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  1. Article ; Online: The role of oxidative stress in blood-brain barrier disruption during ischemic stroke: Antioxidants in clinical trials.

    Lochhead, Jeffrey J / Ronaldson, Patrick T / Davis, Thomas P

    Biochemical pharmacology

    2024  , Page(s) 116186

    Abstract: ... of cerebral blood vessels (i.e., ischemia/reperfusion (I/R) injury) generates reactive oxygen species (ROS ... for ROS-associated alterations in BBB function during ischemia/reperfusion (I/R) injury can lead ... in response to I/R injury, their effects on BBB integrity (i.e., tight junction protein complexes ...

    Abstract Ischemic stroke is one of the leading causes of death and disability. Occlusion and reperfusion of cerebral blood vessels (i.e., ischemia/reperfusion (I/R) injury) generates reactive oxygen species (ROS) that contribute to brain cell death and dysfunction of the blood-brain barrier (BBB) via oxidative stress. BBB disruption influences the pathogenesis of ischemic stroke by contributing to cerebral edema, hemorrhagic transformation, and extravasation of circulating neurotoxic proteins. An improved understanding of mechanisms for ROS-associated alterations in BBB function during ischemia/reperfusion (I/R) injury can lead to improved treatment paradigms for ischemic stroke. Unfortunately, progress in developing ROS targeted therapeutics that are effective for stroke treatment has been slow. Here, we review how ROS are produced in response to I/R injury, their effects on BBB integrity (i.e., tight junction protein complexes, transporters), and the utilization of antioxidant treatments in ischemic stroke clinical trials. Overall, knowledge in this area provides a strong translational framework for discovery of novel drugs for stroke and/or improved strategies to mitigate I/R injury in stroke patients.
    Language English
    Publishing date 2024-03-30
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 208787-x
    ISSN 1873-2968 ; 0006-2952
    ISSN (online) 1873-2968
    ISSN 0006-2952
    DOI 10.1016/j.bcp.2024.116186
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article: Fœtus with Intra-Uterine Peritonitis.

    Ronaldson, T R

    Transactions. Edinburgh Obstetrical Society

    2018  Volume 4, Page(s) 349

    Language English
    Publishing date 2018-04-03
    Publishing country Scotland
    Document type Journal Article
    ISSN 0269-3402
    ISSN 0269-3402
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  3. Article: Case of Early Viability.

    Ronaldson, T R

    Transactions. Edinburgh Obstetrical Society

    2018  Volume 6, Page(s) 46–48

    Language English
    Publishing date 2018-04-03
    Publishing country Scotland
    Document type Journal Article
    ISSN 0269-3402
    ISSN 0269-3402
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  4. Article: Congenital Closure of Posterior Nares.

    Ronaldson, T R

    Transactions. Edinburgh Obstetrical Society

    2018  Volume 6, Page(s) 48–49

    Language English
    Publishing date 2018-04-03
    Publishing country Scotland
    Document type Journal Article
    ISSN 0269-3402
    ISSN 0269-3402
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  5. Article: Two Cases of Labour in Rickety Pelves.

    Ronaldson, T R

    Transactions. Edinburgh Obstetrical Society

    2018  Volume 6, Page(s) 219–221

    Language English
    Publishing date 2018-04-03
    Publishing country Scotland
    Document type Journal Article
    ISSN 0269-3402
    ISSN 0269-3402
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  6. Article: Note of a Case of Hernia into the Umbilical Cord; Operation and Recovery.

    Ronaldson, T R

    Transactions. Edinburgh Obstetrical Society

    2018  Volume 8, Page(s) 101–102

    Language English
    Publishing date 2018-04-03
    Publishing country Scotland
    Document type Journal Article
    ISSN 0269-3402
    ISSN 0269-3402
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  7. Article ; Online: Nrf2 signaling increases expression of ATP-binding cassette subfamily C mRNA transcripts at the blood-brain barrier following hypoxia-reoxygenation stress.

    Ibbotson, Kathryn / Yell, Joshua / Ronaldson, Patrick T

    Fluids and barriers of the CNS

    2017  Volume 14, Issue 1, Page(s) 6

    Abstract: Background: Strategies to maintain BBB integrity in diseases with a hypoxia/reoxygenation (H/R ... multidrug resistance proteins (Mrps). Therefore, characterization of Mrp regulation at the BBB during H/R is ... by nuclear factor E2-related factor (Nrf2) using a well-established H/R model.: Methods: Female ...

