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Sample records for brain hsp90 studied

  1. Phosphorylation and oligomerization states of native pig brain HSP90 studied by mass spectrometry

    DEFF Research Database (Denmark)

    Garnier, C.; Lafitte, D.; Jorgensen, T.J.;

    2001-01-01

    forms of native pig brain alpha-HSP90, with the diphosphorylated form being the most abundant. For the beta isoform, the di-phosphorylated was also the most abundant. MALDI mass spectra of HSP90 samples after chemical cross-linking showed a high percentage of alpha-alpha homodimers. In addition...

  2. Structural and functional studies of Leishmania braziliensis Hsp90.

    Science.gov (United States)

    Silva, K P; Seraphim, T V; Borges, J C

    2013-01-01

    The ubiquitous Hsp90 is critical for protein homeostasis in the cells, stabilizing "client" proteins in a functional state. Hsp90 activity depends on its ability to bind and hydrolyze ATP, involving various conformational changes that are regulated by co-chaperones, posttranslational modifications and small molecules. Compounds like geldanamycin (GA) and radicicol inhibit the Hsp90 ATPase activity by occupying the ATP binding site, which can lead client protein to degradation and also inhibit cell growth and differentiation in protozoan parasites. Our goal was to produce the recombinant Hsp90 of Leishmania braziliensis (LbHsp90) and construct of its N-terminal (LbHsp90N) and N-domain and middle-domain (LbHsp90NM), which lacks the C-terminal dimerization domain, in order to understand how Hsp90 works in protozoa. The recombinant proteins were produced folded as attested by spectroscopy experiments. Hydrodynamic experiments revealed that LbHsp90N and LbHsp90NM behaved as elongated monomers while LbHsp90 is an elongated dimer. All proteins prevented the in vitro citrate synthase and malate dehydrogenase aggregation, attesting that they have chaperone activity, and interacted with adenosine ligands with similar dissociation constants. The LbHsp90 has low ATPase activity (k(cat)=0.320min(-1)) in agreement with Hsp90 orthologs, whereas the LbHsp90NM has negligible activity, suggesting the importance of the dimeric protein for this activity. The GA interacts with LbHsp90 and with its domain constructions with different affinities and also inhibits the LbHsp90 ATPase activity with an IC(50) of 0.7μM. All these results shed light on the LbHsp90 activity and are the first step to understanding the Hsp90 molecular chaperone system in L. braziliensis. PMID:22910377

  3. Decreased Hsp90 expression in infiltrative lobular carcinoma: an immunohistochemical study

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    Zagouri Flora

    2010-08-01

    Full Text Available Abstract Background Elevated Hsp90 expression has been documented in breast ductal carcinomas, whereas decreased Hsp90 expression has been reported in precursor lobular lesions. This study aims to assess Hsp90 expression in infiltrative lobular carcinomas of the breast. Methods Tissue specimens were taken from 32 patients with infiltrative lobular carcinoma. Immunohistochemical assessment of Hsp90 was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. Concerning Hsp90 assessment: i the percentage of positive cells and ii the intensity were separately analyzed. Subsequently, the Allred score was adopted and calculated. The intensity was treated as an ordinal variable-score (0: negative, low: 1, moderate: 2, high: 3. Statistical analysis followed. Results All infiltrative lobular carcinoma foci mainly presented with a positive cytoplasmic immunoreaction for Hsp90. Compared to the adjacent normal ducts and lobules, infiltrative lobular carcinoma exhibited a statistically significant decrease in Hsp90 expression, both in terms of Hsp90 positive cells (% and Allred score (74.2 ± 11.2 vs. 59.1 ± 14.2 p = 0.0001; 7.00 ± 0.95 vs. 6.22 ± 1.01, p = 0.007, Wilcoxon matched-pairs signed-ranks test. Concerning the intensity of Hsp90 immunostaining only a marginal decrease was noted (2.16 ± 0.68 vs. 1.84 ± 0.63, p = 0.087, Wilcoxon matched-pairs signed-ranks test. Conclusion ILC lesions seem to exhibit decreased Hsp90 expression, a finding contrary to what might have been expected, given that high Hsp90 expression is a trait of invasive ductal carcinomas.

  4. Two HSP90 genes in mandarin fish Siniperca chuatsi: identification, characterization and their specific expression profiles during embryogenesis and under stresses.

    Science.gov (United States)

    Wang, Peng-Fei; Zeng, Shuang; Xu, Peng; Zhou, Lei; Li, Gui-Feng

    2016-08-01

    HSP90 plays important roles in multiple cellular stress responses. Here, two cytoplasmic HSP90 isoforms, ScHSP90α and ScHSP90β, were identified from Siniperca chuatsi. Their cDNA and gDNA structures, amino acid sequence features, and sequence identities and phylogenetic analysis with other species were described. Their expression profiles during embryonic development in different tissues and under stressful conditions were analyzed using real-time quantitative PCR. During embryogenesis, transcripts of both genes were detected at low levels during the early developmental stages and were up-regulated from appearance of myomere for ScHSP90a and closure of blastopore for ScHSP90β. ScHSP90α showed a tissue-specific variation with high expression in ovary and brain under non-stressed conditions, while ScHSP90β was ubiquitously highly expressed in different tissues. Acute heat shock resulted in a strong up-regulation of ScHSP90α in heart, liver, and head kidney, while it only weakly induced ScHSP90β in these tissues. ScHSP90α was also markedly induced in liver in a time-dependent manner under hypoxia, while the expression of ScHSP90β was not affected by hypoxia. Additionally, Aeromonas hydrophila infection markedly augmented ScHSP90α in head kidney and spleen and mildly up-regulated ScHSP90β in spleen, while suppressing ScHSP90β in head kidney. These results suggest that ScHSP90α and ScHSP90β are differently involved in embryogenesis and under different environmental conditions including high temperature, hypoxia, and bacterial infection. This study will benefit to further clarify the roles of fish HSP90 isoforms in embryogenesis and under stressful conditions and contribute to further study on enhancing stress tolerance and disease resistance of mandarin fish. PMID:26820141

  5. Low resolution structural studies indicate that the activator of Hsp90 ATPase 1 (Aha1 of Leishmania braziliensis has an elongated shape which allows its interaction with both N- and M-domains of Hsp90.

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    Thiago V Seraphim

    Full Text Available The Hsp90 molecular chaperone is essential for protein homeostasis and in the maturation of proteins involved with cell-cycle control. The low ATPase activity of Hsp90 is critical to drive its functional cycle, which is dependent on the Hsp90 cochaperones. The Activator of Hsp90 ATPase-1 (Aha1 is a protein formed by two domains, N- and C-terminal, that stimulates the Hsp90 ATPase activity by several folds. Although the relevance of Aha1 for Hsp90 functions has been proved, as well as its involvement in the desensitization to inhibitors of the Hsp90, the knowledge on its overall structure and behavior in solution is limited. In this work we present the functional and structural characterization of Leishmania braziliensis Aha1 (LbAha1. This protozoan is the causative agent of cutaneous and mucocutaneous leishmaniasis, a neglected disease. The recombinant LbAha1 behaves as an elongated monomer and is organized into two folded domains interconnected by a flexible linker. Functional experiments showed that LbAha1 interacts with L. braziliensis Hsp90 (LbHsp90 with micromolar dissociation constant in a stoichiometry of 2 LbAha1 to 1 LbHsp90 dimer and stimulates 10-fold the LbHsp90 ATPase activity showing positive cooperativity. Furthermore, the LbHsp90::LbAha1 complex is directed by enthalphy and opposed by entropy, probably due to the spatial freedom restrictions imposed by the proteins' interactions. Small-angle X-ray scattering data allowed the reconstruction of low resolution models and rigid body simulations of LbAha1, indicating its mode of action on LbHsp90. Western blot experiments allowed Aha1 identification (as well as Hsp90 in three Leishmania species at two temperatures, suggesting that Aha1 is a cognate protein. All these data shed light on the LbAha1 mechanism of action, showing that it has structural dimensions and flexibility that allow interacting with both N-terminal and middle domains of the LbHsp90.

  6. Low resolution structural studies indicate that the activator of Hsp90 ATPase 1 (Aha1) of Leishmania braziliensis has an elongated shape which allows its interaction with both N- and M-domains of Hsp90.

    Science.gov (United States)

    Seraphim, Thiago V; Alves, Marina M; Silva, Indjara M; Gomes, Francisco E R; Silva, Kelly P; Murta, Silvane M F; Barbosa, Leandro R S; Borges, Júlio C

    2013-01-01

    The Hsp90 molecular chaperone is essential for protein homeostasis and in the maturation of proteins involved with cell-cycle control. The low ATPase activity of Hsp90 is critical to drive its functional cycle, which is dependent on the Hsp90 cochaperones. The Activator of Hsp90 ATPase-1 (Aha1) is a protein formed by two domains, N- and C-terminal, that stimulates the Hsp90 ATPase activity by several folds. Although the relevance of Aha1 for Hsp90 functions has been proved, as well as its involvement in the desensitization to inhibitors of the Hsp90, the knowledge on its overall structure and behavior in solution is limited. In this work we present the functional and structural characterization of Leishmania braziliensis Aha1 (LbAha1). This protozoan is the causative agent of cutaneous and mucocutaneous leishmaniasis, a neglected disease. The recombinant LbAha1 behaves as an elongated monomer and is organized into two folded domains interconnected by a flexible linker. Functional experiments showed that LbAha1 interacts with L. braziliensis Hsp90 (LbHsp90) with micromolar dissociation constant in a stoichiometry of 2 LbAha1 to 1 LbHsp90 dimer and stimulates 10-fold the LbHsp90 ATPase activity showing positive cooperativity. Furthermore, the LbHsp90::LbAha1 complex is directed by enthalphy and opposed by entropy, probably due to the spatial freedom restrictions imposed by the proteins' interactions. Small-angle X-ray scattering data allowed the reconstruction of low resolution models and rigid body simulations of LbAha1, indicating its mode of action on LbHsp90. Western blot experiments allowed Aha1 identification (as well as Hsp90) in three Leishmania species at two temperatures, suggesting that Aha1 is a cognate protein. All these data shed light on the LbAha1 mechanism of action, showing that it has structural dimensions and flexibility that allow interacting with both N-terminal and middle domains of the LbHsp90. PMID:23826147

  7. Mechanisms of Hsp90 regulation

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    Prodromou, Chrisostomos

    2016-01-01

    Heat shock protein 90 (Hsp90) is a molecular chaperone that is involved in the activation of disparate client proteins. This implicates Hsp90 in diverse biological processes that require a variety of co-ordinated regulatory mechanisms to control its activity. Perhaps the most important regulator is heat shock factor 1 (HSF1), which is primarily responsible for upregulating Hsp90 by binding heat shock elements (HSEs) within Hsp90 promoters. HSF1 is itself subject to a variety of regulatory processes and can directly respond to stress. HSF1 also interacts with a variety of transcriptional factors that help integrate biological signals, which in turn regulate Hsp90 appropriately. Because of the diverse clientele of Hsp90 a whole variety of co-chaperones also regulate its activity and some are directly responsible for delivery of client protein. Consequently, co-chaperones themselves, like Hsp90, are also subject to regulatory mechanisms such as post translational modification. This review, looks at the many different levels by which Hsp90 activity is ultimately regulated. PMID:27515256

  8. Hsp90 inhibition decreases mitochondrial protein turnover.

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    Daciana H Margineantu

    Full Text Available BACKGROUND: Cells treated with hsp90 inhibitors exhibit pleiotropic changes, including an expansion of the mitochondrial compartment, accompanied by mitochondrial fragmentation and condensed mitochondrial morphology, with ultimate compromise of mitochondrial integrity and apoptosis. FINDINGS: We identified several mitochondrial oxidative phosphorylation complex subunits, including several encoded by mtDNA, that are upregulated by hsp90 inhibitors, without corresponding changes in mRNA abundance. Post-transcriptional accumulation of mitochondrial proteins observed with hsp90 inhibitors is also seen in cells treated with proteasome inhibitors. Detailed studies of the OSCP subunit of mitochondrial F1F0-ATPase revealed the presence of mono- and polyubiquitinated OSCP in mitochondrial fractions. We demonstrate that processed OSCP undergoes retrotranslocation to a trypsin-sensitive form associated with the outer mitochondrial membrane. Inhibition of proteasome or hsp90 function results in accumulation of both correctly targeted and retrotranslocated mitochondrial OSCP. CONCLUSIONS: Cytosolic turnover of mitochondrial proteins demonstrates a novel connection between mitochondrial and cytosolic compartments through the ubiquitin-proteasome system. Analogous to defective protein folding in the endoplasmic reticulum, a mitochondrial unfolded protein response may play a role in the apoptotic effects of hsp90 and proteasome inhibitors.

  9. Calcium/calmodulin kinase1 and its relation to thermotolerance and HSP90 in Sporothrix schenckii: an RNAi and yeast two-hybrid study

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    Gonzalez-Mendez Ricardo

    2011-07-01

    Full Text Available Abstract Background Sporothrix schenckii is a pathogenic dimorphic fungus of worldwide distribution. It grows in the saprophytic form with hyaline, regularly septated hyphae and pyriform conidia at 25°C and as the yeast or parasitic form at 35°C. Previously, we characterized a calcium/calmodulin kinase in this fungus. Inhibitors of this kinase were observed to inhibit the yeast cell cycle in S. schenckii. Results The presence of RNA interference (RNAi mechanism in this fungus was confirmed by the identification of a Dicer-1 homologue in S. schenckii DNA. RNAi technology was used to corroborate the role of calcium/calmodulin kinase I in S. schenckii dimorphism. Yeast cells were transformed with the pSilent-Dual2G (pSD2G plasmid w/wo inserts of the coding region of the calcium/calmodulin kinase I (sscmk1 gene. Transformants were selected at 35°C using resistance to geneticin. Following transfer to liquid medium at 35°C, RNAi transformants developed as abnormal mycelium clumps and not as yeast cells as would be expected. The level of sscmk1 gene expression in RNAi transformants at 35°C was less than that of cells transformed with the empty pSD2G at this same temperature. Yeast two-hybrid analysis of proteins that interact with SSCMK1 identified a homologue of heat shock protein 90 (HSP90 as interacting with this kinase. Growth of the fungus similar to that of the RNAi transformants was observed in medium with geldanamycin (GdA, 10 μM, an inhibitor of HSP90. Conclusions Using the RNAi technology we silenced the expression of sscmk1 gene in this fungus. RNAi transformants were unable to grow as yeast cells at 35°C showing decreased tolerance to this temperature. The interaction of SSCMK1 with HSP90, observed using the yeast two-hybrid assay suggests that this kinase is involved in thermotolerance through its interaction with HSP90. SSCMK1 interacted with the C terminal domain of HSP90 where effector proteins and co-chaperones interact. These

  10. Hsp90 Regulates NADPH Oxidase Activity and Is Necessary for Superoxide but Not Hydrogen Peroxide Production

    OpenAIRE

    Chen, Feng; Pandey, Deepesh; Chadli, Ahmed; Catravas, John D.; Chen, Teng; Fulton, David J. R.

    2011-01-01

    The goal of this study was to identify whether heat-shock protein 90 (Hsp90) regulates the production of superoxide and other reactive oxygen species from the NADPH oxidases (Nox). We found that pharmacological and genetic inhibition of Hsp90 directly reduced Nox5-derived superoxide without secondarily modifying signaling events. Coimmunoprecipitation and bioluminescence resonance energy transfer studies suggest that the C-terminus of Nox5 binds to Hsp90. Long-term Hsp90 inhibition reduced No...

  11. The 90-kDa Heat Shock Protein Hsp90 Protects Tubulin against Thermal Denaturation*

    OpenAIRE

    Weis, Felix; Moullintraffort, Laura; Heichette, Claire; Chrétien, Denis; Garnier, Cyrille

    2010-01-01

    Hsp90 and tubulin are among the most abundant proteins in the cytosol of eukaryotic cells. Although Hsp90 plays key roles in maintaining its client proteins in their active state, tubulin is essential for fundamental processes such as cell morphogenesis and division. Several studies have suggested a possible connection between Hsp90 and the microtubule cytoskeleton. Because tubulin is a labile protein in its soluble form, we investigated whether Hsp90 protects it against thermal denaturation....

  12. Phage displaying epitope of Candida albicans HSP90 and serodiagnosis

    Institute of Scientific and Technical Information of China (English)

    杨琼; 王丽; 卢大宁; 邢沈阳; 尹东; 朱筱娟

    2004-01-01

    @@ Recently, the frequent use of immunosuppressants and chemotherapeutic drugs for cancers has caused an increase in the frequency of life-threatening systemic candidiasis.1 Studies by Matthews et al2 indicated HSP90 fragments are major targets for the immune system in infection due to C. albicans, and anti-epitope LKVIRK of HSP90 antibody is a serological marker for diagnosis of invasive candidiasis. Cloning and sequencing HSP90 antigen revealed that the linear epitope LKVIRK, localized near the C-terminus of the 47 kDa protein which circulates in the sera of patients with invasive candidiasis, as a heat-stable breakdown product of large more heat-labile antigen HSP90.2 In this study, epitope LKVIRK was displayed on the surface of phage fd to develop a new serological test for systemic candidiasis.

  13. Tissue-specific induction of Hsp90 mRNA and plasma cortisol response in chinook salmon following heat shock, seawater challenge, and handling challenge

    Science.gov (United States)

    Palmisano, Aldo N.; Winton, J.R.; Dickhoff, Walton W.

    2000-01-01

    In studying the whole-body response of chinook salmon (Oncorhynchus tshawytscha) to various stressors, we found that 5-hour exposure to elevated temperature (mean 21.6??C; + 10.6??C over ambient) induced a marked increase in Hsp90 messenger RNA accumulation in heart, brain, gill, muscle, liver, kidney, and tail fin tissues. The most vital tissues (heart, brain, gill, and muscle) showed the greatest Hsp90-mRNA response, with heart tissue increasing approximately 35-fold, Heat shock induced no increase in plasma cortisol. In contrast, a standard handling challenge induced high plasma cortisol levels, but no elevation in Hsp90 mRNA in any tissue, clearly separating the physiological and cellular stress responses. We saw no increase either in tissue Hsp90 mRNA levels or in plasma cortisol concentrations after exposing the fish to seawater overnight.

  14. Hsp-90 and the biology of nematodes

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    Maitland Kirsty

    2009-10-01

    Full Text Available Abstract Background Hsp-90 from the free-living nematode Caenorhabditis elegans is unique in that it fails to bind to the specific Hsp-90 inhibitor, geldanamycin (GA. Here we surveyed 24 different free-living or parasitic nematodes with the aim of determining whether C. elegans Hsp-90 was the exception or the norm amongst the nematodes. We combined these data with codon evolution models in an attempt to identify whether hsp-90 from GA-binding and non-binding species has evolved under different evolutionary constraints. Results We show that GA-binding is associated with life history: free-living nematodes and those parasitic species with free-living larval stages failed to bind GA. In contrast, obligate parasites and those worms in which the free-living stage in the environment is enclosed within a resistant egg, possess a GA-binding Hsp-90. We analysed Hsp-90 sequences from fifteen nematode species to determine whether nematode hsp-90s have undergone adaptive evolution that influences GA-binding. Our data provide evidence of rapid diversifying selection in the evolution of the hsp-90 gene along three separate lineages, and identified a number of residues showing significant evidence of adaptive evolution. However, we were unable to prove that the selection observed is correlated with the ability to bind geldanamycin or not. Conclusion Hsp-90 is a multi-functional protein and the rapid evolution of the hsp-90 gene presumably correlates with other key cellular functions. Factors other than primary amino acid sequence may influence the ability of Hsp-90 to bind to geldanamycin.

  15. The Double-Edged Sword: Conserved Functions of Extracellular Hsp90 in Wound Healing and Cancer

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    Hance, Michael W.; Nolan, Krystal D.; Isaacs, Jennifer S., E-mail: isaacsj@musc.edu [Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Hollings Cancer Center, Charleston, SC 29412 (United States)

    2014-05-06

    Heat shock proteins (Hsps) represent a diverse group of chaperones that play a vital role in the protection of cells against numerous environmental stresses. Although our understanding of chaperone biology has deepened over the last decade, the “atypical” extracellular functions of Hsps have remained somewhat enigmatic and comparatively understudied. The heat shock protein 90 (Hsp90) chaperone is a prototypic model for an Hsp family member exhibiting a duality of intracellular and extracellular functions. Intracellular Hsp90 is best known as a master regulator of protein folding. Cancers are particularly adept at exploiting this function of Hsp90, providing the impetus for the robust clinical development of small molecule Hsp90 inhibitors. However, in addition to its maintenance of protein homeostasis, Hsp90 has also been identified as an extracellular protein. Although early reports ascribed immunoregulatory functions to extracellular Hsp90 (eHsp90), recent studies have illuminated expanded functions for eHsp90 in wound healing and cancer. While the intended physiological role of eHsp90 remains enigmatic, its evolutionarily conserved functions in wound healing are easily co-opted during malignancy, a pathology sharing many properties of wounded tissue. This review will highlight the emerging functions of eHsp90 and shed light on its seemingly dichotomous roles as a benevolent facilitator of wound healing and as a sinister effector of tumor progression.

  16. Molecular cloning and characterization of the full-length Hsp90 gene from Matricaria recutita.

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    Ling, S P; Su, S S; Zhang, H M; Zhang, X S; Liu, X Y; Pan, G F; Yuan, Y

    2014-01-01

    Heat shock protein 90 (Hsp90) is one of the most abundant and conserved chaperone proteins and plays important roles in plant growth and responses to environmental stimuli. However, little is known regarding the sequence and function of Hsp90s in Matricaria recutita. In the present study, we cloned the full-length cDNA sequence of the hsp90 gene from this species. Using rapid amplification of cDNA ends technologies with 2 degenerate primers that were designed based on the hsp90 gene sequence from other members of Asteraceae, we isolated and characterized an Hsp90 homolog gene from M. recutita (Mr-Hsp90). The full-length Mr-hsp90 cDNA sequence, containing 2097 base pairs, encodes a protein of 698 amino acids. Based on amino acid sequence identity, Mr-Hsp90 showed high similarity to other cloned Hsp90 proteins. The Mr-Hsp90 protein was closely clustered with the Lactuca sativa in a phylogenetic tree. These results indicate that the cloned sequence of Mr-Hsp90 is a member of the Hsp90 family, which is reported for the first time in M. recutita. Next, we conducted a salt stress experiment to determine the protein's function under salt stress conditions. Survival of chamomile seedlings subjected to heat-shock pretreatment was significantly increased compared with groups that had not undergone heat-shock pretreatment in a salt stress environment. This indicates that Mr-Hsp90 plays an important role in the salt resistance of chamomile seedlings. PMID:25526220

  17. Hsp90 is involved in apoptosis of Candida albicans by regulating the calcineurin-caspase apoptotic pathway.

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    Dai, BaoDi; Wang, Yan; Li, DeDong; Xu, Yi; Liang, RongMei; Zhao, LanXue; Cao, YongBing; Jia, JianHui; Jiang, YuanYing

    2012-01-01

    Candida albicans is the most common human fungal pathogen. Recent evidence has revealed the occurrence of apoptosis in C. albicans that is inducible by environmental stresses such as hydrogen peroxide, acetic acid, and amphotericin B. Apoptosis is regulated by the calcineurin-caspase pathway in C. albicans, and calcineurin is under the control of Hsp90 in echinocandin resistance. However, the role of Hsp90 in apoptosis of C. albicans remains unclear. In this study, we investigated the role of Hsp90 in apoptosis of C. albicans by using an Hsp90-compromised strain tetO-HSP90/hsp90 and found that upon apoptotic stimuli, including hydrogen peroxide, acetic acid or amphotericin B treatment, less apoptosis occurred, less ROS was produced, and more cells survived in the Hsp90-compromised strain compared with the Hsp90/Hsp90 wild-type strain. In addition, Hsp90-compromised cells were defective in up-regulating caspase-encoding gene CaMCA1 expression and activating caspase activity upon the apoptotic stimuli. Investigations on the relationship between Hsp90 and calcineurin revealed that activation of calcineurin could up-regulate apoptosis but could not further down-regulate apoptosis in Hsp90-compromised cells, indicating that calcineurin was downstream of Hsp90. Hsp90 inhibitor geldanamycin (GdA) could further decrease the apoptosis in calcineurin-pathway-defect strains, indicating that compromising Hsp90 function had a stronger effect than compromising calcineurin function on apoptosis. Collectively, this study demonstrated that compromised Hsp90 reduced apoptosis in C. albicans, partially through downregulating the calcineurin-caspase pathway. PMID:23028789

  18. Hsp90 is involved in apoptosis of Candida albicans by regulating the calcineurin-caspase apoptotic pathway.

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    BaoDi Dai

    Full Text Available Candida albicans is the most common human fungal pathogen. Recent evidence has revealed the occurrence of apoptosis in C. albicans that is inducible by environmental stresses such as hydrogen peroxide, acetic acid, and amphotericin B. Apoptosis is regulated by the calcineurin-caspase pathway in C. albicans, and calcineurin is under the control of Hsp90 in echinocandin resistance. However, the role of Hsp90 in apoptosis of C. albicans remains unclear. In this study, we investigated the role of Hsp90 in apoptosis of C. albicans by using an Hsp90-compromised strain tetO-HSP90/hsp90 and found that upon apoptotic stimuli, including hydrogen peroxide, acetic acid or amphotericin B treatment, less apoptosis occurred, less ROS was produced, and more cells survived in the Hsp90-compromised strain compared with the Hsp90/Hsp90 wild-type strain. In addition, Hsp90-compromised cells were defective in up-regulating caspase-encoding gene CaMCA1 expression and activating caspase activity upon the apoptotic stimuli. Investigations on the relationship between Hsp90 and calcineurin revealed that activation of calcineurin could up-regulate apoptosis but could not further down-regulate apoptosis in Hsp90-compromised cells, indicating that calcineurin was downstream of Hsp90. Hsp90 inhibitor geldanamycin (GdA could further decrease the apoptosis in calcineurin-pathway-defect strains, indicating that compromising Hsp90 function had a stronger effect than compromising calcineurin function on apoptosis. Collectively, this study demonstrated that compromised Hsp90 reduced apoptosis in C. albicans, partially through downregulating the calcineurin-caspase pathway.

  19. Nematode Hsp90: highly conserved but functionally diverse.

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    Gillan, Victoria; Devaney, Eileen

    2014-08-01

    Nematodes are amongst the most successful and abundant organisms on the planet with approximately 30 000 species described, although the actual number of species is estimated to be one million or more. Despite sharing a relatively simple and invariant body plan, there is considerable diversity within the phylum. Nematodes have evolved to colonize most ecological niches, and can be free-living or can parasitize plants or animals to the detriment of the host organism. In this review we consider the role of heat shock protein 90 (Hsp90) in the nematode life cycle. We describe studies on Hsp90 in the free-living nematode Caenorhabditis elegans and comparative work on the parasitic species Brugia pahangi, and consider whether a dependence upon Hsp90 can be exploited for the control of parasitic species. PMID:24721950

  20. Waddington's widget: Hsp90 and the inheritance of acquired characters.

    Science.gov (United States)

    Ruden, Douglas M; Garfinkel, Mark D; Sollars, Vincent E; Lu, Xiangyi

    2003-10-01

    Conrad Waddington published an influential model for evolution in his 1942 paper, Canalization of Development and Inheritance of Acquired Characters. In this classic, albeit controversial, paper, he proposed that an unknown mechanism exists that conceals phenotypic variation until the organism is stressed. Recent studies have proposed that the highly conserved chaperone Hsp90 could function as a "capacitor," or an "adaptively inducible canalizer," that masks silent phenotypic variation of either genetic or epigenetic origin. This review will discuss evidence for, and arguments against, the role of Hsp90 as a capacitor for morphological evolution, and as a key component of what we call "Waddington's widget." PMID:14986860

  1. Experimentally guided structural modeling and dynamics analysis of Hsp90-p53 interactions: allosteric regulation of the Hsp90 chaperone by a client protein.

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    Blacklock, Kristin; Verkhivker, Gennady M

    2013-11-25

    A fundamental role of the Hsp90 chaperone system in mediating maturation of protein clients is essential for the integrity of signaling pathways involved in cell cycle control and organism development. Molecular characterization of Hsp90 interactions with client proteins is fundamental to understanding the activity of many tumor-inducing signaling proteins and presents an active area of structural and biochemical studies. In this work, we have probed mechanistic aspects of allosteric regulation of Hsp90 by client proteins via a detailed computational study of Hsp90 interactions with the tumor suppressor protein p53. Experimentally guided protein docking and molecular dynamics structural refinement have reconstructed the recognition-competent states of the Hsp90-p53 complexes that are consistent with the NMR studies. Protein structure network analysis has identified critical interacting networks and specific residues responsible for structural integrity and stability of the Hsp90-p53 complexes. Coarse-grained modeling was used to characterize the global dynamics of the regulatory complexes and map p53-induced changes in the conformational equilibrium of Hsp90. The variations in the functional dynamics profiles of the Hsp90-p53 complexes are consistent with the NMR studies and could explain differences in the functional role of the alternative binding sites. Despite the overall similarity of the collective movements and the same global interaction footprint, p53 binding at the C-terminal interaction site of Hsp90 may have a more significant impact on the chaperone dynamics, which is consistent with the stronger allosteric effect of these interactions revealed by the experimental studies. The results suggest that p53-induced modulation of the global dynamics and structurally stable interaction networks can target the regulatory hinge regions and facilitate stabilization of the closed Hsp90 dimer that underlies the fundamental stimulatory effect of the p53 client. PMID

  2. Hsp90: Friends, clients and natural foes.

    Science.gov (United States)

    Verma, Sharad; Goyal, Sukriti; Jamal, Salma; Singh, Aditi; Grover, Abhinav

    2016-08-01

    Hsp90, a homodimeric ATPase, is responsible for the correct folding of a number of newly synthesized polypeptides in addition to the correct folding of denatured/misfolded client proteins. It requires several co-chaperones and other partner proteins for chaperone activity. Due to the involvement of Hsp90-dependent client proteins in a variety of oncogenic signaling pathways, Hsp90 inhibition has emerged as one of the leading strategies for anticancer chemotherapeutics. Most of Hsp90 inhibitors blocks the N terminal ATP binding pocket and prevents the conformational changes which are essential for the loading of co-chaperones and client proteins. Several other inhibitors have also been reported which disrupt chaperone cycle in ways other than binding to N terminal ATP binding pocket. The Hsp90 inhibition is associated with heat shock response, mediated by HSF-1, to overcome the loss of Hsp90 and sustain cell survival. This review is an attempt to give an over view of all the important players of chaperone cycle. PMID:27295069

  3. BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance.

    Science.gov (United States)

    Zhang, Hong; Neely, Laura; Lundgren, Karen; Yang, Yong-Ching; Lough, Rachel; Timple, Noel; Burrows, Francis

    2010-03-01

    17-AAG, the first-generation clinical Hsp90 inhibitor, exhibits promising antitumor activity in clinical studies, but is limited by poor solubility and hepatotoxicity. To pursue compounds with better biopharmaceutical properties, we have developed a series of fully synthetic orally bioavailable inhibitors of Hsp90. Here, we report that 17-AAG and other ansamycin derivatives are inactive in P-gp and/or MRP-1 expressing cell lines and sensitivity could be restored by coadministration of P-gp or MRP inhibitors. In contrast, the synthetic Hsp90 inhibitor, BIIB021 was active in these models. Accordingly, BIIB021 was considerably more active than 17-AAG against adrenocortical carcinoma, a tumor that naturally expresses P-gp, both in vitro and in vivo. This efflux pump-mediated resistance is manifested in both cytotoxicity assays and measurements of target inhibition, such as client protein degradation. Other than this, the cytotoxic activity of BIIB021 was also not influenced by loss of NQO1 or Bcl-2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. Our results indicate that the activity of 17-AAG and other ansamycins may be curtailed in tumors that have upregulated efflux pumps or antiapoptotic proteins or other genetic alterations. These data indicate that the new generation of synthetic anti-Hsp90 drugs, exemplified by BIIB021 that is currently undergoing Phase II testing, may have broader application against tumors with acquired multidrug resistance or tumors located in organs protected by MDR proteins, such as the adrenal glands, brain and testis. PMID:19676042

  4. The regulatory mechanism of Hsp90α secretion from endothelial cells and its role in angiogenesis during wound healing

    International Nuclear Information System (INIS)

    Research highlights: → Growth factors such as bFGF, VEGF, PDGF and SDF-1 stimulate Hsp90α secretion from endothelial cells. → Secreted Hsp90α localizes on the leading edge of activated endothelial cells. → Secreted Hsp90α promotes angiogenesis in wound healing. -- Abstract: Heat shock protein 90α (Hsp90α) is a ubiquitously expressed molecular chaperone, which is essential for the maintenance of eukaryote homeostasis. Hsp90α can also be secreted extracellularly and is associated with several physiological and pathological processes including wound healing, cancer, infectious diseases and diabetes. Angiogenesis, defined as the sprouting of new blood vessels from pre-existing capillaries via endothelial cell proliferation and migration, commonly occurs in and contributes to the above mentioned processes. However, the secretion of Hsp90α from endothelial cells and also its function in angiogenesis are still unclear. Here we investigated the role of extracellular Hsp90α in angiogenesis using dermal endothelial cells in vitro and a wound healing model in vivo. We find that the secretion of Hsp90α but not Hsp90β is increased in activated endothelial cells with the induction of angiogenic factors and matrix proteins. Secreted Hsp90α localizes on the leading edge of endothelial cells and promotes their angiogenic activities, whereas Hsp90α neutralizing antibodies reverse the effect. Furthermore, using a mouse skin wound healing model in vivo, we demonstrate that extracellular Hsp90α localizes on blood vessels in granulation tissues of wounded skin and promotes angiogenesis during wound healing. Taken together, our study reveals that Hsp90α can be secreted by activated endothelial cells and is a positive regulator of angiogenesis, suggesting the potential application of Hsp90α as a stimulator for wound repair.

  5. The regulatory mechanism of Hsp90{alpha} secretion from endothelial cells and its role in angiogenesis during wound healing

    Energy Technology Data Exchange (ETDEWEB)

    Song, Xiaomin [National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084 (China); Luo, Yongzhang, E-mail: yluo@tsinghua.edu.cn [National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084 (China)

    2010-07-16

    Research highlights: {yields} Growth factors such as bFGF, VEGF, PDGF and SDF-1 stimulate Hsp90{alpha} secretion from endothelial cells. {yields} Secreted Hsp90{alpha} localizes on the leading edge of activated endothelial cells. {yields} Secreted Hsp90{alpha} promotes angiogenesis in wound healing. -- Abstract: Heat shock protein 90{alpha} (Hsp90{alpha}) is a ubiquitously expressed molecular chaperone, which is essential for the maintenance of eukaryote homeostasis. Hsp90{alpha} can also be secreted extracellularly and is associated with several physiological and pathological processes including wound healing, cancer, infectious diseases and diabetes. Angiogenesis, defined as the sprouting of new blood vessels from pre-existing capillaries via endothelial cell proliferation and migration, commonly occurs in and contributes to the above mentioned processes. However, the secretion of Hsp90{alpha} from endothelial cells and also its function in angiogenesis are still unclear. Here we investigated the role of extracellular Hsp90{alpha} in angiogenesis using dermal endothelial cells in vitro and a wound healing model in vivo. We find that the secretion of Hsp90{alpha} but not Hsp90{beta} is increased in activated endothelial cells with the induction of angiogenic factors and matrix proteins. Secreted Hsp90{alpha} localizes on the leading edge of endothelial cells and promotes their angiogenic activities, whereas Hsp90{alpha} neutralizing antibodies reverse the effect. Furthermore, using a mouse skin wound healing model in vivo, we demonstrate that extracellular Hsp90{alpha} localizes on blood vessels in granulation tissues of wounded skin and promotes angiogenesis during wound healing. Taken together, our study reveals that Hsp90{alpha} can be secreted by activated endothelial cells and is a positive regulator of angiogenesis, suggesting the potential application of Hsp90{alpha} as a stimulator for wound repair.

  6. Molecular mechanisms of canalization: Hsp90 and beyond

    Indian Academy of Sciences (India)

    Neeraj Salathia; Christine Queitsch

    2007-04-01

    The Hsp90 chaperone machine facilitates the maturation of a diverse set of ‘client’ proteins. Many of these Hsp90 clients are essential nodes in signal transduction pathways and regulatory circuits, accounting for the important role Hsp90 plays in organismal development and responses to the environment. Recent findings suggest a broader impact of the chaperone on phenotype: fully functional Hsp90 canalizes wild-type phenotypes by suppressing underlying genetic and epigenetic variation. This variation can be expressed upon challenging the Hsp90 machinery by environmental stress, genetic or pharmaceutical targeting of Hsp90. The existence of Hsp90-buffered genetic and epigenetic variation together with plausible release mechanisms has wide-ranging implication for phenotype and possibly evolutionary processes. Here, we discuss the role of Hsp90 in canalization and organismal plasticity, and highlight important questions for future experimental inquiry.

  7. Hsp90 modulates CAG repeat instability in human cells

    OpenAIRE

    Mittelman, David; Sykoudis, Kristen; Hersh, Megan; Lin, Yunfu; Wilson, John H.

    2010-01-01

    The Hsp90 molecular chaperone has been implicated as a contributor to evolution in several organisms by revealing cryptic variation that can yield dramatic phenotypes when the chaperone is diverted from its normal functions by environmental stress. In addition, as a cancer drug target, Hsp90 inhibition has been documented to sensitize cells to DNA-damaging agents, suggesting a function for Hsp90 in DNA repair. Here we explore the potential role of Hsp90 in modulating the stability of nucleoti...

  8. FS23 binds to the N-terminal domain of human Hsp90:A novel small inhibitor for Hsp90

    Institute of Scientific and Technical Information of China (English)

    李健; 石峰; 陈丹琦; 曹慧玲; 熊兵; 沈竞康; 何建华

    2015-01-01

    The N-terminal domain of heat shock protein 90 (Hsp90N) is responsible for the catalytic activity of Hsp90. The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here, we synthesized FS23, a small molecule inhibitor of hsp90 and collected X-ray diffraction data of the complex crystal of Hsp90-FS23. High resolution X-ray crystallography shows that FS23 interacted with Hsp90N at the nucleotide binding cleft, and this suggests that FS23 may complete with nucleotides to bind to Hsp90N. The crystal structure and the interaction between Hsp90N and FS23 suggest a rational basis for the design of novel antitumor drugs.

  9. NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies.

    Directory of Open Access Journals (Sweden)

    Yousuf O Ali

    2016-06-01

    Full Text Available Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2 is neuroprotective in numerous preclinical models of neurodegeneration. Here, we show that brain nmnat2 mRNA levels correlate positively with global cognitive function and negatively with AD pathology. In AD brains, NMNAT2 mRNA and protein levels are reduced. NMNAT2 shifts its solubility and colocalizes with aggregated Tau in AD brains, similar to chaperones, which aid in the clearance or refolding of misfolded proteins. Investigating the mechanism of this observation, we discover a novel chaperone function of NMNAT2, independent from its enzymatic activity. NMNAT2 complexes with heat shock protein 90 (HSP90 to refold aggregated protein substrates. NMNAT2's refoldase activity requires a unique C-terminal ATP site, activated in the presence of HSP90. Furthermore, deleting NMNAT2 function increases the vulnerability of cortical neurons to proteotoxic stress and excitotoxicity. Interestingly, NMNAT2 acts as a chaperone to reduce proteotoxic stress, while its enzymatic activity protects neurons from excitotoxicity. Taken together, our data indicate that NMNAT2 exerts its chaperone or enzymatic function in a context-dependent manner to maintain neuronal health.

  10. Arabidopsis HSP90 protein modulates RPP4-mediated temperature-dependent cell death and defense responses.

    Science.gov (United States)

    Bao, Fei; Huang, Xiaozhen; Zhu, Chipan; Zhang, Xiaoyan; Li, Xin; Yang, Shuhua

    2014-06-01

    Plant defense responses are regulated by temperature. In Arabidopsis, the chilling-sensitive mutant chs2-1 (rpp4-1d) contains a gain-of-function mutation in the TIR-NB-LRR (Toll and interleukin 1 receptor-nucleotide binding-leucine-rich repeat) gene, RPP4 (RECOGNITION OF PERONOSPORA PARASITICA 4), which leads to constitutive activation of the defense response at low temperatures. Here, we identified and characterized two suppressors of rpp4-1d from a genetic screen, hsp90.2 and hsp90.3, which carry point mutations in the cytosolic heat shock proteins HSP90.2 and HSP90.3, respectively. The hsp90 mutants suppressed the chilling sensitivity of rpp4-1d, including seedling lethality, activation of the defense responses and cell death under chilling stress. The hsp90 mutants exhibited compromised RPM1 (RESISTANCE TO PSEUDOMONAS MACULICOLA 1)-, RPS4 (RESISTANCE TO P. SYRINGAE 4)- and RPP4-mediated pathogen resistance. The wild-type RPP4 and the mutated form rpp4 could interact with HSP90 to form a protein complex. Furthermore, RPP4 and rpp4 proteins accumulated in the cytoplasm and nucleus at normal temperatures, whereas the nuclear accumulation of the mutated rpp4 was decreased at low temperatures. Genetic analysis of the intragenic suppressors of rpp4-1d revealed the important functions of the NB-ARC and LRR domains of RPP4 in temperature-dependent defense signaling. In addition, the rpp4-1d-induced chilling sensitivity was largely independent of the WRKY70 or MOS (modifier of snc1) genes. [Correction added after online publication 11 March 2013: the expansions of TIR-NB-LRR and RPS4 were amended] This study reveals that Arabidopsis HSP90 regulates RPP4-mediated temperature-dependent cell death and defense responses. PMID:24611624

  11. Identification of the plant compound geraniin as a novel Hsp90 inhibitor.

    Directory of Open Access Journals (Sweden)

    Antonio Vassallo

    Full Text Available Besides its function in normal cellular growth, the molecular chaperone heat shock protein 90 (Hsp90 binds to a large number of client proteins required for promoting cancer cell growth and/or survival. In an effort to discover new small molecules able to inhibit the Hsp90 ATPase and chaperoning activities, we screened, by a surface plasmon resonance assay, a small library including different plant polyphenols. The ellagitannin geraniin, was identified as the most promising molecule, showing a binding affinity to Hsp90α similar to that of 17-(allylamino-17-demethoxygeldanamycin (17AGG. Geraniin was able to inhibit in vitro the Hsp90α ATPase activity in a dose-dependent manner, with an inhibitory efficiency comparable to that measured for 17-AAG. In addition, this compound compromised the chaperone activity of Hsp90α, monitored by the citrate synthase thermal induced aggregation assay. Geraniin decreased the viability of HeLa and Jurkat cell lines and caused an arrest in G2/M phase. We also proved that following exposure to different concentrations of geraniin, the level of expression of the client proteins c-Raf, pAkt, and EGFR was strongly down-regulated in both the cell lines. These results, along with the finding that geraniin did not exert any appreciable cytotoxicity on normal cells, encourage further studies on this compound as a promising chemical scaffold for the design of new Hsp90 inhibitors.

  12. Disruption of the EF-2 kinase/Hsp90 protein complex: a possible mechanism to inhibit glioblastoma by geldanamycin.

    Science.gov (United States)

    Yang, J; Yang, J M; Iannone, M; Shih, W J; Lin, Y; Hait, W N

    2001-05-15

    Glioblastoma multiforme is the most treatment-resistant brain tumor. Elongation factor-2 (EF-2) kinase (calmodulin kinase III) is a unique protein kinase that is overexpressed in glioma cell lines and in human surgical specimens. Several mitogens activate this kinase and inhibitors block mitogen activation and produce cell death. Geldanamycin (GA) is a benzoquinone ansamycin antibiotic that disrupts Hsp90-protein interactions. Because EF-2 kinase is chaperoned by Hsp90, we investigated the effects of GA on the viability of glioma cells, the expression of EF-2 kinase protein, and the interaction between Hsp90 and EF-2 kinase. GA was a potent inhibitor of the clonogenicity of four glioma cells lines with IC(50)s ranging from 1 to 3 nM. 17-allylamino-17-demethoxygeldanamycin (17-AAG), a less toxic and less potent derivative of GA, inhibited the clonogenicity of glioma cells with IC(50) values of 13 nM in C6 cells and 35 nM in T98G cells. Treatment of cell lines for 24-48 h of GA or 17-AAG disrupted EF-2-kinase/Hsp90 interactions as measured by coimmunoprecipitation, resulting in a decreased amount of recoverable kinase in cell lysates. The ability of GA to inhibit the growth of glioma cells was abrogated by overexpressing EF-2 kinase. In addition, 17-AAG significantly inhibited the growth of a glioma xenograft in nude mice. These studies demonstrate for the first time the activity of GAs against human gliomas in vitro and in vivo and suggest that destruction of EF-2 kinase may be an important cytotoxic mechanism of this unique class of drug. PMID:11358819

  13. Interactions between curcumin and Hsp90 and effects of curcumin on Hsp90 ATPase activity%姜黄素与Hsp90相互作用以及对Hsp90ATPase 活性的影响

    Institute of Scientific and Technical Information of China (English)

    范莹娟; 许建华

    2013-01-01

    目的 研究姜黄素(curcumin)与Hsp90的结合作用,及其对Hsp90-ATPase 活性抑制作用.方法 采用荧光光谱实验,选取280 nm为激发波长,290~510 nm的波长范围内进行荧光光谱扫描,研究不同浓度curcumin与Hsp90的相互作用.采用孔雀绿磷钼酸铵-无机磷检测法,研究curcumin对Hsp90-ATPase活性抑制.结果 curcumin解离常数为(21.608±1.752) μmol·L-1,格尔德霉素(GA)为(17.372±1.200) μmol·L-1.当ATP为1 mmol·L-1时,GA作用于Hsp90的IC50值为0.38 μmol·L-1,curcumin的IC50值为3.75 μmol·L-1也有较强的Hsp90-ATPase抑制活性.结论 经过荧光光谱分析,可以确定curcumin与Hsp90的结合机制,且curcumin能抑制Hsp90-ATPase活性.

  14. HSP90 expression correlation with the freezing resistance of bull sperm.

    Science.gov (United States)

    Wang, Peng; Wang, Yan-Feng; Wang, Hong; Wang, Chun-Wei; Zan, Lin-Sen; Hu, Jian-Hong; Li, Qing-Wang; Jia, Yong-Hong; Ma, Guo-Ji

    2014-05-01

    To date, there has been little improvement in cryopreservation of bull sperm due to lack of understanding of the freezing mechanisms. Therefore, this study set out to investigate expression levels of fertility-associated proteins in bull sperm, and in particular the relationship between the 90 kDa heat-shock protein (HSP90) and the sperm characteristics after freezing-thawing. Semen was collected from eight Holstein bulls by artificial vagina. Characteristics of these fresh semen, including sperm motility, morphology, viability and concentration, were evaluated. Sperm quality was also assessed after freezing-thawing. Eight ejaculates were divided into two groups based on freezing resistance and sperm motility. Sperm proteins were extracted and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) analysis and western blotting were performed. SDS-PAGE results showed that there was substantial diversity in 90 kDa proteins in the frozen-thawed sperm and HSP90 was confirmed as one of the 90 kDa proteins by western blot. This study indicated that HSP90 expression correlated positively with sperm quality. The amount of expressed 90 kDa proteins in the high freezing resistance (HFR) group was significantly higher than that in the low freezing resistance (LFR) group (P HSP90 could probably lead to the higher motility and freezing resistance of sperm found after freezing-thawing. Therefore, we concluded that level of HSP90 expression could be used to predict reliably and simply the freezing resistance of bull sperm. PMID:23506739

  15. SGT, a Hsp90β binding partner, is accumulated in the nucleus during cell apoptosis

    International Nuclear Information System (INIS)

    In this study, we reported that small glutamine-rich TPR-containing protein (SGT) interacted with not only Hsp90α but also Hsp90β. Confocal analysis showed that treatment of cells with Hsp90-specific inhibitor geldanamycin (GA) disrupted the interaction of SGT with Hsp90β and this contributed to the increase of nuclear localization of SGT in HeLa cells. The increased nuclear localization of SGT was further confirmed by the Western blotting in GA-treated HeLa cells and H1299 cells. In our previous study, SGT was found to be a new pro-apoptotic factor, so we wondered whether the sub-cellular localization of SGT was related with cell apoptosis. By confocal analysis we found that the nuclear import of SGT was significantly increased in STS-induced apoptotic HeLa cells, which implied that the sub-cellular localization of SGT was closely associated with Hsp90β and apoptosis

  16. Anticancer Inhibitors of Hsp90 Function: Beyond the Usual Suspects.

    Science.gov (United States)

    Garg, Gaurav; Khandelwal, Anuj; Blagg, Brian S J

    2016-01-01

    The 90-kDa heat-shock protein (Hsp90) is a molecular chaperone responsible for the stability and function of a wide variety of client proteins that are critical for cell growth and survival. Many of these client proteins are frequently mutated and/or overexpressed in cancer cells and are therefore being actively pursued as individual therapeutic targets. Consequently, Hsp90 inhibition offers a promising strategy for simultaneous degradation of several anticancer targets. Currently, most Hsp90 inhibitors under clinical evaluation act by blocking the binding of ATP to the Hsp90 N-terminal domain and thereby, induce the degradation of many Hsp90-dependent oncoproteins. Although, they have shown some promising initial results, clinical challenges such as induction of the heat-shock response, retinopathy, and gastrointestinal tract toxicity are emerging from human trials, which constantly raise concerns about the future development of these inhibitors. Novobiocin derivatives, which do not bind the chaperone's N-terminal ATPase pocket, have emerged over the past decade as an alternative strategy to inhibit Hsp90, but to date, no derivative has been investigated in the clinical setting. In recent years, a number of natural or synthetic compounds have been identified that modulate Hsp90 function via various mechanisms. These compounds not only offer new chemotypes for the development of future Hsp90 inhibitors but can also serve as chemical probes to unravel the biology of Hsp90. This chapter presents a synopsis of inhibitors that directly, allosterically, or even indirectly alters Hsp90 function, and highlights their proposed mechanisms of action. PMID:26916001

  17. Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells.

    Science.gov (United States)

    Qin, Dong-Jun; Tang, Cai-Xia; Yang, Li; Lei, Hu; Wei, Wei; Wang, Ying-Ying; Ma, Chun-Min; Gao, Feng-Hou; Xu, Han-Zhang; Wu, Ying-Li

    2015-01-01

    Synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-Me) has been shown as a promising agent against ovarian cancer. However, the underlying mechanism is not well understood. Here, we demonstrate that CDDO-Me directly interacts with Hsp90 in cells by cellular thermal shift assay. CDDO-Me treatment leads to upregulation of Hsp70 and degradation of Hsp90 clients (ErbB2 and Akt), indicating the inhibition of Hsp90 by CDDO-Me in cells. Knockdown of Hsp90 significantly inhibits cell proliferation and enhances the anti-proliferation effect of CDDO-Me in H08910 ovarian cancer cells. Dithiothreitol inhibits the interaction of CDDO-Me with Hsp90 in cells and abrogates CDDO-Me induced upregulation of Hsp70, degradation of Akt and cell proliferation inhibition. This suggests the anti-ovarian cancer effect of CDDO-Me is possibly mediated by the formation of Michael adducts between CDDO-Me and reactive nucleophiles on Hsp90. This study identifies Hsp90 as a novel target protein of CDDO-Me, and provides a novel insight into the mechanism of action of CDDO-Me in ovarian cancer cells. PMID:26134508

  18. Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Dong-Jun Qin

    Full Text Available Synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9(11-dien-28-oate (CDDO-Me has been shown as a promising agent against ovarian cancer. However, the underlying mechanism is not well understood. Here, we demonstrate that CDDO-Me directly interacts with Hsp90 in cells by cellular thermal shift assay. CDDO-Me treatment leads to upregulation of Hsp70 and degradation of Hsp90 clients (ErbB2 and Akt, indicating the inhibition of Hsp90 by CDDO-Me in cells. Knockdown of Hsp90 significantly inhibits cell proliferation and enhances the anti-proliferation effect of CDDO-Me in H08910 ovarian cancer cells. Dithiothreitol inhibits the interaction of CDDO-Me with Hsp90 in cells and abrogates CDDO-Me induced upregulation of Hsp70, degradation of Akt and cell proliferation inhibition. This suggests the anti-ovarian cancer effect of CDDO-Me is possibly mediated by the formation of Michael adducts between CDDO-Me and reactive nucleophiles on Hsp90. This study identifies Hsp90 as a novel target protein of CDDO-Me, and provides a novel insight into the mechanism of action of CDDO-Me in ovarian cancer cells.

  19. Resolving hot spots in the C-terminal dimerization domain that determine the stability of the molecular chaperone Hsp90.

    Directory of Open Access Journals (Sweden)

    Emanuele Ciglia

    Full Text Available Human heat shock protein of 90 kDa (hHsp90 is a homodimer that has an essential role in facilitating malignant transformation at the molecular level. Inhibiting hHsp90 function is a validated approach for treating different types of tumors. Inhibiting the dimerization of hHsp90 via its C-terminal domain (CTD should provide a novel way to therapeutically interfere with hHsp90 function. Here, we predicted hot spot residues that cluster in the CTD dimerization interface by a structural decomposition of the effective energy of binding computed by the MM-GBSA approach and confirmed these predictions using in silico alanine scanning with DrugScore(PPI. Mutation of these residues to alanine caused a significant decrease in the melting temperature according to differential scanning fluorimetry experiments, indicating a reduced stability of the mutant hHsp90 complexes. Size exclusion chromatography and multi-angle light scattering studies demonstrate that the reduced stability of the mutant hHsp90 correlates with a lower complex stoichiometry due to the disruption of the dimerization interface. These results suggest that the identified hot spot residues can be used as a pharmacophoric template for identifying and designing small-molecule inhibitors of hHsp90 dimerization.

  20. Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1

    Science.gov (United States)

    Kim, Hak-Bong; Lee, Su-Hoon; Um, Jee-Hyun; Oh, Won Keun; Kim, Dong-Wan; Kang, Chi-Dug; Kim, Sun-Hee

    2015-01-01

    The effectiveness of Hsp90 inhibitors as anticancer agents was limited in multidrug-resistant (MDR) human cancer cells due to induction of heat shock proteins (Hsps) such as Hsp70/Hsp27 and P-glycoprotein (P-gp)-mediated efflux. In the present study, we showed that resistance to Hsp90 inhibitors of MDR human cancer cells could be overcome with SIRT1 inhibition. SIRT1 knock-down or SIRT1 inhibitors (amurensin G and EX527) effectively suppressed the resistance to Hsp90 inhibitors (17-AAG and AUY922) in several MDR variants of human lymphoblastic leukemia and human breast cancer cell lines. SIRT1 inhibition down-regulated the expression of heat shock factor 1 (HSF1) and subsequently Hsps and facilitated Hsp90 multichaperone complex disruption via hyperacetylation of Hsp90/Hsp70. These findings were followed by acceleration of ubiquitin ligase CHIP-mediated mutant p53 (mut p53) degradation and subsequent down-regulation of P-gp in 17-AAG-treated MDR cancer cells expressing P-gp and mut p53 after inhibition of SIRT1. Therefore, combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be a more effective therapeutic approach for Hsp90 inhibitor-resistant MDR cells via down-regulation of HSF1/Hsps, mut p53 and P-gp. PMID:26416354

  1. Overexpression of GmHsp90s, a heat shock protein 90 (Hsp90 gene family cloning from soybean, decrease damage of abiotic stresses in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Jinyan Xu

    Full Text Available Hsp90 is one of the most conserved and abundant molecular chaperones and is an essential component of the protective stress response; however, its roles in abiotic stress responses in soybean (Glycine max remain obscure. Here, 12 GmHsp90 genes from soybean were identified and found to be expressed and to function differentially under abiotic stresses. The 12 GmHsp90 genes were isolated and named GmHsp90A1-GmHsp90A6, GmHsp90B1, GmHsp90B2, GmHsp90C1.1, GmHsp90C1.2, GmHsp90C2.1 and GmHsp90C2.2 based on their characteristics and high homology to other Hsp90s according to a new nomenclature system. Quantitative real-time PCR expression data revealed that all the genes exhibited higher transcript levels in leaves and could be strongly induced under heat, osmotic and salt stress but not cold stress. Overexpression of five typical genes (GmHsp90A2, GmHsp90A4, GmHsp90B1, GmHsp90C1.1 and GmHsp90C2.1 in Arabidopsis thaliana provided useful evidences that GmHsp90 genes can decrease damage of abiotic stresses. In addition, an abnormal accumulation of proline was detected in some transgenic Arabidopsis plants suggested overexpressing GmHsp90s may affect the synthesis and response system of proline. Our work represents a systematic determination of soybean genes encoding Hsp90s, and provides useful evidence that GmHsp90 genes function differently in response to abiotic stresses and may affect the synthesis and response system of proline.

  2. Structure, Function and Regulation of the Hsp90 Machinery

    Directory of Open Access Journals (Sweden)

    Jing Li

    2013-06-01

    Full Text Available Heat shock protein 90 (Hsp90 is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery.

  3. Hsp90-binding immunophilin FKBP51 forms complexes with hTERT enhancing telomerase activity.

    Science.gov (United States)

    Lagadari, Mariana; Zgajnar, Nadia R; Gallo, Luciana I; Galigniana, Mario D

    2016-08-01

    FK506-binding proteins are members of the immunophilin family of proteins. Those immunophilins associated to the 90-kDa-heat-shock protein, Hsp90, have been proposed as potential modulators of signalling cascade factors chaperoned by Hsp90. FKBP51 and FKBP52 are the best characterized Hsp90-bound immunophilins first described associated to steroid-receptors. The reverse transcriptase subunit of telomerase, hTERT, is also an Hsp90 client-protein and is highly expressed in cancer cells, where it is required to compensate the loss of telomeric DNA after each successive cell division. Because FKBP51 is also a highly expressed protein in cancer tissues, we analyzed its potential association with hTERT·Hsp90 complexes and its possible biological role. In this study it is demonstrated that both immunophilins, FKBP51 and FKBP52, co-immunoprecipitate with hTERT. The Hsp90 inhibitor radicicol disrupts the heterocomplex and favors the partial cytoplasmic relocalization of hTERT in similar manner as the overexpression of the TPR-domain peptide of the immunophilin. While confocal microscopy images show that FKBP51 is primarily localized in mitochondria and hTERT is totally nuclear, upon the onset of oxidative stress, FKBP51 (but not FKBP52) becomes mostly nuclear colocalizing with hTERT, and longer exposure times to peroxide favors hTERT export to mitochondria. Importantly, telomerase activity of hTERT is significantly enhanced by FKBP51. These observations support the emerging role assigned to FKBP51 as antiapoptotic factor in cancer development and progression, and describe for the first time the potential role of this immunophilin favoring the clonal expansion by enhancing telomerase activity. PMID:27233944

  4. Review: The HSP90 molecular chaperone-an enigmatic ATPase.

    Science.gov (United States)

    Pearl, Laurence H

    2016-08-01

    The HSP90 molecular chaperone is involved in the activation and cellular stabilization of a range of 'client' proteins, of which oncogenic protein kinases and nuclear steroid hormone receptors are of particular biomedical significance. Work over the last two decades has revealed a conformational cycle critical to the biological function of HSP90, coupled to an inherent ATPase activity that is regulated and manipulated by many of the co-chaperones proteins with which it collaborates. Pharmacological inhibition of HSP90 ATPase activity results in degradation of client proteins in vivo, and is a promising target for development of new cancer therapeutics. Despite this, the actual function that HSP90s conformationally-coupled ATPase activity provides in its biological role as a molecular chaperone remains obscure. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 594-607, 2016. PMID:26991466

  5. The interplay between inhibition of JAK2 and HSP90

    OpenAIRE

    Fridman, Jordan S.; Sarlis, Nicholas J

    2012-01-01

    A recent article by Weigert et al. published in The Journal of Experimental Medicine described the in vitro generation of synthetic mutations in Janus kinase 2 (JAK 2) that decreased the potency of JAK2 (or JAK1/JAK2) inhibitors in artificial systems. The authors found that heat shock protein 90 (HSP90) inhibitors circumvented the potency shift and suggested that HSP90 inhibition may abrogate JAK inhibitor resistance in these experimental systems. However, the clinical relevance of these labo...

  6. Heat Shock Protein 90 (Hsp90 Expression and Breast Cancer

    Directory of Open Access Journals (Sweden)

    Christos A. Papadimitriou

    2012-09-01

    Full Text Available Hsp90 is an abundant protein in mammalian cells. It forms several discrete complexes, each containing distinct groups of co-chaperones that assist protein folding and refolding during stress, protein transport and degradation. It interacts with a variety of proteins that play key roles in breast neoplasia including estrogen receptors, tumor suppressor p53 protein, angiogenesis transcription factor HIF-1alpha, antiapoptotic kinase Akt, Raf-1 MAP kinase and a variety of receptor tyrosine kinases of the erbB family. Elevated Hsp90 expression has been documented in breast ductal carcinomas contributing to the proliferative activity of breast cancer cells; whilst a significantly decreased Hsp90 expression has been shown in infiltrative lobular carcinomas and lobular neoplasia. Hsp90 overexpression has been proposed as a component of a mechanism through which breast cancer cells become resistant to various stress stimuli. Therefore, pharmacological inhibition of HSPs can provide therapeutic opportunities in the field of cancer treatment. 17-allylamino,17-demethoxygeldanamycin is the first Hsp90 inhibitor that has clinically been investigated in phase II trial, yielding promising results in patients with HER2-overexpressing metastatic breast cancer, whilst other Hsp90 inhibitors (retaspimycin HCL, NVP-AUY922, NVP-BEP800, CNF2024/BIIB021, SNX-5422, STA-9090, etc. are currently under evaluation.

  7. A large animal model to evaluate the effects of Hsp90 inhibitors for the treatment of lung adenocarcinoma

    International Nuclear Information System (INIS)

    Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring lung cancer of sheep caused by Jaagsiekte sheep retrovirus (JSRV). The JSRV envelope glycoprotein (Env) functions as a dominant oncoprotein in vitro and in vivo. In order to develop the basis for the use of OPA as a lung cancer model, we screened a variety of signal transduction inhibitors for their ability to block transformation by the JSRV Env. Most inhibitors were not effective in blocking JSRV Env-induced transformation. On the contrary, various Hsp90 inhibitors efficiently blocked JSRV transformation. This phenomenon was at least partly due to Akt degradation, which is activated in JSRV-transformed cells. Hsp90 was found expressed in tumor cells of sheep with naturally occurring OPA. In addition, Hsp90 inhibitors specifically inhibited proliferation of immortalized and moreover primary cells derived from OPA tumors. Thus, OPA could be used as a large animal model for comprehensive studies investigating the effects of Hsp90 inhibitors in lung adenocarcinoma

  8. A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes.

    Directory of Open Access Journals (Sweden)

    Victoria Gillan

    2014-02-01

    Full Text Available Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties.

  9. Ascorbic acid inhibition of Candida albicans Hsp90-mediated morphogenesis occurs via the transcriptional regulator Upc2.

    Science.gov (United States)

    Van Hauwenhuyse, Frédérique; Fiori, Alessandro; Van Dijck, Patrick

    2014-10-01

    Morphogenetic transitions of the opportunistic fungal pathogen Candida albicans are influenced by temperature changes, with induction of filamentation upon a shift from 30 to 37°C. Hsp90 was identified as a major repressor of an elongated cell morphology at low temperatures, as treatment with specific inhibitors of Hsp90 results in elongated growth forms at 30°C. Elongated growth resulting from a compromised Hsp90 is considered neither hyphal nor pseudohyphal growth. It has been reported that ascorbic acid (vitamin C) interferes with the yeast-to-hypha transition in C. albicans. In the present study, we show that ascorbic acid also antagonizes the morphogenetic change caused by hampered Hsp90 function. Further analysis revealed that Upc2, a transcriptional regulator of genes involved in ergosterol biosynthesis, and Erg11, the target of azole antifungals, whose expression is in turn regulated by Upc2, are required for this antagonism. Ergosterol levels correlate with elongated growth and are reduced in cells treated with the Hsp90 inhibitor geldanamycin (GdA) and restored by cotreatment with ascorbic acid. In addition, we show that Upc2 appears to be required for ascorbic acid-mediated inhibition of the antifungal activity of fluconazole. These results identify Upc2 as a major regulator of ascorbic acid-induced effects in C. albicans and suggest an association between ergosterol content and elongated growth upon Hsp90 compromise. PMID:25084864

  10. The Hsp90 chaperone controls the biogenesis of L7Ae RNPs through conserved machinery

    Science.gov (United States)

    Boulon, Séverine; Marmier-Gourrier, Nathalie; Pradet-Balade, Bérengère; Wurth, Laurence; Verheggen, Céline; Jády, Beáta E.; Rothé, Benjamin; Pescia, Christina; Robert, Marie-Cécile; Kiss, Tamás; Bardoni, Barbara; Krol, Alain; Branlant, Christiane; Allmang, Christine; Bertrand, Edouard; Charpentier, Bruno

    2008-01-01

    RNA-binding proteins of the L7Ae family are at the heart of many essential ribonucleoproteins (RNPs), including box C/D and H/ACA small nucleolar RNPs, U4 small nuclear RNP, telomerase, and messenger RNPs coding for selenoproteins. In this study, we show that Nufip and its yeast homologue Rsa1 are key components of the machinery that assembles these RNPs. We observed that Rsa1 and Nufip bind several L7Ae proteins and tether them to other core proteins in the immature particles. Surprisingly, Rsa1 and Nufip also link assembling RNPs with the AAA + adenosine triphosphatases hRvb1 and hRvb2 and with the Hsp90 chaperone through two conserved adaptors, Tah1/hSpagh and Pih1. Inhibition of Hsp90 in human cells prevents the accumulation of U3, U4, and telomerase RNAs and decreases the levels of newly synthesized hNop58, hNHP2, 15.5K, and SBP2. Thus, Hsp90 may control the folding of these proteins during the formation of new RNPs. This suggests that Hsp90 functions as a master regulator of cell proliferation by allowing simultaneous control of cell signaling and cell growth. PMID:18268104

  11. Interaction of the Hsp90 cochaperone cyclophilin 40 with Hsc70.

    Science.gov (United States)

    Carrello, Amerigo; Allan, Rudi K; Morgan, Sarah L; Owen, Barbara A L; Mok, Danny; Ward, Bryan K; Minchin, Rodney F; Toft, David O; Ratajczak, Thomas

    2004-01-01

    The high-affinity ligand-binding form of unactivated steroid receptors exists as a multicomponent complex that includes heat shock protein (Hsp)90; one of the immunophilins cyclophilin 40 (CyP40), FKBP51, or FKBP52; and an additional p23 protein component. Assembly of this heterocomplex is mediated by Hsp70 in association with accessory chaperones Hsp40, Hip, and Hop. A conserved structural element incorporating a tetratricopeptide repeat (TPR) domain mediates the interaction of the immunophilins with Hsp90 by accommodating the C-terminal EEVD peptide of the chaperone through a network of electrostatic and hydrophobic interactions. TPR cochaperones recognize the EEVD structural motif common to both Hsp90 and Hsp70 through a highly conserved clamp domain. In the present study, we investigated in vitro the molecular interactions between CyP40 and FKBP52 and other stress-related components involved in steroid receptor assembly, namely Hsp70 and Hop. Using a binding protein-retention assay with CyP40 fused to glutathione S-transferase immobilized on glutathione-agarose, we have identified the constitutively expressed form of Hsp70, heat shock cognate (Hsc)70, as an additional target for CyP40. Deletion mapping studies showed the binding determinants to be similar to those for CyP40-Hsp90 interaction. Furthermore, a mutational analysis of CyP40 clamp domain residues confirmed the importance of this motif in CyP40-Hsc70 interaction. Additional residues thought to mediate binding specificity through hydrophobic interactions were also important for Hsc70 recognition. CyP40 was shown to have a preference for Hsp90 over Hsc70. Surprisingly, FKBP52 was unable to compete with CyP40 for Hsc70 binding, suggesting that FKBP52 discriminates between the TPR cochaperone-binding sites in Hsp90 and Hsp70. Hop, which contains multiple units of the TPR motif, was shown to be a direct competitor with CyP40 for Hsc70 binding. Similar to Hop, CyP40 was shown not to influence the adenosine

  12. Hsp90 inhibitors reduce influenza virus replication in cell culture

    International Nuclear Information System (INIS)

    The viral RNA polymerase complex of influenza A virus consists of three subunits PB1, PB2 and PA. Recently, the cellular chaperone Hsp90 was shown to play a role in nuclear import and assembly of the trimeric polymerase complex by binding to PB1 and PB2. Here we show that Hsp90 inhibitors, geldanamycin or its derivative 17-AAG, delay the growth of influenza virus in cell culture resulting in a 1-2 log reduction in viral titre early in infection. We suggest that this is caused by the reduced half-life of PB1 and PB2 and inhibition of nuclear import of PB1 and PA which lead to reduction in viral RNP assembly. Hsp90 inhibitors may represent a new class of antiviral compounds against influenza viruses

  13. HSP90B1, a thyroid hormone-responsive heat shock protein gene involved in photoperiodic signaling.

    Science.gov (United States)

    Graham, Gemma; Sharp, Peter J; Li, Qiushi; Wilson, Peter W; Talbot, Richard T; Downing, Alison; Boswell, Timothy

    2009-05-29

    In order to further advance the understanding of genes involved in avian photoperiodic signaling, a chicken hypothalamic cDNA microarray was made to identify changes in gene expression in the whole hypothalamus of juvenile male domestic chickens after 4 days' photostimulation. The most robust change was a depression in heat shock protein 90B1 (HSP90B1) expression. This observation was confirmed using quantitative PCR, and it was subsequently demonstrated that the depression in HSP90B1 expression first occurs in the anterior hypothalamus after 1 day's photostimulation, and was also depressed in the anterior and basal hypothalamus after 4 days' photostimulation. Four days after an intravenous injection of thyroxine (T4), an avian photomimetic, in short day birds, HSP90B1 expression was depressed in the anterior, but not in the basal hypothalamus. Depressed HSP901 expression after photostimulation or T4 treatment was associated with increased GnRH-I mRNA and plasma LH. HSP90B1 is abundant throughout the brain where it occurs in glial cells, and is involved in regulating white matter plasticity. It is suggested that photoperiodically depressed hypothalamic HSP90B1 may affect glial function in photoperiodic signaling pathways in the neuroendocrine system. This is the first report of a thyroid hormone-responsive gene involved in photoperiodic signaling. PMID:19429192

  14. HSP90 regulates temperature-dependent seedling growth in Arabidopsis by stabilizing the auxin co-receptor F-box protein TIR1

    Science.gov (United States)

    Wang, Renhou; Zhang, Yi; Kieffer, Martin; Yu, Hong; Kepinski, Stefan; Estelle, Mark

    2016-01-01

    Recent studies have revealed that a mild increase in environmental temperature stimulates the growth of Arabidopsis seedlings by promoting biosynthesis of the plant hormone auxin. However, little is known about the role of other factors in this process. In this report, we show that increased temperature promotes rapid accumulation of the TIR1 auxin co-receptor, an effect that is dependent on the molecular chaperone HSP90. In addition, we show that HSP90 and the co-chaperone SGT1 each interact with TIR1, confirming that TIR1 is an HSP90 client. Inhibition of HSP90 activity results in degradation of TIR1 and interestingly, defects in a range of auxin-mediated growth processes at lower as well as higher temperatures. Our results indicate that HSP90 and SGT1 integrate temperature and auxin signalling in order to regulate plant growth in a changing environment. PMID:26728313

  15. The soluble recombinant Neisseria meningitidis adhesin NadA(Δ351-405) stimulates human monocytes by binding to extracellular Hsp90.

