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  1. Article: Small conductance calcium activated K

    Yan, Yannan / Skarsfeldt, Mark Alexander / Diness, Jonas Goldin / Bentzen, Bo Hjorth

    International journal of cardiology. Heart & vasculature

    2021  Volume 37, Page(s) 100898

    Abstract: Background: Atrial dilation is an important risk factor for atrial fibrillation (AF) and animal studies have found that acute atrial dilation shortens the atrial effective refractory period (AERP) and increases the risk of AF. Stretch activated ion ... ...

    Abstract Background: Atrial dilation is an important risk factor for atrial fibrillation (AF) and animal studies have found that acute atrial dilation shortens the atrial effective refractory period (AERP) and increases the risk of AF. Stretch activated ion channels (SACs) and calcium channels play a role in this. The expression profile and calcium dependent activation makes the small conductance calcium activated K
    Objectives: We hypothesized that K
    Methods: The effect of K
    Results: Stretching of the LA by increasing the balloon pressure from 0 to 20 mmHg shortened the AERP by 8.6 ± 1 ms. In comparison, the K
    Conclusion: The K
    Language English
    Publishing date 2021-10-23
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 2818464-6
    ISSN 2352-9067
    ISSN 2352-9067
    DOI 10.1016/j.ijcha.2021.100898
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  2. Article ; Online: Reply to: How Many SARS-CoV-2 "Viroporins" Are Really Ion Channels?

    Toft-Bertelsen, Trine L / Jeppesen, Mads Gravers / Landbrug, Asante / Mujezinovic, Amer / Bentzen, Bo Hjorth / Kledal, Thomas Nitschke / Rosenkilde, Mette Marie

    Communications biology

    2022  Volume 5, Issue 1, Page(s) 860

    MeSH term(s) COVID-19 ; Humans ; Ion Channels ; SARS-CoV-2 ; Viral Proteins/metabolism ; Viroporin Proteins
    Chemical Substances Ion Channels ; Viral Proteins ; Viroporin Proteins
    Language English
    Publishing date 2022-08-25
    Publishing country England
    Document type Letter ; Comment
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-022-03670-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Publisher Correction: Reply to: How many SARS-CoV-2 "viroporins" are really ion channels?

    Toft-Bertelsen, Trine L / Jeppesen, Mads Gravers / Landbrug, Asante / Mujezinovic, Amer / Bentzen, Bo Hjorth / Kledal, Thomas Nitschke / Rosenkilde, Mette Marie

    Communications biology

    2022  Volume 5, Issue 1, Page(s) 1017

    Language English
    Publishing date 2022-09-27
    Publishing country England
    Document type Published Erratum
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-022-03982-w
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  4. Article: Inhibition of Adenosine Pathway Alters Atrial Electrophysiology and Prevents Atrial Fibrillation.

    Soattin, Luca / Lubberding, Anniek Frederike / Bentzen, Bo Hjorth / Christ, Torsten / Jespersen, Thomas

    Frontiers in physiology

    2020  Volume 11, Page(s) 493

    Abstract: Background: Adenosine leads to atrial action potential (AP) shortening through activation of adenosine 1 receptors (A: Objective: The aim of this study was to address whether the pharmacological blockade of endogenous production of adenosine and of ... ...

    Abstract Background: Adenosine leads to atrial action potential (AP) shortening through activation of adenosine 1 receptors (A
    Objective: The aim of this study was to address whether the pharmacological blockade of endogenous production of adenosine and of its signaling prevents atrial fibrillation (AF).
    Methods: The role of A
    Results: As expected, CCPA shortened AP duration at 90% of repolarization (APD
    Conclusion: A
    Language English
    Publishing date 2020-06-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2020.00493
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  5. Article ; Online: Post-infection treatment with the E protein inhibitor BIT225 reduces disease severity and increases survival of K18-hACE2 transgenic mice infected with a lethal dose of SARS-CoV-2.

    Ewart, Gary / Bobardt, Michael / Bentzen, Bo Hjorth / Yan, Yannan / Thomson, Audrey / Klumpp, Klaus / Becker, Stephen / Rosenkilde, Mette M / Miller, Michelle / Gallay, Philippe

    PLoS pathogens

    2023  Volume 19, Issue 8, Page(s) e1011328

    Abstract: The Coronavirus envelope (E) protein is a small structural protein with ion channel activity that plays an important role in virus assembly, budding, immunopathogenesis and disease severity. The viroporin E is also located in Golgi and ER membranes of ... ...

