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  1. Article ; Online: sFlt-1 Impairs Neurite Growth and Neuronal Differentiation in SH-SY5Y Cells and Human Neurons.

    Barron, Aaron / Barrett, Lauren / Tuulari, Jetro / Karlsson, Linnea / Karlsson, Hasse / McCarthy, Cathal M / O'Keeffe, Gerard W

    Bioscience reports

    2024  

    Abstract: Pre-eclampsia (PE) is a hypertensive disorder of pregnancy which is associated with increased risk of neurodevelopmental disorders in exposed offspring. The pathophysiological mechanisms mediating this relationship are currently unknown, and one ... ...

    Abstract Pre-eclampsia (PE) is a hypertensive disorder of pregnancy which is associated with increased risk of neurodevelopmental disorders in exposed offspring. The pathophysiological mechanisms mediating this relationship are currently unknown, and one potential candidate is the anti-angiogenic factor soluble Fms-like tyrosine kinase 1 (sFlt-1), which is highly elevated in PE. While sFlt-1 can impair angiogenesis via inhibition of VEGFA signalling, it is unclear whether it can directly affect neuronal development independently of its effects on the vasculature. To test this hypothesis, the current study differentiated the human neural progenitor cell (NPC) line ReNcell® VM into a mixed culture of mature neurons and glia, and exposed them to sFlt-1 during development. Outcomes measured were neurite growth, cytotoxicity, mRNA expression of nestin, MBP, GFAP, and βIII-tubulin, and neurosphere differentiation. sFlt-1 induced a significant reduction in neurite growth and this effect was timing- and dose-dependent up to 100 ng/mL, with no effect on cytotoxicity. sFlt-1 (100 ng/mL) also reduced βIII-tubulin mRNA and neuronal differentiation of neurospheres. Undifferentiated NPCs and mature neurons/glia expressed VEGFA and VEGFR-2, required for endogenous autocrine and paracrine VEGFA signalling, while sFlt-1 treatment prevented the neurogenic effects of exogenous VEGFA. Overall, these data provide the first experimental evidence for a direct effect of sFlt-1 on neurite growth and neuronal differentiation in human neurons through inhibition of VEGFA signalling, clarifying our understanding of the potential role of sFlt-1 as a mechanism by which PE can affect neuronal development.
    Language English
    Publishing date 2024-05-03
    Publishing country England
    Document type Journal Article
    ZDB-ID 764946-0
    ISSN 1573-4935 ; 0144-8463
    ISSN (online) 1573-4935
    ISSN 0144-8463
    DOI 10.1042/BSR20240562
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1676: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  2. Article ; Online: Preeclampsia and Neurodevelopmental Outcomes: Potential Pathogenic Roles for Inflammation and Oxidative Stress?

    Barron, Aaron / McCarthy, Cathal M / O'Keeffe, Gerard W

    Molecular neurobiology

    2021  Volume 58, Issue 6, Page(s) 2734–2756

    Abstract: Preeclampsia (PE) is a common and serious hypertensive disorder of pregnancy that occurs in approximately 3-5% of first-time pregnancies and is a well-known leading cause of maternal and neonatal mortality and morbidity. In recent years, there has been ... ...

