The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Eric Mayoux - One of the best experts on this subject based on the ideXlab platform.
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the sodium glucose cotransporter type 2 inhibitor empagliflozin preserves β Cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Henrik H Hansen, Thomas Klein, Michael Mark, Jacob Jelsing, Carl Frederik Hansen, Gitte Hansen, Niels Vrang, Eric MayouxAbstract:Type 2 diabetes is characterized by impaired β-Cell function associated with progressive reduction of insulin secretion and β-Cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-Cell Protection and anti-diabetic efficacy. Through an insulin and β-Cell independent mechanism, empagliflozin, a specific sodium glucose co-transporter type-2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the anti-diabetic durability of empagliflozin treatment (10 mg/kg, p.o.) against glibenclamide (3 mg/kg, p.o.) and liraglutide (0.2 mg/kg, s.c.) on deficient glucose homeostasis and β-Cell function in Zucker diabetic Fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and HbA1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared to week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by a less reduction in β-Cell mass with empagliflozin or liraglutide at week 4, while only empagliflozin showed β-Cell sparing effects at week 8. While this study cannot be used to dissociate the absolute anti-diabetic efficacy among those different mechanisms of action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-Cell Protection ZDF rats. In comparison to other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-Cell Protection and anti-diabetic efficacy.
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the sodium glucose cotransporter type 2 inhibitor empagliflozin preserves β Cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Henrik H Hansen, Thomas Klein, Michael Mark, Jacob Jelsing, Carl Frederik Hansen, Gitte Hansen, Niels Vrang, Eric MayouxAbstract:Type 2 diabetes is characterized by impaired β-Cell function associated with progressive reduction of insulin secretion and β-Cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-Cell Protection and antidiabetic efficacy. Through an insulin and β Cell-independent mechanism, empagliflozin, a specific sodium glucose cotransporter type 2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the antidiabetic durability of empagliflozin treatment (10 mg/kg p.o.) against glibenclamide (3 mg/kg p.o.) and liraglutide (0.2 mg/kg s.c.) on deficient glucose homeostasis and β-Cell function in Zucker diabetic fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and hemoglobin A1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared with week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by less reduction in β-Cell mass with empagliflozin or liraglutide at week 4, whereas only empagliflozin showed β-Cell sparing effects also at week 8. Although this study cannot be used to dissociate the absolute antidiabetic efficacy among the different mechanisms of drug action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-Cell Protection in the ZDF rat. In comparison with other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-Cell Protection and antidiabetic efficacy.
Eliot M. Rosen - One of the best experts on this subject based on the ideXlab platform.
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role of src signal transduction pathways in scatter factor mediated Cellular Protection
Journal of Biological Chemistry, 2009Co-Authors: Qinghui Meng, John Laterra, Eliot M. RosenAbstract:Scatter factor (SF) (hepatocyte growth factor) is a pleiotrophic cytokine that accumulates in tumors, where it may induce invasion, angiogenesis, and chemoresistance. We have studied the mechanisms by which SF and its receptor (c-Met) protect Cells against the DNA-damaging agent adriamycin (ADR) as a model for chemoresistance of SF/c-Met-overexpressing tumors. Previous studies identified a phosphatidylinositol 3-kinase/c-Akt/Pak1/NF-κB Cell survival pathway in DU-145 prostate cancer and Madin-Darby canine kidney epithelial Cells. Here we studied Src signaling pathways involved in SF Cell Protection. Src enhanced basal and SF stimulated NF-κB activity and SF Protection against ADR, in a manner dependent upon its kinase and Src homology 3 domains; and endogenous Src was required for SF stimulation of NF-κB activity and Cell Protection. The ability of Src to enhance SF stimulation of NF-κB activity was due, in part, to its ability to stimulate Akt and IκB kinase activity; and Src-mediated stimulation of NF-κB was due, in part, to a Rac1/MKK3/6/p38 pathway and was Akt-dependent. SF caused the activation of Src and the Rac1 effector Pak1. Furthermore, SF induced activating phosphorylations of MKK3, MKK6, and p38 within the c-Met signalsome in an Src-dependent manner. The NF-κB-inducing kinase was found to act downstream of TAK1 (transforming growth factor-β-activated kinase 1) as a mediator of SF- and Src-stimulated NF-κB activity. Finally, the Src/Rac1/MKK3/6/p38 and Src/TAK1/NF-κB-inducing kinase pathways exhibited cross-talk at the level of MKK3. These findings delineate some novel signaling pathways for SF-mediated resistance to ADR.
