The Experts below are selected from a list of 825 Experts worldwide ranked by ideXlab platform
Boris Labar - One of the best experts on this subject based on the ideXlab platform.
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Thiorphan an inhibitor of neutral endopeptidase enkephalinase cd10 calla enhances cell proliferation in bone marrow cultures of patients with acute leukemia in remission
Haematologia, 2000Co-Authors: Silvana Stanovic, Milivoj Boranic, Mladen Petrovecki, Drago Batinic, Jasna Skodlar, Damir Nemet, Boris LabarAbstract:Thiorphan, (DL-mercapto-2-benzylpropanoyl)-glycine is a potent and specific inhibitor of membrane metallo-endopeptidase (EC 3.4.24.11, CD10). We explored its effects in short-term clonal cultures of the bone marrow from 10 patients with acute leukemia in remission. The cell suspensions were incubated with Thiorphan (10-13 to 10-5 M) and seeded for the granulocyte/macrophage-colony forming unit (GM-CFU) assay. In normal bone marrow samples the median seeding efficiency was 119 colonies and clusters per 105 cells and Thiorphan caused slight stimulation of the clonal growth in concentrations above 10-9 M. In the leukemic samples, the median seeding efficiency varied from 10 to 366 colonies and clusters per 105 seeded cells. Meaningful alterations of the clonal growth were noted in 32 out of 83 Thiorphan-treated cultures (39%). In those 32 cultures the stimulatory effects outnumbered the inhibitory effects (24 versus 8). Thus, Thiorphan stimulated the progenitor cell proliferation in bone marrow samples from the normal donor and from the patients with acute leukemia in remission. Thiorphan binding to CD10 might interfere with the processing of neuropeptide hemoregulatory factors and thus influence the progenitor cell proliferation.
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Thiorphan stimulates clonal growth of gm cfu in short term cultures of bone marrow from a healthy donor and from patients with non hodgkin lymphoma
Biomedicine & Pharmacotherapy, 1998Co-Authors: Silvana Stanovic, Mladen Petrovecki, Drago Batinic, Jasna Skodlar, Damir Nemet, M Boranic, Branka Golubiccepulic, Boris LabarAbstract:Summary Thiorphan, a specific inhibitor of membrane neutral endopeptidase (NEP, EC 3.4.24.11) also known as the common acute lymphoblastic leukemia antigen (CALLA, CD 10) was added into short-term clonal cultures of the buffy coat concentrates of human bone marrow obtained from a healthy donor (six experiments) and from ten patients with non-Hodgkin lymphoma (NHL) (eight in complete remission, one in partial remission and one in relapse). Thiorphan concentrations ranged from 10 −5 to 10 −13 M. Nanomolar and higher concentrations of the drug mildly stimulated the granulocyte-macrophage colony-forming unit (GM-CFU) counts in the cultures of normal bone marrow, reaching the significance at 10 −7 M. Meaningful alterations of the GM-CFU counts were noted in 31 of 79 Thiorphan-treated cultures of NHL bone marrow (39%). In those cultures the stimulatory effects (33%) outnumbered the inhibitory ones (6%). The stimulatory effects occurred mainly in the bone marrow samples of the patients with highly malignant NHL. The observations are compatible with the idea that the membrane endopeptidase (CALLA, CD10) participates in processes controlling the proliferation and differentiation of hematopoetic cells by cleaving the neuropeptides and related hemoregulatory peptides.