    Science.gov (United States)

    Cecchini, Paola; Tavano, Regina; Polverino de Laureto, Patrizia; Franzoso, Susanna; Mazzon, Cristina; Montanari, Paolo; Papini, Emanuele

    2011-01-01

    The adhesin NadA favors cell adhesion/invasion by hypervirulent Neisseria meningitidis B (MenB). Its recombinant form NadA(Δ351-405,) devoid of the outer membrane domain, is an immunogenic candidate for an anti-MenB vaccine able to stimulate monocytes, macrophages and dendritic cells. In this study we investigated the molecular mechanism of NadA(Δ351-405) cellular effects in monocytes. We show that NadA(Δ351-405) (against which we obtained polyclonal antibodies in rabbits), binds to hsp90, but not to other extracellular homologous heat shock proteins grp94 and hsp70, in vitro and on the surface of monocytes, in a temperature dependent way. Pre-incubation of monocytes with the MenB soluble adhesin interfered with the binding of anti-hsp90 and anti-hsp70 antibodies to hsp90 and hsp70 at 37°C, a condition in which specific cell-binding occurs, but not at 0°C, a condition in which specific cell-binding is very diminished. Conversely, pre-incubation of monocytes with anti-hsp90 and anti-hsp70 antibodies did not affected NadA(Δ351-405) cell binding in any temperature condition, indicating that it associates to another receptor on their plasma membrane and then laterally diffuses to encounter hsp90. Consistently, polymixin B interfered with NadA(Δ351-405) /hsp90 association, abrogated the decrease of anti-hsp90 antibodies binding to the cell surface due to NadA(Δ351-405) and inhibited adhesin-induced cytokine/chemokine secretion without affecting monocyte-adhesin binding. Co-stimulation of monocytes with anti-hsp90 antibodies and NadA(Δ351-405) determined a stronger but polymixin B insensitive cell activation. This indicated that the formation of a recombinant NadA/hsp90/hsp70 complex, although essential for full monocyte stimulation, can be replaced by anti-hsp90 antibody/hsp90 binding. Finally, the activation of monocytes by NadA(Δ351-405) alone or in the presence of anti-hsp90 antibodies were both inhibited by neutralizing anti-TLR4 antibodies, but not by

  16. Cyclophilin 40 facilitates HSP90-mediated RISC assembly in plants.

    Science.gov (United States)

    Iki, Taichiro; Yoshikawa, Manabu; Meshi, Tetsuo; Ishikawa, Masayuki

    2012-01-18

    Posttranscriptional gene silencing is mediated by RNA-induced silencing complexes (RISCs) that contain AGO proteins and single-stranded small RNAs. The assembly of plant AGO1-containing RISCs depends on the molecular chaperone HSP90. Here, we demonstrate that cyclophilin 40 (CYP40), protein phosphatase 5 (PP5), and several other proteins with the tetratricopeptide repeat (TPR) domain associates with AGO1 in an HSP90-dependent manner in extracts of evacuolated tobacco protoplasts (BYL). Intriguingly, CYP40, but not the other TPR proteins, could form a complex with small RNA duplex-bound AGO1. Moreover, CYP40 that was synthesized by in-vitro translation using BYL uniquely facilitated binding of small RNA duplexes to AGO1, and as a result, increased the amount of mature RISCs that could cleave target RNAs. CYP40 was not contained in mature RISCs, indicating that the association is transient. Addition of PP5 or cyclophilin-binding drug cyclosporine A prevented the association of endogenous CYP40 with HSP90-AGO1 complex and inhibited RISC assembly. These results suggest that a complex of AGO1, HSP90, CYP40, and a small RNA duplex is a key intermediate of RISC assembly in plants. PMID:22045333

  17. Nuclear HSP90 and HSP70 in COPD patients treated with formoterol or formoterol and corticosteroids

    Directory of Open Access Journals (Sweden)

    Holownia A

    2009-12-01

    Full Text Available Abstract Objective Heat shock proteins assist cellular protein folding and are required for the normal activity of steroid receptors. In this study we assessed nuclear HSP90 and HSP70 proteins and mRNA levels in cells isolated from induced sputum of chronic obstructive pulmonary disease patients treated for 4 weeks with formoterol (F or formoterol+budesonide (F/ICS. Methods Nuclear heat shock protein levels were assessed by Western blot and specific mRNAs were quantified in cell lysates using qRT-PCR. Results Both HSP90 and HSP70 protein levels were higher in the F/ICS-treated patients in comparison with the F-treated group (by 31%, P Conclusions It is possible that increased nuclear heat shock proteins may play a role in the attenuation of the response to glucocorticoids in COPD patients.

  18. Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors.

    Science.gov (United States)

    Byrd, Katherine M; Subramanian, Chitra; Sanchez, Jacqueline; Motiwala, Hashim F; Liu, Weiya; Cohen, Mark S; Holzbeierlein, Jeffrey; Blagg, Brian S J

    2016-05-10

    Development of heat shock protein 90 (Hsp90) C-terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti-proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 and 12.1 Å apart along with angles of 180°. PMID:27037933

  19. Stability of the Human Hsp90-p50Cdc37 Chaperone Complex against Nucleotides and Hsp90 Inhibitors, and the Influence of Phosphorylation by Casein Kinase 2

    Directory of Open Access Journals (Sweden)

    Sanne H. Olesen

    2015-01-01

    Full Text Available The molecular chaperone Hsp90 is regulated by co-chaperones such as p50Cdc37, which recruits a wide selection of client protein kinases. Targeted disruption of the Hsp90-p50Cdc37 complex by protein–protein interaction (PPI inhibitors has emerged as an alternative strategy to treat diseases characterized by aberrant Hsp90 activity. Using isothermal microcalorimetry, ELISA and GST-pull down assays we evaluated reported Hsp90 inhibitors and nucleotides for their ability to inhibit formation of the human Hsp90β-p50Cdc37 complex, reconstituted in vitro from full-length proteins. Hsp90 inhibitors, including the proposed PPI inhibitors gedunin and H2-gamendazole, did not affect the interaction of Hsp90 with p50Cdc37 in vitro. Phosphorylation of Hsp90 and p50Cdc37 by casein kinase 2 (CK2 did not alter the thermodynamic signature of complex formation. However, the phosphorylated complex was vulnerable to disruption by ADP (IC50 = 32 µM, while ATP, AMPPNP and Hsp90 inhibitors remained largely ineffective. The differential inhibitory activity of ADP suggests that phosphorylation by CK2 primes the complex for dissociation in response to a drop in ATP/ADP levels. The approach applied herein provides robust assays for a comprehensive biochemical evaluation of potential effectors of the Hsp90-p50Cdc37 complex, such as phosphorylation by a kinase or the interaction with small molecule ligands.

  20. The Correlation between the Up-regulation of Hsp90 
and Drug Resistance to Cisplatin in Lung Cancer Cell Line

    Directory of Open Access Journals (Sweden)

    Ting LIU

    2011-06-01

    Full Text Available Background and objective Hsp90 is a major molecular chaperone, which overexpression is involved in oncogenesis, development and drug resistance in many human cancers. The aim of this study is to investigate the relationship between the GGA-induced overexpression of Hsp90 and chemoresistance to Cisplatin in SPCA-1 and H446 cell line. Methods The protein expressions of Hsp90 induced by GGA at different concentrations were analyzed by Immunofluorescence and Western blotting. Cells survival to Cisplatin was determined using the MTT assays. The effect of Hsp90 expression on the drug resistance to Cisplatin in two Cell Lines was analyzed. Results Compared with the respective control cells, Hsp90 expressions in both experimental cell lines were up-regulated obviously, exhibiting a dose-dependent manner to GGA. MTT assays revealed that the IC50s of cisplatin also showed a substantial elevation for the experimental cells of SPCA-1 and H446, and this elevation was also associated with GGA concerntration. Conclusion GGA is effective for the induction of Hsp90 in the SPCA-1 and H446 cell line. Up-regulated Hsp90 is associated with the chemoresistance to Cisplatin in SPCA-1and H446 cells.

  1. Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Eskew Jeffery D

    2011-10-01

    Full Text Available Abstract Background The molecular chaperone, heat shock protein 90 (Hsp90 has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells. Methods PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies. Results KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model. Conclusions Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer.

  2. Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells

    International Nuclear Information System (INIS)

    The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells. PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies. KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model. Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer

  3. Treatment of Arabidopsis thaliana seeds with an HSP90 inhibitor increases plant resistance

    Science.gov (United States)

    Kozeko, Liudmyla

    2016-07-01

    Resistance of plants to unfavourable conditions is an important feature to use them as an autotrophic link of Life Support Systems in space exploration missions. It significantly depends on basic and stress-induced levels of heat shock proteins (HSP) in cells. It is known that HSP90 can bind and maintain heat shock transcription factors (HSF) as a monomer that lacks DNA binding activity and thereby regulate HSP expression. Modulation of activity of the HSP synthesis and resistance by HSP90 in plants is not well investigated. The objective of this study was to determine how treatment of seeds with an HSP90 inhibitor affects environmental responsiveness in Arabidopsis thaliana. Seed treatment with geldanamycin (GDA) was used to reduce HSP90 function. The affect of space flight stressors was simulated by gamma-irradiation and thermal upshift. Two series of experiments were carried out: 1) exposure of dry seeds to gamma-irradiation (1 kGy, ^{60}Co); 2) heat shock of seedlings. It was shown that GDA treatment of seeds stimulated the seedling growth after seed irradiation. It also increased both the basic thermotolerance (45°C for 45 min) and induced thermotolerance (45°C for 1,5-2,5 h after pretreatment at 37°C for 2 h) in seedlings. In addition, seed treatment with GDA had a prolonged effect on the HSP70 production in seedlings under normal and stressful conditions. It shows that the stimulatory effects of GDA may be caused by induction of HSP70 synthesis. The obtained data demonstrate that pre-treatment of seeds with GDA before planting allows inducing the stress resistance at least at early growth stages of plants.

  4. Molecular Dynamics Simulations Reveal the Mechanisms of Allosteric Activation of Hsp90 by Designed Ligands

    Science.gov (United States)

    Vettoretti, Gerolamo; Moroni, Elisabetta; Sattin, Sara; Tao, Jiahui; Agard, David A.; Bernardi, Anna; Colombo, Giorgio

    2016-04-01

    Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone’s active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators.

  5. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

    Energy Technology Data Exchange (ETDEWEB)

    Gomez-Casal, Roberto; Bhattacharya, Chitralekha [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Epperly, Michael W. [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Radiation Oncology, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Basse, Per H. [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Wang, Hong [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Biostatistics, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Wang, Xinhui [Harvard Medical School, Harvard University, 25 Shattuck Street, Boston, MA 02115 (United States); Proia, David A. [Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421 (United States); Greenberger, Joel S. [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Radiation Oncology, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Socinski, Mark A.; Levina, Vera, E-mail: levinav@upmc.edu [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213 (United States)

    2015-05-22

    The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors.

  6. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

    International Nuclear Information System (INIS)

    The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors

  7. Genome-scale Co-evolutionary Inference Identifies Functions and Clients of Bacterial Hsp90

    OpenAIRE

    Press, Maximilian O.; Li, Hui; Creanza, Nicole; Kramer, Günter; Queitsch, Christine; Sourjik, Victor; Borenstein, Elhanan

    2013-01-01

    The molecular chaperone Hsp90 is essential in eukaryotes, in which it facilitates the folding of developmental regulators and signal transduction proteins known as Hsp90 clients. In contrast, Hsp90 is not essential in bacteria, and a broad characterization of its molecular and organismal function is lacking. To enable such characterization, we used a genome-scale phylogenetic analysis to identify genes that co-evolve with bacterial Hsp90. We find that genes whose gain and loss were coordinate...

  8. High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors

    OpenAIRE

    Jason Davenport; Maurie Balch; Lakshmi Galam; Antwan Girgis; Jessica Hall; Blagg, Brian S. J.; Matts, Robert L.

    2014-01-01

    Hsp90 has become the target of intensive investigation, as inhibition of its function has the ability to simultaneously incapacitate proteins that function in pathways that represent the six hallmarks of cancer. While a number of Hsp90 inhibitors have made it into clinical trials, a number of short-comings have been noted, such that the search continues for novel Hsp90 inhibitors with superior pharmacological properties. To identify new potential Hsp90 inhibitors, we have utilized a high-thro...

  9. Phenotypic diversity and altered environmental plasticity in Arabidopsis thaliana with reduced Hsp90 levels.

    Directory of Open Access Journals (Sweden)

    Todd A Sangster

    Full Text Available The molecular chaperone HSP90 aids the maturation of a diverse but select set of metastable protein clients, many of which are key to a variety of signal transduction pathways. HSP90 function has been best investigated in animal and fungal systems, where inhibition of the chaperone has exceptionally diverse effects, ranging from reversing oncogenic transformation to preventing the acquisition of drug resistance. Inhibition of HSP90 in the model plant Arabidopsis thaliana uncovers novel morphologies dependent on normally cryptic genetic variation and increases stochastic variation inherent to developmental processes. The biochemical activity of HSP90 is strictly conserved between animals and plants. However, the substrates and pathways dependent on HSP90 in plants are poorly understood. Progress has been impeded by the necessity of reliance on light-sensitive HSP90 inhibitors due to redundancy in the A. thaliana HSP90 gene family. Here we present phenotypic and genome-wide expression analyses of A. thaliana with constitutively reduced HSP90 levels achieved by RNAi targeting. HSP90 reduction affects a variety of quantitative life-history traits, including flowering time and total seed set, increases morphological diversity, and decreases the developmental stability of repeated characters. Several morphologies are synergistically affected by HSP90 and growth temperature. Genome-wide expression analyses also suggest a central role for HSP90 in the genesis and maintenance of plastic responses. The expression results are substantiated by examination of the response of HSP90-reduced plants to attack by caterpillars of the generalist herbivore Trichoplusia ni. HSP90 reduction potentiates a more robust herbivore defense response. In sum, we propose that HSP90 exerts global effects on the environmental responsiveness of plants to many different stimuli. The comprehensive set of HSP90-reduced lines described here is a vital instrument to further examine

  10. A novel extracellular Hsp90 mediated co-receptor function for LRP1 regulates EphA2 dependent glioblastoma cell invasion.

    Directory of Open Access Journals (Sweden)

    Udhayakumar Gopal

    Full Text Available BACKGROUND: Extracellular Hsp90 protein (eHsp90 potentiates cancer cell motility and invasion through a poorly understood mechanism involving ligand mediated function with its cognate receptor LRP1. Glioblastoma multiforme (GBM represents one of the most aggressive and lethal brain cancers. The receptor tyrosine kinase EphA2 is overexpressed in the majority of GBM specimens and is a critical mediator of GBM invasiveness through its AKT dependent activation of EphA2 at S897 (P-EphA2(S897. We explored whether eHsp90 may confer invasive properties to GBM via regulation of EphA2 mediated signaling. PRINCIPAL FINDINGS: We find that eHsp90 signaling is essential for sustaining AKT activation, P-EphA2(S897, lamellipodia formation, and concomitant GBM cell motility and invasion. Furthermore, eHsp90 promotes the recruitment of LRP1 to EphA2 in an AKT dependent manner. A finding supported by biochemical methodology and the dual expression of LRP1 and P-EphA2(S897 in primary and recurrent GBM tumor specimens. Moreover, hypoxia mediated facilitation of GBM motility and invasion is dependent upon eHsp90-LRP1 signaling. Hypoxia dramatically elevated surface expression of both eHsp90 and LRP1, concomitant with eHsp90 dependent activation of src, AKT, and EphA2. SIGNIFICANCE: We herein demonstrate a novel crosstalk mechanism involving eHsp90-LRP1 dependent regulation of EphA2 function. We highlight a dual role for eHsp90 in transducing signaling via LRP1, and in facilitating LRP1 co-receptor function for EphA2. Taken together, our results demonstrate activation of the eHsp90-LRP1 signaling axis as an obligate step in the initiation and maintenance of AKT signaling and EphA2 activation, thereby implicating this pathway as an integral component contributing to the aggressive nature of GBM.

  11. 热休克蛋白90的N端与ATP类似物的晶体结构揭示其功能调控%Crystal Structures of N-terminal Domain of Human Hsp90 With ATP Analogues Reveal The Functional Regulation of Hsp90

    Institute of Scientific and Technical Information of China (English)

    李健; 孙丽华; 徐春艳; 郁峰; 周欢; 唐琳; 何建华

    2012-01-01

    Heat shock protein 90 (Hsp90) is essential for folding, maturation and stabilization of many important proteins, which are involved in cell cycle regulation, signal transduction, and cell growth regulation. The highly conserved N-terminal domain contains an ATP binding cleft and thus is responsible for the catalytic activity of Hsp90. In order to further study the function and structure of Hsp90, the N-terminal of the human Hsp90 was cocrystallized with AMPPNP and ATP-γS. The cocrystallization experiments were carried out at 277K using the hanging drop vapor-diffusion method, X-ray diffraction data were collected on beamline 17U at the SSRF and the structures were solved by molecular replacement. The densities of the two nucleotides were captured and the interactions between Hsp90N and nucleotides were clearly described. We confirmed that the γ-phosphate of ATP7S was not hydrolyzed by Hsp90N. The position of S1 and ATP lid in human Hsp90N-AMPPNP differs significantly from that of the structure of yeast Hsp90-AMPPNP. By analyzing the structure of human Hsp90N-AMPPNP, we found that the interactions of E18-K100 and N40-D127 block the moving of S1 and ATP lid, and then prevent the dimerization of Hsp90N. This reflects the complexity and coordination of Hsp90 on the regulation of the function.%分子伴侣热休克蛋白90(Hsp90)对于许多涉及细胞周期调控、信号转导以及细胞生长调控蛋白质的折叠、成熟及稳定是必需的.Hsp90的N端结构高度保守,包含一个ATP结合口袋并具有ATP酶活性,Hsp90的功能依赖于ATP与Hsp90结合后诱导的构象重排及之后的ATP水解.为了深入研究ATP与Hsp90结合后N端的结构及其功能状态,使用悬滴法共结晶了Hsp90的N端与ATP类似物AMPPNP及ATPγS的复合物,并利用分子置换法对其结构进行了解析.两个复合物晶体结构都捕获到了核苷酸的电子密度,尤其是γ-磷酸的电子密度,从而观察到γ-磷酸与蛋白质之间的相互作

  12. High-throughput screen of natural product libraries for hsp90 inhibitors.

    Science.gov (United States)

    Davenport, Jason; Balch, Maurie; Galam, Lakshmi; Girgis, Antwan; Hall, Jessica; Blagg, Brian S J; Matts, Robert L

    2014-01-01

    Hsp90 has become the target of intensive investigation, as inhibition of its function has the ability to simultaneously incapacitate proteins that function in pathways that represent the six hallmarks of cancer. While a number of Hsp90 inhibitors have made it into clinical trials, a number of short-comings have been noted, such that the search continues for novel Hsp90 inhibitors with superior pharmacological properties. To identify new potential Hsp90 inhibitors, we have utilized a high-throughput assay based on measuring Hsp90-dependent refolding of thermally denatured luciferase to screen natural compound libraries. Over 4,000 compounds were screen with over 100 hits. Data mining of the literature indicated that 51 compounds had physiological effects that Hsp90 inhibitors also exhibit, and/or the ability to downregulate the expression levels of Hsp90-dependent proteins. Of these 51 compounds, seven were previously characterized as Hsp90 inhibitors. Four compounds, anthothecol, garcinol, piplartine, and rottlerin, were further characterized, and the ability of these compounds to inhibit the refolding of luciferase, and reduce the rate of growth of MCF7 breast cancer cells, correlated with their ability to suppress the Hsp90-dependent maturation of the heme-regulated eIF2α kinase, and deplete cultured cells of Hsp90-dependent client proteins. Thus, this screen has identified an additional 44 compounds with known beneficial pharmacological properties, but with unknown mechanisms of action as possible new inhibitors of the Hsp90 chaperone machine. PMID:24833337

  13. High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors

    Directory of Open Access Journals (Sweden)

    Jason Davenport

    2014-02-01

    Full Text Available Hsp90 has become the target of intensive investigation, as inhibition of its function has the ability to simultaneously incapacitate proteins that function in pathways that represent the six hallmarks of cancer. While a number of Hsp90 inhibitors have made it into clinical trials, a number of short-comings have been noted, such that the search continues for novel Hsp90 inhibitors with superior pharmacological properties. To identify new potential Hsp90 inhibitors, we have utilized a high-throughput assay based on measuring Hsp90-dependent refolding of thermally denatured luciferase to screen natural compound libraries. Over 4,000 compounds were screen with over 100 hits. Data mining of the literature indicated that 51 compounds had physiological effects that Hsp90 inhibitors also exhibit, and/or the ability to downregulate the expression levels of Hsp90-dependent proteins. Of these 51 compounds, seven were previously characterized as Hsp90 inhibitors. Four compounds, anthothecol, garcinol, piplartine, and rottlerin, were further characterized, and the ability of these compounds to inhibit the refolding of luciferase, and reduce the rate of growth of MCF7 breast cancer cells, correlated with their ability to suppress the Hsp90-dependent maturation of the heme-regulated eIF2α kinase, and deplete cultured cells of Hsp90-dependent client proteins. Thus, this screen has identified an additional 44 compounds with known beneficial pharmacological properties, but with unknown mechanisms of action as possible new inhibitors of the Hsp90 chaperone machine.

  14. Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

    Directory of Open Access Journals (Sweden)

    Dea Shahinas

    2013-02-01

    Full Text Available Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.

  15. Genome-scale co-evolutionary inference identifies functions and clients of bacterial Hsp90.

    Directory of Open Access Journals (Sweden)

    Maximilian O Press

    Full Text Available The molecular chaperone Hsp90 is essential in eukaryotes, in which it facilitates the folding of developmental regulators and signal transduction proteins known as Hsp90 clients. In contrast, Hsp90 is not essential in bacteria, and a broad characterization of its molecular and organismal function is lacking. To enable such characterization, we used a genome-scale phylogenetic analysis to identify genes that co-evolve with bacterial Hsp90. We find that genes whose gain and loss were coordinated with Hsp90 throughout bacterial evolution tended to function in flagellar assembly, chemotaxis, and bacterial secretion, suggesting that Hsp90 may aid assembly of protein complexes. To add to the limited set of known bacterial Hsp90 clients, we further developed a statistical method to predict putative clients. We validated our predictions by demonstrating that the flagellar protein FliN and the chemotaxis kinase CheA behaved as Hsp90 clients in Escherichia coli, confirming the predicted role of Hsp90 in chemotaxis and flagellar assembly. Furthermore, normal Hsp90 function is important for wild-type motility and/or chemotaxis in E. coli. This novel function of bacterial Hsp90 agreed with our subsequent finding that Hsp90 is associated with a preference for multiple habitats and may therefore face a complex selection regime. Taken together, our results reveal previously unknown functions of bacterial Hsp90 and open avenues for future experimental exploration by implicating Hsp90 in the assembly of membrane protein complexes and adaptation to novel environments.

  16. Identification of two p23 co-chaperone isoforms in Leishmania braziliensis exhibiting similar structures and Hsp90 interaction properties despite divergent stabilities.

    Science.gov (United States)

    Batista, Fernanda A H; Almeida, Glessler S; Seraphim, Thiago V; Silva, Kelly P; Murta, Silvane M F; Barbosa, Leandro R S; Borges, Júlio C

    2015-01-01

    The small acidic protein called p23 acts as a co-chaperone for heat-shock protein of 90 kDa (Hsp90) during its ATPase cycle. p23 proteins inhibit Hsp90 ATPase activity and show intrinsic chaperone activity. A search for p23 in protozoa, especially trypanosomatids, led us to identify two putative proteins in the Leishmania braziliensis genome that share approximately 30% identity with each other and with the human p23. To understand the presence of two p23 isoforms in trypanosomatids, we obtained the recombinant p23 proteins of L. braziliensis (named Lbp23A and Lbp23B) and performed structural and functional studies. The recombinant proteins share similar solution structures; however, temperature- and chemical-induced unfolding experiments showed that Lbp23A is more stable than Lbp23B, suggesting that they may have different functions. Lbp23B prevented the temperature-induced aggregation of malic dehydrogenase more efficiently than did Lbp23A, whereas the two proteins had equivalent efficiencies with respect to preventing the temperature-induced aggregation of luciferase. Both proteins interacted with L. braziliensis Hsp90 (LbHsp90) and inhibited its ATPase activity, although their efficiencies differed. In vivo identification studies suggested that both proteins are present in L. braziliensis cells grown under different conditions, although Lbp23B may undergo post-translation modifications. Interaction studies indicated that both Lbp23 proteins interact with LbHsp90. Taken together, our data suggest that the two protozoa p23 isoforms act similarly when regulating Hsp90 function. However, they also have some differences, indicating that the L. braziliensis Hsp90 machine has features providing an opportunity for novel forms of selective inhibition of protozoan Hsp90. PMID:25369258

  17. Whey protein hydrolysate enhances HSP90 but does not alter HSP60 and HSP25 in skeletal muscle of rats.

    Directory of Open Access Journals (Sweden)

    Carolina Soares Moura

    Full Text Available Whey protein hydrolysate (WPH intake has shown to increase HSP70 expression. The aim of the present study was to investigate whether WPH intake would also influences HSP90, HSP60 and HSP25 expression, as well as associated parameters. Forty-eight male Wistar rats were divided into sedentary (unstressed and exercised (stressed groups, and were fed with three different sources of protein: whey protein (WP, whey protein hydrolysate (WPH and casein (CAS as a control, based on the AIN93G diet for 3 weeks. WPH intake increased HSP90 expression in both sedentary and exercised animals compared to WP or CAS, however no alteration was found from exercise or diet to HSP60 or HSP25. Co-chaperone Aha1 and p-HSF1 were also increased in the exercised animals fed with WPH in comparison with WP or CAS, consistent with enhanced HSP90 expression. VEGF and p-AKT were increased in the WPH exercised group. No alteration was found in BCKDH, PI3-Kinase (p85, GFAT, OGT or PGC for diet or exercise. The antioxidant system GPx, catalase and SOD showed different responses to diet and exercise. The data indicate that WPH intake enhanced factors related to cell survival, such as HSP90 and VEGF, but does not alter HSP60 or HSP25 in rat skeletal muscle.

  18. RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation.

    LENUS (Irish Health Repository)

    Walsh, Naomi

    2011-07-28

    We previously identified Hop as over expressed in invasive pancreatic cancer cell lines and malignant tissues of pancreatic cancer patients, suggesting an important role for Hop in the biology of invasive pancreatic cancer. Hop is a co-chaperone protein that binds to both Hsp70\\/Hsp90. We hypothesised that by targeting Hop, signalling pathways modulating invasion and client protein stabilisation involving Hsp90-dependent complexes may be altered. In this study, we show that Hop knockdown by small interfering (si)RNA reduces the invasion of pancreatic cancer cells, resulting in decreased expression of the downstream target gene, matrix metalloproteinases-2 (MMP-2). Hop in conditioned media co-immunoprecipitates with MMP-2, implicating a possible extracellular function for Hop. Knockdown of Hop expression also reduced expression levels of Hsp90 client proteins, HER2, Bcr-Abl, c-MET and v-Src. Furthermore, Hop is strongly expressed in high grade PanINs compared to lower PanIN grades, displaying differential localisation in invasive ductal pancreatic cancer, indicating that the localisation of Hop is an important factor in pancreatic tumours. Our data suggests that the attenuation of Hop expression inactivates key signal transduction proteins which may decrease the invasiveness of pancreatic cancer cells possibly through the modulation of Hsp90 activity. Therefore, targeting Hop in pancreatic cancer may constitute a viable strategy for targeted cancer therapy.

  19. Repercussion of mitochondria deformity induced by anti-Hsp90 drug 17AAG in human tumor cells

    KAUST Repository

    Vishal, Chaturvedi

    2011-06-07

    Inhibiting Hsp90 chaperone roles using 17AAG induces cytostasis or apoptosis in tumor cells through destabilization of several mutated cancer promoting proteins. Although mitochondria are central in deciding the fate of cells, 17AAG induced effects on tumor cell mitochondria were largely unknown. Here, we show that Hsp90 inhibition with 17AAG first affects mitochondrial integrity in different human tumor cells, neuroblastoma, cervical cancer and glial cells. Using human neuroblastoma tumor cells, we found the early effects associated with a change in mitochondrial membrane potential, elongation and engorgement of mitochondria because of an increased matrix vacuolization. These effects are specific to Hsp90 inhibition as other chemotherapeutic drugs did not induce similar mitochondrial deformity. Further, the effects are independent of oxidative damage and cytoarchitecture destabilization since cytoskeletal disruptors and mitochondrial metabolic inhibitors also do not induce similar deformity induced by 17AAG. The 1D PAGE LC MS/ MS mitochondrial proteome analysis of 17AAG treated human neuroblastoma cells showed a loss of 61% proteins from membrane, metabolic, chaperone and ribonucleoprotein families. About 31 unmapped protein IDs were identified from proteolytic processing map using Swiss-Prot accession number, and converted to the matching gene name searching the ExPASy proteomics server. Our studies display that Hsp90 inhibition effects at first embark on mitochondria of tumor cells and compromise mitochondrial integrity. the author(s), publisher and licensee Libertas Academica Ltd.

  20. Cloning and Expression of a Cytosolic HSP90 Gene in Chlorella vulgaris

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    Zhengyi Liu

    2014-01-01

    Full Text Available Heat shock protein 90 (HSP90, a highly conserved molecular chaperone, plays essential roles in folding, keeping structural integrity, and regulating the subset of cytosolic proteins. We cloned the cDNA of Chlorella vulgaris HSP90 (named CvHSP90 by combining homology cloning with rapid amplification of cDNA ends (RACE. Sequence analysis indicated that CvHSP90 is a cytosolic member of the HSP90 family. Quantitative RT-PCR was applied to determine the expression level of messenger RNA (mRNA in CvHSP90 under different stress conditions. C. vulgaris was kept in different temperatures (5–45°C for 1 h. The mRNA expression level of CvHSP90 increased with temperature from 5 to 10°C, went further from 35 to 40°C, and reached the maximum at 40°C. On the other hand, for C. vulgaris kept at 35°C for different durations, the mRNA expression level of CvHSP90 increased gradually and reached the peak at 7 h and then declined progressively. In addition, the expression level of CvHSP90 at 40 or 45 in salinity (‰ was almost fourfold of that at 25 in salinity (‰ for 2 h. Therefore, CvHSP90 may be a potential biomarker to monitor environment changes.

  1. Fever-Range Hyperthermia vs. Hypothermia Effect on Cancer Cell Viability, Proliferation and HSP90 Expression

    Science.gov (United States)

    Kalamida, Dimitra; Karagounis, Ilias V.; Mitrakas, Achilleas; Kalamida, Sofia; Giatromanolaki, Alexandra; Koukourakis, Michael I.

    2015-01-01

    Purpose The current study examines the effect of fever-range hyperthermia and mild hypothermia on human cancer cells focusing on cell viability, proliferation and HSP90 expression. Materials and Methods A549 and H1299 lung carcinoma, MCF7 breast adenocarcinoma, U87MG and T98G glioblastoma, DU145 and PC3 prostate carcinoma and MRC5 normal fetal lung fibroblasts cell lines were studied. After 3-day exposure to 34°C, 37°C and 40°C, cell viability was determined. Cell proliferation (ki67 index), apoptosis (Caspase 9) and HSP90 expression was studied by confocal microscopy. Results Viability/proliferation experiments demonstrated that MRC5 fibroblasts were extremely sensitive to hyperthermia, while they were the most resistant to hypothermia. T98G and A549 were thermo-tolerant, the remaining being thermo-sensitive to a varying degree. Nonetheless, as a universal effect, hypothermia reduced viability/proliferation in all cell lines. Hyperthermia sharply induced Caspase 9 in the U87MG most thermo-sensitive cell line. In T98G and A549 thermo-tolerant cell lines, the levels of Caspase 9 declined. Moreover, hyperthermia strongly induced the HSP90 levels in T98G, whilst a sharp decrease was recorded in the thermo-sensitive PC3 and U87MG cell lines. Hyperthermia sensitized thermo-sensitive cancer cell lines to cisplatin and temozolomide, whilst its sensitizing effect was diminished in thermo-tolerant cell lines. Conclusions The existence of thermo-tolerant and thermo-sensitive cancer cell lines was confirmed, which further encourages research to classify human tumor thermic predilection for patient stratification in clinical trials. Of interest, mild hypothermia had a universal suppressing effect on cancer cell proliferation, further supporting the radio-sensitization hypothesis through reduction of oxygen and metabolic demands. PMID:25635828

  2. Proteomic analyses of the SMYD family interactomes identify HSP90 as a novel target for SMYD2

    Institute of Scientific and Technical Information of China (English)

    Mohamed Abu-Farha; Sylvain Lanouette; Fred Elisma; Véronique Tremblay; Jeffery Butson; Daniel Figeys; Jean-Francois Couture

    2011-01-01

    The SMYD (SET and MYND domain) family of lysine methyltransferases (KMTs) plays pivotal roles in various cellular processes,including gene expression regulation and DNA damage response.Initially identified as genuine histone methyltransferases,specific members of this family have recently been shown to methylate non-histone proteins such as p53,VEGFR,and the retinoblastoma tumor suppressor (pRb).To gain further functional insights into this family of KMTs,we generated the protein interaction network for three different human SMYD proteins (SMYD2,SMYD3,and SMYDS).Characterization of each SMYD protein network revealed that they associate with both shared and unique sets of proteins.Among those,we found that HsP90 and several of its co-chaperones interact specifically with the tetratrico peptide repeat (TPR)-containing SMYD2 and SMYD3.Moreover,using proteomic and biochemical techniques,we provide evidence that SMYD2 methylates K209 and K615 on HSP90 nucleotide-binding and dimerization domains,respectively.In addition,we found that each methylation site displays unique reactivity in regard to the presence of HsP90 co-chaperones,pH,and demethylation by the lysine amine oxidase LSD1,suggesting that alternative mechanisms control HsP90 methylation by SMYD2.Altogether,this study highlights the ability of SMYD proteins to form unique protein complexes that may underlie their various biological functions and the SMYD2-mediated methylation of the key molecular chaperone HSP90.%The SMYD (SET and MYND domain) family of lysine methyltransferases (KMTs) plays pivotal roles in various cellular processes, including gene expression regulation and DNA damage response. Initially identified as genuine histone methyltransferases, specific members of this family have recently been shown to methylate non-histone proteins such as p53, VEGFR, and the retinoblastoma tumor suppressor (pRb). To gain further functional insights into this family of KMTs, we generated the protein interaction

  3. Modelling the role of the Hsp70/Hsp90 system in the maintenance of protein homeostasis.

    Directory of Open Access Journals (Sweden)

    Carole J Proctor

    Full Text Available Neurodegeneration is an age-related disorder which is characterised by the accumulation of aggregated protein and neuronal cell death. There are many different neurodegenerative diseases which are classified according to the specific proteins involved and the regions of the brain which are affected. Despite individual differences, there are common mechanisms at the sub-cellular level leading to loss of protein homeostasis. The two central systems in protein homeostasis are the chaperone system, which promotes correct protein folding, and the cellular proteolytic system, which degrades misfolded or damaged proteins. Since these systems and their interactions are very complex, we use mathematical modelling to aid understanding of the processes involved. The model developed in this study focuses on the role of Hsp70 (IPR00103 and Hsp90 (IPR001404 chaperones in preventing both protein aggregation and cell death. Simulations were performed under three different conditions: no stress; transient stress due to an increase in reactive oxygen species; and high stress due to sustained increases in reactive oxygen species. The model predicts that protein homeostasis can be maintained during short periods of stress. However, under long periods of stress, the chaperone system becomes overwhelmed and the probability of cell death pathways being activated increases. Simulations were also run in which cell death mediated by the JNK (P45983 and p38 (Q16539 pathways was inhibited. The model predicts that inhibiting either or both of these pathways may delay cell death but does not stop the aggregation process and that eventually cells die due to aggregated protein inhibiting proteasomal function. This problem can be overcome if the sequestration of aggregated protein into inclusion bodies is enhanced. This model predicts responses to reactive oxygen species-mediated stress that are consistent with currently available experimental data. The model can be used to

  4. Nuclear HSP90 and HSP70 in COPD patients treated with formoterol or formoterol and corticosteroids

    OpenAIRE

    Holownia A; Mroz RM; Kielek A; Chyczewska E; Braszko JJ

    2009-01-01

    Abstract Objective Heat shock proteins assist cellular protein folding and are required for the normal activity of steroid receptors. In this study we assessed nuclear HSP90 and HSP70 proteins and mRNA levels in cells isolated from induced sputum of chronic obstructive pulmonary disease patients treated for 4 weeks with formoterol (F) or formoterol+budesonide (F/ICS). Methods Nuclear heat shock protein levels were assessed by Western blot and specific mRNAs were quantified in cell lysates usi...

  5. Increased nitric oxide synthase activity and Hsp90 association in skeletal muscle following chronic exercise

    OpenAIRE

    Harris, M. Brennan; Mitchell, Brett M.; Sood, Sarika G.; Webb, R. Clinton; Venema, Richard C.

    2008-01-01

    Exercise training results in dynamic changes in skeletal muscle blood flow and metabolism. Nitric oxide (NO) influences blood flow, oxidative stress, and glucose metabolism. Hsp90 interacts directly with nitric oxide synthases (NOS), increasing NOS activity and altering the balance of superoxide versus NO production. In addition, Hsp90 expression increases in various tissues following exercise. Therefore, we tested the hypothesis that exercise training increases Hsp90 expression as well as Hs...

  6. Impact of Posttranslational Modifications on the Anticancer Activity of Hsp90 Inhibitors.

    Science.gov (United States)

    Woodford, Mark R; Dunn, Diana; Miller, Jonelle B; Jamal, Sami; Neckers, Len; Mollapour, Mehdi

    2016-01-01

    Molecular chaperones are essential for guarding proteins that are indispensable for normal cellular functions. Heat shock protein 90 (Hsp90) is a vital molecular chaperone in eukaryotes that participates in stabilizing and activating approximately 200 target proteins, called "clients," many of which are involved in signal transduction pathways. Cancer cells however utilize Hsp90 to chaperone an array of mutated and overexpressed oncoproteins to protect them from misfolding and degradation. Therefore, Hsp90 is an attractive target in cancer therapy. Hsp90 chaperone function relies on ATP binding and hydrolysis, which in turn guides its carefully orchestrated conformational changes. This chaperone cycle is fine-tuned by another group of proteins called co-chaperones. They are able to accelerate or decelerate the cycle, allowing Hsp90 to chaperone different clients. Posttranslational modifications (PTMs) can also regulate the chaperone cycle at an epigenetic level thereby tailoring Hsp90 function to suit a specific cell type or environmental condition. Recent evidence suggests that inhibition of the enzymes that catalyze the PTM of Hsp90 can act synergistically with Hsp90 inhibitors, providing a novel therapeutic strategy to enhance the efficacy of Hsp90 inhibitors in cancer cells. PMID:26916000

  7. A Novel Extracellular Hsp90 Mediated Co-Receptor Function for LRP1 Regulates EphA2 Dependent Glioblastoma Cell Invasion

    OpenAIRE

    Udhayakumar Gopal; Bohonowych, Jessica E.; Carla Lema-Tome; Angen Liu; Elizabeth Garrett-Mayer; Bingcheng Wang; Isaacs, Jennifer S.

    2011-01-01

    BACKGROUND: Extracellular Hsp90 protein (eHsp90) potentiates cancer cell motility and invasion through a poorly understood mechanism involving ligand mediated function with its cognate receptor LRP1. Glioblastoma multiforme (GBM) represents one of the most aggressive and lethal brain cancers. The receptor tyrosine kinase EphA2 is overexpressed in the majority of GBM specimens and is a critical mediator of GBM invasiveness through its AKT dependent activation of EphA2 at S897 (P-EphA2(S897)). ...

  8. Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast.

    Directory of Open Access Journals (Sweden)

    Michelle D Leach

    2012-12-01

    Full Text Available Thermal adaptation is essential in all organisms. In yeasts, the heat shock response is commanded by the heat shock transcription factor Hsf1. Here we have integrated unbiased genetic screens with directed molecular dissection to demonstrate that multiple signalling cascades contribute to thermal adaptation in the pathogenic yeast Candida albicans. We show that the molecular chaperone heat shock protein 90 (Hsp90 interacts with and down-regulates Hsf1 thereby modulating short term thermal adaptation. In the longer term, thermal adaptation depends on key MAP kinase signalling pathways that are associated with cell wall remodelling: the Hog1, Mkc1 and Cek1 pathways. We demonstrate that these pathways are differentially activated and display cross talk during heat shock. As a result ambient temperature significantly affects the resistance of C. albicans cells to cell wall stresses (Calcofluor White and Congo Red, but not osmotic stress (NaCl. We also show that the inactivation of MAP kinase signalling disrupts this cross talk between thermal and cell wall adaptation. Critically, Hsp90 coordinates this cross talk. Genetic and pharmacological inhibition of Hsp90 disrupts the Hsf1-Hsp90 regulatory circuit thereby disturbing HSP gene regulation and reducing the resistance of C. albicans to proteotoxic stresses. Hsp90 depletion also affects cell wall biogenesis by impairing the activation of its client proteins Mkc1 and Hog1, as well as Cek1, which we implicate as a new Hsp90 client in this study. Therefore Hsp90 modulates the short term Hsf1-mediated activation of the classic heat shock response, coordinating this response with long term thermal adaptation via Mkc1- Hog1- and Cek1-mediated cell wall remodelling.

  9. Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin inhibits the proliferation of ARPE-19 cells

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    Wang Lin

    2010-04-01

    Full Text Available Abstract Background The antiproliferative effect of the Hsp90 inhibitor 17-AAG (17-allylamino-17-demethoxygeldanamycin on human retinal pigment epithelial cells is investigated. Methods MTT and flow cytometry were used to study the antiproliferative effects of the 17-AAG treatment of ARPE-19 cells. 2D gel electrophoresis (2-DE and mass spectrometry were applied to detect the altered expression of proteins, which was verified by real-time PCR. Gene Ontology analysis and Ingenuity Pathway Analysis (IPA were utilized to analyze the signaling pathways, cellular location, function, and network connections of the identified proteins. And SOD assay was employed to confirm the analysis. Results 17-AAG suppressed the proliferation of ARPE-19 cells by inducing cell cycle arrest and apoptosis. Proteomic analysis revealed that the expression of 94 proteins was altered by a factor of more than 1.5 following exposure to 17-AAG. Of these 94, 87 proteins were identified. Real-time PCR results indicated that Hsp90 and Hsp70, which were not identified by proteomic analysis, were both upregulated upon 17-AAG treatment. IPA revealed that most of the proteins have functions that are related to oxidative stress, as verified by SOD assay, while canonical pathway analysis revealed glycolysis/gluconeogenesis. Conclusions 17-AAG suppressed the proliferation of ARPE-19 cells by inducing cell cycle arrest and apoptosis, and possibly by oxidative stress.

  10. The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding

    Science.gov (United States)

    Woodford, Mark R.; Dunn, Diana M.; Blanden, Adam R.; Capriotti, Dante; Loiselle, David; Prodromou, Chrisostomos; Panaretou, Barry; Hughes, Philip F.; Smith, Aaron; Ackerman, Wendi; Haystead, Timothy A.; Loh, Stewart N.; Bourboulia, Dimitra; Schmidt, Laura S.; Marston Linehan, W.; Bratslavsky, Gennady; Mollapour, Mehdi

    2016-01-01

    Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Lastly, downregulation of FNIPs desensitizes cancer cells to Hsp90 inhibitors, whereas FNIPs overexpression in renal tumours compared with adjacent normal tissues correlates with enhanced binding of Hsp90 to its inhibitors. Our findings suggest that FNIPs expression can potentially serve as a predictive indicator of tumour response to Hsp90 inhibitors. PMID:27353360

  11. Hsp90 is a direct target of the anti-allergic drugs disodium cromoglycate and amlexanox.

    Science.gov (United States)

    Okada, Miki; Itoh, Hideaki; Hatakeyama, Takashi; Tokumitsu, Hiroshi; Kobayashi, Ryoji

    2003-09-01

    Hsp90 (heat-shock protein 90) alone can act to prevent protein aggregation and promote refolding in vitro, but in vivo it operates as a part of a multichaperone complex, which includes Hsp70 and cohort proteins. Since the physiological function of Hsp90 is not yet fully understood, the development of specific antagonists might open new lines of investigation on the role of Hsp90. In an effort to discover Hsp90 antagonists, we screened many drugs and found that the anti-allergic drugs DSCG (disodium cromoglycate) and amlexanox target Hsp90. Both drugs were found to bind directly wild-type Hsp90 via the N- and C-terminal domains. Both drugs strongly suppressed the in vitro chaperone activity of native Hsp90 towards citrate synthase at 1.5-3.0 microM. Amlexanox suppressed C-terminal chaperone activity in vitro, but not N-terminal chaperone activity, and inhibited the association of cohort proteins, such as cyclophilin 40 and Hsp-organizing protein, to the C-terminal domain of Hsp90. These data suggest that amlexanox might disrupt the multichaperone complex, including Hsp70 and cohort proteins, both in vitro and in vivo. Although DSCG inhibited the in vitro chaperone activity of the N-terminal domain, the drug had no effect either on the C-terminal chaperone activity or on the association of the cohort proteins with the C-terminus of Hsp90. The physiological significance of these interactions in vivo remains to be investigated further, but undoubtedly must be taken into account when considering the pharmacology of anti-allergic drugs. DSCG and amlexanox may serve as useful tools for evaluating the physiological significance of Hsp90. PMID:12803546

  12. Structural Bioinformatics and Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions: Towards Allosteric Inhibition of Protein Kinases by Targeting the Hsp90-Cdc37 Chaperone Machinery

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    Gennady Verkhivker

    2013-11-01

    Full Text Available A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding structure and function of molecular chaperones, the molecular mechanisms and guiding principles of kinase recruitment to the chaperone system are lacking quantitative characterization. Structural and thermodynamic characterization of Hsp90-Cdc37 binding with protein kinase clients by modern experimental techniques is highly challenging, owing to a transient nature of chaperone-mediated interactions. In this work, we used experimentally-guided protein docking to probe the allosteric nature of the Hsp90-Cdc37 binding with the cyclin-dependent kinase 4 (Cdk4 kinase clients. The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cdc37 targeting of the N-terminal kinase lobe. The interactions of Hsp90 with the C-terminal kinase lobe may provide additional “molecular brakes” that can lock (or unlock kinase from the system during client loading (release stages. The results of this study support a central role of the Cdc37 chaperone in recognition and recruitment of the kinase clients. Structural analysis may have useful implications in developing strategies for allosteric inhibition of protein kinases by targeting the Hsp90-Cdc37 chaperone machinery.

  13. HSF-1, HIF-1and HSP90 expression on recombinant Pichia pastoris under fed-batch fermentation

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    Andrea B. Zepeda

    2014-06-01

    Full Text Available Pichia pastoris is a methylotrophic yeast used as an efficient expression system for heterologous protein production as compared to other expression systems. Considering that every cell must respond to environmental changes to survive and differentiate, determination of endogenous protein related to heat stress responses and hypoxia, it would necessary to establish the temperature and methanol concentration conditions for optimal growth. The aim of this study is characterize the culture conditions through the putative biomarkers in different conditions of temperature and methanol concentration. Three yeast cultures were performed: 3X = 3% methanol -10 °C, 4X = 3% methanol -30 °C, and 5X = 1% methanol -10 °C. The expression level of HIF-1α, HSF-1, HSP-70 and HSP-90 biomarkers were measured by Western blot and in situ detection was performed by immunocytochemistry. The western blot results of HIF-1α and HSP-90 did not indicate statistically significant in the culture conditions studied. Respect to biomarkers location, HIF-1α and HSP-90 presented differences between cultures. In conclusion, the results suggest the cultures in a hypoxic condition produce a high density and yeast cells smaller. Beside the high density would not necessary related with a high production of recombinant proteins in modified-genetically P. pastoris.

  14. Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β

    Science.gov (United States)

    Peng, Yi-Jheng; Huang, Jing-Jia; Wu, Hao-Han; Hsieh, Hsin-Ying; Wu, Chia-Ying; Chen, Shu-Ching; Chen, Tsung-Yu; Tang, Chih-Yung

    2016-01-01

    Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation. PMID:27580824

  15. Multifaceted intervention by the Hsp90 inhibitor ganetespib (STA-9090 in cancer cells with activated JAK/STAT signaling.

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    David A Proia

    Full Text Available There is accumulating evidence that dysregulated JAK signaling occurs in a wide variety of cancer types. In particular, mutations in JAK2 can result in the constitutive activation of STAT transcription factors and lead to oncogenic growth. JAK kinases are established Hsp90 client proteins and here we show that the novel small molecule Hsp90 inhibitor ganetespib (formerly STA-9090 exhibits potent in vitro and in vivo activity in a range of solid and hematological tumor cells that are dependent on JAK2 activity for growth and survival. Of note, ganetespib treatment results in sustained depletion of JAK2, including the constitutively active JAK2(V617F mutant, with subsequent loss of STAT activity and reduced STAT-target gene expression. In contrast, treatment with the pan-JAK inhibitor P6 results in only transient effects on these processes. Further differentiating these modes of intervention, RNA and protein expression studies show that ganetespib additionally modulates cell cycle regulatory proteins, while P6 does not. The concomitant impact of ganetespib on both cell growth and cell division signaling translates to potent antitumor efficacy in mouse models of xenografts and disseminated JAK/STAT-driven leukemia. Overall, our findings support Hsp90 inhibition as a novel therapeutic approach for combating diseases dependent on JAK/STAT signaling, with the multimodal action of ganetespib demonstrating advantages over JAK-specific inhibitors.

  16. Probing molecular mechanisms of the Hsp90 chaperone: biophysical modeling identifies key regulators of functional dynamics.

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    Anshuman Dixit

    Full Text Available Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based "conformational selection" of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected

  17. Resistance to HSP90 inhibition involving loss of MCL1 addiction

    OpenAIRE

    Busacca, S.; Law, E. W P; Powley, I R; Proia, D A; Sequeira, M.; Le Quesne, J; Klabatsa, A.; Edwards, J. M.; Matchett, K. B.; Luo, J. L.; Pringle, J. H.; El-Tanani, M.; MacFarlane, M; Fennell, D A

    2015-01-01

    Inhibition of the chaperone heat-shock protein 90 (HSP90) induces apoptosis, and it is a promising anti-cancer strategy. The mechanisms underpinning apoptosis activation following HSP90 inhibition and how they are modified during acquired drug resistance are unknown. We show for the first time that, to induce apoptosis, HSP90 inhibition requires the cooperation of multi BH3-only proteins (BID, BIK, PUMA) and the reciprocal suppression of the pro-survival BCL-2 family member MCL1, which occurs...

  18. Acquired resistance to HSP90 inhibitor 17-AAG and increased metastatic potential are associated with MUC1 expression in colon carcinoma cells.

    Science.gov (United States)

    Liu, Xin; Ban, Li-Li; Luo, Gang; Li, Zhi-Yao; Li, Yun-Feng; Zhou, Yong-Chun; Wang, Xi-Cai; Jin, Cong-Guo; Ye, Jia-Gui; Ma, Ding-Ding; Xie, Qing; Huang, You-Guang

    2016-06-01

    Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability and function of many proteins. The chaperoning of oncoproteins by HSP90 enhances the survival, growth, and invasive potential of cancer cells. HSP90 inhibitors are promising new anticancer agents, in which the benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in clinical evaluation. However, the implications of acquired resistance to this class of drug remain largely unexplored. In the present study, we have generated isogenic human colon cancer cell lines that are resistant to 17-AAG by continued culturing in the compound. Cross-resistance was found with another HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin. The resistant cells showed obvious morphology changes with a metastatic phenotype and significant increases in migration and adhesion to collagens. Western blotting analysis of epithelial-mesenchymal transition molecular markers found that expression of E-cadherin downregulated, whereas expression of N-cadherin and β-catenin upregulated in the resistant cells. Mucin 1 (MUC1) has been reported to mediate metastasis as well as chemical resistance in many cancers. Here, we found that MUC1 expression was significantly elevated in the acquired drug resistance cells. 17-AAG treatment could decrease MUC1 more in parental cells than in acquired 17-AAG-resistant cells. Further study found that knockdown of MUC1 expression by small interfering RNA could obviously re-sensitize the resistant cells to 17-AAG treatment, and decrease the cell migration and adhesion. These were coupled with a downregulation in N-cadherin and β-catenin. The results indicate that HSP90 inhibitor therapies in colon carcinomas could generate resistance and increase metastatic potential that might mediated by upregulation of MUC1 expression. Findings from this study further our understanding of the potential clinical effects of HSP90-directed therapies in

  19. Loss of Smyhc1 or Hsp90alpha1 function results in different effects on myofibril organization in skeletal muscles of zebrafish embryos.

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    Marta Codina

    Full Text Available BACKGROUND: Myofibrillogenesis requires the correct folding and assembly of sarcomeric proteins into highly organized sarcomeres. Heat shock protein 90alpha1 (Hsp90alpha1 has been implicated as a myosin chaperone that plays a key role in myofibrillogenesis. Knockdown or mutation of hsp90alpha1 resulted in complete disorganization of thick and thin filaments and M- and Z-line structures. It is not clear whether the disorganization of these sarcomeric structures is due to a direct effect from loss of Hsp90alpha1 function or indirectly through the disorganization of myosin thick filaments. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we carried out a loss-of-function analysis of myosin thick filaments via gene-specific knockdown or using a myosin ATPase inhibitor BTS (N-benzyl-p-toluene sulphonamide in zebrafish embryos. We demonstrated that knockdown of myosin heavy chain 1 (myhc1 resulted in sarcomeric defects in the thick and thin filaments and defective alignment of Z-lines. Similarly, treating zebrafish embryos with BTS disrupted thick and thin filament organization, with little effect on the M- and Z-lines. In contrast, loss of Hsp90alpha1 function completely disrupted all sarcomeric structures including both thick and thin filaments as well as the M- and Z-lines. CONCLUSION/SIGNIFICANCE: Together, these studies indicate that the hsp90alpha1 mutant phenotype is not simply due to disruption of myosin folding and assembly, suggesting that Hsp90alpha1 may play a role in the assembly and organization of other sarcomeric structures.

  20. Bcl-2 regulates HIF-1alpha protein stabilization in hypoxic melanoma cells via the molecular chaperone HSP90.

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    Daniela Trisciuoglio

    Full Text Available BACKGROUND: Hypoxia-Inducible Factor 1 (HIF-1 is a transcription factor that is a critical mediator of the cellular response to hypoxia. Enhanced levels of HIF-1alpha, the oxygen-regulated subunit of HIF-1, is often associated with increased tumour angiogenesis, metastasis, therapeutic resistance and poor prognosis. It is in this context that we previously demonstrated that under hypoxia, bcl-2 protein promotes HIF-1/Vascular Endothelial Growth Factor (VEGF-mediated tumour angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: By using human melanoma cell lines and their stable or transient derivative bcl-2 overexpressing cells, the current study identified HIF-1alpha protein stabilization as a key regulator for the induction of HIF-1 by bcl-2 under hypoxia. We also demonstrated that bcl-2-induced accumulation of HIF-1alpha protein during hypoxia was not due to an increased gene transcription or protein synthesis. In fact, it was related to a modulation of HIF-1alpha protein expression at a post-translational level, indeed its degradation rate was faster in the control lines than in bcl-2 transfectants. The bcl-2-induced HIF-1alpha stabilization in response to low oxygen tension conditions was achieved through the impairment of ubiquitin-dependent HIF-1alpha degradation involving the molecular chaperone HSP90, but it was not dependent on the prolyl hydroxylation of HIF-1alpha protein. We also showed that bcl-2, HIF-1alpha and HSP90 proteins form a tri-complex that may contribute to enhancing the stability of the HIF-1alpha protein in bcl-2 overexpressing clones under hypoxic conditions. Finally, by using genetic and pharmacological approaches we proved that HSP90 is involved in bcl-2-dependent stabilization of HIF-1alpha protein during hypoxia, and in particular the isoform HSP90beta is the main player in this phenomenon. CONCLUSIONS/SIGNIFICANCE: We identified the stabilization of HIF-1alpha protein as a mechanism through which bcl-2 induces the

  1. Bcl-2 Regulates HIF-1α Protein Stabilization in Hypoxic Melanoma Cells via the Molecular Chaperone HSP90

    Science.gov (United States)

    Trisciuoglio, Daniela; Gabellini, Chiara; Desideri, Marianna; Ziparo, Elio; Zupi, Gabriella; Del Bufalo, Donatella

    2010-01-01

    Background Hypoxia-Inducible Factor 1 (HIF-1) is a transcription factor that is a critical mediator of the cellular response to hypoxia. Enhanced levels of HIF-1α, the oxygen-regulated subunit of HIF-1, is often associated with increased tumour angiogenesis, metastasis, therapeutic resistance and poor prognosis. It is in this context that we previously demonstrated that under hypoxia, bcl-2 protein promotes HIF-1/Vascular Endothelial Growth Factor (VEGF)-mediated tumour angiogenesis. Methodology/Principal Findings By using human melanoma cell lines and their stable or transient derivative bcl-2 overexpressing cells, the current study identified HIF-1α protein stabilization as a key regulator for the induction of HIF-1 by bcl-2 under hypoxia. We also demonstrated that bcl-2-induced accumulation of HIF-1α protein during hypoxia was not due to an increased gene transcription or protein synthesis. In fact, it was related to a modulation of HIF-1α protein expression at a post-translational level, indeed its degradation rate was faster in the control lines than in bcl-2 transfectants. The bcl-2-induced HIF-1α stabilization in response to low oxygen tension conditions was achieved through the impairment of ubiquitin-dependent HIF-1α degradation involving the molecular chaperone HSP90, but it was not dependent on the prolyl hydroxylation of HIF-1α protein. We also showed that bcl-2, HIF-1α and HSP90 proteins form a tri-complex that may contribute to enhancing the stability of the HIF-1α protein in bcl-2 overexpressing clones under hypoxic conditions. Finally, by using genetic and pharmacological approaches we proved that HSP90 is involved in bcl-2-dependent stabilization of HIF-1α protein during hypoxia, and in particular the isoform HSP90β is the main player in this phenomenon. Conclusions/Significance We identified the stabilization of HIF-1α protein as a mechanism through which bcl-2 induces the activation of HIF-1 in hypoxic tumour cells involving the

  2. Mapping the Hsp90 Genetic Network Reveals Ergosterol Biosynthesis and Phosphatidylinositol-4-Kinase Signaling as Core Circuitry Governing Cellular Stress

    Science.gov (United States)

    O’Meara, Teresa R.; Valaei, Seyedeh Fereshteh; Diezmann, Stephanie; Cowen, Leah E.

    2016-01-01

    Candida albicans is a leading human fungal pathogen that causes life-threatening systemic infections. A key regulator of C. albicans stress response, drug resistance, morphogenesis, and virulence is the molecular chaperone Hsp90. Targeting Hsp90 provides a powerful strategy to treat fungal infections, however, the therapeutic utility of current inhibitors is compromised by toxicity due to inhibition of host Hsp90. To identify components of the Hsp90-dependent circuitry governing virulence and drug resistance that are sufficiently divergent for selective targeting in the pathogen, we pioneered chemical genomic profiling of the Hsp90 genetic network in C. albicans. Here, we screen mutant collections covering ~10% of the genome for hypersensitivity to Hsp90 inhibition in multiple environmental conditions. We identify 158 HSP90 chemical genetic interactors, most of which are important for growth only in specific environments. We discovered that the sterol C-22 desaturase gene ERG5 and the phosphatidylinositol-4-kinase (PI4K) gene STT4 are HSP90 genetic interactors under multiple conditions, suggesting a function upstream of Hsp90. By systematic analysis of the ergosterol biosynthetic cascade, we demonstrate that defects in ergosterol biosynthesis induce cellular stress that overwhelms Hsp90’s functional capacity. By analysis of the phosphatidylinositol pathway, we demonstrate that there is a genetic interaction between the PI4K Stt4 and Hsp90. We also establish that Stt4 is required for normal actin polarization through regulation of Wal1, and suggest a model in which defects in actin remodeling induces stress that creates a cellular demand for Hsp90 that exceeds its functional capacity. Consistent with this model, actin inhibitors are synergistic with Hsp90 inhibitors. We highlight new connections between Hsp90 and virulence traits, demonstrating that Erg5 and Stt4 enable activation of macrophage pyroptosis. This work uncovers novel circuitry regulating Hsp90

  3. The Broad Stroke of Hsp90 Inhibitors: Painting over the RAF Inhibitor Paradox.

    Science.gov (United States)

    Vido, Michael J; Aplin, Andrew E

    2015-10-01

    The novel Hsp90 inhibitor XL888 is undergoing clinical investigation for use in conjunction with the rapidly accelerated fibrosarcoma (RAF) kinase inhibitor vemurafenib to treat unresectable melanoma. The addition of XL888 to current regimens may serve an additional purpose by blocking the RAF inhibitor paradox. Such activity could reduce adverse events in patients and provide a biomarker for the successful inhibition of Hsp90 target proteins. PMID:26358385

  4. Heat Shock Protein 90 (HSP90 and Her2 in Adenocarcinomas of the Esophagus

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    Julia Slotta-Huspenina

    2014-06-01

    Full Text Available Her2 overexpression and amplification can be found in a significant subset of esophageal adenocarcinomas. The activity of Her2 has been shown to be modulated by molecular chaperones such as HSP90. We analyzed expression/amplification data for HSP90 and Her2 on 127 primary resected esophageal adenocarcinomas in order to evaluate a possible relationship between these two molecules. HSP90 expression determined by immunohistochemistry was observed in various levels. Thirty nine (39 tumors (30.7% were classified as Her2-positive according to their immunoreactivity and amplification status. There was a significant correlation between HSP90 expression and Her2-status (p = 0.008. This could also be demonstrated by quantitative protein expression analysis with reverse phase protein arrays (r = 0.9; p < 0.001. Her2-status was associated withpT-category (p = 0.041, lymph node metastases (p = 0.049 and tumor differentiation (p = 0.036 with a higher percentage of cases with negative Her2 status in lower tumor stagesA negative Her2-status was also associated with better survival in univariate and multivariate analysis (p = 0.001 and p = 0.014. For HSP90, no associations between clinical and pathological parameters were found. The observed association between HSP90 expression and Her2 suggests a co-regulation of these molecules in at least a subset of esophageal adenocarcinomas. Anti-HSP90 drugs, which recently have been introduced in cancer treatment, may also be an option for these tumors by targeting HSP90 alone or in combination with Her2.

  5. Tah1 helix-swap dimerization prevents mixed Hsp90 co-chaperone complexes

    Energy Technology Data Exchange (ETDEWEB)

    Morgan, Rhodri M. L.; Pal, Mohinder; Roe, S. Mark; Pearl, Laurence H., E-mail: laurence.pearl@sussex.ac.uk; Prodromou, Chrisostomos, E-mail: laurence.pearl@sussex.ac.uk [University of Sussex, Falmer, Brighton BN1 9RQ (United Kingdom)

    2015-05-01

    A helix swap involving the fifth helix between two adjacently bound Tah1 molecules restores the normal binding environment of the conserved MEEVD peptide of Hsp90. Dimerization also explains how other monomeric TPR-domain proteins are excluded from forming inappropriate mixed co-chaperone complexes with Hsp90 and Tah1. Specific co-chaperone adaptors facilitate the recruitment of client proteins to the Hsp90 system. Tah1 binds the C-terminal conserved MEEVD motif of Hsp90, thus linking an eclectic set of client proteins to the R2TP complex for their assembly and regulation by Hsp90. Rather than the normal complement of seven α-helices seen in other tetratricopeptide repeat (TPR) domains, Tah1 unusually consists of the first five only. Consequently, the methionine of the MEEVD peptide remains exposed to solvent when bound by Tah1. In solution Tah1 appears to be predominantly monomeric, and recent structures have failed to explain how Tah1 appears to prevent the formation of mixed TPR domain-containing complexes such as Cpr6–(Hsp90){sub 2}–Tah1. To understand this further, the crystal structure of Tah1 in complex with the MEEVD peptide of Hsp90 was determined, which shows a helix swap involving the fifth α-helix between two adjacently bound Tah1 molecules. Dimerization of Tah1 restores the normal binding environment of the bound Hsp90 methionine residue by reconstituting a TPR binding site similar to that in seven-helix-containing TPR domain proteins. Dimerization also explains how other monomeric TPR-domain proteins are excluded from forming inappropriate mixed co-chaperone complexes.

  6. The Hsp90 Chaperone Complex Regulates GDI-dependent Rab Recycling

    OpenAIRE

    Chen, Christine Y.; Balch, William E.

    2006-01-01

    Rab GTPase regulated hubs provide a framework for an integrated coding system, the membrome network, that controls the dynamics of the specialized exocytic and endocytic membrane architectures found in eukaryotic cells. Herein, we report that Rab recycling in the early exocytic pathways involves the heat-shock protein (Hsp)90 chaperone system. We find that Hsp90 forms a complex with guanine nucleotide dissociation inhibitor (GDI) to direct recycling of the client substrate Rab1 required for e...

  7. Stability of the Hsp90 inhibitor 17AAG hydroquinone and prevention of metal-catalyzed oxidation

    OpenAIRE

    Guo, Wenchang; Siegel, David; Ross, David

    2008-01-01

    17-(allylamino)-17-demethoxygeldanamycin (17AAG) is a benzoquinone ansamycin Hsp90 inhibitor which has promising anticancer activity in vitro, in animal models and in clinical trials. 17AAG has poor water-solubility which is a potential problem for clinical formulation. The hydroquinone derivative of 17AAG, 17AAGH2, is considerably more water soluble and since we previously demonstrated that 17AAGH2 was a more potent Hsp90 inhibitor than its parent quinone, it is a good candidate for clinical...

  8. Expression of HSP90 and HIF-1α in human colorectal cancer tissue and its significance

    Institute of Scientific and Technical Information of China (English)

    Qiu-Ran; Xu; Xin; Liu; Ying-Min; Yao; Qing-Guang; Liu

    2014-01-01

    Objective:To investigate the expression of HSP90 and HIF-1αin human colorectal cancer tissue,the influence of HSP90 and HIF-1αon human colorectal cancer biological behavior and their related factors.Methods:The expression of HSP90 and HIF-1 a protein in human colorectal cancer as well as normal tissue were detected by imnmnohistochemical method.Results:The positive expression rates of HSP90 and HIF-1αprotein in normal human colorectal tissue as well as colorectal cancer tissue were 30%vs.63.0%,15.0%vs.71.7%,respectively.There were significant difference(P=0.035 and P=0.005 respectively).The expression of HSP90 was significantly correlated with the differentiation,Dukes stages and lymph node metastasis(P<0.05),while the expression of HIF-1 a was significantly correlated with the Dukes stages and lymph node metastasis(P<0.05).Association analysis showed that the expression of HSF90 protein was significantly correlated with that of HIF-1αprotein(P<0.01).Conclusions:The expression of HSP90 and HIF—1αprotein may be related to the development,metastasis and invasion of human colorectal cancer,and their synergistic effects may participate in the development of the colorectal carcinoma.

  9. Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles.

    Science.gov (United States)

    Wang, Tai; Mäser, Pascal; Picard, Didier

    2016-07-14

    Malaria caused by the protozoan parasite Plasmodium falciparum (Pf) remains a major public health problem throughout the developing world. One molecular target that should receive more attention is the molecular chaperone Hsp90. It is essential and highly conserved in all eukaryotes, including in protozoan parasites. We have identified an amino-alcohol carbazole (N-CBZ) as a PfHsp90-selective inhibitor by virtually docking a large set of antimalarial compounds, previously found in a phenotypic screen, into a PfHsp90-specific pocket. By correlating the ability of 30 additional N-CBZ derivatives to bind directly to PfHsp90 with their Pf-inhibitory activity, we found that these types of compounds are more likely to inhibit Pf growth if they bind PfHsp90. For plausible targets such as PfHsp90, our workflow may help identifying the molecular target for compounds found by screening large chemical libraries for a desired biological effect and, conversely, ensuring biological effectiveness for compounds affecting a particular target. PMID:27312008

  10. Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas.

    Science.gov (United States)

    Schwartz, Harvey; Scroggins, Brad; Zuehlke, Abbey; Kijima, Toshiki; Beebe, Kristin; Mishra, Alok; Neckers, Len; Prince, Thomas

    2015-09-01

    The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas. PMID:26070366

  11. Effect of electromagnetic fields at 2.45 GHz on the levels of cellular stress proteins HSP-90 and 70 in the rat thyroid

    International Nuclear Information System (INIS)

    In this study we analyzed the cellular stress levels achieved by heat shock proteins (HSP) 90 and 70 in rat thyroid tissue after exposure to radio waves in TWG experimental system. Parallel measurements of body stress in animals by rectal temperature probes allow us to determine whether there is any interaction between temperature increases and cellular stress.

