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  1. Maria Udan-Johns, Rocio Bengoechea, Shaughn Bell, Jieya Shao, Marc I Diamond, Heather L True, Conrad C Weihl and Robert H Baloh.
    Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones.. Human molecular genetics 23(1):157–70, January 2014.
    Abstract TDP-43 aggregation in the cytoplasm or nucleus is a key feature of the pathology of amyotrophic lateral sclerosis and frontotemporal dementia and is observed in numerous other neurodegenerative diseases, including Alzheimer's disease. Despite this fact, the inciting events leading to TDP-43 aggregation remain unclear. We observed that endogenous TDP-43 undergoes reversible aggregation in the nucleus after the heat shock and that this behavior is mediated by the C-terminal prion domain. Substitution of the prion domain from TIA-1 or an authentic yeast prion domain from RNQ1 into TDP-43 can completely recapitulate heat shock-induced aggregation. TDP-43 is constitutively bound to members of the Hsp40/Hsp70 family, and we found that heat shock-induced TDP-43 aggregation is mediated by the availability of these chaperones interacting with the inherently disordered C-terminal prion domain. Finally, we observed that the aggregation of TDP-43 during heat shock led to decreased binding to hnRNPA1, and a change in TDP-43 RNA-binding partners suggesting that TDP-43 aggregation alters its function in response to misfolded protein stress. These findings indicate that TDP-43 shares properties with physiologic prions from yeast, in that self-aggregation is mediated by a Q/N-rich disordered domain, is modulated by chaperone proteins and leads to altered function of the protein. Furthermore, they indicate that TDP-43 aggregation is regulated by chaperone availability, explaining the recurrent observation of TDP-43 aggregates in degenerative diseases of both the brain and muscle where protein homeostasis is disrupted.
    URL, DOI BibTeX

    @article{Udan-Johns2014,
    	abstract = "TDP-43 aggregation in the cytoplasm or nucleus is a key feature of the pathology of amyotrophic lateral sclerosis and frontotemporal dementia and is observed in numerous other neurodegenerative diseases, including Alzheimer's disease. Despite this fact, the inciting events leading to TDP-43 aggregation remain unclear. We observed that endogenous TDP-43 undergoes reversible aggregation in the nucleus after the heat shock and that this behavior is mediated by the C-terminal prion domain. Substitution of the prion domain from TIA-1 or an authentic yeast prion domain from RNQ1 into TDP-43 can completely recapitulate heat shock-induced aggregation. TDP-43 is constitutively bound to members of the Hsp40/Hsp70 family, and we found that heat shock-induced TDP-43 aggregation is mediated by the availability of these chaperones interacting with the inherently disordered C-terminal prion domain. Finally, we observed that the aggregation of TDP-43 during heat shock led to decreased binding to hnRNPA1, and a change in TDP-43 RNA-binding partners suggesting that TDP-43 aggregation alters its function in response to misfolded protein stress. These findings indicate that TDP-43 shares properties with physiologic prions from yeast, in that self-aggregation is mediated by a Q/N-rich disordered domain, is modulated by chaperone proteins and leads to altered function of the protein. Furthermore, they indicate that TDP-43 aggregation is regulated by chaperone availability, explaining the recurrent observation of TDP-43 aggregates in degenerative diseases of both the brain and muscle where protein homeostasis is disrupted.",
    	author = "Udan-Johns, Maria and Bengoechea, Rocio and Bell, Shaughn and Shao, Jieya and Diamond, Marc I and True, Heather L and Weihl, Conrad C and Baloh, Robert H",
    	doi = "10.1093/hmg/ddt408",
    	issn = "1460-2083",
    	journal = "Human molecular genetics",
    	month = "jan",
    	number = 1,
    	pages = "157--70",
    	pmid = 23962724,
    	title = "{Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23962724",
    	volume = 23,
    	year = 2014
    }
    
  2. Bernadett Kalmar, Ching-Hua Lu and Linda Greensmith.
    The role of heat shock proteins in Amyotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol.. Pharmacology & therapeutics 141(1):40–54, January 2014.
    Abstract Arimoclomol is a hydroxylamine derivative, a group of compounds which have unique properties as co-inducers of heat shock protein expression, but only under conditions of cellular stress. Arimoclomol has been found to be neuroprotective in a number of neurodegenerative disease models, including Amyotrophic Lateral Sclerosis (ALS), and in mutant Superoxide Dismutase 1 (SOD1) mice that model ALS, Arimoclomol rescues motor neurons, improves neuromuscular function and extends lifespan. The therapeutic potential of Arimoclomol is currently under investigation in a Phase II clinical trial for ALS patients with SOD1 mutations. In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by Arimoclomol and other inducers of the Heat Shock Response. ALS is a complex, multifactorial disease affecting a number of cell types and intracellular pathways. Cells and pathways affected by ALS pathology and which may be targeted by a heat shock protein-based therapy are also discussed in this review. For example, protein aggregation is a characteristic pathological feature of neurodegenerative diseases including ALS. Enhanced heat shock protein expression not only affects protein aggregation directly, but can also lead to more effective clearance of protein aggregates via the unfolded protein response, the proteasome-ubiquitin system or by autophagy. However, compounds such as Arimoclomol have effects beyond targeting protein mis-handling and can also affect additional pathological mechanisms such as oxidative stress. Therefore, by targeting multiple pathological mechanisms, compounds such as Arimoclomol may be particularly effective in the development of a disease-modifying therapy for ALS and other neurodegenerative disorders.
    URL, DOI BibTeX

    @article{Kalmar2014,
    	abstract = "Arimoclomol is a hydroxylamine derivative, a group of compounds which have unique properties as co-inducers of heat shock protein expression, but only under conditions of cellular stress. Arimoclomol has been found to be neuroprotective in a number of neurodegenerative disease models, including Amyotrophic Lateral Sclerosis (ALS), and in mutant Superoxide Dismutase 1 (SOD1) mice that model ALS, Arimoclomol rescues motor neurons, improves neuromuscular function and extends lifespan. The therapeutic potential of Arimoclomol is currently under investigation in a Phase II clinical trial for ALS patients with SOD1 mutations. In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by Arimoclomol and other inducers of the Heat Shock Response. ALS is a complex, multifactorial disease affecting a number of cell types and intracellular pathways. Cells and pathways affected by ALS pathology and which may be targeted by a heat shock protein-based therapy are also discussed in this review. For example, protein aggregation is a characteristic pathological feature of neurodegenerative diseases including ALS. Enhanced heat shock protein expression not only affects protein aggregation directly, but can also lead to more effective clearance of protein aggregates via the unfolded protein response, the proteasome-ubiquitin system or by autophagy. However, compounds such as Arimoclomol have effects beyond targeting protein mis-handling and can also affect additional pathological mechanisms such as oxidative stress. Therefore, by targeting multiple pathological mechanisms, compounds such as Arimoclomol may be particularly effective in the development of a disease-modifying therapy for ALS and other neurodegenerative disorders.",
    	author = "Kalmar, Bernadett and Lu, Ching-Hua and Greensmith, Linda",
    	doi = "10.1016/j.pharmthera.2013.08.003",
    	issn = "1879-016X",
    	journal = "Pharmacology \& therapeutics",
    	month = "jan",
    	number = 1,
    	pages = "40--54",
    	pmid = 23978556,
    	title = "{The role of heat shock proteins in Amyotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23978556",
    	volume = 141,
    	year = 2014
    }
    
  3. Samantha Zinkie, Benoit J Gentil, Sandra Minotti and Heather D Durham.
    Expression of the protein chaperone, clusterin, in spinal cord cells constitutively and following cellular stress, and upregulation by treatment with Hsp90 inhibitor.. Cell stress & chaperones 18(6):745–58, November 2013.
    Abstract Clusterin, a protein chaperone found at high levels in physiological fluids, is expressed in nervous tissue and upregulated in several neurological diseases. To assess relevance to amyotrophic lateral sclerosis (ALS) and other motor neuron disorders, clusterin expression was evaluated using long-term dissociated cultures of murine spinal cord and SOD1(G93A) transgenic mice, a model of familial ALS. Motor neurons and astrocytes constitutively expressed nuclear and cytoplasmic forms of clusterin, and secreted clusterin accumulated in culture media. Although clusterin can be stress inducible, heat shock failed to increase levels in these neural cell compartments despite robust upregulation of stress-inducible Hsp70 (HspA1) in non-neuronal cells. In common with HSPs, clusterin was upregulated by treatment with the Hsp90 inhibitor, geldanamycin, and thus could contribute to the neuroprotection previously identified for such compounds in disease models. Clusterin expression was not altered in cultured motor neurons expressing SOD1(G93A) by gene transfer or in presymptomatic SOD1(G93A) transgenic mice; however, clusterin immunolabeling was weakly increased in lumbar spinal cord of overtly symptomatic mice. More striking, mutant SOD1 inclusions, a pathological hallmark, were strongly labeled by anti-clusterin. Since secreted, as well as intracellular, mutant SOD1 contributes to toxicity, the extracellular chaperoning property of clusterin could be important for folding and clearance of SOD1 and other misfolded proteins in the extracellular space. Evaluation of chaperone-based therapies should include evaluation of clusterin as well as HSPs, using experimental models that replicate the control mechanisms operant in the cells and tissue of interest.
    URL, DOI BibTeX