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Thiorphan stimulates clonal growth of gm cfu in short term cultures of bone marrow from patients with acute leukemia
1997 Annual Meeting of the Croatian Immunological Society, 1997Co-Authors: Silvana Stanovic, Mladen Petrovecki, Drago Batinic, Jasna Skodlar, Damir Nemet, Boris Labar, Milivoj BoranicAbstract:Thiorphan is a potent and specific inhibitor of neutral endopeptidase (membrane metallo-endopeptidase, EC 3.4.24.11). That enzyme, also known as the cell surface marker CD10/CALLA is expressed on many cells in various tissues, including the lymphoid tissue and bone marrow. Potential therapeutic applications of Thiorphan include managment of pain, depression, diarrhoea, asthma and hypertension. However, its effects on the human hematopoietic cells have not been investigated. Here we report the effects of Thiorphan in short-term GM-CFU clonal cultures of the bone marrow from 10 patients with acute leukemia. All patients were in complete remission (6 in the first and 4 in the second remmision). At the time of diagnosis, cytomorphological analysis of the bone marrow smears from the patients has shown 7 acute lymphoblastic leukemias (5 patients with L2 type and 2 with L1 type), 2 acute myeloblastic leukemias (1 patient with M1-M2 type and 1 with M2 type) and 1 myelodysplastic syndrome (1 patient with RAEB-t), The immunophenotyping revealed a high content of CD10+ cells in 3 patients (>30% CD10+ cells), medium in 3 patients (15-30% CD10+ cells) and low in 2 patients (0-15% CD10+ cells). Two patients have not been immunophenotyped. The median seeding efficiency of the specimens in the control groups without Thiorphan varied from 10 to 366 colonies and clusters per 105 seeded cells. In order to make the results comparable, GM-CFUs counts in Thiorphan-treated triplicate cultures of each patient were expressed as the percentages of the median count in the control, Thiorphan-free triplicate cultures of that patient. Final concentrations of Thiorphan in the cultures ranged from 10-5 to 10-13 M. Based on the statistical analysis of the data scatter, alterations of the clonal growth for 15 percent or more above or below the control counts were considered meaningful. These criteria were fulfilled in 32 out of 83 Thiorphan-treated cultures (41 percent). In those cultures the stimulatory effects outnumbered the inhibitory ones (24 versus 8). The significance of the observations was confirmed by the c2-test (c2=8,0, p<0,005 with 1 level of freedom). The stimulatory effects of Thiorphan occurred predominantly in bone marrow samples of the patients with T-ALL or with myeloid-type AL, whereas the bone marrow cultures of the patients with 'common'-type ALL were almost refractory. Thiorphan effects on the hematopoietic cells may be attributed to its interactions with the membrane metallo-endopeptidase (the CD10/CALLA marker) resulting in direct and/or indirect interference with cell proliferation.
Nobuhisa Iwata - One of the best experts on this subject based on the ideXlab platform.
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inhibition of neprilysin by infusion of Thiorphan into the hippocampus causes an accumulation of amyloid β and impairment of learning and memory
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: Li Bo Zou, Akihiro Mouri, Nobuhisa Iwata, Takaomi C Saido, Dayong Wang, Min Wei Wang, Yukihiro Noda, Hiroyuki Mizoguchi, Toshitaka NabeshimaAbstract:An imbalance between anabolism and catabolism causes an accumulation of amyloid β-peptide (Aβ), which is a proposed trigger of the onset of Alzheimer9s disease. Neprilysin is a rate-limiting peptidase that participates in the catabolism of Aβ in the brain. We examined whether rats continuously infused with Thiorphan, a specific neprilysin inhibitor, into the hippocampus develop cognitive impairments through accumulation of Aβ. Thiorphan infusion elevated hippocampal Aβ40 and Aβ42 levels in the insoluble but not the soluble fraction. Thiorphan-infused rats displayed cognitive impairments in the ability to discriminate in the object recognition test, associative learning in the conditioned fear learning test, and spatial memory in the water maze test, tasks that depend on the hippocampus. These cognitive abilities in the battery of behavioral tasks inversely correlated with insoluble Aβ contents in the hippocampus. The nicotine-stimulated release of acetylcholine in the hippocampus of Thiorphan-infused rats was significantly lower than that in vehicle-infused rats. These results indicate that continuous infusion of Thiorphan into the hippocampus causes cognitive dysfunction and reduces cholinergic activity by raising the level of Aβ in the hippocampus and suggest that a reduction of neprilysin activity contributes to the deposition of Aβ and development of Alzheimer9s disease.
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inhibition of neprilysin by Thiorphan i c v causes an accumulation of amyloid β and impairment of learning and memory
Behavioural Brain Research, 2006Co-Authors: Akihiro Mouri, Li Bo Zou, Nobuhisa Iwata, Takaomi C Saido, Dayong Wang, Min Wei Wang, Yukihiro Noda, Toshitaka NabeshimaAbstract:An accumulation of amyloid β peptide (Aβ) due to an imbalance between anabolism and catabolism triggers Alzheimer's disease (AD). Neprilysin is a rate-limiting peptidase, which participates in the catabolism of Aβ in brain. We investigated whether rats continuously infused with Thiorphan, a specific inhibitor for neprilysin, into the cerebral ventricle cause cognitive dysfunction, with an accumulation of Aβ in the brain. Thiorphan-infused rats displayed significant cognitive dysfunction in the ability to discriminate in the object recognition test and spatial memory in the water maze test, but not in other hippocampus-dependent learning and memory tasks. Thiorphan infusion also elevated the Aβ40 level in the insoluble fraction of the cerebral cortex, but not that of the hippocampus. There was no significant difference in the nicotine-stimulated release of acetylcholine in the hippocampus between vehicle- and Thiorphan-infused rats. These results indicate that continuous infusion of Thiorphan into the cerebral ventricle causes cognitive dysfunction by raising the level of Aβ in the cerebral cortex, and suggest that a reduction of neprilysin activity contribute to the deposition of Aβ and development of AD.