  12. The combination of Hsp90 inhibitor 17AAG and heavy-ion irradiation provides effective tumor control in human lung cancer cells

    International Nuclear Information System (INIS)

    Hsp90 inhibitors have become well-studied antitumor agents for their selective property against tumors versus normal cells. The combined treatment of Hsp90 inhibitor and conventional photon radiation also showed more effective tumor growth delay than radiation alone. However, little is known regarding the combined treatment of Hsp90 inhibitor and heavy-ion irradiation. In this study, SQ5 human lung tumor cells were used in vitro for clonogenic cell survival and in vivo for tumor growth delay measurement using a mouse xenograft model after 17-allylamino-17-demethoxygeldanamycin (17AAG) pretreatment and carbon ion irradiation. Repair of DNA double strand breaks (DSBs) was also assessed along with expressions of DSB repair-related proteins. Cell cycle analysis after the combined treatment was also performed. The combined treatment of 17AAG and carbon ions revealed a promising treatment option in both in vitro and in vivo studies. One likely cause of this effectiveness was shown to be the inhibition of homologous recombination repair by 17AAG. The more intensified G2 cell cycle delay was also associated with the combined treatment when compared with carbon ion treatment alone. Our findings indicate that the combination of Hsp90 inhibition and heavy-ion irradiation provides a new effective therapeutic alternative for treatment of solid tumors

  13. A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies

    International Nuclear Information System (INIS)

    This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies. Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity. Fifty-three patients were treated at doses escalating from 7 to 259 mg/m2. The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m2), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m2). The MTD was 216 mg/m2 and the recommended phase 2 dose was established at 200 mg/m2 given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%. Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m2, and is associated with an acceptable tolerability profile. http://www.clinicaltrials.gov/NCT00687934

  14. 17-Allylamino-17-demethoxygeldanamycin induces downregulation of critical Hsp90 protein clients and results in cell cycle arrest and apoptosis of human urinary bladder cancer cells

    International Nuclear Information System (INIS)

    17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinone ansamycin antibiotic, specifically targets heat shock protein 90 (Hsp90) and interferes with its function as a molecular chaperone that maintains the structural and functional integrity of various protein clients involved in cellular signaling. In this study, we have investigated the effect of 17-AAG on the regulation of Hsp90-dependent signaling pathways directly implicated in cell cycle progression, survival and motility of human urinary bladder cancer cell lines. We have used MTT-based assays, FACS analysis, Western blotting, semi-quantitative RT-PCR, immunocytochemistry and scratch-wound assay in RT4, RT112 and T24 human urinary bladder cancer cell lines. We have demonstrated that, upon 17-AAG treatment, bladder cancer cells are arrested in the G1 phase of the cell cycle and eventually undergo apoptotic cell death in a dose-dependent manner. Furthermore, 17-AAG administration was shown to induce a pronounced downregulation of multiple Hsp90 protein clients and other downstream effectors, such as IGF-IR, Akt, IKK-α, IKK-β, FOXO1, ERK1/2 and c-Met, resulting in sequestration-mediated inactivation of NF-κB, reduced cell proliferation and decline of cell motility. In total, we have clearly evinced a dose-dependent and cell type-specific effect of 17-AAG on cell cycle progression, survival and motility of human bladder cancer cells, due to downregulation of multiple Hsp90 clients and subsequent disruption of signaling integrity

  15. An Impermeant Ganetespib Analog Inhibits Extracellular Hsp90-Mediated Cancer Cell Migration that Involves Lysyl Oxidase 2-like Protein

    Energy Technology Data Exchange (ETDEWEB)

    McCready, Jessica [Department of Natural Sciences, Assumption College, Worcester, MA 01609 (United States); Wong, Daniel S. [Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111 (United States); Cell and Molecular Physiology Program, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111 (United States); Burlison, Joseph A.; Ying, Weiwen [Synta Pharmaceuticals, Lexington, MA 02421 (United States); Jay, Daniel G., E-mail: daniel.jay@tufts.edu [Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111 (United States); Cell and Molecular Physiology Program, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111 (United States)

    2014-04-30

    Extracellular Hsp90 (eHsp90) activates a number of client proteins outside of cancer cells required for migration and invasion. Therefore, eHsp90 may serve as a novel target for anti-metastatic drugs as its inhibition using impermeant Hsp90 inhibitors would not affect the numerous vital intracellular Hsp90 functions in normal cells. While some eHsp90 clients are known, it is important to establish other proteins that act outside the cell to validate eHsp90 as a drug target to limit cancer spread. Using mass spectrometry we identified two precursor proteins Galectin 3 binding protein (G3BP) and Lysyl oxidase 2-like protein (LOXL2) that associate with eHsp90 in MDA-MB231 breast cancer cell conditioned media and confirmed that LOXL2 binds to eHsp90 in immunoprecipitates. We introduce a novel impermeant Hsp90 inhibitor STA-12-7191 derived from ganetespib and show that it is markedly less toxic to cells and can inhibit cancer cell migration in a dose dependent manner. We used STA-12-7191 to test if LOXL2 and G3BP are potential eHsp90 clients. We showed that while LOXL2 can increase wound healing and compensate for STA-12-7191-mediated inhibition of wound closure, addition of G3BP had no affect on this assay. These findings support of role for LOXL2 in eHsp90 stimulated cancer cell migration and provide preliminary evidence for the use of STA-12-7191 to inhibit eHsp90 to limit cancer invasion.

  16. An Impermeant Ganetespib Analog Inhibits Extracellular Hsp90-Mediated Cancer Cell Migration that Involves Lysyl Oxidase 2-like Protein

    International Nuclear Information System (INIS)

    Extracellular Hsp90 (eHsp90) activates a number of client proteins outside of cancer cells required for migration and invasion. Therefore, eHsp90 may serve as a novel target for anti-metastatic drugs as its inhibition using impermeant Hsp90 inhibitors would not affect the numerous vital intracellular Hsp90 functions in normal cells. While some eHsp90 clients are known, it is important to establish other proteins that act outside the cell to validate eHsp90 as a drug target to limit cancer spread. Using mass spectrometry we identified two precursor proteins Galectin 3 binding protein (G3BP) and Lysyl oxidase 2-like protein (LOXL2) that associate with eHsp90 in MDA-MB231 breast cancer cell conditioned media and confirmed that LOXL2 binds to eHsp90 in immunoprecipitates. We introduce a novel impermeant Hsp90 inhibitor STA-12-7191 derived from ganetespib and show that it is markedly less toxic to cells and can inhibit cancer cell migration in a dose dependent manner. We used STA-12-7191 to test if LOXL2 and G3BP are potential eHsp90 clients. We showed that while LOXL2 can increase wound healing and compensate for STA-12-7191-mediated inhibition of wound closure, addition of G3BP had no affect on this assay. These findings support of role for LOXL2 in eHsp90 stimulated cancer cell migration and provide preliminary evidence for the use of STA-12-7191 to inhibit eHsp90 to limit cancer invasion

  17. A rat retinal damage model predicts for potential clinical visual disturbances induced by Hsp90 inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Dan, E-mail: DZhou@syntapharma.com [Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421 (United States); Liu, Yuan; Ye, Josephine; Ying, Weiwen; Ogawa, Luisa Shin; Inoue, Takayo; Tatsuta, Noriaki; Wada, Yumiko; Koya, Keizo [Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421 (United States); Huang, Qin [Department of Pathology and Laboratory Medicine, Veterans Affairs Boston Healthcare System, 1400 VFW Parkway, West Roxbury, MA 02132 (United States); Bates, Richard C.; Sonderfan, Andrew J. [Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421 (United States)

    2013-12-01

    In human trials certain heat shock protein 90 (Hsp90) inhibitors, including 17-DMAG and NVP-AUY922, have caused visual disorders indicative of retinal dysfunction; others such as 17-AAG and ganetespib have not. To understand these safety profile differences we evaluated histopathological changes and exposure profiles of four Hsp90 inhibitors, with or without clinical reports of adverse ocular effects, using a rat retinal model. Retinal morphology, Hsp70 expression (a surrogate marker of Hsp90 inhibition), apoptotic induction and pharmacokinetic drug exposure analysis were examined in rats treated with the ansamycins 17-DMAG and 17-AAG, or with the second-generation compounds NVP-AUY922 and ganetespib. Both 17-DMAG and NVP-AUY922 induced strong yet restricted retinal Hsp70 up-regulation and promoted marked photoreceptor cell death 24 h after the final dose. In contrast, neither 17-AAG nor ganetespib elicited photoreceptor injury. When the relationship between drug distribution and photoreceptor degeneration was examined, 17-DMAG and NVP-AUY922 showed substantial retinal accumulation, with high retina/plasma (R/P) ratios and slow elimination rates, such that 51% of 17-DMAG and 65% of NVP-AUY922 present at 30 min post-injection were retained in the retina 6 h post-dose. For 17-AAG and ganetespib, retinal elimination was rapid (90% and 70% of drugs eliminated from the retina at 6 h, respectively) which correlated with lower R/P ratios. These findings indicate that prolonged inhibition of Hsp90 activity in the eye results in photoreceptor cell death. Moreover, the results suggest that the retina/plasma exposure ratio and retinal elimination rate profiles of Hsp90 inhibitors, irrespective of their chemical class, may predict for ocular toxicity potential. - Highlights: • In human trials some Hsp90 inhibitors cause visual disorders, others do not. • Prolonged inhibition of Hsp90 in the rat eye results in photoreceptor cell death. • Retina/plasma ratio and retinal

  18. A rat retinal damage model predicts for potential clinical visual disturbances induced by Hsp90 inhibitors

    International Nuclear Information System (INIS)

    In human trials certain heat shock protein 90 (Hsp90) inhibitors, including 17-DMAG and NVP-AUY922, have caused visual disorders indicative of retinal dysfunction; others such as 17-AAG and ganetespib have not. To understand these safety profile differences we evaluated histopathological changes and exposure profiles of four Hsp90 inhibitors, with or without clinical reports of adverse ocular effects, using a rat retinal model. Retinal morphology, Hsp70 expression (a surrogate marker of Hsp90 inhibition), apoptotic induction and pharmacokinetic drug exposure analysis were examined in rats treated with the ansamycins 17-DMAG and 17-AAG, or with the second-generation compounds NVP-AUY922 and ganetespib. Both 17-DMAG and NVP-AUY922 induced strong yet restricted retinal Hsp70 up-regulation and promoted marked photoreceptor cell death 24 h after the final dose. In contrast, neither 17-AAG nor ganetespib elicited photoreceptor injury. When the relationship between drug distribution and photoreceptor degeneration was examined, 17-DMAG and NVP-AUY922 showed substantial retinal accumulation, with high retina/plasma (R/P) ratios and slow elimination rates, such that 51% of 17-DMAG and 65% of NVP-AUY922 present at 30 min post-injection were retained in the retina 6 h post-dose. For 17-AAG and ganetespib, retinal elimination was rapid (90% and 70% of drugs eliminated from the retina at 6 h, respectively) which correlated with lower R/P ratios. These findings indicate that prolonged inhibition of Hsp90 activity in the eye results in photoreceptor cell death. Moreover, the results suggest that the retina/plasma exposure ratio and retinal elimination rate profiles of Hsp90 inhibitors, irrespective of their chemical class, may predict for ocular toxicity potential. - Highlights: • In human trials some Hsp90 inhibitors cause visual disorders, others do not. • Prolonged inhibition of Hsp90 in the rat eye results in photoreceptor cell death. • Retina/plasma ratio and retinal

  19. Hsp90 as a Gatekeeper of Tumor Angiogenesis: Clinical Promise and Potential Pitfalls

    Directory of Open Access Journals (Sweden)

    J. E. Bohonowych

    2010-01-01

    Full Text Available Tumor vascularization is an essential modulator of early tumor growth, progression, and therapeutic outcome. Although antiangiogenic treatments appear promising, intrinsic and acquired tumor resistance contributes to treatment failure. Clinical inhibition of the molecular chaperone heat shock protein 90 (Hsp90 provides an opportunity to target multiple aspects of this signaling resiliency, which may elicit more robust and enduring tumor repression relative to effects elicited by specifically targeted agents. This review highlights several primary effectors of angiogenesis modulated by Hsp90 and describes the clinical challenges posed by the redundant circuitry of these pathways. The four main topics addressed include (1 Hsp90-mediated regulation of HIF/VEGF signaling, (2 chaperone-dependent regulation of HIF-independent VEGF-mediated angiogenesis, (3 Hsp90-dependent targeting of key proangiogenic receptor tyrosine kinases and modulation of drug resistance, and (4 consideration of factors such as tumor microenvironment that pose several challenges for the clinical efficacy of anti-angiogenic therapy and Hsp90-targeted strategies.

  20. Localization of MRP-1 to the outer mitochondrial membrane by the chaperone protein HSP90β.

    Science.gov (United States)

    Roundhill, Elizabeth; Turnbull, Doug; Burchill, Susan

    2016-05-01

    Overexpression of plasma membrane multidrug resistance-associated protein 1 (MRP-1) in Ewing's sarcoma (ES) predicts poor outcome. MRP-1 is also expressed in mitochondria, and we have examined the submitochondrial localization of MRP-1 and investigated the mechanism of MRP-1 transport and role of this organelle in the response to doxorubicin. The mitochondrial localization of MRP-1 was examined in ES cell lines by differential centrifugation and membrane solubilization by digitonin. Whether MRP-1 is chaperoned by heat shock proteins (HSPs) was investigated by immunoprecipitation, immunofluorescence microscopy, and HSP knockout using small hairpin RNA and inhibitors (apoptozole, 17-AAG, and NVPAUY). The effect of disrupting mitochondrial MRP-1-dependent efflux activity on the cytotoxic effect of doxorubicin was investigated by counting viable cell number. Mitochondrial MRP-1 is glycosylated and localized to the outer mitochondrial membrane, where it is coexpressed with HSP90. MRP-1 binds to both HSP90 and HSP70, although only inhibition of HSP90β decreases expression of MRP-1 in the mitochondria. Disruption of mitochondrial MRP-1-dependent efflux significantly increases the cytotoxic effect of doxorubicin (combination index, MRP-1 is expressed in the outer mitochondrial membrane and is a client protein of HSP90β, where it may play a role in the doxorubicin-induced resistance of ES.-Roundhill, E., Turnbull, D., Burchill, S. Localization of MRP-1 to the outer mitochondrial membrane by the chaperone protein HSP90β. PMID:26722004

  1. Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants.

    Directory of Open Access Journals (Sweden)

    Thomas L Prince

    Full Text Available The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress-inducible HSP90α and constitutively expressed HSP90β, fold, assemble and maintain the three-dimensional structure of numerous client proteins. Because many HSP90 clients are important in cancer, several HSP90 inhibitors have been evaluated in the clinic. However, little is known concerning possible unique isoform or conformational preferences of either individual HSP90 clients or inhibitors. In this report, we compare the relative interaction strength of both HSP90α and HSP90β with the transcription factors HSF1 and HIF1α, the kinases ERBB2 and MET, the E3-ubiquitin ligases KEAP1 and RHOBTB2, and the HSP90 inhibitors geldanamycin and ganetespib. We observed unexpected differences in relative client and drug preferences for the two HSP90 isoforms, with HSP90α binding each client protein with greater apparent affinity compared to HSP90β, while HSP90β bound each inhibitor with greater relative interaction strength compared to HSP90α. Stable HSP90 interaction was associated with reduced client activity. Using a defined set of HSP90 conformational mutants, we found that some clients interact strongly with a single, ATP-stabilized HSP90 conformation, only transiently populated during the dynamic HSP90 chaperone cycle, while other clients interact equally with multiple HSP90 conformations. These data suggest different functional requirements among HSP90 clientele that, for some clients, are likely to be ATP-independent. Lastly, the two inhibitors examined, although sharing the same binding site, were differentially able to access distinct HSP90 conformational states.

  2. The HSP90 inhibitor NVP-AUY922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved DNA damage.

    Directory of Open Access Journals (Sweden)

    Shane Zaidi

    Full Text Available Heat shock protein 90 (HSP90 is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies.NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p = <0.0001. NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent.These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G(2/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line

  3. C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis

    Science.gov (United States)

    Harriss, June; Das, Chhaya; Zhu, Li; Edwards, Melissa; Shaaban, Salam; Tucker, Haley

    2015-01-01

    The SMYD3 histone methyl transferase (HMTase) and the nuclear chaperone, HSP90, have been independently implicated as proto-oncogenes in several human malignancies. We show that a degenerate tetratricopeptide repeat (TPR)-like domain encoded in the SMYD3 C-terminal domain (CTD) mediates physical interaction with HSP90. We further demonstrate that the CTD of SMYD3 is essential for its basal HMTase activity and that the TPR-like structure is required for HSP90-enhanced enzyme activity. Loss of SMYD3-HSP90 interaction leads to SMYD3 mislocalization within the nucleus, thereby losing its chromatin association. This results in reduction of SMYD3-mediated cell proliferation and, potentially, impairment of SMYD3′s oncogenic activity. These results suggest a novel approach for blocking HSP90-driven malignancy in SMYD3-overexpressing cells with a reduced toxicity profile over current HSP90 inhibitors. PMID:25738358

  4. A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species

    Directory of Open Access Journals (Sweden)

    Hongliang Zong

    2015-12-01

    Full Text Available Acute myeloid leukemia (AML is a heterogeneous and fatal disease with an urgent need for improved therapeutic regimens given that most patients die from relapsed disease. Irrespective of mutation status, the development of aggressive leukemias is enabled by increasing dependence on signaling networks. We demonstrate that a hyperactive signalosome drives addiction of AML cells to a tumor-specific Hsp90 species (teHsp90. Through genetic, environmental, and pharmacologic perturbations, we demonstrate a direct and quantitative link between hyperactivated signaling pathways and apoptotic sensitivity of AML to teHsp90 inhibition. Specifically, we find that hyperactive JAK-STAT and PI3K-AKT signaling networks are maintained by teHsp90 and, in fact, gradual activation of these networks drives tumors increasingly dependent on teHsp90. Thus, although clinically aggressive AML survives via signalosome activation, this addiction creates a vulnerability that can be exploited with Hsp90-directed therapy.

  5. SBA1 Encodes a Yeast Hsp90 Cochaperone That Is Homologous to Vertebrate p23 Proteins

    OpenAIRE

    Fang, Yifang; Fliss, Albert E.; Rao, Jie; Caplan, Avrom J.

    1998-01-01

    The Saccharomyces cerevisiae SBA1 gene was cloned by PCR amplification from yeast genomic DNA following its identification as encoding an ortholog of human p23, an Hsp90 cochaperone. The SBA1 gene product is constitutively expressed and nonessential, although a disruption mutant grew more slowly than the wild type at both 18 and 37°C. A double deletion of SBA1 and STI1, encoding an Hsp90 cochaperone, displayed synthetic growth defects. Affinity isolation of histidine-tagged Sba1p (Sba1His6) a...

  6. Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells

    OpenAIRE

    Qin, Dong-Jun; Tang, Cai-Xia; Yang, Li; Lei, Hu; Wei, Wei; Wang, Ying-Ying; Ma, Chun-Min; Gao, Feng-Hou; Xu, Han-Zhang; Wu, Ying-Li

    2015-01-01

    Synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-Me) has been shown as a promising agent against ovarian cancer. However, the underlying mechanism is not well understood. Here, we demonstrate that CDDO-Me directly interacts with Hsp90 in cells by cellular thermal shift assay. CDDO-Me treatment leads to upregulation of Hsp70 and degradation of Hsp90 clients (ErbB2 and Akt), indicating the inhibition of Hsp90 by CDDO-Me in cells. Knockdown of Hsp90 significant...

  7. Effect of electromagnetic fields at 2.45 GHz on the levels of cellular stress proteins HSP-90 and 70 in the rat thyroid; Efecto de los campos electromagneticos a 2,45 GHz sobre los niveles de proteinas de estres celular HSP-90 y 70 en el toroides de rata

    Energy Technology Data Exchange (ETDEWEB)

    Misa Agustino, M. J.; Alvarez-Folgueras, M.; Jorge-Mora, M. T.; Jorge Barreiro, F. J.; Ares Pena, F. J.; Lleiro, J.; Lopez Martin, M. E.

    2011-07-01

    In this study we analyzed the cellular stress levels achieved by heat shock proteins (HSP) 90 and 70 in rat thyroid tissue after exposure to radio waves in TWG experimental system. Parallel measurements of body stress in animals by rectal temperature probes allow us to determine whether there is any interaction between temperature increases and cellular stress.

  8. Hsp90 in the continuum of breast ductal carcinogenesis: Evaluation in precursors, preinvasive and ductal carcinoma lesions

    International Nuclear Information System (INIS)

    Hsp90 (heat shock protein90) is a chaperone protein essential for preserving and regulating the function of various cellular proteins. Elevated Hsp90 expression seems to be a trait of breast cancer and may be an integral part of the coping mechanisms that cancer cells exhibit vis-à-vis stress. This manuscript tries to examine the immunohistochemical expression of Hsp90 all along the continuum of breast ductal lesions encompassing ductal hyperplasia without atypia (DHWithoutA), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). Tissue specimens were taken from 30 patients with DHWithoutA, 31 patients with ADH, 51 with DCIS and 51 with IDC. Immunohistochemical assessment of Hsp90 was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. Concerning Hsp90 assessment the percentage of positive cells and the intensity were separately analyzed. Subsequently, the Allred score was calculated. Post hoc analysis on the correlations between Hsp90 Allred score and possible predictors (grade, nodal status, tumor size, ER Allred score, PR Allred score, c-erbB-2 status and triple negative status) was conducted in IDC. Hsp90 exhibited mainly cytoplasmic immunoreactivity. Hsp90 Allred score exhibited an increasing trend along the continuum of breast ductal lesions (Spearman's rho = 0.169, p = 0.031). Compared to the adjacent normal ducts and lobules, no statistically significant differences were noted in DHwithoutA, ADH and DCIS. Hsp90 expression (intensity, positive cells, Allred score) was higher in IDC, compared to the adjacent normal tissue. Higher Hsp90 expression was observed in grade 2/3 IDCs (borderline association) and tumors of larger size. At the univariable analysis, higher Hsp90 expression was associated with higher ER Allred score, PR Allred score and c-erbB-2 positivity in IDC. Triple-negative IDCs exhibited significantly lower Hsp90 expression. The

  9. Hsp90 in the continuum of breast ductal carcinogenesis: Evaluation in precursors, preinvasive and ductal carcinoma lesions

    Directory of Open Access Journals (Sweden)

    Patsouris Effstratios

    2010-07-01

    Full Text Available Abstract Background Hsp90 (heat shock protein90 is a chaperone protein essential for preserving and regulating the function of various cellular proteins. Elevated Hsp90 expression seems to be a trait of breast cancer and may be an integral part of the coping mechanisms that cancer cells exhibit vis-à-vis stress. This manuscript tries to examine the immunohistochemical expression of Hsp90 all along the continuum of breast ductal lesions encompassing ductal hyperplasia without atypia (DHWithoutA, atypical ductal hyperplasia (ADH, ductal carcinoma in situ (DCIS and invasive ductal carcinoma (IDC. Methods Tissue specimens were taken from 30 patients with DHWithoutA, 31 patients with ADH, 51 with DCIS and 51 with IDC. Immunohistochemical assessment of Hsp90 was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. Concerning Hsp90 assessment the percentage of positive cells and the intensity were separately analyzed. Subsequently, the Allred score was calculated. Post hoc analysis on the correlations between Hsp90 Allred score and possible predictors (grade, nodal status, tumor size, ER Allred score, PR Allred score, c-erbB-2 status and triple negative status was conducted in IDC. Results Hsp90 exhibited mainly cytoplasmic immunoreactivity. Hsp90 Allred score exhibited an increasing trend along the continuum of breast ductal lesions (Spearman's rho = 0.169, p = 0.031. Compared to the adjacent normal ducts and lobules, no statistically significant differences were noted in DHwithoutA, ADH and DCIS. Hsp90 expression (intensity, positive cells, Allred score was higher in IDC, compared to the adjacent normal tissue. Higher Hsp90 expression was observed in grade 2/3 IDCs (borderline association and tumors of larger size. At the univariable analysis, higher Hsp90 expression was associated with higher ER Allred score, PR Allred score and c-erbB-2 positivity in IDC. Triple-negative IDCs exhibited

  10. TsDAF-21/Hsp90 is expressed in all examined stages of Trichinella spiralis

    Science.gov (United States)

    Trichinella is an important parasitic nematode of animals worldwide. Heat shock proteins are ubiquitous in nature and allow organisms to quickly respond to environmental stress. A portion of the Tsdaf-21 gene, a Caenorhabditis elegans daf-21 homologue encoding heat-shock protein 90 (Hsp90) was clone...

  11. Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin

    International Nuclear Information System (INIS)

    In order to investigate the mechanism of radio-sensitization by an Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), we studied repair of DNA double strand breaks (DSBs) in irradiated human cells pre-treated with 17-AAG. DSBs are thought to be the critical target for radiation-induced cell death. Two human tumor cell lines DU145 and SQ-5 which showed clear radio-sensitization by 17-AAG revealed a significant inhibition of DSB repair, while normal human cells which did not show radio-sensitization by the drug indicated no change in the DSB repair kinetics with 17-AAG. We further demonstrated that BRCA2 was a novel client protein for Hsp90, and 17-AAG caused the degradation of BRCA2 and in turn altered the behavior of Rad51, a critical protein for homologous recombination (HR) pathway of DSB repair. Our data demonstrate for the first time that 17-AAG inhibits the HR repair process and could provide a new therapeutic strategy to selectively result in higher tumor cell killing

  12. Predicting Allosteric Effects from Orthosteric Binding in Hsp90-Ligand Interactions: Implications for Fragment-Based Drug Design

    Science.gov (United States)

    Larsson, Andreas; Nordlund, Paer; Jansson, Anna; Anand, Ganesh S.

    2016-01-01

    A key question in mapping dynamics of protein-ligand interactions is to distinguish changes at binding sites from those associated with long range conformational changes upon binding at distal sites. This assumes a greater challenge when considering the interactions of low affinity ligands (dissociation constants, KD, in the μM range or lower). Amide hydrogen deuterium Exchange mass spectrometry (HDXMS) is a robust method that can provide both structural insights and dynamics information on both high affinity and transient protein-ligand interactions. In this study, an application of HDXMS for probing the dynamics of low affinity ligands to proteins is described using the N-terminal ATPase domain of Hsp90. Comparison of Hsp90 dynamics between high affinity natural inhibitors (KD ~ nM) and fragment compounds reveal that HDXMS is highly sensitive in mapping the interactions of both high and low affinity ligands. HDXMS reports on changes that reflect both orthosteric effects and allosteric changes accompanying binding. Orthosteric sites can be identified by overlaying HDXMS onto structural information of protein-ligand complexes. Regions distal to orthosteric sites indicate long range conformational changes with implications for allostery. HDXMS, thus finds powerful utility as a high throughput method for compound library screening to identify binding sites and describe allostery with important implications for fragment-based ligand discovery (FBLD). PMID:27253209

  13. Predicting Allosteric Effects from Orthosteric Binding in Hsp90-Ligand Interactions: Implications for Fragment-Based Drug Design.

    Directory of Open Access Journals (Sweden)

    Arun Chandramohan

    2016-06-01

    Full Text Available A key question in mapping dynamics of protein-ligand interactions is to distinguish changes at binding sites from those associated with long range conformational changes upon binding at distal sites. This assumes a greater challenge when considering the interactions of low affinity ligands (dissociation constants, KD, in the μM range or lower. Amide hydrogen deuterium Exchange mass spectrometry (HDXMS is a robust method that can provide both structural insights and dynamics information on both high affinity and transient protein-ligand interactions. In this study, an application of HDXMS for probing the dynamics of low affinity ligands to proteins is described using the N-terminal ATPase domain of Hsp90. Comparison of Hsp90 dynamics between high affinity natural inhibitors (KD ~ nM and fragment compounds reveal that HDXMS is highly sensitive in mapping the interactions of both high and low affinity ligands. HDXMS reports on changes that reflect both orthosteric effects and allosteric changes accompanying binding. Orthosteric sites can be identified by overlaying HDXMS onto structural information of protein-ligand complexes. Regions distal to orthosteric sites indicate long range conformational changes with implications for allostery. HDXMS, thus finds powerful utility as a high throughput method for compound library screening to identify binding sites and describe allostery with important implications for fragment-based ligand discovery (FBLD.

  14. A protective role of HSP90 chaperone in gamma-irradiated Arabidopsis thaliana seeds

    Science.gov (United States)

    Kozeko, Liudmyla; Talalaiev, Oleksandr; Neimash, Volodymyr; Povarchuk, Vasyl

    2015-07-01

    The heat shock protein 90 (HSP90) is required for the maturation and conformational regulation of many regulatory proteins affecting morphogenetic pathways and stress tolerance. The purpose of this work is to disclose a role of HSP90 in radioresistance of seeds. Arabidopsis thaliana (Ler) seeds were exposed to γ-ray irradiation with doses of 0.1-1 kGy using 60Co source to obtain a viable but polymorphic material. A comet assay of the seeds showed a dose-dependent increase in DNA damage. Phenotypic consequences of irradiation included growth stimulation at doses of 0.1-0.25 kGy and negative growth effects at doses from 0.5 kGy and beyond, along with increasing heterogeneity of seedling growth rate and phenotype. The frequencies of abnormal phenotypes were highly correlated with the degree of DNA damage in seeds. Treatment of seeds with geldanamycin (GDA), an inhibitor of HSP90, stimulated the seedling growth at all radiation doses and, at the same time, enhanced the growth rate and morphological diversity. It was also found that HSP70 induction by γ-rays was increased following GDA treatment (shown at 1 kGy). We suppose that the GDA-induced HSP70 can be involved in elimination of detrimental radiation effects that ultimately results in growth stimulation. On the other hand, the increase in phenotypic variation, when HSP90 function was impaired, confirms the supposition that the chaperone may control the concealment of cryptic genetic alterations and the developmental stability. In general, these results demonstrate that HSP90 may interface the stress response and phenotypic expression of genetic alterations induced by irradiation.

  15. Construction of Hsp90β gene specific silencing plasmid and its transfection efficiency

    Institute of Scientific and Technical Information of China (English)

    JI Yewei; NIE Bin; LI Ping; XU Xiaoyu; ZHOU Yuanguo

    2007-01-01

    The purpose of this work was to construct the plasmid that could direct the synthesis of siRNA-like transcripts and thus mediate strong and specific repression of human heat shock protein 90β(Hsp90β)gene expression and to compare the transfection efficiency of the plasmids in varying conditions of transfection.Three 64 nt oligos corresponding to different regions of the target gene were chemically synthesized and annealed and were then ligated with pSUPER EGFP1 plasmid and double-digested with HindⅢ and BglⅡ.Recombinant plasmids were transformed into Escherichia coli,DH5a,and the colonies were picked and grown in the Amp-agarose.The presence of positive clones was checked by the means of endodigestion and sequencing.Three cell strains,HepG2,Human umbilicus vein endothelium cells(HUVEC) and HeK293,were cultured.Then the plasmids were transfected into the cells at difierent ratios of plasmid to Lipofectamine.The transfection efficiency was measured by detection of enhanced green fluorescence protein (EGFP).The presence of positive recombinant clones were verified by double-digestion and sequencing.The bases inserted into the plasmids were correct and the positive colonies were named pSuper-Hsp90β1,pSuper-Hsp90β2 and pSuper-Hsp90β3.After optimizing the ratio of plasmid to Lipofectamine,we achieved high transfection efficiency in HeK293 cells.Transfection efficiency was still low in the HepG2 cells.In conelusion,the si-RNA-synthesizing plasmids targeting Hsp90β were constructed and transfected into cells with different transfection efficiency.

  16. Hsp90 protein interacts with phosphorothioate oligonucleotides containing hydrophobic 2'-modifications and enhances antisense activity.

    Science.gov (United States)

    Liang, Xue-Hai; Shen, Wen; Sun, Hong; Kinberger, Garth A; Prakash, Thazha P; Nichols, Joshua G; Crooke, Stanley T

    2016-05-01

    RNase H1-dependent antisense oligonucleotides (ASOs) are chemically modified to enhance pharmacological properties. Major modifications include phosphorothioate (PS) backbone and different 2'-modifications in 2-5 nucleotides at each end (wing) of an ASO. Chemical modifications can affect protein binding and understanding ASO-protein interactions is important for better drug design. Recently we identified many intracellular ASO-binding proteins and found that protein binding could affect ASO potency. Here, we analyzed the structure-activity-relationships of ASO-protein interactions and found 2'-modifications significantly affected protein binding, including La, P54nrb and NPM. PS-ASOs containing more hydrophobic 2'-modifications exhibit higher affinity for proteins in general, although certain proteins, e.g. Ku70/Ku80 and TCP1, are less affected by 2'-modifications. We found that Hsp90 protein binds PS-ASOs containing locked-nucleic-acid (LNA) or constrained-ethyl-bicyclic-nucleic-acid ((S)-cEt) modifications much more avidly than 2'-O-methoxyethyl (MOE). ASOs bind the mid-domain of Hsp90 protein. Hsp90 interacts with more hydrophobic 2' modifications, e.g. (S)-cEt or LNA, in the 5'-wing of the ASO. Reduction of Hsp90 protein decreased activity of PS-ASOs with 5'-LNA or 5'-cEt wings, but not with 5'-MOE wing. Together, our results indicate Hsp90 protein enhances the activity of PS/LNA or PS/(S)-cEt ASOs, and imply that altering protein binding of ASOs using different chemical modifications can improve therapeutic performance of PS-ASOs. PMID:26945041

  17. Down-regulation of cellular FLICE-inhibitory protein (Long Form contributes to apoptosis induced by Hsp90 inhibition in human lung cancer cells

    Directory of Open Access Journals (Sweden)

    Wang Qilin

    2012-12-01

    Full Text Available Abstract Background Cellular FLICE-Inhibitory Protein (long form, c-FLIPL is a critical negative regulator of death receptor-mediated apoptosis. Overexpression of c-FLIPL has been reported in many cancer cell lines and is associated with chemoresistance. In contrast, down-regulation of c-FLIP may drive cancer cells into cellular apoptosis. This study aims to demonstrate that inhibition of the heat shock protein 90 (Hsp90 either by inhibitors geldanamycin/17-N-Allylamino-17-demethoxygeldanamycin (GA/17-AAG or siRNA technique in human lung cancer cells induces c-FLIPL degradation and cellular apoptosis through C-terminus of Hsp70-interacting protein (CHIP-mediated mechanisms. Methods Calu-1 and H157 cell lines (including H157-c-FLIPL overexpressing c-FLIPL and control cell H157-lacZ were treated with 17-AAG and the cell lysates were prepared to detect the given proteins by Western Blot and the cell survival was assayed by SRB assay. CHIP and Hsp90 α/β proteins were knocked down by siRNA technique. CHIP and c-FLIPL plasmids were transfected into cells and immunoprecipitation experiments were performed to testify the interactions between c-FLIPL, CHIP and Hsp90. Results c-FLIPL down-regulation induced by 17-AAG can be reversed with the proteasome inhibitor MG132, which suggested that c-FLIPL degradation is mediated by a ubiquitin-proteasome system. Inhibition of Hsp90α/β reduced c-FLIPL level, whereas knocking down CHIP expression with siRNA technique inhibited c-FLIPL degradation. Furthermore, c-FLIPL and CHIP were co-precipitated in the IP complexes. In addition, overexpression of c-FLIPL can rescue cancer cells from apoptosis. When 17-AAG was combined with an anti-cancer agent celecoxib(CCB, c-FLIPL level declined further and there was a higher degree of caspase activation. Conclusion We have elucidated c-FLIPL degradation contributes to apoptosis induced by Hsp90 inhibition, suggesting c-FLIP and Hsp90 may be the promising combined targets

  18. Heat shock protein 90 (Hsp90) chaperone complex. A molecular target for enhancement of thermosensitivity and radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Akimoto, Tetsuo; Nonaka, Tetsuo; Kitamoto, Yoshizumi; Sakurai, Hideyuki [Gunma Univ., Maebashi (Japan). School of Medicine; Mitsuhashi, Norio [Tokyo Women' s Medical Coll. (Japan)

    2002-09-01

    Heat shock protein 90 (Hsp90) is a highly conserved heat shock protein in animal and plants, and exists abundantly in the cytoplasm in unstressed condition, accounting for 1-2% in cytoplasmic proteins. Main difference of Hsp90 from other Hsps are its substrate that Hsp90 binds to. These substrates include various signal transduction proteins, kinase, steroid receptors and transcription factors, therefore, Hsp90 plays a key role in maintaining cellular signal transduction networks. Many chaperoned proteins (client proteins) of Hsp90 are associated with cellular proliferation or malignant transformation, thus Hsp90 chaperone complex has been focused as targets for cancer therapy. Among the client proteins, there are several molecules that have been defined as targets or factors for determination or enhancement of radiosensitivity or thermosensitivity. Thus, it is easily speculated that Hsp90 chaperone complex inhibitors that disrupt association of Hsp90 and client protein in combination with radiation or/and heat has potential effect on enhancement of radiosensitivity or thermosensitivity. In this paper, possible mechanisms in enhancing radiosensitivity or thermosensitivity according to the client proteins will be summarized. (author)

  19. 非小细胞肺癌血清标志蛋白HSP90α的鉴定及其临床意义%Serum HSP90α in the clinical stage of non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    黄凌云; 徐安健; 蒋单懿; 郝佳; 谷俊朝; 肖雪媛; 何大澄

    2010-01-01

    Objective To investigate whether HSP90α could be a sensitive and specific serum biomarker for the diagnosis and progression of lung cancer. Methods In the present study, different secretomic analy-ses on the two human lung adenocarcinoma cell lines CL1-0 and CL1-5 with low and high metastatic poten-tial, respectively, were performed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and ma-trix-assisted laser desorption/ionization time-of-flight mass spectrometry. The candidate biomarker was con-firmed by Western blotting, and was further analyzed in 224 serum samples including 141 lung cancer, 37 benign pulmonary diseases, as well as 46 healthy individuals using ELISA assay. Results HSP90α was sig-nificantly upregulated in the CM of CL1-5 cells. It was found that the levels of HSP90α were specifically ele-vated in the sera of non-small cell lung cancer compared with other groups. At the cut-off point 0.535 on the receiver operating oharacteristie curve, HSP90α could comparatively discriminate lung cancer from benign lung disease and healthy control groups with sensitivity of 0. 817, specificity 0. 919 and total accuracy 80. 14%. Conclusion HSP90α may be a potential useful serum biomarker for discriminating lung cancer from benign lung diseases and healthy individuals and staging of non-small cell lung cancer.%目的 证明HSP90α是否可以作为肺癌诊断的血清标志蛋白.方法 利用SDS-PAGE和基质辅助解吸附时间飞行质谱(MALDI-TOF-MS),对具有不同转移能力的肺腺癌细胞系CL1-0(低转移)和CL1-5(高转移)的培养基上清进行分析,并对已鉴定的候选标志蛋白通过免疫印迹方法进行确定.此外,利用酶联免疫吸附技术(ELISA)对141例肺癌、37例良性肺病患者、及46例健康人血清对候选蛋白进行了进一步的分析.结果 HSP90α在CL1-5的培养基中高表达,进一步发现HSP90α在非小细胞肺癌的血清中特异性升高.当ROC曲线(receiver operating

  20. Expression and significance of Hsp90α and p53 in gastric cancer%胃癌中Hsp90α和p53的表达及意义

    Institute of Scientific and Technical Information of China (English)

    余慧

    2010-01-01

    目的:研究Hsp90α及p53在人胃癌组织中的表达,分析胃癌中Hsp90α和p53表达的关系.方法:应用免疫组化S-P法检测胃癌、慢性萎缩性胃炎及慢性浅表性胃炎中Hsp90α及p53的表达.结果:Hsp90α在胃癌、慢性萎缩性胃炎及慢性浅表性胃炎中的阳性率分别为70.0%(21/30)、60.0%(12/20)、30.0%(6/20).p53在胃癌、慢性萎缩性胃炎及慢性浅表性胃炎中的阳性率分别为63.3%(19/30)、10.0%(2/20)、5.0%(1/20).胃癌中Hsp90α及p53的表达明显高于慢性浅表性胃炎(P<0.05);胃癌中Hsp90α及p53表达的关系:56.7%(17/30)的胃癌Hsp90α、p53均为阳性.23.3%(7/30)的胃癌Hsp90α、p53均为阴性,13.3%(4/30)的胃癌Hsp90α阳性但p53阴性,6.7%(2/30)的胃癌p53阳性但Hsp90α阴性,Hsp90α及p53表达呈正相关(P<0.05).结论:Hsp90α及p53的表达与胃癌的发生及发展有关;胃癌组织中Hsp90α及p53表达呈正相关.

  1. Polymorphisms of heat shock protein 90 (Hsp90) in the sea cucumber Apostichopus japonicus and their association with heat-resistance.

    Science.gov (United States)

    Xu, Dongxue; Sun, Lina; Liu, Shilin; Zhang, Libin; Yang, Hongsheng

    2014-12-01

    Heat shock protein 90 (Hsp90) functions as a molecular chaperone and plays an important role in the resistance of organisms to stress, particularly heat-stress. In our study, 12 exons and 11 introns of hsp90 were identified in the sea cucumber Apostichopus japonicus. Twenty-two single nucleotide polymorphisms (SNPs), including three non-synonymous mutations, were detected in the exons. Susceptible and resistant individuals were distinguished using a high-temperature (32 °C) challenge experiment. Three blocks with high linkage disequilibrium were detected among these SNPs. Five of the twenty-two SNPs were shown to be significantly associated with susceptibility/resistance to high temperature by correlation analysis (chi-square test, P japonicus and supports the use of SNP markers in the selective breeding of sea cucumbers. PMID:25270529

  2. Bioactive Metabolites from Chaetomium aureum: Structure Elucidation and Inhibition of the Hsp90 Machine Chaperoning Activity

    Science.gov (United States)

    Kabbaj, Fatima Zahra; Lu, Su; Faouzi, My El Abbés; Meddah, Bouchra; Proksch, Peter; Cherrah, Yahya; Altenbach, Hans-Josef; Aly, Amal H.; Chadli, Ahmed; Debbab, Abdessamad

    2014-01-01

    Chemical investigation of the EtOAc extract of the fungus Chaetomium aureum, an endophyte of the Moroccan medicinal plant Thymelaea lythroides, afforded one new resorcinol derivative named chaetorcinol, together with five known metabolites. The structures of the isolated compounds were determined on the basis of one- and two-dimensional NMR spectroscopy and high-resolution mass spectrometry as well as by comparison with the literature. All compounds were tested for their activity towards the Hsp90 chaperoning machine in vitro using the progesterone receptor (PR) and rabbit reticulocyte lysate (RRL). Among the isolated compounds, only sclerotiorin efficiently inhibited the Hsp90 machine chaperoning activity. However, sclerotiorin showed no cytotoxic effect on breast cancer Hs578T, MDA-MB-231 and prostate cancer LNCaP cell lines. Interestingly, deacetylation of sclerotiorin increased its cytotoxicity toward the tested cell lines over a period of 48h. PMID:25482429

  3. The association of Hsp90 expression induced by aspirin with anti-stress damage in chicken myocardial cells.

    Science.gov (United States)

    Zhang, Xiao-Hui; Zhu, Huai-Sen; Qian, Zhuang; Tang, Shu; Wu, Di; Kemper, Nicole; Hartung, Joerg; Bao, En-Dong

    2016-03-01

    The protective effect of aspirin during exposure to heat stress in broiler chickens was investigated. We assayed pathological damage, expression and distribution of Hsp90 protein and hsp90 mRNA expression in chicken heart tissues after oral administration of aspirin following exposure to high temperature for varying times. Heat stress induced increases in plasma aspartate aminotransferase, creatine kinase and lactate dehydrogenase activities while causing severe heart damage, which was characterized by granular and vacuolar degeneration, nuclear shrinkage and even myocardium fragmentation in cardiac muscle fibers. After aspirin administration, myocardial cells showed fewer pathological lesions than broilers treated with heat alone. A high positive Hsp90 signal was always detected in the nuclei of myocardial cells from broilers treated with aspirin, while in myocardial cells treated with heat alone, Hsp90 in the nuclei decreased, as did that in the cytoplasm. Aspirin induced rapid and significant synthesis of Hsp90 before and at the initial phase of heat stress, and significant expression of hsp90 mRNA was stimulated throughout the experiment when compared with cells exposed to heat stress alone. Thus, specific pre-induction of Hsp90 in cardiovascular tissue was useful for resisting heat stress damage because it produced stable damage-related enzymes and fewer pathologic changes. PMID:27051338

  4. Sequence features and phylogenetic analysis of the stress protein Hsp90α in chinook salmon (Oncorhynchus tshawytscha), a poikilothermic vertebrate

    Science.gov (United States)

    Palmisano, Aldo N.; Winton, James R.; Dickhoff, Walton W.

    1999-01-01

    We cloned and sequenced a chinook salmon Hsp90 cDNA; sequence analysis shows it to be Hsp90??. Phylogenetic analysis supports the hypothesis that ?? and ?? paralogs of Hsp90 arose as a result of a gene duplication event and that they diverged early in the evolution of vertebrates, before tetrapods separated from the teleost lineage. Among several differences distinguishing poikilothermic Hsp90?? sequences from their bird and mammal orthologs, the teleost versions specifically lack a characteristic QTQDQP phosphorylation site near the N-terminus. We used the cDNA to develop an RNA (Northern) blot to quantify cellular Hsp90 mRNA levels. Chinook salmon embryonic (CHSE-214) cells responded to heat shock with a rapid rise in Hsp90 mRNA through 4 h, followed by a gradual decline over the next 20 h. Hsp90 mRNA level may be useful as a stress indicator, especially in a laboratory setting or in response to acute heat stress.

  5. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans

    OpenAIRE

    Marubayashi, Sachie; Koppikar, Priya; Taldone, Tony; Abdel-Wahab, Omar; West, Nathan; Bhagwat, Neha; Caldas-Lopes, Eloisi; Ross, Kenneth N.; Gönen, Mithat; Gozman, Alex; Ahn, James H.; Rodina, Anna; Ouerfelli, Ouathek; Yang, Guangbin; Hedvat, Cyrus

    2010-01-01

    JAK2 kinase inhibitors were developed for the treatment of myeloproliferative neoplasms (MPNs), following the discovery of activating JAK2 mutations in the majority of patients with MPN. However, to date JAK2 inhibitor treatment has shown limited efficacy and apparent toxicities in clinical trials. We report here that an HSP90 inhibitor, PU-H71, demonstrated efficacy in cell line and mouse models of the ...

  6. Interaction of the Hsp90 cochaperone cyclophilin 40 with Hsc70

    OpenAIRE

    Carrello, Amerigo; Allan, Rudi K.; Morgan, Sarah L.; Owen, Barbara A. L.; Mok, Danny; Ward, Bryan K.; Minchin, Rodney F; Toft, David O.; Ratajczak, Thomas

    2004-01-01

    The high-affinity ligand-binding form of unactivated steroid receptors exists as a multicomponent complex that includes heat shock protein (Hsp)90; one of the immunophilins cyclophilin 40 (CyP40), FKBP51, or FKBP52; and an additional p23 protein component. Assembly of this heterocomplex is mediated by Hsp70 in association with accessory chaperones Hsp40, Hip, and Hop. A conserved structural element incorporating a tetratricopeptide repeat (TPR) domain mediates the interaction of the immunophi...

  7. The Assembly and Intermolecular Properties of the Hsp70-Tomm34-Hsp90 Molecular Chaperone Complex

    Czech Academy of Sciences Publication Activity Database

    Trčka, F.; Durech, M.; Hernychová, L.; Man, Petr; Müller, P.; Vojtěšek, B.

    2014-01-01

    Roč. 289, č. 14 (2014), s. 9887-9901. ISSN 0021-9258 R&D Projects: GA ČR(CZ) P301/11/1678; GA MZd(CZ) 00209805 Grant ostatní: Regional Center for Applied Molecular Oncology (CZ) CZ.1.05/2.1.00/03.0101 Institutional support: RVO:61388971 Keywords : HSP90 * chaperone * protein assembly Subject RIV: EE - Microbiology, Virology Impact factor: 4.573, year: 2014

  8. Combination of a Selective HSP90α/β Inhibitor and a RAS-RAF-MEK-ERK Signaling Pathway Inhibitor Triggers Synergistic Cytotoxicity in Multiple Myeloma Cells

    Science.gov (United States)

    Mimura, Naoya; Minami, Jiro; Ohguchi, Hiroto; Yoshida, Yasuhiro; Sagawa, Morihiko; Gorgun, Gullu; Cirstea, Diana; Cottini, Francesca; Jakubikova, Jana; Tai, Yu-Tzu; Chauhan, Dharminder; Richardson, Paul G.; Munshi, Nikhil; Ando, Kiyoshi; Utsugi, Teruhiro; Hideshima, Teru; Anderson, Kenneth C.

    2015-01-01

    Heat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90α/β inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM. PMID:26630652

  9. Identification of the critical therapeutic entity in secreted Hsp90α that promotes wound healing in newly re-standardized healthy and diabetic pig models.

    Directory of Open Access Journals (Sweden)

    Kathryn O'Brien

    Full Text Available Chronic and non-healing skin wounds represent a significant clinical, economic and social problem worldwide. Currently, there are few effective treatments. Lack of well-defined animal models to investigate wound healing mechanisms and furthermore to identify new and more effective therapeutic agents still remains a major challenge. Pig skin wound healing is close to humans. However, standardized pig wound healing models with demonstrated validity for testing new wound healing candidates are unavailable. Here we report a systematic evaluation and establishment of both acute and diabetic wound healing models in pigs, including wound-creating pattern for drug treatment versus control, measurements of diabetic parameters and the time for detecting delayed wound healing. We find that treatment and control wounds should be on the opposite and corresponding sides of a pig. We demonstrate a strong correlation between duration of diabetic conditions and the length of delay in wound closure. Using these new models, we narrow down the minimum therapeutic entity of secreted Hsp90α to a 27-amino acid peptide, called fragment-8 (F-8. In addition, results of histochemistry and immunohistochemistry analyses reveal more organized epidermis and dermis in Hsp90α-healed wounds than the control. Finally, Hsp90α uses a similar signaling mechanism to promote migration of isolated pig and human keratinocytes and dermal fibroblasts. This is the first report that shows standardized pig models for acute and diabetic wound healing studies and proves its usefulness with both an approved drug and a new therapeutic agent.

  10. In silico analysis of regulatory and structural motifs of the ovine HSP90AA1 gene.

    Science.gov (United States)

    González, Carmen; Salces-Ortiz, Judit; Calvo, Jorge H; Serrano, M Magdalena

    2016-05-01

    Gene promoters are essential regions of DNA where the transcriptional molecular machinery to produce RNA molecules is recruited. In this process, DNA epigenetic modifications can acquire a fundamental role in the regulation of gene expression. Recently, in a previous work of our group, functional features and DNA methylation involved in the ovine HSP90AA1 gene expression regulation have been observed. In this work, we report a combination of methylation analysis by bisulfite sequencing in several tissues and at different developmental stages together with in silico bioinformatic analysis of putative regulating factors in order to identify regulative mechanisms both at the promoter and gene body. Our results show a "hybrid structure" (TATA box + CpG island) of the ovine HSP90AA1 gene promoter both in somatic and non-differentiated germ tissues, revealing the ability of the HSP90AA1 gene to be regulated both in an inducible and constitutive fashion. In addition, in silico analysis showed that several putative alternative spliced regulatory motifs, exonic splicing enhancers (ESEs), and G-quadruplex secondary structures were somehow related to the DNA methylation pattern found. The results obtained here could help explain the differences in cell-type transcripts, tissue expression rate, and transcription silencing mechanisms found in this gene. PMID:26810179

  11. Chaperoning the Chaperone: A Role for the Co-chaperone Cpr7 in Modulating Hsp90 Function in Saccharomyces cerevisiae

    OpenAIRE

    Zuehlke, Abbey D.; Johnson, Jill L.

    2012-01-01

    Heat-shock protein 90 (Hsp90) of Saccharomyces cerevisiae is an abundant essential eukaryotic molecular chaperone involved in the activation and stabilization of client proteins, including several transcription factors and oncogenic kinases. Hsp90 undergoes a complex series of conformational changes and interacts with partner co-chaperones such as Sba1, Cpr6, Cpr7, and Cns1 as it binds and hydrolyzes ATP. In the absence of nucleotide, Hsp90 is dimerized only at the carboxy-terminus. In the pr...

  12. Novel 1,6-naphthyridin-2(1H)-ones as potential anticancer agents targeting Hsp90.

    OpenAIRE

    Montoir, David; Barillé-Nion, Sophie; Tonnerre, Alain; Juin, Philippe; Duflos, Muriel; Bazin, Marc-Antoine

    2016-01-01

    International audience Hsp90 is an ATP-dependent chaperone known to be overexpressed in many cancers. This way, Hsp90 is an important target for drug discovery. Novobiocin, an aminocoumarin antibiotic, was reported to inhibit Hsp90 targeting C-terminal domain, and showed anti-proliferative properties, leading to the development of new and more active compounds. Consequently, a new set of novobiocin analogs derived from 1,6-naphthyridin-2(1H)-one scaffold was designed, synthesized and evalu...

  13. Down-regulation of ERK1/2 and AKT-mediated X-ray repair cross-complement group 1 protein (XRCC1) expression by Hsp90 inhibition enhances the gefitinib-induced cytotoxicity in human lung cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Tung, Chun-Liang [Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan (China); Jian, Yi-Jun [Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan (China); Department of Biochemical Science and Technology, National Chiayi University, 300 Syuefu Road, Chiayi 600, Taiwan (China); Syu, Jhan-Jhang; Wang, Tai-Jing; Chang, Po-Yuan; Chen, Chien-Yu; Jian, Yun-Ting [Department of Biochemical Science and Technology, National Chiayi University, 300 Syuefu Road, Chiayi 600, Taiwan (China); Lin, Yun-Wei, E-mail: linyw@mail.ncyu.edu.tw [Department of Biochemical Science and Technology, National Chiayi University, 300 Syuefu Road, Chiayi 600, Taiwan (China)

    2015-05-15

    Gefitinib (Iressa{sup R}, ZD1839) is a selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that blocks growth factor-mediated cell proliferation and extracellular signal-regulated kinases 1/2 (ERK1/2) and AKT signaling activation. It has been shown that inhibition of Hsp90 function can enhance antitumor activity of EGFR-TKI. XRCC1 is an important scaffold protein in base excision repair, which could be regulated by ERK1/2 and AKT pathways. However, the role of ERK1/2 and AKT-mediated XRCC1 expression in gefitinib alone or combination with an Hsp90 inhibitor-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. In this study, gefitinib treatment decreased XRCC1 mRNA and protein expression through ERK1/2 and AKT inactivation in two NSCLC cells, A549 and H1975. Knocking down XRCC1 expression by transfection with small interfering RNA of XRCC1 enhanced the cytotoxicity and cell growth inhibition of gefitinib. Combining treatment of gefitinib with an Hsp90 inhibitor resulted in enhancing the reduction of XRCC1 protein and mRNA levels in gefitinib-exposed A549 and H1975 cells. Compared to a single agent alone, gefitinib combined with an Hsp90 inhibitor resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells. Furthermore, transfection with constitutive active MKK1 or AKT vectors rescued the XRCC1 protein level as well as the cell survival suppressed by an Hsp90 inhibitor and gefitinib. These findings suggested that down-regulation of XRCC1 can enhance the sensitivity of gefitinib for NSCLC cells. - Highlights: • Gefitinib treatment decreased XRCC1 mRNA and protein expression in NSCLC cells. • Knocking down XRCC1 expression enhanced the cytotoxic effect of gefitinib. • Gefitinib combined with an Hsp90 inhibitor resulted in synergistically cytotoxicity.

  14. Down-regulation of ERK1/2 and AKT-mediated X-ray repair cross-complement group 1 protein (XRCC1) expression by Hsp90 inhibition enhances the gefitinib-induced cytotoxicity in human lung cancer cells

    International Nuclear Information System (INIS)

    Gefitinib (IressaR, ZD1839) is a selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that blocks growth factor-mediated cell proliferation and extracellular signal-regulated kinases 1/2 (ERK1/2) and AKT signaling activation. It has been shown that inhibition of Hsp90 function can enhance antitumor activity of EGFR-TKI. XRCC1 is an important scaffold protein in base excision repair, which could be regulated by ERK1/2 and AKT pathways. However, the role of ERK1/2 and AKT-mediated XRCC1 expression in gefitinib alone or combination with an Hsp90 inhibitor-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. In this study, gefitinib treatment decreased XRCC1 mRNA and protein expression through ERK1/2 and AKT inactivation in two NSCLC cells, A549 and H1975. Knocking down XRCC1 expression by transfection with small interfering RNA of XRCC1 enhanced the cytotoxicity and cell growth inhibition of gefitinib. Combining treatment of gefitinib with an Hsp90 inhibitor resulted in enhancing the reduction of XRCC1 protein and mRNA levels in gefitinib-exposed A549 and H1975 cells. Compared to a single agent alone, gefitinib combined with an Hsp90 inhibitor resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells. Furthermore, transfection with constitutive active MKK1 or AKT vectors rescued the XRCC1 protein level as well as the cell survival suppressed by an Hsp90 inhibitor and gefitinib. These findings suggested that down-regulation of XRCC1 can enhance the sensitivity of gefitinib for NSCLC cells. - Highlights: • Gefitinib treatment decreased XRCC1 mRNA and protein expression in NSCLC cells. • Knocking down XRCC1 expression enhanced the cytotoxic effect of gefitinib. • Gefitinib combined with an Hsp90 inhibitor resulted in synergistically cytotoxicity

  15. Combined inhibition of Hsp90 and heme oxygenase-1 induces apoptosis and endoplasmic reticulum stress in melanoma.

    Science.gov (United States)

    Barbagallo, Ignazio; Parenti, Rosalba; Zappalà, Agata; Vanella, Luca; Tibullo, Daniele; Pepe, Francesco; Onni, Toniangelo; Li Volti, Giovanni

    2015-10-01

    Heat shock proteins are ubiquitous molecular chaperones involved in post-translational folding, stability, activation and maturation of many proteins that are essential mediators of signal transduction and cell cycle progression. Heat shock protein 90 (Hsp90) has recently emerged as an attractive therapeutic target in cancer treatment since it may act as a key regulator of various oncogene products and cell-signaling molecules. Heme oxygenase-1 (HO-1; also known as Hsp32) is an inducible enzyme participating in heme degradation and involved in oxidative stress resistance. Recent studies indicate that HO-1 activation may play a role in tumor development and progression. In the present study we investigated the chemotherapic effects of combining an Hsp90 inhibitor (NMS E973) and an HO-1 inhibitor (SnMP) on A375 melanoma cells. NMS E973 treatment was able to reduce cell viability and induce endoplasmic reticulum (ER) stress (i.e. Ire1α, ERO1, PDI, BIP and CHOP). Interestingly, no significant effect was observed in reactive oxygen species (ROS) formation. Finally, NMS E973 treatment resulted in a significant HO-1 overexpression, which in turn serves as a possible chemoresistance molecular mechanism. Interestingly, the combination of NMS E973 and SnMP produced an increase of ROS and reduced cell viability compared to NMS E973 treatment alone. The inhibitors combination exhibited higher ER stress, apoptosis as evidenced by bifunctional apoptosis regulator (BFAR) mRNA expression and lower phosphorylation of Akt when compared to NMS E973 alone. In conclusion, these data suggest that HO-1 inhibition potentiates NMS E973 toxicity and may be exploited as a strategy for melanoma treatment. PMID:26493719

  16. Sperm sorting procedure induces a redistribution of Hsp70 but not Hsp60 and Hsp90 in boar spermatozoa.

    Science.gov (United States)

    Spinaci, Marcella; Volpe, Sara; Bernardini, Chiara; de Ambrogi, Marco; Tamanini, Carlo; Seren, Eraldo; Galeati, Giovanna

    2006-01-01

    Heat shock proteins, besides their protective function against stresses, have been recently indicated as key factors for sperm fertilizing ability. Since sexing sperm by high-speed flow-cytometry subjects them to different physical, mechanical, and chemical stresses, the present study was designed to verify, by immunofluorescence and Western blot, whether the sorting procedure induces any modification in the amount and cellular distribution of heat shock proteins 60, 70, and 90 (Hsp60, Hsp70, Hsp90). Immunolocalization and Western blot quantification of both Hsp60 and Hsp90 did not reveal differences between unsorted and sorted semen. On the contrary, a redistribution of Hsp70 immunoreactivity from the equatorial subsegment toward the equator of sperm cells was recorded after sorting; this relocation suggests capacitation-like changes of sperm membrane. This modification seems to be caused mainly by incubation with Hoechst 33342, while both passage of sperm through flow cytometer and laser beam represent only minor stimuli. A further Hsp70 redistribution seems to be due to the final steps of sperm sorting, charging, and deflection of drops, and to the dilution during collection. On the other hand, staining procedure and mechanical stress seem to be the factors most injurious to sperm viability. Moreover, Hsp70 relocation was deeply influenced by the storage method. In fact, storing sexed spermatozoa, after centrifugation, in a small volume in presence of seminal plasma induced a reversion of Hsp70 redistribution, while storage in the diluted catch fluid of collection tubes caused Hsp70 relocation in most sorted spermatozoa. PMID:16870948

  17. Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model

    International Nuclear Information System (INIS)

    Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition. Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 x 50 mg/kg), and were imaged with PET using either 18F-FDG or 124I-labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining. AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC50 values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with 124I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with 124I-AbD19384 as well as 18F-FDG uptake, were not significantly altered by AT13387 treatment. We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of the drug, and could potentially

  18. Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model

    Energy Technology Data Exchange (ETDEWEB)

    Spiegelberg, Diana; Mortensen, Anja C.; Stenerloew, Bo [Uppsala University, Department of Immunology, Genetics and Pathology, Uppsala (Sweden); Selvaraju, Ram K.; Eriksson, Olof [Uppsala University, Preclinical PET Platform, Uppsala (Sweden); Nestor, Marika [Uppsala University, Department of Immunology, Genetics and Pathology, Uppsala (Sweden); Uppsala University, Unit of Otolaryngology and Head and Neck Surgery, Department of Surgical Sciences, Uppsala (Sweden)

    2016-05-15

    Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition. Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 x 50 mg/kg), and were imaged with PET using either {sup 18}F-FDG or {sup 124}I-labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining. AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC{sub 50} values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with {sup 124}I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with {sup 124}I-AbD19384 as well as {sup 18}F-FDG uptake, were not significantly altered by AT13387 treatment. We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of

  19. An interaction network predicted from public data as a discovery tool: application to the Hsp90 molecular chaperone machine.

    Directory of Open Access Journals (Sweden)

    Pablo C Echeverría

    Full Text Available Understanding the functions of proteins requires information about their protein-protein interactions (PPI. The collective effort of the scientific community generates far more data on any given protein than individual experimental approaches. The latter are often too limited to reveal an interactome comprehensively. We developed a workflow for parallel mining of all major PPI databases, containing data from several model organisms, and to integrate data from the literature for a protein of interest. We applied this novel approach to build the PPI network of the human Hsp90 molecular chaperone machine (Hsp90Int for which previous efforts have yielded limited and poorly overlapping sets of interactors. We demonstrate the power of the Hsp90Int database as a discovery tool by validating the prediction that the Hsp90 co-chaperone Aha1 is involved in nucleocytoplasmic transport. Thus, we both describe how to build a custom database and introduce a powerful new resource for the scientific community.

  20. Novel 1,6-naphthyridin-2(1H)-ones as potential anticancer agents targeting Hsp90.

    Science.gov (United States)

    Montoir, David; Barillé-Nion, Sophie; Tonnerre, Alain; Juin, Philippe; Duflos, Muriel; Bazin, Marc-Antoine

    2016-08-25

    Hsp90 is an ATP-dependent chaperone known to be overexpressed in many cancers. This way, Hsp90 is an important target for drug discovery. Novobiocin, an aminocoumarin antibiotic, was reported to inhibit Hsp90 targeting C-terminal domain, and showed anti-proliferative properties, leading to the development of new and more active compounds. Consequently, a new set of novobiocin analogs derived from 1,6-naphthyridin-2(1H)-one scaffold was designed, synthesized and evaluated against two breast cancer cell lines. Subsequently, cell cycle progression and apoptosis were conducted on best candidates, finally Western Blot analysis was performed to measure their ability to induce degradation of Hsp90 client proteins. PMID:27153346

  1. A Novel Therapeutic Strategy for the Treatment of Glioma, Combining Chemical and Molecular Targeting of Hsp90α

    Energy Technology Data Exchange (ETDEWEB)

    Mehta, Adi; Shervington, Leroy; Munje, Chinmay; Shervington, Amal, E-mail: aashervington@googlemail.com [Brain Tumour North West, Faculty of Science and Technology, University of Central Lancashire, Preston, PR1 2HE (United Kingdom)

    2011-12-08

    Hsp90α's vital role in tumour survival and progression, together with its highly inducible expression profile in gliomas and its absence in normal tissue and cell lines validates it as a therapeutic target for glioma. Hsp90α was downregulated using the post-transcriptional RNAi strategy (sihsp90α) and a post-translational inhibitor, the benzoquinone antibiotic 17-AAG. Glioblastoma U87-MG and normal human astrocyte SVGp12 were treated with sihsp90α, 17-AAG and concurrent sihsp90α/17-AAG (combined treatment). Both Hsp90α gene silencing and the protein inhibitor approaches resulted in a dramatic reduction in cell viability. Results showed that sihsp90α, 17-AAG and a combination of sihsp90α/17-AAG, reduced cell viability by 27%, 75% and 88% (p < 0.001), respectively, after 72 h. hsp90α mRNA copy numbers were downregulated by 65%, 90% and 99% after 72 h treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG, respectively. The relationship between Hsp90α protein expression and its client Akt kinase activity levels were monitored following treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG. Akt kinase activity was downregulated as a direct consequence of Hsp90α inhibition. Both Hsp90α and Akt kinase levels were significantly downregulated after 72 h. Although, 17-AAG when used as a single agent reduces the Hsp90α protein and the Akt kinase levels, the efficacy demonstrated by combinatorial treatment was found to be far more effective. Combination treatment reduced the Hsp90α protein and Akt kinase levels to 4.3% and 43%, respectively, after 72 h. hsp90α mRNA expression detected in SVGp12 was negligible compared to U87-MG, also, the combination treatment did not compromise the normal cell viability. Taking into account the role of Hsp90α in tumour progression and the involvement of Akt kinase in cell signalling and the anti-apoptotic pathways in tumours, this double targets treatment infers a novel therapeutic strategy.

  2. A Novel Therapeutic Strategy for the Treatment of Glioma, Combining Chemical and Molecular Targeting of Hsp90α

    International Nuclear Information System (INIS)

    Hsp90α's vital role in tumour survival and progression, together with its highly inducible expression profile in gliomas and its absence in normal tissue and cell lines validates it as a therapeutic target for glioma. Hsp90α was downregulated using the post-transcriptional RNAi strategy (sihsp90α) and a post-translational inhibitor, the benzoquinone antibiotic 17-AAG. Glioblastoma U87-MG and normal human astrocyte SVGp12 were treated with sihsp90α, 17-AAG and concurrent sihsp90α/17-AAG (combined treatment). Both Hsp90α gene silencing and the protein inhibitor approaches resulted in a dramatic reduction in cell viability. Results showed that sihsp90α, 17-AAG and a combination of sihsp90α/17-AAG, reduced cell viability by 27%, 75% and 88% (p < 0.001), respectively, after 72 h. hsp90α mRNA copy numbers were downregulated by 65%, 90% and 99% after 72 h treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG, respectively. The relationship between Hsp90α protein expression and its client Akt kinase activity levels were monitored following treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG. Akt kinase activity was downregulated as a direct consequence of Hsp90α inhibition. Both Hsp90α and Akt kinase levels were significantly downregulated after 72 h. Although, 17-AAG when used as a single agent reduces the Hsp90α protein and the Akt kinase levels, the efficacy demonstrated by combinatorial treatment was found to be far more effective. Combination treatment reduced the Hsp90α protein and Akt kinase levels to 4.3% and 43%, respectively, after 72 h. hsp90α mRNA expression detected in SVGp12 was negligible compared to U87-MG, also, the combination treatment did not compromise the normal cell viability. Taking into account the role of Hsp90α in tumour progression and the involvement of Akt kinase in cell signalling and the anti-apoptotic pathways in tumours, this double targets treatment infers a novel therapeutic strategy

  3. The association of Hsp90 expression induced by aspirin with anti-stress damage in chicken myocardial cells

    OpenAIRE

    Zhang, Xiao-Hui; Zhu, Huai-sen; Qian, Zhuang; Tang, Shu; Wu, Di; Kemper, Nicole; Hartung, Joerg; Bao, En-dong

    2016-01-01

    The protective effect of aspirin during exposure to heat stress in broiler chickens was investigated. We assayed pathological damage, expression and distribution of Hsp90 protein and hsp90 mRNA expression in chicken heart tissues after oral administration of aspirin following exposure to high temperature for varying times. Heat stress induced increases in plasma aspartate aminotransferase, creatine kinase and lactate dehydrogenase activities while causing severe heart damage, which was charac...

  4. Role of HSP-90 for increased nNOS-mediated vasodilation in mesenteric arteries in portal hypertension

    Institute of Scientific and Technical Information of China (English)

    Lukas; Moleda; Lars; Jurzik; Matthias; Froh; Erwin; Gbele; Claus; Hellerbrand; Rainer; H; Straub; Jürgen; Schlmerich; Reiner; Wiest

    2010-01-01

    AIM:To explore the role of heat shock protein-90 (HSP-90) for nitrergic vasorelaxation in the splanchnic circulation in rats with and without portal hypertension. METHODS: Neuronal nitric oxide synthase (nNOS) and HSP-90 were analyzed by immunofluorescence, western blotting and co-immunoprecipitation in the mesenteric vasculature and isolated nerves of portal-vein-ligated (PVL) rats and sham operated rats. In vitro perfused de-endothelialized mesenteric arterial vasculature was preconstricted with norepinep...

