LIVIVO - Search results -

Search results

Result 1 - 10 of total 36

Search options

Article: Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells.

Sarsons, Christopher D / Gilham, Dean / Tsujikawa, Laura M / Wasiak, Sylwia / Fu, Li / Rakai, Brooke D / Stotz, Stephanie C / Carestia, Agostina / Sweeney, Michael / Kulikowski, Ewelina

Biomedicines

2023 Volume 11, Issue 10

Abstract: Facioscapulohumeral dystrophy (FSHD) is a muscle disease caused by inappropriate expression of the double homeobox 4 (DUX4) gene in skeletal muscle, and its downstream activation of pro-apoptotic transcriptional programs. Inhibitors ... ...

Abstract	Facioscapulohumeral dystrophy (FSHD) is a muscle disease caused by inappropriate expression of the double homeobox 4 (DUX4) gene in skeletal muscle, and its downstream activation of pro-apoptotic transcriptional programs. Inhibitors of
Language	English
Publishing date	2023-09-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11102683
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Article ; Online: Dual mechanism: Epigenetic inhibitor apabetalone reduces SARS-CoV-2 Delta and Omicron variant spike binding and attenuates SARS-CoV-2 RNA induced inflammation.

Fu, Li / Gilham, Dean / Stotz, Stephanie C / Sarsons, Christopher D / Rakai, Brooke D / Tsujikawa, Laura M / Wasiak, Sylwia / Johansson, Jan O / Sweeney, Michael / Wong, Norman C W / Kulikowski, Ewelina

International immunopharmacology

2023 Volume 117, Page(s) 109929

Abstract: The SARS-CoV-2 virus initiates infection via interactions between the viral spike protein and the ACE2 receptors on host cells. Variants of concern have mutations in the spike protein that enhance ACE2 binding affinity, leading to increased virulence and ...

Abstract	The SARS-CoV-2 virus initiates infection via interactions between the viral spike protein and the ACE2 receptors on host cells. Variants of concern have mutations in the spike protein that enhance ACE2 binding affinity, leading to increased virulence and transmission. Viral RNAs released after entry into host cells trigger interferon-I (IFN-I) mediated inflammatory responses for viral clearance and resolution of infection. However, overreactive host IFN-I responses and pro-inflammatory signals drive COVID-19 pathophysiology and disease severity during acute infection. These immune abnormalities also lead to the development of post-COVID syndrome if persistent. Novel therapeutics are urgently required to reduce short- and long-term pathologic consequences associated with SARS-CoV-2 infection. Apabetalone, an inhibitor of epigenetic regulators of the BET protein family, is a candidate for COVID-19 treatment via a dual mechanism of action. In vitro, apabetalone downregulates ACE2 gene expression to limit SARS-CoV-2 entry and propagation. In pre-clinical models and patients treated for cardiovascular disease, apabetalone inhibits expression of inflammatory mediators involved in the pathologic cytokine storm (CS) stimulated by various cytokines. Here we show apabetalone treatment of human lung epithelial cells reduces binding of viral spike protein regardless of mutations found in the highly contagious Delta variant and heavily mutated Omicron. Additionally, we demonstrate that apabetalone counters expression of pro-inflammatory factors with roles in CS and IFN-I signaling in lung cells stimulated with SARS-CoV-2 RNA. Our results support clinical evaluation of apabetalone to treat COVID-19 and post-COVID syndrome regardless of the SARS-CoV-2 variant.
MeSH term(s)	Humans ; SARS-CoV-2 ; RNA, Viral ; COVID-19 ; Angiotensin-Converting Enzyme 2/genetics ; COVID-19 Drug Treatment ; Spike Glycoprotein, Coronavirus/genetics ; Inflammation/drug therapy ; Interferons ; Antibodies ; Cytokine Release Syndrome/drug therapy ; Epigenesis, Genetic
Chemical Substances	RNA, Viral ; apabetalone (8R4A7GDZ1D) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Spike Glycoprotein, Coronavirus ; Interferons (9008-11-1) ; Antibodies ; spike protein, SARS-CoV-2
Language	English
Publishing date	2023-02-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2043785-7
ISSN	1878-1705 ; 1567-5769
ISSN (online)	1878-1705
ISSN	1567-5769
DOI	10.1016/j.intimp.2023.109929
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 5408: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article: The BET inhibitor apabetalone decreases neuroendothelial proinflammatory activation

