Daniela Vecchio, Kirsten Wedervang-Resell, Laura A. Wortinger, Paul M. Thompson, and Ingrid Agartz
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Male ,Pediatric ,Psychiatry ,Adolescent ,Psychology and Cognitive Sciences ,Neurosciences ,Brain ,Biological Sciences ,Serious Mental Illness ,White Matter ,Medical and Health Sciences ,Brain Disorders ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Diffusion Tensor Imaging ,Mental Health ,Good Health and Well Being ,Psychotic Disorders ,Clinical Research ,Schizophrenia ,Humans ,Anisotropy ,Biomedical Imaging ,Female ,Molecular Biology - Abstract
Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset d = 0.37), posterior corona radiata (d = 0.32), and superior fronto‐occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.
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- 2023
11. In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis via the ENIGMA Consortium
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Claudia Barth, Sinead Kelly, Stener Nerland, Neda Jahanshad, Clara Alloza, Sonia Ambrogi, Ole A Andreassen, Dimitrios Andreou, Celso Arango, Inmaculada Baeza, Nerisa Banaj, Carrie E Bearden, Michael Berk, Hannes Bohman, Josefina Castro-Fornieles, Yann Chye, Benedicto Crespo-Facorro, Elena de la Serna, Covadonga M Díaz-Caneja, Tiril P Gurholt, Catherine E Hegarty, Anthony James, Joost Janssen, Cecilie Johannessen, Erik G Jönsson, Katherine H Karlsgodt, Peter Kochunov, Noemi G Lois, Mathias Lundberg, Anne M Myhre, Saül Pascual-Diaz, Fabrizio Piras, Runar E Smelror, Gianfranco Spalletta, Therese S Stokkan, Gisela Sugranyes, Chao Suo, Sophia I Thomopoulos, Diana Tordesillas-Gutiérrez, Daniela Vecchio, Kirsten Wedervang-Resell, Laura A Wortinger, Paul M. Thompson, and Ingrid Agartz
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BackgroundEmerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset MethodsOur sample included 321 adolescents with EOP (mean age: 16.3 ± 1.4 years, 46.4% females) and 265 adolescent CTR (mean age: 16.0 ± 1.7 years, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures.ResultsWe found widespread lower FA in EOP compared to CTR, with the largest effect sizes in the superior longitudinal fasciculus (Cohen’s d = 0.37), posterior corona radiata (d = 0.32), and superior fronto□occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status.ConclusionUsing the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male patients with early-onset schizophrenia and patients with a shorter duration of illness.
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- 2022
12. Development of an ELISA displaying similar reactivity with reduced and oxidized human Thioredoxin-1 (Trx1): The plasma level of Trx1 in early onset psychosis disorders
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Mathias Lundberg, Hannes Bohman, Sophie Curbo, Shiva Mansouri, Ingrid Agartz, Irene Areström, and Niklas Ahlborg
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Thioredoxins ,Psychotic Disorders ,Immunology ,Antibodies, Monoclonal ,Biotin ,Humans ,Immunology and Allergy ,Enzyme-Linked Immunosorbent Assay ,Oxidation-Reduction - Abstract
The plasma level of human thioredoxin-1 (Trx1) has been shown to be increased in various somatic diseases and psychiatric disorders. However, when comparing the reported plasma levels of Trx1, a great inter-study variability, as well as variability in study outcomes of differences between patients and control subjects has been observed, ultimately limiting the possibility to make comparative analyses. Trx1 is a highly redox active protein prone to form various redox forms, e.g. dimers, oligomers or Trx1-protein complexes. We have recently shown that ELISA systems may vary in reactivity to various Trx1 redox forms. The primary aim of the present study was to develop an ELISA system with similar reactivity to various Trx1 redox forms. By evaluating a panel of novel monoclonal antibodies (mAbs), in various paired combinations, three ELISA systems were generated, with observed large variability in reactivity to various Trx1 redox forms. Importantly, an ELISA system (capture mAb MT17R6 and detection mAb MT13X3-biotin), was identified that displayed similar reactivity to oxidized and DTT reduced Trx1. The ELISA system (MT17R6/MT13X3-biotin), was subsequently used to analyze the level of Trx1 in plasma from patients (18 years) with early onset psychosis disorders (EOP). However, no significant (p 0.7) difference in plasma Trx1 levels between patients with EOP (n = 23) and healthy age matched controls (HC) (n = 20) were observed. Furthermore, reliable measurement was shown to be dependent on the establishment of platelet poor plasma samples, enabled by rigorous blood sample centrifugation and by efficient blocking of potentially interfering heterophilic antibodies. In conclusion, we report the design and characterization of a Trx1 ELISA system with similar reactivity to various Trx1 redox forms. Importantly, data indicated that generated ELISA systems show large variability in reactivity to various redox forms with ultimate impact on measured levels of Trx1. Overall, results from this study suggests that future studies may be strongly improved by the use of Trx1 ELISA systems with characterized specificity to various redox forms.
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- 2022
13. Aberrant default mode connectivity in adolescents with early-onset psychosis: A resting state fMRI study
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Ole A. Andreassen, Kirsten Wedervang-Resell, Dimitrios Andreou, Lars T. Westlye, Eva Hilland, Ingrid Agartz, Laura Anne Wortinger, Claudia Barth, Hannes Bohman, Dag Alnæs, Kjetil Nordbø Jørgensen, Rune Jonassen, Erik G. Jönsson, Mathias Lundberg, Stener Nerland, Runar Smelror, and Cecilie Haggag Johannessen
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medicine.medical_specialty ,Adolescent ,Cognitive Neuroscience ,Independent component analysis (ICA) ,Computer applications to medicine. Medical informatics ,Precuneus ,R858-859.7 ,Subgroup analysis ,Independent component analysis ,Audiology ,Default mode network (DMN) ,Psykiatri ,Parietal Lobe ,Resting state fMRI (rsfMRI) ,Neural Pathways ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Early-onset psychosis ,RC346-429 ,Default mode network ,Psychiatry ,Cerebral Cortex ,Brain Mapping ,Resting state fMRI ,business.industry ,Affective psychosis ,Putamen ,Brain ,Regular Article ,medicine.disease ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Neurology ,Psychotic Disorders ,Schizophrenia ,Early-onset psychosis (EOP) ,Posterior cingulate ,Female ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,business ,Insula ,human activities - Abstract
Abnormal default mode network (DMN) connectivity has been found in schizophrenia and other psychotic disorders. However, there are limited studies on early onset psychosis (EOP), and their results show lack of agreement. Here, we investigated within - network DMN connectivity in EOP compared to healthy controls (HC), and its relationship to clinical characteristics. A sample of 68 adolescent patients with EOP (mean age 16.53 ± 1.12 [SD] years, females 66%) and 95 HC (mean age 16.24 ± 1.50 [SD], females 60%) from two Scandinavian cohorts underwent resting state functional magnetic resonance imaging (rsfMRI). A group independent component analysis (ICA) was performed to identify the DMN across all participants. Dual regression was used to estimate spatial maps reflecting each participant’s DMN network, which were compared between EOP and HC using voxel-wise general linear models and permutation-based analyses. Subgroup analyses were performed within the patient group, to explore associations between diagnostic subcategories and current use of psychotropic medication in relation to connectivity strength. The analysis revealed significantly reduced DMN connectivity in EOP compared to HC in the posterior cingulate cortex, precuneus, fusiform cortex, putamen, pallidum, amygdala, and insula. The subgroup analysis in the EOP group showed strongest deviations for affective psychosis, followed by other psychotic disorders and schizophrenia. There was no association between DMN connectivity strength and the current use of psychotropic medication. In conclusion, the findings demonstrate weaker DMN connectivity in adolescent patients with EOP compared to healthy peers, and differential effects across diagnostic subcategories, which may inform our understanding of underlying disease mechanisms in EOP.
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- 2021
14. Inhibition of the thioredoxin system by PX-12 (1-methylpropyl 2-imidazolyl disulfide) impedes HIV-1 infection in TZM-bl cells
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Arne Holmgren, Kathrin Reiser, Åse Mattsson, Sophie Curbo, and Mathias Lundberg
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0301 basic medicine ,lcsh:Medicine ,HIV Infections ,Plasma protein binding ,HIV Envelope Protein gp120 ,Article ,Virus ,Cell Line ,Microtubule polymerization ,03 medical and health sciences ,Thioredoxins ,0302 clinical medicine ,Viral envelope ,Humans ,Disulfides ,Receptor ,lcsh:Science ,Multidisciplinary ,Chemistry ,lcsh:R ,Imidazoles ,virus diseases ,Virus Internalization ,In vitro ,Cell biology ,030104 developmental biology ,Cell culture ,CD4 Antigens ,HIV-1 ,lcsh:Q ,Thioredoxin ,Oxidation-Reduction ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Human immunodeficiency virus (HIV-1) entry is initiated by the binding between the viral envelope glycoprotein gp120 and the host receptor CD4, and followed by reduction of structural disulfides of gp120 and CD4. The host thioredoxin-1 (Trx1) efficiently reduces disulfides of gp120 and CD4 in vitro, and recently CD4-dependent HIV-1 entry was shown to be inhibited by anti-Trx1-antibodies, indicating a central role for Trx1. 1-methylpropyl-2-imidazolyl disulfide (PX-12) is a reversible inhibitor of the Trx1 system that may also cause a slow irreversible thioalkylation of Trx1. It was developed as an antitumor agent, however, the current study aimed to determine if it also has an anti-HIV-1 effect. We show that PX-12 has anti-HIV-1(IIIB) activity in TZM-bl cells, in fact, no virus was detected inside the cells in the presence of 10 µM PX-12. Moreover, PX-12 inhibited the enzymatic activity of Trx1 and the Trx1-dependent disulfide reduction of gp120. Microtubule polymerization and formation of acetylated microtubules were also inhibited, activities shown to be required for HIV-1 life cycle propagation. In conclusion, our data strengthens the notion that the early steps of the HIV-1 life cycle depends on the Trx1 system and indicate that the Trx1 system may be a rational drug target for HIV-1 treatment.