  5. Current Understanding of HSP90 as a Novel Therapeutic Target: An Emerging Approach for the Treatment of Cancer.

    Science.gov (United States)

    Haque, Absarul; Alam, Qamre; Alam, Mohammad Zubair; Azhar, Esam I; Sait, Khalid Hussain Wali; Anfinan, Nisrin; Mushtaq, Gohar; Kamal, Mohammad Amjad; Rasool, Mahmood

    2016-01-01

    Heat Shock Protein 90 (HSP90) is a ubiquitous molecular chaperone that is considered to be the most abundantly expressed protein in various human cancers such as breast, lung, colon, prostate, leukemia and skin. The master regulator, HSP90 plays a pivotal role in the conformational stabilization, maturation and activity of its various labile oncogenic client proteins such as p53, ErbB2, Bcr-Abl, Akt, Her-2, Cdk4, Cdk6, Raf-1 and v-Src in altered cells. Hence, making a guaranteed attempt to inhibit such a master regulator for cancer therapy appears to be a potential approach for combinatorial inhibition of numerous oncogenic signaling pathways simultaneously. Considerable efforts are being under way to develop novel molecular targets and its inhibitors that may block key signaling pathways involved in the process of tumorigenesis and metastasis. In this regards, HSP90 has acquired immense interest as a potent anticancer drug-target due to its key functional link with multiple signaling pathways involved in the process of cell proliferation and cell survival. Notably, geldanamycin and its derivatives (17-AAG, 17-DMAG) have shown quite encouraging results in inhibiting HSP90 function in several cancers and currently almost 17 drug candidates known to be target HSP90 are being under clinical trials either as single agents or combinatorial therapy. Hence, this review is an attempt to get new insight into novel drug target therapy by focusing on recent advances made in understanding HSP90 chaperone structure-function relationships, identification of new HSP90 client proteins and, more importantly, on the advancements of HSP90 targeted therapy based on various existing and emerging classical inhibitors. PMID:27013225

  6. Proteolytic degradation of nitric oxide synthase isoforms by calpain is modulated by the expression levels of HSP90.

    Science.gov (United States)

    Averna, Monica; Stifanese, Roberto; De Tullio, Roberta; Salamino, Franca; Bertuccio, Mara; Pontremoli, Sandro; Melloni, Edon

    2007-12-01

    Ca2+ loading of Jurkat and bovine aorta endothelium cells induces the degradation of the neuronal and endothelial nitric oxide synthases that are selectively expressed in these cell lines. For neuronal nitric oxide synthase, this process involves a conservative limited proteolysis without appreciable loss of catalytic activity. By contrast, endothelial nitic oxide synthase digestion proceeds through a parallel loss of protein and catalytic activity. The chaperone heat shock protein 90 (HSP90) is present in a large amount in Jurkat cells and at significantly lower levels in bovine aorta endothelium cells. The differing ratios of HSP90/nitric oxide synthase (NOS) occurring in the two cell types are responsible for the conservative or nonconservative digestion of NOS isozymes. Consistently, we demonstrate that, in the absence of Ca2+, HSP90 forms binary complexes with NOS isozymes or with calpain. When Ca2+ is present, a ternary complex containing the three proteins is produced. In this associated state, HSP90 and NOS forms are almost completely resistant to calpain digestion, probably due to a structural hindrance and a reduction in the catalytic efficiency of the protease. Thus, the recruitment of calpain in the HSP90-NOS complexes reduces the extent of the proteolysis of these two proteins. We have also observed that calpastatin competes with HSP90 for the binding of calpain in reconstructed systems. Digestion of the proteins present in the complexes can occur only when free active calpain is present in the system. This process can be visualized as a novel mechanism involving the association of NOS with HSP90 and the concomitant recruitment of active calpain in ternary complexes in which the proteolysis of both NOS isozymes and HSP90 is significantly reduced. PMID:17970747

  7. Molecular Characteristic, Protein Distribution and Potential Regulation of HSP90AA1 in the Anadromous Fish Coilia nasus

    OpenAIRE

    Di-An Fang; Jin-Rong Duan; Yan-Feng Zhou; Min-Ying Zhang; Dong-Po Xu; Kai Liu; Pao Xu

    2016-01-01

    Heat shock proteins play essential roles in basic cellular events. Spawning migration is a complex process, with significant structural and biochemical changes taking place in the adult gonad. To date, the molecular mechanisms underlying migration reproductive biology remain undetermined. In this regard, a full length HSP90AA1 comprising 2608 nucleotides from the anadromous fish Coilia nasus was characterized, encoding 742 amino acid (aa) residues with potential phosphorylation sites. HSP90AA...

  8. In vitro assembly of plant RNA-induced silencing complexes facilitated by molecular chaperone HSP90.

    Science.gov (United States)

    Iki, Taichiro; Yoshikawa, Manabu; Nishikiori, Masaki; Jaudal, Mauren C; Matsumoto-Yokoyama, Eiko; Mitsuhara, Ichiro; Meshi, Tetsuo; Ishikawa, Masayuki

    2010-07-30

    RNA-induced silencing complexes (RISCs) play central roles in posttranscriptional gene silencing. In plants, the mechanism of RISC assembly has remained elusive due to the lack of cell-free systems that recapitulate the process. In this report, we demonstrate that plant AGO1 protein synthesized by in vitro translation using an extract of evacuolated tobacco protoplasts incorporates synthetic small interfering RNA (siRNA) and microRNA (miRNA) duplexes to form RISCs that sequester the single-stranded siRNA guide strand and miRNA strand, respectively. The formed RISCs were able to recognize and cleave the complementary target RNAs. In this system, the siRNA duplex was incorporated into HSP90-bound AGO1, and subsequent removal of the passenger strand was triggered by ATP hydrolysis by HSP90. Removal of the siRNA passenger strand required the ribonuclease activity of AGO1, while that of the miRNA star strand did not. Based on these results, the mechanism of plant RISC formation is discussed. PMID:20605502

  9. Translational downregulation of HSP90 expression by iron chelators in neuroblastoma cells.

    Science.gov (United States)

    Sidarovich, Viktoryia; Adami, Valentina; Gatto, Pamela; Greco, Valentina; Tebaldi, Toma; Tonini, Gian Paolo; Quattrone, Alessandro

    2015-01-01

    Iron is an essential cellular nutrient, being a critical cofactor of several proteins involved in cell growth and replication. Compared with normal cells, neoplastic cells have been shown to require a greater amount of iron, thus laying the basis for the promising anticancer activity of iron chelators. In this work, we evaluated the effects of molecules with iron chelation activity on neuroblastoma (NB) cell lines. Of the 17 iron chelators tested, six reduced cell viability of two NB cell lines with an inhibition of growth of 50% below 10 µM; four of the six molecules-ciclopirox olamine (CPX), piroctone, 8-hydroxyquinoline, and deferasirox-were also shown to efficiently chelate intracellular iron within minutes after addition. Effects on cell viability of one of the compounds, CPX, were indeed dependent on chelation of intracellular iron and mediated by both G0/G1 cell cycle block and induction of apoptosis. By combined transcriptome and translatome profiling we identified early translational downregulation of several members of the heat shock protein group as a specific effect of CPX treatment. We functionally confirmed iron-dependent depletion of HSP90 and its client proteins at pharmacologically achievable concentrations of CPX, and we extended this effect to piroctone, 8-hydroxyquinoline, and deferasirox. Given the documented sensitivity of NB cells to HSP90 inhibition, we propose CPX and other iron chelators as investigational antitumor agents in NB therapy. PMID:25564462

  10. Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and Tumors

    Directory of Open Access Journals (Sweden)

    Aarif Ahsan

    2012-08-01

    Full Text Available The epidermal growth factor receptor (EGFR has been targeted for inhibition using tyrosine kinase inhibitors and monoclonal antibodies, with improvement in outcome in subsets of patients with head and neck, lung, and colorectal carcinomas. We have previously found that EGFR stability plays a key role in cell survival after chemotherapy and radiotherapy. Heat shock protein 90 (HSP90 is known to stabilize mutant EGFR and ErbB2, but its role in cancers with wild-type (WT WT-EGFR is unclear. In this report, we demonstrate that fully mature, membrane-bound WT-EGFR interacts with HSP90 independent of ErbB2. Further, the HSP90 inhibitors geldanamycin (GA and AT13387 cause a decrease in WT-EGFR in cultured head and neck cancer cells. This decrease results from a significantly reduced half-life of WT-EGFR. WT-EGFR was also lost in head and neck xenograft specimens after treatment with AT13387 under conditions that inhibited tumor growth and prolonged survival of the mice. Our findings demonstrate that WT-EGFR is a client protein of HSP90 and that their interaction is critical for maintaining both the stability of the receptor as well as the growth of EGFR-dependent cancers. Furthermore, these findings support the search for specific agents that disrupt HSP90's ability to act as an EGFR chaperone.

  11. Heat acclimation attenuates physiological strain and the HSP72, but not HSP90 alpha, mRNA response to acute normobaric hypoxia

    OpenAIRE

    Gibson, OR; Turner, G.; Tuttle, JA; Taylor, L.; Watt, PW; Maxwell, NS

    2015-01-01

    Heat acclimation (HA) attenuates physiological strain in hot conditions via phenotypic and cellular adaptation. The aim of this study was to determine whether HA reduced physiological strain, and heat shock protein (HSP) 72 and HSP90α mRNA responses in acute normobaric hypoxia. Sixteen male participants completed ten 90-min sessions of isothermic HA (40°C/40% relative humidity) or exercise training [control (CON); 20°C/40% relative humidity]. HA or CON were preceded (HYP1) and proceeded (HYP2...

  12. Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer.

    Science.gov (United States)

    Su, Yen-Hao; Tang, Wan-Chun; Cheng, Ya-Wen; Sia, Peik; Huang, Chi-Chen; Lee, Yi-Chao; Jiang, Hsin-Yi; Wu, Ming-Heng; Lai, I-Lu; Lee, Jun-Wei; Lee, Kuen-Haur

    2015-10-01

    There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-β-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC. PMID:25982393

  13. Establish an automated flow injection ESI-MS method for the screening of fragment based libraries: Application to Hsp90.

    Science.gov (United States)

    Riccardi Sirtori, Federico; Caronni, Dannica; Colombo, Maristella; Dalvit, Claudio; Paolucci, Mauro; Regazzoni, Luca; Visco, Carlo; Fogliatto, Gianpaolo

    2015-08-30

    ESI-MS is a well established technique for the study of biopolymers (nucleic acids, proteins) and their non covalent adducts, due to its capacity to detect ligand-target complexes in the gas phase and allows inference of ligand-target binding in solution. In this article we used this approach to investigate the interaction of ligands to the Heat Shock Protein 90 (Hsp90). This enzyme is a molecular chaperone involved in the folding and maturation of several proteins which has been subjected in the last years to intensive drug discovery efforts due to its key role in cancer. In particular, reference compounds, with a broad range of dissociation constants from 40pM to 100μM, were tested to assess the reliability of ESI-MS for the study of protein-ligand complexes. A good agreement was found between the values measured with a fluorescence polarization displacement assay and those determined by mass spectrometry. After this validation step we describe the setup of a medium throughput screening method, based on ESI-MS, suitable to explore interactions of therapeutic relevance biopolymers with chemical libraries. Our approach is based on an automated flow injection ESI-MS method (AFI-MS) and has been applied to screen the Nerviano Medical Sciences proprietary fragment library of about 2000 fragments against Hsp90. In order to discard false positive hits and to discriminate those of them interacting with the N-terminal ATP binding site, competition experiments were performed using a reference inhibitor. Gratifyingly, this group of hits matches with the ligands previously identified by NMR FAXS techniques and confirmed by X-ray co-crystallization experiments. These results support the use of AFI-MS for the screening of medium size libraries, including libraries of small molecules with low affinity typically used in fragment based drug discovery. AFI-MS is a valid alternative to other techniques with the additional opportunities to identify compounds interacting with

  14. Design, synthesis, and anticancer activity of C8-substituted-4'-thionucleosides as potential HSP90 inhibitors.

    Science.gov (United States)

    Qu, Shuhao; Mulamoottil, Varughese A; Nayak, Akshata; Ryu, Seungyeon; Hou, Xiyan; Song, Jayoung; Yu, Jinha; Sahu, Pramod K; Zhao, Long Xuan; Choi, Sun; Lee, Sang Kook; Jeong, Lak Shin

    2016-08-15

    A series of C8-substituted-4'-thioadenosine analogs 3a-3g, 15, and 17 and their truncated derivatives 4a-4j, 23-25, and 27 have been successfully synthesized from d-ribose and d-mannose, respectively, employing Pummerer type or Vorbrüggen condensation reactions and the functionalization at the C8-position of nucleobase via Stille coupling or nucleophilic aromatic substitution reactions as key steps. All the synthesized compounds were assayed for their HSP90 inhibitory activity, but they were found to be inactive up to 100μM. However, the 8-iodo derivatives 15, 17, and 27 exhibited potent anticancer activity, indicating that different mechanism of action might be involved in their biological activity. PMID:27283788

  15. Phylogenetic relationships of organellar Hsp90 homologs reveal fundamental differences to organellar Hsp70 and Hsp60 evolution.

    Science.gov (United States)

    Emelyanov, Victor V

    2002-10-16

    In agreement with endosymbiont theory for the origin of organelles, mitochondria and chloroplasts (plastids) are universally accepted to have monophyletically arisen from within alpha-proteobacteria and cyanobacteria, respectively. Convincing particular evidence in support of this theory emerged from phylogenetic analysis of highly conserved, ubiquitous heat shock proteins (Hsps) chaperonin 60 and Hsp70. These apparently indispensable general chaperones have proven to be highly useful molecular tracers of organellar origin. Phylogenetic relationships of Hsp90--a less conserved and less widely distributed general chaperone--are reported here that are strikingly incongruent with canonical patterns of endosymbiotic ancestry. It appears that Hsp90 of chloroplasts derives from the endoplasmic reticulum-specific isoform while mitochondrial Hsp90 homologs affiliate with a eubacterial lineage other than alpha subdivision of proteobacteria. These data suggest that endosymbiont htpG genes, encoding Hsp90, have been either functionally displaced by pre-existing nuclear genes or completely lost during establishment of organelles and subsequently added to initial organellar complement. PMID:12459260

  16. Early Tumor Response to Hsp90 Therapy Using HER2 PET: Comparison with 18F-FDG PET

    OpenAIRE

    Smith-Jones, Peter M.; Solit, David; Afroze, Farzana; Rosen, Neal; Larson, Steven M.

    2006-01-01

    We compared 68Ga-DOTA-F(ab′)2-herceptin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid [HER2 PET]) and 18F-FDG PET for imaging of tumor response to the heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG).

  17. The mechanism of acetylcholine receptor in binding MuSK in myasthenia gravis and the role of HSP90 molecular chaperone

    Science.gov (United States)

    Chen, Rongbo; Chen, Siqia; Liao, Juan; Chen, Xiaopu; Xu, Xiaoling

    2016-01-01

    As an autoimmune disease, myasthenia gravis is caused by the dysfunction of neural transmission. Acetylcholine is known to exert its function after entering into synaptic cleft through binding onto postsynaptic membrane. The role of acetylcholine in binding MuSK in myasthenia gravis, however, remains unknown. A total of 38 myasthenia gravis patients and 27 healthy controls were included in this study for the detection of the expression of MuSK using immunofluorescent method. Expression of both MuSK and interleukin-6 (IL-6) were measured by Western blot, followed by the correlation analysis between heat shock protein 90 (HSP90) and IL-6 which were measured by enzyme-linked immunosorbent assay (ELISA). In myasthenia gravis patients, MuSK was co-localized with acetylcholine at the postsynaptic membrane. Such accumulation of MuSK, however, did not occur in normal people. Meanwhile we also observed elevated expression of IL-6 in myasthenia gravis patients (pmyasthenia gravis patients, with elevated expression. HSP90 in disease people can activate IL-6 mediated signaling pathways. PMID:27186300

  18. Hsp90 interacts specifically with viral RNA and differentially regulates replication initiation of Bamboo mosaic virus and associated satellite RNA.

    Directory of Open Access Journals (Sweden)

    Ying Wen Huang

    Full Text Available Host factors play crucial roles in the replication of plus-strand RNA viruses. In this report, a heat shock protein 90 homologue of Nicotiana benthamiana, NbHsp90, was identified in association with partially purified replicase complexes from BaMV-infected tissue, and shown to specifically interact with the 3' untranslated region (3' UTR of BaMV genomic RNA, but not with the 3' UTR of BaMV-associated satellite RNA (satBaMV RNA or that of genomic RNA of other viruses, such as Potato virus X (PVX or Cucumber mosaic virus (CMV. Mutational analyses revealed that the interaction occurs between the middle domain of NbHsp90 and domain E of the BaMV 3' UTR. The knockdown or inhibition of NbHsp90 suppressed BaMV infectivity, but not that of satBaMV RNA, PVX, or CMV in N. benthamiana. Time-course analysis further revealed that the inhibitory effect of 17-AAG is significant only during the immediate early stages of BaMV replication. Moreover, yeast two-hybrid and GST pull-down assays demonstrated the existence of an interaction between NbHsp90 and the BaMV RNA-dependent RNA polymerase. These results reveal a novel role for NbHsp90 in the selective enhancement of BaMV replication, most likely through direct interaction with the 3' UTR of BaMV RNA during the initiation of BaMV RNA replication.

  19. Extracellular Hsp90 serves as a co-factor for MAPK activation and latent viral gene expression during de novo infection by KSHV

    International Nuclear Information System (INIS)

    The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an important cause of morbidity and mortality in immunocompromised patients. KSHV interaction with the cell membrane triggers activation of specific intracellular signal transduction pathways to facilitate virus entry, nuclear trafficking, and ultimately viral oncogene expression. Extracellular heat shock protein 90 localizes to the cell surface (csHsp90) and facilitates signal transduction in cancer cell lines, but whether csHsp90 assists in the coordination of KSHV gene expression through these or other mechanisms is unknown. Using a recently characterized non-permeable inhibitor specifically targeting csHsp90 and Hsp90-specific antibodies, we show that csHsp90 inhibition suppresses KSHV gene expression during de novo infection, and that this effect is mediated largely through the inhibition of mitogen-activated protein kinase (MAPK) activation by KSHV. Moreover, we show that targeting csHsp90 reduces constitutive MAPK expression and the release of infectious viral particles by patient-derived, KSHV-infected primary effusion lymphoma cells. These data suggest that csHsp90 serves as an important co-factor for KSHV-initiated MAPK activation and provide proof-of-concept for the potential benefit of targeting csHsp90 for the treatment or prevention of KSHV-associated illnesses.

  20. Exposure to non-ionizing radiation provokes changes in rat thyroid morphology and expression of HSP-90.

    Science.gov (United States)

    Misa-Agustiño, Maria J; Jorge-Mora, Teresa; Jorge-Barreiro, Francisco J; Suarez-Quintanilla, Juan; Moreno-Piquero, Eduardo; Ares-Pena, Francisco J; López-Martín, Elena

    2015-09-01

    Non-ionizing radiation at 2.45 GHz may modify the morphology and expression of genes that codify heat shock proteins (HSP) in the thyroid gland. Diathermy is the therapeutic application of non-ionizing radiation to humans for its beneficial effects in rheumatological and musculo-skeletal pain processes. We used a diathermy model on laboratory rats subjected to maximum exposure in the left front leg, in order to study the effects of radiation on the nearby thyroid tissue. Fifty-six rats were individually exposed once or repeatedly (10 times in two weeks) for 30 min to 2.45 GHz radiation in a commercial chamber at different non-thermal specific absorption rates (SARs), which were calculated using the finite difference time domain technique. We used immunohistochemistry methods to study the expression of HSP-90 and morphological changes in thyroid gland tissues. Ninety minutes after radiation with the highest SAR, the central and peripheral follicles presented increased size and the thickness of the peripheral septa had decreased. Twenty-four hours after radiation, only peripheral follicles radiated at 12 W were found to be smaller. Peripheral follicles increased in size with repeated exposure at 3 W power. Morphological changes in the thyroid tissue may indicate a glandular response to acute or repeated stress from radiation in the hypothalamic-pituitary-thyroid axis. Further research is needed to determine if the effect of this physical agent over time may cause disease in the human thyroid gland. PMID:25649190

  1. 17-DMAG, an HSP90 Inhibitor, Ameliorates Multiple Organ Dysfunction Syndrome via Induction of HSP70 in Endotoxemic Rats.

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    Yi-Li Wang

    Full Text Available Sepsis is a systemic inflammatory disorder, accompanied with elevated oxidative stress, leading to multiple organ dysfunction syndrome (MODS, and disseminated intravascular coagulation. 17-Dimethylaminoethylamino- 17-demethoxygeldanamycin (17-DMAG, a heat shock protein (HSP 90 inhibitor, has been reported to possess anti-inflammatory effects. In this study, the beneficial effects of 17-DMAG on lipopolysaccharide (LPS induced MODS and DIC was evaluated in anesthetized rats. 17-DMAG (5 mg/kg, i.p. was significantly increased survival rate, and prevented hypotension in LPS (30 mg/kg i.v. infused for 4 h induced endotoxemia. The elevated levels of alanine aminotransferase (ALT, creatine phosphokinase (CPK, lactate dehydrogenase, creatinine, nitric oxide (NO metabolites, IL-6, and TNF-α in LPS-exposed rat plasma were significantly reduced by 17-DMAG. Moreover, 17-DMAG suppressed LPS-induced superoxide anion production and caspase 3 activation in heart tissues. LPS induced the prolongation of prothrombin time, and a pronounced decrease in platelet count, which were improved by 17-DMAG. 17-DMAG markedly induced HSP70 and heme oxygenase (HO-1, and suppressed inducible nitric oxide synthase (iNOS and phosphorylated NF-κB p65 protein expression in organs 6 h after LPS initiation. Pretreatment with high dose of quercetin (300 mg/kg, i.p., as an HSP70 inhibitor, reversed the beneficial effects of 17-DMAG on survival rate, plasma levels of ALT, CPK, creatinine, IL-6, and NO metabolites, iNOS induction, and caspase-3 activation in LPS-treated rats. In conclusion, 17-DMAG possesses the anti-inflammatory and antioxidant effects that were proved through LPS-induced acute inflammation, which is associated with induction of HSP70 and HO-1, leading to prevent MODS in sepsis.

  2. 17-DMAG, an HSP90 Inhibitor, Ameliorates Multiple Organ Dysfunction Syndrome via Induction of HSP70 in Endotoxemic Rats.

    Science.gov (United States)

    Wang, Yi-Li; Shen, Hsin-Hsueh; Cheng, Pao-Yun; Chu, Yen-Ju; Hwang, Hwong-Ru; Lam, Kwok-Keung; Lee, Yen-Mei

    2016-01-01

    Sepsis is a systemic inflammatory disorder, accompanied with elevated oxidative stress, leading to multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation. 17-Dimethylaminoethylamino- 17-demethoxygeldanamycin (17-DMAG), a heat shock protein (HSP) 90 inhibitor, has been reported to possess anti-inflammatory effects. In this study, the beneficial effects of 17-DMAG on lipopolysaccharide (LPS) induced MODS and DIC was evaluated in anesthetized rats. 17-DMAG (5 mg/kg, i.p.) was significantly increased survival rate, and prevented hypotension in LPS (30 mg/kg i.v. infused for 4 h) induced endotoxemia. The elevated levels of alanine aminotransferase (ALT), creatine phosphokinase (CPK), lactate dehydrogenase, creatinine, nitric oxide (NO) metabolites, IL-6, and TNF-α in LPS-exposed rat plasma were significantly reduced by 17-DMAG. Moreover, 17-DMAG suppressed LPS-induced superoxide anion production and caspase 3 activation in heart tissues. LPS induced the prolongation of prothrombin time, and a pronounced decrease in platelet count, which were improved by 17-DMAG. 17-DMAG markedly induced HSP70 and heme oxygenase (HO)-1, and suppressed inducible nitric oxide synthase (iNOS) and phosphorylated NF-κB p65 protein expression in organs 6 h after LPS initiation. Pretreatment with high dose of quercetin (300 mg/kg, i.p.), as an HSP70 inhibitor, reversed the beneficial effects of 17-DMAG on survival rate, plasma levels of ALT, CPK, creatinine, IL-6, and NO metabolites, iNOS induction, and caspase-3 activation in LPS-treated rats. In conclusion, 17-DMAG possesses the anti-inflammatory and antioxidant effects that were proved through LPS-induced acute inflammation, which is associated with induction of HSP70 and HO-1, leading to prevent MODS in sepsis. PMID:27224288

  3. Role of ARF6, Rab11 and external Hsp90 in the trafficking and recycling of recombinant-soluble Neisseria meningitidis adhesin A (rNadA in human epithelial cells.

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    Giuseppe Bozza

    Full Text Available Neisseria meningitidis adhesin A (NadA is a meningococcus surface protein thought to assist in the adhesion of the bacterium to host cells. We have previously shown that NadA also promotes bacterial internalization in a heterologous expression system. Here we have used the soluble recombinant NadA (rNadA lacking the membrane anchor region to characterize its internalization route in Chang epithelial cells. Added to the culture medium, rNadA internalizes through a PI3K-dependent endocytosis process not mediated by the canonical clathrin or caveolin scaffolds, but instead follows an ARF6-regulated recycling pathway previously described for MHC-I. The intracellular pool of rNadA reaches a steady state level within one hour of incubation and colocalizes in endocytic vesicles with MHC-I and with the extracellularly labeled chaperone Hsp90. Treatment with membrane permeated and impermeable Hsp90 inhibitors 17-AAG and FITC-GA respectively, lead to intracellular accumulation of rNadA, strongly suggesting that the extracellular secreted pool of the chaperone is involved in rNadA intracellular trafficking. A significant number of intracellular vesicles containing rNadA recruit Rab11, a small GTPase associated to recycling endosomes, but do not contain transferrin receptor (TfR. Interestingly, cell treatment with Hsp90 inhibitors, including the membrane-impermeable FITC-GA, abolished Rab11-rNadA colocalization but do not interfere with Rab11-TfR colocalization. Collectively, these results are consistent with a model whereby rNadA internalizes into human epithelial cells hijacking the recycling endosome pathway and recycle back to the surface of the cell via an ARF6-dependent, Rab11 associated and Hsp90-regulated mechanism. The present study addresses for the first time a meningoccoccal adhesin mechanism of endocytosis and suggests a possible entry pathway engaged by N. meningitidis in primary infection of human epithelial cells.

  4. Design and synthesis of N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides as novel Hsp90 inhibitors.

    Science.gov (United States)

    Liang, Chuanpeng; Hao, Huilin; Wu, Xingkang; Li, Zhenyu; Zhu, Jing; Lu, Chunhua; Shen, Yuemao

    2016-10-01

    Heat shock protein 90 (Hsp90) is an attractive chemotherapeutic target for antitumor drug development. Herein, we reported the design and synthesis of two series of novel N-(5-chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxamides as Hsp90 inhibitors using (S)-Tic (1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid) (A1-13) and (R)-Tic (B1-13) as scaffold, respectively. Cellular thermal shift assay (CETSA) screening showed that compounds B1-13 with (R)-Tic scaffold exhibited potent ability to stabilize Hsp90α. Compound B7 showed not only the most potent ability to induce thermal stabilization of Hsp90α but also the strongest cytotoxicity. The IC50 values of B7 were 0.98 μM and 1.74 μM against the proliferation of human breast cancer MDA-MB-231 and human cervical cancer HeLa cell lines, respectively. Moreover, CETSA melt and ITDRFCETSA (isothermal dose-response fingerprint) curves confirmed that B7 bound to Hsp90α in 293T cells. Western blotting results indicated that B7 induced the degradation of Hsp90 clients CDK4, Her2, Cdc-2 and C-raf. In addition, docking and Molecular dynamics (MD) refinement of the B7-Hsp90 complex showed that the binding model of B7 to Hsp90 was similar with that of 8-benzyladenines. The overall properties warrant compound B7 a promising lead for the development of Hsp90 inhibitor antitumor drugs. PMID:27266997

  5. BAG-1/SODD, HSP70, and HSP90 are potential prognostic markers of poor survival in node-negative breast carcinoma.

    Science.gov (United States)

    Davidson, Ben; Valborg Reinertsen, Kristin; Trinh, Don; Reed, Wenche; Bøhler, Per Johannes

    2016-08-01

    The objective of this study was to analyze the expression and clinical role of 13 signaling molecules in a large cohort of breast carcinoma patients with long follow-up period. Breast carcinomas (n=410) were analyzed for protein expression of phosphorylated mitogen-activated protein kinases (p-ERK, p-JNK, p-p38) and phosphoinositide 3-kinase signaling pathway proteins (p-AKT, p-mTOR, p-p70S6K); the BAG family proteins BAG-1 and BAG-4/SODD; the antiapoptotic protein Bcl-2; the inhibitor of apoptosis family member Survivin; and the heat shock protein family members HSP27, HSP70, and HSP90. Protein expression was studied for association with clinicopathological parameters and survival. Significantly higher expression of p-AKT (Pmarkers in node-negative breast carcinoma that merit further research. PMID:27038683

  6. Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells

    OpenAIRE

    Eskew Jeffery D; Sadikot Takrima; Morales Pedro; Duren Alicia; Dunwiddie Irene; Swink Megan; Zhang Xiaoying; Hembruff Stacey; Donnelly Alison; Rajewski Roger A; Blagg Brian SJ; Manjarrez Jacob R; Matts Robert L; Holzbeierlein Jeffrey M; Vielhauer George A

    2011-01-01

    Abstract Background The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not i...

  7. Low sequence identity but high structural and functional conservation: The case of Hsp70/Hsp90 organizing protein (Hop/Sti1) of Leishmania braziliensis.

    Science.gov (United States)

    Batista, Fernanda A H; Seraphim, Thiago V; Santos, Clelton A; Gonzaga, Marisvanda R; Barbosa, Leandro R S; Ramos, Carlos H I; Borges, Júlio C

    2016-06-15

    Parasites belonging to the genus Leishmania are subjected to extensive environmental changes during their life cycle; molecular chaperones/co-chaperones act as protagonists in this scenario to maintain cellular homeostasis. Hop/Sti1 is a co-chaperone that connects the Hsp90 and Hsp70 systems, modulating their ATPase activities and affecting the fate of client proteins because it facilitates their transfer from the Hsp70 to the Hsp90 chaperone. Hop/Sti1 is one of the most prevalent co-chaperones, highlighting its importance despite the relatively low sequence identity among orthologue proteins. This multi-domain protein comprises three tetratricopeptides domains (TPR1, TPR2A and TPR2B) and two Asp/Pro-rich domains. Given the importance of Hop/Sti1 for the chaperone system and for Leishmania protozoa viability, the Leishmania braziliensis Hop (LbHop) and a truncated mutant (LbHop(TPR2AB)) were characterized. Structurally, both proteins are α-helix-rich and highly elongated monomeric proteins. Functionally, they inhibited the ATPase activity of Leishmania braziliensis Hsp90 (LbHsp90) to a similar extent, and the thermodynamic parameters of their interactions with LbHsp90 were similar, indicating that TPR2A-TPR2B forms the functional center for the LbHop interaction with LbHsp90. These results highlight the structural and functional similarity of Hop/Sti1 proteins, despite their low sequence conservation compared to the Hsp70 and Hsp90 systems, which are phylogenetic highly conserved. PMID:27103305

  8. Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress.

    Science.gov (United States)

    Wang, Chun Yan; Guo, Su Tang; Wang, Jia Yu; Liu, Fen; Zhang, Yuan Yuan; Yari, Hamed; Yan, Xu Guang; Jin, Lei; Zhang, Xu Dong; Jiang, Chen Chen

    2016-03-01

    Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy. Mol Cancer Ther; 15(3); 448-59. ©2016 AACR. PMID:26832792

  9. Hsp90 inhibition suppresses NF-κB transcriptional activation via Sirt-2 in human lung microvascular endothelial cells.

    Science.gov (United States)

    Thangjam, Gagan S; Birmpas, Charalampos; Barabutis, Nektarios; Gregory, Betsy W; Clemens, Mary Ann; Newton, Joseph R; Fulton, David; Catravas, John D

    2016-05-15

    The ability of anti-heat shock protein 90 (Hsp90) drugs to attenuate NF-κB-mediated transcription is the major basis for their anti-inflammatory properties. While the molecular mechanisms underlying this effect are not clear, they appear to be distinct in human endothelial cells. We now show for the first time that type 2 sirtuin (Sirt-2) histone deacetylase binds human NF-κB target gene promoter and prevents the recruitment of NF-κB proteins and subsequent assembly of RNA polymerase II complex in human lung microvascular endothelial cells. Hsp90 inhibitors stabilize the Sirt-2/promoter interaction and impose a "transcriptional block," which is reversed by either inhibition or downregulation of Sirt-2 protein expression. Furthermore, this process is independent of NF-κB (p65) Lysine 310 deacetylation, suggesting that it is distinct from known Sirt-2-dependent mechanisms. We demonstrate that Sirt-2 is recruited to NF-κB target gene promoter via interaction with core histones. Upon inflammatory challenge, chromatin remodeling and core histone H3 displacement from the promoter region removes Sirt-2 and allows NF-κB/coactivator recruitment essential for RNA Pol II-dependent mRNA induction. This novel mechanism may have important implications in pulmonary inflammation. PMID:27036868

  10. Cellular growth kinetics distinguish a cyclophilin inhibitor from an HSP90 inhibitor as a selective inhibitor of hepatitis C virus.

    Directory of Open Access Journals (Sweden)

    Rudolf K F Beran

    Full Text Available During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA and heat-shock protein 90 (HSP90 which have each been reported to inhibit replication of hepatitis C virus (HCV. By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino-17-demethoxygeldanamycin (17-AAG to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA, exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth.

  11. Dual mode of cancer cell destruction for pancreatic cancer therapy using Hsp90 inhibitor loaded polymeric nano magnetic formulation.

    Science.gov (United States)

    Rochani, Ankit K; Balasubramanian, Sivakumar; Ravindran Girija, Aswathy; Raveendran, Sreejith; Borah, Ankita; Nagaoka, Yutaka; Nakajima, Yoshikata; Maekawa, Toru; Kumar, D Sakthi

    2016-09-10

    Heat Shock Protein 90 (Hsp90) has been extensively explored as a potential drug target for cancer therapies. 17- N-allylamino- 17-demethoxygeldanamycin (17AAG) was the first Hsp90 inhibitor to enter clinical trials for cancer therapy. However, native drug is being shown to have considerable anticancer efficacy against pancreatic cancer when used in combination therapy regime. Further, magnetic hyperthermia has shown to have promising effects against pancreatic cancer in combination with known cyto-toxic drugs under both target and non-targeted scenarios. Hence, in order to enhance the efficacy of 17AAG against pancreatic cancer, we developed poly (lactic-co-glycolic acid) (PLGA) coated, 17AAG and Fe3O4 loaded magnetic nanoparticle formulations by varying the relative concentration of polymer. We found that polymer concentration affects the magnetic strength and physicochemical properties of formulation. We were also able to see that our aqueous dispensable formulations were able to provide anti-pancreatic cancer activity for MIA PaCa-2 cell line in dose and time dependent manner in comparison to mice fibroblast cell lines (L929). Moreover, the in-vitro magnetic hyperthermia against MIA PaCa-2 provided proof principle that our 2-in-1 particles may work against cancer cell lines effectively. PMID:27469073

  12. Inhibiting heat shock protein 90 (HSP90 limits the formation of liver cysts induced by conditional deletion of Pkd1 in mice.

    Directory of Open Access Journals (Sweden)

    Zachary B Smithline

    Full Text Available Polycystic liver disease (PLD occurs in 75-90% of patients affected by autosomal dominant polycystic kidney disease (ADPKD, which affects 1∶400-1,000 adults and arises from inherited mutations in the PKD1 or PKD2 genes. PLD can lead to bile duct obstructions, infected or bleeding cysts, and hepatomegaly, which can diminish quality of life. At present, no effective, approved therapy exists for ADPKD or PLD. We recently showed that inhibition of the molecular chaperone heat shock protein 90 (HSP90 with a small molecule inhibitor, STA-2842, induced the degradation of multiple HSP90-dependent client proteins that contribute to ADPKD pathogenesis and slowed the progression of renal cystogenesis in mice with conditional deletion of Pkd1. Here, we analyzed the effects of STA-2842 on liver size and cystic burden in Pkd-/- mice with established PLD. Using magnetic resonance imaging over time, we demonstrate that ten weeks of STA-2842 treatment significantly reduced both liver mass and cystic index suggesting selective elimination of cystic tissue. Pre-treatment cystic epithelia contain abundant HSP90; the degree of reduction in cysts was accompanied by inhibition of proliferation-associated signaling proteins EGFR and others, and induced cleavage of caspase 8 and PARP1, and correlated with degree of HSP90 inhibition and with inactivation of ERK1/2. Our results suggest that HSP90 inhibition is worth further evaluation as a therapeutic approach for patients with PLD.

  13. Measuring the pharmacodynamic effects of a novel Hsp90 inhibitor on HER2/neu expression in mice using Zr-DFO-trastuzumab.

    Directory of Open Access Journals (Sweden)

    Jason P Holland

    Full Text Available BACKGROUND: The positron-emitting radionuclide (89Zr (t(1/2 = 3.17 days was used to prepare (89Zr-radiolabeled trastuzumab for use as a radiotracer for characterizing HER2/neu-positive breast tumors. In addition, pharmacodynamic studies on HER2/neu expression levels in response to therapeutic doses of PU-H71 (a specific inhibitor of heat-shock protein 90 [Hsp90] were conducted. METHODOLOGY/PRINCIPAL FINDINGS: Trastuzumab was functionalized with desferrioxamine B (DFO and radiolabeled with [(89Zr]Zr-oxalate at room temperature using modified literature methods. ImmunoPET and biodistribution experiments in female, athymic nu/nu mice bearing sub-cutaneous BT-474 (HER2/neu positive and/or MDA-MB-468 (HER2/neu negative tumor xenografts were conducted. The change in (89Zr-DFO-trastuzumab tissue uptake in response to high- and low-specific-activity formulations and co-administration of PU-H71 was evaluated by biodistribution studies, Western blot analysis and immunoPET. (89Zr-DFO-trastuzumab radiolabeling proceeded in high radiochemical yield and specific-activity 104.3+/-2.1 MBq/mg (2.82+/-0.05 mCi/mg of mAb. In vitro assays demonstrated >99% radiochemical purity with an immunoreactive fraction of 0.87+/-0.07. In vivo biodistribution experiments revealed high specific BT-474 uptake after 24, 48 and 72 h (64.68+/-13.06%ID/g; 71.71+/-10.35%ID/g and 85.18+/-11.10%ID/g, respectively with retention of activity for over 120 h. Pre-treatment with PU-H71 was followed by biodistribution studies and immunoPET of (89Zr-DFO-trastuzumab. Expression levels of HER2/neu were modulated during the first 24 and 48 h post-administration (29.75+/-4.43%ID/g and 41.42+/-3.64%ID/g, respectively. By 72 h radiotracer uptake (73.64+/-12.17%ID/g and Western blot analysis demonstrated that HER2/neu expression recovered to baseline levels. CONCLUSIONS/SIGNIFICANCE: The results indicate that (89Zr-DFO-trastuzumab provides quantitative and highly-specific delineation of HER2/neu

  14. MicroRNA-27b plays a role in pulmonary arterial hypertension by modulating peroxisome proliferator-activated receptor γ dependent Hsp90-eNOS signaling and nitric oxide production

    Energy Technology Data Exchange (ETDEWEB)

    Bi, Rui; Bao, Chunrong; Jiang, Lianyong; Liu, Hao; Yang, Yang; Mei, Ju; Ding, Fangbao, E-mail: dbcar126@126.com

    2015-05-01

    Pulmonary artery endothelial dysfunction is associated with pulmonary arterial hypertension (PAH). Based on recent studies showing that microRNA (miR)-27b is aberrantly expressed in PAH, we hypothesized that miR-27b may contribute to pulmonary endothelial dysfunction and vascular remodeling in PAH. The effect of miR-27b on pulmonary endothelial dysfunction and the underlying mechanism were investigated in human pulmonary artery endothelial cells (HPAECs) in vitro and in a monocrotaline (MCT)-induced model of PAH in vivo. miR-27b expression was upregulated in MCT-induced PAH and inversely correlated with the levels of peroxisome proliferator-activated receptor (PPAR)-γ, and miR-27b inhibition attenuated MCT-induced endothelial dysfunction and remodeling and prevented PAH associated right ventricular hypertrophy and systolic pressure in rats. PPARγ was confirmed as a direct target of miR-27b in HPAECs and shown to mediate the effect of miR-27b on the disruption of endothelial nitric oxide synthase (eNOS) coupling to Hsp90 and the suppression of NO production associated with the PAH phenotype. We showed that miR-27b plays a role endothelial function and NO release and elucidated a potential mechanism by which miR-27b regulates Hsp90-eNOS and NO signaling by modulating PPARγ expression, providing potential therapeutic targets for the treatment of PAH. - Highlights: • miR-27b plays a role in endothelial function and NO release. • miR-27b inhibition ameliorates MCT-induced endothelial dysfunction and PAH. • miR-27b targets PPARγ in HPAECs. • miR-27b regulates PPARγ dependent Hsp90-eNOS and NO signaling.

  15. MicroRNA-27b plays a role in pulmonary arterial hypertension by modulating peroxisome proliferator-activated receptor γ dependent Hsp90-eNOS signaling and nitric oxide production

    International Nuclear Information System (INIS)

    Pulmonary artery endothelial dysfunction is associated with pulmonary arterial hypertension (PAH). Based on recent studies showing that microRNA (miR)-27b is aberrantly expressed in PAH, we hypothesized that miR-27b may contribute to pulmonary endothelial dysfunction and vascular remodeling in PAH. The effect of miR-27b on pulmonary endothelial dysfunction and the underlying mechanism were investigated in human pulmonary artery endothelial cells (HPAECs) in vitro and in a monocrotaline (MCT)-induced model of PAH in vivo. miR-27b expression was upregulated in MCT-induced PAH and inversely correlated with the levels of peroxisome proliferator-activated receptor (PPAR)-γ, and miR-27b inhibition attenuated MCT-induced endothelial dysfunction and remodeling and prevented PAH associated right ventricular hypertrophy and systolic pressure in rats. PPARγ was confirmed as a direct target of miR-27b in HPAECs and shown to mediate the effect of miR-27b on the disruption of endothelial nitric oxide synthase (eNOS) coupling to Hsp90 and the suppression of NO production associated with the PAH phenotype. We showed that miR-27b plays a role endothelial function and NO release and elucidated a potential mechanism by which miR-27b regulates Hsp90-eNOS and NO signaling by modulating PPARγ expression, providing potential therapeutic targets for the treatment of PAH. - Highlights: • miR-27b plays a role in endothelial function and NO release. • miR-27b inhibition ameliorates MCT-induced endothelial dysfunction and PAH. • miR-27b targets PPARγ in HPAECs. • miR-27b regulates PPARγ dependent Hsp90-eNOS and NO signaling

  16. The targeted inhibition of mitochondrial Hsp90 overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis

    International Nuclear Information System (INIS)

    Previous studies have reported that a Gamitrinib variant containing triphenylphosphonium (G-TPP) binds to mitochondrial Hsp90 and rapidly inhibits its activity, thus inducing the apoptotic pathway in the cells. Accordingly, G-TPP shows a potential as a promising drug for the treatment of cancer. A cell can die from different types of cell death such as apoptosis, necrosis, necroptosis, and autophagic cell death. In this study, we further investigated the mechanisms and modes of cell death in the G-TPP-treated Hep3B and U937 cell lines. We discovered that G-TPP kills the U937 cells through the apoptotic pathway and the overexpression of Bcl-2 significantly inhibits U937 cell death to G-TPP. We further discovered that G-TPP kills the Hep3B cells by activating necroptosis in combination with the partial activation of caspase-dependent apoptosis. Importantly, G-TPP overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis. We also observed that G-TPP induces compensatory autophagy in the Hep3B cell line. We further found that whereas there is a Bcl-2-Beclin 1 interaction in response to G-TPP, silencing the beclin 1 gene failed to block LC3-II accumulation in the Hep3B cells, indicating that G-TPP triggers Beclin 1-independent protective autophagy in Hep3B cells. Taken together, these data reveal that G-TPP induces cell death through a combination of death pathways, including necroptosis and apoptosis, and overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis. These findings are important for the therapeutic exploitation of necroptosis as an alternative cell death program to bypass the resistance to apoptosis. Highlights: ► G-TPP binds to mitochondrial Hsp90. ► G-TPP induces apoptosis in U937 human leukemia cancer cells. ► G-TPP induces combination of death pathways in Hep3B cell. ► G-TPP overcomes the resistance conferred by Bcl-2 in Hep3B cells via necroptosis. ► G-TPP triggers Beclin 1-independent

  17. The targeted inhibition of mitochondrial Hsp90 overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Chunlan [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of); Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058 (China); Oh, Joon Seok; Yoo, Seung Hee; Lee, Jee Suk [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of); Yoon, Young Geol [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of); Department of Biomedical Science, Institute for Biomedical and Health Sciences, Jungwon University, Chungbuk, 367-805 (Korea, Republic of); Oh, Yoo Jin; Jang, Min Seok [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of); Lee, Sang Yeob [Department of Rheumatology, Dong-A University College of Medicine, Busan, 602-714 (Korea, Republic of); Yang, Jun [Department of Toxicology, Hangzhou Normal University School of Public Health, Hangzhou, Zhejiang, 310036 China (China); Lee, Sang Hwa [Department of Microbiology and, Dong-A University College of Medicine, Busan, 602-714 (Korea, Republic of); Kim, Hye Young [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of); Yoo, Young Hyun, E-mail: yhyoo@dau.ac.kr [Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan, 602-714 (Korea, Republic of)

    2013-01-01

    Previous studies have reported that a Gamitrinib variant containing triphenylphosphonium (G-TPP) binds to mitochondrial Hsp90 and rapidly inhibits its activity, thus inducing the apoptotic pathway in the cells. Accordingly, G-TPP shows a potential as a promising drug for the treatment of cancer. A cell can die from different types of cell death such as apoptosis, necrosis, necroptosis, and autophagic cell death. In this study, we further investigated the mechanisms and modes of cell death in the G-TPP-treated Hep3B and U937 cell lines. We discovered that G-TPP kills the U937 cells through the apoptotic pathway and the overexpression of Bcl-2 significantly inhibits U937 cell death to G-TPP. We further discovered that G-TPP kills the Hep3B cells by activating necroptosis in combination with the partial activation of caspase-dependent apoptosis. Importantly, G-TPP overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis. We also observed that G-TPP induces compensatory autophagy in the Hep3B cell line. We further found that whereas there is a Bcl-2-Beclin 1 interaction in response to G-TPP, silencing the beclin 1 gene failed to block LC3-II accumulation in the Hep3B cells, indicating that G-TPP triggers Beclin 1-independent protective autophagy in Hep3B cells. Taken together, these data reveal that G-TPP induces cell death through a combination of death pathways, including necroptosis and apoptosis, and overcomes the apoptosis resistance conferred by Bcl-2 in Hep3B cells via necroptosis. These findings are important for the therapeutic exploitation of necroptosis as an alternative cell death program to bypass the resistance to apoptosis. Highlights: ► G-TPP binds to mitochondrial Hsp90. ► G-TPP induces apoptosis in U937 human leukemia cancer cells. ► G-TPP induces combination of death pathways in Hep3B cell. ► G-TPP overcomes the resistance conferred by Bcl-2 in Hep3B cells via necroptosis. ► G-TPP triggers Beclin 1-independent

  18. Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation

    International Nuclear Information System (INIS)

    Perturbing Hsp90 chaperone function targets hypoxia inducible factor (HIF) function in a von Hippel-Lindau (VHL) independent manner, and represents an approach to combat the contribution of HIF to cell renal carcinoma (CCRCC) progression. However, clinical trials with the prototypic Hsp90 inhibitor 17-AAG have been unsuccessful in halting the progression of advanced CCRCC. Here we evaluated a novel next generation small molecule Hsp90 inhibitor, EC154, against HIF isoforms and HIF-driven molecular and functional endpoints. The effects of EC154 were compared to those of the prototypic Hsp90 inhibitor 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589. The findings indicate that EC154 is a potent inhibitor of HIF, effective at doses 10-fold lower than 17-AAG. While EC154, 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589 impaired HIF transcriptional activity, CCRCC cell motility, and angiogenesis; these effects did not correlate with their ability to diminish HIF protein expression. Further, our results illustrate the complexity of HIF targeting, in that although these agents suppressed HIF transcripts with differential dynamics, these effects were not predictive of drug efficacy in other relevant assays. We provide evidence for EC154 targeting of HIF in CCRCC and for LBH589 acting as a suppressor of both HIF-1 and HIF-2 activity. We also demonstrate that 17-AAG and EC154, but not LBH589, can restore endothelial barrier function, highlighting a potentially new clinical application for Hsp90 inhibitors. Finally, given the discordance between HIF activity and protein expression, we conclude that HIF expression is not a reliable surrogate for HIF activity. Taken together, our findings emphasize the need to incorporate an integrated approach in evaluating Hsp90 inhibitors within the context of HIF suppression

  19. The molecular characterization and expression of heat shock protein 90 (Hsp90) and 26 (Hsp26) cDNAs in sea cucumber (Apostichopus japonicus)

    OpenAIRE

    Zhao, Huan; Yang, Hongsheng; Zhao, Heling; Chen, Muyan; Wang, Tianming

    2011-01-01

    The heat shock proteins (HSPs) are a family of proteins whose expression is enhanced in response to environmental stressors. The Apostichopus japonicus hsp90 and hsp26 genes were cloned using expressed sequence tag and rapid amplification of cDNA ends techniques. The full-length cDNA of Aphsp90 and Aphsp26 contains 3,458 and 1,688 nucleotides encoding 720 and 236 amino acids, respectively. Multiple alignments indicated that the deduced amino acid sequences of ApHsp90 and ApHsp26 shared a high...

  20. Monoclonal antibody 4C5 prevents activation of MMP2 and MMP9 by disrupting their interaction with extracellular HSP90 and inhibits formation of metastatic breast cancer cell deposits

    OpenAIRE

    Patsavoudi Evangelia; El Hamidieh Avraam; Stellas Dimitris

    2010-01-01

    Abstract Background Heat shock protein 90 (HSP90) is a molecular chaperone that is considered a new target for the treatment of cancer. Increasing data reveal an extracellular chaperoning activity for HSP90. Here we investigate the interaction of the secreted isoforms of HSP90 with matrix metalloproteinases (MMP) MMP2 and MMP9. Moreover we examine the role of a monoclonal antibody (mAb) against HSP90, mAb 4C5, regarding these interactions and its value as a potential inhibitor of human breast...

  1. Expression of hsp70, hsp90 and hsf1 in the reef coral Acropora digitifera under prospective acidified conditions over the next several decades

    Directory of Open Access Journals (Sweden)

    Masako Nakamura

    2012-02-01

    Ocean acidification is an ongoing threat for marine organisms due to the increasing atmospheric CO2 concentration. Seawater acidification has a serious impact on physiologic processes in marine organisms at all life stages. On the other hand, potential tolerance to external pH changes has been reported in coral larvae. Information about the possible mechanisms underlying such tolerance responses, however, is scarce. In the present study, we examined the effects of acidified seawater on the larvae of Acropora digitifera at the molecular level. We targeted two heat shock proteins, Hsp70 and Hsp90, and a heat shock transcription factor, Hsf1, because of their importance in stress responses and in early life developmental stages. Coral larvae were maintained under the ambient and elevated CO2 conditions that are expected to occur within next 100 years, and then we evaluated the expression of hsps and hsf1 by quantitative real-time polymerase chain reaction (PCR. Expression levels of these molecules significantly differed among target genes, but they did not change significantly between CO2 conditions. These findings indicate that the expression of hsps is not changed due to external pH changes, and suggest that tolerance to acidified seawater in coral larvae may not be related to hsp expression.

  2. Laboratory utility of coproscopy, copro immunoassays and copro nPCR assay targeting Hsp90 gene for detection of Cryptosporidium in children, Cairo, Egypt.

    Science.gov (United States)

    Ghallab, Marwa M I; Aziz, Inas Z Abdel; Shoeib, Eman Y; El-Badry, Ayman A

    2016-09-01

    Cryptosporidium is a significant cause of diarrhea worldwide especially in children. Infection may end fatally in immunocompromised patients. Multi-attribute analysis was used to determine the lab utility of 4 diagnostics; coproscopy of AF stained fecal smear, fecal immunoassays by ICT and ELISA and copro-nPCR assay targeting Hsp90 gene, for detection of Cryptosporidium in stool of 250 Egyptian children (150 diarrheic and 100 non-diarrhaeic children). Also, to determine Cryptosporidium molecular prevalence. Cryptosporidium was an important enteric pathogen among both diarrheic and non-diarrheic study children with a clearly high prevalence of 16.4 % (n = 41). Conventional methods had perfect specificity (100 %) but couldn`t be used as a consistent single detection method due to their lowered sensitivities. Multi-attribute analysis ranked nPCR the highest test for lab use. Being the test with the best diagnostic yield, nPCR is a reliable diagnostic test and is going to replace conventional methods for reliable detection of Cryptosporidium. PMID:27605806

  3. 2-phenylethynesulphonamide (PFT-μ) enhances the anticancer effect of the novel hsp90 inhibitor NVP-AUY922 in melanoma, by reducing GSH levels.

    Science.gov (United States)

    Yeramian, Andree; Vea, Alvar; Benítez, Sandra; Ribera, Joan; Domingo, Mónica; Santacana, Maria; Martinez, Montserrat; Maiques, Oscar; Valls, Joan; Dolcet, Xavier; Vilella, Ramón; Cabiscol, Elisa; Matias-Guiu, Xavier; Marti, Rosa M

    2016-05-01

    Heat shock proteins (HSPs), are molecular chaperones that assist the proper folding of nascent proteins. This study aims to evaluate the antitumour effects of the hsp90 inhibitor NVP-AUY922 in melanoma, both in vitro and in vivo. Our results show that NVP-AUY922 inhibits melanoma cell growth in vitro, with down regulation of multiple signalling pathways involved in melanoma progression such as NF-ĸB and MAPK/ERK. However, NVP-AUY922 was unable to limit tumour growth in vivo. Cotreatment of A375M xenografts with NVP-AUY922 and PFT-μ, a dual inhibitor of both hsp70 and autophagy, induced a synergistic increase of cell death in vitro, and delayed tumour formation in A375M xenografts. PFT-μ depleted cells from the reduced form of glutathione (GSH) and increased oxidative stress. The oxidative stress induced by PFT-μ further enhanced NVP-AUY922-induced cytotoxic effects. These data suggest a potential therapeutic role for NVP-AUY922 used in combination with PFT-μ, in melanoma. PMID:26988132

  4. Heat shock protein genes (hsp20, hsp75 and hsp90) from Pieris rapae: Molecular cloning and transcription in response to parasitization by Pteromalus puparum

    Institute of Scientific and Technical Information of China (English)

    Jia-Ying Zhu; Guo-Xing Wu; Gong-Yin Ye; Cui Hu

    2013-01-01

    Most molecular work on the roles of heat shock proteins (hsps) in host-parasite interaction has focused on vertebrates,rather than invertebrates.Here the full length complementary DNA (cDNA) sequences of three hsp genes (hsp20,hsp75 and hsp90)were amplified from Pieris rapae,and their transcriptional responsiveness to parasitization by the endoparasitic wasp Pteromalus puparum were investigated.The cDNA sequence analysis of hsp20,hsp75 and hsp90 revealed open reading frames of 531,2 328 and 2 157 bp in length,which encode proteins with calculated molecular weights of 19.5,75.48 and 82.7 kDa,respectively.The comparison of amino acid sequences showed that P.rapae hsp20 shared highly divergent homology to that of other insects,while hsp75 and hsp90 showed high homology to their counterparts of other species.The expression analysis indicated that these three genes were influenced in response to parasitization by P.puparum.The hsp20 transcripts in parasitized pupae were higher compared to nonparasitized pupae.The expression of hsp75 and hsp90 were down-regulated following parasitization.The results indicate that hsps are involved in host-parasitoid interactions.

  5. C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances

    Czech Academy of Sciences Publication Activity Database

    Műller, P.; Růčková, E.; Halada, Petr; Coates, P.J.; Hrstka, R.; Lane, D. P.; Vojtěšek, B.

    -, June 2012 (2012), s. 10.1038. ISSN 0950-9232 Institutional support: RVO:61388971 Keywords : Hsp70 * Hsp90 * CHIP Subject RIV: CE - Biochemistry Impact factor: 7.357, year: 2012 http://www.readcube.com/articles/10.1038/onc.2012.314

  6. Hsp90 regulates processing of NF-κB2 p100 involving protection of NF-κB-inducing kinase (NIK) from autophagy-mediated degradation

    Institute of Scientific and Technical Information of China (English)

    Guoliang Qing; Pengrong Yan; Zhaoxia Qu; Hudan Liu; Gutian Xiao

    2007-01-01

    NF-κB-inducing kinase (NIK) is required for NF-κB activation based on the processing of NF-κB2 p100. Here we report a novel mechanism of NIK regulation involving the chaperone 90 kDa heat shock protein (Hsp90) and autophagy.Functional inhibition of lisp90 by the anti-tumor agent geldanamycin (GA) efficiently disrupts its interaction with NIK,resulting in NIK degradation and subsequent blockage of p100 processing. Surprisingly, GA-induced NIK degradation is mediated by autophagy, but largely independent of the ubiquitin-proteasome system. Hsp90 seems to be specifically involved in the folding/stabilization of NIK protein, because GA inhibition does not affect NIK mRNA transcription and translation. Furthermore, Hsp90 is not required for NIK-mediated recruitment of the α subunit of IκB kinase to p100, a key step in induction of p100 processing. These findings define an alternative mechanism for Hsp90 client degradation and identify a novel function of autophagy in NF-κB regulation. These findings also suggest a new therapeutic strategy for diseases associated with p100 processing.

  7. Activating transcription factor-3 (ATF3) functions as a tumor suppressor in colon cancer and is up-regulated upon heat-shock protein 90 (Hsp90) inhibition

    International Nuclear Information System (INIS)

    Activating transcription factor-3 (ATF3) is involved in the complex process of cellular stress response. However, its exact role in cancer is discussed controversially because both tumor suppressive and oncogenic effects have been described. Here we followed-up on our previous observation that inhibition of Hsp90 may increase ATF3 expression and sought to determine the role of ATF3 in colon cancer. Regulation of ATF3 was determined in cancer cells using signaling inhibitors and a heat-shock protein-90 (Hsp90) antagonist. Human HCT116 cancer cells were stably transfected with an ATF3-shRNA or a luciferase-shRNA expression plasmid and alterations in cell motility were assessed in migration assays. The impact of ATF3 down-regulation on cancer growth and metastasis were investigated in a subcutaneous tumor model, a model of hepatic tumor growth and in a model of peritoneal carcinomatosis. Human colon cancer tissues were analyzed for ATF3 expression. The results show that therapeutic Hsp90 inhibition substantially up-regulates the expression of ATF3 in various cancer cells, including colon, gastric and pancreatic cancer. This effect was evident both in vitro and in vivo. RNAi mediated knock-down of ATF3 in HCT116 colon cancer cells significantly increased cancer cell migration in vitro. Moreover, in xenogenic mouse models, ATF3 knock-down promoted subcutaneous tumor growth and hepatic metastasis, as well as peritoneal carcinomatosis. Importantly, ATF3 expression was lower in human colon cancer specimens, as compared to corresponding normal surrounding tissues, suggesting that ATF3 may represent a down-regulated tumor suppressor in colon cancer. In conclusion, ATF3 down-regulation in colon cancer promotes tumor growth and metastasis. Considering that blocking Hsp90 induces ATF3 expression, Hsp90 inhibition may represent a valid strategy to treat metastatic colon cancer by up-regulating this anti-metastatic transcription factor

  8. Sensitization of Chemo-Resistant Human Chronic Myeloid Leukemia Stem-Like Cells to Hsp90 Inhibitor by SIRT1 Inhibition

    Science.gov (United States)

    Kim, Hak-Bong; Lee, Su-Hoon; Um, Jee-Hyun; Kim, Mi-Ju; Hyun, Suh-Kyung; Gong, Eun-Ji; Oh, Won Keun; Kang, Chi-Dug; Kim, Sun-Hee

    2015-01-01

    Development of effective therapeutic strategies to eliminate cancer stem-like cells (CSCs), which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. The current investigation was undertaken to examine the effectiveness of the combination treatment of Hsp90 inhibitor and SIRT1 inhibitor in inhibiting the growth of chemo-resistant stem-like cells isolated from human chronic myeloid leukemia K562 cells. Inhibition of SIRT1 by use of SIRT1 siRNA or SIRT1 inhibitors (amurensin G and EX527) effectively potentiated sensitivity of Hsp90 inhibitors (17-AAG and AUY922) in CD44high K562 stem-like cells expressing high levels of CSC-related molecules including Oct4, CD34, β-catenin, c-Myc, mutant p53 (mut p53), BCRP and P-glycoprotein (P-gp) as well as CD44. SIRT1 depletion caused significant down-regulation of heat shock factor 1 (HSF1)/heat shock proteins (Hsps) as well as these CSC-related molecules, which led to the sensitization of CD44high K562 cells to Hsp90 inhibitor by SIRT1 inhibitor. Moreover, 17-AAG-mediated activation of HSF1/Hsps and P-gp-mediated efflux, major causes of Hsp90 inhibitor resistance, was suppressed by SIRT1 inhibitor in K562-CD44high cells. Our data suggest that combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be an effective therapeutic approach to target CSCs that are resistant to current therapies. PMID:26157347

  9. Dexamethasone regulates CFTR expression in Calu-3 cells with the involvement of chaperones HSP70 and HSP90.

    Directory of Open Access Journals (Sweden)

    Luiz Felipe M Prota

    Full Text Available BACKGROUND: Dexamethasone is widely used for pulmonary exacerbation in patients with cystic fibrosis, however, not much is known about the effects of glucocorticoids on the wild-type cystic fibrosis channel transmembrane regulator (CFTR. Our aim was to determine the effects of dexamethasone treatment on wild-type CFTR expression. METHODS AND RESULTS: Dose-response (1 nM to 10 µM and time course (3 to 48 h curves were generated for dexamethasone for mRNA expression in Calu-3 cells using a real-time PCR. Within 24 h, dexamethasone (10 nM showed a 0.3-fold decrease in CFTR mRNA expression, and a 3.2-fold increase in αENaC mRNA expression compared with control groups. Dexamethasone (10 nM induced a 1.97-fold increase in the total protein of wild-type CFTR, confirmed by inhibition by mifepristone. To access surface protein expression, biotinylation followed by Western blotting showed that dexamethasone treatment led to a 2.35-fold increase in the amount of CFTR in the cell surface compared with the untreated control groups. Once protein translation was inhibited with cycloheximide, dexamethasone could not increase the amount of CFTR protein. Protein stability was assessed by inhibition of protein synthesis with cycloheximide (50 µg/ml at different times in cells treated with dexamethasone and in untreated cells. Dexamethasone did not alter the degradation of wild-type CFTR. Assessment of the B band of CFTR within 15 min of metabolic pulse labeling showed a 1.5-fold increase in CFTR protein after treatment with dexamethasone for 24 h. Chaperone 90 (HSP90 binding to CFTR increased 1.55-fold after treatment with dexamethasone for 24 h, whereas chaperone 70 (HSP70 binding decreased 0.30 fold in an immunoprecipitation assay. CONCLUSION: Mature wild-type CFTR protein is regulated by dexamethasone post transcription, involving cotranslational mechanisms with HSP90 and HSP70, which enhances maturation and expression of wild-type CFTR.

  10. Expression, purification and polyclonal antibody generation of p23,an Hsp90 cochaperone, in the amphioxus Branchiostoma belcheri

    Institute of Scientific and Technical Information of China (English)

    ZHAO Bosheng; ZHANG Shicui; PANG Qiuxiang; LIU Zhenhui; LIANG Yujun

    2006-01-01

    The cDNA of amphioxus p23, a highly conserved co-chaperone for Hsp90, was cloned into a bacterial expression vector pGEX-6P-1 and the GST-tagged fusion protein was produced in Eschherichia coli cells. The recombinant p23 was purified by affinity purification, and its molecular mass was estimated to be approximately 22 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The N-terminus of purified p23 was sequenced, and the resulting amino acid sequence matches exactly the predicted residues deduced from the amphioxus p23 gene. Besides, polyclonal antibodies against the recombinant p23 were generated, and these antibodies not only recognized specifically the fusion protein GST-p23 from induced E. coli cells, purified GST-p23 and p23 protein, but also reacted with the total protein extracted from the adult amphioxus and formed a single positive band. These results pave the way for identifying its tissue and subcellular localization, and may open the door to clarifying its structure and mechanisms of biological role.

  11. Membrane Phospholipids, EML4-ALK and Hsp90 as Novel Targets in Lung Cancer Treatment

    OpenAIRE

    Laszlo, Andrei; Thotala, Dinesh; Hallahan, Dennis E.

    2013-01-01

    Approximately one third of patients with non-small cell lung cancer have unresectable stage IIIA or stage IIIB disease; combined cytotoxic chemotherapy and radiation therapy delivered concurrently has been established as the standard treatment for such patients. Despite many clinical trials testing many different radiochemotherapy combinations, it seems that a plateau of efficiencies at the acceptable risk of complications has been reached. Clinical studies indicate that the improved efficacy...

  12. Asymmetric dimethylarginine inhibits HSP90 activity in Pulmonary Arterial Endothelial Cells: Role of Mitochondrial Dysfunction

    OpenAIRE

    Sud, Neetu; Wells, Sandra M.; Wiseman, Dean A.; Wilham, Jason; Black, Stephen M.

    2008-01-01

    Increased ADMA levels have been implicated in the pathogenesis of a number of conditions affecting the cardiovascular system. However, the mechanism(s) by which ADMA exerts its effect has not been adequately elucidated. Thus, the purpose of this study was to determine the effect of increased ADMA on nitric oxide (NO) signaling and to begin to elucidate the mechanism by which ADMA acts. Our initial data demonstrated that that ADMA increased NOS uncoupling both in recombinant human endothelial ...

  13. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

    OpenAIRE

    Weigert, Oliver; Bird, Liat; Kopp, Nadja; van Bodegom, Diederik; Marubayashi, Sachie; Christie, Amanda L.; Paranal, Ronald M.; Gaul, Christoph; Vangrevelinghe, Eric; Romanet, Vincent; Murakami, Masato; Tiedt, Ralph; Ebel, Nicolas; Evrot, Emeline; De Pover, Alain

    2012-01-01

    Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor–like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with ...

  14. An Inducible Retroviral Expression System for Tandem Affinity Purification Mass-Spectrometry-Based Proteomics Identifies Mixed Lineage Kinase Domain-like Protein (MLKL) as an Heat Shock Protein 90 (HSP90) Client.

    Science.gov (United States)

    Bigenzahn, Johannes W; Fauster, Astrid; Rebsamen, Manuele; Kandasamy, Richard K; Scorzoni, Stefania; Vladimer, Gregory I; Müller, André C; Gstaiger, Matthias; Zuber, Johannes; Bennett, Keiryn L; Superti-Furga, Giulio

    2016-03-01

    Tandem affinity purification-mass spectrometry (TAP-MS) is a popular strategy for the identification of protein-protein interactions, characterization of protein complexes, and entire networks. Its employment in cellular settings best fitting the relevant physiology is limited by convenient expression vector systems. We developed an easy-to-handle, inducible, dually selectable retroviral expression vector allowing dose- and time-dependent control of bait proteins bearing the efficient streptavidin-hemagglutinin (SH)-tag at their N- or C termini. Concomitant expression of a reporter fluorophore allows to monitor bait-expressing cells by flow cytometry or microscopy and enables high-throughput phenotypic assays. We used the system to successfully characterize the interactome of the neuroblastoma RAS viral oncogene homolog (NRAS) Gly12Asp (G12D) mutant and exploited the advantage of reporter fluorophore expression by tracking cytokine-independent cell growth using flow cytometry. Moreover, we tested the feasibility of studying cytotoxicity-mediating proteins with the vector system on the cell death-inducing mixed lineage kinase domain-like protein (MLKL) Ser358Asp (S358D) mutant. Interaction proteomics analysis of MLKL Ser358Asp (S358D) identified heat shock protein 90 (HSP90) as a high-confidence interacting protein. Further phenotypic characterization established MLKL as a novel HSP90 client. In summary, this novel inducible expression system enables SH-tag-based interaction studies in the cell line proficient for the respective phenotypic or signaling context and constitutes a valuable tool for experimental approaches requiring inducible or traceable protein expression. PMID:26933192

  15. Mutational Analysis of Glycogen Synthase Kinase 3β Protein Kinase Together with Kinome-Wide Binding and Stability Studies Suggests Context-Dependent Recognition of Kinases by the Chaperone Heat Shock Protein 90.