    @article{Zinkie2013,
    	abstract = "Clusterin, a protein chaperone found at high levels in physiological fluids, is expressed in nervous tissue and upregulated in several neurological diseases. To assess relevance to amyotrophic lateral sclerosis (ALS) and other motor neuron disorders, clusterin expression was evaluated using long-term dissociated cultures of murine spinal cord and SOD1(G93A) transgenic mice, a model of familial ALS. Motor neurons and astrocytes constitutively expressed nuclear and cytoplasmic forms of clusterin, and secreted clusterin accumulated in culture media. Although clusterin can be stress inducible, heat shock failed to increase levels in these neural cell compartments despite robust upregulation of stress-inducible Hsp70 (HspA1) in non-neuronal cells. In common with HSPs, clusterin was upregulated by treatment with the Hsp90 inhibitor, geldanamycin, and thus could contribute to the neuroprotection previously identified for such compounds in disease models. Clusterin expression was not altered in cultured motor neurons expressing SOD1(G93A) by gene transfer or in presymptomatic SOD1(G93A) transgenic mice; however, clusterin immunolabeling was weakly increased in lumbar spinal cord of overtly symptomatic mice. More striking, mutant SOD1 inclusions, a pathological hallmark, were strongly labeled by anti-clusterin. Since secreted, as well as intracellular, mutant SOD1 contributes to toxicity, the extracellular chaperoning property of clusterin could be important for folding and clearance of SOD1 and other misfolded proteins in the extracellular space. Evaluation of chaperone-based therapies should include evaluation of clusterin as well as HSPs, using experimental models that replicate the control mechanisms operant in the cells and tissue of interest.",
    	author = "Zinkie, Samantha and Gentil, Benoit J and Minotti, Sandra and Durham, Heather D",
    	doi = "10.1007/s12192-013-0427-x",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zinkie et al. - 2013 - Expression of the protein chaperone, clusterin, in spinal cord cells constitutively and following cellular stress.pdf:pdf",
    	issn = "1466-1268",
    	journal = "Cell stress \& chaperones",
    	keywords = "Amino Acid Substitution,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Astrocytes,Astrocytes: cytology,Astrocytes: metabolism,Benzoquinones,Benzoquinones: pharmacology,Cells, Cultured,Clusterin,Clusterin: metabolism,Disease Models, Animal,Female,HSP90 Heat-Shock Proteins,HSP90 Heat-Shock Proteins: antagonists \& inhibitor,HSP90 Heat-Shock Proteins: metabolism,Lactams, Macrocyclic,Lactams, Macrocyclic: pharmacology,Male,Mice,Mice, Transgenic,Motor Neurons,Motor Neurons: cytology,Motor Neurons: metabolism,Spinal Cord,Spinal Cord: cytology,Spinal Cord: metabolism,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,Temperature,Up-Regulation,Up-Regulation: drug effects",
    	month = "nov",
    	number = 6,
    	pages = "745--58",
    	pmid = 23595219,
    	title = "{Expression of the protein chaperone, clusterin, in spinal cord cells constitutively and following cellular stress, and upregulation by treatment with Hsp90 inhibitor.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3789872\&tool=pmcentrez\&rendertype=abstract",
    	volume = 18,
    	year = 2013
    }
    
  4. Ari M Chow, Derek W F Tang, Asad Hanif and Ian R Brown.
    Induction of heat shock proteins in cerebral cortical cultures by celastrol.. Cell stress & chaperones 18(2):155–60, March 2013.
    Abstract Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) are 'protein misfolding disorders' of the mature nervous system that are characterized by the accumulation of protein aggregates and selective cell loss. Different brain regions are impacted, with Alzheimer's affecting cells in the cerebral cortex, Parkinson's targeting dopaminergic cells in the substantia nigra and ALS causing degeneration of cells in the spinal cord. These diseases differ widely in frequency in the human population. Alzheimer's is more frequent than Parkinson's and ALS. Heat shock proteins (Hsps) are 'protein repair agents' that provide a line of defense against misfolded, aggregation-prone proteins. We have suggested that differing levels of constitutively expressed Hsps (Hsc70 and Hsp27) in neural cell populations confer a variable buffering capacity against 'protein misfolding disorders' that correlates with the relative frequencies of these neurodegenerative diseases. The high relative frequency of Alzheimer's may due to low levels of Hsc70 and Hsp27 in affected cell populations that results in a reduced defense capacity against protein misfolding. Here, we demonstrate that celastrol, but not classical heat shock treatment, is effective in inducing a set of neuroprotective Hsps in cultures derived from cerebral cortices, including Hsp70, Hsp27 and Hsp32. This set of Hsps is induced by celastrol at 'days in vitro' (DIV) 13 when cultured cortical cells reached maturity. The inducibility of a set of neuroprotective Hsps in mature cortical cultures at DIV13 suggests that celastrol is a potential agent to counter Alzheimer's disease, a neurodegenerative 'protein misfolding disorder' of the adult brain that targets cells in the cerebral cortex.
    URL, DOI BibTeX

    @article{Chow2013,
    	abstract = "Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) are 'protein misfolding disorders' of the mature nervous system that are characterized by the accumulation of protein aggregates and selective cell loss. Different brain regions are impacted, with Alzheimer's affecting cells in the cerebral cortex, Parkinson's targeting dopaminergic cells in the substantia nigra and ALS causing degeneration of cells in the spinal cord. These diseases differ widely in frequency in the human population. Alzheimer's is more frequent than Parkinson's and ALS. Heat shock proteins (Hsps) are 'protein repair agents' that provide a line of defense against misfolded, aggregation-prone proteins. We have suggested that differing levels of constitutively expressed Hsps (Hsc70 and Hsp27) in neural cell populations confer a variable buffering capacity against 'protein misfolding disorders' that correlates with the relative frequencies of these neurodegenerative diseases. The high relative frequency of Alzheimer's may due to low levels of Hsc70 and Hsp27 in affected cell populations that results in a reduced defense capacity against protein misfolding. Here, we demonstrate that celastrol, but not classical heat shock treatment, is effective in inducing a set of neuroprotective Hsps in cultures derived from cerebral cortices, including Hsp70, Hsp27 and Hsp32. This set of Hsps is induced by celastrol at 'days in vitro' (DIV) 13 when cultured cortical cells reached maturity. The inducibility of a set of neuroprotective Hsps in mature cortical cultures at DIV13 suggests that celastrol is a potential agent to counter Alzheimer's disease, a neurodegenerative 'protein misfolding disorder' of the adult brain that targets cells in the cerebral cortex.",
    	author = "Chow, Ari M and Tang, Derek W F and Hanif, Asad and Brown, Ian R",
    	doi = "10.1007/s12192-012-0364-0",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Chow et al. - 2013 - Induction of heat shock proteins in cerebral cortical cultures by celastrol.pdf:pdf",
    	issn = "1466-1268",
    	journal = "Cell stress \& chaperones",
    	keywords = "Animals,Blotting, Western,Cells, Cultured,Cerebral Cortex,Cerebral Cortex: cytology,Cerebral Cortex: drug effects,Cerebral Cortex: metabolism,HSP27 Heat-Shock Proteins,HSP27 Heat-Shock Proteins: metabolism,HSP70 Heat-Shock Proteins,HSP70 Heat-Shock Proteins: metabolism,Heat-Shock Proteins,Heat-Shock Proteins: metabolism,Heme Oxygenase-1,Heme Oxygenase-1: metabolism,Potassium Channel Blockers,Potassium Channel Blockers: pharmacology,Rats,Rats, Sprague-Dawley,Temperature,Triterpenes,Triterpenes: pharmacology",
    	month = "mar",
    	number = 2,
    	pages = "155--60",
    	pmid = 22865541,
    	title = "{Induction of heat shock proteins in cerebral cortical cultures by celastrol.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3581628\&tool=pmcentrez\&rendertype=abstract",
    	volume = 18,
    	year = 2013
    }
    
