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Thomas Eschenhagen - One of the best experts on this subject based on the ideXlab platform.
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Guanabenz Interferes with ER Stress and Exerts Protective Effects in Cardiac Myocytes
2016Co-Authors: Christiane Neuber, June Uebeler, Thomas Schulze, Hannieh Sotoud, Ali El-armouche, Thomas EschenhagenAbstract:Endoplasmic reticulum (ER) stress has been implicated in a variety of cardiovascular diseases. During ER stress, disruption of the complex of protein phosphatase 1 regulatory subunit 15A and catalytic subunit of protein phosphatase 1 by the small molecule Guanabenz (antihypertensive, a2-adrenoceptor agonist) and subsequent inhibition of stress-induced dephos-phorylation of eukaryotic translation initiation factor 2a (eIF2a) results in prolonged eIF2a phosphorylation, inhibition of protein synthesis and protection from ER stress. In this study we assessed whether Guanabenz protects against ER stress in cardiac myocytes and affects the function of 3 dimensional engineered heart tissue (EHT). We utilized neonatal rat cardiac myocytes for the assessment of cell viability and activation of ER stress-signalling pathways and EHT for functional analysis. (i) Tunicamycin induced ER stress as measured by increased mRNA and protein levels of glucose-regulated protein 78 kDa, P-eIF2a, activating transcription factor 4, C/EBP homologous protein, and cell death. (ii) Guanabenz had no measurable effect alone, but antagonized the effects of tunicamycin on ER stress markers. (iii) Tunicamycin and other known inducers of ER stress (hydrogen peroxide, doxorubicin, thapsigargin) induced cardiac myocyte death, and this was antagonized by Guanabenz in a concentration- and time-dependent manner. (iv) ER stressors also induced acute or delayed contractile dysfunction in spontaneously beating EHTs and this was, with the notable exception of relaxation deficits under thapsigargin, not significantly affected by Guanabenz. The data confirm that Guanabenz interferes with ER stress-signallin
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Guanabenz interferes with ER stress and exerts protective effects in cardiac myocytes.
PloS one, 2014Co-Authors: Christiane Neuber, June Uebeler, Thomas Schulze, Hannieh Sotoud, Ali El-armouche, Thomas EschenhagenAbstract:Endoplasmic reticulum (ER) stress has been implicated in a variety of cardiovascular diseases. During ER stress, disruption of the complex of protein phosphatase 1 regulatory subunit 15A and catalytic subunit of protein phosphatase 1 by the small molecule Guanabenz (antihypertensive, α2-adrenoceptor agonist) and subsequent inhibition of stress-induced dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) results in prolonged eIF2α phosphorylation, inhibition of protein synthesis and protection from ER stress. In this study we assessed whether Guanabenz protects against ER stress in cardiac myocytes and affects the function of 3 dimensional engineered heart tissue (EHT). We utilized neonatal rat cardiac myocytes for the assessment of cell viability and activation of ER stress-signalling pathways and EHT for functional analysis. (i) Tunicamycin induced ER stress as measured by increased mRNA and protein levels of glucose-regulated protein 78 kDa, P-eIF2α, activating transcription factor 4, C/EBP homologous protein, and cell death. (ii) Guanabenz had no measurable effect alone, but antagonized the effects of tunicamycin on ER stress markers. (iii) Tunicamycin and other known inducers of ER stress (hydrogen peroxide, doxorubicin, thapsigargin) induced cardiac myocyte death, and this was antagonized by Guanabenz in a concentration- and time-dependent manner. (iv) ER stressors also induced acute or delayed contractile dysfunction in spontaneously beating EHTs and this was, with the notable exception of relaxation deficits under thapsigargin, not significantly affected by Guanabenz. The data confirm that Guanabenz interferes with ER stress-signalling and has protective effects on cell survival. Data show for the first time that this concept extends to cardiac myocytes. The modest protection in EHTs points to more complex mechanisms of force regulation in intact functional heart muscle.
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Impact of Guanabenz on EHT contractility during exposure to ER stress.