    Science.gov (United States)

    Jin, Jing; Tian, Ruijun; Pasculescu, Adrian; Dai, Anna Yue; Williton, Kelly; Taylor, Lorne; Savitski, Mikhail M; Bantscheff, Marcus; Woodgett, James R; Pawson, Tony; Colwill, Karen

    2016-01-01

    The heat shock protein 90 (HSP90) and cell division cycle 37 (CDC37) chaperones are key regulators of protein kinase folding and maturation. Recent evidence suggests that thermodynamic properties of kinases, rather than primary sequences, are recognized by the chaperones. In concordance, we observed a striking difference in HSP90 binding between wild-type (WT) and kinase-dead (KD) glycogen synthase kinase 3β (GSK3β) forms. Using model cell lines stably expressing these two GSK3β forms, we observed no interaction between WT GSK3β and HSP90, in stark contrast to KD GSK3β forming a stable complex with HSP90 at a 1:1 ratio. In a survey of 91 ectopically expressed kinases in DLD-1 cells, we compared two parameters to measure HSP90 dependency: static binding and kinase stability following HSP90 inhibition. We observed no correlation between HSP90 binding and reduced stability of a kinase after pharmacological inhibition of HSP90. We expanded our stability study to >50 endogenous kinases across four cell lines and demonstrated that HSP90 dependency is context dependent. These observations suggest that HSP90 binds to its kinase client in a particular conformation that we hypothesize to be associated with the nucleotide-processing cycle. Lastly, we performed proteomics profiling of kinases and phosphopeptides in DLD-1 cells to globally define the impact of HSP90 inhibition on the kinome. PMID:26755559

  16. Expression of HSP70 family and HSP90 family in skeletal muscles of transport stressed pigs%运输应激猪骨骼肌中热应激蛋白HSP70和HSP90家族的表达

    Institute of Scientific and Technical Information of China (English)

    鲍恩东; Sultan,KR; 等

    2001-01-01

    To demonstrate the expression of heat shock protein s(HSP)in skeletal muscles and to estimate the relationship between expression of HSP and pork quality, using Western blot four kinds of HSP which belongs to HSP70 family and HSP90 family respectively in porcine skeletal muscle tissues were determined after a long distance transport.All four HSP,namely HSP70,HSP72,HSP86 and HSP90,were regularly detected in M.longissimus dorsi and M.gluteus medius of both the transported and the cont rol group.The expression of HSP in control pigs showed that HSPs have some indep endent physiological from stress response undetermined functions.after 6 h trans port,the induction of the HSP70 and HSP72 in skeletal muscle tissues was slightly elevated(P>0.05).However,expression of the HSP 86 and the HSP90,especially HSP90,markedly decreased(P<0.01)in skelet al muscles.The results are implied that the reduction tendency of HSP90 fa mily is relative to pork quality and may serve as a potential marker for stress response.%利用Western blot技术,检测长途运输试验猪骨骼肌(背最长肌和臀大肌)中分属于HSP70家族和HSP90家族的4种应激蛋白(HSP70,HSP 72,HSP86和HSP90)的表达。所有运输应激猪和对照猪肌肉组织中均检测到了上述4种HSP。对照猪组织中HSP的表达说明HSP除了在受应激的细胞内行使生理功能外,还具有独立于应激刺激应答以外的其它作用。6 h的长途运输后,HSP的表达量明显不同,HSP70和HSP72在肌肉组织中的表达虽然有一定的增加,但统计学分析差异不显著(P>0.05);而HSP86和HSP90在骨骼肌中的表达明显下降,尤以HS P90下降最为显著(P<0.01)。提示HSP90家族成员与肉品品质相关,可能作为判断应激损伤的指征。

  17. The Hsp90 inhibitor SNX-7081 is synergistic with fludarabine nucleoside via DNA damage and repair mechanisms in human, p53-negative chronic lymphocytic leukemia.

    Science.gov (United States)

    Kaufman, Kimberley L; Jenkins, Yiping; Alomari, Munther; Mirzaei, Mehdi; Best, O Giles; Pascovici, Dana; Mactier, Swetlana; Mulligan, Stephen P; Haynes, Paul A; Christopherson, Richard I

    2015-12-01

    Clinical trials of heat shock protein 90 (Hsp90) inhibitors have been limited by high toxicity. We previously showed that the Hsp90 inhibitor, SNX-7081, synergizes with and restores sensitivity to fludarabine nucleoside (2-FaraA) in human chronic lymphocytic leukemia (CLL) cells with lesions in the p53 pathway (Best OG, et al., Leukemia Lymphoma 53:1367-75, 2012). Here, we used label-free quantitative shotgun proteomics and comprehensive bioinformatic analysis to determine the mechanism of this synergy. We propose that 2-FaraA-induced DNA damage is compounded by SNX-7081-mediated inhibition of DNA repair, resulting in enhanced induction of apoptosis. DNA damage responses are impaired in part due to reductions in checkpoint regulators BRCA1 and cyclin D1, and cell death is triggered following reductions of MYC and nucleolin and an accumulation of apoptosis-inducing NFkB2 p100 subunit. Loss of nucleolin can activate Fas-mediated apoptosis, leading to the increase of pro-apoptotic proteins (BID, fas-associated factor-2) and subsequent apoptosis of p53-negative, 2-FaraA refractory CLL cells. A significant induction of DNA damage, indicated by increases in DNA damage marker γH2AX, was observed following the dual drug treatment of additional cell lines, indicating that a similar mechanism may operate in other p53-mutated human B-lymphoid cancers. These results provide valuable insight into the synergistic mechanism between SNX-7081 and 2-FaraA that may provide an alternative treatment for CLL patients with p53 mutations, for whom therapeutic options are currently limited. Moreover, this drug combination reduces the effective dose of the Hsp90 inhibitor and may therefore alleviate any toxicity encountered. PMID:26556860

  18. CNS1 Encodes an Essential p60/Sti1 Homolog in Saccharomyces cerevisiae That Suppresses Cyclophilin 40 Mutations and Interacts with Hsp90

    OpenAIRE

    Dolinski, Kara J.; Cardenas, Maria E; Heitman, Joseph

    1998-01-01

    Cyclophilins are cis-trans-peptidyl-prolyl isomerases that bind to and are inhibited by the immunosuppressant cyclosporin A (CsA). The toxic effects of CsA are mediated by the 18-kDa cyclophilin A protein. A larger cyclophilin of 40 kDa, cyclophilin 40, is a component of Hsp90-steroid receptor complexes and contains two domains, an amino-terminal prolyl isomerase domain and a carboxy-terminal tetratricopeptide repeat (TPR) domain. There are two cyclophilin 40 homologs in the yeast Saccharomyc...

  19. HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Akahane, K; Sanda, T; Mansour, M R; Radimerski, T; DeAngelo, D J; Weinstock, D M; Look, A T

    2016-01-01

    We previously found that tyrosine kinase 2 (TYK2) signaling through its downstream effector phospho-STAT1 acts to upregulate BCL2, which in turn mediates aberrant survival of T-cell acute lymphoblastic leukemia (T-ALL) cells. Here we show that pharmacologic inhibition of heat shock protein 90 (HSP90) with a small-molecule inhibitor, NVP-AUY922 (AUY922), leads to rapid degradation of TYK2 and apoptosis in T-ALL cells. STAT1 protein levels were not affected by AUY922 treatment, but phospho-STAT1 (Tyr-701) levels rapidly became undetectable, consistent with a block in signaling downstream of TYK2. BCL2 expression was downregulated after AUY922 treatment, and although this effect was necessary for AUY922-induced apoptosis, it was not sufficient because many T-ALL cell lines were resistant to ABT-199, a specific inhibitor of BCL2. Unlike ABT-199, AUY922 also upregulated the proapoptotic proteins BIM and BAD, whose increased expression was required for AUY922-induced apoptosis. Thus, the potent cytotoxicity of AUY922 involves the synergistic combination of BCL2 downregulation coupled with upregulation of the proapoptotic proteins BIM and BAD. This two-pronged assault on the mitochondrial apoptotic machinery identifies HSP90 inhibitors as promising drugs for targeting the TYK2-mediated prosurvival signaling axis in T-ALL cells. PMID:26265185

  20. Measurement of Nanomolar Dissociation Constants by Titration Calorimetry and Thermal Shift Assay – Radicicol Binding to Hsp90 and Ethoxzolamide Binding to CAII

    Directory of Open Access Journals (Sweden)

    Vilma Michailovienė

    2009-06-01

    Full Text Available The analysis of tight protein-ligand binding reactions by isothermal titration calorimetry (ITC and thermal shift assay (TSA is presented. The binding of radicicol to the N-terminal domain of human heat shock protein 90 (Hsp90aN and the binding of ethoxzolamide to human carbonic anhydrase (hCAII were too strong to be measured accurately by direct ITC titration and therefore were measured by displacement ITC and by observing the temperature-denaturation transitions of ligand-free and ligand-bound protein. Stabilization of both proteins by their ligands was profound, increasing the melting temperature by more than 10 ºC, depending on ligand concentration. Analysis of the melting temperature dependence on the protein and ligand concentrations yielded dissociation constants equal to 1 nM and 2 nM for Hsp90aN-radicicol and hCAII-ethoxzolamide, respectively. The ligand-free and ligand-bound protein fractions melt separately, and two melting transitions are observed. This phenomenon is especially pronounced when the ligand concentration is equal to about half the protein concentration. The analysis compares ITC and TSA data, accounts for two transitions and yields the ligand binding constant and the parameters of protein stability, including the Gibbs free energy and the enthalpy of unfolding.

  1. Quantitative Phosphoproteomics of Tomato Mounting a Hypersensitive Response Reveals a Swift Suppression of Photosynthetic Activity and a Differential Role for Hsp90 Isoforms

    DEFF Research Database (Denmark)

    Stulemeijer, Iris J E; Joosten, Matthieu H A J; Jensen, Ole N

    2009-01-01

    An important mechanism by which plants defend themselves against pathogens is the rapid execution of a hypersensitive response (HR). Tomato plants containing the Cf-4 resistance gene mount an HR that relies on the activation of phosphorylation cascades, when challenged with the Avr4 elicitor....... We show that label-free relative quantification of the phosphoproteome of complex samples is feasible, allowing extension of our knowledge on the general physiology and defense signaling of plants mounting the HR.......-dependent way during the very early stages of HR development. In addition, phosphopeptides originating from four Hsp90 isoforms exhibited altered abundances in Cf-4/Avr4 seedlings compared to control seedlings, suggesting that the isoforms of this chaperone protein have a different function in defense signaling...

  2. Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice

    International Nuclear Information System (INIS)

    In the peripheral blood leukocytes (PBLs) from the carriers of the human T-lymphotropic virus type-1 (HTLV-1) or the patients with adult T-cell leukemia (ATL), nuclear factor kappaB (NF-κB)-mediated antiapoptotic signals are constitutively activated primarily by the HTLV-1-encoded oncoprotein Tax. Tax interacts with the I κB kinase regulatory subunit NEMO (NF-κB essential modulator) to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, heat-shock protein 90 (HSP90), and its co-chaperone cell division cycle 37 (CDC37). The antibiotic geldanamycin (GA) inhibits HSP90's ATP binding for its proper interaction with client proteins. Administration of a novel water-soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), to Tax-expressing ATL-transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines, although this treatment has no apparent effects on normal PBLs. 17-DMAG also downregulated Tax-mediated intracellular signals including the activation of NF-κB, activator protein 1 or HTLV-1 long terminal repeat in Tax-transfected HEK293 cells. Oral administration of 17-DMAG to ATL model mice xenografted with lymphomatous transgenic Lck-Tax (Lck proximal promoter-driven Tax transgene) cells or HTLV-1-producing tumor cells dramatically attenuated aggressive infiltration into multiple organs, inhibited de novo viral production and improved survival period. These observations identified 17-DMAG as a promising candidate for the prevention of ATL progression

  3. Effect of heat stress on performance and expression of selected amino acid and glucose transporters, HSP90, leptin and ghrelin in growing pigs.

    Science.gov (United States)

    Cervantes, Miguel; Cota, Margarita; Arce, Néstor; Castillo, Gilberto; Avelar, Ernesto; Espinoza, Salvador; Morales, Adriana

    2016-07-01

    Exposing animals to high ambient temperature provokes heat stress (HS) that may affect cellular function and reduced productive performance. The effect of chronic exposure (21d) of pigs to high ambient temperature on expression of amino acid (b(0,+)AT, CAT1) and glucose (SGLT1, GLUT4) transporters, ghrelin, leptin and HSP90 was evaluated. Eighteen pigs (32.6kg body weight) were distributed into 3 groups: (1) pigs housed under natural high ambient temperature conditions, and fed ad libitum (HS); (2) pigs housed in an air-conditioned room at 24°C (thermo-neutral) fed ad libitum (TNad); (3) pigs housed as in (2), but pair-fed with the HS pigs (TNpf). Body temperature, respiratory frequency, weight gain, feed intake, and feed conversion ratio were measured. At d-21 pigs were euthanized and samples from stomach, duodenum, jejunum, liver, longissimus and semitendinosus muscles, and white adipose tissue were collected for mRNA analysis. In the HS room ambient temperature fluctuated every day (23.6-37.6°C). Respiratory frequency and body temperature were higher in HS pigs (Pleptin and b(0,+)AT were not affected by ambient temperature (P>0.050). CAT1 expression in liver was higher (P=0.050) but in longissimus was lower (P=0.017) in HS than in TNpf pigs. Expression of SGLT1 was higher (P=0.045) in duodenum of HS than in TNpf but it was not different in jejunum (P=0.545); GLUT4 tended to be higher in liver and semitendinosus of HS pigs (P=0.063). In conclusion, feed intake remains low whereas respiratory frequency and body temperature remain higher; and expression of HSP90, CAT1, SGLT1 and GLUT4 increases in some tissues in pigs under chronic HS conditions. PMID:27264891

  4. Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain

    Science.gov (United States)

    Richards, Mark W.; Law, Edward W. P.; Rennalls, La’Verne P.; Busacca, Sara; O’Regan, Laura; Fry, Andrew M.; Fennell, Dean A.; Bayliss, Richard

    2014-01-01

    Proteins of the echinoderm microtubule-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-Å crystal structure of the representative ∼70-kDa core of EML1, revealing an intimately associated pair of β-propellers, which we term a TAPE (tandem atypical propeller in EMLs) domain. One propeller is highly atypical, having a discontinuous subdomain unrelated to a WD40 motif in place of one of its blades. This unexpected feature shows how a propeller structure can be assembled from subdomains with distinct folds. The HELP motif is not an independent domain but forms part of the hydrophobic core that joins the two β-propellers. The TAPE domain binds α/β-tubulin via its conserved, concave surface, including part of the atypical blade. Mapping the characteristic breakpoints of each EML4-ALK variant onto our structure indicates that the EML4 TAPE domain is truncated in many variants in a manner likely to make the fusion protein structurally unstable. We found that the heat shock protein 90 (Hsp90) inhibitor ganetespib induced degradation of these variants whereas others lacking a partial TAPE domain were resistant in both overexpression models and patient-derived cell lines. The Hsp90-sensitive EML4-ALK variants are exceptions to the rule that oncogenic fusion proteins involve breakpoints in disordered regions of both partners. PMID:24706829

  5. Effect of inhibition of the Ubiquitin-Proteasome System and Hsp90 on growth and survival of Rhabdomyosarcoma cells in vitro

    Directory of Open Access Journals (Sweden)

    Peron Marica

    2012-06-01

    Full Text Available Abstract Background The ubiquitin-proteasome system (UPS and the heat shock response (HSR are two critical regulators of cell homeostasis, as their inhibition affects growth and survival of normal cells, as well as stress response and invasiveness of cancer cells. We evaluated the effects of the proteasome inhibitor Bortezomib and of 17-DMAG, a competitive inhibitor of Hsp90, in rhabdomyosarcoma (RMS cells, and analyzed the efficacy of single-agent exposures with combination treatments. Methods To assess cytotoxicity induced by Bortezomib and 17-DMAG in RMS cells, viability was measured by MTT assay after 24, 48 and 72 hours. Western blotting and immunofluorescence analyses were carried out to elucidate the mechanisms of action. Apoptosis was measured by FACS with Annexin-V-FITC and Propidium Iodide. Results Bortezomib and 17-DMAG, when combined at single low-toxic concentrations, enhanced growth inhibition of RMS cells, with signs of autophagy that included intensive cytoplasmic vacuolization and conversion of cytosolic LC3-I protein to its autophagosome-associated form. Treatment with lysosomal inhibitor chloroquine facilitates apoptosis, whereas stimulation of autophagy by rapamycin prevents LC3-I conversion and cell death, suggesting that autophagy is a resistance mechanism in RMS cells exposed to proteotoxic drugs. However, combination treatment also causes caspase-dependent apoptosis, PARP cleavage and Annexin V staining, as simultaneous inhibition of both UPS and HSR systems limits cytoprotective autophagy, exacerbating stress resulting from accumulation of misfolded proteins. Conclusion The combination of proteasome inhibitor Bortezomib with Hsp90 inhibitor 17-DMAG, appears to have important therapeutic advantages in the treatment of RMS cells compared with single-agent exposure, because compensatory survival mechanisms that occur as side effects of treatment may be prevented.

  6. Expression of Recombinant GFP-Hsp90P E47A Gene by Lentiviral Vector Transfection and Its Effect on Cell Proliferation in HepG2 Cells%慢病毒介导的GFP-Hsp90αE47A基冈在HepG2细胞表达及对细胞增殖性影响的研究

    Institute of Scientific and Technical Information of China (English)

    尹强兵; 王晓捷; 马晓姣; 邹飞; 陈雪梅

    2011-01-01

    目的:建立真核细胞表达的GFP-Hsp90α FA7A基因重组慢病毒栽体三质粒包装细胞系统,并检测其对细胞增殖性的影响,为进一步研究HSP90分子伴侣功能奠定基础.方法:制备完整的重组慢病毒载体三质粒系统:转移质粒(Hsp90αE47A/psin-GFP),包装质粒(△NRF)及包膜蛋白质粒(VSV-G).磷酸钙法将三质粒共转染293T包装细胞,48 h后收集病毒上清.将制备好的慢病毒颗粒感染HepG2细胞,在荧光显微镜下观察报告基因GFP的表达情况,Western blot检测HepG2细胞GFP-Hsp90α表达.MTT法检测细胞增殖情况.结果:转染后的293T和感染后的HepG2细胞能观察到较强的绿色荧光,培养液上清病毒滴度约为3.0× 103ifu/μl,HepG2细胞中有GFP-Hsp90α蛋白的表达.内源性Hsp90α表达无明显上升(为对照组的1.05±0.15倍,P<0.05,t检验),有明显外源性GFP-HspgoaFA7A蛋白的表达,为对照组内源性Hspgoa的0.68±0.12倍.外源性GFP-Hsp90αE47A蛋白的表达HepG2细胞增殖活性于第4d有明显抑制.(1.051±0.03 vs 1.349± 0.05,P<0.05,t检验).结论:成功建立重组慢病毒载体的三质粒包装细胞系统,并将GFP-Hsp90αE47A基因在HepG2细胞中稳定表达,且并未引起细胞明显的热休克反应而导致的内源性Hsp90α增高:且能明显抑制细胞增殖,为后期Hsp90α分子伴侣功能进行研究奠定基础.%Objective: To construct the three-plasmid packaging cell line of the recombinant lentiviral vector encoding Hsp90α E47A/psin-GFP gene and investigate the molecular chaperon function of hsp90α. Methods: The three-plasmid recombinant lentiviral vector, which was made up of the vector plasmid (Hsp90αE47A/psin-GFP), the packaging plasmid (△ NRF) and the envelop plasmid encoding the vesicular stomatitis virus-glycoprotein (VSV-G), was isolated and purified. Human embryonic kidney 293T cells were co-transfected with the three plasmids by calcium phosphate method. 48 hours after the transfection, the viral

  7. Endoplasmic Reticulum-resident Heat Shock Protein 90 (HSP90) Isoform Glucose-regulated Protein 94 (GRP94) Regulates Cell Polarity and Cancer Cell Migration by Affecting Intracellular Transport.

    Science.gov (United States)

    Ghosh, Suman; Shinogle, Heather E; Galeva, Nadezhda A; Dobrowsky, Rick T; Blagg, Brian S J

    2016-04-15

    Heat shock protein 90 (HSP90) is a molecular chaperone that is up-regulated in cancer and is required for the folding of numerous signaling proteins. Consequently, HSP90 represents an ideal target for the development of new anti-cancer agents. The human HSP90 isoform, glucose-regulated protein 94 (GRP94), resides in the endoplasmic reticulum and regulates secretory pathways, integrins, and Toll-like receptors, which contribute to regulating immunity and metastasis. However, the cellular function of GRP94 remains underinvestigated. We report that GRP94 knockdown cells are defective in intracellular transport and, consequently, negatively impact the trafficking of F-actin toward the cellular cortex, integrin α2 and integrin αL toward the cell membrane and filopodia, and secretory vesicles containing the HSP90α-AHA1-survivin complex toward the leading edge. As a result, GRP94 knockdown cells form a multipolar spindle instead of bipolar morphology and consequently manifest a defect in cell migration and adhesion. PMID:26872972

  8. Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases

    International Nuclear Information System (INIS)

    Despite aggressive treatment with radiation therapy and concurrent adjuvant temozolomide (TMZ), glioblastoma multiform (GBM) still has a dismal prognosis. We aimed to identify strategies to improve the therapeutic outcome of combined radiotherapy and TMZ in GBM by targeting pro-survival signaling from the epidermal growth factor receptor (EGFR). Glioma cell lines U251, T98G were used. Colony formation, DNA damage repair, mode of cell death, invasion, migration and vasculogenic mimicry as well as protein expression were determined. U251 cells showing a low level of methyl guanine transferase (MGMT) were highly responsive to the radiosensitizing effect of TMZ compared to T98G cells having a high level of MGMT. Treatment with a dual inhibitor of Class I PI3K/mTOR, PI103; a HSP90 inhibitor, 17-DMAG; or a HDAC inhibitor, LBH589, further increased the cytotoxic effect of radiation therapy plus TMZ in U251 cells than in T98G cells. However, treatment with a mTOR inhibitor, rapamycin, did not discernibly potentiate the radiosensitizing effect of TMZ in either cell line. The mechanism of enhanced radiosensitizing effects of TMZ was multifactorial, involving impaired DNA damage repair, induction of autophagy or apoptosis, and reversion of EMT (epithelial-mesenchymal transition). Our results suggest possible strategies for counteracting the pro-survival signaling from EGFR to improve the therapeutic outcome of combined radiotherapy and TMZ for high-grade gliomas

  9. Ahsa1 and Hsp90 activity confers more severe craniofacial phenotypes in a zebrafish model of hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR

    Directory of Open Access Journals (Sweden)

    Kelly Sheehan-Rooney

    2013-09-01

    The severity of most human birth defects is highly variable. Our ability to diagnose, treat and prevent defects relies on our understanding of this variability. Mutation of the transcription factor GATA3 in humans causes the highly variable hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR syndrome. Although named for a triad of defects, individuals with HDR can also exhibit craniofacial defects. Through a forward genetic screen for craniofacial mutants, we isolated a zebrafish mutant in which the first cysteine of the second zinc finger of Gata3 is mutated. Because mutation of the homologous cysteine causes HDR in humans, these zebrafish mutants could be a quick and effective animal model for understanding the role of gata3 in the HDR disease spectrum. We demonstrate that, unexpectedly, the chaperone proteins Ahsa1 and Hsp90 promote severe craniofacial phenotypes in our zebrafish model of HDR syndrome. The strengths of the zebrafish system, including rapid development, genetic tractability and live imaging, make this an important model for variability.

  10. Immunohistochemical evaluation of expression of heat shock proteins HSP70 and HSP90 in mammary gland neoplasms in bitches.

    Science.gov (United States)

    Badowska-Kozakiewicz, A M; Malicka, E

    2012-01-01

    Heat shock proteins have essential roles in a number of pathophysiologic conditions including carcinogenesis and represent a group of novel molecular markers in cancer management. The aim of this study was to investigate heat shock protein expression in correlation with other neoplasm traits such as: histological type, differentiation grade, proliferative activity, estrogenic receptor expression, and cyclooxygenase-2 and p53 proteins. Material for the investigation comprised 133 tumors of the mammary gland collected from bitches. In total 14 adenomas, 66 complex carcinomas, 47 simple carcinomas and 6 solid carcinomas were collected. Evaluations were conducted with histopathological and immunohistochemical methods using suitable antibodies. Expression of heat shock protein 70 was observed in all types of evaluated neoplasms. A higher average number of cells undergoing expression of heat shock protein 70, which was statistically insignificant, was established in complex and simple cancers and in cancers with the 1st and the 2nd degree of histological malignancy. Expression of heat shock protein 90 was observed in all studied neoplasms; it was very insignificant in adenomas, compared to cancers, and the highest expression was established in the solid cancers, as well as in cancers with the 2nd degree of histological malignancy. This high expression of heat shock protein 90 was correlated with proliferative activity. The results suggest that heat shock protein 90 is involved in canine mammary gland carcinogenesis. The results also suggest that heat shock protein 90 may be a prognostic factor, but this requires detailed clinical confirmation. PMID:22844695

  11. Ligand stimulation induces clathrin- and Rab5-dependent downregulation of the kinase-dead EphB6 receptor preceded by the disruption of EphB6-Hsp90 interaction.

    Science.gov (United States)

    Allonby, Odette; El Zawily, Amr M; Freywald, Tanya; Mousseau, Darrell D; Chlan, Jennifer; Anderson, Deborah; Benmerah, Alexandre; Sidhu, Vishaldeep; Babu, Mohan; DeCoteau, John; Freywald, Andrew

    2014-12-01

    Ligand-induced internalisation and subsequent downregulation of receptor tyrosine kinases (RTKs) serve to determine biological outputs of their signalling. Intrinsically kinase-deficient RTKs control a variety of biological responses, however, the mechanism of their downregulation is not well understood and its analysis is focused exclusively on the ErbB3 receptor. The Eph group of RTKs is represented by the EphA and EphB subclasses. Each bears one kinase-inactive member, EphA10 and EphB6, respectively, suggesting an important role for these molecules in the Eph signalling network. While EphB6 effects on cell behaviour have been assessed, the mechanism of its downregulation remains elusive. Our work reveals that EphB6 and its kinase-active relative, and signalling partner, EphB4, are downregulated in a similar manner in response to their common ligand, ephrin-B2. Following stimulation, both receptors are internalised through clathrin-coated pits and are degraded in lysosomes. Their targeting for lysosomal degradation relies on the activity of an early endosome regulator, the Rab5 GTPase, as this process is inhibited in the presence of a Rab5 dominant-negative mutant. EphB6 also interacts with the Hsp90 chaperone and EphB6 downregulation is preceded by their rapid dissociation. Moreover, the inhibition of Hsp90 results in EphB6 degradation, mimicking its ligand-induced downregulation. These processes appear to rely on overlapping mechanisms, since Hsp90 inhibition does not significantly enhance ligand-induced EphB6 elimination. Taken together, our observations define a novel mechanism for intrinsically kinase-deficient RTK downregulation and support an intriguing model, where Hsp90 dissociation acts as a trigger for ligand-induced receptor removal. PMID:25152371

  12. Increased radiosensitivity and radiothermosensitivity of human pancreatic MIA PaCa-2 and U251 glioblastoma cell lines treated with the novel Hsp90 inhibitor NVP-HSP990

    International Nuclear Information System (INIS)

    Heat shock Protein 90 (Hsp90) is a molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins involved in oncogenic signaling and in the regulation of radiosensitivity. It is upregulated in response to stress such a heat. Hyperthermia is a potent radiosensitizer, but induction of Hsp90 may potentially limit its efficacy. Our aim was to investigate whether the new Hsp90 inhibitor NVP-HSP990 increases radiosensitivity, thermosensitivity and radiothermosensitivity of human tumor cell lines. U251 glioblastoma and MIA PaCa-2 pancreatic carcinoma cells were used. To determine clonogenic survival, colony forming assays were performed. Cell viability and proliferation were assesed by Trypan blue staining. Cell cycle and apoptosis analyses were performed by flow cytometry. DAPI staining was used to detect mitotic catastrophe. NVP-HSP990 increased the thermosensitivity, radiosensitivity and radio-thermosensitivity of both cell lines in clonogenic assays. 72 hours after irradiation with 4 Gy, a significant reduction in cell number associated with considerable G2/M acumulation and mitotic catastrophe as well as cell death by apoptosis/necrosis was observed. Treatment with NVP-HSP990 strongly sensitized U251 and MIA PaCa-2 cells to hyperthermia and ionizing radiation or combination thereof through augmentation of G2/M arrest, mitotic catastrophe and associated apoptosis

  13. Integrated proteomic platforms for the comparative characterization of medulloblastoma and pilocytic astrocytoma pediatric brain tumors: a preliminary study.

    Science.gov (United States)

    Martelli, Claudia; Iavarone, Federica; D'Angelo, Luca; Arba, Morena; Vincenzoni, Federica; Inserra, Ilaria; Delfino, Daniela; Rossetti, Diana Valeria; Caretto, Marta; Massimi, Luca; Tamburrini, Gianpiero; Di Rocco, Concezio; Caldarelli, Massimo; Messana, Irene; Castagnola, Massimo; Sanna, Maria Teresa; Desiderio, Claudia

    2015-06-01

    A top-down/bottom-up integrated proteomic approach based on LC-MS and 2-DE analysis was applied for comparative characterization of medulloblastoma and pilocytic astrocytoma posterior cranial fossa pediatric brain tumor tissues. Although rare, primary brain tumors are the most frequent solid tumors in the pediatric age. Among them the medulloblastoma is the prevalent malignant tumor in childhood while pilocytic astrocytoma is the most common, rarely showing a malignant progression. Due to the limited availability of this kind of sample, the study was applied to pooled tumor tissues for a preliminary investigation. The results showed different proteomic profiles of the two tumors and evidenced interesting differential expression of several proteins and peptides. Top-down proteomics of acid-soluble fractions of brain tumor homogenates ascribed a potential biomarker role of malignancy to β- and α-thymosins and their truncated proteoforms and to C-terminal truncated (des-GG) ubiquitin, resulting exclusively detected or over-expressed in the highly malignant medulloblastoma. The bottom-up proteomics of the acid-soluble fraction identified several proteins, some of them in common with 2-DE analysis of acid-insoluble pellets. Peroxiredoxin-1, peptidyl-prolyl cis-trans isomerase A, triosephosphate isomerase, pyruvate kinase PKM, tubulin beta and alpha chains, heat shock protein HSP-90-beta and different histones characterized the medulloblastoma while the Ig kappa chain C region, serotransferrin, tubulin beta 2A chain and vimentin the pilocytic astrocytoma. The two proteomic strategies, with their pros and cons, well complemented each other in characterizing the proteome of brain tumor tissues and in disclosing potential disease biomarkers to be validated in a future study on individual samples of both tumor histotypes. PMID:25909245

  14. Caracterización in silico de las proteínas del choque térmico Hsp70 y Hsp90 deBemisia tabaci (Hemiptera: Aleyrodidae y su posible actividad adaptativa

    Directory of Open Access Journals (Sweden)

    Eneida Torres Cabra

    2014-06-01

    Full Text Available La mosca blanca, Bemisia tabaci (Hemiptera: Aleyrodidae es una de las plagas más destructivas e invasivas en el mundo, ataca una gran cantidad de cultivos. Se adapta fácilmente a plantas hospederas y a nuevas regiones geográficas, lo que sugiere el desarrollo de mecanismos de control a daños producidos por factores estresantes. Las proteínas Hsp se expresanen los organismos como mecanismo de defensa, actúan como chaperonas en el correcto ensamblaje de las proteínas. En este estudio se realizó una caracterizaciónin silico de las proteínas Hsp70 y Hsp90 de B. tabaci, secuencias obtenidas de NCBI. La determinaciónde los perfiles de hidrofobicidad, polaridad, accesibilidady flexibilidad se obtuvieron con “ProScale” de ExPASy, el perfil de antigenicidad con JaMBW. La secuencia aminoacídica se analizó con GOR IV y SOPMA y la composición de aminoácidos con ProtParam. Para analizar el peso molecular, índice deinestabilidad, índice alifático y gradiente hidropático,con GRAVY. La estructura terciaria se obtuvo con HHpred, y ESyPred3D. Para validar las estructuras 3D se utilizó Procheck, What_check y errat. Hsp70 y Hsp90 de B. tabaci presentan valores bajos de hidrofobicidady altos de polaridad, flexibilidad y accesibilidad, características que le permiten a las proteínas extender su capacidad como chaperonas. La Hsp70tiene una estructura secundaria compuesta por 41-45% alfa hélices, 30-43% coil y menos del 6% en hoja plegada y la Hsp90 por 52 y 53% hélices, 26-34% coily 6% hoja plegada. Las Hsp juegan un rol importante en los insectos debido a su tamaño y corto ciclo de vida, pues la temperatura influye en su distribución y abundancia.

  15. The Box H/ACA snoRNP Assembly Factor Shq1p is a Chaperone Protein Homologous to Hsp90 Cochaperones that Binds to the Cbf5p Enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Godin, Katherine S.; Walbott, Helene; Leulliot, Nicolas; van Tilbeurgh, Herman; Varani, Gabriele

    2009-05-06

    Box H/ACA small nucleolar (sno) ribonucleoproteins (RNPs) are responsible for the formation of pseudouridine in a variety of RNAs and are essential for ribosome biogenesis, modification of spliceosomal RNAs, and telomerase stability. A mature snoRNP has been reconstituted in vitro and is composed of a single RNA and four proteins. However, snoRNP biogenesis in vivo requires multiple factors to coordinate a complex and poorly understood assembly and maturation process. Among the factors required for snoRNP biogenesis in yeast is Shq1p, an essential protein necessary for stable expression of box H/ACA snoRNAs. We have found that Shq1p consists of two independent domains that contain casein kinase 1 phosphorylation sites. We also demonstrate that Shq1p binds the pseudourydilating enzyme Cbf5p through the C-terminal domain, in synergy with the N-terminal domain. The NMR solution structure of the N-terminal domain has striking homology to the ‘Chord and Sgt1’ domain of known Hsp90 cochaperones, yet Shq1p does not interact with the yeast Hsp90 homologue in vitro. Surprisingly, Shq1p has stand-alone chaperone activity in vitro. This activity is harbored by the C-terminal domain, but it is increased by the presence of the N-terminal domain. These results provide the first evidence of a specific biochemical activity for Shq1p and a direct link to the H/ACA snoRNP.

  16. Brains studying brains: look before you think in vision

    OpenAIRE

    Zhaoping, L.

    2016-01-01

    Using our own brains to study our brains is extraordinary. For example, in vision this makes us naturally blind to our own blindness, since our impression of seeing our world clearly is consistent with our ignorance of what we do not see. Our brain employs its 'conscious' part to reason and make logical deductions using familiar rules and past experience. However, human vision employs many 'subconscious' brain parts that follow rules alien to our intuition. Our blindness to our unknown unknow...

  17. Brain and heart disease studies

    International Nuclear Information System (INIS)

    Highlights of important studies completed during the past year using the Donner 280-crystal positron ring tomograph are summarized in this article. Using rubidium-82, images of a brain tumor and an arteriovenous malformation are described. An image demonstrating methionine uptake in a patient with schizophrenia and an image reflecting sugar metabolism in the brain of a man with Alzheimer's disease are also included. Uptake of rubidium-82 in subjects before and after exercise is being investigated. The synthesis of new radiopharmaceuticals and the development of a new synthesis for C-taurine for use in the study of metabolism in the human heart are also being studied

  18. Activation of Hsp90/NOS and increased NO generation does not impair mitochondrial respiratory chain by competitive binding at cytochrome C Oxidase in low oxygen concentrations

    OpenAIRE

    Presley, Tennille; Vedam, Kaushik; Liu, Xiaoping; Zweier, Jay L.; Ilangovan, Govindasamy

    2009-01-01

    Nitric oxide (NO) is known to regulate mitochondrial respiration, especially during metabolic stress and disease, by nitrosation of the mitochondrial electron transport chain (ETC) complexes (irreversible) and by a competitive binding at O2 binding site of cytochrome c oxidase (CcO) in complex IV (reversible). In this study, by using bovine aortic endothelial cells, we demonstrate that the inhibitory effect of endogenously generated NO by nitric oxide synthase (NOS) activation, by either NOS ...

  19. Brains studying brains: look before you think in vision

    Science.gov (United States)

    Zhaoping, Li

    2016-06-01

    Using our own brains to study our brains is extraordinary. For example, in vision this makes us naturally blind to our own blindness, since our impression of seeing our world clearly is consistent with our ignorance of what we do not see. Our brain employs its ‘conscious’ part to reason and make logical deductions using familiar rules and past experience. However, human vision employs many ‘subconscious’ brain parts that follow rules alien to our intuition. Our blindness to our unknown unknowns and our presumptive intuitions easily lead us astray in asking and formulating theoretical questions, as witnessed in many unexpected and counter-intuitive difficulties and failures encountered by generations of scientists. We should therefore pay a more than usual amount of attention and respect to experimental data when studying our brain. I show that this can be productive by reviewing two vision theories that have provided testable predictions and surprising insights.

  20. Brain-Science Based Cohort Studies

    Science.gov (United States)

    Koizumi, Hideaki

    2011-01-01

    This article describes a number of human cohort studies based on the concept of brain-science and education. These studies assess the potential effects of new technologies on babies, children and adolescents, and test hypotheses drawn from animal and genetic case studies to see if they apply to people. A flood of information, virtual media,…

  1. In vivo Dynamic Studies of Brain Metabolism

    Institute of Scientific and Technical Information of China (English)

    LUO Xuechun; JIANG Yufeng; ZHANG Riqing

    2005-01-01

    Nuclear magnetic resonance (NMR) can noninvasively monitor intracellular concentrations and kinetic properties of numerous inorganic and organic compounds. A 31P NMR surface coil was used in vivo to dynamically measure phosphocreatine (PCr), adenosine triphosphate (ATP), and intracellular inorganic phosphate (Pi) levels in mouse brain during ischemia-reperfusion to study the damage of cerebral tissues caused by ischemia and effects of herbs on cerebral energy metabolism during ischemia-reperfusion. The study provides dynamic brain energy metabolism data during different periods. The data show that some herbs more rapidly increase the PCr level during the recovery phase than in the control group.

  2. Longitudinal MRI studies of brain morphometry

    DEFF Research Database (Denmark)

    Skimminge, Arnold Jesper Møller

    the accompanying deformation field. Deformation fields from high dimensional warping founds tensor based morphometry (TBM), and provides unique opportunities to study human brain morphology and plasticity. In this thesis, specially adapted image processing streams utilizing several image registration......High resolution MR images acquired at multiple time points of the brain allow quantification of localized changes induced by external factors such as maturation, ageing or disease progression/recovery. High-dimensional warping of such MR images incorporates changes induced by external factors into...

  3. Metallochelating liposomes with associated lipophilised norAbuMDP as biocompatible platform for construction of vaccines with recombinant His-tagged 3 antigens: Preparation, structural study and immune response towards rHsp90

    Czech Academy of Sciences Publication Activity Database

    Mašek, J.; Bartheldyová, E.; Turánek-Knotigová, P.; Škrabalová, M.; Korvasová, Z.; Plocková, J.; Koudelka, Š.; Škodová, P.; Kulich, P.; Křupka, M.; Zachová, K.; Czerneková, L.; Horynová, M.; Kratochvílová, Irena; Miller, A. D.; Zyka, Daniel; Michálek, J.; Vrbová, J.; Šebela, M.; Ledvina, Miroslav; Raška, M.; Turánek, J.

    2011-01-01

    Roč. 151, č. 2 (2011), s. 193-201. ISSN 0168-3659 R&D Projects: GA ČR(CZ) GAP304/10/1951; GA AV ČR KAN200520703; GA AV ČR KAN200100801 Institutional research plan: CEZ:AV0Z10100520; CEZ:AV0Z40550506 Keywords : recombinant vaccine * liposome Subject RIV: EC - Immunology Impact factor: 5.732, year: 2011 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3D-520M1P7-1&_user=625012&_coverDate=01%2F21%2F2011&_rdoc=1&_fmt=high&_orig=gateway&_origi

  4. A study of rotational brain injury.

    Science.gov (United States)

    Misra, J C; Chakravarty, S

    1984-01-01

    Of concern in the paper is an investigation on brain injuries which may occur owing to an input angular acceleration of the head. The study is based on the use of an improved mathematical model for the cranium. The eccentricity of the braincase is incorporated through the consideration of a prolate spheroidal shell as the representative of the skull. Also the dissipative mechanical behaviour of the brain material (as per the observations of experimenters) has been accounted for by considering the material contained in the shell as viscoelastic. The problem is formulated in terms of prolate spheroidal coordinates. The singularities of the governing equations of motion (when expressed in the prolate coordinate system) are removed by a suitable transformation of the concerned dependent variable, viz. the one that stands for the angular displacement of a representative point of the system. In the first place the solution of the boundary value problem is sought in the Laplace transform space, by employing a finite difference technique. Use of the alternating-direction-implicit method together with Thomas algorithm was made for obtaining the angular acceleration in the transformed space. The Laplace inversion is also carried out with the help of numerical procedures (Gauss quadrature formula is used for this purpose). The results of the parametric study are presented through graphs. The plots illustrate the shear stresses and strains in the brain medium. A meaningful comparison of the computational results with those of previous investigations indicate that the eccentricity of the braincase plays a significant role in causing injury to the brain. PMID:6480621

  5. Studies of aluminum in rat brain

    International Nuclear Information System (INIS)

    The effects of high aluminum concentrations in rat brains were studied using 14C autoradiography to measure the uptake of 14C 2-deoxy-D-glucose (14C-2DG) and microbeam proton-induced x-ray emission (microPIXE) with a 20-μm resolution to measure concentrations of magnesium, aluminum, potassium, and calcium. The aluminum was introduced intracisternally in the form of aluminum tartrate (Al-T) while control animals were given sodium tartrate (Na-T). The 14C was administered intravenously. The animals receiving Al-T developed seizure disorders and had pathological changes that included cerebral cortical atrophy. The results showed that there was a decreased uptake of 14C-2DG in cortical regions in which increased aluminum levels were measured, i.e., there is a correlation between the aluminum in the rat brain and decreased brain glucose metabolism. A minimum detection limit of about 16 ppM (mass fraction) or 3 x 109 Al atoms was obtained for Al under the conditions employed. 14 refs., 4 figs., 1 tab

  6. Study on MRI findings in postresuscitation brains

    International Nuclear Information System (INIS)

    We evaluated chronological changes in T1/T2-weighted and diffusion-weighted magnetic resonance imaging (MRI) findings in patients with global cerebral ischemia compared to computed tomography (CT) and single photon emission computed tomography (SPECT) to determine the advantages this presents in determining a patient's prognosis. We retrospectively studied MRI in 28 patients resuscitated after cardiopulmonary arrest. Patients were divided by outcome into 4 groups -- good outcome in 5, moderate disability in 2, vegetative in 17, and 4 brain-dead. Those with good recovery had normal CT and MRI findings. Those with moderate disability demonstrated high signal intensity in basal ganglia and posterior cerebral cortex during the chronic period. All vegetative patients had abnormal CT findings and their T2-weighted images during the acute period demonstrated high signal intensity in the cerebral cortex and basal ganglia; T1-weighted image during the chronic period showed similar findings, while diffusion-weighted images indicated high signal intensity in the cerebral cortex from the very acute period, during which abnormal findings were seen in the cortex, putamen, and thalamus more frequently than in T2-weighted images. Moreover, regional cerebral blood flow significantly decreased during the chronic period. All brain-dead patients had CT findings of diffuse cerebral edema and loss of density difference between gray and white matter. T2-weighted images respectively showed an extraordinary high density difference between gray and white matter and diffusion-weighted images high signal density in the whole brain. MRI detects chronologic changes in postresuscitation brain damage better than CT findings. Diffusion-weighted images identify hypoxic-ischemic lesions during the very acute period. MRI thus appears useful in evaluating patient prognosis and care. (author)

  7. Can Taichi Reshape the Brain? A Brain Morphometry Study

    OpenAIRE

    Wei, Gao-Xia; Xu, Ting; Fan, Feng-Mei; Dong, Hao-Ming; Jiang, Li-Li; Li, Hui-Jie; Yang, Zhi; Luo, Jing; Zuo, Xi-Nian

    2013-01-01

    Although research has provided abundant evidence for Taichi-induced improvements in psychological and physiological well-being, little is known about possible links to brain structure of Taichi practice. Using high-resolution MRI of 22 Tai Chi Chuan (TCC) practitioners and 18 controls matched for age, sex and education, we set out to examine the underlying anatomical correlates of long-term Taichi practice at two different levels of regional specificity. For this purpose, parcel-wise and vert...

  8. Animal imaging studies of potential brain damage

    Science.gov (United States)

    Gatley, S. J.; Vazquez, M. E.; Rice, O.

    To date, animal studies have not been able to predict the likelihood of problems in human neurological health due to HZE particle exposure during space missions outside the Earth's magnetosphere. In ongoing studies in mice, we have demonstrated that cocaine stimulated locomotor activity is reduced by a moderate dose (120 cGy) of 1 GeV 56Fe particles. We postulate that imaging experiments in animals may provide more sensitive and earlier indicators of damage due to HZE particles than behavioral tests. Since the small size of the mouse brain is not well suited to the spatial resolution offered by microPET, we are now repeating some of our studies in a rat model. We anticipate that this will enable us to identify imaging correlates of behavioral endpoints. A specific hypothesis of our studies is that changes in the metabolic rate for glucose in striatum of animals will be correlated with alterations in locomotor activity. We will also evaluate whether the neuroprotective drug L-deprenyl reduces the effect of radiation on locomotor activity. In addition, we will conduct microPET studies of brain monoamine oxidase A and monoamine oxidase B in rats before and at various times after irradiation with HZE particles. The hypothesis is that monoamine oxidase A, which is located in nerve terminals, will be unchanged or decreased after irradiation, while monoamine oxidase B, which is located in glial cells, will be increased after irradiation. Neurochemical effects that could be measured using PET could in principle be applied in astronauts, in terms of detecting and monitoring subtle neurological damage that might have occurred during long space missions. More speculative uses of PET are in screening candidates for prolonged space missions (for example, for adequate reserve in critical brain circuits) and in optimizing medications to treat impairments after missions.

  9. Laser Unlocks Blood-Brain Barrier for Chemotherapy, Study Shows

    Science.gov (United States)

    ... nlm.nih.gov/medlineplus/news/fullstory_157444.html Laser Unlocks Blood-Brain Barrier for Chemotherapy, Study Shows ... 24, 2016 WEDNESDAY, Feb. 24, 2016 (HealthDay News) -- Laser surgery can open the protective blood-brain barrier, ...

  10. Brain

    Science.gov (United States)

    ... will return after updating. Resources Archived Modules Updates Brain Cerebrum The cerebrum is the part of the ... the outside of the brain and spinal cord. Brain Stem The brain stem is the part of ...

  11. Involvement of the NADPH Oxidase NOX2-Derived Brain Oxidative Stress in an Unusual Fatal Case of Cocaine-Related Neurotoxicity Associated With Excited Delirium Syndrome.

    Science.gov (United States)

    Schiavone, Stefania; Riezzo, Irene; Turillazzi, Emanuela; Trabace, Luigia

    2016-10-01

    Here, we investigated the possible role of the Nicotinamide Adenine Dinucleotide Phosphate oxidase NOX2-derived brain oxidative stress in a fatal case of cocaine-related neurotoxicity, associated to excited delirium syndrome. We detected a strong NOX2 immunoreactivity, mainly in cortical GABAergic neurons and astrocytes, with a minor presence in microglia, glutamatergic and dopaminergic neurons as well as a significant immunostaining for other markers of oxidative stress (8OhDG, HSP70, HSP90, and NF-κB) and apoptotic phenomena. These results support a crucial role of NOX2-derived brain oxidative stress in cocaine-induced brain dysfunctions and neurotoxicity. PMID:27533346

  12. Brain imaging studies of sleep disorder

    International Nuclear Information System (INIS)

    Brain imaging studies of narcolepsy (NA)/cataplexy (CA), a typical sleep disorder, are summarized together with techniques of functional and structural imaging means. single photon emission CT (SPECT) is based on the distribution of tracers labeled by single photon emitters like 99mTc and 123I for seeing the blood flow and receptors. PET using positron emitters like 15O and 18F for blood flow and for glucose metabolism, respectively, is of higher resolution and more quantitative than SPECT. Functional MRI (fMRI) depicts the cerebral activity through signal difference by blood oxygenation level dependence (BOLD) effect, and MR spectroscopy (MRS) depicts and quantifies biomaterials through the difference of their nuclear chemical shifts in the magnetic field. Morphologic imaging studies involve the measurement of the volume of the region of interest by comparison with the reference region such as the whole brain volume. Voxel-based morphometry (VBM) has changed to its more advanced surface-based analysis (SBA) of T1-enhanced image. Diffusion tensor imaging (DTI) is based on the tissue water diffusion. Functional SPECT/PET studies have suggested the decrease of blood flow and metabolic activity in the hypothalamus (HT) and other related regions at the conscious resting state, and locally increased blood flow in cingulate gyrus (CG) and amygdaloid complex (AC) at affective CA/PA seizure. fMRI has suggested the hypoactivity of HT and hyperactivity of AC at the seizure. VBM-based studies have not given the consistent results, but DTI studies have suggested an important participation of AC at the seizure. (T.T.)

  13. Nematode Hsp90: highly conserved but functionally diverse

    OpenAIRE

    Gillan, Victoria; Devaney, Eileen

    2014-01-01

    Nematodes are amongst the most successful and abundant organisms on the planet with approximately 30 000 species described, although the actual number of species is estimated to be one million or more. Despite sharing a relatively simple and invariant body plan, there is considerable diversity within the phylum. Nematodes have evolved to colonize most ecological niches, and can be free-living or can parasitize plants or animals to the detriment of the host organism. In this review we consider...

  14. Can Taichi reshape the brain? A brain morphometry study.

    Science.gov (United States)

    Wei, Gao-Xia; Xu, Ting; Fan, Feng-Mei; Dong, Hao-Ming; Jiang, Li-Li; Li, Hui-Jie; Yang, Zhi; Luo, Jing; Zuo, Xi-Nian

    2013-01-01

    Although research has provided abundant evidence for Taichi-induced improvements in psychological and physiological well-being, little is known about possible links to brain structure of Taichi practice. Using high-resolution MRI of 22 Tai Chi Chuan (TCC) practitioners and 18 controls matched for age, sex and education, we set out to examine the underlying anatomical correlates of long-term Taichi practice at two different levels of regional specificity. For this purpose, parcel-wise and vertex-wise analyses were employed to quantify the difference between TCC practitioners and the controls based on cortical surface reconstruction. We also adopted the Attention Network Test (ANT) to explore the effect of TCC on executive control. TCC practitioners, compared with controls, showed significantly thicker cortex in precentral gyrus, insula sulcus and middle frontal sulcus in the right hemisphere and superior temporal gyrus and medial occipito-temporal sulcus and lingual sulcus in the left hemisphere. Moreover, we found that thicker cortex in left medial occipito-temporal sulcus and lingual sulcus was associated with greater intensity of TCC practice. These findings indicate that long-term TCC practice could induce regional structural change and also suggest TCC might share similar patterns of neural correlates with meditation and aerobic exercise. PMID:23585869

  15. Can Taichi reshape the brain? A brain morphometry study.

    Directory of Open Access Journals (Sweden)

    Gao-Xia Wei

    Full Text Available Although research has provided abundant evidence for Taichi-induced improvements in psychological and physiological well-being, little is known about possible links to brain structure of Taichi practice. Using high-resolution MRI of 22 Tai Chi Chuan (TCC practitioners and 18 controls matched for age, sex and education, we set out to examine the underlying anatomical correlates of long-term Taichi practice at two different levels of regional specificity. For this purpose, parcel-wise and vertex-wise analyses were employed to quantify the difference between TCC practitioners and the controls based on cortical surface reconstruction. We also adopted the Attention Network Test (ANT to explore the effect of TCC on executive control. TCC practitioners, compared with controls, showed significantly thicker cortex in precentral gyrus, insula sulcus and middle frontal sulcus in the right hemisphere and superior temporal gyrus and medial occipito-temporal sulcus and lingual sulcus in the left hemisphere. Moreover, we found that thicker cortex in left medial occipito-temporal sulcus and lingual sulcus was associated with greater intensity of TCC practice. These findings indicate that long-term TCC practice could induce regional structural change and also suggest TCC might share similar patterns of neural correlates with meditation and aerobic exercise.

  16. Statistical physics, neural networks, brain studies

    International Nuclear Information System (INIS)

    An overview of some aspects of a vast domain, located at the crossroads of physics, biology and computer science is presented: (1) During the last fifteen years, physicists advancing along various pathways have come into contact with biology (computational neurosciences) and engineering (formal neural nets). (2) This move may actually be viewed as one component in a larger picture. A prominent trend of recent years, observable over many countries, has been the establishment of interdisciplinary centers devoted to the study of: cognitive sciences; natural and artificial intelligence; brain, mind and behaviour; perception and action; learning and memory; robotics; man-machine communication, etc. What are the promising lines of development? What opportunities for physicists? An attempt will be made to address such questions and related issues

  17. Statistical Physics, Neural Networks, Brain Studies

    Science.gov (United States)

    Toulouse, Gerard

    1999-01-01

    An overview of some aspects of a vast domain, located at the crossroads of physics, biology and computer science is presented: 1) During the last fifteen years, physicists advancing along various pathways have come into contact with biology (computational neurosciences) and engineering (formal neural nets). 2) This move may actually be viewed as one component in a larger picture. A prominent trend of recent years, observable over many countries, has been the establishment of interdisciplinary centers devoted to the study of: cognitive sciences; natural and artificial intelligence; brain, mind and behaviour; perception and action; learning and memory; robotics; man-machine communication, etc. What are the promising lines of development? What opportunities for physicists? An attempt will be made to address such questions, and related issues.

  18. PCB disruption of the hypothalamus-pituitary-interrenal axis involves brain glucocorticoid receptor downregulation in anadromous Arctic charr

    Science.gov (United States)

    Aluru, N.; Jorgensen, E.H.; Maule, A.G.; Vijayan, M.M.

    2004-01-01

    We examined whether brain glucocorticoid receptor (GR) modulation by polychlorinated biphenyls (PCBs) was involved in the abnormal cortisol response to stress seen in anadromous Arctic charr (Salvelinus alpinus). Fish treated with Aroclor 1254 (0, 1, 10, and 100 mg/kg body mass) were maintained for 5 mo without feeding in the winter to mimic their seasonal fasting cycle, whereas a fed group with 0 and 100 mg/kg Aroclor was maintained for comparison. Fasting elevated plasma cortisol levels and brain GR content but depressed heat shock protein 90 (hsp90) and interrenal cortisol production capacity. Exposure of fasted fish to Aroclor 1254 resulted in a dose-dependent increase in brain total PCB content. This accumulation in fish with high PCB dose was threefold higher in fasted fish compared with fed fish. PCBs depressed plasma cortisol levels but did not affect in vitro interrenal cortisol production capacity in fasted charr. At high PCB dose, the brain GR content was significantly lower in the fasted fish and this corresponded with a lower brain hsp70 and hsp90 content. The elevation of plasma cortisol levels and upregulation of brain GR content may be an important adaptation to extended fasting in anadromous Arctic charr, and this response was disrupted by PCBs. Taken together, the hypothalamus-pituitary- interrenal axis is a target for PCB impact during winter emaciation in anadromous Arctic charr.

  19. MR connectomics: a conceptual framework for studying the developing brain

    OpenAIRE

    Patric eHagmann; Patricia Ellen Grant; Fair, Damien A.

    2012-01-01

    THE COMBINATION OF ADVANCED NEUROIMAGING TECHNIQUES AND MAJOR DEVELOPMENTS IN COMPLEX NETWORK SCIENCE, HAVE GIVEN BIRTH TO A NEW FRAMEWORK FOR STUDYING THE BRAIN: "connectomics." This framework provides the ability to describe and study the brain as a dynamic network and to explore how the coordination and integration of information processing may occur. In recent years this framework has been used to investigate the developing brain and has shed light on many dynamic changes occurring from i...

  20. Interphone study - on mobile phones and brain tumors

    International Nuclear Information System (INIS)

    Interphone study is the largest study on mobile phone use and risk of brain tumors that have been implemented. The study does not provide reliable answers to whether there is an increased risk of brain tumors using the mobile phone, but is an important contribution. (AG)

  1. Computed tomography studies of human brain movements

    International Nuclear Information System (INIS)

    Rhythmic brain movements have been revealed by sets of sequential computed tomography scans of human brains (seen retrospectively to be normal). These scans have shown that both (unenhanced) brain parenchymal density and the shapes of the elements of the supratentorial ventricular/cisternal system are subject to wave motions having similar periods - ranging from 26 s through 56 s, 77-96 s, 109 s and 224 s to 224 X 2 s (or even longer), with good correlation between peak values. These motions, as well as phase variations between the waves, suggest a peristaltic movement of cerebrospinal fluid through the ventricular/cisternal system with progressive axial damping

  2. A study of ICAM expression in brain tumors

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Chang Hoon; Lee, Seung Hoon; Hong, Seok Il [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    1995-12-01

    The purpose of this study is to test the possibility of using sICAM-1 as a marker for follow-up of treatment. The micro-ELISA method was adopted. The brain stem gliomas showed positive results in 67%. Overall, 23% of brain tumors showed positive results. It is possible that we can use sICAM-1 as a marker for metastatic brain tumors, and measurement after radiation therapy is not reliable. 6 refs. (Author) (Author).

  3. Preliminary study of MR elastography in brain tumors

    International Nuclear Information System (INIS)

    Objective: To investigate the potential values of magnetic resonance elastography (MRE) for evaluating the brain tumor consistency in vivo. Methods: Fourteen patients with known solid brain tumor (5 male, 9 female; age range: 16-63 years) underwent brain MRE studies. Informed consent was obtained from all patients. A dedicated external force actuator for brain MRE study was developed. The actuator was fixed to the head coil. During scan, one side of the actuator was attached to the patients' head. Low frequency oscillation was produced by the actuator and caused shear waves propagating into brain tissue. The pulse sequence used in the study was phase-contrast gradient-echo sequence. Phase images of the brain were obtained and the shear waves within the brain were directly imaged. Phase images were processed with local frequency estimation (LFE) technique to obtain the elasticity image. Consistency of brain tumors was evaluated at surgery and was classified as soft, intermediate, or hard with comparison to the white matter of the brain. Correspondence of MRE evaluation with operative results was studied. Results: The elastic modulus of the tumor was lower than that of white matter in 1 patient, higher in 11 patients, and similar in 2 patients. At surgery, the tumor manifested a soft consistency in 1 patient, hard consistency in 11 patients, intermediate consistency in 2 patients. The elasticity of tumors in 14 patients evaluated by MRE was correlated with the tumor consistency on the operation. Conclusion: MRE can noninvasively display the elasticity of brain tumors in vivo, and evaluate the brain tumor consistency before operation. (authors)

  4. Accelerated brain aging in schizophrenia : A longitudinal pattern recognition study

    NARCIS (Netherlands)

    Schnack, Hugo G.; Van Haren, Neeltje E M; Nieuwenhuis, Mireille; Pol, Hilleke E Hulshoff; Cahn, Wiepke; Kahn, René S.

    2016-01-01

    OBJECTIVE: Despite the multitude of longitudinal neuroimaging studies that have been published, a basic question on the progressive brain loss in schizophrenia remains unaddressed: Does it reflect accelerated aging of the brain, or is it caused by a fundamentally different process? The authors used

  5. Using autopsy brain tissue to study alcohol-related brain damage in the genomic age

    OpenAIRE

    Sutherland, Greg T.; Sheedy, Donna; Kril, Jillian J.

    2013-01-01

    The New South Wales Tissue Resource Centre (NSW TRC) at the University of Sydney, Australia is one of the few human brain banks dedicated to the study of the effects of chronic alcoholism. The bank was affiliated in 1994 as a member of the National Network of Brain Banks and also focuses on schizophrenia and healthy control tissue. Alcohol abuse is a major problem worldwide, manifesting in such conditions as fetal alcohol syndrome, adolescent binge drinking, alcohol dependency and alcoholic n...

  6. Study Suggests Brain Is Hard-Wired for Chronic Pain

    Science.gov (United States)

    ... News Release Tuesday, September 17, 2013 NIH-funded study suggests brain is hard-wired for chronic pain ... Apkarian, Ph.D., a senior author of the study and professor of physiology at Northwestern University Feinberg ...

  7. Brain-oriented care in the NICU: a case study.

    Science.gov (United States)

    Bader, Lisa

    2014-01-01

    With the advances of technology and treatment in the field of neonatal care, researchers can now study how the brains of preterm infants are different from full-term infants. The differences are significant, and the outcomes are poor overall for premature infants as a whole. Caregivers at the bedside must know that every interaction with the preterm infant affects brain development-it is critical to the developmental outcome of the infant. The idea of neuroprotection is not new to the medical field but is a fairly new idea to the NICU. Neuroprotection encompasses all interventions that promote normal development of the brain. The concept of brain-oriented care is a necessary extension of developmental care in the NICU. By following the journey of 26-week preterm twin infants through a case study, one can better understand the necessity of brain-oriented care at the bedside. PMID:25161134

  8. Structural MRI studies of language function in the undamaged brain

    OpenAIRE

    Richardson, F. M.; Price, C.J.

    2009-01-01

    In recent years, the demonstration that structural changes can occur in the human brain beyond those associated with development, ageing and neuropathology has revealed a new approach to studying the neural basis of behaviour. In this review paper, we focus on structural imaging studies of language that have utilised behavioural measures in order to investigate the neural correlates of language skills in the undamaged brain. We report studies that have used two different techniques: voxel-bas...

  9. Magnetoencephalography in studies of human cognitive brain function.

    Science.gov (United States)

    Näätänen, R; Ilmoniemi, R J; Alho, K

    1994-09-01

    Magnetoencephalography provides a new dimension to the functional imaging of the brain. The cerebral magnetic fields recorded noninvasively enable the accurate determination of locations of cerebral activity with an uncompromized time resolution. The first whole-scalp sensor arrays have just recently come into operation, and significant advances are to be expected in both neurophysiological and cognitive studies, as well as in clinical practice. However, although the accuracy of locating isolated sources of brain activity has improved, identification of multiple simultaneous sources can still be a problem. Therefore, attempts are being made to combine magnetoencephalography with other brain-imaging methods to improve spatial localization of multiple sources and, simultaneously, to achieve a more complete characterization of different aspects of brain activity during cognitive processing. Owing to its good time resolution and considerably better spatial accuracy than that provided by EEG, magnetoencephalography holds great promise as a tool for revealing information-processing sequences of the human brain. PMID:7529443

  10. Preliminary study on computer automatic quantification of brain atrophy

    International Nuclear Information System (INIS)

    Objective: To study the variability of normal brain volume with the sex and age, and put forward an objective standard for computer automatic quantification of brain atrophy. Methods: The cranial volume, brain volume and brain parenchymal fraction (BPF) of 487 cases of brain atrophy (310 males, 177 females) and 1901 cases of normal subjects (993 males, 908 females) were calculated with the newly developed algorithm of automatic quantification for brain atrophy. With the technique of polynomial curve fitting, the mathematical relationship of BPF with age in normal subjects was analyzed. Results: The cranial volume, brain volume and BPF of normal subjects were (1 271 322 ± 128 699) mm3, (1 211 725 ± 122 077) mm3 and (95.3471 ± 2.3453)%, respectively, and those of atrophy subjects were (1 276 900 ± 125 180) mm3, (1 203 400 ± 117 760) mm3 and BPF(91.8115 ± 2.3035)% respectively. The difference of BPF between the two groups was extremely significant (P0.05). The expression P(x)=-0.0008x2 + 0.0193x + 96.9999 could accurately describe the mathematical relationship between BPF and age in normal subject (lower limit of 95% CI y=-0.0008x2+0.0184x+95.1090). Conclusion: The lower limit of 95% confidence interval mathematical relationship between BPF and age could be used as an objective criteria for automatic quantification of brain atrophy with computer. (authors)

  11. A prospective study to evaluate a new residential community reintegration programme for severe chronic brain injury: the Brain Integration Programme.

    NARCIS (Netherlands)

    Geurtsen, G.J.; Martina, J.D.; Heugten, C.M. van; Geurts, A.C.H.

    2008-01-01

    PURPOSE: To assess the effectiveness of a residential community reintegration programme for participants with chronic sequelae of severe acquired brain injury that hamper community functioning. DESIGN: Prospective cohort study. SUBJECTS: Twenty-four participants with acquired brain injury (traumatic

  12. Magnetic resonance elastography in normal human brain: preliminary study

    International Nuclear Information System (INIS)

    Objective: To study the application of magnetic resonance elastography (MRE) in the human brain. Methods: An external force actuator was developed. The actuator was fixed to the head coil. During MRE scan, one side of the actuator was attached to the volunteers' head. Low frequency oscillation was produced by the actuator and generated shear waves propagating into brain tissue. The pulse sequence of MRE was designed. A modified gradient echo sequence was developed with motion sensitizing gradient (MSG) imposed along X, Y or Z direction. Cyclic displacement within brain tissue induced by shear waves caused a measurable phase shift in the received MR signal. From the measured phase shift, the displacement at each voxel could be calculated, and the shear waves within the brain were directly imaged. By adjusting the phase offset, the dynamic propagation of shear waves in a wave cycle was obtained. Phase images were processed with local frequency estimation (LFE) technique to obtain the elasticity images. Shear waves at 100 Hz, 150 Hz, and 200 Hz were applied. Results: The phase images of MRE directly imaged the propagating shear waves within the brain. The direction of the propagation was from surface of the brain to the center. The wavelength of shear waves varied with the change of actuating frequency. The change of wavelength of shear waves in gray and white matter of the brain was identified. The wavelength of shear waves in gray matter was shorter than that in white matter. The elasticity image of the brain revealed that the shear modulus of the white matter was higher than that of gray matter. Conclusion: The phase images of MRE can directly visualize the propagation of shear waves in the brain tissue. The elasticity image of the brain can demonstrate the change of elasticity between gray and white matter. (authors)

  13. Using autopsy brain tissue to study alcohol-related brain damage in the genomic age.

    Science.gov (United States)

    Sutherland, Greg T; Sheedy, Donna; Kril, Jillian J

    2014-01-01

    The New South Wales Tissue Resource Centre at the University of Sydney, Australia, is one of the few human brain banks dedicated to the study of the effects of chronic alcoholism. The bank was affiliated in 1994 as a member of the National Network of Brain Banks and also focuses on schizophrenia and healthy control tissue. Alcohol abuse is a major problem worldwide, manifesting in such conditions as fetal alcohol syndrome, adolescent binge drinking, alcohol dependency, and alcoholic neurodegeneration. The latter is also referred to as alcohol-related brain damage (ARBD). The study of postmortem brain tissue is ideally suited to determining the effects of long-term alcohol abuse, but it also makes an important contribution to understanding pathogenesis across the spectrum of alcohol misuse disorders and potentially other neurodegenerative diseases. Tissue from the bank has contributed to 330 peer-reviewed journal articles including 120 related to alcohol research. Using the results of these articles, this review chronicles advances in alcohol-related brain research since 2003, the so-called genomic age. In particular, it concentrates on transcriptomic approaches to the pathogenesis of ARBD and builds on earlier reviews of structural changes (Harper et al. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:951) and proteomics (Matsumoto et al. Expert Rev Proteomics 2007;4:539). PMID:24033426

  14. Vocal emotion of humanoid robots: a study from brain mechanism.

    Science.gov (United States)

    Wang, Youhui; Hu, Xiaohua; Dai, Weihui; Zhou, Jie; Kuo, Taitzong

    2014-01-01

    Driven by rapid ongoing advances in humanoid robot, increasing attention has been shifted into the issue of emotion intelligence of AI robots to facilitate the communication between man-machines and human beings, especially for the vocal emotion in interactive system of future humanoid robots. This paper explored the brain mechanism of vocal emotion by studying previous researches and developed an experiment to observe the brain response by fMRI, to analyze vocal emotion of human beings. Findings in this paper provided a new approach to design and evaluate the vocal emotion of humanoid robots based on brain mechanism of human beings. PMID:24587712

  15. Using MARCM to study Drosophila brain development.

    Science.gov (United States)

    Viktorin, Gudrun

    2014-01-01

    Mosaic analysis with a repressible cell marker (MARCM) generates positively labeled, wild-type or mutant mitotic clones by unequally distributing a repressor of a cell lineage marker, originally tubP-driven GAL80 repressing the GAL4/UAS system. Variations of the technique include labeling of both sister clones (twin spot MARCM), the simultaneous use of two different drivers within the same clone (dual MARCM), as well as the use of different repressible transcription systems (Q-MARCM). MARCM can be combined with any UAS-based construct, such as localized GFP fusions to visualize subcellular compartments, genes for rescue and ectopic expression, and modifiers of neural activity. A related technique, the twin spot generator, generates positively labeled clones without the use of a repressor, thus minimizing the lag time between clone induction and appearance of label. The present protocol provides a detailed description of a standard MARCM analysis of brain development that includes generation of MARCM stocks and crosses, induction of clones, brain dissection at various stages of development, immunohistochemistry, and confocal microscopy, and can be modified for similar experiments involving mitotic clones. PMID:24048928

  16. Adapting Parcellation Schemes to Study Fetal Brain Connectivity in Serial Imaging Studies

    DEFF Research Database (Denmark)

    Cheng, Xi; Wilm, Jakob; Seshamani, Sharmishtaa;

    2013-01-01

    developing fetal brain such functional and associated structural markers are not consistently present over time. In this study we adapt two non-atlas based parcellation schemes to study the development of connectivity networks of a fetal monkey brain using Diffusion Weighted Imaging techniques. Results...... demonstrate that the fetal brain network exhibits small-world characteristics and a pattern of increased cluster coefficients and decreased global efficiency. These findings may provide a route to creating a new biomarker for healthy fetal brain development....

  17. Neuroimaging studies of the aging HIV-1-infected brain

    OpenAIRE

    Holt, John L.; Kraft-Terry, Stephanie D.; Chang, Linda

    2012-01-01

    Highly active antiretroviral therapy (HAART) has increased life expectancy among HIV-infected individuals, and by 2015, at least half of all HIV-infected individuals will be over 50 years of age. Neurodegenerative processes associated with aging may be facilitated by HIV-1 infection, resulting in premature brain aging. This review will highlight brain abnormalities in HIV patients in the setting of aging, focusing on recent neuroimaging studies of the structural, physiological, functional and...

  18. Statistical Approaches for the Study of Cognitive and Brain Aging

    Science.gov (United States)

    Chen, Huaihou; Zhao, Bingxin; Cao, Guanqun; Proges, Eric C.; O'Shea, Andrew; Woods, Adam J.; Cohen, Ronald A.