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role of nf κb signaling in hepatocyte growth factor scatter factor mediated Cell Protection
Oncogene, 2005Co-Authors: Qinghui Meng, Itzhak D Goldberg, John Laterra, Sal Coniglio, Marc Symons, Richard G Pestell, Eliot M. RosenAbstract:The cytokine scatter factor/hepatocyte growth factor (HGF/SF) protects epithelial, carcinoma, and other Cell types against cytotoxicity and apoptosis induced by DNA-damaging agents such as ionizing radiation and adriamycin (ADR, a topoisomerase IIα inhibitor). We investigated the role of nuclear factor kappa B (NF-κB) signaling in HGF/SF-mediated Protection of human prostate cancer (DU-145) and Madin–Darby canine kidney (MDCK) epithelial Cells against ADR. HGF/SF caused the rapid nuclear translocation of the p65 (RelA) subunit of NF-κB associated with the transient loss of the inhibitory subunit IκB-α. Exposure to HGF/SF caused the activation of an NF-κB luciferase reporter that was blocked or attenuated by the expression of a mutant ‘super-repressor’ IκB-α. Electrophoretic mobility shift assay supershift assays revealed that HGF/SF treatment induced the transient binding of various NF-κB family proteins (p65, p50, c-Rel, and RelB) with radiolabeled NF-κB-binding oligonucleotides. The HGF/SF-mediated Protection of DU-145 and MDCK Cells against ADR (demonstrated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays) was abrogated by the IκB-α super-repressor. The ability of HGF/SF to activate NF-κB signaling was dependent on c-Akt → Pak1 (p21-associated kinase-1) signaling (with Pak1 downstream of c-Akt) and was inhibited by the tumor suppressor PTEN (phosphatase and tensin homolog). Inhibitors of phosphatidylinositol-3′-kinase and Src family kinases significantly inhibited HGF/SF-mediated activation of NF-κB, while inhibitors of MEK, protein kinase C, and p70 S6 kinase had a modest effect or no effect on NF-κB activity. HGF/SF induced the expression of several known NF-κB target genes (cIAP-1 (Cellular inhibitor of apoptosis-1), cIAP-2, and TRAF-2 (TNF receptor-associated factor-2)) in an NF-κB-dependent manner; HGF/SF blocked the inhibition of expression of these genes by ADR. Experimental manipulation of expression of these genes suggests that they (particularly TRAF-2 and cIAP-2) contribute to the Protection against ADR by HGF/SF. These findings suggest that HGF/SF activates NF-κB through a c-Akt → Pak1 signaling pathway that is also dependent on Src, and that NF-κB contributes to HGF/SF-mediated Protection against ADR.
Henrik H Hansen - One of the best experts on this subject based on the ideXlab platform.
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the sodium glucose cotransporter type 2 inhibitor empagliflozin preserves β Cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Henrik H Hansen, Thomas Klein, Michael Mark, Jacob Jelsing, Carl Frederik Hansen, Gitte Hansen, Niels Vrang, Eric MayouxAbstract:Type 2 diabetes is characterized by impaired β-Cell function associated with progressive reduction of insulin secretion and β-Cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-Cell Protection and anti-diabetic efficacy. Through an insulin and β-Cell independent mechanism, empagliflozin, a specific sodium glucose co-transporter type-2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the anti-diabetic durability of empagliflozin treatment (10 mg/kg, p.o.) against glibenclamide (3 mg/kg, p.o.) and liraglutide (0.2 mg/kg, s.c.) on deficient glucose homeostasis and β-Cell function in Zucker diabetic Fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and HbA1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared to week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by a less reduction in β-Cell mass with empagliflozin or liraglutide at week 4, while only empagliflozin showed β-Cell sparing effects at week 8. While this study cannot be used to dissociate the absolute anti-diabetic efficacy among those different mechanisms of action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-Cell Protection ZDF rats. In comparison to other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-Cell Protection and anti-diabetic efficacy.
