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Publications (10 of 81) Show all publications
Ahmed, A. S., Gedin, P., Hugo, A., Bakalkin, G., Kanar, A., Hart, D. A., . . . Kosek, E. (2018). Activation of NF-kappa B in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis: A Potential Contributor to Inflammatory Aspects of Disease Progression. Journal of Immunology, 201(7), 1918-1927
Open this publication in new window or tab >>Activation of NF-kappa B in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis: A Potential Contributor to Inflammatory Aspects of Disease Progression
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2018 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 201, no 7, p. 1918-1927Article in journal (Refereed) Published
Abstract [en]

The aim was to assess the activation and association of the NF-kappa B system across synovial membrane (SM) and articular cartilage (AC) in patients with knee osteoarthritis (OA) and ascertain its potential effects on catabolic mediator expression in advanced OA. SM and AC were obtained from 40 OA patients undergoing total knee arthroplasty and from 19 postmortem control subjects. NF-kappa B subunit RelA in nuclear and cytosolic fractions and NF-kappa B1-DNA binding in nuclear extracts was assessed by ELISA, whereas NFKB1, RELA, IL-8, IL-6, and MMP3 gene expression were analyzed by reverse transcriptase-quantitative PCR in tissues. We observed higher SM nuclear RelA protein levels and upregulated NF-kappa B1-DNA binding in OA patients compared with postmortem controls. However, in AC, lower nuclear RelA levels were observed compared with cytosolic extracts in patients. Nuclear RelA levels correlated positively with NF-kappa B1-DNA binding in SM and AC in patients. SM RELA and MMP3 mRNA levels were upregulated, whereas IL-8 and IL-6 as well as AC RELA were downregulated in patients compared with controls. In SM, nuclear RelA levels correlated positively with MMP3 gene expression in patients. A negative correlation was observed between SM nuclear RelA levels and AC NF-kappa B1-DNA binding, and SM nuclear NF-kappa B1-DNA binding correlated negatively with AC MMP3 and NFKB1 mRNA levels in patients. These findings highlight NF-kappa B-triggered cross-talk and feedback mechanisms between SM and AC in OA. Further, our findings strongly support a role for an activated NF-kappa B system in the transcriptional mechanism of inflammatory processes, especially in SM of patients with advanced OA.

Place, publisher, year, edition, pages
AMER ASSOC IMMUNOLOGISTS, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-366723 (URN)10.4049/jimmunol.1800486 (DOI)000444804300013 ()30135182 (PubMedID)
Funder
Swedish Research Council, K2013-52X-22199-01-3Swedish Research Council, 542-2013-8373Swedish Rheumatism Association
Available from: 2018-12-13 Created: 2018-12-13 Last updated: 2018-12-13Bibliographically approved
Watanabe, H., Zhang, M., Sarkisyan, D., Kononenko, O., Clausen, F., Iakovleva, T., . . . Bakalkin, G. (2018). Asymmetric Hindlimb Motor Response To Focal Traumatic Brain Injury Is Controlled By Side-Specific Opioid Mechanism. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A79-A79
Open this publication in new window or tab >>Asymmetric Hindlimb Motor Response To Focal Traumatic Brain Injury Is Controlled By Side-Specific Opioid Mechanism
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A79-A79Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Therapeutics / Drug Discovery, Rehabilitation, Receptor Mediated / Signaling, Neuropathology
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-363881 (URN)000441527400221 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Zhang, M., Watanabe, H., Sarkisyan, D., Thelin, J., Schouenborg, J. & Bakalkin, G. (2018). ASYMMETRIC HINDLIMB POSTURE AND WITHDRAW REFLEXES INDUCED BY UNILATERAL BRAIN INJURY ARE ENCODED IN SPINAL CORD. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A208-A208
Open this publication in new window or tab >>ASYMMETRIC HINDLIMB POSTURE AND WITHDRAW REFLEXES INDUCED BY UNILATERAL BRAIN INJURY ARE ENCODED IN SPINAL CORD
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A208-A208Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Rehabilitation, Electophysiology, Neuropathology
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-363882 (URN)000441527400561 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Lukoyanov, N., Carvalho, L., Watanabe, H., Zhang, M., Sarkisyan, D., Kononenko, O., . . . Bakalkin, G. (2018). Contralesional Hindlimb Motor Response Induced By Unilateral Brain Injury: Evidence For Extra Spinal Mechanism. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A201-A201
Open this publication in new window or tab >>Contralesional Hindlimb Motor Response Induced By Unilateral Brain Injury: Evidence For Extra Spinal Mechanism
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A201-A201Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Gene Expression, Neurotransmitter, Rehabilitation, Electophysiology, Endocrine
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-363878 (URN)000441527400543 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2018-11-14Bibliographically approved
Kononenko, O., Mityakina, I., Galatenko, V., Watanabe, H., Bazov, I., Gerashchenko, A., . . . Bakalkin, G. (2018). Differential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord. Brain Research, 1695, 78-83
Open this publication in new window or tab >>Differential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord
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2018 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1695, p. 78-83Article in journal (Refereed) Published
Abstract [en]