  5. Zaorui Zhao, Alan I Faden, David J Loane, Marta M Lipinski, Boris Sabirzhanov and Bogdan A Stoica.
    Neuroprotective effects of geranylgeranylacetone in experimental traumatic brain injury.. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 33(12):1897–908, 2013.
    Abstract Geranylgeranylacetone (GGA) is an inducer of heat-shock protein 70 (HSP70) that has been used clinically for many years as an antiulcer treatment. It is centrally active after oral administration and is neuroprotective in experimental brain ischemia/stroke models. We examined the effects of single oral GGA before treatment (800 mg/kg, 48 hours before trauma) or after treatment (800 mg/kg, 3 hours after trauma) on long-term functional recovery and histologic outcomes after moderate-level controlled cortical impact, an experimental traumatic brain injury (TBI) model in mice. The GGA pretreatment increased the number of HSP70(+) cells and attenuated posttraumatic $\alpha$-fodrin cleavage, a marker of apoptotic cell death. It also improved sensorimotor performance on a beam walk task; enhanced recovery of cognitive/affective function in the Morris water maze, novel object recognition, and tail-suspension tests; and improved outcomes using a composite neuroscore. Furthermore, GGA pretreatment reduced the lesion size and neuronal loss in the hippocampus, cortex, and thalamus, and decreased microglial activation in the cortex when compared with vehicle-treated TBI controls. Notably, GGA was also effective in a posttreatment paradigm, showing significant improvements in sensorimotor function, and reducing cortical neuronal loss. Given these neuroprotective actions and considering its longstanding clinical use, GGA should be considered for the clinical treatment of TBI.
    URL, DOI BibTeX

    @article{Zhao2013,
    	abstract = "Geranylgeranylacetone (GGA) is an inducer of heat-shock protein 70 (HSP70) that has been used clinically for many years as an antiulcer treatment. It is centrally active after oral administration and is neuroprotective in experimental brain ischemia/stroke models. We examined the effects of single oral GGA before treatment (800 mg/kg, 48 hours before trauma) or after treatment (800 mg/kg, 3 hours after trauma) on long-term functional recovery and histologic outcomes after moderate-level controlled cortical impact, an experimental traumatic brain injury (TBI) model in mice. The GGA pretreatment increased the number of HSP70(+) cells and attenuated posttraumatic $\alpha$-fodrin cleavage, a marker of apoptotic cell death. It also improved sensorimotor performance on a beam walk task; enhanced recovery of cognitive/affective function in the Morris water maze, novel object recognition, and tail-suspension tests; and improved outcomes using a composite neuroscore. Furthermore, GGA pretreatment reduced the lesion size and neuronal loss in the hippocampus, cortex, and thalamus, and decreased microglial activation in the cortex when compared with vehicle-treated TBI controls. Notably, GGA was also effective in a posttreatment paradigm, showing significant improvements in sensorimotor function, and reducing cortical neuronal loss. Given these neuroprotective actions and considering its longstanding clinical use, GGA should be considered for the clinical treatment of TBI.",
    	author = "Zhao, Zaorui and Faden, Alan I and Loane, David J and Lipinski, Marta M and Sabirzhanov, Boris and Stoica, Bogdan A",
    	doi = "10.1038/jcbfm.2013.144",
    	issn = "1559-7016",
    	journal = "Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism",
    	keywords = "Animals,Brain,Brain Injuries,Brain Injuries: drug therapy,Brain Injuries: metabolism,Brain Injuries: pathology,Brain Injuries: physiopathology,Brain: drug effects,Brain: metabolism,Brain: pathology,Brain: physiopathology,Diterpenes,Diterpenes: administration \& dosage,Diterpenes: therapeutic use,HSP70 Heat-Shock Proteins,HSP70 Heat-Shock Proteins: analysis,HSP70 Heat-Shock Proteins: metabolism,Male,Maze Learning,Maze Learning: drug effects,Memory,Memory: drug effects,Mice,Mice, Inbred C57BL,Motor Activity,Motor Activity: drug effects,Neurons,Neurons: drug effects,Neurons: metabolism,Neurons: pathology,Neuroprotective Agents,Neuroprotective Agents: administration \& dosage,Neuroprotective Agents: therapeutic use",
    	month = "",
    	number = 12,
    	pages = "1897--908",
    	pmid = 23942364,
    	publisher = "International Society for Cerebral Blood Flow \& Metabolism, Inc.",
    	shorttitle = "J Cereb Blood Flow Metab",
    	title = "{Neuroprotective effects of geranylgeranylacetone in experimental traumatic brain injury.}",
    	url = "http://dx.doi.org/10.1038/jcbfm.2013.144",
    	volume = 33,
    	year = 2013
    }
    
  6. V F Lazarev, D V Sverchinskyi, M V Ippolitova, A V Stepanova, I V Guzhova and B A Margulis.
    Factors Affecting Aggregate Formation in Cell Models of Huntington's Disease and Amyotrophic Lateral Sclerosis.. Acta naturae 5(2):81–9, 2013.
    Abstract Most neurodegenerative pathologies stem from the formation of aggregates of mutant proteins, causing dysfunction and ultimately neuronal death. This study was aimed at elucidating the role of the protein factors that promote aggregate formation or prevent the process, respectively, glyceraldehyde-3-dehydrogenase (GAPDH) and tissue transglutaminase (tTG) and Hsp70 molecular chaperone. The siRNA technology was used to show that the inhibition of GAPDH expression leads to a 45-50% reduction in the aggregation of mutant huntingtin, with a repeat of 103 glutamine residues in a model of Huntington's disease (HD). Similarly, the blockage of GAPDH synthesis was found for the first time to reduce the degree of aggregation of mutant superoxide dismutase 1 (G93A) in a model of amyotrophic lateral sclerosis (ALS). The treatment of cells that imitate HD and ALS with a pharmacological GAPDH inhibitor, hydroxynonenal, was also shown to reduce the amount of the aggregating material in both disease models. Tissue transglutaminase is another factor that promotes the aggregation of mutant proteins; the inhibition of its activity with cystamine was found to prevent aggregate formation of mutant huntingtin and SOD1. In order to explore the protective function of Hsp70 in the control of the aggregation of mutant huntingtin, a cell model with inducible expression of the chaperone was used. The amount and size of polyglutamine aggregates were reduced by increasing the intracellular content of Hsp70. Thus, pharmacological regulation of the function of three proteins, GAPDH, tTG, and Hsp70, can affect the pathogenesis of two significant neurodegenerative diseases.
    URL BibTeX

    @article{Lazarev2013,
    	abstract = "Most neurodegenerative pathologies stem from the formation of aggregates of mutant proteins, causing dysfunction and ultimately neuronal death. This study was aimed at elucidating the role of the protein factors that promote aggregate formation or prevent the process, respectively, glyceraldehyde-3-dehydrogenase (GAPDH) and tissue transglutaminase (tTG) and Hsp70 molecular chaperone. The siRNA technology was used to show that the inhibition of GAPDH expression leads to a 45-50\% reduction in the aggregation of mutant huntingtin, with a repeat of 103 glutamine residues in a model of Huntington's disease (HD). Similarly, the blockage of GAPDH synthesis was found for the first time to reduce the degree of aggregation of mutant superoxide dismutase 1 (G93A) in a model of amyotrophic lateral sclerosis (ALS). The treatment of cells that imitate HD and ALS with a pharmacological GAPDH inhibitor, hydroxynonenal, was also shown to reduce the amount of the aggregating material in both disease models. Tissue transglutaminase is another factor that promotes the aggregation of mutant proteins; the inhibition of its activity with cystamine was found to prevent aggregate formation of mutant huntingtin and SOD1. In order to explore the protective function of Hsp70 in the control of the aggregation of mutant huntingtin, a cell model with inducible expression of the chaperone was used. The amount and size of polyglutamine aggregates were reduced by increasing the intracellular content of Hsp70. Thus, pharmacological regulation of the function of three proteins, GAPDH, tTG, and Hsp70, can affect the pathogenesis of two significant neurodegenerative diseases.",
    	author = "Lazarev, V F and Sverchinskyi, D V and Ippolitova, M V and Stepanova, A V and Guzhova, I V and Margulis, B A",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lazarev et al. - 2013 - Factors Affecting Aggregate Formation in Cell Models of Huntington's Disease and Amyotrophic Lateral Sclerosis.pdf:pdf",
    	issn = "2075-8251",
    	journal = "Acta naturae",
    	month = "",
    	number = 2,
    	pages = "81--9",
    	pmid = 23819039,
    	title = "{Factors Affecting Aggregate Formation in Cell Models of Huntington's Disease and Amyotrophic Lateral Sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3695356\&tool=pmcentrez\&rendertype=abstract",
    	volume = 5,
    	year = 2013
    }
    