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- 2019
15. Autoantibodies to the
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Kristine Engen, Laura Anne Wortinger, Kjetil Nordbø Jørgensen, Mathias Lundberg, Hannes Bohman, Runar Elle Smelror, Anne Margrethe Myhre, Leslie Jacobson, Angela Vincent, and Ingrid Agartz
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medicine.medical_specialty ,Psychosis ,endocrine system diseases ,lcsh:RC435-571 ,Early onset psychosis ,Context (language use) ,Neurological examination ,NMDAr antibodies ,Psykiatri ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,lcsh:Psychiatry ,Medicine ,Clinical significance ,psychosis ,Receptor ,early onset psychosis ,Autoimmune disease ,MRI autoantibodies ,Psychiatry ,Autoimmune encephalitis ,D aspartate ,medicine.diagnostic_test ,business.industry ,Prominent psychiatric symptoms ,Autoantibody ,nutritional and metabolic diseases ,Brief Research Report ,medicine.disease ,Hyperintensity ,030227 psychiatry ,Psychiatry and Mental health ,nervous system ,Immunology ,adolescence ,business ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
BackgroundAutoantibodies to the N-methyl-D-aspartate receptor (NMDAR-Abs) in autoimmune encephalitis have been associated with prominent psychiatric symptoms. The aims of the present study are to identify the prevalence of NMDAR-Abs in adolescents with early onset psychosis disorders (EOP) and healthy controls (HC) and examine its clinical significance.MethodPlasma samples were acquired from 46 adolescent EOP patients and 69 age- and sex matched HC, and assessed for the presence of immunoglobulin G NMDAR-Abs. All participants underwent psychiatric evaluation, neurological examination and head magnetic resonance imaging.ResultsNMDAR-Abs were detected in three of 46 (6.5%) EOP patients and in two of 69 (2.9%) HC. One NMDAR-Abs EOP patient presented with unusual psychopathology and minor T1 weighted lesions of vasculopathological origin located bi-frontally and in the basal ganglia, and had a recent diagnosis of a separate autoimmune disease. One NMDAR-Abs HC displayed a T2 weighted FLAIR hyperintensity lesion in the left frontal lobe. The remaining three NMDAR-Abs participants were two EOP patients without neurological or radiological findings, and one HC without any clinical findings.ConclusionsWe report the presence of NMDAR-Abs in both adolescent EOP patients and HC, similar to the incidence in other studies. This may support the hypothesis of an immunological disease component in a small proportion of adolescent psychosis, but the positive antibody tests must be carefully interpreted and reviewed within the individual clinical context.
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- 2020
16. Clozapine protects adult neural stem cells from ketamine-induced cell death in correlation with decreased apoptosis and autophagy
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Ingrid Agartz, Shiva Mansouri, Hannes Bohman, Sven-Ove Ögren, Sophie Curbo, Mathias Lundberg, and Cesare Patrone
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0301 basic medicine ,Male ,Cell- och molekylärbiologi ,Apoptosis ,Pharmacology ,Biochemistry ,Molecular Bases of Health & Disease ,haloperidol ,0302 clinical medicine ,Neural Stem Cells ,Lateral Ventricles ,Haloperidol ,Clozapine ,Research Articles ,Cells, Cultured ,reproductive and urinary physiology ,Chemistry ,Caspase 3 ,Stem Cells ,Neurogenesis ,Neural stem cell ,Adult Stem Cells ,medicine.anatomical_structure ,Neuroprotective Agents ,Proto-Oncogene Proteins c-bcl-2 ,neuroprotection ,biological phenomena, cell phenomena, and immunity ,Microtubule-Associated Proteins ,medicine.drug ,Signal Transduction ,Programmed cell death ,Cell Homeostasis & Autophagy ,autophagy ,ketamine ,Biophysics ,Subventricular zone ,03 medical and health sciences ,medicine ,Animals ,Viability assay ,Molecular Biology ,Dentate gyrus ,fluoxetine ,Cell Biology ,Mice, Inbred C57BL ,030104 developmental biology ,nervous system ,Excitatory Amino Acid Antagonists ,Cell and Molecular Biology ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Adult neurogenesis, the production of newborn neurons from neural stem cells (NSCs) has been suggested to be decreased in patients with schizophrenia. A similar finding was observed in an animal model of schizophrenia, as indicated by decreased bromodeoxyuridine (BrdU) labelling cells in response to a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist. The antipsychotic drug clozapine was shown to counteract the observed decrease in BrdU-labelled cells in hippocampal dentate gyrus (DG). However, phenotypic determination by immunohistochemistry analysis could not reveal whether BrdU-positive cells were indeed NSCs. Using a previously established cell model for analysing NSC protection in vitro, we investigated a protective effect of clozapine on NSCs. Primary NSCs were isolated from the mouse subventricular zone (SVZ), we show that clozapine had a NSC protective activity alone, as evident by employing an ATP cell viability assay. In contrast, haloperidol did not show any NSC protective properties. Subsequently, cells were exposed to the non-competitive NMDA-receptor antagonist ketamine. Clozapine, but not haloperidol, had a NSC protective/anti-apoptotic activity against ketamine-induced cytotoxicity. The observed NSC protective activity of clozapine was associated with increased expression of the anti-apoptotic marker Bcl-2, decreased expression of the pro-apoptotic cleaved form of caspase-3 and associated with decreased expression of the autophagosome marker 1A/1B-light chain 3 (LC3-II). Collectively, our findings suggest that clozapine may have a protective/anti-apoptotic effect on NSCs, supporting previous in vivo observations, indicating a neurogenesis-promoting activity for clozapine. If the data are further confirmed in vivo, the results may encourage an expanded use of clozapine to restore impaired neurogenesis in schizophrenia.
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- 2020
17. Healthy Adolescent Performance With Standardized Scoring Tables for the MATRICS Consensus Cognitive Battery: A Multisite Study
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Mary Cannon, Vera Lonning, Bjørn Rishovd Rund, Neil Cleland, Torill Ueland, Katherine H. Karlsgodt, Ian Kelleher, Runar Smelror, Kjetil Nordbø Jørgensen, Anil K. Malhotra, Mathias Lundberg, Tobias Edbom, Pamela DeRosse, Ole A. Andreassen, Ingrid Agartz, and Anne Margrethe Myhre
- Subjects
Adult ,Male ,Percentile ,Adolescent ,neurocognition ,neuropsychology ,Neuropsychological Tests ,Standard score ,Young Adult ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Social cognition ,Task Performance and Analysis ,Humans ,psychosis ,Child ,Neuropsychology ,Cognition ,Reference Standards ,030227 psychiatry ,Test (assessment) ,schizophrenia ,Psychiatry and Mental health ,Cohort ,Female ,early-onset ,Psychology ,Neurocognitive ,030217 neurology & neurosurgery ,Regular Articles ,Clinical psychology - Abstract
Author(s): Smelror, Runar Elle; Jorgensen, Kjetil Nordbo; Lonning, Vera; Kelleher, Ian; Cannon, Mary; DeRosse, Pamela; Malhotra, Anil K; Karlsgodt, Katherine H; Andreassen, Ole A; Lundberg, Mathias; Edbom, Tobias; Cleland, Neil; Ueland, Torill; Myhre, Anne Margrethe; Rund, Bjorn Rishovd; Agartz, Ingrid | Abstract: ObjectiveThe aim of this study was to develop standardized scores and scoring tables for test performance in healthy adolescents for the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) for each year from 11 to 19 years of age, by sex, with T scores and percentile ranks.MethodsA total of 502 healthy participants (aged 11-19 years) from 7 cohorts from Ireland, Norway, Sweden, and United States, were included in this multisite study. Regression-predicted means for the MCCB tests, except the social cognition subtest, were calculated using the MCCB test scores as outcome variables and age, age2, sex, age × sex as predictors. The regression-predicted means for each combination of age and sex were added with the residuals from the entire cohort to yield the expected distribution of that group. Age effects were examined using regression models with age and age2 as predictors. Sex differences were examined using Student's t-tests.ResultsSignificant positive age effects were found for all tests, except for the Brief Visuospatial Memory Test, revised (BVMT-R; measure of visual learning). Females performed significantly better than males on BACS Symbol coding (measure of speed of processing) and BVMT-R, while males performed significantly better than females on NAB Mazes (measure of reasoning and problem solving). Based on the regression-predicted distributions of scores, 19 standardized scoring tables for each test and domain were created.ConclusionsWith the results from this study, we have developed an accessible standardized data set of healthy adolescent test performance for the MCCB.
- Published
- 2018
18. Validation of crill measurements in a high-yield pulp refining process for improved fines material control
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Mathias Lundberg, Magnus Norgren, and Håkan Edlund
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040101 forestry ,Materials science ,Pulp (paper) ,Peeling action ,Industrial chemistry ,Forestry ,04 agricultural and veterinary sciences ,02 engineering and technology ,engineering.material ,021001 nanoscience & nanotechnology ,Pulp and paper industry ,engineering ,0401 agriculture, forestry, and fisheries ,General Materials Science ,0210 nano-technology - Abstract
In high-yield pulp (HYP) refining, fine material is created by peeling action on the fibre surface. This fine material is usually characterized using conventional camera technology and image analysis. The smallest particles, the crill, also created in the refining process are too small to be visible in a camera image, and are therefore measured using light sources in the UV and IR wavelength spectrum. This research sought to determine whether the crill could be characterized in the presence of large fines material in a HYP refining process, and the results indicated that the larger fines material had little impact. In addition, the variation in crill measurements declined as the fibre treatment increased and remained low and stable during an extended period. Due to the great need to monitor and control pulp processes using rapid online measurements, cost-reduction actions at mills running close to specification targets put high demands on the measuring devices characterizing the production. The outcome of this study enables the use of the crill method to improve our knowledge of fibre treatment and its contribution to fibre adhesion in complex refining processes. Finally, combining conventional camera technology and the crill method could improve the overall fines material control.