    2016-01-01

    Neuroimaging studies of cognitive and brain aging often yield massive datasets that create many analytic and statistical challenges. In this paper, we discuss and address several limitations in the existing work. (1) Linear models are often used to model the age effects on neuroimaging markers, which may be inadequate in capturing the potential nonlinear age effects. (2) Marginal correlations are often used in brain network analysis, which are not efficient in characterizing a complex brain network. (3) Due to the challenge of high-dimensionality, only a small subset of the regional neuroimaging markers is considered in a prediction model, which could miss important regional markers. To overcome those obstacles, we introduce several advanced statistical methods for analyzing data from cognitive and brain aging studies. Specifically, we introduce semiparametric models for modeling age effects, graphical models for brain network analysis, and penalized regression methods for selecting the most important markers in predicting cognitive outcomes. We illustrate these methods using the healthy aging data from the Active Brain Study. PMID:27486400

  19. Ventricles of brain: A morphometric study by computerized tomography

    Directory of Open Access Journals (Sweden)

    Brij Raj Singh, Ujwal Gajbe, Amit Agrawal, Anilkumar Reddy Y, Sunita Bhartiya

    2014-04-01

    Full Text Available Introduction: As the human brain ages, characteristic structural changes occur that are considered to be normal and are expected. Thus the thorough knowledge of the age related normal changes that occur in the brain is required before any abnormal findings are analyzed. As ageing advances, the brain undergoes many gross and histopathological changes with regression of the brain tissue leading to the enlargement of the ventricles. To understand these changes the knowledge of normal morphometry and size of normal ventricular system of brain is important. Materials & Methods: For the present study 358 (Males – 207 and Females – 151 individuals Computerized Tomography (CT images of brain studied. Measurements of fourth ventricle, third ventricle and lateral ventricle were noted down from CT images and it was statistically analyzed. Results: After analysis it was observed that the height and width of the fourth ventricle was larger in males as compared to females. The length of the third ventricle was observed to be greater in females than in males. The width of the third ventricle it was observed to be greater in males than in females. Antero-posterior extent of the left frontal horn (males = 26.26 ± 2.94, 95% CI 25.86 – 26.66 mm and females = 26.53 ± 3.38, 95% CI 25.99 – 27.08 mm was greater than that of the right ones (males = 25.00 ± 3.18, 95% CI 24.57 – 25.44 mm and females = 25.34 ± 3.50, 95% CI 24.78 – 25.90 mm. Conclusion: Advances in sensitive imaging techniques like the Computerized Tomography helps in dramatic expansion of our understanding of the normal structure of brain. The present study has defined the morphometric measurements of the lateral ventricles, third ventricle, and fourth ventricle of the brain which has clinical correlations in diagnosis and for further line of treatment.

  20. A longitudinal study of brain volume changes in normal aging

    International Nuclear Information System (INIS)

    Purpose: To evaluate the effect of normal aging on brain volumes and examine the effects of age and sex on the rates of changes in global and regional brain volumes. Methods: A total of 199 normal subjects (65 females and 134 males, mean age = 56.4 ± 9.9 years, age range = 38.1–82.9 years) were included in this study. Each subject was scanned twice, at an interval of about 2 years (range = 1.5–2.3 years). Two-time-point percentage brain volume change (PBVC) was estimated with SIENA 2.6. Results: The mean annualized PBVC was −0.23%/y. Analysis of covariance (ANCOVA) for annual brain volume changes revealed a main effect of age. There was no main effect of sex, nor was there a sex-by-age interaction. Voxel-wise analysis revealed a negative correlation between age and edge displacement values mainly in the periventricular region. Conclusions: The results of our study indicate that brain atrophy accelerates with increasing age and that there is no gender difference in the rate of brain atrophy

  1. A longitudinal study of brain volume changes in normal aging

    Energy Technology Data Exchange (ETDEWEB)

    Takao, Hidemasa, E-mail: takaoh-tky@umin.ac.jp [Department of Radiology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 (Japan); Hayashi, Naoto [Department of Computational Diagnostic Radiology and Preventive Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 (Japan); Ohtomo, Kuni [Department of Radiology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 (Japan)

    2012-10-15

    Purpose: To evaluate the effect of normal aging on brain volumes and examine the effects of age and sex on the rates of changes in global and regional brain volumes. Methods: A total of 199 normal subjects (65 females and 134 males, mean age = 56.4 ± 9.9 years, age range = 38.1–82.9 years) were included in this study. Each subject was scanned twice, at an interval of about 2 years (range = 1.5–2.3 years). Two-time-point percentage brain volume change (PBVC) was estimated with SIENA 2.6. Results: The mean annualized PBVC was −0.23%/y. Analysis of covariance (ANCOVA) for annual brain volume changes revealed a main effect of age. There was no main effect of sex, nor was there a sex-by-age interaction. Voxel-wise analysis revealed a negative correlation between age and edge displacement values mainly in the periventricular region. Conclusions: The results of our study indicate that brain atrophy accelerates with increasing age and that there is no gender difference in the rate of brain atrophy.

  2. Brain activation studies with PET and functional MRI

    International Nuclear Information System (INIS)

    Application of PET and functional MRI in brain activation studies is reviewed. 3D-PET images obtained repeatedly after intravenous injection of about 370 MBq of H215O can detect a faint blood flow change in the brain. Functional MRI can also detect the blood flow change in the brain due to blood oxygen level-dependent effect. Echo-planar imaging is popular in MRI with 1.5 or 3 T. Images are analyzed by statistical parametric mapping with correction of cerebral regions, anatomical normalization and statistics. PET data give the blood flow change by the H215O incorporation into the brain and MRI data, by the scarce tissue oxygen consumption despite the change. Actual images during the cognition task-performance and of frequent artifacts are given. PET is suitable for studies of brain functions like sensibility and emotion and functional MRI, like cortex functions and clinical practices in identification of functional regions prior to surgery and evaluation of functional recovery of damaged brain. (K.H.)

  3. Brain activation study during urine withhold by 99Tcm-HMPAO SPECT brain imaging

    International Nuclear Information System (INIS)

    Objective: Lose of urinary continence control is related with the pathological process of many brain damages. The aim of this study was to identify cerebral activation areas during withholding urine in healthy subjects with cerebral perfusion agent [99Tcm-hexamethylpropylene amine oxime (HMPAO)]. Methods: Fifteen right-handed healthy male volunteers (age ranged 24 to 45 years old) was recruited. All had two brain perfusion SPECT scans (15 volunteers with 30 scans). One was at resting state with empty bladder and the other was at urine withholding state with full bladder. The images were analyzed by neurological statistical image analysis software (NEUROSTAT) and was displayed on Z-score images at a significance threshold of P<0.05 with correction for multiple comparisons. Results: As compared with resting, the urine withholding state showed a significant increase cerebral perfusion in bilateral inferior frontal gyri, the right superior and middle temporal gyri, with the most significant in the right inferior frontal gyms. Conclusions: Although the control of urinary continence in healthy men was associated with bilateral inferior frontal gyri and the right superior and middle temporal gyri, the results showed that the right inferior frontal gyms might also be important. Moreover, the combination of brain perfusion SPECT and NEUROSTAT was a rather easy method for further understanding the mechanism of urinary control in brain and could be popularized as a research tool for clinical use. (authors)

  4. Study Reveals Brain Biology behind Self-Control

    Science.gov (United States)

    Sparks, Sarah D.

    2011-01-01

    A new neuroscience twist on a classic psychology study offers some clues to what makes one student able to buckle down for hours of homework before a test while his classmates party. The study published in the September 2011 edition of "Proceedings of the National Academy of Science," suggests environmental cues may "hijack" the brain's mechanisms…

  5. MR connectomics: a conceptual framework for studying the developing brain.

    Science.gov (United States)

    Hagmann, Patric; Grant, Patricia E; Fair, Damien A

    2012-01-01

    THE COMBINATION OF ADVANCED NEUROIMAGING TECHNIQUES AND MAJOR DEVELOPMENTS IN COMPLEX NETWORK SCIENCE, HAVE GIVEN BIRTH TO A NEW FRAMEWORK FOR STUDYING THE BRAIN: "connectomics." This framework provides the ability to describe and study the brain as a dynamic network and to explore how the coordination and integration of information processing may occur. In recent years this framework has been used to investigate the developing brain and has shed light on many dynamic changes occurring from infancy through adulthood. The aim of this article is to review this work and to discuss what we have learned from it. We will also use this body of work to highlight key technical aspects that are necessary in general for successful connectome analysis using today's advanced neuroimaging techniques. We look to identify current limitations of such approaches, what can be improved, and how these points generalize to other topics in connectome research. PMID:22707934

  6. MR Connectomics: A Conceptual Framework for Studying The Developing Brain

    Directory of Open Access Journals (Sweden)

    Patric eHagmann

    2012-06-01

    Full Text Available The combination of advanced neuroimaging techniques and major developments in complex network science, have given birth to a new framework for studying the brain: connectomics. This framework provides the ability to describe and study the brain as a dynamic network and to explore how the coordination and integration of information processing may occur. In recent years this framework has been used to investigate the developing brain and has shed light on many dynamic changes occurring from infancy through adulthood. The aim of this article is to review this work and to discuss what we have learned from it. We will also use this body of work to highlight key technical aspects that are necessary in general for successful connectome analysis using today’s advanced neuroimaging techniques. We look to identify current limitations of such approaches, what can be improved, and how these points generalize to other topics in connectome research.

  7. The costs of disorders of the brain in Switzerland: an update from the European Brain Council Study for 2010

    OpenAIRE

    Maercker, Andreas; Perkonigg, A; Preisig, M; Schaller, K; Weller, M.

    2013-01-01

    BACKGROUND: In 2005, findings of the first "cost of disorders of the brain in Europe" study of the European Brain Council (EBC) showed that these costs cause a substantial economic burden to the Swiss society. In 2010 an improved update with a broader range of disorders has been analysed. This report shows the new findings for Switzerland and discusses changes. METHODS: Data are derived from the EBC 2010 census study that estimates 12-month prevalence of 12 groups of disorders of the brain...

  8. Thermal dosimetry studies of ultrasonically induced hyperthermia in normal dog brain and in experimental brain tumors

    International Nuclear Information System (INIS)

    In a series of 16 acute experiments on pentobarbital anesthetized dogs, thermal distributions generated by ultrasonic heating using a 1 MHz PZT transducer were compared with intensity distributions mapped in a test tank. Relatively flat distributions from 1 to 3 cm have been mapped in normal dog brain using ''shaped'' intensity distributions generated from ultrasonic emission patterns which are formed by the interaction between compressional, transverse and flexural modes activated within the crystal. In contrast, these same intensity distributions generated marked temperature variations in 3 malignant brain tumors presumably due to variations in tumor blood flow. The results of this study suggest that a practical clinical system for uniform heating of large tumor volumes with varying volumes and geometries is not an achievable goal. The author's laboratory is developing a scanning ultrasonic rapid hyperthermia treatment system which will be able to sequentially heat small volume of tumor tissue either to temperatures which will sterilize tumor or to a more conventional thermal dose. Time-temperature studies of threshold for thermal damage in normal dog brain are currently in progress

  9. The effect of chemotherapy on rat brain PET: preliminary study

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Su; Kim, Il Han; Yu, A Ram; Park, Ji Ae; Woo, Sang Keun; Kim, Jong Guk; Cheon, Gi Jeong; Kim, Byeong Il; Choi, Chang Woon; Lim, Sang Moo; Kim, Hee Joung; Kim, Kyeong Min [Korea Institute Radiological and Medical Science, Seoul (Korea, Republic of)

    2010-10-15

    Chemotherapy was widely used for the therapy of cancer patients. When chemotherapy was performed, transient cognitive memory problem was occurred. This cognitive problem in brain was called as chemobrain. In this study, we have developed rat model for chemobrain. Cerebral glucose metabolism after chemotherapy was assessed using animal PET and voxel based statistical analysis method

  10. DSC Study on Brain Tubulin and the Effect of Cisplatin

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The thermal property of the polymerization of brain tubulin was studied by a high-sensitivity differential scanning calorimeter. The phenomenon that heat flows increased and decreased consistently and obviously was observed. This phenomenon was called heat flow oscillation. It was probably correlated to the dynamic instability of microtubules. The effect of cisplatin on it was reported, too.

  11. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study

    OpenAIRE

    Shim, Youn K.; Mlynarek, Steven P.; van Wijngaarden, Edwin

    2009-01-01

    Background The etiology of childhood brain cancer remains largely unknown. However, previous studies have yielded suggestive associations with parental pesticide use. Objectives We aimed to evaluate parental exposure to pesticides at home and on the job in relation to the occurrence of brain cancer in children. Methods We included 526 one-to-one–matched case–control pairs. Brain cancer cases were diagnosed at < 10 years of age, and were identified from statewide cancer registries of four U.S....

  12. Brain Basics

    Medline Plus

    Full Text Available ... Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies show that brain growth in children with autism ...

  13. Does studying abroad induce a brain drain?

    NARCIS (Netherlands)

    H. Oosterbeek; D. Webbink

    2011-01-01

    This paper investigates whether studying abroad increases the propensity to live abroad later on. We use an instrumental variable approach based on cut-offs in the ranking of Dutch higher education graduates who applied for a scholarship programme for outstanding students. Applicants ranked above th

  14. Results of whole brain radiotherapy in patients with brain metastases from breast cancer: a retrospective study

    International Nuclear Information System (INIS)

    Purpose: To analyze the factors that affect survival in patients with brain metastases (BM) from breast cancer who were treated with whole brain radiotherapy (WBRT). Methods and Materials: We identified 116 women with breast cancer who were treated with WBRT alone between February 1984 and September 2000. All patients had treatment and follow-up data available in their medical charts, which we extracted for this retrospective study. We evaluated a number of potential predictors of survival after WBRT: age, primary tumor stage, control of primary tumor, presence of other systemic metastases, site of systemic metastases, Karnofsky performance status, Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis class, total dose of WBRT, and number of BM. Eighteen patients received a total dose >3000 cGy and 7 received a partial brain boost. Results: For the entire cohort, the median survival from the start of WBRT was 4.2 months. The 1-year survival rate was 17%, and the 2-year survival rate was 2%. Using univariate analysis, only Karnofsky performance status (p=0. 0084), recursive partitioning analysis class (p=0. 0147), and total WBRT dose (p=0.0001) were predictive of longer survival. In multivariate analysis, Karnofsky performance status was the only significant predictor. Conclusion: Overall survival in breast cancer patients with BM treated with WBRT is poor. We recommend breast cancer patients with BM be enrolled in prospective trials to improve results

  15. Studies of the brain cannabinoid system using positron emission tomography

    International Nuclear Information System (INIS)

    Studies using radiolabeled psychoactive drugs in conjunction with positron emission tomography (PET) have permitted the imaging of binding sites in the human brain. Similar studies of marijuana have been hampered by the unsuitability of radiolabeled THC for PET studies, and the current unavailability of other in vivo imaging agents for cannabinoid receptors. Recent developments in medicinal chemistry suggest that a PET radiotracer for cannabinoid receptors will soon become available. This chapter briefly reviews these developments, together with the results of PET studies of the effects of marijuana and other abused drugs on brain metabolism. It also reviews PET studies of cocaine binding sites, to demonstrate the kind of investigations that will be possible when a cannabinoid receptor PET radioligand becomes available

  16. Studies of the brain cannabinoid system using positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Gatley, S.J.; Volkow, N.D.

    1995-10-01

    Studies using radiolabeled psychoactive drugs in conjunction with positron emission tomography (PET) have permitted the imaging of binding sites in the human brain. Similar studies of marijuana have been hampered by the unsuitability of radiolabeled THC for PET studies, and the current unavailability of other in vivo imaging agents for cannabinoid receptors. Recent developments in medicinal chemistry suggest that a PET radiotracer for cannabinoid receptors will soon become available. This chapter briefly reviews these developments, together with the results of PET studies of the effects of marijuana and other abused drugs on brain metabolism. It also reviews PET studies of cocaine binding sites, to demonstrate the kind of investigations that will be possible when a cannabinoid receptor PET radioligand becomes available.

  17. Study of functional brain imaging for bilingual language cognition

    International Nuclear Information System (INIS)

    Bilingual and multilingual brain studies of language recognition is an interdisciplinary subject which needs to identify different levels involved in the neural representation of languages, such as neuroanatomical, neurofunctional, biochemical, psychological and linguistic levels. Furthermore, specific factor's such as age, manner of acquisition and environmental factors seem to affect the neural representation. Functional brain imaging, such as PET, SPECT and functional MRI can explore the neurolinguistics representation of bilingualism in the brain in subjects, and elucidate the neuronal mechanisms of bilingual language processing. Functional imaging methods show differences in the pattern of cerebral activation associated with a second language compared with the subject's native language. It shows that verbal memory processing in two unrelated languages is mediated by a common neural system with some distinct cortical areas. The different patterns of activation differ according to the language used. It also could be ascribed either to age of acquisition or to proficiency level. And attained proficiency is more important than age of acquisition as a determinant of the cortical representation of the second language. The study used PET and SPECT shows that sign and spoken language seem to be localized in the same brain areas, and elicit similar regional cerebral blood flow patterns. But for sign language perception, the functional anatomy overlaps that of language processing contain both auditory and visual components. And the sign language is dependent on spatial information too. (authors)

  18. STUDY OF BRAIN TUMOURS BY NOVE L MAGNETIC RESONANCE TECHNIQUE

    Directory of Open Access Journals (Sweden)

    Mohammad Shamim

    2015-01-01

    Full Text Available In the present study , thirty patients in the age range of 22 to 63 years of age were included after being diagnosed to be having brain tumour on CT scan or conventional MRI. In addition DWI , MRS , and PWI were carried out i n these patients. All the patients with suspicious malignant lesions were then subjected to FDG - PET examination . Histopathological correlation was obtained in all the patients to serve as gold standard against which other modalities will be assessed for th eir sensitivity , specificity , positive predictive value , negative predictive value and diagnostic accuracy. Out of thirty patients selected for this study , twenty cases were found to be malignant and ten cases were benign on Histopathological evaluation. Majority of malignant lesions were glioblastoma multiforme. Amongst benign cases , majorities were meningioma , one was a Granulomatous lesion and one was a benign cystic lesion. MRI including the novel techniques showed high sensitivity and spe cificity in identifying malignant brain lesions and has a future role in better characterization of brain tumours. Wherever available , it should be integrated in routine workup of patients presenting with brain tumours or for follow up of patients undergon e surgery / adjuvant chemotherapy.

  19. Study on QSAR of brain radiopharmaceuticals of iodoamphetamines

    International Nuclear Information System (INIS)

    According to the Fick's law, it is assumed that brain radiopharmaceuticals can pass through Brain Blood Barrier by simple diffusion process. After investigation of parameters of fourteen iodoamphetamines, a linear relationship among initial brain uptake, partition coefficient, protein binding and molecular weight has been established. This relationship may be useful in designing new brain radiopharmaceuticals and predicting initial brain uptake

  20. Brain computer tomography in critically ill patients -- a prospective cohort study

    OpenAIRE

    Purmer Ilse M; van Iperen Erik P; Beenen Ludo F M; Kuiper Michael J; Binnekade Jan M; Vandertop Peter W; Schultz Marcus J; Horn Janneke

    2012-01-01

    Abstract Background Brain computer tomography (brain CT) is an important imaging tool in patients with intracranial disorders. In ICU patients, a brain CT implies an intrahospital transport which has inherent risks. The proceeds and consequences of a brain CT in a critically ill patient should outweigh these risks. The aim of this study was to critically evaluate the diagnostic and therapeutic yield of brain CT in ICU patients. Methods In a prospective observational study data were collected ...

  1. Memory Networks in Tinnitus: A Functional Brain Image Study

    OpenAIRE

    Laureano, Maura Regina; Onishi, Ektor Tsuneo; Bressan, Rodrigo Affonseca; Castiglioni, Mario Luiz Vieira; Batista, Ilza Rosa; Reis, Marilia Alves; Garcia, Michele Vargas; de Andrade, Adriana Neves; de Almeida, Roberta Ribeiro; Garrido, Griselda J.; Jackowski, Andrea Parolin

    2014-01-01

    Tinnitus is characterized by the perception of sound in the absence of an external auditory stimulus. The network connectivity of auditory and non-auditory brain structures associated with emotion, memory and attention are functionally altered in debilitating tinnitus. Current studies suggest that tinnitus results from neuroplastic changes in the frontal and limbic temporal regions. The objective of this study was to use Single-Photon Emission Computed Tomography (SPECT) to evaluate changes i...

  2. BRAIN-COMPUTER INTERFACE (BCI) LITERATURE - A BIBLIOMETRIC STUDY

    OpenAIRE

    Hamadicharef, Brahim

    2010-01-01

    Brain-Computer Interface (BCI) is a relatively young research field which has seen a growing interest with associated number of publications over the last two decades. In this study we present the first bibliometric analysis of the BCI literature (1990–2008) from the Thomson Reuters's Institute for Scientific Information (ISI) Web of Knowledge. Thus, the main objectives of this bibliometric study are: 1) to explore the growth of BCI literature, 2) to assess if it follows Lotka's law of scient...

  3. Abnormal brain processing of pain in migraine without aura: a high-density EEG brain mapping study

    DEFF Research Database (Denmark)

    Egsgaard, L L; Jensen, R; Buchgreitz, L; Egsgaard, Line Lindhardt; Jensen, Rigmor Højland; Arendt-Nielsen, L; Bendtsen, L

    2010-01-01

    In the present study we used high-density EEG brain mapping to investigate spatio-temporal aspects of brain activity in response to experimentally induced muscle pain in 17 patients with migraine without aura and 15 healthy controls. Painful electrical stimuli were applied to the trapezius muscle...

  4. Connecting Brain Research to Classroom Learning: A Mixed-Method Study on How Teachers Apply Brain Research to Their Instruction

    Science.gov (United States)

    McAteer, Todd C.

    2010-01-01

    Purpose. The purpose of this study was to examine how knowledgeable teachers are in utilizing brain-researched instructional strategies. The research focused on determining which brain-researched strategies are implemented, the accuracy with which they are employed, and the degree to which they are utilized. A literature review revealed the most…

  5. Imaging study of brain damage from methanol intoxication of wine

    International Nuclear Information System (INIS)

    Objective: To investigate the imaging of CT and MRI in brain damage caused by methanol intoxication from false wine, and to study the relations between imaging manifestation and different degrees of the methanol intoxication. Method: Thirty nine cases with methanol intoxication from false wine were retrospectively reported, The latent period of these patients was 0-4 days, and the average latent period of these patients was 0.5 days, All cases were performed by serology examination, brain CT scan, and four cases performed by MRI scan after average 2.5 days (range, 1-6 days) the onset of methanol intoxication. Results: Six cases showed hyperintense signals in bilateral putamen, two cases also showed hyperintense signals in biolateral subcortex white substance regions. Four cases showed hyperintense signals in unilateral internal capsule. One case showed hyperintense changess in subcortex white substance regions. Our study showed the positive correlation between CT features and the amount of methanol and stage of clinic manifestation(χ2=4.232, P2=0.001, P>0.05). Conclusions: MRI was better than CT in finding early brain damage caused by methanol intoxication from false wine. The characteristic finding changes of the patients was showed mainly in in bilateral putamen, Prognosis for the patients combined with subcortex white substance lesion wasn't hopeful. (authors)

  6. Electrical stunning and exsanguination decrease the extracellular volume in the broiler brain as studied with brain impendance recordings.

    Science.gov (United States)

    Savenije, B; Lambooij, E; Pieterse, C; Korf, J

    2000-07-01

    Electrical stunning in the process of slaughtering poultry is used to induce unconsciousness and immobilize the animal for easier processing. Unconsciousness is a function of brain damage. Brain damage has been studied with brain impedance recordings under ischemic conditions. This experiment studies brain impedance as a response to a general epileptiform insult caused by electrical stunning and ischemia caused by exsanguination. Brain impedance was recorded in 10 broiler chickens for each of three killing methods: whole body electrical stunning, which induces cardiac arrest; head only electrical stunning followed by exsanguination; and exsanguination without stunning. Brain impedance was converted into relative extracellular volume (ECV) values. Results showed that, immediately after electrical stunning, the ECV decreased 5.5% from base ECV. With exsanguination only, the ECV decreased from base ECV only after 4 min after neck cutting. The ECV decrease after 10 min did not differ between treatments. With a time of 228 s to reach one-half of the ECV decrease found at 10 min, electrical stunning resulted in a much faster change in ECV than exsanguination only (373 s). Within the head only stunning group, six animals showed a response similar to that found with whole body stunning; the other four animals responded similarly to the animals that were exsanguinated only. It was concluded that brain impedance recordings used with electrical stunning reflect brain damage. This damage was both epileptic and ischemic in nature. Whole body stunning induced immediate brain damage, suggesting that an adequate stun was delivered. The dual response found with head only stunning might indicate that this stunning method does not always produce an adequate stun. PMID:10901211

  7. The effects of Psychotropic drugs On Developing brain (ePOD) study : methods and design

    NARCIS (Netherlands)

    Bottelier, Marco A.; Schouw, Marieke L. J.; Klomp, Anne; Tamminga, Hyke G. H.; Schrantee, Anouk G. M.; Bouziane, Cheima; de Ruiter, Michiel B.; Boer, Frits; Ruhe, Henricus G.; Denys, Damiaan; Rijsman, Roselyne; Lindauer, Ramon J. L.; Reitsma, Hans B.; Geurts, Hilde M.; Reneman, Liesbeth

    2014-01-01

    Background: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of dif

  8. Anticipatory Processing in the Brain on the Perception of Müller-Lyer Illusionary Figures—A Brain Potential Study

    Science.gov (United States)

    Nomura, Shusaku; Sasaki, Shuntaro; Hirakawa, Masato; Hiwaki, Osamu

    2010-11-01

    We investigated the brain potential in relation with the recognition of Müller-Lyer (ML) illusionary figure, which was a famous optical illusion. Although it is frequently assumed that the ML illusionary effect could be derived from its geometrical construction, it derives the same length miss-estimation effect on the sense of touch; haptic illusion. Moreover it occurs in people who are blindfolded or congenital blind. Thus somehow higher information processing than the optical one within the brain could be expected to involve with the recognition of ML figure while few brain studies have demonstrated it. We then investigated the brain waves under subjects' perceiving ML illusionary figure. As a result the marked difference of the brain potential between ML and the control condition around the midline of parietal brain, where the multi-modal perception information was thought to associate within the brain, was observed. This result implies that the anticipatory processing on the perception of ML illusionary figures would be derived by integrating multi-sensory information.

  9. Recent progress of neuroimaging studies on sleeping brain

    International Nuclear Information System (INIS)

    Although sleep is a familiar phenomenon, its functions are yet to be elucidated. Understanding these functions of sleep is an important focus area in neuroscience. Electroencephalography (EEG) has been the predominantly used method in human sleep research but does not provide detailed spatial information about brain activation during sleep. To supplement the spatial information provided by this method, researchers have started using a combination of EEG and various advanced neuroimaging techniques that have been recently developed, including positron emission tomography (PET) and magnetic resonance imaging (MRI). In this paper, we will review the recent progress in sleep studies, especially studies that have used such advanced neuroimaging techniques. First, we will briefly introduce several neuroimaging techniques available for use in sleep studies. Next, we will review the spatiotemporal brain activation patterns during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, the dynamics of functional connectivity during sleep, and the consolidation of learning and memory during sleep; studies on the neural correlates of dreams, which have not yet been identified, will also be discussed. Lastly, possible directions for future research in this area will be discussed. (author)

  10. Endocasts-the direct evidence and recent advances in the study of human brain evolution

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Brain evolution is one of the most important aspects of human evolution, usually studied through endocasts. Analysis of fossil hominid endocasts allows inferences on functional anatomy, physiology, and phylogeny. In this paper, we describe the general features of endocast studies and review some of the major topics in paleoneurology. These are: absolute and relative brain size evolution; brain shape variation; brain asymmetry and lateralization; middle meningeal vessels and venous sinuses; application of computed tomography and virtual imaging; the history of Chinese brain endocast studies. In particular, this review emphasizes endocast studies on Chinese hominin fossils.

  11. Exploratory case-control study of brain tumors in adults

    International Nuclear Information System (INIS)

    An exploratory study of brain tumors in adults was carried out using 215 cases diagnosed in Southern Ontario between 1979 and 1982, with an individually matched, hospital control series. Significantly elevated risks were observed for reported use of spring water, drinking of wine, and consumption of pickled fish, together with a significant protective effect for the regular consumption of any of several types of fruit. While these factors are consistent with a role for N-nitroso compounds in the etiology of these tumors, for several other factors related to this hypothesis, no association was observed. Occupation in the rubber industry was associated with a significant relative risk of 9.0, though no other occupational associations were seen. Two previously unreported associations were with smoking nonfilter cigarettes with a significant trend and with the use of hair dyes or sprays. The data do not support an association between physical head trauma requiring medical attention and risk of brain tumors and indicate that exposure to ionizing radiation and vinyl chloride monomer does not contribute any appreciable fraction of attributable risk in the population studied. The findings warrant further detailed investigation in future epidemiologic studies

  12. Memory Networks in Tinnitus: A Functional Brain Image Study

    Science.gov (United States)

    Laureano, Maura Regina; Onishi, Ektor Tsuneo; Bressan, Rodrigo Affonseca; Castiglioni, Mario Luiz Vieira; Batista, Ilza Rosa; Reis, Marilia Alves; Garcia, Michele Vargas; de Andrade, Adriana Neves; de Almeida, Roberta Ribeiro; Garrido, Griselda J.; Jackowski, Andrea Parolin

    2014-01-01

    Tinnitus is characterized by the perception of sound in the absence of an external auditory stimulus. The network connectivity of auditory and non-auditory brain structures associated with emotion, memory and attention are functionally altered in debilitating tinnitus. Current studies suggest that tinnitus results from neuroplastic changes in the frontal and limbic temporal regions. The objective of this study was to use Single-Photon Emission Computed Tomography (SPECT) to evaluate changes in the cerebral blood flow in tinnitus patients with normal hearing compared with healthy controls. Methods: Twenty tinnitus patients with normal hearing and 17 healthy controls, matched for sex, age and years of education, were subjected to Single Photon Emission Computed Tomography using the radiotracer ethylenedicysteine diethyl ester, labeled with Technetium 99 m (99 mTc-ECD SPECT). The severity of tinnitus was assessed using the “Tinnitus Handicap Inventory” (THI). The images were processed and analyzed using “Statistical Parametric Mapping” (SPM8). Results: A significant increase in cerebral perfusion in the left parahippocampal gyrus (pFWE <0.05) was observed in patients with tinnitus compared with healthy controls. The average total THI score was 50.8+18.24, classified as moderate tinnitus. Conclusion: It was possible to identify significant changes in the limbic system of the brain perfusion in tinnitus patients with normal hearing, suggesting that central mechanisms, not specific to the auditory pathway, are involved in the pathophysiology of symptoms, even in the absence of clinically diagnosed peripheral changes. PMID:24516567

  13. Functional brain studies with H215O-PET

    International Nuclear Information System (INIS)

    Positron emission tomography (PET) with intravenous injection of H215O allows us to obtain regional cerebral blood flow (rCBF) images repeatedly within a short period of time. Since the increase of electrical activity in a specific brain region is followed by the abrupt increase of rCBF, the technique with H215O-PET is suitable for functional stimulation-activation studies. In this study, we examined the following fundamental issues : (1) reproducibility of rCBF during resting condition (2) effect of physiological stimulation on CBF (3) anatomical identification of activated area. Our data suggest that relative CBF images and their paired subtraction are suitable for tapping functional localization. The changes in rCBF in association cortex for more complicated tasks are, in general, smaller than those in primary cortex. Combination display of PET image with MR-3D reconstructed brain surface image in each subject is the most reliable technique for anatomical identification of activated site. (J.P.N.)

  14. Memory networks in tinnitus: a functional brain image study.

    Directory of Open Access Journals (Sweden)

    Maura Regina Laureano

    Full Text Available Tinnitus is characterized by the perception of sound in the absence of an external auditory stimulus. The network connectivity of auditory and non-auditory brain structures associated with emotion, memory and attention are functionally altered in debilitating tinnitus. Current studies suggest that tinnitus results from neuroplastic changes in the frontal and limbic temporal regions. The objective of this study was to use Single-Photon Emission Computed Tomography (SPECT to evaluate changes in the cerebral blood flow in tinnitus patients with normal hearing compared with healthy controls.Twenty tinnitus patients with normal hearing and 17 healthy controls, matched for sex, age and years of education, were subjected to Single Photon Emission Computed Tomography using the radiotracer ethylenedicysteine diethyl ester, labeled with Technetium 99 m (99 mTc-ECD SPECT. The severity of tinnitus was assessed using the "Tinnitus Handicap Inventory" (THI. The images were processed and analyzed using "Statistical Parametric Mapping" (SPM8.A significant increase in cerebral perfusion in the left parahippocampal gyrus (pFWE <0.05 was observed in patients with tinnitus compared with healthy controls. The average total THI score was 50.8+18.24, classified as moderate tinnitus.It was possible to identify significant changes in the limbic system of the brain perfusion in tinnitus patients with normal hearing, suggesting that central mechanisms, not specific to the auditory pathway, are involved in the pathophysiology of symptoms, even in the absence of clinically diagnosed peripheral changes.

  15. STUDY ABOUT CLINICAL APPLICATION OF BRAIN ATLAS IN PAEDIATRICS

    Institute of Scientific and Technical Information of China (English)

    MENG Fanhang; LIU Cuiping; RENG Xiaoping; JIANG Lian

    2002-01-01

    Objectives To explore clinical application on brain atlas in paediatrics. Methode: Brain atlas was applied in diagnosis and treatment of paediatric diseases and its clinical value was discussed in 1990 ~2001. The manifestation of these diseases in brain atlas were analysed and the manifestation of CT of 67 cases and manifestations of EEG of 37 cases with that of BA were compared. Results The changes of cerebral electrical activity of these diseases were reflected objectively and showed directly in BA. Conclusion Brain atlas not only can point out quality of disease but also define position of disease. Therefore, brain atlas has important clinical value in paediatrics.

  16. Paradoxical effects of brain death and associated trauma on rat mesenteric microcirculation: an intravital microscopic study

    OpenAIRE

    Rafael Simas; Paulina Sannomiya; José Walber M. C Cruz; Cristiano de Jesus Correia; Fernando Luiz Zanoni; Maurício Kase; Laura Menegat; Isaac Azevedo Silva; Moreira, Luiz Felipe P.

    2012-01-01

    OBJECTIVE: Experimental findings support clinical evidence that brain death impairs the viability of organs for transplantation, triggering hemodynamic, hormonal, and inflammatory responses. However, several of these events could be consequences of brain death–associated trauma. This study investigated microcirculatory alterations and systemic inflammatory markers in brain-dead rats and the influence of the associated trauma. METHOD: Brain death was induced using intracranial balloon inflatio...

  17. Comparison of in vitro and in vivo approaches to studying brain colonization by breast cancer cells

    OpenAIRE

    Lorger, M.; Lee, H.; Forsyth, J S; Felding-Habermann, B.

    2011-01-01

    Brain metastases occur in 20 to 40% of patients with metastatic breast cancer. The process is complex and depends on successful cancer cell evasion from the primary tumor, distribution and survival within the blood stream and cerebral microvasculature, penetration of the blood brain barrier and proliferation within the brain microenvironment. The initial steps of brain colonization are difficult to study in vivo. Therefore, in vitro assays have been developed to mimic this process. Most commo...

  18. A Delphi Study on Brain-based Instructional Model in Science

    OpenAIRE

    Duangkamon Charnsirirattana; Prasart Nuangchalerm

    2010-01-01

    Development of science instructional model for brain-based learning by using knowledge of the brain to be the tool designed of learning process is now interesting. This study aimed to develop science instructional model for brain-based learning. Delphi method was employed with 18 panel members. The findings can be showed that science instructional model for brain-based learning consisted of five steps of learning organization (PRADA- Preparation, Relaxation, Action, Discussion, and Applicatio...

  19. THE MICROBIOTA-GUT-BRAIN AXIS. A STUDY IN ZEBRAFISH (DANIO RERIO)

    OpenAIRE

    Borrelli, Luca

    2015-01-01

    The microbiota is essential in the host's physiology, development, reproduction, immune system, nutrient metabolism, in brain chemistry and behavior. The gut microbiota plays a crucial role in the bidirectional gut–brain axis, a communication that integrates the gut and central nervous system (CNS) activities, and thus, the concept of microbiota–gut–brain axis is emerging where the microbes have considered as signaling components in the gut-brain axis. Animal studies reveals, in particular, t...

  20. Brain Basics

    Medline Plus

    Full Text Available ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies ...

  1. Brain Basics

    Medline Plus

    Full Text Available ... brain's structure, studies show that brain growth in children with autism appears to peak early. And as ... grow there are differences in brain development in children who develop bipolar disorder than children who do ...

  2. Brain computer tomography in critically ill patients - a prospective cohort study

    International Nuclear Information System (INIS)

    Brain computer tomography (brain CT) is an important imaging tool in patients with intracranial disorders. In ICU patients, a brain CT implies an intrahospital transport which has inherent risks. The proceeds and consequences of a brain CT in a critically ill patient should outweigh these risks. The aim of this study was to critically evaluate the diagnostic and therapeutic yield of brain CT in ICU patients. In a prospective observational study data were collected during one year on the reasons to request a brain CT, expected abnormalities, abnormalities found by the radiologist and consequences for treatment. An “expected abnormality” was any finding that had been predicted by the physician requesting the brain CT. A brain CT was “diagnostically positive”, if the abnormality found was new or if an already known abnormality was increased. It was “diagnostically negative” if an already known abnormality was unchanged or if an expected abnormality was not found. The treatment consequences of the brain CT, were registered as “treatment as planned”, “treatment changed, not as planned”, “treatment unchanged”. Data of 225 brain CT in 175 patients were analyzed. In 115 (51%) brain CT the abnormalities found were new or increased known abnormalities. 115 (51%) brain CT were found to be diagnostically positive. In the medical group 29 (39%) of brain CT were positive, in the surgical group 86 (57%), p 0.01. After a positive brain CT, in which the expected abnormalities were found, treatment was changed as planned in 33%, and in 19% treatment was changed otherwise than planned. The results of this study show that the diagnostic and therapeutic yield of brain CT in critically ill patients is moderate. The development of guidelines regarding the decision rules for performing a brain CT in ICU patients is needed

  3. Studying variability in human brain aging in a population-based German cohort – Rationale and design of 1000BRAINS

    Directory of Open Access Journals (Sweden)

    Svenja eCaspers

    2014-07-01

    Full Text Available The ongoing 1000 brains study (1000BRAINS is an epidemiological and neuroscientific investigation of structural and functional variability in the human brain during aging. The two recruitment sources are the 10-year follow-up cohort of the German Heinz Nixdorf Recall (HNR Study, and the HNR MultiGeneration Study cohort, which comprises spouses and offspring of HNR subjects. The HNR is a longitudinal epidemiological investigation of cardiovascular risk factors, with a comprehensive collection of clinical, laboratory, socioeconomic, and environmental data from population-based subjects aged 45-75 years on inclusion. HNR subjects underwent detailed assessments in 2000, 2006, and 2011, and completed annual postal questionnaires on health status. 1000BRAINS accesses these HNR data and applies a separate protocol comprising: neuropsychological tests of attention, memory, executive functions & language; examination of motor skills; ratings of personality, life quality, mood & daily activities; analysis of laboratory and genetic data; and state-of-the-art magnetic resonance imaging (MRI, 3 Tesla of the brain. The latter includes (i 3D-T1- and 3D-T2-weighted scans for structural analyses and myelin mapping; (ii three diffusion imaging sequences optimized for diffusion tensor imaging, high-angular resolution diffusion imaging for detailed fibre tracking and for diffusion kurtosis imaging; (iii resting-state and task-based functional MRI; and (iv fluid-attenuated inversion recovery and MR angiography for the detection of vascular lesions and the mapping of white matter lesions. The unique design of 1000BRAINS allows: (i comprehensive investigation of various influences including genetics, environment and health status on variability in brain structure and function during aging; and (ii identification of the impact of selected influencing factors on specific cognitive subsystems and their anatomical correlates.

  4. Studying variability in human brain aging in a population-based German cohort-rationale and design of 1000BRAINS.

    Science.gov (United States)

    Caspers, Svenja; Moebus, Susanne; Lux, Silke; Pundt, Noreen; Schütz, Holger; Mühleisen, Thomas W; Gras, Vincent; Eickhoff, Simon B; Romanzetti, Sandro; Stöcker, Tony; Stirnberg, Rüdiger; Kirlangic, Mehmet E; Minnerop, Martina; Pieperhoff, Peter; Mödder, Ulrich; Das, Samir; Evans, Alan C; Jöckel, Karl-Heinz; Erbel, Raimund; Cichon, Sven; Nöthen, Markus M; Sturma, Dieter; Bauer, Andreas; Jon Shah, N; Zilles, Karl; Amunts, Katrin

    2014-01-01

    The ongoing 1000 brains study (1000BRAINS) is an epidemiological and neuroscientific investigation of structural and functional variability in the human brain during aging. The two recruitment sources are the 10-year follow-up cohort of the German Heinz Nixdorf Recall (HNR) Study, and the HNR MultiGeneration Study cohort, which comprises spouses and offspring of HNR subjects. The HNR is a longitudinal epidemiological investigation of cardiovascular risk factors, with a comprehensive collection of clinical, laboratory, socioeconomic, and environmental data from population-based subjects aged 45-75 years on inclusion. HNR subjects underwent detailed assessments in 2000, 2006, and 2011, and completed annual postal questionnaires on health status. 1000BRAINS accesses these HNR data and applies a separate protocol comprising: neuropsychological tests of attention, memory, executive functions and language; examination of motor skills; ratings of personality, life quality, mood and daily activities; analysis of laboratory and genetic data; and state-of-the-art magnetic resonance imaging (MRI, 3 Tesla) of the brain. The latter includes (i) 3D-T1- and 3D-T2-weighted scans for structural analyses and myelin mapping; (ii) three diffusion imaging sequences optimized for diffusion tensor imaging, high-angular resolution diffusion imaging for detailed fiber tracking and for diffusion kurtosis imaging; (iii) resting-state and task-based functional MRI; and (iv) fluid-attenuated inversion recovery and MR angiography for the detection of vascular lesions and the mapping of white matter lesions. The unique design of 1000BRAINS allows: (i) comprehensive investigation of various influences including genetics, environment and health status on variability in brain structure and function during aging; and (ii) identification of the impact of selected influencing factors on specific cognitive subsystems and their anatomical correlates. PMID:25071558

  5. Heat-shock protein 90 promotes nuclear transport of herpes simplex virus 1 capsid protein by interacting with acetylated tubulin.

    Science.gov (United States)

    Zhong, Meigong; Zheng, Kai; Chen, Maoyun; Xiang, Yangfei; Jin, Fujun; Ma, Kaiqi; Qiu, Xianxiu; Wang, Qiaoli; Peng, Tao; Kitazato, Kaio; Wang, Yifei

    2014-01-01

    Although it is known that inhibitors of heat shock protein 90 (Hsp90) can inhibit herpes simplex virus type 1 (HSV-1) infection, the role of Hsp90 in HSV-1 entry and the antiviral mechanisms of Hsp90 inhibitors remain unclear. In this study, we found that Hsp90 inhibitors have potent antiviral activity against standard or drug-resistant HSV-1 strains and viral gene and protein synthesis are inhibited in an early phase. More detailed studies demonstrated that Hsp90 is upregulated by virus entry and it interacts with virus. Hsp90 knockdown by siRNA or treatment with Hsp90 inhibitors significantly inhibited the nuclear transport of viral capsid protein (ICP5) at the early stage of HSV-1 infection. In contrast, overexpression of Hsp90 restored the nuclear transport that was prevented by the Hsp90 inhibitors, suggesting that Hsp90 is required for nuclear transport of viral capsid protein. Furthermore, HSV-1 infection enhanced acetylation of α-tubulin and Hsp90 interacted with the acetylated α-tubulin, which is suppressed by Hsp90 inhibition. These results demonstrate that Hsp90, by interacting with acetylated α-tubulin, plays a crucial role in viral capsid protein nuclear transport and may provide novel insight into the role of Hsp90 in HSV-1 infection and offer a promising strategy to overcome drug-resistance. PMID:24901434

  6. A placebo-controlled, randomized phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancer

    DEFF Research Database (Denmark)

    Grønberg, Bjørn H; Ciuleanu, Tudor; Fløtten, Øystein; Knuuttila, Aija; Abel, Edvard; Langer, Seppo W; Krejcy, Kurt; Liepa, Astra M; Munoz, Maria; Hahka-Kemppinen, Marjo; Sundstrøm, Stein

    2012-01-01

    Enzastaurin is a protein kinase C inhibitor with anti-tumor activity. This study was designed to determine if maintenance enzastaurin improved the outcome of whole brain radiotherapy (WBRT) in lung cancer (LC) patients with brain metastases (BMs).......Enzastaurin is a protein kinase C inhibitor with anti-tumor activity. This study was designed to determine if maintenance enzastaurin improved the outcome of whole brain radiotherapy (WBRT) in lung cancer (LC) patients with brain metastases (BMs)....

  7. Computational anatomy for studying use-dependant brain plasticity

    Science.gov (United States)

    Draganski, Bogdan; Kherif, Ferath; Lutti, Antoine

    2014-01-01

    In this article we provide a comprehensive literature review on the in vivo assessment of use-dependant brain structure changes in humans using magnetic resonance imaging (MRI) and computational anatomy. We highlight the recent findings in this field that allow the uncovering of the basic principles behind brain plasticity in light of the existing theoretical models at various scales of observation. Given the current lack of in-depth understanding of the neurobiological basis of brain structure changes we emphasize the necessity of a paradigm shift in the investigation and interpretation of use-dependent brain plasticity. Novel quantitative MRI acquisition techniques provide access to brain tissue microstructural properties (e.g., myelin, iron, and water content) in-vivo, thereby allowing unprecedented specific insights into the mechanisms underlying brain plasticity. These quantitative MRI techniques require novel methods for image processing and analysis of longitudinal data allowing for straightforward interpretation and causality inferences. PMID:25018716

  8. Computational anatomy for studying use-dependant brain plasticity

    Directory of Open Access Journals (Sweden)

    Bogdan eDraganski

    2014-06-01

    Full Text Available In this article we provide a comprehensive literature review on the in vivo assessment of use-dependant brain structure changes in humans using magnetic resonance imaging and computational anatomy. We highlight the recent findings in this field that allow the uncovering of the basic principles behind brain plasticity in light of the existing theoretical models at various scales of observation. Given the current lack of in-depth understanding of the neurobiological basis of brain structure changes we emphasize the necessity of a paradigm shift in the investigation and interpretation of use-dependent brain plasticity. Novel quantitative MRI acquisition techniques provide access to brain tissue microstructural properties (e.g. myelin, iron and water content in-vivo, thereby allowing unprecedented specific insights into the mechanisms underlying brain plasticity. These quantitative MRI techniques require novel methods for image processing and analysis of longitudinal data allowing for straightforward interpretation and causality inferences.

  9. Computational anatomy for studying use-dependant brain plasticity

    OpenAIRE

    Draganski, Bogdan; Kherif, Ferath; Lutti, Antoine

    2014-01-01

    In this article we provide a comprehensive literature review on the in vivo assessment of use-dependant brain structure changes in humans using magnetic resonance imaging (MRI) and computational anatomy. We highlight the recent findings in this field that allow the uncovering of the basic principles behind brain plasticity in light of the existing theoretical models at various scales of observation. Given the current lack of in-depth understanding of the neurobiological basis of brain structu...

  10. Computational anatomy for studying use-dependant brain plasticity

    OpenAIRE

    Bogdan eDraganski; Ferath eKherif; Antoine eLutti

    2014-01-01

    In this article we provide a comprehensive literature review on the in vivo assessment of use-dependant brain structure changes in humans using magnetic resonance imaging and computational anatomy. We highlight the recent findings in this field that allow the uncovering of the basic principles behind brain plasticity in light of the existing theoretical models at various scales of observation. Given the current lack of in-depth understanding of the neurobiological basis of brain structure cha...

  11. A STUDY ON BRAIN – MACHINE INTERFACE (BMI)

    OpenAIRE

    Abdul Muqeeth*,

    2015-01-01

    A brain – machine interface (BMI), sometimes called a mind - machine interface (MMI), or sometimes called a direct neural interface (DNI), synthetic telepathy interface (STI) or a brain – machine interface (BMI), is a direct communication pathway between the brain and an external device. BCIs are often directed at assisting, augmenting, or repairing human cognitive or se nsory - motor functions. The field of BCI research and developmen...

  12. Whole Brain Radiotherapy With Hippocampal Avoidance and Simultaneously Integrated Brain Metastases Boost: A Planning Study

    International Nuclear Information System (INIS)

    Purpose: To evaluate the feasibility of using tomotherapy to deliver whole brain radiotherapy with hippocampal avoidance, hypothesized to reduce the risk of memory function decline, and simultaneously integrated boost to brain metastases to improve intracranial tumor control. Methods and Materials: Ten patients treated with radiosurgery and whole brain radiotherapy underwent repeat planning using tomotherapy with the original computed tomography scans and magnetic resonance imaging-computed tomography fusion-defined target and normal structure contours. The individually contoured hippocampus was used as a dose-limiting structure (2 and 5.8 ± 1.9 Gy2 for 2.5- and 1.0-cm FW, respectively. The mean treatment delivery time for the 2.5- and 1.0-cm FW plans was 10.2 ± 1.0 and 21.8 ± 1.8 min, respectively. Conclusion: Composite tomotherapy plans achieved three objectives: homogeneous whole brain dose distribution equivalent to conventional whole brain radiotherapy; conformal hippocampal avoidance; and radiosurgically equivalent dose distributions to individual metastases

  13. Vergence in mild traumatic brain injury: A pilot study

    Directory of Open Access Journals (Sweden)

    Dora Szymanowicz, OD, MS

    2012-10-01

    Full Text Available Vergence dysfunction in individuals with mild traumatic brain injury (mTBI may have a negative effect on quality of life, functional abilities, and rehabilitative progress. In this study, we used a range of dynamic and static objective and subjective measures of vergence to assess 21 adult patients with mTBI and nearwork symptoms. The results were compared with 10 control adult subjects. With respect to dynamic parameters, responses in those with mTBI were slowed, variable, and delayed. With respect to static parameters, reduced near point of convergence and restricted near vergence ranges were found in those with mTBI. The present results provide evidence for the substantial adverse effect of mTBI on vergence function.

  14. Regional habit of coca chewing: Brain perfusion study

    International Nuclear Information System (INIS)

    A comparison was made of brain perfusion findings obtained using single photon emission computed tomography (SPECT) and 99Tcm-HMPAO (hexamethyl propylene amine oxime) in a study involving, on the one hand, cocaine dependent, HIV negative volunteers with different degrees of addiction (group G-II) and coca leaf chewers (group G-III) and, on the other, an abstinent control group (G-I). Urinary concentrations, determined by immunoassay, of benzolmethylecgonines (bmecg) - cocaine metabolites - were correlated with brain perfusion results. The maximum age of the subjects was 44 years. The results of neuropsychomotor examinations were normal for all of them. The number of persons in the different groups was as follows: three in G-I (control); seven in G-II (moderate and heavy cocaine users); and ten in G-III (continuous or intermittent coca leaf chewers). Cerebral SPECT readings were obtained with 30 mCi of 99Tcm-MPAO, after the appropriate quality checks on the instruments and radiochemicals. In G-I there were no perfusion irregularities and the urinary concentration were negative. In G-II (6/7) patchy asymmetric hypoperfusion was observed, with bmecg values of up to 17,000 ng/mL. In G-III (7/10) there appeared asymmetric areas of moderate hypoperfusion with left predominance and bmecg values above those of G-I, reaching 1000 ng/mL. Hypoperfused basal ganglions were observed in some G-II cases and, to a lesser extent, in G-III. The greats (in terms of number and dimensions) perfusion irregularities, with the highest bmecg values and the greatest probability of morbidity, occurred among the cocaine addicts (G-II). Among the coca leaf chewers (G-III), moderate spotted hypoperfusion was observed, also with left predominance and with moderate bmecg values. The study should be broadened in order to substantiate the findings. (author). 9 refs, 3 figs, 2 tabs

  15. Brain drain, brain gain or brain sharing?: New studies of the migration routes of scientists show that international mobility benefits all parties including countries that are net exporters of researchers

    OpenAIRE

    Hunter, Philip

    2013-01-01

    Scientific migration has long been seen in terms of brain drain and brain gain. Recent studies show that the reality is more complex and that even exporters of skilled scientists gain in the long term.

  16. Ultrastructural pathology of prion diseases revisited: brain biopsy studies.

    Science.gov (United States)

    Liberski, P P; Streichenberger, N; Giraud, P; Soutrenon, M; Meyronnet, D; Sikorska, B; Kopp, N

    2005-02-01

    We report here a detailed ultrastructural comparison of brain biopsies from 13 cases of Creutzfeldt-Jakob disease (CJD) and from one case of fatal familial insomnia (FFI). The latter disease has not heretofore benefited from ultrastructural study. In particular, we searched for tubulovesicular structures (TVS), 35-nm particles regarded as the only disease-specific structures at the level of thin-section electron microscopy. Our material consisted of brain biopsies obtained by open surgery from one FFI case from a new French family, one case of variant CJD (vCJD), nine cases of sporadic CJD (sCJD), two cases of iatrogenic (human growth hormone) CJD and one case of hereditary CJD (Val203Iso). The ultrastructural picture of the cerebral cortex of the FFI patient was virtually indistinguishable from that of CJD. TVS were found, albeit only after prolonged search. Typical spongiform change was observed, consisting of intracellular membrane-bound vacuoles containing secondary chambers (vacuoles within vacuoles) and amorphous material. Neuronal degeneration was widespread: some processes contained degenerating mitochondria and lysosomal electron-dense bodies and these met the criteria for neuroaxonal dystrophy. Other processes contained branching cisterns; still others were filled with electron-dense masses and amorphous vesicles. The overall ultrastructural appearance of variant CJD was similar to that of FFI cerebral cortex, except for a much higher number of cellular processes containing TVS. We detected TVS in the majority of sCJD cases that, in addition to typical spongiform change and robust astrocytic reaction, showed widespread neuritic and synaptic degeneration and autophagic vacuoles. We conclude that TVS are readily found in FFI, vCJD and sCJD and that widespread neuritic degeneration is a part of ultrastructural pathology in prion diseases. PMID:15634235

  17. MR Diffusion Studies of Human Brain in-vivo

    Directory of Open Access Journals (Sweden)

    M Nezamzadeh

    2005-10-01

    Full Text Available Diffusion MRI has become one of the most powerful tools for the detection of acute stroke. The signal attenuation caused by the diffusion process is normally assumed to be exponential .The decay constant which is often called the “apparent diffusion coefficient”(ADC is measured by 2 or 3 points in clinical applications yielding mono-exponential decay curves. The diffusion signal attenuation of water molecules on human brain was measured with a certain pulse sequence. The sequence was modified to work over a range of diffusion times and high gradients. The decay was measured precisely for 96 b-values up to the maximum possible gradient amplitude of 28.8 mT/m. A significant deviation from mono-exponential behavior was observed consistent to the multi-exponential model. The NNLS-diff computational code, using a non-negative least squares (NNLS algorithm was developed for the data analysis. The diffusion time dependence of human brain tissue was studied for diffusion times between 20 to 53 ms using 16 b-values ranged from b=0 to the maximum possible b-value in each case. At all diffusion times, there was a diffusion coefficient at approximately 1x10-3 mm2/s and another at about 6x10–5 mm2/s. For some diffusion times a small contribution at about 1x10 -2 mm2/s was also detected. Our results were consistent with work of others. However, we observe small diffusion time dependence for the smallest diffusion coefficient, which has not previously been reported. More work is required to identify the source of the new observation.

  18. The automatic brain: studies on practice and brain function in healthy subjects and patients with schizophrenia

    NARCIS (Netherlands)

    van Raalten, T.R.

    2009-01-01

    Practice makes perfect. The neural mechanisms behind the behavioral improvement of practice (automatization) however are largely unknown. Here we investigate how practice changes brain function and how this can improve our processing capacity. We also examine whether a deficit in automatization can

  19. Incidence of Brain Atrophy and Decline in Mini-Mental State Examination Score After Whole-Brain Radiotherapy in Patients With Brain Metastases: A Prospective Study

    International Nuclear Information System (INIS)

    Purpose: To determine the incidence of brain atrophy and dementia after whole-brain radiotherapy (WBRT) in patients with brain metastases not undergoing surgery. Methods and Materials: Eligible patients underwent WBRT to 40 Gy in 20 fractions with or without a 10-Gy boost. Brain magnetic resonance imaging or computed tomography and Mini-Mental State Examination (MMSE) were performed before and soon after radiotherapy, every 3 months for 18 months, and every 6 months thereafter. Brain atrophy was evaluated by change in cerebrospinal fluid-cranial ratio (CCR), and the atrophy index was defined as postradiation CCR divided by preradiation CCR. Results: Of 101 patients (median age, 62 years) entering the study, 92 completed WBRT, and 45, 25, and 10 patients were assessable at 6, 12, and 18 months, respectively. Mean atrophy index was 1.24 ± 0.39 (SD) at 6 months and 1.32 ± 0.40 at 12 months, and 18% and 28% of the patients had an increase in the atrophy index by 30% or greater, respectively. No apparent decrease in mean MMSE score was observed after WBRT. Individually, MMSE scores decreased by four or more points in 11% at 6 months, 12% at 12 months, and 0% at 18 months. However, about half the decrease in MMSE scores was associated with a decrease in performance status caused by systemic disease progression. Conclusions: Brain atrophy developed in up to 30% of patients, but it was not necessarily accompanied by MMSE score decrease. Dementia after WBRT unaccompanied by tumor recurrence was infrequent

  20. Cross-frequency coupling of brain oscillations in studying motivation and emotion

    OpenAIRE

    Schutter, Dennis J. L. G.; Knyazev, Gennady G.

    2011-01-01

    Research has shown that brain functions are realized by simultaneous oscillations in various frequency bands. In addition to examining oscillations in pre-specified bands, interactions and relations between the different frequency bandwidths is another important aspect that needs to be considered in unraveling the workings of the human brain and its functions. In this review we provide evidence that studying interdependencies between brain oscillations may be a valuable approach to study the ...

  1. Brain mapping as a tool to study neurodegeneration

    OpenAIRE

    Apostolova, Liana G.; Thompson, Paul M.

    2007-01-01

    Alzheimer’s disease (AD) is the most common neurodegenerative disorder for those 65 years or older, currently affects 4.5 million Americans, and is predicted to rise to 13.2 million by the year 2050 in the U.S. alone. Neuroimaging and brain mapping techniques provide extraordinary power to understand AD, providing spatially detailed information on the extent and trajectory of the disease as it spreads in the living brain. Computational anatomy techniques, applied to large databases of brain M...

  2. The Effect of Aging on Resting-State Brain Function: An fMRI Study

    Directory of Open Access Journals (Sweden)

    A. H. Batouli

    2009-11-01

    Full Text Available Background/Objective: Healthy aging may be accompanied by some types of cognitive impairment; moreover, normal aging may cause natural atrophy in the healthy human brain. The hypothesis of the healthy aging brain is the structural changes together with the functional impairment happening. The brain struggles to over-compensate for those functional age-related impairments to continue as a healthy brain in its functions. Our goal in this study was to evaluate the effects of aging on the resting-state activation network of the brain using the multi-session probabilistic independent component analysis algorithm (PICA. "nPatients and Methods: We compared the resting-state brain activities between two groups of healthy aged and young subjects, so we examined 30 right-handed subjects and finally 12 healthy aging and 11 controls were enrolled in the study. "nResults: Our results showed that during the resting-state, older brains benefit from larger areas of activation, while in young competent brains, higher activation occurs in terms of greater intensity. These results were obtained in prefrontal areas as regions with regard to memory function as well as the posterior cingulate cortex (PCC as parts of the default mode network. Meanwhile, we reached the same results after normalization of activation size with total brain volume. "nConclusion: The difference in activation patterns between the two groups shows the brain's endeavor to compensate the functional impairment.

  3. Learning and Study Strategies of Students with Traumatic Brain Injury: A Mixed Method Study

    Science.gov (United States)

    Bush, Erin; Hux, Karen; Zickefoose, Samantha; Simanek, Gina; Holmberg, Michelle; Henderson, Ambyr

    2011-01-01

    The purpose of this research was to explore the perceptions of four college students with severe traumatic brain injury and people associated with them regarding the use of learning skills and study strategies. The researchers employed a concurrent mixed method design using descriptive quantitative data as well as qualitative multiple case study…

  4. The automatic brain: studies on practice and brain function in healthy subjects and patients with schizophrenia

    OpenAIRE

    Raalten, T.R. van

    2009-01-01

    Practice makes perfect. The neural mechanisms behind the behavioral improvement of practice (automatization) however are largely unknown. Here we investigate how practice changes brain function and how this can improve our processing capacity. We also examine whether a deficit in automatization can explain the severely limited processing capacity in schizophrenia. Previous research implicates working memory (WM) in the development of automatization and the ability to improve processing capaci...

  5. Revisiting hydrocephalus as a model to study brain resilience.

    Directory of Open Access Journals (Sweden)

    Matheus Fernandes De Oliveira

    2012-01-01

    Full Text Available Hydrocephalus is an entity which embraces a variety of diseases whose final result is the enlarged size of cerebral ventricular system, partially or completely. The physiopathology of hydrocephalus lies in the dynamics of circulation of cerebrospinal fluid (CSF. The consequent CSF stasis in hydrocephalus interferes with cerebral and ventricular system development. Children and adults who sustain congenital or acquired brain injury typically experience a diffuse insult that impacts many areas of the brain. Development and recovery after such injuries reflects both restoration and reorganization of cognitive functions. Classic examples were already reported in literature. This suggests the presence of biological mechanisms associated with resilient adaptation of brain networks. We will settle a link between the notable modifications to neurophysiology secondary to hydrocephalus and the ability of neuronal tissue to reassume and reorganize its functions.Key words: hydrocephalus; resilience; brain; neural networks; plasticity.

  6. Brain Basics

    Medline Plus

    Full Text Available ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies show that brain growth in children with autism appears to peak early. And as ...

  7. Brain Basics

    Medline Plus

    Full Text Available ... Research Modern research tools and techniques are giving scientists a more detailed understanding of the brain than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies ...

  8. Functional brain imaging study on brain processes involved in visual awareness

    International Nuclear Information System (INIS)

    Recently, there has been great interest in visual awareness because it is thought that it may provide valuable information in understanding aspects of consciousness. An important but still controversial issue is what region in the brain is involved in visual awareness. When viewing ambiguous figures, observers can be aware of only one of multiple competing percepts at any given moment, but experience spontaneous alternations among the percepts over time. This phenomenon is known as multistable perceptions and thought to be essential in understanding the brain processes involved in visual awareness. We used functional magnetic resonance imaging to investigate the brain activities associated with multistable perceptions. Two separate experiments were performed based on two different multistable phenomena known as binocular rivalry and perceptions of ambiguous figures. Significant differential activations in the parietal and prefrontal areas were commonly observed under multistable conditions compared to monostable control conditions in the two separate experiments. These findings suggest that neural processes in the parietal and prefrontal areas may be involved in perceptual alternations in situations involving multistable phenomena. (author)

  9. Plastic Neuroscience: Studying What the Brain Cares About

    Directory of Open Access Journals (Sweden)

    Joseph eDumit

    2014-04-01

    Full Text Available Drawing on Allan Newell’s You can’t play 20 questions with nature and win, this article proposes that neuroscience needs to go beyond binary hypothesis testing and design experiments that follow what neurons care about. Examples from Lettvin et. al. are used to demonstrate that one can experimentally play with neurons and generate surprising results. In this manner, brains are not confused with persons, rather, persons are understood to do things with their brains.

  10. TRANSLATIONAL STUDIES ON REGULATION OF BRAIN DOCOSAHEXAENOIC ACID (DHA) METABOLISM IN VIVO

    OpenAIRE

    Rapoport, Stanley I.

    2012-01-01

    One goal in the field of brain polyunsaturated fatty acid (PUFA) metabolism is to translate the many studies that have been conducted in vitro and in animal models to the clinical setting. Doing so should elucidate the role of PUFAs in the human brain, and effects of diet, drugs, disease and genetics. This review briefly discusses new in vivo radiotracer kinetic and neuroimaging techniques that allow us to do this, with a focus on docosahexaenoic acid (DHA). We illustrate how brain PUFA metab...

  11. Brain activity during driving with distraction: an immersive fMRI study

    OpenAIRE

    Tom A Schweizer; Karen Kan; Yuwen Hung; Fred Tam; Gary Naglie; Simon Graham

    2013-01-01

    Introduction: Non-invasive measurements of brain activity have an important role to play in understanding driving ability. The current study aimed to identify the neural underpinnings of human driving behavior by visualizing the areas of the brain involved in driving under different levels of demand, such as driving while distracted or making left turns at busy intersections. Materials and Methods: To capture brain activity during driving, we placed a driving simulator with a fully functio...

  12. Impact of brain tissue filtering on neurostimulation fields: A modeling study

    OpenAIRE

    Wagner, Tim; Eden, Uri; Rushmore, Jarrett; Russo, Christopher J.; Dipietro, Laura; Fregni, Felipe; Simon, Stephen; Rotman, Stephen; Pitskel, Naomi B.; Ramos-Estebanez, Ciro; PASCUAL-LEONE, ALVARO; Grodzinsky, Alan J.; Zahn, Markus; Valero-Cabre, Antoni

    2013-01-01

    Electrical neurostimulation techniques, such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS), are increasingly used in the neurosciences, e.g., for studying brain function, and for neurotherapeutics, e.g., for treating depression, epilepsy, and Parkinson’s disease. The characterization of electrical properties of brain tissue has guided our fundamental understanding and application of these methods, from electrophysiologic theory to clinical dosing-metrics. Nonethe...

  13. A DTI-Based Template-Free Cortical Connectome Study of Brain Maturation

    OpenAIRE

    Tymofiyeva, O; Hess, CP; Ziv, E; Lee, PN; Glass, HC; Ferriero, DM; Barkovich, AJ; Xu, D.

    2013-01-01

    Improved understanding of how the human brain is "wired" on a macroscale may now be possible due to the emerging field of MRI connectomics. However, mapping the rapidly developing infant brain networks poses challenges. In this study, we applied an automated template-free "baby connectome" framework using diffusion MRI to non-invasively map the structural brain networks in subjects of different ages, including premature neonates, term-born neonates, six-month-old infants, and adults. We obser...

  14. Neurobiological origin of spurious brain morphological changes: A quantitative MRI study

    OpenAIRE

    Lorio, S.; Kherif, F.; Ruef, A.; Melie-Garcia, L.; Frackowiak, R; Ashburner, J.; Helms, G.; Lutti, A.; Draganski, B.

    2016-01-01

    The high gray-white matter contrast and spatial resolution provided by T1-weighted magnetic resonance imaging (MRI) has made it a widely used imaging protocol for computational anatomy studies of the brain. While the image intensity in T1-weighted images is predominantly driven by T1, other MRI parameters affect the image contrast, and hence brain morphological measures derived from the data. Because MRI parameters are correlates of different histological properties of brain tissue, this mixe...

  15. The influence of low-grade glioma on resting state oscillatory brain activity: a magnetoencephalography study

    OpenAIRE

    Bosma, I.; Stam, C.; Douw, L.; Bartolomei, F.; Heimans, J.; van Dijk; Postma, T.; Klein, M.; Reijneveld, J.

    2008-01-01

    Purpose: In the present MEG-study, power spectral analysis of oscillatory brain activity was used to compare resting state brain activity in both low-grade glioma (LGG) patients and healthy controls. We hypothesized that LGG patients show local as well as diffuse slowing of resting state brain activity compared to healthy controls and that particularly global slowing correlates with neurocognitive dysfunction. Patient and methods Resting state MEG recordings were obtained from 17 LGG patients...

  16. Brain-Based Learning and Classroom Practice: A Study Investigating Instructional Methodologies of Urban School Teachers

    Science.gov (United States)

    Morris, Lajuana Trezette

    2010-01-01

    The purpose of this study was to examine the implementation of brain-based instructional strategies by teachers serving at Title I elementary, middle, and high schools within the Memphis City School District. This study was designed to determine: (a) the extent to which Title I teachers applied brain-based strategies, (b) the differences in…

  17. A neurological comparative study of the harp seal (Pagophilus groenlandicus) and harbor porpoise (Phocoena phocoena) brain

    DEFF Research Database (Denmark)

    Walløe, Solveig; Eriksen, Nina; Dabelsteen, Torben;

    2010-01-01

    The cetacean brain is well studied. However, few comparisons have been done with other marine mammals. In this study, we compared the harp seal (Pagophilus groenlandicus) and the harbor porpoise brain (Phocoena phocoena). Stereological methods were applied to compare three areas of interest: the ...

  18. CT ASSESSMENT OF BRAIN VENTRICULAR SIZE BASED ON AGE AND SEX: A STUDY OF 112 CASES

    Directory of Open Access Journals (Sweden)

    Vinoo

    2013-12-01

    Full Text Available CT being the primary modality of choice in many centers for the diagnosis of brain pathology, normal brain ventricular size measurem ents is an important parameter for the diagnosis of conditions like hydrocephalus, age related atrophic changes and also other brain pathologies producing ventriculomegaly. It is also important for knowing the normal upper and lower limits of the brain ven tricular system in the different age groups, and in both sexes so as to diagnose brain pathology.The ventricular system of the brain undergoes changes with aging and varies with gender.Our study consists of 48 female, and 64 male patients. Apart from the v entricular measurements, two ratios and two indices were also calculated – which included the right and left Evan’s ratio, CM index, and ventricular size inde

  19. Experimental and numerical study on the mechanical behavior of rat brain tissue.

    Science.gov (United States)

    Karimi, A; Navidbakhsh, M; Yousefi, H; Haghi, A Motevalli; Sadati, Sja

    2014-02-01

    Brain tissue is a very soft tissue in which the mechanical properties depend on the loading direction. While few studies have characterized these biomechanical properties, it is worth knowing that accurate characterization of the mechanical properties of brain tissue at different loading directions is a key asset for neuronavigation and surgery simulation through haptic devices. In this study, the hyperelastic mechanical properties of rat brain tissue were measured experimentally and computationally. Prepared cylindrical samples were excised from the parietal lobes of rats' brains and experimentally tested by a tensile testing machine. The effects of loading direction on the mechanical properties of brain tissue were measured by applying load on both longitudinal and circumferential directions. The general prediction ability of the proposed hyperelastic model was verified using finite element (FE) simulations of brain tissue tension experiments. The uniaxial experimental results compared well with those predicted by the FE models. The results revealed the influence of loading direction on the mechanical properties of brain tissue. The Ogden hyperelastic material model was suitably represented by the non-linear behavior of the brain tissue, which can be used in future biomechanical simulations. The hyperelastic properties of brain tissue provided here have interest to the medical research community as there are several applications where accurate characterization of these properties are crucial for an accurate outcome, such as neurosurgery, robotic surgery, haptic device design or car manufacturing to evaluate possible trauma due to an impact. PMID:24519528

  20. Moessbauer Studies of Pathological Brain Tissues Affected by PSP Disease

    International Nuclear Information System (INIS)

    Progressive supranuclear palsy (PSP) is a neurological disease leading to the damage of two brain structures: globus pallidus and substantia nigra. The pathomechanism of this disease is still unknown. One of the hypotheses is oxidative stress. Oxidative stress is an overproduction of free radicals in which iron may be involved. To verify the hypothesis that iron may play a role in PSP we performed the Moessbauer comparative studies of pathological and control tissues. Ten samples of PSP globus pallidus, ten samples of PSP substantia nigra, twelve control samples of globus pallidus and nine control samples of substantia nigra were measured in a conventional Moessbauer spectrometer at 90 K. The Moessbauer spectra obtained for all samples showed well resolved doublets with an isomer shift of 0.46 ± 0.01 mm/s and a quadruple splitting of 0.70 ± 0.02 mm/s. The main difference in these preliminary studies was in the concentration of iron. The concentration in PSP samples in globus pallidus was found to be 257 ± 19 ng/mg tissue, compared to 183 ± 22 ng/mg in control samples and 301 ± 26 ng/mg in substantia nigra compared to 188 ± 22 ng/mg in control samples. Taking into consideration that we did not notice any substantial increase in iron concentration in Parkinsonian substantia nigra compared to control substantia nigra, but a substantial increase in both substantia nigra and globus pallidus in PSP, may suggest that iron plays a different role in the pathomechanisms of PSP and of Parkinson's disease. (authors)

  1. An ultra­high field Magnetic Resonance Spectroscopy study of post exercise brain lactate, glutamate and glutamine change in the human brain.