2014Co-Authors: Christiane Neuber, June Uebeler, Thomas Schulze, Hannieh Sotoud, Ali El-armouche, Thomas EschenhagenAbstract:(A) Force development of EHTs after treatment with tunicamycin (Tm; 2.5 µg/ml) for 12, 24, 36 and 48 hours, with or without Guanabenz (Ga; 2.5 µM). Pre-drug values Tm: 0.17±0.01 vs. Ga: 0.17±0.02. (B) Force development of EHTs with or without Guanabenz (2.5 µM) during 30 min acute exposure to H2O2 (600 µM) and during following 20 hours recovery time. Pre-drug values Tm: 0.16±0.01 vs. Ga: 0.16±0.01. (C) Representative beating pattern of an EHT treated with thapsigargin (Tg; 500 nM) for 1 hour, with or without Guanabenz (3 µM, 10 µM) compared to an untreated control EHT. (D) Force development of EHTs after treatment with doxorubicin (Dox; 100 nM) for 12, 24 and 48 hours, with or without Guanabenz (2.5 µM). Pre-drug values Tm: 0.15±0.03 vs. Ga: 0.16±0.02. Data are means ± SEM (n = 4–6). All drugs showed a time-dependent effect on EHT contractility (Two-way ANOVA, row factor, P
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Effects of tunicamycin and Guanabenz on different branches of the UPR in NRCM on the protein level.
2014Co-Authors: Christiane Neuber, June Uebeler, Thomas Schulze, Hannieh Sotoud, Ali El-armouche, Thomas EschenhagenAbstract:Upper panel – representative immunoblots of lysates of NRCMs treated with tunicamycin (left) or Guanabenz (right) for 12 and 24 hours, respectively. Lower panel – concentration-dependent increase of UPR targets proteins after treatment with tunicamycin (Tm) or Guanabenz (Ga) compared to DMSO control. Please note that the intensity of the upper unspecific band for GRP78 is caused by differences in blotting conditions (10% acrylamide/bisacrylamide gel). Data are means ± SEM (n = 3); *P
Ruqaiyyah Siddiqui - One of the best experts on this subject based on the ideXlab platform.
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repositioning of Guanabenz in conjugation with gold and silver nanoparticles against pathogenic amoebae acanthamoeba castellanii and naegleria fowleri
ACS Infectious Diseases, 2019Co-Authors: Areeba Anwar, Naveed Ahmed Khan, Mohammad Ridwane Mungroo, Ayaz Anwar, William Sullivan, Ruqaiyyah SiddiquiAbstract:Brain-eating amoebae cause devastating infections in the central nervous system of humans, resulting in a mortality rate of 95%. There are limited effective therapeutic options available clinically for treating granulomatous amoebic encephalitis and primary amoebic meningoencephalitis caused by Acanthamoeba castellanii (A. castellanii) and Naegleria fowleri (N. fowleri), respectively. Here, we report for the first time that Guanabenz conjugated to gold and silver nanoparticles has significant antiamoebic activity against both A. castellanii and N. fowleri. Gold and silver conjugated Guanabenz nanoparticles were synthesized by the one-phase reduction method and were characterized by ultraviolet–visible spectrophotometry and atomic force microscopy. Both metals were facilely stabilized by the coating of Guanabenz, which was examined by surface plasmon resonance determination. The average size of gold nanoconjugated Guanabenz was found to be 60 nm, whereas silver nanoparticles were produced in a larger size ...
Alexandre Dalet - One of the best experts on this subject based on the ideXlab platform.
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Guanabenz inhibits tlr9 signaling through a pathway that is independent of eif2α dephosphorylation by the gadd34 pp1c complex
Science Signaling, 2018Co-Authors: Jessica Perego, Andreia Mendes, Clarisse Bourbon, Voahirana Camosseto, Alexis Combes, Hong Liu, Thienphong Vu Manh, Alexandre DaletAbstract:Endoplasmic reticulum (ER) stress triggers or amplifies inflammatory signals and cytokine production in immune cells. Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2α, thereby enabling protein translation to resume. Several aminoguanidine compounds, such as Guanabenz, perturb the eIF2α phosphorylation-dephosphorylation cycle and protect different cell or tissue types from protein misfolding and degeneration. We investigated how pharmacological interference with the eIF2α pathway could be beneficial to treat autoinflammatory diseases dependent on proinflammatory cytokines and type I interferons (IFNs), the production of which is regulated by GADD34 in dendritic cells (DCs). In mouse and human DCs and B cells, Guanabenz prevented the activation of Toll-like receptor 9 (TLR9) by CpG oligodeoxynucleotides or DNA-immunoglobulin complexes in endosomes. In vivo, Guanabenz protected mice from CpG oligonucleotide–dependent cytokine shock and decreased autoimmune symptom severity in a chemically induced model of systemic lupus erythematosus. However, we found that Guanabenz exerted its inhibitory effect independently of GADD34 activity on eIF2α and instead decreased the abundance of CH25H, a cholesterol hydroxylase linked to antiviral immunity. Our results therefore suggest that Guanabenz and similar compounds could be used to treat type I IFN–dependent pathologies and that CH25H could be a therapeutic target to control these diseases.