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neprilysin degrades both amyloid beta peptides 1 40 and 1 42 most rapidly and efficiently among Thiorphan and phosphoramidon sensitive endopeptidases
Journal of Biological Chemistry, 2001Co-Authors: Keiro Shirotani, Nobuhisa Iwata, Satoshi Tsubuki, Yoshie Takaki, Wakako Harigaya, Kei Maruyama, Sumiko Kiryuseo, Hiroshi Kiyama, Hiroshi Iwata, Taisuke TomitaAbstract:To identify the amyloid beta peptide (Abeta) 1-42-degrading enzyme whose activity is inhibited by Thiorphan and phosphoramidon in vivo, we searched for neprilysin (NEP) homologues and cloned neprilysin-like peptidase (NEPLP) alpha, NEPLP beta, and NEPLP gamma cDNAs. We expressed NEP, phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PEX), NEPLPs, and damage-induced neuronal endopeptidase (DINE) in 293 cells as 95- to 125-kDa proteins and found that the enzymatic activities of PEX, NEPLP alpha, and NEPLP beta, as well as those of NEP and DINE, were sensitive to Thiorphan and phosphoramidon. Among the peptidases tested, NEP degraded both synthetic and cell-secreted Abeta1-40 and Abeta1-42 most rapidly and efficiently. PEX degraded cold Abeta1-40 and NEPLP alpha degraded both cold Abeta1-40 and Abeta1-42, although the rates and the extents of the digestion were slower and less efficient than those exhibited by NEP. These data suggest that, among the endopeptidases whose activities are sensitive to Thiorphan and phosphoramidon, NEP is the most potent Abeta-degrading enzyme in vivo. Therefore, manipulating the activity of NEP would be a useful approach in regulating Abeta levels in the brain.
Maria Gabriella Matera - One of the best experts on this subject based on the ideXlab platform.
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contribution of sensory nerves to lps induced hyperresponsiveness of human isolated bronchi
Life Sciences, 2015Co-Authors: Luigino Calzetta, Livio Luongo, Mario Cazzola, Clive P Page, Paola Rogliani, Francesco Facciolo, Sabatino Maione, Annalisa Capuano, Barbara Rinaldi, Maria Gabriella MateraAbstract:Abstract Aims Bacterial lipopolysaccharide (LPS) can induce bronchial hyperresponsiveness (BHR), but the underlying mechanisms remain to be determined. Here, the possible contribution of sensory nerves to LPS-induced BHR was examined in human isolated bronchi to pharmacologically identify the mechanisms underlying this phenomenon. Main methods Human isolated bronchial tone was induced by electrical field stimulation (EFS). The responses of airways to LPS, with or without capsaicin desensitization or Thiorphan treatment were studied and the transient receptor potential vanilloid type 1 (TRPV1) expression was assessed. We performed similar experiments in the presence of a TRPV1 or a neurokinin (NK) 2 receptor antagonist using SB366791 and GR159897, respectively. Key findings LPS increased (≃ 2.3-fold, P 0.05) the EFS contractile response, nor after treatment with Thiorphan. Capsaicin desensitization reduced (≃ 0.4-fold, P Significance Our results demonstrate the involvement of capsaicin-sensitive sensory nerves and neutral endopeptidases in LPS-induced BHR of the human bronchi, associated with an upregulation of TRPV1 and release of NKA.
Silvana Stanovic - One of the best experts on this subject based on the ideXlab platform.