    Abstract Background: Strategies to maintain BBB integrity in diseases with a hypoxia/reoxygenation (H/R) component involve preventing glutathione (GSH) loss from endothelial cells. GSH efflux transporters include multidrug resistance proteins (Mrps). Therefore, characterization of Mrp regulation at the BBB during H/R is required to advance these transporters as therapeutic targets. Our goal was to investigate, in vivo, regulation of Abcc1, Abcc2, and Abcc4 mRNA expression (i.e., genes encoding Mrp isoforms that transport GSH) by nuclear factor E2-related factor (Nrf2) using a well-established H/R model.
    Methods: Female Sprague-Dawley rats (200-250 g) were subjected to normoxia (Nx, 21% O
    Results: We observed increased microvascular expression of Abcc1, Abcc2, and Abcc4 mRNA following H/R treatment with reoxygenation times of 10 min, 30 min, and 1 h and in animals treated with sulforaphane. Using a biotinylated Nrf2 probe, we observed an upward band shift in brain microvessels isolated from H/R animals or animals administered sulforaphane. ChIP studies showed increased Nrf2 binding to antioxidant response elements on Abcc1, Abcc2, and Abcc4 promoters following H/R or sulforaphane treatment, suggesting a role for Nrf2 signaling in Abcc gene regulation.
    Conclusions: Our data show increased Abcc1, Abcc2, and Abcc4 mRNA expression at the BBB in response to H/R stress and that Abcc gene expression is regulated by Nrf2 signaling. Since these Mrp isoforms transport GSH, these results may point to endogenous transporters that can be targeted for BBB protection during H/R stress. Experiments are ongoing to examine functional implications of Nrf2-mediated increases in Abcc transcript expression. Such studies will determine utility of targeting Mrp isoforms for BBB protection in diseases with an H/R component.
    MeSH term(s) Animals ; Anticarcinogenic Agents/pharmacology ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/cytology ; Chromatin Immunoprecipitation ; Disease Models, Animal ; Electrophoretic Mobility Shift Assay ; Female ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/physiology ; Hyperbaric Oxygenation ; Hypoxia/metabolism ; Hypoxia/pathology ; Hypoxia/therapy ; Isothiocyanates/pharmacology ; Microvessels/drug effects ; Microvessels/metabolism ; Multidrug Resistance-Associated Proteins/genetics ; Multidrug Resistance-Associated Proteins/metabolism ; NF-E2-Related Factor 2/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Time Factors
    Chemical Substances Anticarcinogenic Agents ; Isothiocyanates ; Multidrug Resistance-Associated Proteins ; NF-E2-Related Factor 2 ; Nfe2l2 protein, rat ; RNA, Messenger ; sulforaphane (GA49J4310U)
    Language English
    Publishing date 2017-03-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 2595406-4
    ISSN 2045-8118 ; 2045-8118
    ISSN (online) 2045-8118
    ISSN 2045-8118
    DOI 10.1186/s12987-017-0055-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

    Abdullahi, Wazir / Davis, Thomas P / Ronaldson, Patrick T

    The AAPS journal

    2017  Volume 19, Issue 4, Page(s) 931–939

    Abstract: ... including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB ... that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be ...

    Abstract Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.
    MeSH term(s) ATP-Binding Cassette, Sub-Family B, Member 1/metabolism ; Animals ; Blood-Brain Barrier ; Central Nervous System/metabolism ; Drug Delivery Systems ; Humans ; Organic Anion Transporters/metabolism
    Chemical Substances ATP-Binding Cassette, Sub-Family B, Member 1 ; Organic Anion Transporters
    Language English
    Publishing date 2017-04-26
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ISSN 1550-7416
    ISSN (online) 1550-7416
    DOI 10.1208/s12248-017-0081-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke.

    Brzica, Hrvoje / Abdullahi, Wazir / Ibbotson, Kathryn / Ronaldson, Patrick T

    Journal of central nervous system disease

    2017  Volume 9, Page(s) 1179573517693802

    Abstract: ... tissue plasminogen activator (r-tPA). A short therapeutic window and serious adverse events (ie, hemorrhage, excitotoxicity ... greatly limit r-tPA therapy, which indicates an essential need to develop novel stroke treatment paradigms ...