    Abstract Preeclampsia (PE) is a common and serious hypertensive disorder of pregnancy that occurs in approximately 3-5% of first-time pregnancies and is a well-known leading cause of maternal and neonatal mortality and morbidity. In recent years, there has been accumulating evidence that in utero exposure to PE acts as an environmental risk factor for various neurodevelopmental disorders, particularly autism spectrum disorder and ADHD. At present, the mechanism(s) mediating this relationship are uncertain. In this review, we outline the most recent evidence implicating a causal role for PE exposure in the aetiology of various neurodevelopmental disorders and provide a novel interpretation of neuroanatomical alterations in PE-exposed offspring and how these relate to their sub-optimal neurodevelopmental trajectory. We then postulate that inflammation and oxidative stress, two prominent features of the pathophysiology of PE, are likely to play a major role in mediating this association. The increased inflammation in the maternal circulation, placenta and fetal circulation in PE expose the offspring to both prenatal maternal immune activation-a risk factor for neurodevelopmental disorders, which has been well-characterised in animal models-and directly higher concentrations of pro-inflammatory cytokines, which adversely affect neuronal development. Similarly, the exaggerated oxidative stress in the mother, placenta and foetus induces the placenta to secrete factors deleterious to neurons, and exposes the fetal brain to directly elevated oxidative stress and thus adversely affects neurodevelopmental processes. Finally, we describe the interplay between inflammation and oxidative stress in PE, and how both systems interact to potentially alter neurodevelopmental trajectory in exposed offspring.
    MeSH term(s) Animals ; Female ; Fetus/pathology ; Humans ; Inflammation/etiology ; Inflammation/pathology ; Nervous System/growth & development ; Nervous System/physiopathology ; Neurodevelopmental Disorders/etiology ; Neurodevelopmental Disorders/physiopathology ; Oxidative Stress ; Pre-Eclampsia/pathology ; Pregnancy
    Language English
    Publishing date 2021-01-25
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 645020-9
    ISSN 1559-1182 ; 0893-7648
    ISSN (online) 1559-1182
    ISSN 0893-7648
    DOI 10.1007/s12035-021-02290-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2411: Show issues Location:
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  3. Article: Maternal pre-eclampsia serum increases neurite growth and mitochondrial function through a potential IL-6-dependent mechanism in differentiated SH-SY5Y cells.

    Barron, Aaron / Manna, Samprikta / McElwain, Colm J / Musumeci, Andrea / McCarthy, Fergus P / O'Keeffe, Gerard W / McCarthy, Cathal M

    Frontiers in physiology

    2023  Volume 13, Page(s) 1043481

    Abstract: Introduction: ...

    Abstract Introduction:
    Language English
    Publishing date 2023-01-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2022.1043481
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing.

    Morales-Prieto, Noelia / Bevans, Rebekah / O'Mahony, Adam / Barron, Aaron / Giles Doran, Conor / McCarthy, Erin / Concannon, Ruth M / Goulding, Susan R / McCarthy, Cathal M / Collins, Louise M / Sullivan, Aideen M / O'Keeffe, Gerard W

    Aging cell

    2024  , Page(s) e14155

    Abstract: Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but ... ...

    Abstract Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague-Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.
    Language English
    Publishing date 2024-03-26
    Publishing country England
    Document type Journal Article
    ZDB-ID 2113083-8
    ISSN 1474-9726 ; 1474-9718
    ISSN (online) 1474-9726
    ISSN 1474-9718
    DOI 10.1111/acel.14155
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6581: Show issues Location:
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  5. Article ; Online: Juvenile stress exerts sex-independent effects on anxiety, antidepressant-like behaviours and dopaminergic innervation of the prelimbic cortex in adulthood and does not alter hippocampal neurogenesis.

    Harris, Erin P / McGovern, Andrew J / Melo, Thieza G / Barron, Aaron / Nolan, Yvonne M / O'Leary, Olivia F

    Behavioural brain research

    2021  Volume 421, Page(s) 113725

    Abstract: Stress, particularly during childhood, is a major risk factor for the development of depression. Depression is twice as prevalent in women compared to men, which suggests that biological sex also contributes to depression susceptibility. However, the ... ...