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Thiorphan an inhibitor of neutral endopeptidase enkephalinase cd10 calla enhances cell proliferation in bone marrow cultures of patients with acute leukemia in remission
Haematologia, 2000Co-Authors: Silvana Stanovic, Milivoj Boranic, Mladen Petrovecki, Drago Batinic, Jasna Skodlar, Damir Nemet, Boris LabarAbstract:Thiorphan, (DL-mercapto-2-benzylpropanoyl)-glycine is a potent and specific inhibitor of membrane metallo-endopeptidase (EC 3.4.24.11, CD10). We explored its effects in short-term clonal cultures of the bone marrow from 10 patients with acute leukemia in remission. The cell suspensions were incubated with Thiorphan (10-13 to 10-5 M) and seeded for the granulocyte/macrophage-colony forming unit (GM-CFU) assay. In normal bone marrow samples the median seeding efficiency was 119 colonies and clusters per 105 cells and Thiorphan caused slight stimulation of the clonal growth in concentrations above 10-9 M. In the leukemic samples, the median seeding efficiency varied from 10 to 366 colonies and clusters per 105 seeded cells. Meaningful alterations of the clonal growth were noted in 32 out of 83 Thiorphan-treated cultures (39%). In those 32 cultures the stimulatory effects outnumbered the inhibitory effects (24 versus 8). Thus, Thiorphan stimulated the progenitor cell proliferation in bone marrow samples from the normal donor and from the patients with acute leukemia in remission. Thiorphan binding to CD10 might interfere with the processing of neuropeptide hemoregulatory factors and thus influence the progenitor cell proliferation.
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Thiorphan stimulates clonal growth of gm cfu in short term cultures of bone marrow from a healthy donor and from patients with non hodgkin lymphoma
Biomedicine & Pharmacotherapy, 1998Co-Authors: Silvana Stanovic, Mladen Petrovecki, Drago Batinic, Jasna Skodlar, Damir Nemet, M Boranic, Branka Golubiccepulic, Boris LabarAbstract:Summary Thiorphan, a specific inhibitor of membrane neutral endopeptidase (NEP, EC 3.4.24.11) also known as the common acute lymphoblastic leukemia antigen (CALLA, CD 10) was added into short-term clonal cultures of the buffy coat concentrates of human bone marrow obtained from a healthy donor (six experiments) and from ten patients with non-Hodgkin lymphoma (NHL) (eight in complete remission, one in partial remission and one in relapse). Thiorphan concentrations ranged from 10 −5 to 10 −13 M. Nanomolar and higher concentrations of the drug mildly stimulated the granulocyte-macrophage colony-forming unit (GM-CFU) counts in the cultures of normal bone marrow, reaching the significance at 10 −7 M. Meaningful alterations of the GM-CFU counts were noted in 31 of 79 Thiorphan-treated cultures of NHL bone marrow (39%). In those cultures the stimulatory effects (33%) outnumbered the inhibitory ones (6%). The stimulatory effects occurred mainly in the bone marrow samples of the patients with highly malignant NHL. The observations are compatible with the idea that the membrane endopeptidase (CALLA, CD10) participates in processes controlling the proliferation and differentiation of hematopoetic cells by cleaving the neuropeptides and related hemoregulatory peptides.
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Thiorphan stimulates clonal growth of gm cfu in short term cultures of bone marrow from patients with acute leukemia
1997 Annual Meeting of the Croatian Immunological Society, 1997Co-Authors: Silvana Stanovic, Mladen Petrovecki, Drago Batinic, Jasna Skodlar, Damir Nemet, Boris Labar, Milivoj BoranicAbstract:Thiorphan is a potent and specific inhibitor of neutral endopeptidase (membrane metallo-endopeptidase, EC 3.4.24.11). That enzyme, also known as the cell surface marker CD10/CALLA is expressed on many cells in various tissues, including the lymphoid tissue and bone marrow. Potential therapeutic applications of Thiorphan include managment of pain, depression, diarrhoea, asthma and hypertension. However, its effects on the human hematopoietic cells have not been investigated. Here we report the effects of Thiorphan in short-term GM-CFU clonal cultures of the bone marrow from 10 patients with acute leukemia. All patients were in complete remission (6 in the first and 4 in the second remmision). At the time of diagnosis, cytomorphological analysis of the bone marrow smears from the patients has shown 7 acute lymphoblastic leukemias (5 patients with L2 type and 2 with L1 type), 2 acute myeloblastic leukemias (1 patient with M1-M2 type and 1 with M2 type) and 1 myelodysplastic syndrome (1 patient with RAEB-t), The immunophenotyping revealed a high content of CD10+ cells in 3 patients (>30% CD10+ cells), medium in 3 patients (15-30% CD10+ cells) and low in 2 patients (0-15% CD10+ cells). Two patients have not been immunophenotyped. The median seeding efficiency of the specimens in the control groups without Thiorphan varied from 10 to 366 colonies and clusters per 105 seeded cells. In order to make the results comparable, GM-CFUs counts in Thiorphan-treated triplicate cultures of each patient were expressed as the percentages of the median count in the control, Thiorphan-free triplicate cultures of that patient. Final concentrations of Thiorphan in the cultures ranged from 10-5 to 10-13 M. Based on the statistical analysis of the data scatter, alterations of the clonal growth for 15 percent or more above or below the control counts were considered meaningful. These criteria were fulfilled in 32 out of 83 Thiorphan-treated cultures (41 percent). In those cultures the stimulatory effects outnumbered the inhibitory ones (24 versus 8). The significance of the observations was confirmed by the c2-test (c2=8,0, p<0,005 with 1 level of freedom). The stimulatory effects of Thiorphan occurred predominantly in bone marrow samples of the patients with T-ALL or with myeloid-type AL, whereas the bone marrow cultures of the patients with 'common'-type ALL were almost refractory. Thiorphan effects on the hematopoietic cells may be attributed to its interactions with the membrane metallo-endopeptidase (the CD10/CALLA marker) resulting in direct and/or indirect interference with cell proliferation.