    Abstract The Coronavirus envelope (E) protein is a small structural protein with ion channel activity that plays an important role in virus assembly, budding, immunopathogenesis and disease severity. The viroporin E is also located in Golgi and ER membranes of infected cells and is associated with inflammasome activation and immune dysregulation. Here we evaluated in vitro antiviral activity, mechanism of action and in vivo efficacy of BIT225 for the treatment of SARS-CoV-2 infection. BIT225 showed broad-spectrum direct-acting antiviral activity against SARS-CoV-2 in Calu3 and Vero cells with similar potency across 6 different virus strains. BIT225 inhibited ion channel activity of E protein but did not inhibit endogenous currents or calcium-induced ion channel activity of TMEM16A in Xenopus oocytes. BIT225 administered by oral gavage for 12 days starting 12 hours before infection completely prevented body weight loss and mortality in SARS-CoV-2 infected K18 mice (100% survival, n = 12), while all vehicle-dosed animals reached a mortality endpoint by Day 9 across two studies (n = 12). When treatment started at 24 hours after infection, body weight loss, and mortality were also prevented (100% survival, n = 5), while 4 of 5 mice maintained and increased body weight and survived when treatment started 48 hours after infection. Treatment efficacy was dependent on BIT225 dose and was associated with significant reductions in lung viral load (3.5 log10), virus titer (4000 pfu/ml) and lung and serum cytokine levels. These results validate viroporin E as a viable antiviral target and support the clinical study of BIT225 for treatment and prophylaxis of SARS-CoV-2 infection.
    MeSH term(s) Chlorocebus aethiops ; Mice ; Animals ; Antiviral Agents/pharmacology ; Vero Cells ; SARS-CoV-2 ; Mice, Transgenic ; Viroporin Proteins ; COVID-19 ; Hepatitis C, Chronic ; Transcription Factors ; Patient Acuity ; Weight Loss ; Ion Channels ; Disease Models, Animal
    Chemical Substances Antiviral Agents ; N-(5-(1-methyl-1H-pyrazol-4-yl)-napthalene-2-carbonyl)guanidine ; Viroporin Proteins ; K-18 conjugate ; Transcription Factors ; Ion Channels
    Language English
    Publishing date 2023-08-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1011328
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  6. Article ; Online: Increased Density of Endogenous Adenosine A

    Godoy-Marín, Héctor / Jiménez-Sábado, Verónica / Tarifa, Carmen / Ginel, Antonino / Santos, Joana Larupa Dos / Bentzen, Bo Hjorth / Hove-Madsen, Leif / Ciruela, Francisco

    International journal of molecular sciences

    2023  Volume 24, Issue 4

    Abstract: Adenosine, an endogenous nucleoside, plays a critical role in maintaining homeostasis during stressful situations, such as energy deprivation or cellular damage. Therefore, extracellular adenosine is generated locally in tissues under conditions such as ... ...

    Abstract Adenosine, an endogenous nucleoside, plays a critical role in maintaining homeostasis during stressful situations, such as energy deprivation or cellular damage. Therefore, extracellular adenosine is generated locally in tissues under conditions such as hypoxia, ischemia, or inflammation. In fact, plasma levels of adenosine in patients with atrial fibrillation (AF) are elevated, which also correlates with an increased density of adenosine A
    MeSH term(s) Animals ; Humans ; Adenosine/metabolism ; Atrial Fibrillation/metabolism ; Heart Atria/metabolism ; Leukocytes, Mononuclear/metabolism ; Myocytes, Cardiac/metabolism ; Receptor, Adenosine A2A/metabolism ; Swine
    Chemical Substances Adenosine (K72T3FS567) ; Receptor, Adenosine A2A
    Language English
    Publishing date 2023-02-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24043668
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  7. Article ; Online: Endocannabinoids enhance hK

    Hiniesto-Iñigo, Irene / Castro-Gonzalez, Laura M / Corradi, Valentina / Skarsfeldt, Mark A / Yazdi, Samira / Lundholm, Siri / Nikesjö, Johan / Noskov, Sergei Yu / Bentzen, Bo Hjorth / Tieleman, D Peter / Liin, Sara I

    EBioMedicine

    2023  Volume 89, Page(s) 104459

    Abstract: Background: Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease ... ...