  7. Eun-Hyun Kim, Hyo-Soon Jeong, Hye-Young Yun, Kwang Jin Baek, Nyoun Soo Kwon, Kyoung-Chan Park and Dong-Seok Kim.
    Geranylgeranylacetone inhibits melanin synthesis via ERK activation in Mel-Ab cells.. Life sciences 93(5-6):226–32, 2013.
    Abstract AIMS: Geranylgeranylacetone (GGA) has shown cytoprotective activity through induction of a 70-kDa heat shock protein (HSP70). Although HSP70 is reported to regulate melanogenesis, the effects of GGA on melanin synthesis in melanocytes have not been previously studied. Therefore, this study investigated the effects of GGA on melanogenesis and the related signaling pathways. MAIN METHODS: Melanin content and tyrosinase activities were measured in Mel-Ab cells. GGA-induced signal transduction pathways were investigated by western blot analysis. KEY FINDINGS: Our results showed that GGA significantly decreased melanin content in a concentration-dependent manner. Similarly, GGA reduced tyrosinase activity dose-dependently, but it did not directly inhibit tyrosinase. Western blot analysis indicated that GGA downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase protein expression, whereas it increased the phosphorylation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR). Furthermore, a specific ERK pathway inhibitor, PD98059, blocked GGA-induced melanin reduction and then prevented downregulation of MITF and tyrosinase by GGA. However, a specific mTOR inhibitor, rapamycin, only slightly restored inhibition of melanin production by GGA, indicating that mTOR signaling is not a key mechanism regulating the inhibition of melanin production. SIGNIFICANCE: These findings suggest that activation of ERK by GGA reduces melanin synthesis in Mel-Ab cells through downregulation of MITF and tyrosinase expression.
    URL, DOI BibTeX

    @article{Kim2013,
    	abstract = "AIMS: Geranylgeranylacetone (GGA) has shown cytoprotective activity through induction of a 70-kDa heat shock protein (HSP70). Although HSP70 is reported to regulate melanogenesis, the effects of GGA on melanin synthesis in melanocytes have not been previously studied. Therefore, this study investigated the effects of GGA on melanogenesis and the related signaling pathways. MAIN METHODS: Melanin content and tyrosinase activities were measured in Mel-Ab cells. GGA-induced signal transduction pathways were investigated by western blot analysis. KEY FINDINGS: Our results showed that GGA significantly decreased melanin content in a concentration-dependent manner. Similarly, GGA reduced tyrosinase activity dose-dependently, but it did not directly inhibit tyrosinase. Western blot analysis indicated that GGA downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase protein expression, whereas it increased the phosphorylation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR). Furthermore, a specific ERK pathway inhibitor, PD98059, blocked GGA-induced melanin reduction and then prevented downregulation of MITF and tyrosinase by GGA. However, a specific mTOR inhibitor, rapamycin, only slightly restored inhibition of melanin production by GGA, indicating that mTOR signaling is not a key mechanism regulating the inhibition of melanin production. SIGNIFICANCE: These findings suggest that activation of ERK by GGA reduces melanin synthesis in Mel-Ab cells through downregulation of MITF and tyrosinase expression.",
    	author = "Kim, Eun-Hyun and Jeong, Hyo-Soon and Yun, Hye-Young and Baek, Kwang Jin and Kwon, Nyoun Soo and Park, Kyoung-Chan and Kim, Dong-Seok",
    	doi = "10.1016/j.lfs.2013.06.008",
    	issn = "1879-0631",
    	journal = "Life sciences",
    	keywords = "Animals,Antineoplastic Agents,Antineoplastic Agents: pharmacology,Cell Line, Transformed,Cell Survival,Cell Survival: drug effects,Cell Survival: physiology,Diterpenes,Diterpenes: pharmacology,Dose-Response Relationship, Drug,Down-Regulation,Down-Regulation: drug effects,Down-Regulation: physiology,Extracellular Signal-Regulated MAP Kinases,Extracellular Signal-Regulated MAP Kinases: metabo,Extracellular Signal-Regulated MAP Kinases: physio,Melanins,Melanins: antagonists \& inhibitors,Melanins: biosynthesis,Melanocytes,Melanocytes: drug effects,Melanocytes: enzymology,Melanocytes: pathology,Mice,Signal Transduction,Signal Transduction: drug effects,Signal Transduction: physiology",
    	month = "",
    	number = "5-6",
    	pages = "226--32",
    	pmid = 23792203,
    	title = "{Geranylgeranylacetone inhibits melanin synthesis via ERK activation in Mel-Ab cells.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23792203",
    	volume = 93,
    	year = 2013
    }
    
  8. Tatsuya Hoshino, Koichiro Suzuki, Takahide Matsushima, Naoki Yamakawa, Toshiharu Suzuki and Tohru Mizushima.
    Suppression of Alzheimer's disease-related phenotypes by geranylgeranylacetone in mice.. PloS one 8(10):e76306, January 2013.
    Abstract Amyloid-$\beta$ peptide (A$\beta$) plays an important role in the pathogenesis of Alzheimer's disease (AD). A$\beta$ is generated by the secretase-mediated proteolysis of $\beta$-amyloid precursor protein (APP), and cleared by enzyme-mediated degradation and phagocytosis. Transforming growth factor (TGF)-$\beta$1 stimulates this phagocytosis. We recently reported that the APP23 mouse model for AD showed fewer AD-related phenotypes when these animals were crossed with transgenic mice expressing heat shock protein (HSP) 70. We here examined the effect of geranylgeranylacetone, an inducer of HSP70 expression, on the AD-related phenotypes. Repeated oral administration of geranylgeranylacetone to APP23 mice for 9 months not only improved cognitive function but also decreased levels of A$\beta$, A$\beta$ plaque deposition and synaptic loss. The treatment also up-regulated the expression of an A$\beta$-degrading enzyme and TGF-$\beta$1 but did not affect the maturation of APP and secretase activities. These outcomes were similar to those observed in APP23 mice genetically modified to overexpress HSP70. Although the repeated oral administration of geranylgeranylacetone did not increase the level of HSP70 in the brain, a single oral administration of geranylgeranylacetone significantly increased the level of HSP70 when A$\beta$ was concomitantly injected directly into the hippocampus. Since geranylgeranylacetone has already been approved for use as an anti-ulcer drug and its safety in humans has been confirmed, we propose that this drug be considered as a candidate drug for the prevention of AD.
    URL, DOI BibTeX

    @article{Hoshino2013,
    	abstract = "Amyloid-$\beta$ peptide (A$\beta$) plays an important role in the pathogenesis of Alzheimer's disease (AD). A$\beta$ is generated by the secretase-mediated proteolysis of $\beta$-amyloid precursor protein (APP), and cleared by enzyme-mediated degradation and phagocytosis. Transforming growth factor (TGF)-$\beta$1 stimulates this phagocytosis. We recently reported that the APP23 mouse model for AD showed fewer AD-related phenotypes when these animals were crossed with transgenic mice expressing heat shock protein (HSP) 70. We here examined the effect of geranylgeranylacetone, an inducer of HSP70 expression, on the AD-related phenotypes. Repeated oral administration of geranylgeranylacetone to APP23 mice for 9 months not only improved cognitive function but also decreased levels of A$\beta$, A$\beta$ plaque deposition and synaptic loss. The treatment also up-regulated the expression of an A$\beta$-degrading enzyme and TGF-$\beta$1 but did not affect the maturation of APP and secretase activities. These outcomes were similar to those observed in APP23 mice genetically modified to overexpress HSP70. Although the repeated oral administration of geranylgeranylacetone did not increase the level of HSP70 in the brain, a single oral administration of geranylgeranylacetone significantly increased the level of HSP70 when A$\beta$ was concomitantly injected directly into the hippocampus. Since geranylgeranylacetone has already been approved for use as an anti-ulcer drug and its safety in humans has been confirmed, we propose that this drug be considered as a candidate drug for the prevention of AD.",
    	author = "Hoshino, Tatsuya and Suzuki, Koichiro and Matsushima, Takahide and Yamakawa, Naoki and Suzuki, Toshiharu and Mizushima, Tohru",
    	doi = "10.1371/journal.pone.0076306",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hoshino et al. - 2013 - Suppression of Alzheimer's disease-related phenotypes by geranylgeranylacetone in mice.pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	month = "jan",
    	number = 10,
    	pages = "e76306",
    	pmid = 24098472,
    	title = "{Suppression of Alzheimer's disease-related phenotypes by geranylgeranylacetone in mice.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3788141\&tool=pmcentrez\&rendertype=abstract",
    	volume = 8,
    	year = 2013
    }
    
  9. Sarah J Weisberg, Roman Lyakhovetsky, Ayelet-chen Werdiger, Aaron D Gitler, Yoav Soen and Daniel Kaganovich.
    Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity.. Proceedings of the National Academy of Sciences of the United States of America 109(39):15811–6, 2012.
    Abstract Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability.
    URL, DOI BibTeX

