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  1. Christiane Neuber, June Uebeler, Thomas Schulze, Hannieh Sotoud, Ali El-Armouche and Thomas Eschenhagen.
    Guanabenz Interferes with ER Stress and Exerts Protective Effects in Cardiac Myocytes.. PloS one 9(6):e98893, January 2014.
    Abstract 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, $\alpha$2-adrenoceptor agonist) and subsequent inhibition of stress-induced dephosphorylation of eukaryotic translation initiation factor 2$\alpha$ (eIF2$\alpha$) results in prolonged eIF2$\alpha$ 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-eIF2$\alpha$, 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.
    URL, DOI BibTeX

    @article{Neuber2014,
    	abstract = "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, $\alpha$2-adrenoceptor agonist) and subsequent inhibition of stress-induced dephosphorylation of eukaryotic translation initiation factor 2$\alpha$ (eIF2$\alpha$) results in prolonged eIF2$\alpha$ 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-eIF2$\alpha$, 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.",
    	author = "Neuber, Christiane and Uebeler, June and Schulze, Thomas and Sotoud, Hannieh and El-Armouche, Ali and Eschenhagen, Thomas",
    	doi = "10.1371/journal.pone.0098893",
    	issn = "1932-6203",
    	journal = "PloS one",
    	month = "jan",
    	number = 6,
    	pages = "e98893",
    	pmid = 24892553,
    	title = "{Guanabenz Interferes with ER Stress and Exerts Protective Effects in Cardiac Myocytes.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4044035\&tool=pmcentrez\&rendertype=abstract",
    	volume = 9,
    	year = 2014
    }
    
  2. H-Q Jiang, M Ren, H-Z Jiang, J Wang, J Zhang, X Yin, S-Y Wang, Y Qi, X-D Wang and H-L Feng.
    Guanabenz delays the onset of disease symptoms, extends lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis.. Neuroscience, 2014.
    Abstract Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease characterized by the loss of motor neurons in the motor cortex, brain stem and spinal cord. Currently, there is no cure for this lethal disease. Although the mechanism underlying neuronal cell death in ALS remains elusive, growing evidence supports a crucial role of endoplasmic reticulum (ER) stress in the pathogenesis of ALS. Recent reports show that guanabenz, a novel inhibitor of eukaryotic initiation factor 2$\alpha$ (eIF2$\alpha$) dephosphorylation, possesses anti-prion properties, attenuates ER stress and reduces paralysis and neurodegeneration in mTDP-43 Caenorhabditis elegans and Danio rerio models of ALS. However, the therapeutic potential of guanabenz for the treatment of ALS has not yet been assessed in a mouse model of ALS. In the present study, guanabenz was administered to a widely used mouse model of ALS expressing copper zinc superoxide dismutase-1 (SOD1) with a glycine to alanine mutation at position 93 (G93A). The results showed that the administration of guanabenz significantly extended the lifespan, delayed the onset of disease symptoms, improved motor performance and attenuated motor neuron loss in female SOD1 G93A mice. Moreover, western blotting results revealed that guanabenz dramatically increased the levels of phosphorylated-eIF2$\alpha$ (P-eIF2$\alpha$) protein, without affecting total eIF2$\alpha$ protein levels. The results also revealed a significant decrease in the levels of the ER chaperone glucose-regulated protein 78 (BiP/Grp78) and markers of another two ER stress pathways, activating transcription factor 6$\alpha$ (ATF6$\alpha$) and inositol-requiring enzyme 1 (IRE1). In addition, guanabenz increased the protein levels of anti-apoptotic B cell lymphoma/lewkmia-2 (Bcl-2), and down-regulated the pro-apoptotic protein levels of C/EBP homologous protein (CHOP), Bcl-2-associated X protein (BAX) and cytochrome C in SOD1 G93A mice. Our findings indicate that guanabenz may represent a novel therapeutic candidate for the treatment of ALS, a lethal human disease with an underlying mechanism involving the attenuation of ER stress and mitochondrial stress via prolonging eIF2$\alpha$ phosphorylation.
    URL, DOI BibTeX

    @article{Jiang2014,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease characterized by the loss of motor neurons in the motor cortex, brain stem and spinal cord. Currently, there is no cure for this lethal disease. Although the mechanism underlying neuronal cell death in ALS remains elusive, growing evidence supports a crucial role of endoplasmic reticulum (ER) stress in the pathogenesis of ALS. Recent reports show that guanabenz, a novel inhibitor of eukaryotic initiation factor 2$\alpha$ (eIF2$\alpha$) dephosphorylation, possesses anti-prion properties, attenuates ER stress and reduces paralysis and neurodegeneration in mTDP-43 Caenorhabditis elegans and Danio rerio models of ALS. However, the therapeutic potential of guanabenz for the treatment of ALS has not yet been assessed in a mouse model of ALS. In the present study, guanabenz was administered to a widely used mouse model of ALS expressing copper zinc superoxide dismutase-1 (SOD1) with a glycine to alanine mutation at position 93 (G93A). The results showed that the administration of guanabenz significantly extended the lifespan, delayed the onset of disease symptoms, improved motor performance and attenuated motor neuron loss in female SOD1 G93A mice. Moreover, western blotting results revealed that guanabenz dramatically increased the levels of phosphorylated-eIF2$\alpha$ (P-eIF2$\alpha$) protein, without affecting total eIF2$\alpha$ protein levels. The results also revealed a significant decrease in the levels of the ER chaperone glucose-regulated protein 78 (BiP/Grp78) and markers of another two ER stress pathways, activating transcription factor 6$\alpha$ (ATF6$\alpha$) and inositol-requiring enzyme 1 (IRE1). In addition, guanabenz increased the protein levels of anti-apoptotic B cell lymphoma/lewkmia-2 (Bcl-2), and down-regulated the pro-apoptotic protein levels of C/EBP homologous protein (CHOP), Bcl-2-associated X protein (BAX) and cytochrome C in SOD1 G93A mice. Our findings indicate that guanabenz may represent a novel therapeutic candidate for the treatment of ALS, a lethal human disease with an underlying mechanism involving the attenuation of ER stress and mitochondrial stress via prolonging eIF2$\alpha$ phosphorylation.",
    	author = "Jiang, H-Q and Ren, M and Jiang, H-Z and Wang, J and Zhang, J and Yin, X and Wang, S-Y and Qi, Y and Wang, X-D and Feng, H-L",
    	doi = "10.1016/j.neuroscience.2014.03.047",
    	issn = "1873-7544",
    	journal = "Neuroscience",
    	month = "",
    	pmid = 24699224,
    	title = "{Guanabenz delays the onset of disease symptoms, extends lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24699224",
    	year = 2014
    }
    