    Abstract Background: Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease severity to move towards an individualized clinical management of LQTS. One possible factor influencing the disease phenotype is the endocannabinoid system, which has emerged as a modulator of cardiovascular function. In this study, we aim to elucidate whether endocannabinoids target the cardiac voltage-gated potassium channel K
    Methods: We used two-electrode voltage clamp, molecular dynamics simulations and the E4031 drug-induced LQT2 model of ex-vivo guinea pig hearts.
    Findings: We found a set of endocannabinoids that facilitate channel activation, seen as a shifted voltage-dependence of channel opening and increased overall current amplitude and conductance. We propose that negatively charged endocannabinoids interact with known lipid binding sites at positively charged amino acids on the channel, providing structural insights into why only specific endocannabinoids modulate K
    Interpretation: We consider the endocannabinoids as an interesting class of hK
    Funding: ERC (No. 850622), Canadian Institutes of Health Research, Canada Research Chairs and Compute Canada, Swedish National Infrastructure for Computing.
    MeSH term(s) Animals ; Guinea Pigs ; Endocannabinoids ; Action Potentials ; Mutation ; KCNQ1 Potassium Channel/genetics ; KCNQ1 Potassium Channel/metabolism ; Canada ; Long QT Syndrome/genetics ; Long QT Syndrome/metabolism
    Chemical Substances Endocannabinoids ; KCNQ1 Potassium Channel
    Language English
    Publishing date 2023-02-14
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2023.104459
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 7090: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  8. Article ; Online: A phase 1 trial of AP30663, a K

    Yfanti, Christina / Vestbjerg, Birgitte / Van't Westende, Juliette / Edvardsson, Nils / Monfort, Laia Meseguer / Olesen, Morten Salling / Bentzen, Bo Hjorth / Grunnet, Morten / Eveleens Maarse, Boukje C / Diness, Jonas Goldin / Kemme, Michiel J B / Sørensen, Ulrik / Moerland, Matthijs / van Esdonk, Michiel J / Klaassen, Erica S / Gal, Pim / Holst, Anders G

    British journal of clinical pharmacology

    2024  Volume 90, Issue 4, Page(s) 1027–1035

    Abstract: Aims: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca: Methods: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous ... ...

    Abstract Aims: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca
    Methods: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected.
    Results: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h.
    Conclusion: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the I
    MeSH term(s) Humans ; Male ; Atrial Fibrillation/chemically induced ; Atrial Fibrillation/drug therapy ; Dose-Response Relationship, Drug ; Double-Blind Method ; Electrocardiography ; Heart Rate ; Injection Site Reaction
    Language English
    Publishing date 2024-01-08
    Publishing country England
    Document type Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial
    ZDB-ID 188974-6
    ISSN 1365-2125 ; 0306-5251 ; 0264-3774
    ISSN (online) 1365-2125
    ISSN 0306-5251 ; 0264-3774
    DOI 10.1111/bcp.15973
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1118: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  9. Article: Whole-Exome Sequencing Implicates Neuronal Calcium Channel with Familial Atrial Fibrillation.

    Vad, Oliver Bundgaard / Yan, Yannan / Denti, Federico / Ahlberg, Gustav / Refsgaard, Lena / Bomholtz, Sofia Hammami / Santos, Joana Larupa / Rasmussen, Simon / Haunsø, Stig / Svendsen, Jesper Hastrup / Christophersen, Ingrid Elizabeth / Schmitt, Nicole / Olesen, Morten Salling / Bentzen, Bo Hjorth

    Frontiers in genetics

    2022  Volume 13, Page(s) 806429

    Abstract: Background: ...

    Abstract Background:
    Language English
    Publishing date 2022-01-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2606823-0
    ISSN 1664-8021
    ISSN 1664-8021
    DOI 10.3389/fgene.2022.806429
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  10. Article: Inhibition of K

    Citerni, Carlotta / Kirchhoff, Jeppe / Olsen, Lisbeth Høier / Sattler, Stefan Michael / Grunnet, Morten / Edvardsson, Nils / Bentzen, Bo Hjorth / Diness, Jonas Goldin

    Frontiers in pharmacology

    2020  Volume 11, Page(s) 556

    Abstract: Background: Inhibition of K: Methods: Landrace pigs were randomized into an AF group (n = 6) and two control groups: SHAM1 (n = 8) and SHAM2 (n = 4). AF pigs were atrially tachypaced (A-TP) for 43 ± 4 days until sustained AF and LVD developed. A-TP ... ...

    Abstract Background: Inhibition of K
    Methods: Landrace pigs were randomized into an AF group (n = 6) and two control groups: SHAM1 (n = 8) and SHAM2 (n = 4). AF pigs were atrially tachypaced (A-TP) for 43 ± 4 days until sustained AF and LVD developed. A-TP and SHAM1 pigs received 20 mg/kg AP14145 followed by 100 µg/kg dofetilide whereas SHAM2 pigs received the same drugs in the opposite order. Proarrhythmic markers such as short-term variability of QT (STV
    Results: I
    Conclusion: I
    Language English
    Publishing date 2020-05-06
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2020.00556
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