- Published
- 2018
19. PACAP Protects Adult Neural Stem Cells from the Neurotoxic Effect of Ketamine Associated with Decreased Apoptosis, ER Stress and mTOR Pathway Activation
- Author
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Cesare Patrone, Mathias Lundberg, Shiva Mansouri, Ingrid Agartz, and Sven-Ove Ögren
- Subjects
0301 basic medicine ,Male ,lcsh:Medicine ,Gene Expression ,Apoptosis ,Mice ,0302 clinical medicine ,Neural Stem Cells ,Animal Cells ,Medicine and Health Sciences ,lcsh:Science ,Neurons ,Multidisciplinary ,Cell Death ,Stem Cells ,TOR Serine-Threonine Kinases ,Neurogenesis ,Animal Models ,Endoplasmic Reticulum Stress ,Neural stem cell ,Adult Stem Cells ,medicine.anatomical_structure ,Neuroprotective Agents ,Experimental Organism Systems ,Cell Processes ,Pituitary Adenylate Cyclase-Activating Polypeptide ,Ketamine ,Cellular Types ,Research Article ,Signal Transduction ,medicine.medical_specialty ,Cell Survival ,Neurotoxins ,Subventricular zone ,AMPA receptor ,Biology ,Research and Analysis Methods ,Neuroprotection ,03 medical and health sciences ,Developmental Neuroscience ,Internal medicine ,Mental Health and Psychiatry ,medicine ,Genetics ,Animals ,Viability assay ,Animal Models of Disease ,PI3K/AKT/mTOR pathway ,lcsh:R ,Adult Neurogenesis ,Biology and Life Sciences ,Cell Biology ,030104 developmental biology ,Endocrinology ,Cellular Neuroscience ,Unfolded protein response ,Schizophrenia ,Animal Studies ,lcsh:Q ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Ketamine administration is a well-established approach to mimic experimentally some aspects of schizophrenia. Adult neurogenesis dysregulation is associated with psychiatric disorders, including schizophrenia. The potential role of neurogenesis in the ketamine-induced phenotype is largely unknown. Recent results from human genetic studies have shown the pituitary adenylate cyclase-activating polypeptide (PACAP) gene is a risk factor for schizophrenia. Its potential role on the regulation of neurogenesis in experimental model of schizophrenia remains to be investigated. We aimed to determine whether ketamine affects the viability of adult neural stem cells (NSC). We also investigated whether the detrimental effect mediated by ketamine could be counteracted by PACAP. NSCs were isolated from the subventricular zone of the mouse and exposed to ketamine with/without PACAP. After 24 hours, cell viability, potential involvement of apoptosis, endoplasmic reticulum (ER) stress, mTOR and AMPA pathway activation were assessed by quantitative RT-PCR and Western blot analysis. We show that ketamine impairs NSC viability in correlation with increased apoptosis, ER stress and mTOR activation. The results also suggest that the effect of ketamine occurs via AMPA receptor activation. Finally, we show that PACAP counteracted the decreased NSC viability induced by ketamine via the specific activation of the PAC-1 receptor subtype. Our study shows that the NSC viability may be negatively affected by ketamine with putative importance for the development of a schizophrenia phenotype in the ketamine induced animal model of schizophrenia. The neuroprotective effect via PAC-1 activation suggests a potentially novel pharmacological target for the treatment of schizophrenia, via neurogenesis normalization.
- Published
- 2017
20. The cellular thioredoxin-1/thioredoxin reductase-1 driven oxidoreduction represents a chemotherapeutic target for HIV-1 entry inhibition
- Author
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Sophie Curbo, Mathias Lundberg, Sandra Liekens, Christophe Pannecouque, Anna Karlsson, Leen Mathys, Sam Noppen, Lars Engman, Jan Balzarini, Kathrin Reiser, and Pöhlmann, Stefan
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0301 basic medicine ,RNA viruses ,viruses ,Human immunodeficiency virus (HIV) ,lcsh:Medicine ,Infektionsmedicin ,HIV Infections ,HIV Envelope Protein gp120 ,medicine.disease_cause ,Pathology and Laboratory Medicine ,Biochemistry ,0302 clinical medicine ,Thioredoxins ,Immunodeficiency Viruses ,Medicine and Health Sciences ,Drug Interactions ,Enzyme-Linked Immunoassays ,lcsh:Science ,Multidisciplinary ,Disulfide bond ,virus diseases ,Thioredoxin-1 ,Proteases ,Enzymes ,Medical Microbiology ,030220 oncology & carcinogenesis ,Viral Pathogens ,Viruses ,Biological Cultures ,Pathogens ,Tellurium ,Oxidation-Reduction ,Research Article ,Infectious Medicine ,Thioredoxin Reductase 1 ,Viral Entry ,Biology ,Research and Analysis Methods ,Microbiology ,Antiviral Agents ,Virus ,Cell Line ,03 medical and health sciences ,Virology ,Retroviruses ,medicine ,Humans ,Immunoassays ,Microbial Pathogens ,Pharmacology ,lcsh:R ,Lentivirus ,Organisms ,Biology and Life Sciences ,HIV ,Proteins ,Oxidation reduction ,Cell Cultures ,Virus Internalization ,Viral Replication ,030104 developmental biology ,Cell culture ,Cancer research ,HIV-1 ,Enzymology ,Immunologic Techniques ,lcsh:Q ,Viral Transmission and Infection - Abstract
Background The entry of HIV into its host cell is an interesting target for chemotherapeutic intervention in the life-cycle of the virus. During entry, reduction of disulfide bridges in the viral envelope glycoprotein gp120 by cellular oxidoreductases is crucial. The cellular thioredoxin reductase-1 plays an important role in this oxidoreduction process by recycling electrons to thioredoxin-1. Therefore, thioredoxin reductase-1 inhibitors may inhibit gp120 reduction during HIV-1 entry. In this present study, tellurium-based thioredoxin reductase-1 inhibitors were investigated as potential inhibitors of HIV entry. Results The organotellurium compounds inhibited HIV-1 and HIV-2 replication in cell culture at low micromolar concentrations by targeting an early event in the viral infection cycle. Time-of-drug-addition studies pointed to virus entry as the drug target, more specifically: the organotellurium compound TE-2 showed a profile similar or close to that of the fusion inhibitor enfuvirtide (T-20). Surface plasmon resonance-based interaction studies revealed that the compounds do not directly interact with the HIV envelope glycoproteins gp120 and gp41, nor with soluble CD4, but instead, dose-dependently bind to thioredoxin reductase-1. By inhibiting the thioredoxin-1/thioredoxin reductase-1-directed oxidoreduction of gp120, the organotellurium compounds prevent conformational changes in the viral glycoprotein which are necessary during viral entry. Conclusion Our findings revealed that thioredoxin-1/thioredoxin reductase-1 acts as a cellular target for the inhibition of HIV entry.
- Published
- 2016
21. Thioredoxin-1 and protein disulfide isomerase catalyze the reduction of similar disulfides in HIV gp120
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Anna Karlsson, Dominique Schols, Jan Balzarini, Hans Jörnvall, Mathias Lundberg, Katrien O. François, Kathrin Reiser, and Tomas Bergman
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Auranofin ,Protein Conformation ,viruses ,Allosteric regulation ,Protein Disulfide-Isomerases ,HIV Infections ,HIV Envelope Protein gp120 ,Virus Replication ,Antiviral Agents ,Biochemistry ,Mass Spectrometry ,chemistry.chemical_compound ,Thioredoxins ,Protein structure ,Allosteric Regulation ,Viral entry ,Thioredoxin Reductase 1 ,medicine ,Animals ,Humans ,Disulfides ,Protein disulfide-isomerase ,Host cell surface ,Chemistry ,virus diseases ,Cell Biology ,Glutathione ,Virus Internalization ,Rats ,HIV-1 ,Cattle ,Oxidation-Reduction ,medicine.drug - Abstract
HIV-1 enters cells via interaction of the viral glycoprotein gp120, the host cell surface receptor CD4 and the co-receptors CCR5 or CXCR4. For entry, gp120 undergoes conformational changes that depend on the reduction of one or more disulfides. Previous studies indicate that protein disulfide isomerase (PDI), thioredoxin-1 (Trx1), and glutaredoxin-1 (Grx1) catalyze gp120 reduction, but their specific disulfide targets are not known. Here, it was demonstrated that PDI and Trx1 have similar gp120 disulfide targets as determined by labeling after reduction, but with some pattern differences, including overall stronger labeling with Trx1 than with PDI. Furthermore, uneven labeling of the residues of a disulfide may reflect altered accessibility by conformational changes upon the reduction process. Since both PDI and Trx1 may be involved in viral entry, compounds that target the host redox system or the viral gp120 were tested in vitro to investigate whether redox regulation is a target for anti-HIV therapy. Carbohydrate binding agents (CBAs), previously shown to bind gp120 and inhibit HIV entry, were now demonstrated to inhibit gp120 disulfide reduction. Auranofin, an inhibitor of thioredoxin reductase 1 (TrxR1), also showed inhibitory activity towards HIV infection, although close to its cytotoxic concentration. Our results demonstrate that both the host redox system and the viral surface glycoproteins are of interest for the development of new generations of anti-HIV therapeutics.