    Abstract Stress, particularly during childhood, is a major risk factor for the development of depression. Depression is twice as prevalent in women compared to men, which suggests that biological sex also contributes to depression susceptibility. However, the neurobiology underpinning sex differences in the long-term consequences of childhood stress remains unknown. Thus, the aim of this study was to determine whether stress applied during the prepubertal juvenile period (postnatal day 27-29) in rats induces sex-specific changes in anxiety-like behaviour, anhedonia, and antidepressant-like behaviour in adulthood in males and females. The impact of juvenile stress on two systems in the brain associated with these behaviours and that develop during the juvenile period, the mesocorticolimbic dopaminergic system and hippocampal neurogenesis, were also investigated. Juvenile stress altered escape-oriented behaviours in the forced swim test in both sexes, decreased latency to drink a palatable substance in a novel environment in the novelty-induced hypophagia test in both sexes, and decreased open field supported rearing behavior in females. These behavioural changes were accompanied by stress-induced increases in tyrosine hydroxylase immunoreactivity in the prefrontal cortex of both sexes, but not other regions of the mesocorticolimbic dopaminergic system. Juvenile stress did not impact anhedonia in adulthood as measured by the saccharin preference test and had no effect hippocampal neurogenesis across the longitudinal axis of the hippocampus. These results suggest that juvenile stress has long-lasting impacts on antidepressant-like and reward-seeking behaviour in adulthood and these changes may be due to alterations to catecholaminergic innervation of the medial prefrontal cortex.
    MeSH term(s) Age Factors ; Anhedonia/physiology ; Animals ; Anxiety/physiopathology ; Behavior, Animal/physiology ; Depression/physiopathology ; Female ; Hippocampus/physiology ; Male ; Neurogenesis/physiology ; Prefrontal Cortex/metabolism ; Rats ; Rats, Sprague-Dawley ; Reward ; Sex Characteristics ; Stress, Psychological/physiopathology
    Language English
    Publishing date 2021-12-17
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 449927-x
    ISSN 1872-7549 ; 0166-4328
    ISSN (online) 1872-7549
    ISSN 0166-4328
    DOI 10.1016/j.bbr.2021.113725
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1599: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  6. Article ; Online: Gene Co-expression Analysis of the Human Substantia Nigra Identifies ZNHIT1 as an SNCA Co-expressed Gene that Protects Against α-Synuclein-Induced Impairments in Neurite Growth and Mitochondrial Dysfunction in SH-SY5Y Cells.

    McCarthy, Erin / Barron, Aaron / Morales-Prieto, Noelia / Mazzocchi, Martina / McCarthy, Cathal M / Collins, Louise M / Sullivan, Aideen M / O'Keeffe, Gerard W

    Molecular neurobiology

    2022  Volume 59, Issue 5, Page(s) 2745–2757

    Abstract: Parkinson's disease (PD) is neurodegenerative disorder with the pathological hallmarks of progressive degeneration of midbrain dopaminergic neurons from the substantia nigra (SN), and accumulation and spread of inclusions of aggregated α-synuclein (α-Syn) ...

    Abstract Parkinson's disease (PD) is neurodegenerative disorder with the pathological hallmarks of progressive degeneration of midbrain dopaminergic neurons from the substantia nigra (SN), and accumulation and spread of inclusions of aggregated α-synuclein (α-Syn). Since current PD therapies do not prevent neurodegeneration, there is a need to identify therapeutic targets that can prevent α-Syn-induced reductions in neuronal survival and neurite growth. We hypothesised that genes that are normally co-expressed with the α-Syn gene (SNCA), and whose co-expression pattern is lost in PD, may be important for protecting against α-Syn-induced dopaminergic degeneration, since broken correlations can be used as an index of functional misregulation. Gene co-expression analysis of the human SN showed that nuclear zinc finger HIT-type containing 1 (ZNHIT1) is co-expressed with SNCA and that this co-expression pattern is lost in PD. Overexpression of ZNHIT1 was found to increase deposition of the H2A.Z histone variant in SH-SY5Y cells, to promote neurite growth and to prevent α-Syn-induced reductions in neurite growth and cell viability. Analysis of ZNHIT1 co-expressed genes showed significant enrichment in genes associated with mitochondrial function. In agreement, bioenergetic state analysis of mitochondrial function revealed that ZNHIT1 increased cellular ATP synthesis. Furthermore, α-Syn-induced impairments in basal respiration, maximal respiration and spare respiratory capacity were not seen in ZNHIT1-overexpressing cells. These data show that ZNHIT1 can protect against α-Syn-induced degeneration and mitochondrial dysfunction, which rationalises further investigation of ZNHIT1 as a therapeutic target for PD.
    MeSH term(s) Dopaminergic Neurons/metabolism ; Humans ; Mitochondria/metabolism ; Neurites/metabolism ; Parkinson Disease/pathology ; Phosphoproteins ; Substantia Nigra/pathology ; alpha-Synuclein/metabolism
    Chemical Substances Phosphoproteins ; SNCA protein, human ; ZNHIT1 protein, human ; alpha-Synuclein
    Language English
    Publishing date 2022-02-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 645020-9
    ISSN 1559-1182 ; 0893-7648
    ISSN (online) 1559-1182
    ISSN 0893-7648
    DOI 10.1007/s12035-022-02768-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2411: Show issues Location:
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