    @article{Weisberg2012,
    	abstract = "Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability.",
    	author = "Weisberg, Sarah J and Lyakhovetsky, Roman and Werdiger, Ayelet-chen and Gitler, Aaron D and Soen, Yoav and Kaganovich, Daniel",
    	doi = "10.1073/pnas.1205829109",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Weisberg et al. - 2012 - Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity.pdf:pdf",
    	issn = "1091-6490",
    	journal = "Proceedings of the National Academy of Sciences of the United States of America",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Cell Line,Cell Survival,HSP70 Heat-Shock Proteins,HSP70 Heat-Shock Proteins: genetics,HSP70 Heat-Shock Proteins: metabolism,Humans,Inclusion Bodies,Inclusion Bodies: genetics,Inclusion Bodies: metabolism,Proteasome Endopeptidase Complex,Protein Folding,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism",
    	month = "",
    	number = 39,
    	pages = "15811--6",
    	pmid = 22967507,
    	title = "{Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3465386\&tool=pmcentrez\&rendertype=abstract",
    	volume = 109,
    	year = 2012
    }
    
  10. David J Gifondorwa, Ramon Jimenz-Moreno, Crystal D Hayes, Hesam Rouhani, Mac B Robinson, Jane L Strupe, James Caress and Carol Milligan.
    Administration of Recombinant Heat Shock Protein 70 Delays Peripheral Muscle Denervation in the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.. Neurology research international 2012:170426, 2012.
    Abstract A prominent clinical feature of ALS is muscle weakness due to dysfunction, denervation and degeneration of motoneurons (MNs). While MN degeneration is a late stage event in the ALS mouse model, muscle denervation occurs significantly earlier in the disease. Strategies to prevent this early denervation may improve quality of life by maintaining muscle control and slowing disease progression. The precise cause of MN dysfunction and denervation is not known, but several mechanisms have been proposed that involve potentially toxic intra- and extracellular changes. Many cells confront these changes by mounting a stress response that includes increased expression of heat shock protein 70 (Hsp70). MNs do not upregulate Hsp70, and this may result in a potentially increased vulnerability. We previously reported that recombinant human hsp70 (rhHsp70) injections delayed symptom onset and increased lifespan in SOD1(G93A) mice. The exogenous rhHsp70 was localized to the muscle and not to spinal cord or brain suggesting it modulates peripheral pathophysiology. In the current study, we focused on earlier administration of Hsp70 and its effect on initial muscle denervation. Injections of the protein appeared to arrest denervation with preserved large myelinated peripheral axons, and reduced glial activation.
    URL, DOI BibTeX

    @article{Gifondorwa2012,
    	abstract = "A prominent clinical feature of ALS is muscle weakness due to dysfunction, denervation and degeneration of motoneurons (MNs). While MN degeneration is a late stage event in the ALS mouse model, muscle denervation occurs significantly earlier in the disease. Strategies to prevent this early denervation may improve quality of life by maintaining muscle control and slowing disease progression. The precise cause of MN dysfunction and denervation is not known, but several mechanisms have been proposed that involve potentially toxic intra- and extracellular changes. Many cells confront these changes by mounting a stress response that includes increased expression of heat shock protein 70 (Hsp70). MNs do not upregulate Hsp70, and this may result in a potentially increased vulnerability. We previously reported that recombinant human hsp70 (rhHsp70) injections delayed symptom onset and increased lifespan in SOD1(G93A) mice. The exogenous rhHsp70 was localized to the muscle and not to spinal cord or brain suggesting it modulates peripheral pathophysiology. In the current study, we focused on earlier administration of Hsp70 and its effect on initial muscle denervation. Injections of the protein appeared to arrest denervation with preserved large myelinated peripheral axons, and reduced glial activation.",
    	author = "Gifondorwa, David J and Jimenz-Moreno, Ramon and Hayes, Crystal D and Rouhani, Hesam and Robinson, Mac B and Strupe, Jane L and Caress, James and Milligan, Carol",
    	doi = "10.1155/2012/170426",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gifondorwa et al. - 2012 - Administration of Recombinant Heat Shock Protein 70 Delays Peripheral Muscle Denervation in the SOD1(G93A) Mo.pdf:pdf",
    	issn = "2090-1860",
    	journal = "Neurology research international",
    	month = "",
    	pages = 170426,
    	pmid = 22900172,
    	title = "{Administration of Recombinant Heat Shock Protein 70 Delays Peripheral Muscle Denervation in the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3415202\&tool=pmcentrez\&rendertype=abstract",
    	volume = 2012,
    	year = 2012
    }
    
  11. Gong-Jhe Wu, Wu-Fu Chen, Han-Chun Hung, Yen-Hsuan Jean, Chun-Sung Sung, Chiranjib Chakraborty, Hsin-Pai Lee, Nan-Fu Chen and Zhi-Hong Wen.
    Effects of propofol on proliferation and anti-apoptosis of neuroblastoma SH-SY5Y cell line: new insights into neuroprotection.. Brain research 1384:42–50, April 2011.
    Abstract Recently, it has been suggested that anesthetic agents may have neuroprotective potency. The notion that anesthetic agents can offer neuroprotection remains controversial. Propofol, which is a short-acting intravenous anesthetic agent, may have potential as a neuroprotective agent. In this study, we tried to determine whether propofol affected the viability of human neuroblastoma SH-SY5Y cells by using the MTT assay. Surprisingly, our results showed that propofol at a dose of 1-10 $\mu$M could improve cell proliferation. However, at higher doses (200 $\mu$M), propofol appears to be cytotoxic. On the other hand, propofol could up-regulate the expression of key proteins involved in neuroprotection including B-cell lymphoma 2 at a dose range of 1-10 $\mu$M, activation of phospho-serine/threonine protein kinase at a dose range of 0.5-10 $\mu$M, and activation of phospho-extracellular signal-regulated kinases at a dose range of 5-10 $\mu$M. Similarly, we demonstrate that propofol (10 $\mu$M) could elevate protein levels of heat shock protein 90 and heat shock protein 70. Therefore, we choose to utilize a 10 $\mu$M concentration of propofol to assess neuroprotective activities in our studies. In the following experiments, we used dynorphin A to generate cytotoxic effects on SH-SY5Y cells. Our data indicate that propofol (10 $\mu$M) could inhibit the cytotoxicity in SH-SY5Y cells induced by dynorphin A. Furthermore, propofol (10 $\mu$M) could decrease the expression of the p-P38 protein as well. These data together suggest that propofol may have the potential to act as a neuroprotective agent against various neurologic diseases. However, further delineation of the precise neuroprotective effects of propofol will need to be examined.
    URL, DOI BibTeX

    @article{Wu2011,
    	abstract = "Recently, it has been suggested that anesthetic agents may have neuroprotective potency. The notion that anesthetic agents can offer neuroprotection remains controversial. Propofol, which is a short-acting intravenous anesthetic agent, may have potential as a neuroprotective agent. In this study, we tried to determine whether propofol affected the viability of human neuroblastoma SH-SY5Y cells by using the MTT assay. Surprisingly, our results showed that propofol at a dose of 1-10 $\mu$M could improve cell proliferation. However, at higher doses (200 $\mu$M), propofol appears to be cytotoxic. On the other hand, propofol could up-regulate the expression of key proteins involved in neuroprotection including B-cell lymphoma 2 at a dose range of 1-10 $\mu$M, activation of phospho-serine/threonine protein kinase at a dose range of 0.5-10 $\mu$M, and activation of phospho-extracellular signal-regulated kinases at a dose range of 5-10 $\mu$M. Similarly, we demonstrate that propofol (10 $\mu$M) could elevate protein levels of heat shock protein 90 and heat shock protein 70. Therefore, we choose to utilize a 10 $\mu$M concentration of propofol to assess neuroprotective activities in our studies. In the following experiments, we used dynorphin A to generate cytotoxic effects on SH-SY5Y cells. Our data indicate that propofol (10 $\mu$M) could inhibit the cytotoxicity in SH-SY5Y cells induced by dynorphin A. Furthermore, propofol (10 $\mu$M) could decrease the expression of the p-P38 protein as well. These data together suggest that propofol may have the potential to act as a neuroprotective agent against various neurologic diseases. However, further delineation of the precise neuroprotective effects of propofol will need to be examined.",
    	author = "Wu, Gong-Jhe and Chen, Wu-Fu and Hung, Han-Chun and Jean, Yen-Hsuan and Sung, Chun-Sung and Chakraborty, Chiranjib and Lee, Hsin-Pai and Chen, Nan-Fu and Wen, Zhi-Hong",
    	doi = "10.1016/j.brainres.2011.02.004",
    	issn = "1872-6240",
    	journal = "Brain research",
    	keywords = "Apoptosis,Apoptosis: drug effects,Cell Line, Tumor,Cell Proliferation,Cell Proliferation: drug effects,Dose-Response Relationship, Drug,Dynorphins,Dynorphins: pharmacology,Gene Expression Regulation, Neoplastic,Gene Expression Regulation, Neoplastic: drug effec,Heat-Shock Proteins,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Humans,In Situ Nick-End Labeling,In Situ Nick-End Labeling: methods,Neuroblastoma,Neuroblastoma: pathology,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Neurotransmitter Agents,Neurotransmitter Agents: pharmacology,Propofol,Propofol: pharmacology,Time Factors",
    	month = "apr",
    	pages = "42--50",
    	pmid = 21315692,
    	title = "{Effects of propofol on proliferation and anti-apoptosis of neuroblastoma SH-SY5Y cell line: new insights into neuroprotection.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21315692",
    	volume = 1384,
    	year = 2011
    }
    