- Published
- 2012
22. Human glutaredoxin-1 catalyzes the reduction of HIV-1 gp120 and CD4 disulfides and its inhibition reduces HIV-1 replication
- Author
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Magnus Johansson, Jan Balzarini, Johan Söderlund, Mathias Lundberg, Joeri Auwerx, and Ola Isacsson
- Subjects
Polymers ,Protein Disulfide-Isomerases ,Isomerase ,HIV Envelope Protein gp120 ,Virus Replication ,Biochemistry ,Catalysis ,chemistry.chemical_compound ,Naphthalenesulfonates ,Viral entry ,Glutaredoxin ,Animals ,Humans ,Disulfides ,Protein disulfide-isomerase ,Glutaredoxins ,chemistry.chemical_classification ,virus diseases ,Cell Biology ,Glutathione ,Virus Internalization ,Recombinant Proteins ,In vitro ,Enzyme ,chemistry ,CD4 Antigens ,HIV-1 ,Cattle ,Thioredoxin ,Oxidation-Reduction - Abstract
Reduction of intramolecular disulfides in the HIV-1 envelope protein gp120 occurs after its binding to the CD4 receptor. Protein disulfide isomerase (PDI) catalyzes the disulfide reduction in vitro and inhibition of this enzyme blocks viral entry. PDI belongs to the thioredoxin protein superfamily that also includes human glutaredoxin-1 (Grx1). Grx1 is secreted from cells and the protein has also been found within the HIV-1 virion. We show that Grx1 efficiently catalyzes gp120, and CD4 disulfide reduction in vitro, even at low plasma levels of glutathione. Grx1 catalyzes the reduction of two disulfide bridges in gp120 in a similar manner as PDI. Purified anti-Grx1 antibodies were shown to inhibit the Grx1 activity in vitro and block HIV-1 replication in cultured peripheral blood mononuclear cells. Also, the polyanion PRO2000, that was previously shown to prevent HIV entry, inhibits the Grx1- and PDI-dependent reduction of gp120 disulfides. Our findings suggest that Grx1 activity is important for HIV-1 entry and that Grx1 and the gp120 intramolecular disulfides are novel pharmacological targets for rational drug development.
- Published
- 2009
23. Human glutaredoxin 2 affinity tag for recombinant peptide and protein purification
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Mathias Lundberg, Magnus Johansson, and Arne Holmgren
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Tandem affinity purification ,biology ,Recombinant Fusion Proteins ,Genetic Vectors ,Green Fluorescent Proteins ,Protein tag ,beta-Galactosidase ,Fusion protein ,Chromatography, Affinity ,Peptide Fragments ,Gene Expression Regulation ,FLAG-tag ,Affinity chromatography ,Biochemistry ,Protein purification ,biology.protein ,Humans ,Protein G ,Cloning, Molecular ,Oxidoreductases ,Glutaredoxins ,Biotechnology ,Myc-tag - Abstract
Recombinant proteins are commonly expressed in fusion with an affinity tag to facilitate purification. We have in the present study evaluated the possible use of the human glutaredoxin 2 (Grx2) as an affinity tag for purification of heterologous proteins. Grx2 is a glutathione binding protein and we have shown in the present study that the protein can be purified from crude bacterial extracts by a one-step affinity chromatography on glutathione-Sepharose. We further showed that short peptides could be fused to either the N- or C-terminus of Grx2 without affecting its ability to bind to the glutathione column. However, when Grx2 was fused to either the 27 kDa green fluorescent protein or the 116 kDa beta-galactosidase, the fusion proteins lost their ability to bind glutathione-Sepharose. Insertion of linker sequences between the Grx2 and the fusion protein did not restore binding to the column. In summary, our findings suggest that Grx2 may be used as an affinity tag for purification of short peptides and possibly also certain proteins that do not interfere with the binding to glutathione-Sepharose. However, the failure of purifying either green fluorescent protein or beta-galactosidase fused to Grx2 suggests that the use of Grx2 as an affinity tag for recombinant protein purification is limited.
- Published
- 2006
24. Enigma-collaborative Analyses of Neuroimaging eop Data: What have we Achieved?
- Author
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Tobias Edbom, Tiril P. Gurholt, Vera Lonning, Runar Smelror, Mathias Lundberg, and Ingrid Agartz
- Subjects
Psychosis ,medicine.medical_specialty ,Research groups ,medicine.diagnostic_test ,Magnetic resonance imaging ,Right amygdala ,Audiology ,medicine.disease ,Developmental psychology ,Psychiatry and Mental health ,Neuroimaging ,Cohort ,Linear regression ,medicine ,Statistical analysis ,Psychology - Abstract
IntroductionThe ENIGMA-EOP collaboration aims to identify structural phenotypic markers that robustly discriminate adolescents with early-onset psychosis (EOP) from healthy controls through mega- or meta-analysis of magnetic resonance imaging (MR) data. Through larger samples we will obtain sufficient power to detect the brain structural correlates, overcome some of the clinical heterogeneity and characterize the developmental trajectories.MethodsMultiple linear regression was used to investigate structural brain differences in two Scandinavian adolescent EOP cohorts (altogether 50 patients; ages 12.1-18.3 years (mean 16.4 years), 60% female; 68 controls; ages 12.0-18.8 years (mean 16.2 years), 62% female) acquired on two different 3 T GE MRI scanners. The statistical analysis included site as a covariate in addition to age, sex and intracranial volume (ICV). The results are presented by p-values, Cohens's-d effect size and with an indication of directionality. MRI scans were processed following the ENIGMA (http://enigma.ini.usc.edu/) structural image processing protocols using FreeSurfer (Fischl 2012) version 5.3.0 to measure subcortical brain volumes.ResultsPreliminary results show significant or trend-significant group effects on right amygdala (P = 0.001, d = 0.33, patients < controls), total grey matter volume (P = 0.037, d = 0.21, patients < controls), ICV (P = 0.028, d = 0.22, patients < controls) and third ventricle (P = 0.067, d = 0.19, patients > controls). Sub-analyses in the two individual groups show overlapping findings in right amygdala. Previously reported enlarged lateral and 4th ventricles, and caudate, from a similar Scandinavian adolescent EOP cohort (Juuhl-Langseth, 2012) were not replicated.ConclusionThere is a need for larger subject samples in EOP to better capture disease mechanisms. Research groups interested in participating can join ENIGMA-EOP through: http://enigma.ini.usc.edu/ongoing/enigma-eop-working-group/.Disclosure of interestThe authors have not supplied their declaration of competing interest.
- Published
- 2017
25. Crill : A novel technique to characterize nano-ligno-cellulose
- Author
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Per Engstrand, Sinke H. Osong, Peter Hansen, Sven Norgren, and Mathias Lundberg
- Subjects
chemistry.chemical_classification ,Homogenization ,Materials science ,Crill ,Pulp (paper) ,Mechanical pulp fines ,Forestry ,Polymer ,engineering.material ,Chemical Engineering ,Biorefinery ,Pulp and paper industry ,Nanocellulose ,Nano-ligno-cellulose ,chemistry.chemical_compound ,chemistry ,Kraft process ,Kemiteknik ,Nano ,engineering ,Lignin ,General Materials Science ,Fractionation ,Cellulose ,Composite material - Abstract
Almost all research on biorefinery concepts are based on chemical pulping processes and ways of utilising lignin, hemicelluloses and extractives as well as a part of the remaining cellulose for production of nano materials in order to create more valuable products than today. Within the Forest as a Resource (FORE) research program at FSCN we are utilising the whole chain of unit processes from forestry to final products as paper and board, where the pulping process research focus on high yield process as TMP and CTMP. As these process solutions are preserving or only slightly changing the properties of the original wood polymers and extractives, the idea is to find high value adding products designed by nature.From an economic perspective, the production of nanocellulose from a chemical pulp is quite expensive as the pulp has to be either enzymatically (e.g. mono-component endoglucanase) pre-treated or chemically oxidised using the TEMPO (2,2,6,6 - tetramethyl-piperidine-1-oxil) - mediated oxidation method in order to make it possible to disrupt the fibres by means of homogenisation.In high yield pulping processes such as in TMP and CTMP, the idea with this study was to investigate the possibility to use fractions of low quality materials from fines fractions for the production of nano-ligno-cellulose (NLC). The integration of a NLC unit process in a high yield pulping production line has a potential to become a future way to improve the quality level of traditional products such as paper and board grades. The intention of this research work was that, by using this concept, a knowledge base can be created so that it becomes possible to develop a low-cost production method for its implementation.In order to study the potential of this concept, treatment of thermo-mechanical pulp (TMP) fines fractions were studied by means of homogenisation It seems possible to homogenise fine particles of thermo-mechanical pulp (1% w/v) to NLC. A correspond fines fraction from bleached kraft pulp (BKP) was tested as a reference at 0.5% w/v concentration.The objective presented in this work was to develop a methodology for producing mechanical pulp based NLC from fines fractions and to utilise this material as strength additives in paper and board grades. Laboratory sheets of CTMP and BKP, with addition of their respective NLC, were made in a Rapid Kothen sheet former. It was found that handsheets of pulp fibres blended with NLC improved the z-strength and other important mechanical properties for similar sheet densities.The characterisation of the particle size distribution of NLC is both important and challenging and the crill methodology developed at Innventia (former STFI) already during the 1980s was tested to see if it would be both fast and reliable enough. The crill measurement technique is based on the optical responses of a micro/nano particle suspension at two wavelengths of light; UV and IR. The crill value of TMP and CTMP based nano-ligno-cellulose were measured as a function of the homogenisation time. Results showed that the crill value of both TMP-NLC and CTMP-NLC correlated with the homogenisation time.