Wasiak, Sylwia / Fu, Li / Daze, Emily / Gilham, Dean / Rakai, Brooke D / Stotz, Stephanie C / Tsujikawa, Laura M / Sarsons, Chris D / Studer, Deborah / Rinker, Kristina D / Jahagirdar, Ravi / Wong, Norman C W / Sweeney, Michael / Johansson, Jan O / Kulikowski, Ewelina

Translational neuroscience

2023 Volume 14, Issue 1, Page(s) 20220332

Abstract: Brain vascular inflammation is characterized by endothelial activation and immune cell recruitment to the blood vessel wall, potentially causing a breach in the blood - brain barrier, brain parenchyma inflammation, and a decline of cognitive function. ... ...

Abstract	Brain vascular inflammation is characterized by endothelial activation and immune cell recruitment to the blood vessel wall, potentially causing a breach in the blood - brain barrier, brain parenchyma inflammation, and a decline of cognitive function. The clinical-stage small molecule, apabetalone, reduces circulating vascular endothelial inflammation markers and improves cognitive scores in elderly patients by targeting epigenetic regulators of gene transcription, bromodomain and extraterminal proteins. However, the effect of apabetalone on cytokine-activated brain vascular endothelial cells (BMVECs) is unknown. Here, we show that apabetalone treatment of BMVECs reduces hallmarks of
Language	English
Publishing date	2023-12-31
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2581219-1
ISSN	2081-6936 ; 2081-3856
ISSN (online)	2081-6936
ISSN	2081-3856
DOI	10.1515/tnsci-2022-0332
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy.

Fu, Li / Wasiak, Sylwia / Tsujikawa, Laura M / Rakai, Brooke D / Stotz, Stephanie C / Wong, Norman C W / Johansson, Jan O / Sweeney, Michael / Mohan, Connie M / Khan, Aneal / Kulikowski, Ewelina

Pharmacology research & perspectives

2022 Volume 10, Issue 3, Page(s) e00949

Abstract: Fabry disease (FD) is a rare X-linked disorder of lipid metabolism, characterized by the accumulation of globotriaosylceramide (Gb3) due to defective the lysosomal enzyme, α-galactosidase. Gb3 deposits activate immune-mediated systemic inflammation, ... ...

Abstract	Fabry disease (FD) is a rare X-linked disorder of lipid metabolism, characterized by the accumulation of globotriaosylceramide (Gb3) due to defective the lysosomal enzyme, α-galactosidase. Gb3 deposits activate immune-mediated systemic inflammation, ultimately leading to life-threatening consequences in multiple organs such as the heart and kidneys. Enzyme replacement therapy (ERT), the standard of care, is less effective with advanced tissue injury and inflammation in patients with FD. Here, we showed that MCP-1 and TNF-α cytokine levels were almost doubled in plasma from ERT-treated FD patients. Chemokine receptor CCR2 surface expression was increased by twofold on monocytes from patients with low eGFR. We also observed an increase in IL12B transcripts in unstimulated peripheral blood mononuclear cells (PBMCs) over a 2-year period of continuous ERT. Apabetalone is a clinical-stage oral bromodomain and extra terminal protein inhibitor (BETi), which has beneficial effects on cardiovascular and kidney disease related pathways including inflammation. Here, we demonstrate that apabetalone, a BD2-selective BETi, dose dependently reduced the production of MCP-1 and IL-12 in stimulated PBMCs through transcriptional regulation of their encoding genes. Reactive oxygen species production was diminished by up to 80% in stimulated neutrophils following apabetalone treatment, corresponding with inhibition of NOX2 transcription. This study elucidates that inhibition of BET proteins by BD2-selective apabetalone alleviates inflammatory processes and oxidative stress in innate immune cells in general and in FD. These results suggest potential benefit of BD2-selective apabetalone in controlling inflammation and oxidative stress in FD, which will be further investigated in clinical trials.
MeSH term(s)	Cytokines/metabolism ; Enzyme Replacement Therapy ; Epigenesis, Genetic ; Fabry Disease/drug therapy ; Fabry Disease/genetics ; Fabry Disease/metabolism ; Humans ; Immunity, Innate ; Inflammation/drug therapy ; Inflammation/genetics ; Leukocytes, Mononuclear/metabolism ; Quinazolinones
Chemical Substances	Cytokines ; Quinazolinones ; apabetalone (8R4A7GDZ1D)
Language	English
Publishing date	2022-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2740389-0
ISSN	2052-1707 ; 2052-1707
ISSN (online)	2052-1707
ISSN	2052-1707
DOI	10.1002/prp2.949
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Breaking boundaries: Pan BETi disrupt 3D chromatin structure, BD2-selective BETi are strictly epigenetic transcriptional regulators.