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Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complex.
Science signaling, 2018Co-Authors: Jessica Perego, Andreia Mendes, Clarisse Bourbon, Voahirana Camosseto, Alexis Combes, Hong Liu, Thienphong Vu Manh, Alexandre Dalet, Lionel Chasson, Lionel SpinelliAbstract:Endoplasmic reticulum (ER) stress triggers or amplifies inflammatory signals and cytokine production in immune cells. Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2α, thereby enabling protein translation to resume. Several aminoguanidine compounds, such as Guanabenz, perturb the eIF2α phosphorylation-dephosphorylation cycle and protect different cell or tissue types from protein misfolding and degeneration. We investigated how pharmacological interference with the eIF2α pathway could be beneficial to treat autoinflammatory diseases dependent on proinflammatory cytokines and type I interferons (IFNs), the production of which is regulated by GADD34 in dendritic cells (DCs). In mouse and human DCs and B cells, Guanabenz prevented the activation of Toll-like receptor 9 (TLR9) by CpG oligodeoxynucleotides or DNA-immunoglobulin complexes in endosomes. In vivo, Guanabenz protected mice from CpG oligonucleotide–dependent cytokine shock and decreased autoimmune symptom severity in a chemically induced model of systemic lupus erythematosus. However, we found that Guanabenz exerted its inhibitory effect independently of GADD34 activity on eIF2α and instead decreased the abundance of CH25H, a cholesterol hydroxylase linked to antiviral immunity. Our results therefore suggest that Guanabenz and similar compounds could be used to treat type I IFN–dependent pathologies and that CH25H could be a therapeutic target to control these diseases.
Andreia Mendes - One of the best experts on this subject based on the ideXlab platform.
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Guanabenz inhibits tlr9 signaling through a pathway that is independent of eif2α dephosphorylation by the gadd34 pp1c complex
Science Signaling, 2018Co-Authors: Jessica Perego, Andreia Mendes, Clarisse Bourbon, Voahirana Camosseto, Alexis Combes, Hong Liu, Thienphong Vu Manh, Alexandre DaletAbstract:Endoplasmic reticulum (ER) stress triggers or amplifies inflammatory signals and cytokine production in immune cells. Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2α, thereby enabling protein translation to resume. Several aminoguanidine compounds, such as Guanabenz, perturb the eIF2α phosphorylation-dephosphorylation cycle and protect different cell or tissue types from protein misfolding and degeneration. We investigated how pharmacological interference with the eIF2α pathway could be beneficial to treat autoinflammatory diseases dependent on proinflammatory cytokines and type I interferons (IFNs), the production of which is regulated by GADD34 in dendritic cells (DCs). In mouse and human DCs and B cells, Guanabenz prevented the activation of Toll-like receptor 9 (TLR9) by CpG oligodeoxynucleotides or DNA-immunoglobulin complexes in endosomes. In vivo, Guanabenz protected mice from CpG oligonucleotide–dependent cytokine shock and decreased autoimmune symptom severity in a chemically induced model of systemic lupus erythematosus. However, we found that Guanabenz exerted its inhibitory effect independently of GADD34 activity on eIF2α and instead decreased the abundance of CH25H, a cholesterol hydroxylase linked to antiviral immunity. Our results therefore suggest that Guanabenz and similar compounds could be used to treat type I IFN–dependent pathologies and that CH25H could be a therapeutic target to control these diseases.
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Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complex.