- Published
- 2014
26. Exendin-4 Protects Neural Progenitor Cells from Glucolipoapoptosis
- Author
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Mohamed Eweida, Cesare Patrone, David Nathanson, Mathias Lundberg, Shiva Mansouri, and Vladimer Darsalia
- Subjects
Agonist ,endocrine system ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Cell growth ,digestive, oral, and skin physiology ,Neurogenesis ,Stimulation ,Neural stem cell ,Endocrinology ,Apoptosis ,Internal medicine ,medicine ,Progenitor cell ,business ,Receptor ,hormones, hormone substitutes, and hormone antagonists - Abstract
Type 2 diabetic and obese patients are under high risk to prematurely develop neurological complications such as stroke and Alzheimer’s disease. Interestingly, type 2-diabetes impairs adult neurogenesis in rodent animal models and this impairment has been suggested to play a role in the brain complications of this disease. Recent work from us and others showed that the treatment with the Glucagon-Like Peptide 1 Receptor (GLP-1R) agonist Exendin-4 stimulates adult neurogenesis in rodents. Based on these findings we have raised the hypothesis that Exendin-4 may counteract the detrimental effects induced by diabetes in neural stem/progenitor cells. The aim of this study was to investigate whether Exendin-4 protect neural progenitor cells from glucolipotoxicity and to analyse if the regulation of apoptosis may be involved in the Exendin-4 protecting effect. Murine neural progenitor cells were exposed to high palmitate and glucose, which characterize diabetic glucolipotoxicity, in presence/absence of Exendin-4. To determine whether neural progenitor cells proliferation was impacted by the Exendin-4 treatment, [3H] thymidine incorporation experiments were also performed. The expression of apoptosis key players, such as cleaved-caspase 3 and Bcl-2, were evaluated by western blotting. We show that Exendin-4 counteracts the impaired neural progenitor cell viability induced by glucolipotoxicity. Cell proliferation was not influenced by the Exendin-4 treatment. The protective effect induced by Exendin-4 correlated with decreased apoptosis. In addition, the Exendin-4 protective effect was completely abolished by using the GLP- 1R antagonist Ex-9-39, indicating that the protective effect by Exendin-4 was GLP-1R-mediated. In conclusion, we show a direct survival effect of GLP-1R activation on neural progenitor cells challenged by diabetic-like conditions. The results support a potential therapeutic role of GLP-1R agonists, based on neurogenesis stimulation, for the treatment of the neurological complications in Type 2-diabetes and obesity.
- Published
- 2014
27. Methodological aspects of ELISA analysis of thioredoxin 1 in human plasma and cerebrospinal fluid
- Author
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Niklas Ahlborg, Irene Areström, Thomas Masterman, Sten Braesch-Andersen, Sophie Curbo, Mathias Lundberg, and Kathrin Reiser
- Subjects
Adult ,Male ,Immunology ,Blotting, Western ,lcsh:Medicine ,Enzyme-Linked Immunosorbent Assay ,medicine.disease_cause ,Biochemistry ,Antibodies ,law.invention ,Cerebrospinal fluid ,Thioredoxins ,law ,Blood plasma ,Medicine and Health Sciences ,Medicine ,Humans ,lcsh:Science ,Multidisciplinary ,Immune System Proteins ,biology ,business.industry ,Immunochemistry ,lcsh:R ,Biology and Life Sciences ,Proteins ,Neurochemistry ,Middle Aged ,Blood proteins ,Recombinant Proteins ,Enzymes ,Blot ,Oxidative Stress ,Neurology ,Human plasma ,Recombinant DNA ,biology.protein ,Enzymology ,Female ,lcsh:Q ,Antibody ,Nervous System Diseases ,business ,Oxidative stress ,Research Article ,Neuroscience - Abstract
Thioredoxin-1 (Trx1) is a protein antioxidant involved in major cellular processes. Increased plasma levels of Trx1 have been associated with human diseases suggesting that Trx1 is a marker for oxidative stress with putative clinical use. However, the reported mean levels of Trx1 in the control cohorts vary a hundred-fold between studies (0.8–87 ng/ml), possibly due to methodological differences between the capture ELISA used in the different studies. The aim of this study was to investigate methodological aspects related to the ELISA measurement of Trx1. ELISAs utilizing different capture and detection combinations of antibodies to Trx1 and as well as recombinant human (rh) Trx1 standards from two sources were characterized. The different ELISAs were subsequently used to measure Trx1 in human plasma and cerebrospinal fluid samples (CSF) from healthy donors and from patients with various neurological diagnoses. The Trx1 standards differed in their content of monomeric and oligomeric Trx1, which affected the ELISAs composed of different antibody combinations. Thus, the levels of Trx1 determined in human plasma and CSF samples varied depending on the antibody used in the ELISAs and on the rhTrx1 standard. Furthermore, the relevance of preventing interference by heterophilic antibodies (HA) in human plasma and CSF was investigated. The addition of a HA blocking buffer to human samples drastically reduced the ELISA signals in many samples showing that HA are likely to cause false positive results unless they are blocked. In conclusion, the study shows that the design of a Trx1 ELISA in regards to antibodies and standards used has an impact on the measured Trx1 levels. Importantly, analyses of human plasma and CSF without preventing HA interference may obscure the obtained data. Overall, the results of this study are crucial for the improvement of future studies on the association of Trx1 levels with various diseases.
- Published
- 2014
28. Cloning and Expression of a Novel Human Glutaredoxin (Grx2) with Mitochondrial and Nuclear Isoforms
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Mathias Lundberg, Mari Enoksson, Magnus Johansson, Catrine Johansson, Arne Holmgren, Gunilla Jacobsson, Joya Chandra, and Johanna Ljung
- Subjects
Gene isoform ,Molecular Sequence Data ,Biology ,Thioredoxin fold ,Biochemistry ,Glutaredoxin ,Humans ,Protein Isoforms ,Amino Acid Sequence ,Cloning, Molecular ,Binding site ,Molecular Biology ,Gene ,Peptide sequence ,Glutaredoxins ,Cell Nucleus ,Glutaredoxin 2 ,Proteins ,Cell Biology ,Molecular biology ,Mitochondria ,Ribonucleotide reductase ,Gene Expression Regulation ,Protein Biosynthesis ,Oxidoreductases ,Sequence Alignment - Abstract
Glutaredoxin (Grx) is a glutathione-dependent hydrogen donor for ribonucleotide reductase. Today glutaredoxins are known as a multifunctional family of GSH-disulfide-oxidoreductases belonging to the thioredoxin fold superfamily. In contrast to Escherichia coli and yeast, a single human glutaredoxin is known. We have identified and cloned a novel 18-kDa human dithiol glutaredoxin, named glutaredoxin-2 (Grx2), which is 34% identical to the previously known cytosolic 12-kDa human Grx1. The human Grx2 sequence contains three characteristic regions of the glutaredoxin family: the dithiol/disulfide active site, CSYC, the GSH binding site, and a hydrophobic surface area. The human Grx2 gene, located at chromosome 1q31.2--31.3, consisted of five exons that were transcribed to a 0.9-kilobase human Grx2 mRNA ubiquitously expressed in several tissues. Two alternatively spliced Grx2 mRNA isoforms that differed in their 5' region were identified. These corresponded to alternative proteins with a common 125-residue C-terminal Grx domain but with different N-terminal extensions of 39 and 40 residues, respectively. The 125-residue Grx domain and the two full-length variants were expressed in E. coli and exhibited GSH-dependent hydroxyethyl disulfide and dehydroascorbate reducing activities. Western blot analysis of subcellular fractions from Jurkat cells with a specific anti-Grx2 antibody showed that human Grx2 was predominantly located in the nucleus but also present in the mitochondria. We further showed that one of the mRNA isoforms corresponding to Grx2a encoded a functional N-terminal mitochondrial translocation signal.
- Published
- 2001
29. Pituitary Adenlylate Cyclase Activating Peptide Protects Adult Neural Stem Cells from a Hypoglycaemic milieu
- Author
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Grazyna Lietzau, Thomas Nyström, David Nathanson, Mathias Lundberg, Cesare Patrone, and Shiva Mansouri
- Subjects
Male ,0301 basic medicine ,Critical Care and Emergency Medicine ,endocrine system diseases ,Gene Expression ,lcsh:Medicine ,Apoptosis ,Hippocampus ,Endocrinology ,0302 clinical medicine ,Neural Stem Cells ,Hippocampal Neurogenesis ,Medicine and Health Sciences ,Brain Damage ,lcsh:Science ,Receptor ,Trauma Medicine ,Cells, Cultured ,Cognitive Impairment ,Multidisciplinary ,Cell Death ,Organic Compounds ,Cognitive Neurology ,Caspase 3 ,Reverse Transcriptase Polymerase Chain Reaction ,Monosaccharides ,Neurogenesis ,Brain ,Endoplasmic Reticulum Stress ,Neural stem cell ,Chemistry ,Neurology ,Cell Processes ,Physical Sciences ,Pituitary Adenylate Cyclase-Activating Polypeptide ,Anatomy ,medicine.symptom ,hormones, hormone substitutes, and hormone antagonists ,Research Article ,Agonist ,medicine.medical_specialty ,Endocrine Disorders ,Cell Survival ,medicine.drug_class ,Cognitive Neuroscience ,Blotting, Western ,Carbohydrates ,Brain damage ,Biology ,Protective Agents ,03 medical and health sciences ,Developmental Neuroscience ,Internal medicine ,Diabetes Mellitus ,medicine ,Animals ,Hypoglycemic Agents ,RNA, Messenger ,Venoms ,Endoplasmic reticulum ,Organic Chemistry ,lcsh:R ,Chemical Compounds ,Adult Neurogenesis ,Biology and Life Sciences ,Cell Biology ,Mice, Inbred C57BL ,Glucose ,030104 developmental biology ,Cellular Neuroscience ,Metabolic Disorders ,Cognitive Science ,Exenatide ,lcsh:Q ,Peptides ,Transcription Factor CHOP ,030217 neurology & neurosurgery ,Neuroscience ,Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - Abstract
Hypoglycaemia is a common side-effect of glucose-lowering therapies for type-2 diabetic patients, which may cause cognitive/neurological impairment. Although the effects of hypoglycaemia in the brain have been extensively studied in neurons, how hypoglycaemia impacts the viability of adult neural stem cells (NSCs) has been poorly investigated. In addition, the cellular and molecular mechanisms of how hypoglycaemia regulates NSCs survival have not been characterized. Recent work others and us have shown that the pituitary adenylate cyclase-activating polypeptide (PACAP) and the glucagon-like peptide-1 receptor (GLP-1R) agonist Exendin-4 stimulate NSCs survival against glucolipoapoptosis. The aim of this study was to establish an in vitro system where to study the effects of hypoglycaemia on NSC survival. Furthermore, we determine the potential role of PACAP and Exendin-4 in counteracting the effect of hypoglycaemia. A hypoglycaemic in vitro milieu was mimicked by exposing subventricular zone-derived NSC to low levels of glucose. Moreover, we studied the potential involvement of apoptosis and endoplasmic reticulum stress by quantifying protein levels of Bcl-2, cleaved caspase-3 and mRNA levels of CHOP. We show that PACAP via PAC-1 receptor and PKA activation counteracts impaired NSC viability induced by hypoglycaemia. The protective effect induced by PACAP correlated with endoplasmic reticulum stress, Exendin-4 was ineffective. The results show that hypoglycaemia decreases NSC viability and that this effect can be substantially counteracted by PACAP via PAC-1 receptor activation. The data supports a potential therapeutic role of PAC-1 receptor agonists for the treatment of neurological complications, based on neurogenesis impairment by hypoglycaemia.