Tsujikawa, Laura M / Kharenko, Olesya A / Stotz, Stephanie C / Rakai, Brooke D / Sarsons, Christopher D / Gilham, Dean / Wasiak, Sylwia / Fu, Li / Sweeney, Michael / Johansson, Jan O / Wong, Norman C W / Kulikowski, Ewelina

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2022 Volume 152, Page(s) 113230

Abstract: Background: Bromodomain and extraterminal proteins (BETs) are more than just epigenetic regulators of transcription. Here we highlight a new role for the BET protein BRD4 in the maintenance of higher order chromatin structure at Topologically ... ...

Abstract	Background: Bromodomain and extraterminal proteins (BETs) are more than just epigenetic regulators of transcription. Here we highlight a new role for the BET protein BRD4 in the maintenance of higher order chromatin structure at Topologically Associating Domain Boundaries (TADBs). BD2-selective and pan (non-selective) BET inhibitors (BETi) differentially support chromatin structure, selectively affecting transcription and cell viability. Methods: Using RNA-seq and BRD4 ChIP-seq, the differential effect of BETi treatment on the transcriptome and BRD4 chromatin occupancy of human aortic endothelial cells from diabetic patients (dHAECs) stimulated with TNFα was evaluated. Chromatin decondensation and DNA fragmentation was assessed by immunofluorescence imaging and quantification. Key dHAEC findings were verified in proliferating monocyte-like THP-1 cells using real time-PCR, BRD4 co-immunoprecipitation studies, western blots, proliferation and apoptosis assays. Findings: We discovered that 1) BRD4 co-localizes with Ying-Yang 1 (YY1) at TADBs, critical chromatin structure complexes proximal to many DNA repair genes. 2) BD2-selective BETi enrich BRD4/YY1 associations, while pan-BETi do not. 3) Failure to support chromatin structures through BRD4/YY1 enrichment inhibits DNA repair gene transcription, which induces DNA damage responses, and causes widespread chromatin decondensation, DNA fragmentation, and apoptosis. 4) BD2-selective BETi maintain high order chromatin structure and cell viability, while reducing deleterious pro-inflammatory transcription. Interpretation: BRD4 plays a previously unrecognized role at TADBs. BETi differentially impact TADB stability. Our results provide translational insight for the development of BETi as therapeutics for a range of diseases including CVD, chronic kidney disease, cancer, and COVID-19.
MeSH term(s)	COVID-19 ; Cell Cycle Proteins/metabolism ; Chromatin ; Endothelial Cells/metabolism ; Epigenesis, Genetic ; Humans ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Transcription Factors/metabolism
Chemical Substances	BRD4 protein, human ; Cell Cycle Proteins ; Chromatin ; Nuclear Proteins ; Transcription Factors
Language	English
Publishing date	2022-06-07
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2022.113230
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Ud II Zs.198: 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)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Epigenetic BET reader inhibitor apabetalone (RVX-208) counters proinflammatory aortic gene expression in a diet induced obesity mouse model and in human endothelial cells.

Wasiak, Sylwia / Tsujikawa, Laura M / Daze, Emily / Gilham, Dean / Stotz, Stephanie C / Rakai, Brooke D / Sarsons, Chris D / Fu, Li / Azhar, Salman / Jahagirdar, Ravi / Sweeney, Michael / Johansson, Jan O / Wong, Norman C W / Kulikowski, Ewelina

Atherosclerosis

2022 Volume 364, Page(s) 10–19

Abstract: Background and aims: Obese patients are at risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). A lipid-rich diet promotes arterial changes by inducing hypertension, oxidative stress, and inflammation. Bromodomain and extraterminal ...