Toshitaka Nabeshima - One of the best experts on this subject based on the ideXlab platform.
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inhibition of neprilysin by infusion of Thiorphan into the hippocampus causes an accumulation of amyloid β and impairment of learning and memory
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: Li Bo Zou, Akihiro Mouri, Nobuhisa Iwata, Takaomi C Saido, Dayong Wang, Min Wei Wang, Yukihiro Noda, Hiroyuki Mizoguchi, Toshitaka NabeshimaAbstract:An imbalance between anabolism and catabolism causes an accumulation of amyloid β-peptide (Aβ), which is a proposed trigger of the onset of Alzheimer9s disease. Neprilysin is a rate-limiting peptidase that participates in the catabolism of Aβ in the brain. We examined whether rats continuously infused with Thiorphan, a specific neprilysin inhibitor, into the hippocampus develop cognitive impairments through accumulation of Aβ. Thiorphan infusion elevated hippocampal Aβ40 and Aβ42 levels in the insoluble but not the soluble fraction. Thiorphan-infused rats displayed cognitive impairments in the ability to discriminate in the object recognition test, associative learning in the conditioned fear learning test, and spatial memory in the water maze test, tasks that depend on the hippocampus. These cognitive abilities in the battery of behavioral tasks inversely correlated with insoluble Aβ contents in the hippocampus. The nicotine-stimulated release of acetylcholine in the hippocampus of Thiorphan-infused rats was significantly lower than that in vehicle-infused rats. These results indicate that continuous infusion of Thiorphan into the hippocampus causes cognitive dysfunction and reduces cholinergic activity by raising the level of Aβ in the hippocampus and suggest that a reduction of neprilysin activity contributes to the deposition of Aβ and development of Alzheimer9s disease.
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inhibition of neprilysin by Thiorphan i c v causes an accumulation of amyloid β and impairment of learning and memory
Behavioural Brain Research, 2006Co-Authors: Akihiro Mouri, Li Bo Zou, Nobuhisa Iwata, Takaomi C Saido, Dayong Wang, Min Wei Wang, Yukihiro Noda, Toshitaka NabeshimaAbstract:An accumulation of amyloid β peptide (Aβ) due to an imbalance between anabolism and catabolism triggers Alzheimer's disease (AD). Neprilysin is a rate-limiting peptidase, which participates in the catabolism of Aβ in brain. We investigated whether rats continuously infused with Thiorphan, a specific inhibitor for neprilysin, into the cerebral ventricle cause cognitive dysfunction, with an accumulation of Aβ in the brain. Thiorphan-infused rats displayed significant cognitive dysfunction in the ability to discriminate in the object recognition test and spatial memory in the water maze test, but not in other hippocampus-dependent learning and memory tasks. Thiorphan infusion also elevated the Aβ40 level in the insoluble fraction of the cerebral cortex, but not that of the hippocampus. There was no significant difference in the nicotine-stimulated release of acetylcholine in the hippocampus between vehicle- and Thiorphan-infused rats. These results indicate that continuous infusion of Thiorphan into the cerebral ventricle causes cognitive dysfunction by raising the level of Aβ in the cerebral cortex, and suggest that a reduction of neprilysin activity contribute to the deposition of Aβ and development of AD.