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the sodium glucose cotransporter type 2 inhibitor empagliflozin preserves β Cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Henrik H Hansen, Thomas Klein, Michael Mark, Jacob Jelsing, Carl Frederik Hansen, Gitte Hansen, Niels Vrang, Eric MayouxAbstract:Type 2 diabetes is characterized by impaired β-Cell function associated with progressive reduction of insulin secretion and β-Cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-Cell Protection and antidiabetic efficacy. Through an insulin and β Cell-independent mechanism, empagliflozin, a specific sodium glucose cotransporter type 2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the antidiabetic durability of empagliflozin treatment (10 mg/kg p.o.) against glibenclamide (3 mg/kg p.o.) and liraglutide (0.2 mg/kg s.c.) on deficient glucose homeostasis and β-Cell function in Zucker diabetic fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and hemoglobin A1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared with week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by less reduction in β-Cell mass with empagliflozin or liraglutide at week 4, whereas only empagliflozin showed β-Cell sparing effects also at week 8. Although this study cannot be used to dissociate the absolute antidiabetic efficacy among the different mechanisms of drug action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-Cell Protection in the ZDF rat. In comparison with other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-Cell Protection and antidiabetic efficacy.
Qinghui Meng - One of the best experts on this subject based on the ideXlab platform.
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role of src signal transduction pathways in scatter factor mediated Cellular Protection
Journal of Biological Chemistry, 2009Co-Authors: Qinghui Meng, John Laterra, Eliot M. RosenAbstract:Scatter factor (SF) (hepatocyte growth factor) is a pleiotrophic cytokine that accumulates in tumors, where it may induce invasion, angiogenesis, and chemoresistance. We have studied the mechanisms by which SF and its receptor (c-Met) protect Cells against the DNA-damaging agent adriamycin (ADR) as a model for chemoresistance of SF/c-Met-overexpressing tumors. Previous studies identified a phosphatidylinositol 3-kinase/c-Akt/Pak1/NF-κB Cell survival pathway in DU-145 prostate cancer and Madin-Darby canine kidney epithelial Cells. Here we studied Src signaling pathways involved in SF Cell Protection. Src enhanced basal and SF stimulated NF-κB activity and SF Protection against ADR, in a manner dependent upon its kinase and Src homology 3 domains; and endogenous Src was required for SF stimulation of NF-κB activity and Cell Protection. The ability of Src to enhance SF stimulation of NF-κB activity was due, in part, to its ability to stimulate Akt and IκB kinase activity; and Src-mediated stimulation of NF-κB was due, in part, to a Rac1/MKK3/6/p38 pathway and was Akt-dependent. SF caused the activation of Src and the Rac1 effector Pak1. Furthermore, SF induced activating phosphorylations of MKK3, MKK6, and p38 within the c-Met signalsome in an Src-dependent manner. The NF-κB-inducing kinase was found to act downstream of TAK1 (transforming growth factor-β-activated kinase 1) as a mediator of SF- and Src-stimulated NF-κB activity. Finally, the Src/Rac1/MKK3/6/p38 and Src/TAK1/NF-κB-inducing kinase pathways exhibited cross-talk at the level of MKK3. These findings delineate some novel signaling pathways for SF-mediated resistance to ADR.