Abstract	Background and aims: Obese patients are at risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). A lipid-rich diet promotes arterial changes by inducing hypertension, oxidative stress, and inflammation. Bromodomain and extraterminal (BET) proteins contribute to endothelial and immune cell activation in vitro and in atherosclerosis mouse models. We aim to determine if BET inhibition can reduce lipid-rich diet-induced vascular inflammation in mice. Methods: Body weight, serum glucose and lipid levels were measured in mice fed a high-fat diet (HFD) or low-fat diet (LFD) for 6 weeks and at study termination. BET inhibitors apabetalone and JQ1 were co-administered with the HFD for additional 16 weeks. Aortic gene expression was analyzed post necropsy by PCR, Nanostring nCounter® Inflammation Panel and bioinformatics pathway analysis. Transcription changes and BRD4 chromatin occupancy were analyzed in primary human endothelial cells in response to TNFα and apabetalone. Results: HFD induced weight gain, visceral obesity, high fasting blood glucose, glucose intolerance and insulin resistance compared to LFD controls. HFD upregulated the aortic expression of 47 genes involved in inflammation, innate immunity, cytoskeleton and complement pathways. Apabetalone and JQ1 treatment reduced HFD-induced aortic expression of proinflammatory genes. Congruently, bioinformatics predicted enhanced signaling by TNFα in the HFD versus LFD aorta, which was countered by BETi treatment. TNFα-stimulated human endothelial cells had increased expression of HFD-sensitive genes and higher BRD4 chromatin occupancy, which was countered by apabetalone treatment. Conclusions: HFD induces vascular inflammation in mice through TNFα signaling. Apabetalone treatment reduces this proinflammatory phenotype, providing mechanistic insight into how BET inhibitors may reduce CVD risk in obese patients.
MeSH term(s)	Animals ; Humans ; Mice ; Aorta/metabolism ; Cardiovascular Diseases/metabolism ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/genetics ; Diet, High-Fat/adverse effects ; Endothelial Cells/metabolism ; Epigenesis, Genetic ; Gene Expression/drug effects ; Inflammation/drug therapy ; Inflammation/genetics ; Lipids ; Mice, Inbred C57BL ; Nuclear Proteins/genetics ; Obesity/complications ; Obesity/drug therapy ; Obesity/genetics ; Transcription Factors/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Nerve Tissue Proteins/genetics ; Receptors, Cell Surface/genetics ; Mice, Obese
Chemical Substances	apabetalone (8R4A7GDZ1D) ; BRD4 protein, human ; Lipids ; Nuclear Proteins ; Transcription Factors ; Tumor Necrosis Factor-alpha ; DNER protein, human ; Dner protein, mouse ; Nerve Tissue Proteins ; Receptors, Cell Surface
Language	English
Publishing date	2022-11-23
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2022.11.015
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 226: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Anion-sensitive fluorophore identifies the Drosophila swell-activated chloride channel in a genome-wide RNA interference screen.

Stotz, Stephanie C / Clapham, David E

PloS one

2012 Volume 7, Issue 10, Page(s) e46865

Abstract: When cells swell in hypo-osmotic solutions, chloride-selective ion channels (Cl(swell)) activate to reduce intracellular osmolality and prevent catastrophic cell rupture. Despite intensive efforts to assign a molecular identity to the mammalian Cl(swell) ...