  12. Atsushi Sanbe, Takuya Daicho, Reiko Mizutani, Toshiya Endo, Noriko Miyauchi, Junji Yamauchi, Kouichi Tanonaka, Charles Glabe and Akito Tanoue.
    Protective effect of geranylgeranylacetone via enhancement of HSPB8 induction in desmin-related cardiomyopathy.. PloS one 4(4):e5351, January 2009.
    Abstract BACKGROUND: An arg120gly (R120G) missense mutation in HSPB5 (alpha-beta-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain. METHODOLOGY/PRINCIPAL FINDINGS: In order to extend the previous in vitro findings to in vivo, we used geranylgeranylacetone (GGA), a potent HSP inducer. Oral administration of GGA resulted not only in up-regulation of the expression level of HSPB8 and HSPB1 in the heart of HSPB5 R120G transgenic (R120G TG) mice, but also reduced amyloid oligomer levels and aggregates. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size and less interstitial fibrosis, as well as improved cardiac function and survival compared to untreated R120G TG mice. To address possible mechanism(s) for these beneficial effects, cardiac-specific transgenic mice expressing HSPB8 were generated. Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. Treatment with GGA as well as the overexpression of HSPB8 also inhibited cytochrome c release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice. CONCLUSIONS/SIGNIFICANCE: Expression of small HSPs such as HSPB8 and HSPB1 by GGA may be a new therapeutic strategy for patients with DRM.
    URL, DOI BibTeX

    @article{Sanbe2009a,
    	abstract = "BACKGROUND: An arg120gly (R120G) missense mutation in HSPB5 (alpha-beta-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain. METHODOLOGY/PRINCIPAL FINDINGS: In order to extend the previous in vitro findings to in vivo, we used geranylgeranylacetone (GGA), a potent HSP inducer. Oral administration of GGA resulted not only in up-regulation of the expression level of HSPB8 and HSPB1 in the heart of HSPB5 R120G transgenic (R120G TG) mice, but also reduced amyloid oligomer levels and aggregates. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size and less interstitial fibrosis, as well as improved cardiac function and survival compared to untreated R120G TG mice. To address possible mechanism(s) for these beneficial effects, cardiac-specific transgenic mice expressing HSPB8 were generated. Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. Treatment with GGA as well as the overexpression of HSPB8 also inhibited cytochrome c release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice. CONCLUSIONS/SIGNIFICANCE: Expression of small HSPs such as HSPB8 and HSPB1 by GGA may be a new therapeutic strategy for patients with DRM.",
    	author = "Sanbe, Atsushi and Daicho, Takuya and Mizutani, Reiko and Endo, Toshiya and Miyauchi, Noriko and Yamauchi, Junji and Tanonaka, Kouichi and Glabe, Charles and Tanoue, Akito",
    	doi = "10.1371/journal.pone.0005351",
    	editor = "Malaga, German",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sanbe et al. - 2009 - Protective effect of geranylgeranylacetone via enhancement of HSPB8 induction in desmin-related cardiomyopathy(2).pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Amyloid,Amyloid: metabolism,Animals,Apoptosis,Apoptosis: drug effects,Cardiomyopathies,Cardiomyopathies: genetics,Cardiomyopathies: metabolism,Cardiomyopathies: prevention \& control,Caspase 3,Caspase 3: metabolism,Cytochromes c,Cytochromes c: metabolism,Desmin,Desmin: metabolism,Diterpenes,Diterpenes: pharmacology,HSP20 Heat-Shock Proteins,HSP20 Heat-Shock Proteins: biosynthesis,HSP20 Heat-Shock Proteins: genetics,Heat-Shock Proteins,Heat-Shock Proteins: biosynthesis,Heat-Shock Proteins: genetics,Male,Mice,Mice, Inbred C57BL,Mice, Transgenic,Muscle Proteins,Muscle Proteins: biosynthesis,Muscle Proteins: genetics,Mutation, Missense,Myocardium,Myocardium: metabolism,Myocardium: pathology,Myocytes, Cardiac,Myocytes, Cardiac: drug effects,Myocytes, Cardiac: metabolism,Neoplasm Proteins,Neoplasm Proteins: biosynthesis,Neoplasm Proteins: genetics,Rats,Up-Regulation,Up-Regulation: drug effects",
    	month = "jan",
    	number = 4,
    	pages = "e5351",
    	pmid = 19399179,
    	publisher = "Public Library of Science",
    	title = "{Protective effect of geranylgeranylacetone via enhancement of HSPB8 induction in desmin-related cardiomyopathy.}",
    	url = "http://dx.plos.org/10.1371/journal.pone.0005351",
    	volume = 4,
    	year = 2009
    }
    
  13. Satoshi Endo, Nobuhiko Hiramatsu, Kunihiro Hayakawa, Maro Okamura, Ayumi Kasai, Yasuhiro Tagawa, Norifumi Sawada, Jian Yao and Masanori Kitamura.
    Geranylgeranylacetone, an inducer of the 70-kDa heat shock protein (HSP70), elicits unfolded protein response and coordinates cellular fate independently of HSP70.. Molecular pharmacology 72(5):1337–48, 2007.
    Abstract Geranylgeranylacetone (GGA), an antiulcer agent, has the ability to induce 70-kDa heat shock protein (HSP70) in various cell types and to protect cells from apoptogenic insults. However, little is known about effects of GGA on other HSP families of molecules. We found that, at concentrations >/=100 microM, GGA caused selective expression of 78-kDa glucose-regulated protein (GRP78), an HSP70 family member inducible by endoplasmic reticulum (ER) stress, without affecting the level of HSP70 in various cell types. Induction of ER stress by GGA was also evidenced by expression of another endogenous marker, CCAAT/enhancer-binding protein-homologous protein (CHOP); decreased activity of ER stress-responsive alkaline phosphatase; and unfolded protein response (UPR), including activation of the activating transcription factor 6 (ATF6) pathway and the inositol-requiring ER-to-nucleus signal kinase 1-X-box-binding protein 1 (IRE1-XBP1) pathway. Incubation of mesangial cells with GGA caused significant apoptosis, which was attenuated by transfection with inhibitors of caspase-12 (i.e., a dominant-negative mutant of caspase-12 and MAGE-3). Dominant-negative suppression of IRE1 or XBP1 significantly attenuated apoptosis without affecting the levels of CHOP and GRP78. Inhibition of c-Jun NH(2)-terminal kinase, the molecule downstream of IRE1, by 1,9-pyrazoloanthrone (SP600125) did not improve cell survival. Blockade of ATF6 by 4-(2-aminoethyl) benzenesulfonyl fluoride enhanced apoptosis by GGA, and it was correlated with attenuated induction of both GRP78 and CHOP. Overexpression of GRP78 or dominant-negative inhibition of CHOP significantly attenuated GGA-induced apoptosis. These results suggested that GGA triggers both proapoptotic (IRE1-XBP1, ATF6-CHOP) and antiapoptotic (ATF6-GRP78) UPR and thereby coordinates cellular fate even without induction of HSP70.
    URL, DOI BibTeX