- Published
- 2016
30. Increased plasma levels of thioredoxin-1 in patients with first episode psychosis and long-term schizophrenia
- Author
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Urban Ösby, Karin Ekdahl, Tobias Edbom, Christer Lundberg, Mathias Lundberg, Håkan Karlsson, and Björn Owe-Larsson
- Subjects
Adult ,Male ,medicine.medical_specialty ,Psychosis ,Adolescent ,Population ,Enzyme-Linked Immunosorbent Assay ,medicine.disease_cause ,Young Adult ,Thioredoxins ,Internal medicine ,Schizophrenic Psychology ,medicine ,Humans ,Young adult ,Psychiatry ,education ,Biological Psychiatry ,Aged ,Pharmacology ,First episode ,education.field_of_study ,Middle Aged ,medicine.disease ,Diagnostic and Statistical Manual of Mental Disorders ,Schizophrenia ,Chronic Disease ,Biomarker (medicine) ,Female ,Psychology ,Oxidation-Reduction ,Oxidative stress ,Biomarkers - Abstract
Excessive level of radicals and/or dysfunctional antioxidant response, oxidative stress, is implicated in the pathogenesis of schizophrenia. A condition of oxidative stress has been detected in the brain, peripheral tissues and fluids including plasma. Plasma thioredoxin-1 (Trx1) is well characterized and a putative marker for oxidative stress and recently shown to be increased in plasma at the onset of schizophrenia. The present study aimed to explore whether Trx1 can be used as a marker to identify schizophrenic patients at the time-point when patients have their first episode of psychosis as compared to patients with long-term schizophrenia and mentally healthy patients, respectively. Plasma samples obtained from 18 patients at first episode of psychosis, from 49 long-term schizophrenic patients and from 20 mentally healthy controls (admitted with minor physical injury to the general ward) where analyzed by ELISA for Trx1. The patients with first episode of psychosis were diagnosed at least 6 months later and shown to constitute various psychotic syndromes, including schizophrenia, or affective disorder. The concentration of Trx1 in the patients with first episode of psychosis was 1.5 ± 1.0 ng/ml and 0.8 ± 0.6 ng/ml in controls. In the long-term schizophrenic patients the plasma concentration was 1.5 ± 0.7. The differences between the groups of acute psychotic or long-term schizophrenia patients to controls were significant (p < 0.016 and p < 0.001, respectively). Our data indicate that Trx1 may not be used as an early marker to identify schizophrenic patients in a mixed population of first episode psychotic patients. Further, Trx1 did not discriminate with reliable accuracy patients with psychotic disorder from mentally healthy controls on an individual basis due to overlap in levels of Trx1. However, our observations show that psychotic patients in general are in a significant long-term condition of oxidative stress, with possible implications for the profound morbidity and mortality found in this patient population.
- Published
- 2010
31. Regulation of interleukin-4 signaling by extracellular reduction of intramolecular disulfides
- Author
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Raphael Gaudin, Karl-Johan Malmberg, Marita Troye-Blomberg, Anna Karlsson, Mathias Lundberg, Mattias Carlsten, Niklas Ahlborg, Magnus Johansson, Sophie Curbo, Karolinska Institutet, Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska University Hospital [Stockholm], Stockholm University, Department of Rheumatology & Inflammation Research, University of Gothenburg (GU), and From the Department of Laboratory Medicine
- Subjects
Auranofin ,Thioredoxin reductase ,[SDV]Life Sciences [q-bio] ,Protein Disulfide-Isomerases ,Biophysics ,Biochemistry ,HeLa ,03 medical and health sciences ,Thioredoxins ,0302 clinical medicine ,Extracellular ,medicine ,Humans ,Protein disulfide-isomerase ,Molecular Biology ,Interleukin 4 ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Interleukin-4 Receptor alpha Subunit ,Cell Biology ,biology.organism_classification ,Ethylmaleimide ,030220 oncology & carcinogenesis ,Cystine ,Interleukin-4 ,Thioredoxin ,Signal transduction ,Oxidation-Reduction ,HeLa Cells ,Signal Transduction ,medicine.drug - Abstract
Interleukin-4 (IL-4) contains three structurally important intramolecular disulfides that are required for the bioactivity of the cytokine. We show that the cell surface of HeLa cells and endotoxin-activated monocytes can reduce IL-4 intramolecular disulfides in the extracellular space and inhibit binding of IL-4 to the IL-4Ralpha receptor. IL-4 disulfides were in vitro reduced by thioredoxin 1 (Trx1) and protein disulfide isomerase (PDI). Reduction of IL-4 disulfides by the cell surface of HeLa cells was inhibited by auranofin, an inhibitor of thioredoxin reductase that is an electron donor to both Trx1 and PDI. Both Trx1 and PDI have been shown to be located at the cell surface and our data suggests that these enzymes are involved in catalyzing reduction of IL-4 disulfides. The pro-drug N-acetylcysteine (NAC) that promotes T-helper type 1 responses was also shown to mediate the reduction of IL-4 disulfides. Our data provides evidence for a novel redox dependent pathway for regulation of cytokine activity by extracellular reduction of intramolecular disulfides at the cell surface by members of the thioredoxin enzyme family.
- Published
- 2009
32. Cellular and plasma levels of human glutaredoxin 1 and 2 detected by sensitive ELISA systems
- Author
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Arne Holmgren, Sushil Kumar, Mathias Lundberg, and Aristi P. Fernandes
- Subjects
Gene isoform ,Placenta ,Biophysics ,Enzyme-Linked Immunosorbent Assay ,Biology ,Biochemistry ,Peripheral blood mononuclear cell ,Cell Line ,chemistry.chemical_compound ,Thioredoxins ,Glutaredoxin ,Extracellular ,medicine ,Humans ,Protein Isoforms ,Secretion ,Molecular Biology ,Glutaredoxins ,Tissue Extracts ,Dithiol ,Membrane Proteins ,Cell Biology ,Reference Standards ,Molecular biology ,Recombinant Proteins ,medicine.anatomical_structure ,chemistry ,Cytoplasm ,Leukocytes, Mononuclear ,Tetradecanoylphorbol Acetate ,Oxidoreductases - Abstract
Glutaredoxins (Grx) catalyze glutathione-dependent thiol-disulfide oxidoreduction reactions. Mammalian cells contain at least two dithiol glutaredoxins, the well-characterized cytoplasmic (12 kDa) Grx1 and the recently identified (18 kDa) Grx2 with mitochondrial and nuclear isoforms. We have developed two sensitive and specific sandwich ELISAs to study the levels of human Grx1 and Grx2. Both Grx1 and Grx2 were present in placenta extracts and in cell lysates prepared from various tumor cell lines. However, the levels of Grx1 were at least 20 times higher than those of Grx2. Plasma from healthy blood donors contained 13.4 ± 7.9 ng/ml of Grx1, while Grx2 was not detected. Unstimulated peripheral blood mononuclear cells were shown to secrete Grx1, but upon 12-O-tetradecanoylphorbol-13-acetate activation, the secretion of Grx1 was strongly suppressed. This effect was shown to occur at the transcriptional level. The secretion of Grx1 and its presence in plasma suggests extracellular functions as found for mammalian thioredoxin 1.
- Published
- 2004
33. Lipid-mediated protein delivery of suicide nucleoside kinases
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Xinyu, Zheng, Mathias, Lundberg, Anna, Karlsson, and Magnus, Johansson
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Osteosarcoma ,Phosphatidylethanolamines ,Bone Neoplasms ,CHO Cells ,Herpesvirus 1, Human ,Thymidine Kinase ,Endocytosis ,Recombinant Proteins ,Phosphotransferases (Alcohol Group Acceptor) ,Drosophila melanogaster ,Bromodeoxyuridine ,Cell Line, Tumor ,Cricetinae ,Liposomes ,Animals ,Humans ,Arabinonucleosides ,Ganciclovir ,Thymidine - Abstract
Nucleoside kinases from several species are investigated as suicide genes for treatment of malignant tumors by combined gene/chemotherapy. In the present study, we have investigated a novel strategy where nucleoside kinase proteins are directly delivered to cells without delivery of genetic material. We used a mix of a trifluoroacetylated lipopolyamine and dioleoyl phosphatidylethanolamine (BioPorter) to form protein-lipid complexes containing either recombinant herpes simplex virus type-1 thymidine kinase or Drosophila melanogaster multisubstrate deoxyribonucleoside kinase. We showed that the nucleoside kinase containing protein-lipid complexes was imported into human osteosarcoma and Chinese hamster ovary cell lines by endocytosis and that the enzymes were delivered to the cytosol and nucleus. The nucleoside kinases imported into the cell lines retained enzymatic activity, and the cells treated with the enzyme-lipid complexes showed increased sensitivity to nucleoside analogues, such as ganciclovir, (E)-5-(2-bromovinyl)-2'-deoxyuridine, and 1-beta-D-arabinofuranosylthymine. Our results show that direct delivery of suicide gene proteins to cells may be an alternative approach to conventional suicide gene therapy strategies.