Abstract	When cells swell in hypo-osmotic solutions, chloride-selective ion channels (Cl(swell)) activate to reduce intracellular osmolality and prevent catastrophic cell rupture. Despite intensive efforts to assign a molecular identity to the mammalian Cl(swell) channel, it remains unknown. In an unbiased genome-wide RNA interference (RNAi) screen of Drosophila cells stably expressing an anion-sensitive fluorescent indicator, we identify Bestrophin 1 (dBest1) as the Drosophila Cl(swell) channel. Of the 23 screen hits with mammalian homologs and predicted transmembrane domains, only RNAi specifically targeting dBest1 eliminated the Cl(swell) current (I(Clswell)). We further demonstrate the essential contribution of dBest1 to Drosophila I(Clswell) with the introduction of a human Bestrophin disease-associated mutation (W94C). Overexpression of the W94C construct in Drosophila cells significantly reduced the endogenous I(Clswell). We confirm that exogenous expression of dBest1 alone in human embryonic kidney (HEK293) cells creates a clearly identifiable Drosophila-like I(Clswell). In contrast, activation of mouse Bestrophin 2 (mBest2), the closest mammalian ortholog of dBest1, is swell-insensitive. The first 64 residues of dBest1 conferred swell activation to mBest2. The chimera, however, maintains mBest2-like pore properties, strongly indicating that the Bestrophin protein forms the Cl(swell) channel itself rather than functioning as an essential auxiliary subunit. dBest1 is an anion channel clearly responsive to swell; this activation depends upon its N-terminus.
MeSH term(s)	Amino Acid Sequence ; Animals ; Bestrophins ; Chloride Channels/chemistry ; Chloride Channels/deficiency ; Chloride Channels/genetics ; Chloride Channels/metabolism ; Drosophila Proteins/chemistry ; Drosophila Proteins/deficiency ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/cytology ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Genomics ; Humans ; Luminescent Proteins/metabolism ; Mice ; Molecular Sequence Data ; Mutation ; RNA Interference
Chemical Substances	Bestrophins ; Chloride Channels ; Drosophila Proteins ; Luminescent Proteins ; best1 protein, Drosophila
Language	English
Publishing date	2012-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0046865
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article: Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-Cov-2 Infection In Vitro.

Gilham, Dean / Smith, Audrey L / Fu, Li / Moore, Dalia Y / Muralidharan, Abenaya / Reid, St Patrick M / Stotz, Stephanie C / Johansson, Jan O / Sweeney, Michael / Wong, Norman C W / Kulikowski, Ewelina / El-Gamal, Dalia

Biomedicines

2021 Volume 9, Issue 4

Abstract: Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively ... ...

Abstract	Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.
Language	English
Publishing date	2021-04-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines9040437
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response

Wasiak, Sylwia / Gilham, Dean / Daze, Emily / Tsujikawa, Laura M / Halliday, Christopher / Stotz, Stephanie C / Rakai, Brooke D / Fu, Li / Jahagirdar, Ravi / Sweeney, Michael / Johansson, Jan O / Wong, Norman C W / Kulikowski, Ewelina

Cardiovascular therapeutics

2020 Volume 2020, Page(s) 9397109

Abstract: ... the expression of C-reactive protein (CRP), alpha-2-macroglobulin, and serum amyloid P. The latter two are also ...

Abstract	Chronic systemic inflammation contributes to cardiovascular disease (CVD) and correlates with the abundance of acute phase response (APR) proteins in the liver and plasma. Bromodomain and extraterminal (BET) proteins are epigenetic readers that regulate inflammatory gene transcription. We show that BET inhibition by the small molecule apabetalone reduces APR gene and protein expression in human hepatocytes, mouse models, and plasma from CVD patients. Steady-state expression of serum amyloid P, plasminogen activator inhibitor 1, and ceruloplasmin, APR proteins linked to CVD risk, is reduced by apabetalone in cultured hepatocytes and in humanized mouse liver. In cytokine-stimulated hepatocytes, apabetalone reduces the expression of C-reactive protein (CRP), alpha-2-macroglobulin, and serum amyloid P. The latter two are also reduced by apabetalone in the liver of endotoxemic mice. BET knockdown
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Binding Sites ; C-Reactive Protein/genetics ; C-Reactive Protein/metabolism ; Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/metabolism ; Cells, Cultured ; Ceruloplasmin/genetics ; Ceruloplasmin/metabolism ; Cytokines/genetics ; Cytokines/metabolism ; Disease Models, Animal ; Endotoxemia/drug therapy ; Endotoxemia/genetics ; Endotoxemia/metabolism ; Epigenesis, Genetic/drug effects ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Male ; Mice, Inbred C57BL ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Plasminogen Activator Inhibitor 1/metabolism ; Promoter Regions, Genetic ; Quinazolinones/pharmacology ; Serum Amyloid P-Component/metabolism ; Signal Transduction ; Transcription Factors/genetics ; Transcription Factors/metabolism ; alpha-Macroglobulins/genetics ; alpha-Macroglobulins/metabolism
Chemical Substances	A2M protein, human ; Anti-Inflammatory Agents ; Brd4 protein, mouse ; Cytokines ; Nuclear Proteins ; Plasminogen Activator Inhibitor 1 ; Quinazolinones ; SERPINE1 protein, human ; Serum Amyloid P-Component ; Transcription Factors ; alpha-Macroglobulins ; apabetalone (8R4A7GDZ1D) ; C-Reactive Protein (9007-41-4) ; Ceruloplasmin (EC 1.16.3.1)
Language	English
Publishing date	2020-07-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2428378-2
ISSN	1755-5922 ; 1755-5914
ISSN (online)	1755-5922
ISSN	1755-5914
DOI	10.1155/2020/9397109
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 2474: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: BET protein inhibitor apabetalone (RVX-208) suppresses pro-inflammatory hyper-activation of monocytes from patients with cardiovascular disease and type 2 diabetes.