  3. Melissa J Fullwood, Wei Zhou and Shirish Shenolikar.
    Targeting phosphorylation of eukaryotic initiation factor-2$\alpha$ to treat human disease.. Progress in molecular biology and translational science 106:75–106, 2012.
    Abstract The unfolded protein response, also known as endoplasmic reticulum (ER) stress, has been implicated in numerous human diseases, including atherosclerosis, cancer, diabetes, and neurodegenerative disorders. Protein misfolding activates one or more of the three ER transmembrane sensors to initiate a complex network of signaling that transiently suppresses protein translation while also enhancing protein folding and proteasomal degradation of misfolded proteins to ensure full recovery from ER stress. Gene disruption studies in mice have provided critical insights into the role of specific signaling components and pathways in the differing responses of animal tissues to ER stress. These studies have emphasized an important contribution of translational repression to sustained insulin synthesis and $\beta$-cell viability in experimental models of type-2 diabetes. This has focused attention on the recently discovered small-molecule inhibitors of eIF2$\alpha$ phosphatases that prolong eIF2$\alpha$ phosphorylation to reduce cell death in several animal models of human disease. These compounds show significant cytoprotection in cellular and animal models of neurodegenerative disorders, highlighting a potential strategy for future development of drugs to treat human protein misfolding disorders.
    URL, DOI BibTeX

    @article{Fullwood2012,
    	abstract = "The unfolded protein response, also known as endoplasmic reticulum (ER) stress, has been implicated in numerous human diseases, including atherosclerosis, cancer, diabetes, and neurodegenerative disorders. Protein misfolding activates one or more of the three ER transmembrane sensors to initiate a complex network of signaling that transiently suppresses protein translation while also enhancing protein folding and proteasomal degradation of misfolded proteins to ensure full recovery from ER stress. Gene disruption studies in mice have provided critical insights into the role of specific signaling components and pathways in the differing responses of animal tissues to ER stress. These studies have emphasized an important contribution of translational repression to sustained insulin synthesis and $\beta$-cell viability in experimental models of type-2 diabetes. This has focused attention on the recently discovered small-molecule inhibitors of eIF2$\alpha$ phosphatases that prolong eIF2$\alpha$ phosphorylation to reduce cell death in several animal models of human disease. These compounds show significant cytoprotection in cellular and animal models of neurodegenerative disorders, highlighting a potential strategy for future development of drugs to treat human protein misfolding disorders.",
    	author = "Fullwood, Melissa J and Zhou, Wei and Shenolikar, Shirish",
    	doi = "10.1016/B978-0-12-396456-4.00005-5",
    	issn = "1878-0814",
    	journal = "Progress in molecular biology and translational science",
    	keywords = "Animals,Atherosclerosis,Atherosclerosis: drug therapy,Atherosclerosis: metabolism,Cinnamates,Cinnamates: pharmacology,Cinnamates: therapeutic use,Diabetes Mellitus,Diabetes Mellitus: drug therapy,Diabetes Mellitus: metabolism,Endoplasmic Reticulum Stress,Endoplasmic Reticulum Stress: drug effects,Endoplasmic Reticulum Stress: genetics,Endoplasmic Reticulum Stress: physiology,Eukaryotic Cells,Eukaryotic Cells: metabolism,Eukaryotic Initiation Factor-2,Eukaryotic Initiation Factor-2: metabolism,Gene Knock-In Techniques,Guanabenz,Guanabenz: pharmacology,Guanabenz: therapeutic use,Humans,Mice,Mice, Knockout,Mice, Transgenic,Models, Biological,Molecular Targeted Therapy,Neoplasms,Neoplasms: drug therapy,Neoplasms: metabolism,Neurodegenerative Diseases,Neurodegenerative Diseases: drug therapy,Neurodegenerative Diseases: metabolism,Phosphoprotein Phosphatases,Phosphoprotein Phosphatases: antagonists \& inhibit,Phosphoprotein Phosphatases: metabolism,Phosphorylation,Phosphorylation: drug effects,Proteasome Endopeptidase Complex,Proteasome Endopeptidase Complex: metabolism,Protein Biosynthesis,Protein Biosynthesis: drug effects,Protein Folding,Protein Folding: drug effects,Protein Processing, Post-Translational,Protein Processing, Post-Translational: drug effec,Thiourea,Thiourea: analogs \& derivatives,Thiourea: pharmacology,Thiourea: therapeutic use,Unfolded Protein Response,Unfolded Protein Response: drug effects,Unfolded Protein Response: genetics",
    	month = "",
    	pages = "75--106",
    	pmid = 22340715,
    	title = "{Targeting phosphorylation of eukaryotic initiation factor-2$\alpha$ to treat human disease.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22340715",
    	volume = 106,
    	year = 2012
    }