    @article{Endo2007,
    	abstract = "Geranylgeranylacetone (GGA), an antiulcer agent, has the ability to induce 70-kDa heat shock protein (HSP70) in various cell types and to protect cells from apoptogenic insults. However, little is known about effects of GGA on other HSP families of molecules. We found that, at concentrations >/=100 microM, GGA caused selective expression of 78-kDa glucose-regulated protein (GRP78), an HSP70 family member inducible by endoplasmic reticulum (ER) stress, without affecting the level of HSP70 in various cell types. Induction of ER stress by GGA was also evidenced by expression of another endogenous marker, CCAAT/enhancer-binding protein-homologous protein (CHOP); decreased activity of ER stress-responsive alkaline phosphatase; and unfolded protein response (UPR), including activation of the activating transcription factor 6 (ATF6) pathway and the inositol-requiring ER-to-nucleus signal kinase 1-X-box-binding protein 1 (IRE1-XBP1) pathway. Incubation of mesangial cells with GGA caused significant apoptosis, which was attenuated by transfection with inhibitors of caspase-12 (i.e., a dominant-negative mutant of caspase-12 and MAGE-3). Dominant-negative suppression of IRE1 or XBP1 significantly attenuated apoptosis without affecting the levels of CHOP and GRP78. Inhibition of c-Jun NH(2)-terminal kinase, the molecule downstream of IRE1, by 1,9-pyrazoloanthrone (SP600125) did not improve cell survival. Blockade of ATF6 by 4-(2-aminoethyl) benzenesulfonyl fluoride enhanced apoptosis by GGA, and it was correlated with attenuated induction of both GRP78 and CHOP. Overexpression of GRP78 or dominant-negative inhibition of CHOP significantly attenuated GGA-induced apoptosis. These results suggested that GGA triggers both proapoptotic (IRE1-XBP1, ATF6-CHOP) and antiapoptotic (ATF6-GRP78) UPR and thereby coordinates cellular fate even without induction of HSP70.",
    	author = "Endo, Satoshi and Hiramatsu, Nobuhiko and Hayakawa, Kunihiro and Okamura, Maro and Kasai, Ayumi and Tagawa, Yasuhiro and Sawada, Norifumi and Yao, Jian and Kitamura, Masanori",
    	doi = "10.1124/mol.107.039164",
    	issn = "0026-895X",
    	journal = "Molecular pharmacology",
    	keywords = "Activating Transcription Factor 6,Activating Transcription Factor 6: metabolism,Animals,Anti-Ulcer Agents,Anti-Ulcer Agents: pharmacology,Apoptosis,Cell Line,DNA-Binding Proteins,DNA-Binding Proteins: metabolism,Diterpenes,Diterpenes: pharmacology,Endoplasmic Reticulum,Endoplasmic Reticulum: drug effects,Endoplasmic Reticulum: metabolism,HSC70 Heat-Shock Proteins,HSC70 Heat-Shock Proteins: metabolism,Heat-Shock Proteins,Heat-Shock Proteins: metabolism,Membrane Proteins,Membrane Proteins: metabolism,Mice,Molecular Chaperones,Molecular Chaperones: metabolism,Nuclear Proteins,Nuclear Proteins: metabolism,Protein Folding,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: metabolism,Rats,Transcription Factor CHOP,Transcription Factor CHOP: metabolism,Transcription Factors",
    	month = "",
    	number = 5,
    	pages = "1337--48",
    	pmid = 17702888,
    	title = "{Geranylgeranylacetone, an inducer of the 70-kDa heat shock protein (HSP70), elicits unfolded protein response and coordinates cellular fate independently of HSP70.}",
    	url = "http://molpharm.aspetjournals.org/content/72/5/1337.long",
    	volume = 72,
    	year = 2007
    }
    
  14. Rachel L Galli, Donna F Bielinski, Aleksandra Szprengiel, Barbara Shukitt-Hale and James A Joseph.
    Blueberry supplemented diet reverses age-related decline in hippocampal HSP70 neuroprotection.. Neurobiology of aging 27(2):344–50, 2006.
    Abstract Dietary supplementation with antioxidant rich foods can decrease the level of oxidative stress in brain regions and can ameliorate age-related deficits in neuronal and behavioral functions. We examined whether short-term supplementation with blueberries might enhance the brain's ability to generate a heat shock protein 70 (HSP70) mediated neuroprotective response to stress. Hippocampal (HC) regions from young and old rats fed either a control or a supplemented diet for 10 weeks were subjected to an in vitro inflammatory challenge (LPS) and then examined for levels of HSP70 at various times post LPS (30, 90 and 240 min). While baseline levels of HSP70 did not differ among the various groups compared to young control diet rats, increases in HSP70 protein levels in response to an in vitro LPS challenge were significantly less in old as compared to young control diet rats at the 30, 90 and 240 min time points. However, it appeared that the blueberry diet completely restored the HSP70 response to LPS in the old rats at the 90 and 240 min times. This suggests that a short-term blueberry (BB) intervention may result in improved HSP70-mediated protection against a number of neurodegenerative processes in the brain. Results are discussed in terms of the multiplicity of the effects of the BB supplementation which appear to range from antioxidant/anti-inflammatory activity to signaling.
    URL, DOI BibTeX

    @article{Galli2006,
    	abstract = "Dietary supplementation with antioxidant rich foods can decrease the level of oxidative stress in brain regions and can ameliorate age-related deficits in neuronal and behavioral functions. We examined whether short-term supplementation with blueberries might enhance the brain's ability to generate a heat shock protein 70 (HSP70) mediated neuroprotective response to stress. Hippocampal (HC) regions from young and old rats fed either a control or a supplemented diet for 10 weeks were subjected to an in vitro inflammatory challenge (LPS) and then examined for levels of HSP70 at various times post LPS (30, 90 and 240 min). While baseline levels of HSP70 did not differ among the various groups compared to young control diet rats, increases in HSP70 protein levels in response to an in vitro LPS challenge were significantly less in old as compared to young control diet rats at the 30, 90 and 240 min time points. However, it appeared that the blueberry diet completely restored the HSP70 response to LPS in the old rats at the 90 and 240 min times. This suggests that a short-term blueberry (BB) intervention may result in improved HSP70-mediated protection against a number of neurodegenerative processes in the brain. Results are discussed in terms of the multiplicity of the effects of the BB supplementation which appear to range from antioxidant/anti-inflammatory activity to signaling.",
    	author = "Galli, Rachel L and Bielinski, Donna F and Szprengiel, Aleksandra and Shukitt-Hale, Barbara and Joseph, James A",
    	doi = "10.1016/j.neurobiolaging.2005.01.017",
    	issn = "0197-4580",
    	journal = "Neurobiology of aging",
    	keywords = "Age Factors,Aging,Aging: physiology,Animals,Blotting, Western,Blotting, Western: methods,Blueberry Plant,Food, Formulated,Gene Expression Regulation,Gene Expression Regulation: drug effects,Gene Expression Regulation: physiology,HSP70 Heat-Shock Proteins,HSP70 Heat-Shock Proteins: metabolism,Hippocampus,Hippocampus: drug effects,Hippocampus: metabolism,Lipopolysaccharides,Lipopolysaccharides: adverse effects,Male,Rats,Rats, Inbred F344,Stress, Physiological,Stress, Physiological: chemically induced,Stress, Physiological: prevention \& control,Time Factors",
    	month = "",
    	number = 2,
    	pages = "344--50",
    	pmid = 15869824,
    	title = "{Blueberry supplemented diet reverses age-related decline in hippocampal HSP70 neuroprotection.}",
    	url = "http://www.mendeley.com/catalog/blueberry-supplemented-diet-reverses-agerelated-decline-hippocampal-hsp70-neuroprotection/",
    	volume = 27,
    	year = 2006
    }
    
  15. Masahisa Katsuno, Chen Sang, Hiroaki Adachi, Makoto Minamiyama, Masahiro Waza, Fumiaki Tanaka, Manabu Doyu and Gen Sobue.
    Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease.. Proceedings of the National Academy of Sciences of the United States of America 102(46):16801–6, November 2005.
    Abstract Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the first exon of the androgen receptor gene (AR). The pathogenic, polyglutamine-expanded AR protein accumulates in the cell nucleus in a ligand-dependent manner and inhibits transcription by interfering with transcriptional factors and coactivators. Heat-shock proteins (HSPs) are stress-induced chaperones that facilitate the refolding and, thus, the degradation of abnormal proteins. Geranylgeranylacetone (GGA), a nontoxic antiulcer drug, has been shown to potently induce HSP expression in various tissues, including the central nervous system. In a cell model of SBMA, GGA increased the levels of Hsp70, Hsp90, and Hsp105 and inhibited cell death and the accumulation of pathogenic AR. Oral administration of GGA also up-regulated the expression of HSPs in the central nervous system of SBMA-transgenic mice and suppressed nuclear accumulation of the pathogenic AR protein, resulting in amelioration of polyglutamine-dependent neuromuscular phenotypes. These observations suggest that, although a high dose appears to be needed for clinical effects, oral GGA administration is a safe and promising therapeutic candidate for polyglutamine-mediated neurodegenerative diseases, including SBMA.
    URL, DOI BibTeX

    @article{Katsuno2005,
    	abstract = "Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the first exon of the androgen receptor gene (AR). The pathogenic, polyglutamine-expanded AR protein accumulates in the cell nucleus in a ligand-dependent manner and inhibits transcription by interfering with transcriptional factors and coactivators. Heat-shock proteins (HSPs) are stress-induced chaperones that facilitate the refolding and, thus, the degradation of abnormal proteins. Geranylgeranylacetone (GGA), a nontoxic antiulcer drug, has been shown to potently induce HSP expression in various tissues, including the central nervous system. In a cell model of SBMA, GGA increased the levels of Hsp70, Hsp90, and Hsp105 and inhibited cell death and the accumulation of pathogenic AR. Oral administration of GGA also up-regulated the expression of HSPs in the central nervous system of SBMA-transgenic mice and suppressed nuclear accumulation of the pathogenic AR protein, resulting in amelioration of polyglutamine-dependent neuromuscular phenotypes. These observations suggest that, although a high dose appears to be needed for clinical effects, oral GGA administration is a safe and promising therapeutic candidate for polyglutamine-mediated neurodegenerative diseases, including SBMA.",
    	author = "Katsuno, Masahisa and Sang, Chen and Adachi, Hiroaki and Minamiyama, Makoto and Waza, Masahiro and Tanaka, Fumiaki and Doyu, Manabu and Sobue, Gen",
    	doi = "10.1073/pnas.0506249102",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Katsuno et al. - 2005 - Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease.pdf:pdf",
    	issn = "0027-8424",
    	journal = "Proceedings of the National Academy of Sciences of the United States of America",
    	keywords = "Animals,Cell Line, Tumor,Cell Nucleus,Cell Nucleus: drug effects,Cell Nucleus: metabolism,Diterpenes,Diterpenes: pharmacology,Heat-Shock Proteins,Heat-Shock Proteins: biosynthesis,Heat-Shock Proteins: genetics,Humans,Mice,Motor Neuron Disease,Motor Neuron Disease: chemically induced,Motor Neuron Disease: metabolism,Motor Neuron Disease: physiopathology,Peptides,Peptides: toxicity,Receptors, Androgen,Receptors, Androgen: metabolism",
    	month = "nov",
    	number = 46,
    	pages = "16801--6",
    	pmid = 16260738,
    	title = "{Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1275598\&tool=pmcentrez\&rendertype=abstract",
    	volume = 102,
    	year = 2005
    }
    