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role of nf κb signaling in hepatocyte growth factor scatter factor mediated Cell Protection
Oncogene, 2005Co-Authors: Qinghui Meng, Itzhak D Goldberg, John Laterra, Sal Coniglio, Marc Symons, Richard G Pestell, Eliot M. RosenAbstract:The cytokine scatter factor/hepatocyte growth factor (HGF/SF) protects epithelial, carcinoma, and other Cell types against cytotoxicity and apoptosis induced by DNA-damaging agents such as ionizing radiation and adriamycin (ADR, a topoisomerase IIα inhibitor). We investigated the role of nuclear factor kappa B (NF-κB) signaling in HGF/SF-mediated Protection of human prostate cancer (DU-145) and Madin–Darby canine kidney (MDCK) epithelial Cells against ADR. HGF/SF caused the rapid nuclear translocation of the p65 (RelA) subunit of NF-κB associated with the transient loss of the inhibitory subunit IκB-α. Exposure to HGF/SF caused the activation of an NF-κB luciferase reporter that was blocked or attenuated by the expression of a mutant ‘super-repressor’ IκB-α. Electrophoretic mobility shift assay supershift assays revealed that HGF/SF treatment induced the transient binding of various NF-κB family proteins (p65, p50, c-Rel, and RelB) with radiolabeled NF-κB-binding oligonucleotides. The HGF/SF-mediated Protection of DU-145 and MDCK Cells against ADR (demonstrated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays) was abrogated by the IκB-α super-repressor. The ability of HGF/SF to activate NF-κB signaling was dependent on c-Akt → Pak1 (p21-associated kinase-1) signaling (with Pak1 downstream of c-Akt) and was inhibited by the tumor suppressor PTEN (phosphatase and tensin homolog). Inhibitors of phosphatidylinositol-3′-kinase and Src family kinases significantly inhibited HGF/SF-mediated activation of NF-κB, while inhibitors of MEK, protein kinase C, and p70 S6 kinase had a modest effect or no effect on NF-κB activity. HGF/SF induced the expression of several known NF-κB target genes (cIAP-1 (Cellular inhibitor of apoptosis-1), cIAP-2, and TRAF-2 (TNF receptor-associated factor-2)) in an NF-κB-dependent manner; HGF/SF blocked the inhibition of expression of these genes by ADR. Experimental manipulation of expression of these genes suggests that they (particularly TRAF-2 and cIAP-2) contribute to the Protection against ADR by HGF/SF. These findings suggest that HGF/SF activates NF-κB through a c-Akt → Pak1 signaling pathway that is also dependent on Src, and that NF-κB contributes to HGF/SF-mediated Protection against ADR.
Gitte Hansen - One of the best experts on this subject based on the ideXlab platform.
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the sodium glucose cotransporter type 2 inhibitor empagliflozin preserves β Cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Henrik H Hansen, Thomas Klein, Michael Mark, Jacob Jelsing, Carl Frederik Hansen, Gitte Hansen, Niels Vrang, Eric MayouxAbstract:Type 2 diabetes is characterized by impaired β-Cell function associated with progressive reduction of insulin secretion and β-Cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-Cell Protection and anti-diabetic efficacy. Through an insulin and β-Cell independent mechanism, empagliflozin, a specific sodium glucose co-transporter type-2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the anti-diabetic durability of empagliflozin treatment (10 mg/kg, p.o.) against glibenclamide (3 mg/kg, p.o.) and liraglutide (0.2 mg/kg, s.c.) on deficient glucose homeostasis and β-Cell function in Zucker diabetic Fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and HbA1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared to week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by a less reduction in β-Cell mass with empagliflozin or liraglutide at week 4, while only empagliflozin showed β-Cell sparing effects at week 8. While this study cannot be used to dissociate the absolute anti-diabetic efficacy among those different mechanisms of action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-Cell Protection ZDF rats. In comparison to other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-Cell Protection and anti-diabetic efficacy.
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the sodium glucose cotransporter type 2 inhibitor empagliflozin preserves β Cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Henrik H Hansen, Thomas Klein, Michael Mark, Jacob Jelsing, Carl Frederik Hansen, Gitte Hansen, Niels Vrang, Eric MayouxAbstract:Type 2 diabetes is characterized by impaired β-Cell function associated with progressive reduction of insulin secretion and β-Cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-Cell Protection and antidiabetic efficacy. Through an insulin and β Cell-independent mechanism, empagliflozin, a specific sodium glucose cotransporter type 2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the antidiabetic durability of empagliflozin treatment (10 mg/kg p.o.) against glibenclamide (3 mg/kg p.o.) and liraglutide (0.2 mg/kg s.c.) on deficient glucose homeostasis and β-Cell function in Zucker diabetic fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and hemoglobin A1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared with week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by less reduction in β-Cell mass with empagliflozin or liraglutide at week 4, whereas only empagliflozin showed β-Cell sparing effects also at week 8. Although this study cannot be used to dissociate the absolute antidiabetic efficacy among the different mechanisms of drug action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-Cell Protection in the ZDF rat. In comparison with other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-Cell Protection and antidiabetic efficacy.