The endogenous opioid system (EOS) controls the processing of nociceptive stimuli and is a pharmacological target for opioids. Alterations in expression of the EOS genes under neuropathic pain condition may account for low efficacy of opioid drugs. We here examined whether EOS expression patterns are altered in the lumbar spinal cord of the rats with spinal nerve ligation (SNL) as a neuropathic pain model. Effects of the left- and right-side SNL on expression of EOS genes in the ipsi- and contralateral spinal domains were analysed. The SNL-induced changes were complex and different between the genes; between the dorsal and ventral spinal domains; and between the left and right sides of the spinal cord. Prodynorphin (Pdyn) expression was upregulated in the ipsilateral dorsal domains by each the left and right-side SNL, while changes in expression mu-opioid receptor (Oprm I) and proenkephalin (Penk) genes were dependent on the SNL side. Changes in expression of the Pdyn and kappa-opioid receptor (Oprk1) genes were coordinated between the ipsi- and contralateral sides. Withdrawal response thresholds, indicators of mechanical allodynia correlated negatively with Pdyn expression in the right ventral domain after right side SNL. These findings suggest multiple roles of the EOS gene products in spinal sensitization and changes in motor reflexes, which may differ between the left and right sides. (C) 2018 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Rat model, Neuropathic pain, Gene expression, Opioid system, Lumbar spinal cord, Lateralization
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-364899 (URN)10.1016/j.brainres.2018.05.043 (DOI)000440390700009 ()29852138 (PubMedID)
Funder
Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and WelfareSwedish Research Council FormasSwedish Institute
Available from: 2018-11-09 Created: 2018-11-09 Last updated: 2018-11-09Bibliographically approved
Bazov, I., Sarkisyan, D., Kononenko, O., Watanabe, H., Karpyak, V. M., Yakovleva, T. & Bakalkin, G. (2018). Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics. Translational Psychiatry, 8, Article ID 122.
Open this publication in new window or tab >>Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics
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2018 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, article id 122Article in journal (Refereed) Published
Abstract [en]

Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Neurosciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-358683 (URN)10.1038/s41398-017-0075-5 (DOI)000437025300001 ()29925858 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2009-1709Forte, Swedish Research Council for Health, Working Life and Welfare, 259-2012-23Swedish Research Council, K2014-62X-12190-19-5
Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-17Bibliographically approved
Bazov, I., Sarkisyan, D., Kononenko, O., Watanabe, H., Yakovleva, T., Hansson, A. C., . . . Bakalkin, G. (2018). Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.. Molecular Neurobiology, 55(8), 7049-7061
Open this publication in new window or tab >>Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.
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2018 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 8, p. 7049-7061Article in journal (Refereed) Published
Abstract [en]

Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/κ-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2-containing pathways which may lead to the negative affective state in human alcoholics.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Alcohol addiction, Co-expression of gene clusters, D1-pathway, D2-pathway, Dynorphin, Dysphoria, Nucleus accumbens, Post-mortem human brain tissue, Reward system, κ-opioid receptor
National Category
Biochemistry and Molecular Biology Neurology
Identifiers
urn:nbn:se:uu:diva-343195 (URN)10.1007/s12035-017-0844-4 (DOI)000439758300057 ()29383684 (PubMedID)
Funder
Swedish Research Council, K2014-62X-12190-19-5Forte, Swedish Research Council for Health, Working Life and Welfare, 2009-1709 259-2012-23
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-10-17Bibliographically approved
Ruggeri, B., Macare, C., Stopponi, S., Jia, T., Carvalho, F. M., Robert, G., . . . Schumann, G. (2018). Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents. Journal of Child Psychology and Psychiatry and Allied Disciplines, 9(6), 50-658
Open this publication in new window or tab >>Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents
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2018 (English)In: Journal of Child Psychology and Psychiatry and Allied Disciplines, ISSN 0021-9630, E-ISSN 1469-7610, Vol. 9, no 6, p. 50-658Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Nociceptin is a key regulator linking environmental stress and alcohol drinking. In a genome-wide methylation analysis, we recently identified an association of a methylated region in the OPRL1 gene with alcohol-use disorders.