Science signaling, 2018Co-Authors: Jessica Perego, Andreia Mendes, Clarisse Bourbon, Voahirana Camosseto, Alexis Combes, Hong Liu, Thienphong Vu Manh, Alexandre Dalet, Lionel Chasson, Lionel SpinelliAbstract:Endoplasmic reticulum (ER) stress triggers or amplifies inflammatory signals and cytokine production in immune cells. Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2α, thereby enabling protein translation to resume. Several aminoguanidine compounds, such as Guanabenz, perturb the eIF2α phosphorylation-dephosphorylation cycle and protect different cell or tissue types from protein misfolding and degeneration. We investigated how pharmacological interference with the eIF2α pathway could be beneficial to treat autoinflammatory diseases dependent on proinflammatory cytokines and type I interferons (IFNs), the production of which is regulated by GADD34 in dendritic cells (DCs). In mouse and human DCs and B cells, Guanabenz prevented the activation of Toll-like receptor 9 (TLR9) by CpG oligodeoxynucleotides or DNA-immunoglobulin complexes in endosomes. In vivo, Guanabenz protected mice from CpG oligonucleotide–dependent cytokine shock and decreased autoimmune symptom severity in a chemically induced model of systemic lupus erythematosus. However, we found that Guanabenz exerted its inhibitory effect independently of GADD34 activity on eIF2α and instead decreased the abundance of CH25H, a cholesterol hydroxylase linked to antiviral immunity. Our results therefore suggest that Guanabenz and similar compounds could be used to treat type I IFN–dependent pathologies and that CH25H could be a therapeutic target to control these diseases.
Voahirana Camosseto - One of the best experts on this subject based on the ideXlab platform.
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Guanabenz inhibits tlr9 signaling through a pathway that is independent of eif2α dephosphorylation by the gadd34 pp1c complex
Science Signaling, 2018Co-Authors: Jessica Perego, Andreia Mendes, Clarisse Bourbon, Voahirana Camosseto, Alexis Combes, Hong Liu, Thienphong Vu Manh, Alexandre DaletAbstract:Endoplasmic reticulum (ER) stress triggers or amplifies inflammatory signals and cytokine production in immune cells. Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2α, thereby enabling protein translation to resume. Several aminoguanidine compounds, such as Guanabenz, perturb the eIF2α phosphorylation-dephosphorylation cycle and protect different cell or tissue types from protein misfolding and degeneration. We investigated how pharmacological interference with the eIF2α pathway could be beneficial to treat autoinflammatory diseases dependent on proinflammatory cytokines and type I interferons (IFNs), the production of which is regulated by GADD34 in dendritic cells (DCs). In mouse and human DCs and B cells, Guanabenz prevented the activation of Toll-like receptor 9 (TLR9) by CpG oligodeoxynucleotides or DNA-immunoglobulin complexes in endosomes. In vivo, Guanabenz protected mice from CpG oligonucleotide–dependent cytokine shock and decreased autoimmune symptom severity in a chemically induced model of systemic lupus erythematosus. However, we found that Guanabenz exerted its inhibitory effect independently of GADD34 activity on eIF2α and instead decreased the abundance of CH25H, a cholesterol hydroxylase linked to antiviral immunity. Our results therefore suggest that Guanabenz and similar compounds could be used to treat type I IFN–dependent pathologies and that CH25H could be a therapeutic target to control these diseases.
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Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complex.
Science signaling, 2018Co-Authors: Jessica Perego, Andreia Mendes, Clarisse Bourbon, Voahirana Camosseto, Alexis Combes, Hong Liu, Thienphong Vu Manh, Alexandre Dalet, Lionel Chasson, Lionel SpinelliAbstract:Endoplasmic reticulum (ER) stress triggers or amplifies inflammatory signals and cytokine production in immune cells. Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2α, thereby enabling protein translation to resume. Several aminoguanidine compounds, such as Guanabenz, perturb the eIF2α phosphorylation-dephosphorylation cycle and protect different cell or tissue types from protein misfolding and degeneration. We investigated how pharmacological interference with the eIF2α pathway could be beneficial to treat autoinflammatory diseases dependent on proinflammatory cytokines and type I interferons (IFNs), the production of which is regulated by GADD34 in dendritic cells (DCs). In mouse and human DCs and B cells, Guanabenz prevented the activation of Toll-like receptor 9 (TLR9) by CpG oligodeoxynucleotides or DNA-immunoglobulin complexes in endosomes. In vivo, Guanabenz protected mice from CpG oligonucleotide–dependent cytokine shock and decreased autoimmune symptom severity in a chemically induced model of systemic lupus erythematosus. However, we found that Guanabenz exerted its inhibitory effect independently of GADD34 activity on eIF2α and instead decreased the abundance of CH25H, a cholesterol hydroxylase linked to antiviral immunity. Our results therefore suggest that Guanabenz and similar compounds could be used to treat type I IFN–dependent pathologies and that CH25H could be a therapeutic target to control these diseases.