  16. Hiroaki Adachi, Masahisa Katsuno, Makoto Minamiyama, Chen Sang, Gerassimos Pagoulatos, Charalampos Angelidis, Moriaki Kusakabe, Atsushi Yoshiki, Yasushi Kobayashi, Manabu Doyu and Gen Sobue.
    Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein.. The Journal of neuroscience : the official journal of the Society for Neuroscience 23(6):2203–11, 2003.
    Abstract Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR). The nuclear inclusions consisting of the mutant AR protein are characteristic and combine with many components of ubiquitin-proteasome and molecular chaperone pathways, raising the possibility that misfolding and altered degradation of mutant AR may be involved in the pathogenesis. We have reported that the overexpression of heat shock protein (HSP) chaperones reduces mutant AR aggregation and cell death in a neuronal cell model (Kobayashi et al., 2000). To determine whether increasing the expression level of chaperone improves the phenotype in a mouse model, we cross-bred SBMA transgenic mice with mice overexpressing the inducible form of human HSP70. We demonstrated that high expression of HSP70 markedly ameliorated the motor function of the SBMA model mice. In double-transgenic mice, the nuclear-localized mutant AR protein, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 overexpression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, probably caused by enhanced mutant AR degradation. Our study may provide the basis for the development of an HSP70-related therapy for SBMA and other polyQ diseases.
    URL BibTeX

    @article{Adachi2003,
    	abstract = "Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR). The nuclear inclusions consisting of the mutant AR protein are characteristic and combine with many components of ubiquitin-proteasome and molecular chaperone pathways, raising the possibility that misfolding and altered degradation of mutant AR may be involved in the pathogenesis. We have reported that the overexpression of heat shock protein (HSP) chaperones reduces mutant AR aggregation and cell death in a neuronal cell model (Kobayashi et al., 2000). To determine whether increasing the expression level of chaperone improves the phenotype in a mouse model, we cross-bred SBMA transgenic mice with mice overexpressing the inducible form of human HSP70. We demonstrated that high expression of HSP70 markedly ameliorated the motor function of the SBMA model mice. In double-transgenic mice, the nuclear-localized mutant AR protein, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 overexpression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, probably caused by enhanced mutant AR degradation. Our study may provide the basis for the development of an HSP70-related therapy for SBMA and other polyQ diseases.",
    	author = "Adachi, Hiroaki and Katsuno, Masahisa and Minamiyama, Makoto and Sang, Chen and Pagoulatos, Gerassimos and Angelidis, Charalampos and Kusakabe, Moriaki and Yoshiki, Atsushi and Kobayashi, Yasushi and Doyu, Manabu and Sobue, Gen",
    	issn = "1529-2401",
    	journal = "The Journal of neuroscience : the official journal of the Society for Neuroscience",
    	keywords = "Animals,Blotting, Western,Cell Nucleus,Cell Nucleus: metabolism,Cell Nucleus: pathology,Crosses, Genetic,Disease Models, Animal,Disease Progression,Gene Expression,HSP70 Heat-Shock Proteins,HSP70 Heat-Shock Proteins: biosynthesis,HSP70 Heat-Shock Proteins: genetics,Humans,Immunohistochemistry,Macromolecular Substances,Male,Mice,Mice, Transgenic,Molecular Chaperones,Molecular Chaperones: biosynthesis,Molecular Chaperones: genetics,Motor Activity,Motor Activity: genetics,Muscular Atrophy, Spinal,Muscular Atrophy, Spinal: genetics,Muscular Atrophy, Spinal: pathology,Muscular Atrophy, Spinal: physiopathology,Mutation,Phenotype,Receptors, Androgen,Receptors, Androgen: genetics,Receptors, Androgen: metabolism,Trinucleotide Repeat Expansion,Trinucleotide Repeat Expansion: genetics",
    	month = "",
    	number = 6,
    	pages = "2203--11",
    	pmid = 12657679,
    	title = "{Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/12657679",
    	volume = 23,
    	year = 2003
    }
    
  17. T Ooie, N Takahashi, T Saikawa, T Nawata, M Arikawa, K Yamanaka, M Hara, T Shimada and T Sakata.
    Single Oral Dose of Geranylgeranylacetone Induces Heat-Shock Protein 72 and Renders Protection Against Ischemia/Reperfusion Injury in Rat Heart. Circulation 104(15):1837–1843, 2001.
    Abstract Background– Induction of heat-shock proteins (HSPs) results in cardioprotection against ischemic insult. Geranylgeranylacetone (GGA), known as an antiulcer agent, reportedly induces HSP72 in the gastric mucosa and small intestine of rats. The present study tested the hypothesis that oral GGA would induce HSP72 in the heart and thus render cardioprotection against ischemia/reperfusion injury in rats. Methods and Results– Cardiac expression of HSPs was quantitatively evaluated in rats by Western blot analysis. Ten minutes of whole-body hyperthermia induced HSP72 expression in the rat hearts. A single oral dose of GGA (200 mg/kg) also induced expression of HSP72, which peaked at 24 hours after administration. Therefore, isolated perfused heart experiments using a Langendorff apparatus were performed 24 hours after administration of 200 mg/kg GGA (GGA group) or vehicle (control group). After a 5-minute stabilization period, no-flow global ischemia was given for 20, 40, or 60 minutes, followed by 30 minutes of reperfusion. During reperfusion, the functional recovery was greater and the released creatine kinase was less in the GGA group than in the control group. Electron microscopy findings revealed that the ischemia/reperfusion-induced damage of myocardial cells was prevented in GGA-treated myocytes. Conclusions– The results suggest that oral GGA is cardioprotective against ischemic insult through its induction of HSP72.
    URL, DOI BibTeX

    @article{Ooie2001,
    	abstract = "Background-- Induction of heat-shock proteins (HSPs) results in cardioprotection against ischemic insult. Geranylgeranylacetone (GGA), known as an antiulcer agent, reportedly induces HSP72 in the gastric mucosa and small intestine of rats. The present study tested the hypothesis that oral GGA would induce HSP72 in the heart and thus render cardioprotection against ischemia/reperfusion injury in rats. Methods and Results-- Cardiac expression of HSPs was quantitatively evaluated in rats by Western blot analysis. Ten minutes of whole-body hyperthermia induced HSP72 expression in the rat hearts. A single oral dose of GGA (200 mg/kg) also induced expression of HSP72, which peaked at 24 hours after administration. Therefore, isolated perfused heart experiments using a Langendorff apparatus were performed 24 hours after administration of 200 mg/kg GGA (GGA group) or vehicle (control group). After a 5-minute stabilization period, no-flow global ischemia was given for 20, 40, or 60 minutes, followed by 30 minutes of reperfusion. During reperfusion, the functional recovery was greater and the released creatine kinase was less in the GGA group than in the control group. Electron microscopy findings revealed that the ischemia/reperfusion-induced damage of myocardial cells was prevented in GGA-treated myocytes. Conclusions-- The results suggest that oral GGA is cardioprotective against ischemic insult through its induction of HSP72.",
    	author = "Ooie, T. and Takahashi, N. and Saikawa, T. and Nawata, T. and Arikawa, M. and Yamanaka, K. and Hara, M. and Shimada, T. and Sakata, T.",
    	doi = "10.1161/hc3901.095771",
    	issn = "0009-7322",
    	journal = "Circulation",
    	month = "",
    	number = 15,
    	pages = "1837--1843",
    	title = "{Single Oral Dose of Geranylgeranylacetone Induces Heat-Shock Protein 72 and Renders Protection Against Ischemia/Reperfusion Injury in Rat Heart}",
    	url = "http://circ.ahajournals.org/content/104/15/1837.full",
    	volume = 104,
    	year = 2001
    }