METHODS: Here, we investigate the biological basis of this observation by analysing psychosocial stressors, methylation of the OPRL1 gene, brain response during reward anticipation and alcohol drinking in 660 fourteen-year-old adolescents of the IMAGEN study. We validate our findings in marchigian sardinian (msP) alcohol-preferring rats that are genetically selected for increased alcohol drinking and stress sensitivity.

RESULTS: We found that low methylation levels in intron 1 of OPRL1 are associated with higher psychosocial stress and higher frequency of binge drinking, an effect mediated by OPRL1 methylation. In individuals with low methylation of OPRL1, frequency of binge drinking is associated with stronger BOLD response in the ventral striatum during reward anticipation. In msP rats, we found that stress results in increased alcohol intake and decreased methylation of OPRL1 in the nucleus accumbens.

CONCLUSIONS: Our findings describe an epigenetic mechanism that helps to explain how psychosocial stress influences risky alcohol consumption and reward processing, thus contributing to the elucidation of biological mechanisms underlying risk for substance abuse.

Keywords
OPRL1 methylation, adolescence, binge drinking, nucleus accumbens, stressful life events
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-343194 (URN)10.1111/jcpp.12843 (DOI)000433335100005 ()29197086 (PubMedID)
Funder
EU, European Research Council, LSHM-CT- 2007-037286EU, European Research Council, LSHM-CT- 2007-602450EU, European Research Council, LSHM-CT- 2007-602805EU, European Research Council, LSHM-CT- 2007-603016Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and WelfareSwedish Research Council FormasWellcome trustGerman Research Foundation (DFG), SM 80/7-1German Research Foundation (DFG), SM 80/7-2German Research Foundation (DFG), SFB 940/1NIH (National Institute of Health)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-08-16Bibliographically approved
Bazov, I., Sarkisyan, D., Kononenko, O., Watanabe, H., Taqi, M. M., Stålhandske, L., . . . Bakalkin, G. (2018). Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain. Cerebral Cortex, 28(9), 3129-3142
Open this publication in new window or tab >>Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain
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2018 (English)In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 28, no 9, p. 3129-3142Article in journal (Refereed) Published
Abstract [en]

Molecular mechanisms that define patterns of neuropeptide expression are essential for the formation and rewiring of neural circuits. The prodynorphin gene (PDYN) gives rise to dynorphin opioid peptides mediating depression and substance dependence. We here demonstrated that PDYN is expressed in neurons in human dorsolateral prefrontal cortex (dlPFC), and identified neuronal differentially methylated region in PDYN locus framed by CCCTC-binding factor binding sites. A short, nucleosome size human-specific promoter CpG island (CGI), a core of this region may serve as a regulatory module, which is hypomethylated in neurons, enriched in 5-hydroxymethylcytosine, and targeted by USF2, a methylation-sensitive E-box transcription factor (TF). USF2 activates PDYN transcription in model systems, and binds to nonmethylated CGI in dlPFC. USF2 and PDYN expression is correlated, and USF2 and PDYN proteins are co-localized in dlPFC. Segregation of activatory TF and repressive CGI methylation may ensure contrasting PDYN expression in neurons and glia in human brain.

Keywords
DNA methylation, cell type-specific expression, human brain, neuropeptides, transcription
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-343193 (URN)10.1093/cercor/bhx181 (DOI)28968778 (PubMedID)
Funder
Swedish Research Council, K2014-62X-12190-19-5Forte, Swedish Research Council for Health, Working Life and Welfare, 2009-1709Forte, Swedish Research Council for Health, Working Life and Welfare, 259-2012-23NIH (National Institute of Health), P30 GM103328
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-11-08Bibliographically approved
Sarkisyan, D., Bazov, I., Watanabe, H., Kononenko, O., Syvänen, A.-C., Schumann, G., . . . Bakalkin, G. (2017). Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation [Letter to the editor]. Acta Neuropathologica, 133(3), 485-487
Open this publication in new window or tab >>Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation
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2017 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 133, no 3, p. 485-487Article in journal, Letter (Refereed) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-316837 (URN)10.1007/s00401-017-1675-0 (DOI)000394961100011 ()28097436 (PubMedID)
Note

Shared first authorship for Sarkisyan D., Bazov I.

Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2017-04-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8074-9833

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