    Directory of Open Access Journals (Sweden)

    Andrea eDennis

    2015-12-01

    Full Text Available During strenuous exercise there is a progressive increase in lactate uptake and metabolism into the brain as workload and plasma lactate levels increase. Although it is now widely accepted that the brain can metabolise lactate, few studies have directly measured brain lactate following vigorous exercise. Here, we used ultra-high field Magnetic Resonance Spectroscopy of the brain to obtain static measures of brain lactate, as well as brain glutamate and glutamine after vigorous exercise. The aims of our experiment were to (a track the changes in brain lactate following recovery from exercise and, (b to simultaneously measure the signals from brain glutamate and glutamine. The results of our experiment showed that vigorous exercise resulted in a significant increase in brain lactate. Furthermore, both glutamate and glutamine were successfully resolved, and as expected, although contrary to some previous reports, we did not observe any significant change in either amino acid after exercise. We did however observe a negative correlation between glutamate and a measure of fitness. These results support the hypothesis that peripherally-derived lactate is taken up by the brain when available. Our data additionally highlight the potential of ultra-high field magnetic resonance spectroscopy as a non-invasive way of measuring multiple brain metabolite changes with exercise.

  2. A study of brain MRI findings and clinical response of bladder empting failure in brain bladder

    Energy Technology Data Exchange (ETDEWEB)

    Miyakoda, Keiichi (Yamashina Aiseikai Hospital, Kyoto (Japan)); Watanabe, Kousuke

    1993-02-01

    In 45 patients (38 males and 7 females; average age:78 years) with brain bladder, who did not have any peripheral neuropathies and spinal disturbance, cerebral findings of MRI (1.5 T) T[sub 2] enhanced image were analyzed in comparison with those of 7 control patients with normal urination after BPH operations. Patients with neurogenic bladder were divided into three groups as follows: 33 patients with a chief complaint of urinary disturbance (Group I), 9 patients with urinary incontinence (Group II) and 3 patients with balanced bladder (Group III). High frequency of lacune (24%) of the globus pallidus and low signalling of the corpus striatum (30%) was found in Group I patients, but low frequency in other Group patients and control patients. Furthermore, pathologic changes with various grades in the globus pallidus were observed in 91% of Group I patients. In the treatment of urinary disturbance, a high improvement rate of micturition disorder (77%) was obtained in patients treated with a combination of dantrolene and TURp (TUIbn for females). However, patients who had clear lacune of the globus pallidus showed the low improvement rate. It should be possible that the globus pallidus contributes to control the movement of the external sphincter and the pelvic base muscles as well as other striated muscles. Moreover, lacune was rarely found in the urination center of the brain-stem on MRI. (author).

  3. Traumatic Brain Injury Studies in Britain during World War II.

    Science.gov (United States)

    Lanska, Douglas J

    2016-01-01

    As a result of the wartime urgency to understand, prevent, and treat patients with traumatic brain injury (TBI) during World War II (WWII), clinicians and basic scientists in Great Britain collaborated on research projects that included accident investigations, epidemiologic studies, and development of animal and physical models. Very quickly, investigators from different disciplines shared information and ideas that not only led to new insights into the mechanisms of TBI but also provided very practical approaches for preventing or ameliorating at least some forms of TBI. Neurosurgeon Hugh Cairns (1896-1952) conducted a series of influential studies on the prevention and treatment of head injuries that led to recognition of a high rate of fatal TBI among motorcycle riders and subsequently to demonstrations of the utility of helmets in lowering head injury incidence and case fatality. Neurologists Derek Denny-Brown (1901-1981) and (William) Ritchie Russell (1903-1980) developed an animal model of TBI that demonstrated the fundamental importance of sudden acceleration (i.e., jerking) of the head in causing concussion and forced a distinction between head injury associated with sudden acceleration/deceleration and that associated with crush or compression. Physicist A.H.S. Holbourn (1907-1962) used theoretical arguments and simple physical models to illustrate the importance of shear stress in TBI. The work of these British neurological clinicians and scientists during WWII had a strong influence on subsequent clinical and experimental studies of TBI and also eventually resulted in effective (albeit controversial) public health campaigns and legislation in several countries to prevent head injuries among motorcycle riders and others through the use of protective helmets. Collectively, these studies accelerated our understanding of TBI and had subsequent important implications for both military and civilian populations. As a result of the wartime urgency to understand

  4. TENIPOSIDE FOR BRAIN METASTASES OF SMALL-CELL LUNG-CANCER - A PHASE-II STUDY

    NARCIS (Netherlands)

    POSTMUS, PE; SMIT, EF; HAAXMAREICHE, H; VANZANDWIJK, N; ARDIZZONI, A; QUOIX, E; KIRKPATRICK, A; SAHMOUD, T; GIACCONE, G

    1995-01-01

    Purpose: Here we report the results of a phase II study of teniposide, one of the most active drugs against small-cell lung cancer (SCLC), in patients with brain metastases. Patients and Methods: Patients with SCLC who presented with brain metastases at diagnosis (n = 11) or during follow-up evaluat

  5. Brain Potentials for Derivational Morphology: An ERP Study of Deadjectival Nominalizations in Spanish

    Science.gov (United States)

    Havas, Viktoria; Rodriguez-Fornells, Antoni; Clahsen, Harald

    2012-01-01

    This study investigates brain potentials to derived word forms in Spanish. Two experiments were performed on derived nominals that differ in terms of their productivity and semantic properties but are otherwise similar, an acceptability judgment task and a reading experiment using event-related brain potentials (ERPs) in which correctly and…

  6. Domiciliary therapy during inpatient rehabilitation treatment for patients with an acquired brain injury : A preliminary study

    NARCIS (Netherlands)

    Boonstra, AM; Spikman, JM; Wijbrandi, Wilma

    2005-01-01

    The objective was to assess the feasibility of additional domiciliary treatment for patients with an acquired brain injury while they are still inpatients at a rehabilitation centre. This cohort study included 22 patients with an acquired brain injury (mainly stroke) and with moderate to severe neur

  7. Brain type carnosinase in dementia: a pilot study

    Directory of Open Access Journals (Sweden)

    Papaioannou Alexandra

    2007-11-01

    Full Text Available Abstract Background The pathological processes underlying dementia are poorly understood and so are the markers which identify them. Carnosinase is a dipeptidase found almost exclusively in brain and serum. Carnosinase and its substrate carnosine have been linked to neuropathophysiological processes. Methods Carnosinase activity was measured by a flourometric method in 37 patients attending a Geriatric Outpatient Clinic. There were 17 patients without dementia, 13 had Alzheimer's disease (AD and 7 had mixed dementia (MD. Results The range of serum carnosinase activity for patients without dementia was 14.5 – 78.5 μmol/ml/h. There was no difference in carnosinase activity between patients without dementia (40.3 ± 15.2 μmol/ml/h and patients with AD (44.4 ± 12.4 μmol/ml/h or MD (26.6 ± 15 μmol/ml/h. However, levels in the MD group were significantly lower than the AD group (p = 0.01. This difference remained significant after adjusting for gender, MMSE score, exercise, but not age, one at a time and all combined. The effect of other medical conditions did not remove the significance between the AD and MD groups. The MD group, but not the AD group, demonstrated a significant trend with carnosinase activity decreasing with duration of disease (from first recorded date of diagnosis to date of blood collection (r = -0.76, p = 0.049. There was no association with carnosinase activity and MMSE score in the AD or MD group. Both AD and MD patients on any dementia medication (donepezil, galantamine, memantine had higher carnosinase activity compared to those not taking a dementia medication. Carnosinase activity was higher in patients who regularly exercised (n = 20 compared to those who did not exercise regularly (n = 17(p = 0.006. Conclusion This exploratory study has shown altered activities of the enzyme carnosinase in patients with dementia.

  8. Brain activity during driving with distraction: an immersive fMRI study

    Directory of Open Access Journals (Sweden)

    Tom A Schweizer

    2013-02-01

    Full Text Available Introduction: Non-invasive measurements of brain activity have an important role to play in understanding driving ability. The current study aimed to identify the neural underpinnings of human driving behavior by visualizing the areas of the brain involved in driving under different levels of demand, such as driving while distracted or making left turns at busy intersections. Methods: To capture brain activity during driving, we placed a driving simulator with a fully functional steering wheel and pedals in a 3.0 Tesla functional magnetic resonance imaging (fMRI system. To identify the brain areas involved while performing different real-world driving maneuvers, participants completed tasks ranging from simple (right turns to more complex (left turns at busy intersections. To assess the effects of driving while distracted, participants were asked to perform an auditory task while driving analogous to speaking on a hands-free device and driving. Results: A widely distributed brain network was identified, especially when making left turns at busy intersections compared to more simple driving tasks. During distracted driving, brain activation shifted dramatically from the posterior, visual and spatial areas to the prefrontal cortex. Conclusions: Our findings suggest that the distracted brain sacrificed areas in the posterior brain important for visual attention and alertness to recruit enough brain resources to perform a secondary, cognitive task. The present findings offer important new insights into the scientific understanding of the neuro-cognitive mechanisms of driving behavior and lay down an important foundation for future clinical research.

  9. Is the ferret a suitable species for studying perinatal brain injury?

    Science.gov (United States)

    Empie, Kristen; Rangarajan, Vijayeta; Juul, Sandra E

    2015-10-01

    Complications of prematurity often disrupt normal brain development and/or cause direct damage to the developing brain, resulting in poor neurodevelopmental outcomes. Physiologically relevant animal models of perinatal brain injury can advance our understanding of these influences and thereby provide opportunities to develop therapies and improve long-term outcomes. While there are advantages to currently available small animal models, there are also significant drawbacks that have limited translation of research findings to humans. Large animal models such as newborn pig, sheep and nonhuman primates have complex brain development more similar to humans, but these animals are expensive, and developmental testing of sheep and piglets is limited. Ferrets (Mustela putorius furo) are born lissencephalic and undergo postnatal cortical folding to form complex gyrencephalic brains. This review examines whether ferrets might provide a novel intermediate animal model of neonatal brain disease that has the benefit of a gyrified, altricial brain in a small animal. It summarizes attributes of ferret brain growth and development that make it an appealing animal in which to model perinatal brain injury. We postulate that because of their innate characteristics, ferrets have great potential in neonatal neurodevelopmental studies. PMID:26102988

  10. Study of Teen Brains Offers Clues to Timing of Mental Illness

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_160114.html Study of Teen Brains Offers Clues to Timing of ... see that the changes refine the detail," explained study first author Kirstie Whitaker, from the department of ...

  11. In vivo study of drug interaction with brain benzodiazepine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, O.; Shinotoh, H.; Ito, T.; Suzuki, K.; Hashimoto, K.; Yamasaki, T.

    1985-05-01

    The possibility of direct estimation of in vivo Bz receptor occupancy in brain was evaluated using C-11, or H-3-flumazepil (Ro15-1788). In animal experiments, 1 ..mu..Ci of H-3-Ro15-1788 was injected at 0.5 or 20 hr after i.v. injection of various dosage of clonazepam. Then radioactivity in cerebral cortex, cerebellum and blood at 5 min. after injection of the tracer was compared. Competitive inhibition of in vivo binding was clearly observed when clonazepam was pretreated at 0.5 hr before injection of the tracer. On the other hand, brain radioactivity was increased when clonazepam was administered at 20 hr before injection of the tracer. This increase in binding of H-3-Ro15-1788 might be caused by rebound of Bz receptor function by treatment with Bz agonist, and this rebound may have an important role in physiological function. Clinical investigation concerning drug interaction with brain Bz receptor was performed in normal volunteer and patients with neurological disorders. The distribution of C-11-Ro15-1788 in the brain of patients chronically treated with clonazepam were significantly heterogeneous. However, cerebral blood flow estimated with N-13 NH3 of these patients were normal.

  12. In vivo study of drug interaction with brain benzodiazepine receptor

    International Nuclear Information System (INIS)

    The possibility of direct estimation of in vivo Bz receptor occupancy in brain was evaluated using C-11, or H-3-flumazepil (Ro15-1788). In animal experiments, 1 μCi of H-3-Ro15-1788 was injected at 0.5 or 20 hr after i.v. injection of various dosage of clonazepam. Then radioactivity in cerebral cortex, cerebellum and blood at 5 min. after injection of the tracer was compared. Competitive inhibition of in vivo binding was clearly observed when clonazepam was pretreated at 0.5 hr before injection of the tracer. On the other hand, brain radioactivity was increased when clonazepam was administered at 20 hr before injection of the tracer. This increase in binding of H-3-Ro15-1788 might be caused by rebound of Bz receptor function by treatment with Bz agonist, and this rebound may have an important role in physiological function. Clinical investigation concerning drug interaction with brain Bz receptor was performed in normal volunteer and patients with neurological disorders. The distribution of C-11-Ro15-1788 in the brain of patients chronically treated with clonazepam were significantly heterogeneous. However, cerebral blood flow estimated with N-13 NH3 of these patients were normal

  13. Brain dopamine receptors in relation to clinical PET-studies

    International Nuclear Information System (INIS)

    A number of published PET Models are discussed with regard to their structure and some of the underlying assumptions. Results of experiments with spiperone and N-methylspiperone in the rat and human brain, which challenge some of these assumptions, are summarized. (author). 37 refs.; 6 figs.; 1 tab

  14. Introductory study of brain function data processing; No kino joho shori no sendo kenkyu

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-03-01

    An investigational study was conducted of the brain function aiming at developing an interface with the same function as humans have. In the study, the most up-to-date information/knowledge and future problems were examined on brain measurement, brain modeling, making a model an element, and the brain function data processing system. As to the brain measurement, the paper took up the multielectrode simultaneous measuring method and the optical multipoint measuring method as an invasive measuring method, and the functional magnetic resonance imaging, near-infrared spectroscopy, magneto-encephalography, and electro-encephalography as a non-invasive measuring method. Relating to the brain modeling, studies were made on senses of sight and smell, the movement control and the learning. As to making a model an element, how to make the modeled function a chip on silicone for example becomes the problem. Reported were two reports on making the sense of sight an element and one report on making the parallel dispersed processing mechanism of brain an element. About the brain function data processing system, three reports were made on the present situation, matters in question, and the future development of the system in the case of catching data processing as a system taking a step ahead from making the model an element. 250 refs., 74 figs., 11 tabs.

  15. Laser technique for anatomical-functional study of the medial prefrontal cortex of the brain

    Science.gov (United States)

    Sanchez-Huerta, Laura; Hernandez, Adan; Ayala, Griselda; Marroquin, Javier; Silva, Adriana B.; Khotiaintsev, Konstantin S.; Svirid, Vladimir A.; Flores, Gonzalo; Khotiaintsev, Sergei N.

    1999-05-01

    The brain represents one of the most complex systems that we know yet. In its study, non-destructive methods -- in particular, behavioral studies play an important role. By alteration of brain functioning (e.g. by pharmacological means) and observation of consequent behavior changes an important information on brain organization and functioning is obtained. For inducing local alterations, permanent brain lesions are employed. However, for correct results this technique has to be quasi-non-destructive, i.e. not to affect the normal brain function. Hence, the lesions should be very small, accurate and applied precisely over the structure (e.g. the brain nucleus) of interest. These specifications are difficult to meet with the existing techniques for brain lesions -- specifically, neurotoxical, mechanical and electrical means because they result in too extensive damage. In this paper, we present new laser technique for quasi-non- destructive anatomical-functional mapping in vivo of the medial prefrontal cortex (MPFC) of the rat. The technique is based on producing of small-size, well-controlled laser- induced lesions over some areas of the MPFC. The anesthetized animals are subjected to stereotactic surgery and certain points of the MPFC are exposed the confined radiation of the 10 W cw CO2 laser. Subsequent behavioral changes observed in neonatal and adult animals as well as histological data prove effectiveness of this technology for anatomical- functional studies of the brain by areas, and as a treatment method for some pathologies.

  16. MRI as a tool to study brain structure from mouse models for mental retardation

    Science.gov (United States)

    Verhoye, Marleen; Sijbers, Jan; Kooy, R. F.; Reyniers, E.; Fransen, E.; Oostra, B. A.; Willems, Peter; Van der Linden, Anne-Marie

    1998-07-01

    Nowadays, transgenic mice are a common tool to study brain abnormalities in neurological disorders. These studies usually rely on neuropathological examinations, which have a number of drawbacks, including the risk of artefacts introduced by fixation and dehydration procedures. Here we present 3D Fast Spin Echo Magnetic Resonance Imaging (MRI) in combination with 2D and 3D segmentation techniques as a powerful tool to study brain anatomy. We set up MRI of the brain in mouse models for the fragile X syndrome (FMR1 knockout) and Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus (CRASH) syndrome (L1CAM knockout). Our major goal was to determine qualitative and quantitative differences in specific brain structures. MRI of the brain of fragile X and CRASH patients has revealed alterations in the size of specific brain structures, including the cerebellar vermis and the ventricular system. In the present MRI study of the brain from fragile X knockout mice, we have measured the size of the brain, cerebellum and 4th ventricle, which were reported as abnormal in human fragile X patients, but found no evidence for altered brain regions in the mouse model. In CRASH syndrome, the most specific brain abnormalities are vermis hypoplasia and abnormalities of the ventricular system with some degree of hydrocephalus. With the MRI study of L1CAM knockout mice we found vermis hypoplasia, abnormalities of the ventricular system including dilatation of the lateral and the 4th ventricles. These subtle abnormalities were not detected upon standard neuropathological examination. Here we proved that this sensitive MRI technique allows to measure small differences which can not always be detected by means of pathology.

  17. Weight Gain following Pallidal Deep Brain Stimulation: A PET Study.

    Science.gov (United States)

    Sauleau, Paul; Drapier, Sophie; Duprez, Joan; Houvenaghel, Jean-François; Dondaine, Thibaut; Haegelen, Claire; Drapier, Dominique; Jannin, Pierre; Robert, Gabriel; Le Jeune, Florence; Vérin, Marc

    2016-01-01

    The mechanisms behind weight gain following deep brain stimulation (DBS) surgery seem to be multifactorial and suspected depending on the target, either the subthalamic nucleus (STN) or the globus pallidus internus (GPi). Decreased energy expenditure following motor improvement and behavioral and/or metabolic changes are possible explanations. Focusing on GPi target, our objective was to analyze correlations between changes in brain metabolism (measured with PET) and weight gain following GPi-DBS in patients with Parkinson's disease (PD). Body mass index was calculated and brain activity prospectively measured using 2-deoxy-2[18F]fluoro-D-glucose PET four months before and four months after the start of GPi-DBS in 19 PD patients. Dopaminergic medication was included in the analysis to control for its possible influence on brain metabolism. Body mass index increased significantly by 0.66 ± 1.3 kg/m2 (p = 0.040). There were correlations between weight gain and changes in brain metabolism in premotor areas, including the left and right superior gyri (Brodmann area, BA 6), left superior gyrus (BA 8), the dorsolateral prefrontal cortex (right middle gyrus, BAs 9 and 46), and the left and right somatosensory association cortices (BA 7). However, we found no correlation between weight gain and metabolic changes in limbic and associative areas. Additionally, there was a trend toward a correlation between reduced dyskinesia and weight gain (r = 0.428, p = 0.067). These findings suggest that, unlike STN-DBS, motor improvement is the major contributing factor for weight gain following GPi-DBS PD, confirming the motor selectivity of this target. PMID:27070317

  18. Comparative anatomy of the pig brain : an integrative magnetic resonance imaging (MRI) study of the porcine brain with special emphasis on the external morphology of the cerebral cortex

    OpenAIRE

    Schmidt, Verena

    2015-01-01

    For this study the healthy brains of the domestic pigs are examined post mortem. MRI (magnetic resonance imaging) scans in transverse, sagittal and dorsal orientation (native and formalin fixed) are produced with a 1.0 Tesla scanner. 12 sagittal, 13 dorsal and 22 transverse scans are selected and labelled to produce a MRI picture atlas of the porcine brain. With the aid of the graphical software programs AMIRA® and AVIZO® (Mercury Computer Systems Inc.) it was possible to identify brain s...

  19. Influence of type 2 diabetes on brain volumes and changes in brain volumes: Results from the Women's Health Initiative Magnetic Resonance Imaging Studies

    OpenAIRE

    Espeland, MA; Bryan, RN; Goveas, JS; Robinson, JG; Siddiqui, MS; Liu, S.; Hogan, PE; Casanova, R; Coker, LH; Yaffe, K.; Masaki, K.; Rossom, R; Resnick, SM

    2012-01-01

    OBJECTIVE - To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function. RESEARCH DESIGN AND METHODS - Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72-89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that...

  20. A study of brain networks associated with swallowing using graph-theoretical approaches.

    Directory of Open Access Journals (Sweden)

    Bo Luan

    Full Text Available Functional connectivity between brain regions during swallowing tasks is still not well understood. Understanding these complex interactions is of great interest from both a scientific and a clinical perspective. In this study, functional magnetic resonance imaging (fMRI was utilized to study brain functional networks during voluntary saliva swallowing in twenty-two adult healthy subjects (all females, [Formula: see text] years of age. To construct these functional connections, we computed mean partial correlation matrices over ninety brain regions for each participant. Two regions were determined to be functionally connected if their correlation was above a certain threshold. These correlation matrices were then analyzed using graph-theoretical approaches. In particular, we considered several network measures for the whole brain and for swallowing-related brain regions. The results have shown that significant pairwise functional connections were, mostly, either local and intra-hemispheric or symmetrically inter-hemispheric. Furthermore, we showed that all human brain functional network, although varying in some degree, had typical small-world properties as compared to regular networks and random networks. These properties allow information transfer within the network at a relatively high efficiency. Swallowing-related brain regions also had higher values for some of the network measures in comparison to when these measures were calculated for the whole brain. The current results warrant further investigation of graph-theoretical approaches as a potential tool for understanding the neural basis of dysphagia.

  1. Housekeeping while brain's storming Validation of normalizing factors for gene expression studies in a murine model of traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Escriou Virginie

    2008-07-01

    Full Text Available Abstract Background Traumatic brain injury models are widely studied, especially through gene expression, either to further understand implied biological mechanisms or to assess the efficiency of potential therapies. A large number of biological pathways are affected in brain trauma models, whose elucidation might greatly benefit from transcriptomic studies. However the suitability of reference genes needed for quantitative RT-PCR experiments is missing for these models. Results We have compared five potential reference genes as well as total cDNA level monitored using Oligreen reagent in order to determine the best normalizing factors for quantitative RT-PCR expression studies in the early phase (0–48 h post-trauma (PT of a murine model of diffuse brain injury. The levels of 18S rRNA, and of transcripts of β-actin, glyceraldehyde-3P-dehydrogenase (GAPDH, β-microtubulin and S100β were determined in the injured brain region of traumatized mice sacrificed at 30 min, 3 h, 6 h, 12 h, 24 h and 48 h post-trauma. The stability of the reference genes candidates and of total cDNA was evaluated by three different methods, leading to the following rankings as normalization factors, from the most suitable to the less: by using geNorm VBA applet, we obtained the following sequence: cDNA(Oligreen; GAPDH > 18S rRNA > S100β > β-microtubulin > β-actin; by using NormFinder Excel Spreadsheet, we obtained the following sequence: GAPDH > cDNA(Oligreen > S100β > 18S rRNA > β-actin > β-microtubulin; by using a Confidence-Interval calculation, we obtained the following sequence: cDNA(Oligreen > 18S rRNA; GAPDH > S100β > β-microtubulin > β-actin. Conclusion This work suggests that Oligreen cDNA measurements, 18S rRNA and GAPDH or a combination of them may be used to efficiently normalize qRT-PCR gene expression in mouse brain trauma injury, and that β-actin and β-microtubulin should be avoided. The potential of total cDNA as measured by Oligreen as a

  2. Parenchymal lymphoma of the brain on initial MR imaging: A comparative study between primary and secondary brain lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Senocak, Efsun, E-mail: eurger@yahoo.com [Hacettepe University, Faculty of Medicine, Department of Radiology, 06100 Sihhiye-Ankara (Turkey); Oguz, Kader Karli; Ozgen, Burce [Hacettepe University, Faculty of Medicine, Department of Radiology, 06100 Sihhiye-Ankara (Turkey); Mut, Melike; Ayhan, Selim; Berker, Mustafa [Hacettepe University, Faculty of Medicine, Department of Neurosurgery (Turkey); Ozdemir, Pinar [Hacettepe University, Faculty of Medicine, Department of Biostatistics and Medical Informatics (Turkey); Cila, Aysenur [Hacettepe University, Faculty of Medicine, Department of Radiology, 06100 Sihhiye-Ankara (Turkey)

    2011-08-15

    Background and purpose: Parenchymal lymphomatous brain masses have not been investigated considering if they are primary or as a part of systemic lymphoma (secondary) on imaging studies previously. We aimed to determine characteristics of the secondary parenchymal lymphomatous involvement of the brain and to find if there is any radiologic feature to help discrimination of untreated primary and secondary central nervous system lymphoma on patients' initial magnetic resonance imaging. Materials and methods: We evaluated MR images of 18 patients with the diagnosis of primary (n = 12) and secondary central nervous system lymphoma (n = 6). We considered the number, localization, enhancement pattern, signal characteristics, diffusion properties, presence of hemorrhage and presence of butterfly pattern on MR imaging at initial presentation. Results: Secondary central nervous system lymphomas predominantly presented as multiple (n = 4, 66.7%) lesions. Homogenous nodular enhancement and supratentorial white matter involvement were present in all patients with butterfly pattern and infiltrative/perivenular enhancement in half (n = 3) of the patients. Deep gray matter (n = 1, 16.7%) and infratentorial involvement (n = 1, 16.7%) were scarce and no ring enhancement was observed. There was no statistically significant difference in any of the investigated MR features between the two groups. Conclusion: Statistical analyses revealed no significant distinctive radiologic characteristics between primary and secondary lymphoma of the brain parenchyma.

  3. Suicide after traumatic brain injury: a population study

    DEFF Research Database (Denmark)

    Teasdale, T W; Engberg, A W

    2001-01-01

    OBJECTIVES: To determine the rates of suicide among patients who have had a traumatic brain injury. METHODS: From a Danish population register of admissions to hospital covering the years 1979-93 patients were selected who had had either a concussion (n=126 114), a cranial fracture (n=7560), or a......). There was, however, no evidence of a specific risk period for suicide after injury. CONCLUSION: The increased risk of suicide among patients who had a mild traumatic brain injury may result from concomitant risk factors such as psychiatric conditions and psychosocial disadvantage. The greater risk among...... the more serious cases implicates additionally the physical, psychological, and social consequences of the injuries as directly contributing to the suicides....

  4. Brain Basics

    Medline Plus

    Full Text Available ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ... depression experience when starting treatment. Gene Studies Advanced technologies are also making it faster, easier, and more ...

  5. Brain Basics

    Medline Plus

    Full Text Available ... have been linked to many mental disorders, including autism , obsessive compulsive disorder (OCD) , schizophrenia , and depression . Brain ... studies show that brain growth in children with autism appears to peak early. And as they grow ...

  6. Brain Basics

    Medline Plus

    Full Text Available ... of brain scan called magnetoencephalography, or MEG, can capture split-second changes in the brain. Using MEG, ... The study of how environmental factors like diet, stress and post-natal care can change gene expression ( ...

  7. Brain Basics

    Medline Plus

    Full Text Available ... neurons, the most highly specialized cells of all, conduct messages. Every cell in our bodies contains a ... brain's structure, studies show that brain growth in children with autism appears to peak early. And as ...

  8. Brain Basics

    Medline Plus

    Full Text Available ... may help improve treatments for anxiety disorders like phobias or post-traumatic stress disorder (PTSD) . Prefrontal cortex ( ... brain's structure, studies show that brain growth in children with autism appears to peak early. And as ...

  9. Clinical study and numerical simulation of brain cancer dynamics under radiotherapy

    Science.gov (United States)

    Nawrocki, S.; Zubik-Kowal, B.

    2015-05-01

    We perform a clinical and numerical study of the progression of brain cancer tumor growth dynamics coupled with the effects of radiotherapy. We obtained clinical data from a sample of brain cancer patients undergoing radiotherapy and compare it to our numerical simulations to a mathematical model of brain tumor cell population growth influenced by radiation treatment. We model how the body biologically receives a physically delivered dose of radiation to the affected tumorous area in the form of a generalized LQ model, modified to account for the conversion process of sublethal lesions into lethal lesions at high radiation doses. We obtain good agreement between our clinical data and our numerical simulations of brain cancer progression given by the mathematical model, which couples tumor growth dynamics and the effect of irradiation. The correlation, spanning a wide dataset, demonstrates the potential of the mathematical model to describe the dynamics of brain tumor growth influenced by radiotherapy.

  10. A DTI-based template-free cortical connectome study of brain maturation.

    Directory of Open Access Journals (Sweden)

    Olga Tymofiyeva

    Full Text Available Improved understanding of how the human brain is "wired" on a macroscale may now be possible due to the emerging field of MRI connectomics. However, mapping the rapidly developing infant brain networks poses challenges. In this study, we applied an automated template-free "baby connectome" framework using diffusion MRI to non-invasively map the structural brain networks in subjects of different ages, including premature neonates, term-born neonates, six-month-old infants, and adults. We observed increasing brain network integration and decreasing segregation with age in term-born subjects. We also explored how the equal area nodes can be grouped into modules without any prior anatomical information--an important step toward a fully network-driven registration and analysis of brain connectivity.

  11. Magnetic resonance studies of brain function and neurochemistry

    OpenAIRE

    Uǧurbil, K.; Adriany, G.; Andersen, P; Chen, W.; Gruetter, R.; Hu, X.; Merkle, H; Kim, D.-S.; Kim, S. -G.; Strupp, J.; Zhu, X H; Ogawa, S

    2000-01-01

    In the short time since its introduction, magnetic resonance imaging (MRI) has rapidly evolved to become an indispensable tool for clinical diagnosis and biomedical research. Recently, this methodology has been successfully used for the acquisition of functional, physiological, and biochemical information in intact systems, particularly in the human body. The ability to map areas of altered neuronal activity in the brain, often referred to as functional magnetic resonance imaging (fMRI), is p...

  12. A study of brain MRI findings in children with epilepsy

    International Nuclear Information System (INIS)

    Magnetic resonance imaging in the brain was performed in 293 patients with childhood-onset (<15 y.o.) epilepsy who had been classified into 4 groups, idiopathic localization-related epilepsy (ILRE), 78 patients; idiopathic generalized epilepsy (IGE), 116 patients; symptomatic localization-related epilepsy (SLRE), 68 patients and symptomatic generalized epilepsy (SGE), 31 patients, with the Classification of Epilepsies and Epileptic Syndrome (1989 International League Against Epilepsy). The examination was performed with a 1.5 T magnet. One hundred twenty-five patients (42.7%) showed abnormal findings, and the incidence in each group was as follows: Idiopathic epilepsy: The rate of abnormal findings in the ILRE and IGE groups was 21.8% and 20.7%, respectively. Most of the abnormal findings were secondary changes, such as diffuse or localized brain atrophy. Of the congenital abnormalities, the main finding was arachnoid cyst. Symptomatic epilepsy: The rate of abnormality in the SLRE patients was 88.2%, and 85% of the findings were secondary changes, i.e., brain atrophy, or degeneration of the white matter. In the SGE group, the rate was 77.4%, with an almost equal percentage of congenital and secondary changes. Of 255 patients who were examined by electroencephalography (EEG) on the same day as MRI, about 50% showed a correlation between the EEG records and the MRI abnormalities. However, only 8 patients showed a correlation in localization between the EEG and MRI abnormalities. (author)

  13. STUDY OF REGIONAL STABILITY OF ECD DISTRIBUTION IN NORMAL BRAIN

    Institute of Scientific and Technical Information of China (English)

    李培勇; 陈刚; 朱承谟

    2001-01-01

    Objective To evaluate in vivo stability of ethylenedylbis cysteine diethylester ( ECD ) brain SPECT. Methods Each of13 normal volunteers (31.2±11.8 years) has12 dynamic SPECT scans acquired in 60min 1h after an injection of 99mTc-ECD using a triple headed gamma camera equipped with ultra high resolution fan beam collimators. Average counts per pixel were measured from frontal, temporal, parietal, occipital regions, cerebellum, basal ganglia, thalamus and white matter. Regional ECD clearance rates, regional gray-to-white matter (G/W) ratios and the change of the G /W ratio were calculated. Results The average ECD clearance rate was 4.2%/h, ranged from 3.03%/h to 5.41%/h corresponding to white matter and occipital. There was no significant difference between regional ECD clearance rates. Regional G/W ratio was between 1.27 to 1.75. The G /W ratio of temporal lobe was lower than the occipital (P<0.05). The change of regional G /W ratio with time is slow. Cbnclusion Regional ECD distribution is stable in normal brain. ECD clearance from brain is slow and no significant regional difference.

  14. Functional brain study of chronic traumatic head injury

    International Nuclear Information System (INIS)

    Explosive aggressive behaviour is a significant clinical and medico-legal problem in patients suffering from head injury. However, experts in neuropsychiatry have proposed a specific category for this disorder: the organic aggressive syndrome:. The basic reason for proposing this diagnosis is that it describes the specificity of the violent conduct secondary to 'brain damage' with greater precision. Early diagnosis and treatment of the injury is critical. The impact of hnetium-99m-hexamethylpropuleneamine oxime (HMPAO) was examined for measuring brain damage in correlation to neuropsychological performance in patients with traumatic brain injury (TBI). We thus report the case of a twelve-year-old child with a history of CET, who presents with serious episodes of heteroaggressiveness and suggest the usefulness of single photon emission computerized tomography (SPECT) to establish the validity of this psychiatric diagnosis. The appearance of modern functional neuro-image techniques (SPECT) may help to increase the validity of clinical diagnoses in the field of psychiatry in general and of forensic psychiatry in particularly, as the related findings may be used as demarcation criteria to establish syndromic diagnoses (Au)

  15. The study on brain targeting of the amphotericin B liposomes.

    Science.gov (United States)

    Zhang, Xiaobin; Xie, Jieqiong; Li, Sha; Wang, Xiangtao; Hou, Xinpu

    2003-02-01

    To improve transporting drugs across the Blood Brain Barrier (BBB) into the brain, RMP-7 was conjugated to the surface of liposomes containing Amphotericin B (AmB) for cerebral inflammation, because it can selectively bound to the B2 receptors on the capillary blood vessel. First, RMP-7 was conjugated to DSPE-PEG-NHS [1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly (ethylenegly-col)]-hydroxy succinamide, PEG M 3400] under mild condition to obtain a predominantly 1:1 conjugate (DSPE-PEG-RMP-7), as evidenced by the Matrix-Assisted Laser Desorption-Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF-MS). The second, endothelium cell was cultured on the cell insert to form an in vitro BBB model and the stereoscan microscope, electric resistance and permeation of horse-radish peroxidase (HRP) across the endothelium cell monolayer were used as indicators to evaluate the integrality of the monolayer, and then the in vitro BBB model was used to determine the bioactivity of DSPE-PEG-RMP-7 "opening" BBB. The results demonstrated the in vitro BBB model was set up, RMP-7 and DSPE-PEG-RMP-7 could improve the transporting of HRP across the BBB. The third, the liposomes containing AmB (AmB-L-PEG) was prepared by modified Film-sonication method and DSPE-PEG-RMP-7 was used to modify the AmB-L-PEG to obtain AmB-L-PEG-RMP-7. The fourth, tissue distribution of AmB in the rats of three groups was determined: Group I, AmB-L-PEG; Group II, AmB-L-PEG+RMP-7 (the physical mixture of AmB-L-PEG and RMP-7); Group III, AmB-PEG-RMP-7. The drugs were transfused into the rats through the femoral vein. The concentration of AmB in the tissue was checked using High-Performance Liquid Chromatography (HPLC) method. The rank of AmB concentration in the brain were as follows: III>II>I. The AmB concentration in the liver, spleen, lung and kidney had no significant difference. The concentration of AmB in the brain of the group III was raised several times higher than that in the other two groups

  16. Pattern of congenital brain malformations at a referral hospital in Saudi Arabia: An MRI study

    International Nuclear Information System (INIS)

    More than 2000 different congenital cerebral malformations have been described in the literature, for which several classification systems have been proposed. With the help of these classification systems, it is now possible, with neuroimaging, to time neuroembtyologic events. Magnetic resonance imaging (MRI), in particular, is useful in studying these malformations. This study evaluated the pattern of congenital brain malformations in a university referral hospital setting. The records of all MRI brain examinations at our hospital over a period of 3 years for children younger than 15 years of age were reviewed. Cases of congenital cerebral malformations were analyzed by sex, age at presentation, type of congenital cerebral malformation and other associated congenital cerebral malformations. Of the 808 MR examinations of different parts of the body for children in the study period, 719 (89%), on 581 patients, were of the brain. Eighty-six children (14.8%) were found to have single or multiple congenital brain malformations. In these children, 114 congenital brain malformations were identified, the commonest being cortical migrational defects (25 patients, 22%), neural tube closure defects (22 patients, 19%), and corpus callosum dysgenesis (22 patients 19%). The least common was vascular malformation. Sixteen patients (18.6%) had more than one congenital brain malformations. Neural tube closer defects, cortical migrational abnormalities, and corpus callosum anomalies were the commonest congenital brain malformations, while vascular malformations were the least common. Most of the identified malformations demonstrated the usual pattern, but a few showed unusual patterns and associations. (author)

  17. Cross-frequency coupling of brain oscillations in studying motivation and emotion.

    Science.gov (United States)

    Schutter, Dennis J L G; Knyazev, Gennady G

    2012-03-01

    Research has shown that brain functions are realized by simultaneous oscillations in various frequency bands. In addition to examining oscillations in pre-specified bands, interactions and relations between the different frequency bandwidths is another important aspect that needs to be considered in unraveling the workings of the human brain and its functions. In this review we provide evidence that studying interdependencies between brain oscillations may be a valuable approach to study the electrophysiological processes associated with motivation and emotional states. Studies will be presented showing that amplitude-amplitude coupling between delta-alpha and delta-beta oscillations varies as a function of state anxiety and approach-avoidance-related motivation, and that changes in the association between delta-beta oscillations can be observed following successful psychotherapy. Together these studies suggest that cross-frequency coupling of brain oscillations may contribute to expanding our understanding of the neural processes underlying motivation and emotion. PMID:22448078

  18. Perceiving musical scale structures. A cross-cultural event-related brain potentials study.

    Science.gov (United States)

    Neuhaus, Christiane

    2003-11-01

    In this study, event-related brain potentials (ERPs) are used to investigate the processing of musical scale structures from a cross-cultural perspective. ERP reactions reveal that universal listening strategies per se are modified by culture. PMID:14681138

  19. Hsp40s specify functions of Hsp104 and Hsp90 protein chaperone machines.

    Directory of Open Access Journals (Sweden)

    Michael Reidy

    2014-10-01

    Full Text Available Hsp100 family chaperones of microorganisms and plants cooperate with the Hsp70/Hsp40/NEF system to resolubilize and reactivate stress-denatured proteins. In yeast this machinery also promotes propagation of prions by fragmenting prion polymers. We previously showed the bacterial Hsp100 machinery cooperates with the yeast Hsp40 Ydj1 to support yeast thermotolerance and with the yeast Hsp40 Sis1 to propagate [PSI+] prions. Here we find these Hsp40s similarly directed specific activities of the yeast Hsp104-based machinery. By assessing the ability of Ydj1-Sis1 hybrid proteins to complement Ydj1 and Sis1 functions we show their C-terminal substrate-binding domains determined distinctions in these and other cellular functions of Ydj1 and Sis1. We find propagation of [URE3] prions was acutely sensitive to alterations in Sis1 activity, while that of [PIN+] prions was less sensitive than [URE3], but more sensitive than [PSI+]. These findings support the ideas that overexpressing Ydj1 cures [URE3] by competing with Sis1 for interaction with the Hsp104-based disaggregation machine, and that different prions rely differently on activity of this machinery, which can explain the various ways they respond to alterations in chaperone function.

  20. Functional requirement of p23 and Hsp90 in telomerase complexes

    OpenAIRE

    Holt, Shawn E.; Aisner, Dara L.; Baur, Joseph; Tesmer, Valerie M.; Dy, Marife; Ouellette, Michel; Trager, James B.; Morin, Gregg B.; Toft, David O.; Jerry W Shay; Wright, Woodring E.; White, Michael A.

    1999-01-01

    Most normal human diploid cells have no detectable telomerase; however, expression of the catalytic subunit of telomerase is sufficient to induce telomerase activity and, in many cases, will bypass normal senescence. We and others have previously demonstrated in vitro assembly of active telomerase by combining the purified RNA component with the reverse transcriptase catalytic component synthesized in rabbit reticulocyte extract. Here we show that assembly of active telomerase from in vitro-s...

  1. HSP90 Inhibitor AT13387 and Paclitaxel in Treating Patients With Advanced Triple Negative Breast Cancer

    Science.gov (United States)

    2016-08-08

    Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  2. Novel candidate genes AuxRP and Hsp90 influence the chip color of potato tubers

    OpenAIRE

    Sołtys-Kalina, Dorota; Szajko, Katarzyna; Sierocka, Izabela; Śliwka, Jadwiga; Strzelczyk-Żyta, Danuta; Wasilewicz-Flis, Iwona; Jakuczun, Henryka; Szweykowska-Kulinska, Zofia; Marczewski, Waldemar

    2015-01-01

    Potato (Solanum tuberosum L.) tubers exhibit significant variation in reducing sugar content directly after harvest, cold storage and reconditioning. Here, we performed QTL analysis for chip color, which is strongly influenced by reducing sugar content, in a diploid potato mapping population. Two QTL on chromosomes I and VI were detected for chip color after harvest and reconditioning. Only one region on chromosome VI was linked with cold-induced sweetening. Using the RT-PCR technique, we sho...

  3. The Genetic Response to Snowball Earth: Role of HSP90 in the Cambrian Explosion

    OpenAIRE

    Baker, Michael E.

    2006-01-01

    The events that shaped the Cambrian explosion from 545 to 530 myr ago, when multicellular animals suddenly appeared in the fossil record, are not fully understood. It is likely that the evolution of new transcription factors and other signal transduction proteins that regulated developmental networks were important in the emergence of diverse animal phyla seen in the Cambrian. I propose that one or both extensive glaciations that ended about 670 myr and 635 myr ago were important in the evo...

  4. Treatment outcomes in patients with multiple brain metastases: A prospective randomized study

    OpenAIRE

    Animesh Saha; Sajal Kumar Ghosh; Chhaya Roy; Priyanjit Kayal

    2014-01-01

    Context: There is controversy regarding the radiotherapeutic dose fractionation in brain metastases (bm). Aims: The aim of this study is to analyze the treatment outcomes in patients with multiple bm. Settings and Design: Prospective, randomized study. Subjects and Methods: Patients with multiple bm with Eastern Cooperative Oncology Group performance status ≤2 were included. In arm-A patient received whole brain radiotherapy (WBRT) 30 GY in 10# over 2 weeks and in arm-B patients received 20 G...

  5. Decompressive craniectomy in traumatic brain injury: the randomized multicenter RESCUEicp study (www.RESCUEicp.com).

    Science.gov (United States)

    Hutchinson, P J; Corteen, E; Czosnyka, M; Mendelow, A D; Menon, D K; Mitchell, P; Murray, G; Pickard, J D; Rickels, E; Sahuquillo, J; Servadei, F; Teasdale, G M; Timofeev, I; Unterberg, A; Kirkpatrick, P J

    2006-01-01

    The RESCUEicp (Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of intracranial pressure) study has been established to determine whether decompressive craniectomy has a role in the management of patients with traumatic brain injury and raised intracranial pressure that does not respond to initial treatment measures. We describe the concept of decompressive craniectomy in traumatic brain injury and the rationale and protocol of the RESCUEicp study. PMID:16671415

  6. Effects of Diet on Brain Plasticity in Animal and Human Studies: Mind the Gap

    OpenAIRE

    Tytus Murphy; Gisele Pereira Dias; Sandrine Thuret

    2014-01-01

    Dietary interventions have emerged as effective environmental inducers of brain plasticity. Among these dietary interventions, we here highlight the impact of caloric restriction (CR: a consistent reduction of total daily food intake), intermittent fasting (IF, every-other-day feeding), and diet supplementation with polyphenols and polyunsaturated fatty acids (PUFAs) on markers of brain plasticity in animal studies. Moreover, we also discuss epidemiological and intervention studies reporting ...

  7. Learning about brain physiology and complexity from the study of the epilepsies

    Directory of Open Access Journals (Sweden)

    N. Garcia-Cairasco

    2009-01-01

    Full Text Available The brain is a complex system, which produces emergent properties such as those associated with activity-dependent plasticity in processes of learning and memory. Therefore, understanding the integrated structures and functions of the brain is well beyond the scope of either superficial or extremely reductionistic approaches. Although a combination of zoom-in and zoom-out strategies is desirable when the brain is studied, constructing the appropriate interfaces to connect all levels of analysis is one of the most difficult challenges of contemporary neuroscience. Is it possible to build appropriate models of brain function and dysfunctions with computational tools? Among the best-known brain dysfunctions, epilepsies are neurological syndromes that reach a variety of networks, from widespread anatomical brain circuits to local molecular environments. One logical question would be: are those complex brain networks always producing maladaptive emergent properties compatible with epileptogenic substrates? The present review will deal with this question and will try to answer it by illustrating several points from the literature and from our laboratory data, with examples at the behavioral, electrophysiological, cellular and molecular levels. We conclude that, because the brain is a complex system compatible with the production of emergent properties, including plasticity, its functions should be approached using an integrated view. Concepts such as brain networks, graphics theory, neuroinformatics, and e-neuroscience are discussed as new transdisciplinary approaches dealing with the continuous growth of information about brain physiology and its dysfunctions. The epilepsies are discussed as neurobiological models of complex systems displaying maladaptive plasticity.

  8. Short-hairpin RNA-mediated Heat shock protein 90 gene silencing inhibits human breast cancer cell growth in vitro and in vivo

    International Nuclear Information System (INIS)

    Highlights: ► Hsp90 is over-expressed in human breast cancer. ► The shRNA-mediated gene silencing of Hsp90 resulted in inhibition of cell growth. ► Akt and NF-kB were down-regulation after transfection due to Hsp90 silencing. ► The tumor growth ratio was decline due to Hsp90 silencing. ► The PCNA expression was down-regulation due to Hsp90 silencing. -- Abstract: Hsp90 interacts with proteins that mediate signaling pathways involved in the regulation of essential processes such as proliferation, cell cycle control, angiogenesis and apoptosis. Hsp90 inhibition is therefore an attractive strategy for blocking abnormal pathways that are crucial for cancer cell growth. In the present study, the role of Hsp90 in human breast cancer MCF-7 cells was examined by stably silencing Hsp90 gene expression with an Hsp90-silencing vector (Hsp90-shRNA). RT-PCR and Western blot analyses showed that Hsp90-shRNA specifically and markedly down-regulated Hsp90 mRNA and protein expression. NF-kB and Akt protein levels were down-regulated in Hsp90-shRNA transfected cells, indicating that Hsp90 knockout caused a reduction of survival factors and induced apoptosis. Treatment with Hsp90-shRNA significantly increased apoptotic cell death and caused cell cycle arrest in the G1/S phase in MCF-7 cells, as shown by flow cytometry. Silencing of Hsp90 also reduced cell viability, as determined by MTT assay. In vivo experiments showed that MCF-7 cells stably transfected with Hsp90-shRNA grew slowly in nude mice as compared with control groups. In summary, the Hsp90-shRNA specifically silenced the Hsp90 gene, and inhibited MCF-7 cell growth in vitro and in vivo. Possible molecular mechanisms underlying the effects of Hsp90-shRNA include the degradation of Hsp90 breast cancer-related client proteins, the inhibition of survival signals and the upregulation of apoptotic pathways. shRNA-mediated interference may have potential therapeutic utility in human breast cancer.

  9. Study of brain metabolism using positron emission computed tomography

    International Nuclear Information System (INIS)

    Positron emission tomography permits the three-dimensional regional measurement of metabolism and blood flow in the brain. For the determination of cerebral metabolic rates of glucose by PET 18fluordeoxyglucose is usually applied: cerebral metabolic rate of glucose was found to be 36 to 47 μmol/100 g/min in the grey matter and 23 to 29 μmol/100 g/min in the white matter of normal volunteers. During physiologic activation metabolic rate of glucose is increased in the respective brain areas in relation to the strength and complexity of the stimulation. In patients suffering from ischaemic stroke glucose metabolism is markedly decreased within the infarction. Additonally, glucose metabolism is reduced by 20% in morphologically intact areas of the homolateral cortex, in the basal ganglia, in the cortical area contralateral to the infarction and in the contralateral cerebellum. This remote reduction of glucose utilization is probably caused by functional inactivation of these brain structures; it could be responsible for the diffuse organic syndrome in stroke victims not caused by the focal lesion. In patients suffering from dementia of the multi-infarct type and of the Alzheimer type glucose metabolism is reduced; the lesions in Alzheimer cases are most prominent in partietal and frontal cortical areas. In Chorea Huntington cases glucose metabolism is primarily disturbed in the striate, especially in the caudate nucleus; in these cases the metabolic disturbance can be detected earlier than the atrophy in computed tomograms. Disturbances of glucose and oxygen utilization are not necessary causes, but may also be sequelae od functional impairment. Additional information on pathogentic mechanisms may be obtained by the investigation of the protein synthesis. (orig.)

  10. Paradoxical effects of brain death and associated trauma on rat mesenteric microcirculation: an intravital microscopic study

    Directory of Open Access Journals (Sweden)

    Rafael Simas

    2012-01-01

    Full Text Available OBJECTIVE: Experimental findings support clinical evidence that brain death impairs the viability of organs for transplantation, triggering hemodynamic, hormonal, and inflammatory responses. However, several of these events could be consequences of brain death-associated trauma. This study investigated microcirculatory alterations and systemic inflammatory markers in brain-dead rats and the influence of the associated trauma. METHOD: Brain death was induced using intracranial balloon inflation; sham-operated rats were trepanned only. After 30 or 180 min, the mesenteric microcirculation was observed using intravital microscopy. The expression of Pselectin and ICAM-1 on the endothelium was evaluated using immunohistochemistry. The serum cytokine, chemokine, and corticosterone levels were quantified using enzyme-linked immunosorbent assays. White blood cell counts were also determined. RESULTS: Brain death resulted in a decrease in the mesenteric perfusion to 30%, a 2.6-fold increase in the expression of ICAM-1 and leukocyte migration at the mesentery, a 70% reduction in the serum corticosterone level and pronounced leukopenia. Similar increases in the cytokine and chemokine levels were seen in the both the experimental and control animals. CONCLUSION: The data presented in this study suggest that brain death itself induces hypoperfusion in the mesenteric microcirculation that is associated with a pronounced reduction in the endogenous corticosterone level, thereby leading to increased local inflammation and organ dysfunction. These events are paradoxically associated with induced leukopenia after brain damage

  11. A Voxel-Based Morphometry Study of the Brain of University Students Majoring in Music and Nonmusic Disciplines

    OpenAIRE

    2015-01-01

    The brain changes flexibly due to various experiences during the developmental stages of life. Previous voxel-based morphometry (VBM) studies have shown volumetric differences between musicians and nonmusicians in several brain regions including the superior temporal gyrus, sensorimotor areas, and superior parietal cortex. However, the reported brain regions depend on the study and are not necessarily consistent. By VBM, we investigated the effect of musical training on the brain structure by...

  12. [Paradise lost - Reflexion of preterm birth from the perspective after a brain injury. A case study].

    Science.gov (United States)

    Cignacco, Eva; Zuñiga, Franziska; Kurth, Elisabeth

    2011-04-01

    This case study describes the history of an older person, born in 1942 preterminally, who suffered from a brain injury in 2005. Problems in rehabilitation elicited the search for a new meaning in life. In analysing and interpreting the brain injury, preterm birth played a crucial role. The theme of lifelong compensation of deficits, caused by preterm birth, gained new importance. The consequences of brain injury left unsuccessful his former modes of compensation. He was confronted with finding new strategies in order to counterbalance the growing decompensation. This report is based on and was developed through respect for the principles of user involvement in research. PMID:21480177

  13. Study of Inter- and Intra-fraction Motion in Brain Tumor Patients Undergoing VMAT Treatment

    International Nuclear Information System (INIS)

    Conforming dose to the tumor and sparing normal tissue can be challenging for brain tumors with complex shapes in close proximity to critical structures. The goal of this study was to evaluate the inter- and intra-fraction motion in brain tumor patients undergoing volumetric modulated arc therapy (VMAT). The image matching software was found to be very sensitive to the choice of the region of matching. It is recommended to use the same region of interest for comparing the image sets and perform the automatic matching based on bony landmarks in brain tumor cases. (Author)

  14. In vivo imaging of brain androgen receptors in rats: a [18F]FDHT PET study

    International Nuclear Information System (INIS)

    Introduction: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16β-[18F]fluoro-5α-dihydrotestosterone ([18F]FDHT) to image AR expression in the brain. Methods: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [18F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1 mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution. Results: PET imaging and ex vivo biodistribution studies showed low [18F]FDHT uptake in all brain regions, except pituitary. [18F]FDHT uptake in the surrounding cranial bones was high and increased over time. [18F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [18F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone. Conclusion: The results of this study indicate that imaging of AR availability in rat brain with [18F]FDHT PET is not feasible. The low AR expression in the brain, the rapid metabolism of

  15. Psychogenic seizures in brain injury: diagnosis, treatment and case study.

    Science.gov (United States)

    Conder, R L; Zasler, N D

    1990-01-01

    Psychogenic seizures are a functional phenomena in which a person experiences a paroxysmal event that may be interpreted as epileptiform in nature. By definition, psychogenic seizures imply a sudden episode of change in behaviour or psychic state that is not associated with an identifiable process, either vasculogenic or neurogenic, and during which there is an absence of characteristic epileptiform changes on the electroencephalogram. Prevalence rates range from 5% to 50% in outpatient populations seen in epilepsy clinics. However, approximately 20% of true seizure patients also have psychogenic seizures. As psychogenic seizures are not a pathophysiological phenomena, pharmacological interventions do not alter their aetiology and can cloud the cognitive skills necessary to ameliorate the psychogenic seizure behaviour. In non-aphasic true seizure patients, as well as psychogenic seizure patients, self-control relaxation paradigms have been successful where pharmacological intervention has failed. This case involved an aphasic brain-injured patient who had both psychogenic and true seizures. For this patient, the self-control paradigm was modified to include use of gesture and prosody to achieve similar psychotherapeutic effects. Additionally, family therapy was instituted to provide a constructive means for the patient's family to participate in the reduction of psychogenic seizures. As seizures are a common sequelae of brain injury, the differential diagnosis of seizures and knowledge of standard and alternative treatment is essential for rehabilitation professionals. PMID:1701326

  16. PET study of cholinergic system in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Shinotoh, Hitoshi [Chiba Univ. (Japan). School of Medicine

    1999-01-01

    Recently, we have developed a method to measure acetylcholinesterase (AChE) activity, a functional marker for cholinergic system, by positron emission tomography (PET) and carbon-11 labeled N-methyl-4-piperidyl acetate. Kinetic analysis of the radioactivity in the brain and the plasma yielded a rate constant ``k 3`` as an index of AChE activity. The ratios for the k 3 values for the cerebral cortex/thalamus/cerebellum/striatum found in healthy participants were 1/ 3/ 8/ 10, respectively, corresponding well with AChE activity ratios in the brain at necropsy (1/ 3/ 8/ 38), except for the striatum. In 23 healthy volunteers (age range: 24-89 years), there was no age-related decline of k 3 values in the cerebral cortex, suggesting AChE activity is preserved in aged cerebral cortex. In 11 patients with Alzheimer`s disease, there was a significant reduction (-24%) of k 3 values in the cerebral cortex and hippocampus, suggesting a loss of ascending cholinergic system from the basal forebrain to the cerebral cortex and hippocampus. In 16 patients with Parkinson`s disease, there was a significant reduction (-18%) of k 3 values in the cerebral cortex. In 10 patients with progressive supra nuclear palsy, there was a significant reduction (-38%) of k 3 values in the thalamus. This technique is useful for investigating central cholinergic system in neuro degenerative disorders with dementia. (author)

  17. Brain Activity Associated with Emoticons: An fMRI Study

    Science.gov (United States)

    Yuasa, Masahide; Saito, Keiichi; Mukawa, Naoki

    In this paper, we describe that brain activities associated with emoticons by using fMRI. In communication over a computer network, we use abstract faces such as computer graphics (CG) avatars and emoticons. These faces convey users' emotions and enrich their communications. However, the manner in which these faces influence the mental process is as yet unknown. The human brain may perceive the abstract face in an entirely different manner, depending on its level of reality. We conducted an experiment using fMRI in order to investigate the effects of emoticons. The results show that right inferior frontal gyrus, which associated with nonverbal communication, is activated by emoticons. Since the emoticons were created to reflect the real human facial expressions as accurately as possible, we believed that they would activate the right fusiform gyrus. However, this region was not found to be activated during the experiment. This finding is useful in understanding how abstract faces affect our behaviors and decision-making in communication over a computer network.

  18. PET study of cholinergic system in the brain

    International Nuclear Information System (INIS)

    Recently, we have developed a method to measure acetylcholinesterase (AChE) activity, a functional marker for cholinergic system, by positron emission tomography (PET) and carbon-11 labeled N-methyl-4-piperidyl acetate. Kinetic analysis of the radioactivity in the brain and the plasma yielded a rate constant ''k 3'' as an index of AChE activity. The ratios for the k 3 values for the cerebral cortex/thalamus/cerebellum/striatum found in healthy participants were 1/ 3/ 8/ 10, respectively, corresponding well with AChE activity ratios in the brain at necropsy (1/ 3/ 8/ 38), except for the striatum. In 23 healthy volunteers (age range: 24-89 years), there was no age-related decline of k 3 values in the cerebral cortex, suggesting AChE activity is preserved in aged cerebral cortex. In 11 patients with Alzheimer's disease, there was a significant reduction (-24%) of k 3 values in the cerebral cortex and hippocampus, suggesting a loss of ascending cholinergic system from the basal forebrain to the cerebral cortex and hippocampus. In 16 patients with Parkinson's disease, there was a significant reduction (-18%) of k 3 values in the cerebral cortex. In 10 patients with progressive supra nuclear palsy, there was a significant reduction (-38%) of k 3 values in the thalamus. This technique is useful for investigating central cholinergic system in neuro degenerative disorders with dementia. (author)

  19. MR study of the brain in patients with tetrahydrobiopterin deficiency

    International Nuclear Information System (INIS)

    Objective: To observe the brain abnormalities of the white matter and myelination in patients with BH4 deficiency using MRI examination, and to further estimate the effect of treatment. Methods: Eleven patients with BH4 deficiency aged 17 weeks to 4 years were observed, including 9 cases who were detected by newborn screening program. Although those patients were treated with low phenylalaninediet, and the blood phenylalanine 1evels maintained to 120-240 μmol/L, the patients presented progressive hypotonia, convulsion, and mental retardation. All cases were diagnosed as BH4 deficiency by analysis of urinarypterins profile, BH4 loading test, and determination of dihydropteridine reductase in RBC. The patients received MRI examination using a 0.5 TMR system. Results: Delayed myelination was found in 11 cases (100%) in frontal lobe, 8 cases (72.2%) in occipital lobe, 4 cases (36.3%) in temporal lobe, and 3 cases (27.3%) in parietal lobe. Delayed myelination of corpus callosum could be found in 6 cases (54.5%). There were abnormal diffuse high signals in the white matter on T2WI in all cases. Conclusion: Patients with BH4 deficiency demonstrate a high occurrence of brain abnormalities in the white matter. Those abnormalities are related not only with hyperphenylalaninemia, but also due to the decreased synthesis of neurotransmitters, such as L-Dopa and 5-HTP, all of these could be the reasons of adverse effect of the development of white matter. (authors)

  20. Prevalence of brain atrophy in dogs submitted to cranial tomography in FMVZ - UNESP Botucatu: retrospective study

    International Nuclear Information System (INIS)

    Brain atrophy is diagnosed by imaging methods that allow the verification of the widening of cerebral sulci and ventricular dilatation. In this retrospective study, in which the cranial CT scans of 150 dogs were evaluated, brain atrophy was identified in 16 animals. Mixed breed dogs were the most affected, followed by poodles, maltese, dachshunds, yorkshires, pinschers and cockers. Brain atrophy was observed in animals of all age groups, being more prevalent in middle aged dogs followed by elderly animals, in which this alteration can be commonly found. The identification of reduced brain volume, however, may not be the cause of neurological signs expressed by animals since in some dogs of this study it was considered a finding. (author)

  1. Disrupted small-world brain networks in moderate Alzheimer's disease: a resting-state FMRI study.

    Directory of Open Access Journals (Sweden)

    Xiaohu Zhao

    Full Text Available The small-world organization has been hypothesized to reflect a balance between local processing and global integration in the human brain. Previous multimodal imaging studies have consistently demonstrated that the topological architecture of the brain network is disrupted in Alzheimer's disease (AD. However, these studies have reported inconsistent results regarding the topological properties of brain alterations in AD. One potential explanation for these inconsistent results lies with the diverse homogeneity and distinct progressive stages of the AD involved in these studies, which are thought to be critical factors that might affect the results. We investigated the topological properties of brain functional networks derived from resting functional magnetic resonance imaging (fMRI of carefully selected moderate AD patients and normal controls (NCs. Our results showed that the topological properties were found to be disrupted in AD patients, which showing increased local efficiency but decreased global efficiency. We found that the altered brain regions are mainly located in the default mode network, the temporal lobe and certain subcortical regions that are closely associated with the neuropathological changes in AD. Of note, our exploratory study revealed that the ApoE genotype modulates brain network properties, especially in AD patients.

  2. Studying the brain from adolescence to adulthood through sparse multi-view matrix factorisations

    OpenAIRE

    Wang, Zi; Karolis, Vyacheslav; Nosarti, Chiara; Montana, Giovanni

    2016-01-01

    Men and women differ in specific cognitive abilities and in the expression of several neuropsychiatric conditions. Such findings could be attributed to sex hormones, brain differences, as well as a number of environmental variables. Existing research on identifying sex-related differences in brain structure have predominantly used cross-sectional studies to investigate, for instance, differences in average gray matter volumes (GMVs). In this article we explore the potential of a recently prop...

  3. Cohort study of multiple brain lesions in sport divers: role of a patent foramen ovale.

    OpenAIRE

    Knauth, M; Ries, S.; Pohimann, S.; Kerby, T.; Forsting, M; Daffertshofer, M.; HENNERICI, M; Sartor, K

    1997-01-01

    OBJECTIVE: To investigate the role of a patient foramen ovale in the pathogenesis of multiple brain lesions acquired by sport divers in the absence of reported decompression symptoms. DESIGN: Prospective double blind cohort study. SETTING: Diving clubs around Heidelberg and departments of neuroradiology and neurology. SUBJECTS: 87 sport divers with a minimum of 160 scuba dives (dives with self contained underwater breathing apparatus). MAIN OUTCOME MEASURES: Presence of multiple brain lesions...

  4. The Drosophila neural lineages: a model system to study brain development and circuitry

    OpenAIRE

    Spindler, Shana R; Hartenstein, Volker

    2010-01-01

    In Drosophila, neurons of the central nervous system are grouped into units called lineages. Each lineage contains cells derived from a single neuroblast. Due to its clonal nature, the Drosophila brain is a valuable model system to study neuron development and circuit formation. To better understand the mechanisms underlying brain development, genetic manipulation tools can be utilized within lineages to visualize, knock down, or over-express proteins. Here, we will introduce the formation an...

  5. Advances in near-infrared spectroscopy to study the brain of the preterm and term neonate

    DEFF Research Database (Denmark)

    Wolf, Martin; Greisen, Gorm

    2009-01-01

    This article reviews tissue oximetry and imaging to study the preterm and newborn infant brain by near-infrared spectroscopy. These two technologies are now advanced; nearly 100 reports on their use in newborn infants have been published, and commercial instruments are available. The precision...... of oximetry, however, is a limitation for its clinical use of assessing cerebral oxygenation. Imaging of brain function needs very well defined protocols for sensory stimulation as well as signal analysis to provide meaningful results....

  6. Electrical Stimulation of the Suprahyoid Muscles in Brain-injured Patients with Dysphagia: A Pilot Study

    OpenAIRE

    Beom, Jaewon; Kim, Sang Jun; Han, Tai Ryoon

    2011-01-01

    Objective To investigate the therapeutic effects of repetitive electrical stimulation of the suprahyoid muscles in brain-injured patients with dysphagia. Method Twenty-eight brain-injured patients who showed reduced laryngeal elevation and supraglottic penetration or subglottic aspiration during a videofluoroscopic swallowing study (VFSS) were selected. The patients received either conventional dysphagia management (CDM) or CDM with repetitive electrical stimulation of the suprahyoid muscles ...

  7. The Influence of Sour Taste on Dysphagia in Brain Injury: Blind Study

    OpenAIRE

    Lee, Kwang Lae; Kim, Doo Young; Kim, Wan Ho; Kim, Eun Joo; Lee, Won Seok; Hahn, Soo Jung; Kang, Min Sung; Ahn, So Yeon

    2012-01-01

    Objective To verify the influence of sour taste on swallowing and the presence of reflex cough when sour material was swallowed in patients with dysphagia secondary to brain injury. Method Fifty dysphagic brain injury patients who underwent videofluoroscopic swallowing study (VFSS) were recruited. The patients who had shown severe aspiration at 2 ml of liquid were excluded. The dysphagic patients were given 5 ml each of a sour tasting liquid (SOUR) and a thin liquid barium (LIQUID) in random ...

  8. Traumatic Brain Injury: a Case Study of the School Reintegration Process

    OpenAIRE

    McWilliams, Karen P.

    2004-01-01

    The purpose of this linear-analytic exploratory case study is to illustrate the reintegration process from acute care and rehabilitative care to the traditional school setting after one has sustained a Traumatic Brain Injury (TBI). TBI is an unrecognized educational challenge. Few educational professionals are aware of the divarication of TBI. Traumatic Brain Injury is the leading cause of death and disability in children and adolescents in the United States. The review of literature reveals ...

  9. Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial.

    LENUS (Irish Health Repository)

    Nichol, Alistair

    2015-02-08

    Traumatic brain injury is a leading cause of death and disability worldwide. Laboratory and clinical studies demonstrate a possible beneficial effect of erythropoietin in improving outcomes in the traumatic brain injury cohort. However, there are concerns regarding the association of erythropoietin and thrombosis in the critically ill. A large-scale, multi-centre, blinded, parallel-group, placebo-controlled, randomised trial is currently underway to address this hypothesis.

  10. Brain structure and the relationship with neurocognitive functioning in schizophrenia and bipolar disorder : MRI studies

    OpenAIRE

    2011-01-01

    Brain structural abnormalities as well as neurocognitive dysfunction, are found in schizophrenia and in bipolar disorder. Based on the fact that both brain structure and neurocognitive functioning are significantly heritable and affected in both schizophrenia and bipolar disorder, relationships between them are expected. However, previous studies report inconsistent findings. Also, schizophrenia and bipolar disorder are classified as separate disease entities, but demonstrate overlap with reg...

  11. Traumatic brain injuries in children: A hospital-based study in Nigeria

    OpenAIRE

    David O Udoh; Adeyemo, Adebolajo A.

    2013-01-01

    Background: Traumatic Brain Injury (TBI) is a significant cause of morbidity and mortality worldwide. Our previous studies showed a high frequency of motor vehicle accidents among neurosurgical patients. However, there is a dearth of data on head injuries in children in Nigeria. Aims: To determine the epidemiology of paediatric traumatic brain injuries. Setting and Design: This is a prospective analysis of paediatric head trauma at the University of Benin Teaching Hospital, a major referral c...

  12. Multicenter Study of Brain Volume Abnormalities in Children and Adolescent-Onset Psychosis

    OpenAIRE

    Reig, S. (Santiago); Parellada, M.; Castro-Fornieles, J.; Janssen, J.; Moreno, D.; Baeza, I.; Bargallo, N.; Gonzalez-Pinto, A.; Graell, M. (Montserrat); Ortuño-Sánchez-Pedreño, F. (Felipe); Otero, S.; C. Arango; Desco, M

    2010-01-01

    The goal of the study is to determine the extent of structural brain abnormalities in a multicenter sample of children and adolescents with a recent-onset first episode of psychosis (FEP), compared with a sample of healthy controls. Total brain and lobar volumes and those of gray matter (GM), white matter, and cerebrospinal fluid (CSF) were measured in 92 patients with a FEP and in 94 controls, matched for age, gender, and years of education. Male patients (n = 64) showed several significant ...