- Published
- 2003
34. Cell surface adherence and endocytosis of protein transduction domains
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Sara Wikström, Mathias Lundberg, and Magnus Johansson
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Endosome ,media_common.quotation_subject ,Recombinant Fusion Proteins ,Green Fluorescent Proteins ,CHO Cells ,Cell Separation ,Biology ,Endocytosis ,Cytosol ,Cricetinae ,Drug Discovery ,Genetics ,Cell Adhesion ,Animals ,Cell adhesion ,Internalization ,Molecular Biology ,media_common ,Pharmacology ,Cell Nucleus ,Viral Structural Proteins ,Cell Membrane ,Receptor-mediated endocytosis ,Flow Cytometry ,Fusion protein ,Cell biology ,Transport protein ,Protein Structure, Tertiary ,Luminescent Proteins ,Protein Transport ,Molecular Medicine ,Peptides - Abstract
Protein transduction domains (PTD), such as the HIV TAT and the herpes simplex virus VP22 proteins, are reported to translocate across the membranes of mammalian cells. The mechanism of PTD membrane translocation has largely remained elusive, but recent studies suggest that the reported PTD translocation is due to a fixation artifact. We have constructed and expressed the PTDs VP22, TAT, polyarginine, and polylysine fused to the green fluorescent protein to visualize these proteins in both living and fixed cells. The investigated PTDs strongly adhered to the surface of living cells and were internalized by constitutive endocytosis. No cytosolic or nuclear import of the proteins was detected. In contrast, the PTD-GFP fusion proteins were redistributed to the cytosol and nucleus directly after fixation. Our findings suggest that the PTDs only mediate cell surface adherence, a property shared with many other positively charged macromolecules. The cell surface adherence results in endocytosis and accumulation of proteins in endosomes. We suggest that the biological effects observed for PTD fusion proteins are due to cell surface interactions and internalization of the proteins into cells by classical endocytosis.
- Published
- 2003
35. Visualization of the compartmentalization of glutathione and protein-glutathione mixed disulfides in cultured cells
- Author
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Ian A. Cotgreave, Sten Orrenius, George Bolcsfoldi, Therese Söderdahl, Ole Petter Ottersen, Mathias Lundberg, Mari Enoksson, and Arne Holmgren
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Population ,Biology ,Biochemistry ,Models, Biological ,Cell Line ,chemistry.chemical_compound ,Genetics ,Animals ,Buthionine sulfoximine ,Propidium iodide ,education ,Molecular Biology ,Cells, Cultured ,A549 cell ,Diamide ,education.field_of_study ,Microscopy, Confocal ,Glutathione Disulfide ,Cell Cycle ,Proteins ,Glutathione ,Flow Cytometry ,Molecular biology ,Staining ,Cell Compartmentation ,Mitochondria ,Cytosol ,Oxidative Stress ,chemistry ,Glutathione disulfide ,Biotechnology - Abstract
Fluorescence microscopy of A549 cells stained with a glutathione (L-gamma-glutamyl-L-cysteinylglycine, GSH)-specific polyclonal antibody displayed uniform staining of the peri-nuclear cytosol, with the nuclear region apparently lacking GSH staining. This discontinuous staining was confirmed in other cell types and also corroborated in A549 cells stained with the thiol-reactive dye mercury orange. The selectivity of antibody binding was confirmed by buthionine sulfoximine (BSO)-dependent inhibition of GSH synthesis. However, confocal visualization of antibody-stained A549 cells in the z-plane revealed the majority of the peri-nuclear staining intensity in the upper half of the cell to be associated with mitochondria, as confirmed by double staining for cytochrome oxidase. Integration of the confocal signals from the nuclear and cytosolic regions halfway down the z-plane showed that the GSH concentrations of these compartments are close to equilibrium. Confirmation of the relatively high levels of mitochondrial glutathione was provided in cells treated with BSO and visualized in z-section, revealing the mitochondrial GSH content of these cells to be well preserved in apposition to near-complete depletion of cytosolic/nuclear GSH. Localized gradients within the cytosolic compartment were also visible, particularly in the z-plane. The antibody also provided initial visualization of the compartmentalization of protein-GSH mixed disulfides formed in A549 cells exposed to diamide. Discontinuous staining was again evident, with heavy staining in membrane blebs and in the nuclear region. Using FACS analysis of anti-GSH antibody-stained Jurkat T lymphocytes, we also demonstrated population variations in the cellular compliment of GSH and protein-GSH mixed disulfides, formed in response to diamide. In addition, we showed cell-cycle variation in GSH content of the cells, with the highest levels of GSH associated with the G2/M mitotic phase of the cell cycle, using double staining with propidium iodide. Similar FACS analyses performed in isolated mitochondria presented a considerable variation in GSH content within mitochondria of uniform granularity from the same preparation.
- Published
- 2002
36. Positively charged DNA-binding proteins cause apparent cell membrane translocation
- Author
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Magnus Johansson and Mathias Lundberg
- Subjects
Vesicle-associated membrane protein 8 ,Tissue Fixation ,Recombinant Fusion Proteins ,Cell ,Green Fluorescent Proteins ,Biophysics ,Active Transport, Cell Nucleus ,CHO Cells ,Biology ,Biochemistry ,Cell membrane ,Histones ,Fixatives ,Histone H1 ,Cricetinae ,medicine ,Animals ,Molecular Biology ,Integral membrane protein ,Cell Nucleus ,Viral Structural Proteins ,Methanol ,Peripheral membrane protein ,Cell Membrane ,Cell Biology ,Cell biology ,DNA-Binding Proteins ,Cell nucleus ,Luminescent Proteins ,medicine.anatomical_structure ,Membrane protein ,Microscopy, Fluorescence ,Artifacts - Abstract
Several positively charged DNA-binding proteins such as the human immunodeficiency virus Tat protein, the Antennapedia (Antp) homeobox protein, and the herpes simplex virus VP22 protein have been reported to translocate across cell membranes and accumulate in cell nuclei. The import occurs by a poorly understood mechanism that appears to be receptor- and energy-independent. We showed that both VP22 and the positively charged histone H1 adhered to the cell membrane of living cells and were not removed by extensive washing. However, after fixation the proteins relocated to the cell nucleus. The nuclear accumulation of VP22 and histone H1 after fixation shows that positively charged proteins may appear to translocate across the cell membrane because of a fixation artifact. The majority of studies on "membrane permeable" proteins and peptides have been performed using fixation techniques, and our study shows that influx of these proteins may occur during fixation rather than in living cells.
- Published
- 2002
37. Is VP22 nuclear homing an artifact?
- Author
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Mathias Lundberg and Magnus Johansson
- Subjects
Viral Structural Proteins ,Time Factors ,Chemistry ,Recombinant Fusion Proteins ,Green Fluorescent Proteins ,Biomedical Engineering ,Active Transport, Cell Nucleus ,Temperature ,Bioengineering ,CHO Cells ,Applied Microbiology and Biotechnology ,Recombinant Proteins ,Cell biology ,Protein Structure, Tertiary ,Cell nucleus ,Luminescent Proteins ,medicine.anatomical_structure ,Cricetinae ,medicine ,Escherichia coli ,Molecular Medicine ,Animals ,Biotechnology ,Homing (hematopoietic) - Published
- 2001
38. Thiols decrease cytokine levels and down-regulate the expression of CD30 on human allergen-specific T helper (Th) 0 and Th2 cells
- Author
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G. Jacobsson, Mathias Lundberg, Arne Holmgren, Annika Scheynius, Å. Bengtsson, and Javier Avila-Cariño
- Subjects
Chronic bronchitis ,Allergy ,medicine.medical_treatment ,T cell ,Immunology ,Down-Regulation ,Ki-1 Antigen ,Biology ,Dermatitis, Atopic ,chemistry.chemical_compound ,Th2 Cells ,medicine ,Immunology and Allergy ,Humans ,Sulfhydryl Compounds ,Receptor ,Interleukin 4 ,CD40 ,Dose-Response Relationship, Drug ,CD28 ,Glutathione ,T-Lymphocytes, Helper-Inducer ,Acetylcysteine ,Clone Cells ,Cytokine ,medicine.anatomical_structure ,chemistry ,biology.protein ,Cytokines ,Interleukin-4 - Abstract
SummaryThe thiol antioxidant N-acetyl- l-cysteine (NAC), known as a precursor of glutathione (GSH), is used in AIDS treatment trials, as a chemoprotectant in cancer chemotherapy and in treatment of chronic bronchitis. In vitro, GSH and NAC are known to enhance T cell proliferation, production of IL-2 and up-regulation of the IL-2 receptor. The 120-kD CD30 surface antigen belongs to the tumour necrosis factor (TNF) receptor superfamily. It is expressed by activated T helper (Th) cells and its expression is sustained in Th2 cells. We have analysed the effect of GSH and NAC on the cytokine profile and CD30 expression on human allergen-specific T cell clones (TCC). TCC were stimulated with anti-CD3 antibodies in the presence of different concentrations of GSH and NAC. Both thiols caused a dose dependent down-regulation of IL-4, IL-5 and IFN-γ levels in Th0 and Th2 clones, with the most pronounced decrease of IL-4. Furthermore, they down-regulated the surface expression of CD30, and the levels of soluble CD30 (sCD30) in the culture supernatants were decreased. In contrast, the surface expression of CD28 or CD40 ligand (CD40L) was not significantly changed after treatment with 20 m m NAC. These results indicate that GSH and NAC favour a Th1 response by a preferential down-regulation of IL-4. In addition, the expression of CD30 was down regulated by GSH and NAC, suggesting that CD30 expression is dependent on IL-4, or modified by NAC. In the likely event that CD30 and its soluble counterpart prove to contribute to the pathogenesis in Th2 related diseases such as allergy, NAC may be considered as a future therapeutic agent in the treatment of these diseases.