    Abstract Ischemic stroke is a leading cause of morbidity and mortality in the United States. The only approved pharmacologic treatment for ischemic stroke is thrombolysis via recombinant tissue plasminogen activator (r-tPA). A short therapeutic window and serious adverse events (ie, hemorrhage, excitotoxicity) greatly limit r-tPA therapy, which indicates an essential need to develop novel stroke treatment paradigms. Transporters expressed at the blood-brain barrier (BBB) provide a significant opportunity to advance stroke therapy via central nervous system delivery of drugs that have neuroprotective properties. Examples of such transporters include organic anion-transporting polypeptides (Oatps) and organic cation transporters (Octs). In addition, multidrug resistance proteins (Mrps) are transporter targets in brain microvascular endothelial cells that can be exploited to preserve BBB integrity in the setting of stroke. Here, we review current knowledge on stroke pharmacotherapy and demonstrate how endogenous BBB transporters can be targeted for improvement of ischemic stroke treatment.
    Language English
    Publishing date 2017-04-06
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2586873-1
    ISSN 1179-5735
    ISSN 1179-5735
    DOI 10.1177/1179573517693802
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: HIV-1 viral envelope glycoprotein gp120 produces oxidative stress and regulates the functional expression of multidrug resistance protein-1 (Mrp1) in glial cells.

    Ronaldson, Patrick T / Bendayan, Reina

    Journal of neurochemistry

    2008  Volume 106, Issue 3, Page(s) 1298–1313

    Abstract: Brain human immunodeficiency virus type-1 (HIV-1) infection is associated with oxidative stress, which may lead to HIV-1 encephalitis, a chronic neurodegenerative condition. In vitro, oxidative stress can be induced in glial cells by exposure to HIV-1 ... ...

    Abstract Brain human immunodeficiency virus type-1 (HIV-1) infection is associated with oxidative stress, which may lead to HIV-1 encephalitis, a chronic neurodegenerative condition. In vitro, oxidative stress can be induced in glial cells by exposure to HIV-1 envelope protein glycoprotein (gp120). Multidrug resistance proteins (Mrps) are known to efflux endogenous substrates (i.e. GSH and GSSG) involved in cellular defense against oxidative stress. Altered GSH/GSSG export may contribute to oxidative damage during HIV-1 encephalitis. At present, it is unknown if gp120 exposure can alter the functional expression of Mrp isoforms. Heat-shock protein 70, inducible nitric oxide synthase, intracellular GSSG, 2',7'-dichlorofluorescein fluorescence, and extracellular nitrite were increased in primary cultures of rat astrocytes triggered with gp120, suggesting an oxidative stress response. RT-PCR and immunoblot analysis demonstrated increased Mrp1 mRNA (2.3-fold) and protein (2.2-fold), respectively, in gp120 treated astrocytes while Mrp4 mRNA or protein expression was not changed. Cellular retention of 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, an established Mrp substrate, was reduced (twofold) in gp120-treated astrocytes, suggesting increased Mrp-mediated transport. In addition, GSH and GSSG export were enhanced in gp120-triggered cells. These data suggest that gp120 can up-regulate Mrp1, but not Mrp4, functional expression in cultured astrocytes. Our observation of increased GSH/GSSG efflux in response to gp120 treatment implies that Mrp isoforms may be involved in regulating the oxidative stress response in glial cells.
    MeSH term(s) ATP-Binding Cassette, Sub-Family B, Member 1/biosynthesis ; ATP-Binding Cassette, Sub-Family B, Member 1/genetics ; ATP-Binding Cassette, Sub-Family B, Member 1/physiology ; Animals ; Cells, Cultured ; Gene Expression Regulation, Viral/physiology ; HIV Envelope Protein gp120/physiology ; HIV Infections/metabolism ; HIV Infections/pathology ; HeLa Cells ; Humans ; Neuroglia/metabolism ; Neuroglia/physiology ; Oxidative Stress/physiology ; Rats ; Rats, Wistar ; Up-Regulation/physiology
    Chemical Substances ATP-Binding Cassette, Sub-Family B, Member 1 ; HIV Envelope Protein gp120
    Language English
    Publishing date 2008-08
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80158-6
    ISSN 1471-4159 ; 0022-3042 ; 1474-1644
    ISSN (online) 1471-4159
    ISSN 0022-3042 ; 1474-1644
    DOI 10.1111/j.1471-4159.2008.05479.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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