  13. Brain blood flow studies with single photon emission computed tomography in patients with plateau waves

    International Nuclear Information System (INIS)

    The authors studied brain blood flow with single photon emission computed tomography (SPECT) in two patients with plateau waves. The intracranial pressure and blood pressure were also monitored continuously in these patients. They included one patient with brain-tumor (rt. sphenoid ridge meningioma) and another with hydrocephalus after subarachnoid hemorrhage due to rupture of lt. internal carotid aneurysm. The intracranial pressure was monitored through an indwelling ventricular catheter attached to a pressure transducer. The blood pressure was recorded through an intraarterial catheter placed in the dorsalis pedis artery. Brain blood flow was studied with Headtome SET-011 (manufactured by Shimazu Co., Ltd.). For this flow measurement study, an intravenous injection of Xenon-133 of about 30 mCi was given via an antecubital vein. The position of the slice for the SPECT was selected so as to obtain information not only from the cerebral hemisphere but also from the brain stem : a cross section 25 deg over the orbito-meatal line, passing through the inferior aspect of the frontal horn, the basal ganglia, the lower recessus of the third ventricle and the brain stem. The results indicated that, in the cerebral hemisphere, plateau waves were accompanied by a decrease in blood flow, whereas, in the brain stem, the blood flow showed little change during plateau waves as compared with the interval phase between two plateau waves. These observations may explain why there is no rise in the blood pressure and why patients are often alert during plateau waves. (author)

  14. A biexponential DWI study in rat brain intracellular oedema

    Energy Technology Data Exchange (ETDEWEB)

    Steier, Roy, E-mail: roy.steier@gmail.com [Department of Neurosurgery, Faculty of Medicine University of Pecs, H-7623 Pecs, Ret street 2 (Hungary); Pecs Diagnostic Center, Faculty of Medicine University of Pecs, H-7623 Pecs, Ret street 2 (Hungary); Aradi, Mihaly [Department of Neurosurgery, Faculty of Medicine University of Pecs, H-7623 Pecs, Ret street 2 (Hungary); Pecs Diagnostic Center, Faculty of Medicine University of Pecs, H-7623 Pecs, Ret street 2 (Hungary); Pal, Jozsef [Department of Neurosurgery, Faculty of Medicine University of Pecs, H-7623 Pecs, Ret street 2 (Hungary); Perlaki, Gabor; Orsi, Gergely; Bogner, Peter [Pecs Diagnostic Center, Faculty of Medicine University of Pecs, H-7623 Pecs, Ret street 2 (Hungary); Galyas, Ferenc [Department of Neurosurgery, Faculty of Medicine University of Pecs, H-7623 Pecs, Ret street 2 (Hungary); and others

    2012-08-15

    Purpose: To examine the changes in MR parameters derived from diffusion weighted imaging (DWI) biexponential analysis in an in vivo intracellular brain oedema model, and to apply electron microscopy (EM) to shed more light on the morphological background of MR-related observations. Materials and methods: Intracellular oedema was induced in ten male Wistar rats (380-450 g) by way of water load, using a 20% body weight intraperitoneal injection of 140 mmol/L dextrose solution. A 3T MRI instrument was used to perform serial DWI, and MR specroscopy (water signal) measurements. Following the MR examination the brains of the animals were analyzed for EM. Results: Following the water load induction, apparent diffusion coefficient (ADC) values started declining from 724 {+-} 43 {mu}m{sup 2}/s to 682 {+-} 26 {mu}m{sup 2}/s (p < 0.0001). ADC-fast values dropped from 948 {+-} 122 to 840 {+-} 66 {mu}m{sup 2}/s (p < 0.001). ADC-slow showed a decrease from 226 {+-} 66 to 191 {+-} 74 {mu}m{sup 2}/s (p < 0.05). There was a shift from the slow to the fast component at 110 min time point. The percentage of the fast component demonstrated moderate, yet significant increase from 76.56 {+-} 7.79% to 81.2 {+-} 7.47% (p < 0.05). The water signal was increasing by 4.98 {+-} 3.52% compared to the base line (p < 0.01). The results of the E.M. revealed that water was detected intracellularly, within astrocytic preivascular end-feet and cell bodies. Conclusion: The unexpected volume fraction changes (i.e. increase in fast component) detected in hypotonic oedema appear to be substantially different from those observed in stroke. It may suggest that ADC decrease in stroke, in contrast to general presumptions, cannot be explained only by water shift from extra to intracellular space (i.e. intracellular oedema).

  15. A biexponential DWI study in rat brain intracellular oedema

    International Nuclear Information System (INIS)

    Purpose: To examine the changes in MR parameters derived from diffusion weighted imaging (DWI) biexponential analysis in an in vivo intracellular brain oedema model, and to apply electron microscopy (EM) to shed more light on the morphological background of MR-related observations. Materials and methods: Intracellular oedema was induced in ten male Wistar rats (380–450 g) by way of water load, using a 20% body weight intraperitoneal injection of 140 mmol/L dextrose solution. A 3T MRI instrument was used to perform serial DWI, and MR specroscopy (water signal) measurements. Following the MR examination the brains of the animals were analyzed for EM. Results: Following the water load induction, apparent diffusion coefficient (ADC) values started declining from 724 ± 43 μm2/s to 682 ± 26 μm2/s (p 2/s (p 2/s (p < 0.05). There was a shift from the slow to the fast component at 110 min time point. The percentage of the fast component demonstrated moderate, yet significant increase from 76.56 ± 7.79% to 81.2 ± 7.47% (p < 0.05). The water signal was increasing by 4.98 ± 3.52% compared to the base line (p < 0.01). The results of the E.M. revealed that water was detected intracellularly, within astrocytic preivascular end-feet and cell bodies. Conclusion: The unexpected volume fraction changes (i.e. increase in fast component) detected in hypotonic oedema appear to be substantially different from those observed in stroke. It may suggest that ADC decrease in stroke, in contrast to general presumptions, cannot be explained only by water shift from extra to intracellular space (i.e. intracellular oedema).

  16. A heat shock protein 90 β isoform involved in immune response to bacteria challenge and heat shock from Miichthys miiuy.

    Science.gov (United States)

    Wei, Tao; Gao, Yunhang; Wang, Rixin; Xu, Tianjun

    2013-08-01

    Heat shock protein 90 (HSP90) is highly conserved molecular chaperone that plays a critical role in cellular stress response. In this study, we reported the identification and functional analysis of a heat shock protein 90 gene from miiuy croaker (designated Mimi-HSP90). Mimi-HSP90 contained five conserved HSP90 protein family signatures and shared 89.6%-99.5% similarity with other known HSP90 β isoform. Homology analysis and structure comparison further indicated that Mimi-HSP90 should be β isoform member of the HSP90 family. The molecular evolutionary analysis showed that HSP90 was under an overall strong purifying select pressure among fish species. Mimi-HSP90 gene was constitutively expressed in ten examined tissues, and the expression level of liver was higher than in other tissues. The expression level of Mimi-HSP90 gene under bacterial infection and heat shock were analyzed by real-time quantitative RT-PCR, resulted in significant changes in liver, spleen, and kidney tissues. The purified recombinant pET-HSP90 protein was used to produce the polyclonal antibody in mice. The specificity of the antibody was determined by Western blot analysis. All results suggested that Mimi-HSP90 was involved in thermal stress and immune response in miiuy croaker. PMID:23684810

  17. A longitudinal study of structural brain network changes with normal aging

    Directory of Open Access Journals (Sweden)

    Kai eWu

    2013-04-01

    Full Text Available The aim of this study was to investigate age-related changes in the topological organization of structural brain networks by applying a longitudinal design over 6 years. Structural brain networks were derived from measurements of regional gray matter volume and were constructed in age-specific groups from baseline and follow-up scans. The structural brain networks showed economical small-world properties, providing high global and local efficiency for parallel information processing at low connection costs. In the analysis of the global network properties, the local and global efficiency of the baseline scan were significantly lower compared to the follow-up scan. Moreover, the annual rate of changes in local and global efficiency showed a positive and negative quadratic correlation with the baseline age, respectively; both curvilinear correlations peaked at approximately the age of 50. In the analysis of the regional nodal properties, significant negative correlations between the annual rate of changes in nodal strength and the baseline age were found in the brain regions primarily involved in the visual and motor/ control systems, whereas significant positive quadratic correlations were found in the brain regions predominately associated with the default-mode, attention, and memory systems. The results of the longitudinal study are consistent with the findings of our previous cross-sectional study: the structural brain networks develop into a fast distribution from young to middle age (approximately 50 years old and eventually became a fast localization in the old age. Our findings elucidate the network topology of structural brain networks and its longitudinal changes, thus enhancing the understanding of the underlying physiology of normal aging in the human brain.

  18. The impact of glucose disorders on cognition and brain volumes in the elderly: the Sydney Memory and Ageing Study

    OpenAIRE

    Samaras, Katherine; Lutgers, Helen L.; Kochan, Nicole A.; Crawford, John D.; Campbell, Lesley V; Wen, Wei; Slavin, Melissa J.; Baune, Bernard T.; Lipnicki, Darren M; Brodaty, Henry; Julian N Trollor; Perminder S Sachdev

    2014-01-01

    Type 2 diabetes predicts accelerated cognitive decline and brain atrophy. We hypothesized that impaired fasting glucose (IFG) and incident glucose disorders have detrimental effects on global cognition and brain volume. We further hypothesized that metabolic and inflammatory derangements accompanying hyperglycaemia contribute to change in brain structure and function. This was a longitudinal study of a community-dwelling elderly cohort with neuropsychological testing (n = 880) and brain volum...

  19. Brain injury biomechanics in closed-head impact : Studies on injury epidemiology, tolerance criteria, biomechanics and traffic injury prevention

    OpenAIRE

    Viano, David

    1997-01-01

    Permanent disability from traumatic brain injury is a devastating consequence of traffic crashes. Injury prevention is a fruitful approach to reduce the incidence and severity of disabling brain injury. However, the development of effective prevention techniques requires better knowledge on the mechanisms and biomechanics of brain injury in closed-head impact. The overall aim of this study is focused on brain injury mechanisms, biomechanics, and tolerances in closed-head ...

  20. A Prospective Randomized Study of Brain Tissue Oxygen Pressure-Guided Management in Moderate and Severe Traumatic Brain Injury Patients

    Directory of Open Access Journals (Sweden)

    Chien-Min Lin

    2015-01-01

    Full Text Available The purpose of this study was to compare the effect of PbtO2-guided therapy with traditional intracranial pressure- (ICP- guided treatment on the management of cerebral variables, therapeutic interventions, survival rates, and neurological outcomes of moderate and severe traumatic brain injury (TBI patients. From 2009 to 2010, TBI patients with a Glasgow coma scale 20 mmHg, and 27 patients were treated with ICP-guided therapy (ICP 60 mmHg in the neurosurgical intensive care unit (NICU; demographic characteristics were similar across groups. The survival rate in the PbtO2-guided group was also significantly increased at 3 and 6 months after injury. Moreover, there was a significant correlation between the PbtO2 signal and Glasgow outcome scale-extended in patients from 1 to 6 months after injury. This finding demonstrates that therapy directed by PbtO2 monitoring is valuable for the treatment of patients with moderate and severe TBI and that increasing PaO2 to 150 mmHg may be efficacious for preventing cerebral hypoxic events after brain trauma.

  1. MR-visible water content in human brain: a proton MRS study

    DEFF Research Database (Denmark)

    Christiansen, P; Toft, P B; Gideon, P; Danielsen, E R; Ring, P; Henriksen, O

    1994-01-01

    In vivo measurement of metabolite concentrations in the human brain by means of proton-MRS contributes significantly to the clinical evaluation of patients with diseases of the brain. The fully relaxed water signal has been proposed as an internal standard for calibration of the MRS measurements...... groups: newborn (0-23 days), adolescents (10-15 yr), adults (22-28 yr), and elderly people (60-74 yr). The examinations were carried out using a Siemens Helicon SP 63/84 MR-scanner operating at 1.5 T. Except for the newborn, four regions were studied in each subject using stimulated echo (STEAM....... The major drawbacks are the necessity to make the assumptions that the water concentrations in the brain and that all tissue water is MR-visible. A number of in vivo measurements were carried out to estimate the concentration of MR-visible water in the brain of healthy volunteers divided into four age...

  2. A pilot case-cohort study of brain cancer in poultry and control workers.

    Science.gov (United States)

    Gandhi, S; Felini, M J; Ndetan, H; Cardarelli, K; Jadhav, S; Faramawi, M; Johnson, E S

    2014-01-01

    We conducted an exploratory study to investigate which exposures (including poultry oncogenic viruses) are associated with brain cancer in poultry workers. A total of 46,819 workers in poultry and nonpoultry plants from the same union were initially followed for mortality. Brain cancer was observed to be in excess among poultry workers. Here we report on a pilot case-cohort study with cases consisting of 26 (55%) of the 47 brain cancer deaths recorded in the cohort, and controls consisting of a random sample of the cohort (n = 124). Exposure information was obtained from telephone interviews, and brain cancer mortality risk estimated by odds ratios. Increased risk of brain cancer was associated with killing chickens, odds ratio (OR) = 5.8 (95% confidence interval, 1.2-28.3); working in a shell-fish farm, OR = 13.0 (95% CI, 1.9-84.2); and eating uncooked fish, OR = 8.2 (95% CI, 1.8-37.0). Decreased risks were observed for chicken pox illness, OR = 0.2 (95% CI, 0.1-0.6), and measles vaccination, OR = 0.2 (95% CI, 0.1-0.6). Killing chickens, an activity associated with the highest occupational exposure to poultry oncogenic viruses, was associated with brain cancer mortality, as were occupational and dietary shellfish exposures. These findings are novel. PMID:24564367

  3. Building a brain under nutritional restriction: insights on sparing and plasticity from Drosophila studies

    Science.gov (United States)

    Lanet, Elodie; Maurange, Cédric

    2014-01-01

    While the growth of the developing brain is known to be well-protected compared to other organs in the face of nutrient restriction (NR), careful analysis has revealed a range of structural alterations and long-term neurological defects. Yet, despite intensive studies, little is known about the basic principles that govern brain development under nutrient deprivation. For over 20 years, Drosophila has proved to be a useful model for investigating how a functional nervous system develops from a restricted number of neural stem cells (NSCs). Recently, a few studies have started to uncover molecular mechanisms as well as region-specific adaptive strategies that preserve brain functionality and neuronal repertoire under NR, while modulating neuron numbers. Here, we review the developmental constraints that condition the response of the developing brain to NR. We then analyze the recent Drosophila work to highlight key principles that drive sparing and plasticity in different regions of the central nervous system (CNS). As simple animal models start to build a more integrated picture, understanding how the developing brain copes with NR could help in defining strategies to limit damage and improve brain recovery after birth. PMID:24723892

  4. Comparison study of ferrofluid and powder iron oxide nanoparticle permeability across the blood-brain barrier.

    Science.gov (United States)

    Hoff, Dan; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J

    2013-01-01

    In the present study, the permeability of 11 different iron oxide nanoparticle (IONP) samples (eight fluids and three powders) was determined using an in vitro blood-brain barrier model. Importantly, the results showed that the ferrofluid formulations were statistically more permeable than the IONP powder formulations at the blood-brain barrier, suggesting a role for the presently studied in situ synthesized ferrofluid formulations using poly(vinyl) alcohol, bovine serum albumin, collagen, glutamic acid, graphene, and their combinations as materials which can cross the blood-brain barrier to deliver drugs or have other neurological therapeutic efficacy. Conversely, the results showed the least permeability across the blood-brain barrier for the IONP with collagen formulation, suggesting a role as a magnetic resonance imaging contrast agent but limiting IONP passage across the blood-brain barrier. Further analysis of the data yielded several trends of note, with little correlation between permeability and fluid zeta potential, but a larger correlation between permeability and fluid particle size (with the smaller particle sizes having larger permeability). Such results lay the foundation for simple modification of iron oxide nanoparticle formulations to either promote or inhibit passage across the blood-brain barrier, and deserve further investigation for a wide range of applications. PMID:23426527

  5. Spectrum of pediatric brain tumors in India: A multi-institutional study

    Directory of Open Access Journals (Sweden)

    Ayushi Jain

    2011-01-01

    Full Text Available Background : Till date there is no published multi-institutional data regarding the epidemiological profile of pediatric brain tumors in India. Aim : The present retrospective study analyses the histological spectrum of pediatric age group brain tumors in seven tertiary care hospitals in India. Material and Methods : Data regarding frequencies of various primary brain tumors (diagnosed according to the World Health Organization (WHO classification, in 3936 pediatric patients (<18 yrs of age, was collected from seven tertiary care hospitals in India.Results : The most common primary pediatric brain tumors were astrocytic tumors (34.7%, followed by medulloblastoma and supratentorial primitive neuro-ectodermal tumors (22.4%, craniopharyngiomas (10.2% and ependymal tumors (9.8%. The most common astrocytic tumor was pilocytic astrocytoma. In comparison to adults, oligodendrogliomas and lymphomas were rare in children. Conclusions : Our study is the first such report on the histological spectrum of brain tumors in children in India. Except for a slightly higher frequency of craniopharyngiomas, the histological profile of pediatric brain tumors in India is similar to that reported in the Western literature.

  6. Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.

    Science.gov (United States)

    Eising, Else; Huisman, Sjoerd M H; Mahfouz, Ahmed; Vijfhuizen, Lisanne S; Anttila, Verneri; Winsvold, Bendik S; Kurth, Tobias; Ikram, M Arfan; Freilinger, Tobias; Kaprio, Jaakko; Boomsma, Dorret I; van Duijn, Cornelia M; Järvelin, Marjo-Riitta R; Zwart, John-Anker; Quaye, Lydia; Strachan, David P; Kubisch, Christian; Dichgans, Martin; Davey Smith, George; Stefansson, Kari; Palotie, Aarno; Chasman, Daniel I; Ferrari, Michel D; Terwindt, Gisela M; de Vries, Boukje; Nyholt, Dale R; Lelieveldt, Boudewijn P F; van den Maagdenberg, Arn M J M; Reinders, Marcel J T

    2016-04-01

    Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology. PMID:26899160

  7. Brain activity modification produced by a single radioelectric asymmetric brain stimulation pulse: a new tool for neuropsychiatric treatments. Preliminary fMRI study

    Directory of Open Access Journals (Sweden)

    Castagna A

    2011-10-01

    Full Text Available Salvatore Rinaldi1,2, Vania Fontani1, Alessandro Castagna1 1Department of Neuro-Psycho-Physio Pathology, Rinaldi Fontani Institute, Florence, Italy; 2Medical School of Occupational Medicine, University of Florence, Florence, Italy Purpose: Radioelectric asymmetric brain stimulation technology with its treatment protocols has shown efficacy in various psychiatric disorders. The aim of this work was to highlight the mechanisms by which these positive effects are achieved. The current study was conducted to determine whether a single 500-millisecond radioelectric asymmetric conveyor (REAC brain stimulation pulse (BSP, applied to the ear, can effect a modification of brain activity that is detectable using functional magnetic resonance imaging (fMRI. Methods: Ten healthy volunteers, six females and four males, underwent fMRI during a simple finger-tapping motor task before and after receiving a single 500-millisecond REAC-BSP. Results: The fMRI results indicate that the average variation in task-induced encephalic activation patterns is lower in subjects following the single REAC pulse. Conclusion: The current report demonstrates that a single REAC-BSP is sufficient to modulate brain activity in awake subjects, able to be measured using fMRI. These initial results open new perspectives into the understanding of the effects of weak and brief radio pulses upon brain activity, and provide the basis for further indepth studies using REAC-BSP and fMRI. Keywords: fMRI, brain stimulation, brain modulation, REAC, neuropsychiatric treatments

  8. Whole Brain Irradiation With Hippocampal Sparing and Dose Escalation on Multiple Brain Metastases: A Planning Study on Treatment Concepts

    International Nuclear Information System (INIS)

    Purpose: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). Methods and Materials: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individual brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. Results: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55 ± 0.62 Gy and 6.29 ± 0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8 ± 1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2 ± 0.7 Gy and 32.7 ± 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23 ± 1.42 Gy in SC. Conclusions: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.

  9. Whole Brain Irradiation With Hippocampal Sparing and Dose Escalation on Multiple Brain Metastases: A Planning Study on Treatment Concepts

    Energy Technology Data Exchange (ETDEWEB)

    Prokic, Vesna, E-mail: vesna.prokic@uniklinik-freiburg.de [Department of Radiation Oncology, University Medical Center Freiburg, Freiburg (Germany); Wiedenmann, Nicole; Fels, Franziska; Schmucker, Marianne [Department of Radiation Oncology, University Medical Center Freiburg, Freiburg (Germany); Nieder, Carsten [Department of Oncology and Palliative Medicine, Nordland Hospital, Bodo (Norway); Institute of Clinical Medicine, Faculty of Health Sciences, University of Tromso, Tromso (Norway); Grosu, Anca-Ligia [Department of Radiation Oncology, University Medical Center Freiburg, Freiburg (Germany)

    2013-01-01

    Purpose: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). Methods and Materials: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individual brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. Results: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55 {+-} 0.62 Gy and 6.29 {+-} 0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8 {+-} 1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2 {+-} 0.7 Gy and 32.7 {+-} 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23 {+-} 1.42 Gy in SC. Conclusions: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.

  10. Effects of Diet on Brain Plasticity in Animal and Human Studies: Mind the Gap

    Directory of Open Access Journals (Sweden)

    Tytus Murphy

    2014-01-01

    Full Text Available Dietary interventions have emerged as effective environmental inducers of brain plasticity. Among these dietary interventions, we here highlight the impact of caloric restriction (CR: a consistent reduction of total daily food intake, intermittent fasting (IF, every-other-day feeding, and diet supplementation with polyphenols and polyunsaturated fatty acids (PUFAs on markers of brain plasticity in animal studies. Moreover, we also discuss epidemiological and intervention studies reporting the effects of CR, IF and dietary polyphenols and PUFAs on learning, memory, and mood. In particular, we evaluate the gap in mechanistic understanding between recent findings from animal studies and those human studies reporting that these dietary factors can benefit cognition, mood, and anxiety, aging, and Alzheimer’s disease—with focus on the enhancement of structural and functional plasticity markers in the hippocampus, such as increased expression of neurotrophic factors, synaptic function and adult neurogenesis. Lastly, we discuss some of the obstacles to harnessing the promising effects of diet on brain plasticity in animal studies into effective recommendations and interventions to promote healthy brain function in humans. Together, these data reinforce the important translational concept that diet, a modifiable lifestyle factor, holds the ability to modulate brain health and function.

  11. Effects of Diet on Brain Plasticity in Animal and Human Studies: Mind the Gap

    Science.gov (United States)

    Dias, Gisele Pereira

    2014-01-01

    Dietary interventions have emerged as effective environmental inducers of brain plasticity. Among these dietary interventions, we here highlight the impact of caloric restriction (CR: a consistent reduction of total daily food intake), intermittent fasting (IF, every-other-day feeding), and diet supplementation with polyphenols and polyunsaturated fatty acids (PUFAs) on markers of brain plasticity in animal studies. Moreover, we also discuss epidemiological and intervention studies reporting the effects of CR, IF and dietary polyphenols and PUFAs on learning, memory, and mood. In particular, we evaluate the gap in mechanistic understanding between recent findings from animal studies and those human studies reporting that these dietary factors can benefit cognition, mood, and anxiety, aging, and Alzheimer's disease—with focus on the enhancement of structural and functional plasticity markers in the hippocampus, such as increased expression of neurotrophic factors, synaptic function and adult neurogenesis. Lastly, we discuss some of the obstacles to harnessing the promising effects of diet on brain plasticity in animal studies into effective recommendations and interventions to promote healthy brain function in humans. Together, these data reinforce the important translational concept that diet, a modifiable lifestyle factor, holds the ability to modulate brain health and function. PMID:24900924

  12. Progesterone mediates brain functional connectivity changes during the menstrual cycle - A pilot resting state MRI study

    Directory of Open Access Journals (Sweden)

    Katrin eArelin

    2015-02-01

    Full Text Available The growing interest in intrinsic brain organization has sparked various innovative approaches to generating comprehensive connectivity-based maps of the human brain. Prior reports point to a sexual dimorphism of the structural and functional human connectome. However, it is uncertain whether subtle changes in sex hormones, as occur during the monthly menstrual cycle, substantially impact the functional architecture of the female brain. Here, we performed eigenvector centrality (EC mapping in 32 longitudinal resting state fMRI scans of a single healthy subject without oral contraceptive use, across four menstrual cycles, and assessed estrogen and progesterone levels. To investigate associations between cycle-dependent hormones and brain connectivity, we performed correlation analyses between the EC maps and the respective hormone levels. On the whole brain level, we found a significant positive correlation between progesterone and EC in the bilateral DLPFC and bilateral sensorimotor cortex. In a secondary region-of-interest analysis, we detected a progesterone-modulated increase in functional connectivity of both bilateral DLPFC and bilateral sensorimotor cortex with the hippocampus. Our results suggest that the menstrual cycle substantially impacts intrinsic functional connectivity, particularly in brain areas associated with contextual memory-regulation, such as the hippocampus. These findings are the first to link the subtle hormonal fluctuations that occur during the menstrual cycle, to significant changes in regional functional connectivity in the hippocampus in a longitudinal design, given the limitation of data acquisition in a single subject. Our study demonstrates the feasibility of such a longitudinal rs-fMRI design and illustrates a means of creating a personalized map of the human brain by integrating potential mediators of brain states, such as menstrual cycle phase.

  13. A case study for outreach: the Auckland experience of the New Zealand Brain Bee Challenge.

    Science.gov (United States)

    Dowie, Megan J; Nicholson, Louise F B

    2011-02-01

    The 3rd hosting of the Auckland region New Zealand Brain Bee Challenge was held in 2009. Designed as a neuroscience quiz for high school students, the competition provides a valuable case study for science outreach. By engaging with teenagers, the field of neuroscience presents an exciting area of science but also stimulates those in the field to promote and share their research. Neuroscience is the ideal subject to highlight and promote science to young people and the community, as the brain defines unique features such as our personality, emotions, creativity, and intelligence. Understanding brain function and, importantly, determining dysfunction is a growing area of research interest, with relevance to health care systems and government policy, especially in light of the aging population. Feedback from students and teachers indicated that they had learned something about research and the brain, were more aware of options within science including considering neuroscience as a career option, and would recommend participation in the Brain Bee Challenge to other students. A number of participants indicated it was interesting/valuable to have interaction with neuroscientists. Although there are many synergistic benefits resulting from an undertaking such as the Brain Bee Challenge, the following profile highlights the value of the interaction and promotion of research to the community. PMID:20656982

  14. Mechanism of case processing in the brain: an fMRI study.

    Directory of Open Access Journals (Sweden)

    Satoru Yokoyama

    Full Text Available In sentence comprehension research, the case system, which is one of the subsystems of the language processing system, has been assumed to play a crucial role in signifying relationships in sentences between noun phrases (NPs and other elements, such as verbs, prepositions, nouns, and tense. However, so far, less attention has been paid to the question of how cases are processed in our brain. To this end, the current study used fMRI and scanned the brain activity of 15 native English speakers during an English-case processing task. The results showed that, while the processing of all cases activates the left inferior frontal gyrus and posterior part of the middle temporal gyrus, genitive case processing activates these two regions more than nominative and accusative case processing. Since the effect of the difference in behavioral performance among these three cases is excluded from brain activation data, the observed different brain activations would be due to the different processing patterns among the cases, indicating that cases are processed differently in our brains. The different brain activations between genitive case processing and nominative/accusative case processing may be due to the difference in structural complexity between them.

  15. Recommended Methods for Brain Processing and Quantitative Analysis in Rodent Developmental Neurotoxicity Studies.

    Science.gov (United States)

    Garman, Robert H; Li, Abby A; Kaufmann, Wolfgang; Auer, Roland N; Bolon, Brad

    2016-01-01

    Neuropathology methods in rodent developmental neurotoxicity (DNT) studies have evolved with experience and changing regulatory guidance. This article emphasizes principles and methods to promote more standardized DNT neuropathology evaluation, particularly procurement of highly homologous brain sections and collection of the most reproducible morphometric measurements. To minimize bias, brains from all animals at all dose levels should be processed from brain weighing through paraffin embedding at one time using a counterbalanced design. Morphometric measurements should be anchored by distinct neuroanatomic landmarks that can be identified reliably on the faced block or in unstained sections and which address the region-specific circuitry of the measured area. Common test article-related qualitative changes in the developing brain include abnormal cell numbers (yielding altered regional size), displaced cells (ectopia and heterotopia), and/or aberrant differentiation (indicated by defective myelination or synaptogenesis), but rarely glial or inflammatory reactions. Inclusion of digital images in the DNT pathology raw data provides confidence that the quantitative analysis was done on anatomically matched (i.e., highly homologous) sections. Interpreting DNT neuropathology data and their presumptive correlation with neurobehavioral data requires an integrative weight-of-evidence approach including consideration of maternal toxicity, body weight, brain weight, and the pattern of findings across brain regions, doses, sexes, and ages. PMID:26296631

  16. The Gini coefficient: a methodological pilot study to assess fetal brain development employing postmortem diffusion MRI

    International Nuclear Information System (INIS)

    Diffusion-weighted imaging (DWI) is important in the assessment of fetal brain development. However, it is clinically challenging and time-consuming to prepare neuromorphological examinations to assess real brain age and to detect abnormalities. To demonstrate that the Gini coefficient can be a simple, intuitive parameter for modelling fetal brain development. Postmortem fetal specimens(n = 28) were evaluated by diffusion-weighted imaging (DWI) on a 3-T MRI scanner using 60 directions, 0.7-mm isotropic voxels and b-values of 0, 150, 1,600 s/mm2. Constrained spherical deconvolution (CSD) was used as the local diffusion model. Fractional anisotropy (FA), apparent diffusion coefficient (ADC) and complexity (CX) maps were generated. CX was defined as a novel diffusion metric. On the basis of those three parameters, the Gini coefficient was calculated. Study of fetal brain development in postmortem specimens was feasible using DWI. The Gini coefficient could be calculated for the combination of the three diffusion parameters. This multidimensional Gini coefficient correlated well with age (Adjusted R2 = 0.59) between the ages of 17 and 26 gestational weeks. We propose a new method that uses an economics concept, the Gini coefficient, to describe the whole brain with one simple and intuitive measure, which can be used to assess the brain's developmental state. (orig.)

  17. Dynamics of the brain: Mathematical models and non-invasive experimental studies

    Science.gov (United States)

    Toronov, V.; Myllylä, T.; Kiviniemi, V.; Tuchin, V. V.

    2013-10-01

    Dynamics is an essential aspect of the brain function. In this article we review theoretical models of neural and haemodynamic processes in the human brain and experimental non-invasive techniques developed to study brain functions and to measure dynamic characteristics, such as neurodynamics, neurovascular coupling, haemodynamic changes due to brain activity and autoregulation, and cerebral metabolic rate of oxygen. We focus on emerging theoretical biophysical models and experimental functional neuroimaging results, obtained mostly by functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS). We also included our current results on the effects of blood pressure variations on cerebral haemodynamics and simultaneous measurements of fast processes in the brain by near-infrared spectroscopy and a very novel functional MRI technique called magnetic resonance encephalography. Based on a rapid progress in theoretical and experimental techniques and due to the growing computational capacities and combined use of rapidly improving and emerging neuroimaging techniques we anticipate during next decade great achievements in the overall knowledge of the human brain.

  18. The Gini coefficient: a methodological pilot study to assess fetal brain development employing postmortem diffusion MRI

    Energy Technology Data Exchange (ETDEWEB)

    Viehweger, Adrian; Sorge, Ina; Hirsch, Wolfgang [University Hospital Leipzig, Department of Pediatric Radiology, Leipzig (Germany); Riffert, Till; Dhital, Bibek; Knoesche, Thomas R.; Anwander, Alfred [Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig (Germany); Stepan, Holger [University Leipzig, Department of Obstetrics, Leipzig (Germany)

    2014-10-15

    Diffusion-weighted imaging (DWI) is important in the assessment of fetal brain development. However, it is clinically challenging and time-consuming to prepare neuromorphological examinations to assess real brain age and to detect abnormalities. To demonstrate that the Gini coefficient can be a simple, intuitive parameter for modelling fetal brain development. Postmortem fetal specimens(n = 28) were evaluated by diffusion-weighted imaging (DWI) on a 3-T MRI scanner using 60 directions, 0.7-mm isotropic voxels and b-values of 0, 150, 1,600 s/mm{sup 2}. Constrained spherical deconvolution (CSD) was used as the local diffusion model. Fractional anisotropy (FA), apparent diffusion coefficient (ADC) and complexity (CX) maps were generated. CX was defined as a novel diffusion metric. On the basis of those three parameters, the Gini coefficient was calculated. Study of fetal brain development in postmortem specimens was feasible using DWI. The Gini coefficient could be calculated for the combination of the three diffusion parameters. This multidimensional Gini coefficient correlated well with age (Adjusted R{sup 2} = 0.59) between the ages of 17 and 26 gestational weeks. We propose a new method that uses an economics concept, the Gini coefficient, to describe the whole brain with one simple and intuitive measure, which can be used to assess the brain's developmental state. (orig.)

  19. Functional MRI studies of acupuncture analgesia modulating within the human brain

    International Nuclear Information System (INIS)

    Objective: To evaluate the correlation between acupuncture analgesia and specific functional areas of the brain using functional magnetic resonance imaging (fMRI). Methods: Acupuncture stimulation was induced by manipulating acupuncture needle at the acupuncture point, large intestine 4 (LI 4, Hegu) on the right (dominant) hand of 8 healthy subjects. Functional MRI data were obtained from scanning the whole brain. A block-design paradigm was applied. Functional responses were established by students' group t-test analysis. Results: The data sets from 6 of 8 subjects were used in the study. Signal increases and signal decreases elicited by acupuncture stimulating were demonstrated in multiple brain regions. Signal increases in periaqueductal gray matter and ventral posterior nucleus of the left thalamus, and signal decreases in bilateral anterior cingulate cortex and bilateral occipital lobes were considered as the response to the acupuncture modulating within the human brain. Conclusion: The therapeutic effect of acupuncture analgesia was probably produced by the interaction of multiple brain structures of functional connectivity rather than through the activation of a single brain region

  20. A 18F-FDG uptake study of brain and abnormal brain connection in advanced Parkinson's disease

    International Nuclear Information System (INIS)

    Objective: To assess the changes in regional glucose metabolism and abnormal brain connection in advanced Parkinson's disease (PD) with 18F-fluorodeoxyglucose (FDG) PET imaging. Methods: Ten advanced PD patients and 10 age-matched healthy subjects underwent 18F-FDG PET imaging at rest-state. Statistical parametric mapping (SPM) was used to investigate regional cerebral metabolic rate of glucose. Results: Compared to age-matched healthy subjects, the regional glucose metabolism increased in bilateral hippocampus, thalamus, precentral cortex (BA6) and lentiform, whereas decreased in bilateral prefrontal motor area (BA46, BA47), parietal area (BA7, BA39) in advanced PD cases. Conclusions: Hypermetabolism in thalamus and lentiform accompany with hypometabolism in prefrontal motor and parietal cortex area was found in advanced PD patients, thereby the abnormal functional connection showed by FDG PET imaging is helpful to the diagnosis and also for the study of the pathophysiology of PD

  1. Human brain cancer studied by resonance Raman spectroscopy

    Science.gov (United States)

    Zhou, Yan; Liu, Cheng-Hui; Sun, Yi; Pu, Yang; Boydston-White, Susie; Liu, Yulong; Alfano, Robert R.

    2012-11-01

    The resonance Raman (RR) spectra of six types of human brain tissues are examined using a confocal micro-Raman system with 532-nm excitation in vitro. Forty-three RR spectra from seven subjects are investigated. The spectral peaks from malignant meningioma, stage III (cancer), benign meningioma (benign), normal meningeal tissues (normal), glioblastoma multiforme grade IV (cancer), acoustic neuroma (benign), and pituitary adenoma (benign) are analyzed. Using a 532-nm excitation, the resonance-enhanced peak at 1548 cm-1 (amide II) is observed in all of the tissue specimens, but is not observed in the spectra collected using the nonresonance Raman system. An increase in the intensity ratio of 1587 to 1605 cm-1 is observed in the RR spectra collected from meningeal cancer tissue as compared with the spectra collected from the benign and normal meningeal tissue. The peak around 1732 cm-1 attributed to fatty acids (lipids) are diminished in the spectra collected from the meningeal cancer tumors as compared with the spectra from normal and benign tissues. The characteristic band of spectral peaks observed between 2800 and 3100 cm-1 are attributed to the vibrations of methyl (-CH3) and methylene (-CH2-) groups. The ratio of the intensities of the spectral peaks of 2935 to 2880 cm-1 from the meningeal cancer tissues is found to be lower in comparison with that of the spectral peaks from normal, and benign tissues, which may be used as a distinct marker for distinguishing cancerous tissues from normal meningeal tissues. The statistical methods of principal component analysis and the support vector machine are used to analyze the RR spectral data collected from meningeal tissues, yielding a diagnostic sensitivity of 90.9% and specificity of 100% when two principal components are used.

  2. Structure and Functional Studies of the CS Domain of the Essential H/ACA Ribonucleoparticle Assembly Protein SHQ1

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Mahavir; Gonzales, Fernando A.; Cascio, Duilio; Heckmann, Nathanael; Chanfreau, Guillaume; Feigon, Juli; (UCLA)

    2009-03-16

    H/ACA ribonucleoprotein particles are essential for ribosomal RNA and telomerase RNA processing and metabolism. Shq1p has been identified as an essential eukaryotic H/ACA small nucleolar (sno) ribonucleoparticle (snoRNP) biogenesis and assembly factor. Shq1p is postulated to be involved in the early biogenesis steps of H/ACA snoRNP complexes, and Shq1p depletion leads to a specific decrease in H/ACA small nucleolar RNA levels and to defects in ribosomal RNA processing. Shq1p contains two predicted domains as follows: an N-terminal CS (named after CHORD-containing proteins and SGT1) or HSP20-like domain, and a C-terminal region of high sequence homology called the Shq1 domain. Here we report the crystal structure and functional studies of the Saccharomyces cerevisiae Shq1p CS domain. The structure consists of a compact anti-parallel {beta}-sandwich fold that is composed of two {beta}-sheets containing four and three {beta}-strands, respectively, and a short {alpha}-helix. Deletion studies showed that the CS domain is required for the essential functions of Shq1p. Point mutations in residues Phe-6, Gln-10, and Lys-80 destabilize Shq1p in vivo and induce a temperature-sensitive phenotype with depletion of H/ACA small nucleolar RNAs and defects in rRNA processing. Although CS domains are frequently found in co-chaperones of the Hsp90 molecular chaperone, no interaction was detected between the Shq1p CS domain and yeast Hsp90 in vitro. These results show that the CS domain is essential for Shq1p function in H/ACA snoRNP biogenesis in vivo, possibly in an Hsp90-independent manner.

  3. A Phase I Study of Short-Course Accelerated Whole Brain Radiation Therapy for Multiple Brain Metastases

    Energy Technology Data Exchange (ETDEWEB)

    Caravatta, Luciana; Deodato, Francesco; Ferro, Marica [Department of Radiation Oncology, Fondazione di Ricerca e Cura ' Giovanni Paolo II' , Universita Cattolica del S. Cuore, Campobasso (Italy); Macchia, Gabriella, E-mail: gmacchia@rm.unicatt.it [Department of Radiation Oncology, Fondazione di Ricerca e Cura ' Giovanni Paolo II' , Universita Cattolica del S. Cuore, Campobasso (Italy); Massaccesi, Mariangela [Department of Radiation Oncology, Fondazione di Ricerca e Cura ' Giovanni Paolo II' , Universita Cattolica del S. Cuore, Campobasso (Italy); Cilla, Savino [Medical Physics Unit, Fondazione di Ricerca e Cura ' Giovanni Paolo II,' Universita Cattolica del S. Cuore, Campobasso (Italy); Padula, Gilbert D.A. [Department of Radiation Oncology, The Lacks Cancer Center Saint Mary' s Health Care, Grand Rapids, Michigan (United States); Mignogna, Samantha; Tambaro, Rosa [Department of Palliative Therapies, Fondazione di Ricerca e Cura ' Giovanni Paolo II' , Universita Cattolica del S. Cuore, Campobasso (Italy); Carrozza, Francesco [Department of Oncology, A. Cardarelli Hospital, Campobasso (Italy); Flocco, Mariano [Madre Teresa di Calcutta Hospice, Larino (Italy); Cantore, Giampaolo [Department of Neurological Sciences, Istituto Neurologico Mediterraneo Neuromed, Istituto di Ricovero e Cura a Carattere Scientifico, Pozzilli (Italy); Scapati, Andrea [Department of Radiation Oncology, ' San Francesco' Hospital, Nuoro (Italy); Buwenge, Milly [Department of Radiotherapy, Mulago Hospital, Kampala (Uganda); and others

    2012-11-15

    Purpose: To define the maximum tolerated dose (MTD) of a SHort-course Accelerated whole brain RadiatiON therapy (SHARON) in the treatment of patients with multiple brain metastases. Methods and Materials: A phase 1 trial in 4 dose-escalation steps was designed: 12 Gy (3 Gy per fraction), 14 Gy (3.5 Gy per fraction), 16 Gy (4 Gy per fraction), and 18 Gy (4.5 Gy per fraction). Eligibility criteria included patients with unfavorable recursive partitioning analysis (RPA) class > or =2 with at least 3 brain metastases or metastatic disease in more than 3 organ systems, and Eastern Cooperative Oncology Group (ECOG) performance status {<=}3. Treatment was delivered in 2 days with twice-daily fractionation. Patients were treated in cohorts of 6-12 to define the MTD. The dose-limiting toxicity (DLT) was defined as any acute toxicity {>=}grade 3, according to the Radiation Therapy Oncology Group scale. Information on the status of the main neurologic symptoms and quality of life were recorded. Results: Characteristics of the 49 enrolled patients were as follows: male/female, 30/19; median age, 66 years (range, 23-83 years). ECOG performance status was <3 in 46 patients (94%). Fourteen patients (29%) were considered to be in recursive partitioning analysis (RPA) class 3. Grade 1-2 acute neurologic (26.4%) and skin (18.3%) toxicities were recorded. Only 1 patient experienced DLT (neurologic grade 3 acute toxicity). With a median follow-up time of 5 months (range, 1-23 months), no late toxicities have been observed. Three weeks after treatment, 16 of 21 symptomatic patients showed an improvement or resolution of presenting symptoms (overall symptom response rate, 76.2%; confidence interval 0.95: 60.3-95.9%). Conclusions: Short-course accelerated radiation therapy in twice-daily fractions for 2 consecutive days is tolerated up to a total dose of 18 Gy. A phase 2 study has been planned to evaluate the efficacy on overall survival, symptom control, and quality of life indices.

  4. Comparison of two brain tumor-localizing MRI agent. GD-BOPTA and GD-DTPA. MRI and ICP study of rat brain tumor model

    International Nuclear Information System (INIS)

    In this study, we compared the behavior of Gd-BOPTA as a brain tumor selective contrast agent with Gd-DTPA in a common dose of 0.1 mmol/kg. We performed a MRI study using those two agent as contrast material, and we measured tissue Gd-concentrations by ICP-AES. As a result, Gd-BOPTA showed a better MRI enhancement in brain tumor. ICP showed significantly greater uptake of Gd-BOPTA in tumor samples, at all time course peaked at 5 minutes after administration, Gd being retained for a longer time in brain tumor till 2 hours, without rapid elimination as Gd-DTPA. We conclude that Gd-BOPTA is a new useful contrast material for MR imaging in brain tumor and an effective absorption agent for neutron capture therapy for further research. (author)

  5. Study of cerebral metabolism of glucose in normal human brain correlated with age

    International Nuclear Information System (INIS)

    sensory-motor cortex(BA5, 7).In spite of the cerebral atrophy of aging, these relative hypometabolic brain areas are considered to be correlated with structural and functional cerebral changes and cognitive dysfunction such as verbal and spatial working memory deficit in the process of normal brain aging. The study of cerebral metabolism of glucose in normal human brains can be used for reference and instruction in future clinical studies and in normal brain aging. (author)

  6. A PROSPECTIVE HISTOPATHOLOGICAL-BASED STUDY OF BRAIN TUMOURS IN A REFERRAL CENTRE

    Directory of Open Access Journals (Sweden)

    Prathima Gujjaru

    2016-07-01

    Full Text Available BACKGROUND Brain neoplasms occur at all ages and account for around 2-3 percent of all deaths in adults. In children, the frequency increases to more than twenty percent. In children, it forms the second most common type of malignancy. Most of the tumours encountered are not related to any identifiable risk factors except for irradiation and some hereditary syndromes like subependymal giant cell astrocytoma, glioblastoma multiforme, cerebellar haemangioblastoma, meningioma, Schwannoma of 7 th cranial nerve. Gliomas constitute fifty percent of the brain tumours and sixty percent of all gliomas are glioblastoma multiforme. Meningiomas constitute twenty percent and cerebral metastasis is seen in fifteen percent of the cases. Seventy percent of supratentorial tumours are found in adults and seventy percent of brain tumours in children are infratentorial. The three common tumours of cerebellum are medulloblastoma, haemangioblastoma and juvenile pilocytic astrocytoma. Brain tumours are space occupying lesions and cause compression and destruction of adjacent structures, brain oedema (Peritumoural tissue, infarction and ischaemia of brain by compressing/infiltrating cerebral blood vessels, obstruction of CSF flow causing hydrocephalus, and rise in intracranial pressure with herniations. Tumours can undergo ischaemic necrosis and necrotic tumours tend to bleed. Brain tumours generally do not metastasise. Schwannoma and meningioma are benign tumours. Medulloblastoma of childhood may have drop metastasis via CSF. A sincere effort has been put in this study to identify the incidence of each variety of brain tumour among the fifty confirmed and identified cases of brain tumours. METHODS The age range of the cases in present study was 5-72 years with a mean age of occurrence of 44.11 years and the peak age group affected were in the 3 rd and 4 th decades. Cerebral hemisphere was the commonest site for intracranial tumours. RESULT In the present study, fifty

  7. Association rule mining based study for identification of clinical parameters akin to occurrence of brain tumor.

    Science.gov (United States)

    Sengupta, Dipankar; Sood, Meemansa; Vijayvargia, Poorvika; Hota, Sunil; Naik, Pradeep K

    2013-01-01

    Healthcare sector is generating a large amount of information corresponding to diagnosis, disease identification and treatment of an individual. Mining knowledge and providing scientific decision-making for the diagnosis & treatment of disease from the clinical dataset is therefore increasingly becoming necessary. Aim of this study was to assess the applicability of knowledge discovery in brain tumor data warehouse, applying data mining techniques for investigation of clinical parameters that can be associated with occurrence of brain tumor. In this study, a brain tumor warehouse was developed comprising of clinical data for 550 patients. Apriori association rule algorithm was applied to discover associative rules among the clinical parameters. The rules discovered in the study suggests - high values of Creatinine, Blood Urea Nitrogen (BUN), SGOT & SGPT to be directly associated with tumor occurrence for patients in the primary stage with atleast 85% confidence and more than 50% support. A normalized regression model is proposed based on these parameters along with Haemoglobin content, Alkaline Phosphatase and Serum Bilirubin for prediction of occurrence of STATE (brain tumor) as 0 (absent) or 1 (present). The results indicate that the methodology followed will be of good value for the diagnostic procedure of brain tumor, especially when large data volumes are involved and screening based on discovered parameters would allow clinicians to detect tumors at an early stage of development. PMID:23888095

  8. Prolonged repeated acupuncture stimulation induces habituation effects in pain-related brain areas: an FMRI study.

    Directory of Open Access Journals (Sweden)

    Chuanfu Li

    Full Text Available Most previous studies of brain responses to acupuncture were designed to investigate the acupuncture instant effect while the cumulative effect that should be more important in clinical practice has seldom been discussed. In this study, the neural basis of the acupuncture cumulative effect was analyzed. For this experiment, forty healthy volunteers were recruited, in which more than 40 minutes of repeated acupuncture stimulation was implemented at acupoint Zhusanli (ST36. Three runs of acupuncture fMRI datasets were acquired, with each run consisting of two blocks of acupuncture stimulation. Besides general linear model (GLM analysis, the cumulative effects of acupuncture were analyzed with analysis of covariance (ANCOVA to find the association between the brain response and the cumulative duration of acupuncture stimulation in each stimulation block. The experimental results showed that the brain response in the initial stage was the strongest although the brain response to acupuncture was time-variant. In particular, the brain areas that were activated in the first block and the brain areas that demonstrated cumulative effects in the course of repeated acupuncture stimulation overlapped in the pain-related areas, including the bilateral middle cingulate cortex, the bilateral paracentral lobule, the SII, and the right thalamus. Furthermore, the cumulative effects demonstrated bimodal characteristics, i.e. the brain response was positive at the beginning, and became negative at the end. It was suggested that the cumulative effect of repeated acupuncture stimulation was consistent with the characteristic of habituation effects. This finding may explain the neurophysiologic mechanism underlying acupuncture analgesia.

  9. Implantation of Miniosmotic Pumps and Delivery of Tract Tracers to Study Brain Reorganization in Pathophysiological Conditions.

    Science.gov (United States)

    Sanchez-Mendoza, Eduardo H; Carballo, Jeismar; Longart, Marines; Hermann, Dirk M; Doeppner, Thorsten R

    2016-01-01

    Pharmacological treatment in animal models of cerebral disease imposes the problem of repeated injection protocols that may induce stress in animals and result in impermanent tissue levels of the drug. Additionally, drug delivery to the brain is delicate due to the blood brain barrier (BBB), thus significantly reducing intracerebral concentrations of selective drugs after systemic administration. Therefore, a system that allows both constant drug delivery without peak levels and circumvention of the BBB is in order to achieve sufficiently high intracerebral concentrations of drugs that are impermeable to the BBB. In this context, miniosmotic pumps represent an ideal system for constant drug delivery at a fixed known rate that eludes the problem of daily injection stress in animals and that may also be used for direct brain delivery of drugs. Here, we describe a method for miniosmotic pump implantation and post operatory care that should be given to animals in order to successfully apply this technique. We embed the aforementioned experimental paradigm in standard procedures that are used for studying neuroplasticity within the brain of C57BL6 mice. Thus, we exposed animals to 30 min brain infarct and implanted with miniosmotic pumps connected to the skull via a cannula in order to deliver a pro-plasticity drug. Behavioral testing was done during 30 days of treatment. After removal the animals received injections of anterograde tract tracers to analyze neuronal plasticity in the chronic phase of recovery. Results indicated that neuroprotection by the delivered drug was accompanied with increase in motor fibers crossing the midline of the brain at target structures. The results affirm the value of these techniques for drug administration and brain plasticity studies in modern neuroscience. PMID:26863287

  10. Comparison study of ferrofluid and powder iron oxide nanoparticle permeability across the blood–brain barrier

    Directory of Open Access Journals (Sweden)

    Hoff D

    2013-02-01

    Full Text Available Dan Hoff,1 Lubna Sheikh,2 Soumya Bhattacharya,2 Suprabha Nayar,2 Thomas J Webster11School of Engineering, Brown University, Providence, RI, USA; 2Biomaterials Group, Materials Science and Technology Division, CSIR-National Metallurgical Laboratory, Burmamines, Jamshedpur, IndiaAbstract: In the present study, the permeability of 11 different iron oxide nanoparticle (IONP samples (eight fluids and three powders was determined using an in vitro blood–brain barrier model. Importantly, the results showed that the ferrofluid formulations were statistically more permeable than the IONP powder formulations at the blood–brain barrier, suggesting a role for the presently studied in situ synthesized ferrofluid formulations using poly(vinyl alcohol, bovine serum albumin, collagen, glutamic acid, graphene, and their combinations as materials which can cross the blood–brain barrier to deliver drugs or have other neurological therapeutic efficacy. Conversely, the results showed the least permeability across the blood–brain barrier for the IONP with collagen formulation, suggesting a role as a magnetic resonance imaging contrast agent but limiting IONP passage across the blood–brain barrier. Further analysis of the data yielded several trends of note, with little correlation between permeability and fluid zeta potential, but a larger correlation between permeability and fluid particle size (with the smaller particle sizes having larger permeability. Such results lay the foundation for simple modification of iron oxide nanoparticle formulations to either promote or inhibit passage across the blood–brain barrier, and deserve further investigation for a wide range of applications.Keywords: ferrofluids, iron oxide nanoparticles, permeability, blood–brain barrier

  11. Brain structure in bipolar disorder : A longitudinal neuroimaging study in twins

    NARCIS (Netherlands)

    Bootsman, F

    2016-01-01

    In this longitudinal twin study, the goal was to ascertain the extent to which BD shows abnormalities in subcortical and cortical brain regions at baseline and over time. Baseline assessments in this study revealed that BD was associated with smaller volumes of the thalamus, putamen and nucleus accu

  12. Sustained Effects of Ecstasy on the Human Brain: A Prospective Neuroimaging Study in Novel Users

    Science.gov (United States)

    de Win, Maartje M. L.; Jager, Gerry; Booij, Jan; Reneman, Liesbeth; Schilt, Thelma; Lavini, Christina; Olabarriaga, Silvia D.; den Heeten, Gerard J.; van den Brink, Wim

    2008-01-01

    Previous studies have suggested toxic effects of recreational ecstasy use on the serotonin system of the brain. However, it cannot be excluded that observed differences between users and non-users are the cause rather than the consequence of ecstasy use. As part of the Netherlands XTC Toxicity (NeXT) study, we prospectively assessed sustained…

  13. Organotypic hippocampal slice cultures for studies of brain damage, neuroprotection and neurorepair

    DEFF Research Database (Denmark)

    Noraberg, Jens; Poulsen, Frantz Rom; Blaabjerg, Morten;

    2005-01-01

    ), Alzheimer's disease (AD) and epilepsia. Studies of non-excitotoxic neurotoxic compounds and the experimental use of slice cultures in studies of HIV neurotoxicity, traumatic brain injury (TBI) and neurogenesis are included. For cerebral ischemia, experimental models with oxygen-glucose deprivation (OGD) and......-line biosensor monitoring, and time-lapse fluorescence microscopy are also presented....

  14. Time Perception in Severe Traumatic Brain Injury Patients: A Study Comparing Different Methodologies

    Science.gov (United States)

    Mioni, G.; Mattalia, G.; Stablum, F.

    2013-01-01

    In this study, we investigated time perception in patients with traumatic brain injury (TBI). Fifteen TBI patients and 15 matched healthy controls participated in the study. Participants were tested with durations above and below 1s on three different temporal tasks that involved time reproduction, production, and discrimination tasks. Data…

  15. Anaphoric Reference to Quantified Antecedents: An Event-Related Brain Potential Study

    Science.gov (United States)

    Filik, Ruth; Leuthold, Hartmut; Moxey, Linda M.; Sanford, Anthony J.

    2011-01-01

    We report an event-related brain potential (ERP) study examining how readers process sentences containing anaphoric reference to quantified antecedents. Previous studies indicate that positive (e.g. "many") and negative (e.g. "not many") quantifiers cause readers to focus on different sets of entities. For example in "Many of the fans attended the…

  16. Reverse Brain Drain of South Asian IT Professionals: A Quantitative Repatriation Study

    Science.gov (United States)

    Suppiah, Nithiyananthan

    2014-01-01

    The purpose of the present quantitative correlational study was to examine if a relationship existed between the RBD phenomenon and cultural, economic, or political factors of the native countries of South Asian IT professionals living in the United States. The study on reverse brain drain was conducted to explore a growing phenomenon in the…

  17. Brain correlates of aesthetic expertise: A parametric fMRI study

    DEFF Research Database (Denmark)

    Kirk, Ulrich; Skov, Martin; Christensen, Mark Schram;

    2009-01-01

    Several studies have demonstrated that acquired expertise influences aesthetic judgments. In this paradigm we used functional magnetic resonance imaging (fMRI) to study aesthetic judgments of visually presented architectural stimuli and control-stimuli (faces) for a group of architects and a group...... of non-architects. This design allowed us to test whether level of expertise modulates neural activity in brain areas associated with either perceptual processing, memory, or reward processing. We show that experts and non-experts recruit bilateral medial orbitofrontal cortex (OFC) and subcallosal...... processing, but also modulates the response in reward related brain areas....

  18. The dynamic interactome of human Aha1 upon Y223 phosphorylation

    OpenAIRE

    Donald Wolfgeher; Dunn, Diana M; Woodford, Mark R.; Dimitra Bourboulia; Gennady Bratslavsky; Mehdi Mollapour; Kron, Stephen J.; Truman, Andrew W.

    2015-01-01

    Heat Shock Protein 90 (Hsp90) is an essential chaperone that supports the function of a wide range of signaling molecules. Hsp90 binds to a suite of co-chaperone proteins that regulate Hsp90 function through alteration of intrinsic ATPase activity. Several studies have determined Aha1 to be an important co-chaperone whose binding to Hsp90 is modulated by phosphorylation, acetylation and SUMOylation of Hsp90 [1], [2]. In this study, we applied quantitative affinity-purification mass spectromet...

  19. Study on Brain Dynamics by Non Linear Analysis of Music Induced EEG Signals

    Science.gov (United States)

    Banerjee, Archi; Sanyal, Shankha; Patranabis, Anirban; Banerjee, Kaushik; Guhathakurta, Tarit; Sengupta, Ranjan; Ghosh, Dipak; Ghose, Partha

    2016-02-01

    Music has been proven to be a valuable tool for the understanding of human cognition, human emotion, and their underlying brain mechanisms. The objective of this study is to analyze the effect of Hindustani music on brain activity during normal relaxing conditions using electroencephalography (EEG). Ten male healthy subjects without special musical education participated in the study. EEG signals were acquired at the frontal (F3/F4) lobes of the brain while listening to music at three experimental conditions (rest, with music and without music). Frequency analysis was done for the alpha, theta and gamma brain rhythms. The finding shows that arousal based activities were enhanced while listening to Hindustani music of contrasting emotions (romantic/sorrow) for all the subjects in case of alpha frequency bands while no significant changes were observed in gamma and theta frequency ranges. It has been observed that when the music stimulus is removed, arousal activities as evident from alpha brain rhythms remain for some time, showing residual arousal. This is analogous to the conventional 'Hysteresis' loop where the system retains some 'memory' of the former state. This is corroborated in the non linear analysis (Detrended Fluctuation Analysis) of the alpha rhythms as manifested in values of fractal dimension. After an input of music conveying contrast emotions, withdrawal of music shows more retention as evidenced by the values of fractal dimension.

  20. The brain as a distributed intelligent processing system: an EEG study.

    Directory of Open Access Journals (Sweden)

    Armando Freitas da Rocha

    Full Text Available BACKGROUND: Various neuroimaging studies, both structural and functional, have provided support for the proposal that a distributed brain network is likely to be the neural basis of intelligence. The theory of Distributed Intelligent Processing Systems (DIPS, first developed in the field of Artificial Intelligence, was proposed to adequately model distributed neural intelligent processing. In addition, the neural efficiency hypothesis suggests that individuals with higher intelligence display more focused cortical activation during cognitive performance, resulting in lower total brain activation when compared with individuals who have lower intelligence. This may be understood as a property of the DIPS. METHODOLOGY AND PRINCIPAL FINDINGS: In our study, a new EEG brain mapping technique, based on the neural efficiency hypothesis and the notion of the brain as a Distributed Intelligence Processing System, was used to investigate the correlations between IQ evaluated with WAIS (Wechsler Adult Intelligence Scale and WISC (Wechsler Intelligence Scale for Children, and the brain activity associated with visual and verbal processing, in order to test the validity of a distributed neural basis for intelligence. CONCLUSION: The present results support these claims and the neural efficiency hypothesis.

  1. Brain's reward circuits mediate itch relief. a functional MRI study of active scratching.

    Directory of Open Access Journals (Sweden)

    Alexandru D P Papoiu

    Full Text Available Previous brain imaging studies investigating the brain processing of scratching used an exogenous intervention mimicking scratching, performed not by the subjects themselves, but delivered by an investigator. In real life, scratching is a conscious, voluntary, controlled motor response to itching, which is directed to the perceived site of distress. In this study we aimed to visualize in real-time by brain imaging the core mechanisms of the itch-scratch cycle when scratching was performed by subjects themselves. Secondly, we aimed to assess the correlations between brain patterns of activation and psychophysical ratings of itch relief or pleasurability of scratching. We also compared the patterns of brain activity evoked by self-scratching vs. passive scratching. We used a robust tridimensional Arterial Spin Labeling fMRI technique that is less sensitive to motion artifacts: 3D gradient echo and spin echo (GRASE--Propeller. Active scratching was accompanied by a higher pleasurability and induced a more pronounced deactivation of the anterior cingulate cortex and insula, in comparison with passive scratching. A significant involvement of the reward system including the ventral tegmentum of the midbrain, coupled with a mechanism deactivating the periaqueductal gray matter (PAG, suggests that itch modulation operates in reverse to the mechanism known to suppress pain. Our findings not only confirm a role for the central networks processing reward in the pleasurable aspects of scratching, but also suggest they play a role in mediating itch relief.

  2. Dysfunctional whole brain networks in mild cognitive impairment patients: an fMRI study

    Science.gov (United States)

    Liu, Zhenyu; Bai, Lijun; Dai, Ruwei; Zhong, Chongguang; Xue, Ting; You, Youbo; Tian, Jie

    2012-03-01

    Mild cognitive impairment (MCI) was recognized as the prodromal stage of Alzheimer's disease (AD). Recent researches have shown that cognitive and memory decline in AD patients is coupled with losses of small-world attributes. However, few studies pay attention to the characteristics of the whole brain networks in MCI patients. In the present study, we investigated the topological properties of the whole brain networks utilizing graph theoretical approaches in 16 MCI patients, compared with 18 age-matched healthy subjects as a control. Both MCI patients and normal controls showed small-world architectures, with large clustering coefficients and short characteristic path lengths. We detected significantly longer characteristic path length in MCI patients compared with normal controls at the low sparsity. The longer characteristic path lengths in MCI indicated disrupted information processing among distant brain regions. Compared with normal controls, MCI patients showed decreased nodal centrality in the brain areas of the angular gyrus, heschl gyrus, hippocampus and superior parietal gyrus, while increased nodal centrality in the calcarine, inferior occipital gyrus and superior frontal gyrus. These changes in nodal centrality suggested a widespread rewiring in MCI patients, which may be an integrated reflection of reorganization of the brain networks accompanied with the cognitive decline. Our findings may be helpful for further understanding the pathological mechanisms of MCI.

  3. Sonographic evaluation of overall and regional vascularization of fetal brain: a preliminary methodological study

    Directory of Open Access Journals (Sweden)

    M. Oberto

    2011-01-01

    Full Text Available The aim of this preliminary study is to develop a methodology to evaluate the vascularization of fetal brain in normal and abnormal canditions by three-dimensional sonography associated to Power Doppler (3DPD, with application of Virtual Organ Computer-aided Analysis (VOCAL that allows to derive vascularization and flow indexes. In this connction, we propose a new method of standardization of the setting and the acquisition mode, choosing in different fetuses and at different gestational ages the same anatomical volumes, corresponding to five spherical regions of interest. In particular, tu study the overall vascularization of the fetal brain, we use a sphere with a diameter corresponding to the bi-parietal distance. To evaluate the regional vascularization, we identify four sampling spherical sites, two in each hemisphere. This standard technical approach according to correct morphological criteria allows to exclude from the analysis vascular territories external to the brain.

  4. Experimental studies on local radiation injuries of the brain as a result of sup(99m)Tc penetration through the blood-brain barrier

    Energy Technology Data Exchange (ETDEWEB)

    Zolotov, V.A.; Lomanov, M.F.; Luk' yashin, V.E.; Shimchuk, G.G.; Minakova, E.I.; Lundkvist, Kh.; Rozander, Ch. (Gosudarstvennyj Komitet po Ispol' zovaniyu Atomnoj Ehnergii SSSR, Moscow. Inst. Teoreticheskoj i Ehksperimental' noj Fiziki; Akademiya Meditsinskikh Nauk SSSR, Moscow. Inst. Nevrologii)

    1982-07-01

    Studies on the blood-brain barrier have shown that disturbance of its permeability with reference to some dyes and radioactive tracers precedes histological changes found in the brain tissues. The paper is concerned with the techniques of detection of early changes in the blood-brain barrier during life-time after local irradiation of the brain with the proton beam, 5-7 mm in diameter. The use of sup(99m)Tc-pertechnate makes it possible to give a qualitative evaluation of the time course of radiation reactions in animals and to gain quite rapidly experimental data on the development of radiation injuries without killing large groups of experimental animals.

  5. The effect of somatic disorders on brain aging and dementia : Findings from population studies

    OpenAIRE

    Atti, Anna Rita

    2009-01-01

    This doctoral thesis investigates the effect of somatic disorders on dementia, Alzheimer s disease (AD) and brain aging in late-life. The data for the studies are provided by the Kungsholmen Project (Studies I and II) and the Faenza Project (Studies III and IV). The Kungsholmen Project is a population-based longitudinal study on aging and dementia carried out on 75+ years old people, living in Stockholm, Sweden. The Faenza Project is a cross-sectional population-based study ...

  6. Type 2 diabetes is not a risk factor for asymptomatic ischemic brain lesion. The Funagata study

    International Nuclear Information System (INIS)

    The purpose of this study is to clarify whether type 2 diabetes (DM) is a risk factor for asymptomatic (silent) ischemic brain lesion, which is controversial at present. The subjects (n=187), who showed normal results on both neurological and neuropsychological examinations, underwent a 75-g OGTT and were examined by brain MRI on T1-weighted, T2-weighted, and FLAIR (fluid-attenuated inversion recovery) images. Their brain MRIs were evaluated quantitatively with the ischemia rating scale defined here. The subjects were grouped based on their glucose tolerance: normal glucose tolerance (NGT) (n=48), impaired glucose tolerance (IGT) (n=62), and DM (n=65). The subjects with DM were further divided based on their duration of illness: 20 with short duration (short DM: 1.3±0.8 years) and 45 with long duration (long DM; 8.9±5.4 years). Ages were matched among the groups. The percentages of individuals with asymptomatic ischemic brain lesion were 81% in NGT, 74% in IGT, 65% in short DM, and 78% in long DM. No significant difference was observed among the groups in terms of the percentage. Namely, even in individuals with a long history of DM without clinical stroke, the prevalence of asymptomatic ischemic brain lesion was not different from that of the other groups. Multiple regression and multiple logistic regression analyses showed that age and hypertension were significant independent risk factors for asymptomatic ischemic brain lesion, whereas hypercholesterolemia, smoking, and glucose intolerance, including IGT, short DM and long DM, were not. DM is not a risk factor for asymptomatic ischemic brain lesion. (author)

  7. Type 2 diabetes is not a risk factor for asymptomatic ischemic brain lesion. The Funagata study

    Energy Technology Data Exchange (ETDEWEB)

    Saitoh, Tamotsu; Daimon, Makoto; Eguchi, Hideyuki; Hosoya, Takaaki; Kawanami, Toru; Kurita, Keiji; Tominaga, Makoto; Kato, Takeo [Yamagata Univ. (Japan). School of Medicine

    2002-05-01

    The purpose of this study is to clarify whether type 2 diabetes (DM) is a risk factor for asymptomatic (silent) ischemic brain lesion, which is controversial at present. The subjects (n=187), who showed normal results on both neurological and neuropsychological examinations, underwent a 75-g OGTT and were examined by brain MRI on T1-weighted, T2-weighted, and FLAIR (fluid-attenuated inversion recovery) images. Their brain MRIs were evaluated quantitatively with the ischemia rating scale defined here. The subjects were grouped based on their glucose tolerance: normal glucose tolerance (NGT) (n=48), impaired glucose tolerance (IGT) (n=62), and DM (n=65). The subjects with DM were further divided based on their duration of illness: 20 with short duration (short DM: 1.3{+-}0.8 years) and 45 with long duration (long DM; 8.9{+-}5.4 years). Ages were matched among the groups. The percentages of individuals with asymptomatic ischemic brain lesion were 81% in NGT, 74% in IGT, 65% in short DM, and 78% in long DM. No significant difference was observed among the groups in terms of the percentage. Namely, even in individuals with a long history of DM without clinical stroke, the prevalence of asymptomatic ischemic brain lesion was not different from that of the other groups. Multiple regression and multiple logistic regression analyses showed that age and hypertension were significant independent risk factors for asymptomatic ischemic brain lesion, whereas hypercholesterolemia, smoking, and glucose intolerance, including IGT, short DM and long DM, were not. DM is not a risk factor for asymptomatic ischemic brain lesion. (author)

  8. An Ultra-High Field Magnetic Resonance Spectroscopy Study of Post Exercise Lactate, Glutamate and Glutamine Change in the Human Brain

    OpenAIRE

    Dennis, Andrea; Thomas, Adam G.; Rawlings, Nancy B.; Near, Jamie; Nichols, Thomas E.; Clare, Stuart; Johansen-Berg, Heidi; Stagg, Charlotte J.

    2015-01-01

    During strenuous exercise there is a progressive increase in lactate uptake and metabolism into the brain as workload and plasma lactate levels increase. Although it is now widely accepted that the brain can metabolize lactate, few studies have directly measured brain lactate following vigorous exercise. Here, we used ultra-high field magnetic resonance spectroscopy of the brain to obtain static measures of brain lactate, as well as brain glutamate and glutamine after vigorous exercise. The a...

  9. 采用CT技术研究颅脑损伤患者的早期神经功能恢复:脑水肿和脑肿胀的比较%CT study of patients neurological function recovery in the acute stage of brain injury:compared brain swelling and brain edema

    Institute of Scientific and Technical Information of China (English)

    李龙; 池晓宇; 黄新才; 刘卫国; 蒋德清

    2002-01-01

    @@ ckground: Secondary clinical manifestations following brain injury may be due to either intracranial hemorrhage or brain edema and brain swelling.But brain swelling hasn't been understand adequately in clinical practice.Objective: 71 patients with brain edema or brain swelling following brain injury admitted to our hospital during Jan 1998 to Dec 1999 were selected for this study.Their CT findings were compared,and CT characters of traumatic brain swelling and neurological function reco