- Published
- 2001
39. FC08-06 - Distress or depression? does socioeconomic position matter?
- Author
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Christina Dalman, Mathias Lundberg, Johan Hallqvist, Cecilia Magnusson, Kyriaki Kosidou, and Göran Isacsson
- Subjects
Psychiatry and Mental health ,education.field_of_study ,Distress ,Socioeconomic position ,Population ,Household income ,General Health Questionnaire ,Family income ,Psychology ,education ,Socioeconomic status ,Depression (differential diagnoses) ,Clinical psychology - Abstract
IntroductionIt is not well known whether the association between common mental disorders and low socioeconomic status vary with symptom severity, type of socioeconomic indicator or gender.ObjectivesTo study the association between socioeconomic status and risk for different severity levels of psychological distress as well as depression.MethodsA population-based survey was conducted among a random sample of Stockholm County residents aged 18–84 years in 2002, and respondents were reassessed via a follow-up questionnaire in 2007. Participants in both surveys (n = 23 794) were categorized according to socioeconomic status at baseline and followed up for onset of psychological distress (according to the twelve-item general health questionnaire) and depression (according to health data registers).ResultsOccupational class had little impact on risk for distress regardless of severity or gender, but was strongly associated with onset of depression - albeit only in men (ORs being 3.0 [95% CI 1.5–5.9] in men and 1.1 [95% CI (0.7–1.7]) in women, comparing unskilled manual workers with higher non-manual workers). Income was associated with risk for onset of all outcomes and the association grew stronger with symptom severity. High household income was particularly protective of depression in women. Education was unrelated to either outcome in men and women overall.ConclusionsWhile psychological distress appears to occur at a similar rate regardless of socioeconomic position, risks for severe distress and especially clinically overt depression are markedly linked with occupational class in men and with family income in women. The socioeconomic gradient in common mental disorders increases with symptom severity.
- Published
- 2011
40. Qualitative evaluation of microfibrillated cellulose using the crill method and some aspects of microscopy
- Author
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Mathias Lundberg, Mehedi Reza, Sinke H. Osong, Per Engstrand, Vuorinen Tapani, Sven Norgren, Mid Sweden University, PulpEye AB, Department of Applied Physics, Department of Forest Products Technology, Aalto-yliopisto, and Aalto University
- Subjects
0106 biological sciences ,Materials science ,Crill ,Polymers and Plastics ,Scanning electron microscope ,02 engineering and technology ,engineering.material ,01 natural sciences ,Nanocellulose ,chemistry.chemical_compound ,010608 biotechnology ,Teknik och teknologier ,Microscopy ,Cellulose ,Composite material ,Hydrogen peroxide ,Pulp (paper) ,021001 nanoscience & nanotechnology ,chemistry ,Chemical engineering ,Microfibrillated cellulose ,Transmission electron microscopy ,SEM ,engineering ,Engineering and Technology ,Particle size ,0210 nano-technology ,TEMPO - Abstract
It has been a challenge to develop rapid online characterisation techniques for nanocellulose given the fibrillar structure of the nanoparticles. The crill optical analyser uses optical response signals in the infrared (IR) and ultraviolet (UV) wavelength ranges to evaluate the particle size properties of micro/nanofibrillar cellulosic materials. In this work, the crill analyser was used to measure the projected areas of UV and IR light sources by measuring the light blocked by nanocellulosic particles. This work uses the crill methodology as a new, simplified technique to characterise the particle size distribution of nanocellulosic material based on chemi-thermomechanical pulp (CTMP), thermomechanical pulp (TMP), and sulphite pulp (SP). In the first part, hydrogen peroxide pretreatment of CTMP and TMP in a wing mill refiner followed by high-pressure homogenisation to produce microfibrillated cellulose (MFC) was evaluated using the crill method. In the second part, TEMPO oxidation of CTMP and SP combined with high-shear homogenisation to produce MFC was studied using the crill method. With 4 % hydrogen peroxide pretreatment, the crill values of the unhomogenised samples were 218 and 214 for the TMP and CTMP, respectively, improving to 234 and 229 after 18 homogenisation passes. The results of the TEMPO method indicated that, for the 5 mmol NaClO SP-MFC, the crill value was 108 units at 0 min and 355 units after 90 min of treatment, a 228 % improvement. The CTMP and TMP fibres and the MFC were freeze dried and fibrillar structure of the fibres and microfibrils was visualised using scanning electron and transmission electron microscopy.
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41. The expression of glutaredoxin is increased in the human cervix in term pregnancy and immediately post-partum, particularly after prostaglandin-induced delivery
- Author
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Hong Wang, Ylva Vladic Stjernholm, Arne Holmgren, Lena Sahlin, Håkan Eriksson, Mathias Lundberg, and G. Ekman
- Subjects
Adult ,Embryology ,medicine.medical_specialty ,medicine.medical_treatment ,Uterus ,Prostaglandin ,Gene Expression ,Cervix Uteri ,Biology ,Dinoprostone ,chemistry.chemical_compound ,Pregnancy ,Glutaredoxin ,Internal medicine ,Genetics ,medicine ,Humans ,Labor, Induced ,RNA, Messenger ,Molecular Biology ,Cervix ,Glutaredoxins ,Labor, Obstetric ,Abortifacient Agents, Steroidal ,Obstetrics and Gynecology ,Proteins ,Cell Biology ,Middle Aged ,Delivery, Obstetric ,Mifepristone ,medicine.anatomical_structure ,Endocrinology ,Reproductive Medicine ,chemistry ,In utero ,Protein Biosynthesis ,Solution hybridization ,Female ,Thioredoxin ,Oxidoreductases ,Developmental Biology ,Prostaglandin E - Abstract
Glutaredoxins are glutathione disulphide oxidoreductases catalysing disulphide reductions via a redox active disulphide. We have examined the presence of glutaredoxin in the human cervix, and its differential expression during cervical remodelling in term pregnancy and immediately post-partum as compared to the non-pregnant state. Cervical biopsies were obtained from 24 term-pregnant and 24 post-partal women, of which 10 were taken after spontaneous delivery, 10 after prostaglandin-induced delivery and four after mifepristone-induced delivery, all obtained within 15 min after delivery. Six non-pregnant women served as controls. The tissues were analysed for the glutaredoxin mRNA levels using a solution hybridization method. Glutaredoxin mRNA was expressed in the human cervix, the level increased > or =2-fold at term pregnancy and immediately post-partum. The level of cervical glutaredoxin mRNA from prostaglandin E(2)-treated women was 3-fold higher than after spontaneous ripening and delivery. Localization of glutaredoxin was visualized with immunohistochemistry in cervices from two post-partal women, and was compared to that of thioredoxin. We conclude that glutaredoxin may be involved in the regulation of cervical ripening in humans, particularly in the inflammatory reaction seen during this process. Glutaredoxin mRNA levels are up-regulated after prostaglandin treatment, which is effective and the most commonly used substance for cervical priming and induction of labour.
42. Glutathionylation of beta-actin via a cysteinyl sulfenic acid intermediary
- Author
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Mathias Lundberg and Magnus Johansson
- Subjects
Arsenites ,lcsh:Animal biochemistry ,Enzyme-Linked Immunosorbent Assay ,macromolecular substances ,medicine.disease_cause ,Biochemistry ,Sulfenic Acids ,lcsh:Biochemistry ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Protein Isoforms ,Beta-actin ,lcsh:QD415-436 ,Cysteine ,Cytoskeleton ,lcsh:QP501-801 ,Molecular Biology ,Actin ,Glutathione Disulfide ,Antibodies, Monoclonal ,Glutathione ,Actins ,chemistry ,Glutathione disulfide ,Sulfenic acid ,Rabbits ,Oxidation-Reduction ,Protein Processing, Post-Translational ,Oxidative stress ,Research Article - Abstract
Background Cysteinyl residues in actin are glutathionylated, ie. form a mixed disulfide with glutathione, even in the absence of exogenous oxidative stress. Glutathionylation inhibits actin polymerization and reversible actin glutathionylation is a redox dependent mechanism for regulation of the cytoskeleton structure. The molecular mechanism that mediates actin glutathionylation in vivo is unclear. Results We have studied glutathionylation of α- and β-actin in vitro using an enzyme-linked immunosorbant assay with a monoclonal anti-glutathione antibody. α- and β-actin were both glutathionylated when incubated with reduced glutathione (GSH) combined with diamide as a thiol oxidant. However, β-actin was also glutathionylated by both glutathione disulfide (GSSG) and GSH in the absence of diamide whereas α-actin was poorly glutathionylated by GSH or GSSG. Glutathionylation of β-actin by GSSG is likely to be mediated by a thiol-exchange mechanism whereas glutathionylation by GSH requires thiol oxidation. β-actin glutathionylation by GSH was inhibited by arsenite and dimedone suggesting that the mechanism involved formation of a cysteinyl sulfenic acid residue in β-actin. Conclusion We conclude that glutathionylation of β-actin may occur via spontaneous oxidation of a cysteinyl residue to a sulfenic acid that readily reacts with GSH to form a mixed disulfide. We also show that the reactivity and oxidation to a reactive protein thiol intermediary differ between different actin isoforms.
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