Wasiak, Sylwia / Dzobo, Kim E / Rakai, Brooke D / Kaiser, Yannick / Versloot, Miranda / Bahjat, Mahnoush / Stotz, Stephanie C / Fu, Li / Sweeney, Michael / Johansson, Jan O / Wong, Norman C W / Stroes, Erik S G / Kroon, Jeffrey / Kulikowski, Ewelina

Clinical epigenetics

2020 Volume 12, Issue 1, Page(s) 166

Abstract: Background: Patients with cardiovascular disease (CVD) and type 2 diabetes (DM2) have a high residual risk for experiencing a major adverse cardiac event. Dysregulation of epigenetic mechanisms of gene transcription in innate immune cells contributes to ...

Abstract	Background: Patients with cardiovascular disease (CVD) and type 2 diabetes (DM2) have a high residual risk for experiencing a major adverse cardiac event. Dysregulation of epigenetic mechanisms of gene transcription in innate immune cells contributes to CVD development but is currently not targeted by therapies. Apabetalone (RVX-208) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins-histone acetylation readers that drive pro-inflammatory and pro-atherosclerotic gene transcription. Here, we assess the impact of apabetalone on ex vivo inflammatory responses of monocytes from DM2 + CVD patients. Results: Monocytes isolated from DM2 + CVD patients and matched controls were treated ex vivo with apabetalone, interferon γ (IFNγ), IFNγ + apabetalone or vehicle and phenotyped for gene expression and protein secretion. Unstimulated DM2 + CVD monocytes had higher baseline IL-1α, IL-1β and IL-8 cytokine gene expression and Toll-like receptor (TLR) 2 surface abundance than control monocytes, indicating pro-inflammatory activation. Further, DM2 + CVD monocytes were hyper-responsive to stimulation with IFNγ, upregulating genes within cytokine and NF-κB pathways > 30% more than control monocytes (p < 0.05). Ex vivo apabetalone treatment countered cytokine secretion by DM2 + CVD monocytes at baseline (GROα and IL-8) and during IFNγ stimulation (IL-1β and TNFα). Apabetalone abolished pro-inflammatory hyper-activation by reducing TLR and cytokine gene signatures more robustly in DM2 + CVD versus control monocytes. Conclusions: Monocytes isolated from DM2 + CVD patients receiving standard of care therapies are in a hyper-inflammatory state and hyperactive upon IFNγ stimulation. Apabetalone treatment diminishes this pro-inflammatory phenotype, providing mechanistic insight into how BET protein inhibition may reduce CVD risk in DM2 patients.
MeSH term(s)	Aged ; Atherosclerosis/genetics ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/immunology ; Cardiovascular Diseases/pathology ; Case-Control Studies ; Cytokines/drug effects ; DNA Methylation ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/immunology ; Diabetes Mellitus, Type 2/pathology ; Epigenesis, Genetic ; Female ; Humans ; Inflammation/metabolism ; Interleukin-18/genetics ; Male ; Middle Aged ; Monocytes/drug effects ; Monocytes/metabolism ; Phenotype ; Proteins/antagonists & inhibitors ; Quinazolinones/pharmacology ; Quinazolinones/therapeutic use ; Toll-Like Receptor 2/drug effects ; Transcription Factors
Chemical Substances	Cytokines ; Interleukin-18 ; Proteins ; Quinazolinones ; TLR2 protein, human ; Toll-Like Receptor 2 ; Transcription Factors ; bromodomain and extra-terminal domain protein, human ; apabetalone (8R4A7GDZ1D)
Language	English
Publishing date	2020-11-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553921-8
ISSN	1868-7083 ; 1868-7075
ISSN (online)	1868-7083
ISSN	1868-7075
DOI	10.1186/s13148-020-00943-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

To top

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito