The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Junbo Ge - One of the best experts on this subject based on the ideXlab platform.
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A protective role of Ciglitazone in ox-LDL-induced rat microvascular endothelial cells via modulating PPARγ-dependent AMPK/eNOS pathway
Journal of Cellular and Molecular Medicine, 2015Co-Authors: Lei Xu, Aijun Sun, Yunzeng Zou, Bingyu Li, Shijun Wang, Junbo GeAbstract:Thiazolidinediones, the antidiabetic agents such as Ciglitazone, has been proved to be effective in limiting atherosclerotic events. However, the underlying mechanism remains elucidative. Ox-LDL receptor-1 (LOX-1) plays a central role in ox-LDL-mediated atherosclerosis via endothelial nitric oxide synthase (eNOS) uncoupling and nitric oxide reduction. Therefore, we tested the hypothesis that Ciglitazone, the PPARγ agonist, protected endothelial cells against ox-LDL through regulating eNOS activity and LOX-1 signalling. In the present study, rat microvascular endothelial cells (RMVECs) were stimulated by ox-LDL. The impact of Ciglitazone on cell apoptosis and angiogenesis, eNOS expression and phosphorylation, nitric oxide synthesis and related AMPK, Akt and VEGF signalling pathway were observed. Our data showed that both eNOS and Akt phosphorylation, VEGF expression and nitric oxide production were significantly decreased, RMVECs ageing and apoptosis increased after ox-LDL induction for 24 hrs, all of which were effectively reversed by Ciglitazone pre-treatment. Meanwhile, phosphorylation of AMP-activated protein kinase (AMPK) was suppressed by ox-LDL, which was also prevented by Ciglitazone. Of interest, AMPK inhibition abolished Ciglitazone-mediated eNOS function, nitric oxide synthesis and angiogenesis, and increased RMVECs ageing and apoptosis. Further experiments showed that inhibition of PPARγ significantly suppressed AMPK phosphorylation, eNOS expression and nitric oxide production. Ciglitazone-mediated angiogenesis and reduced cell ageing and apoptosis were reversed. Furthermore, LOX-1 protein expression in RMVECs was suppressed by Ciglitazone, but re-enhanced by blocking PPARγ or AMPK. Ox-LDL-induced suppression of eNOS and nitric oxide synthesis were largely prevented by silencing LOX-1. Collectively, these data demonstrate that Ciglitazone-mediated PPARγ activation suppresses LOX-1 and moderates AMPK/eNOS pathway, which contributes to endothelial cell survival and function preservation.
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a protective role of Ciglitazone in ox ldl induced rat microvascular endothelial cells via modulating pparγ dependent ampk enos pathway
Journal of Cellular and Molecular Medicine, 2015Co-Authors: Lei Xu, Bingyu Li, Shijun Wang, Junbo GeAbstract:Thiazolidinediones, the antidiabetic agents such as Ciglitazone, has been proved to be effective in limiting atherosclerotic events. However, the underlying mechanism remains elucidative. Ox-LDL receptor-1 (LOX-1) plays a central role in ox-LDL-mediated atherosclerosis via endothelial nitric oxide synthase (eNOS) uncoupling and nitric oxide reduction. Therefore, we tested the hypothesis that Ciglitazone, the PPARγ agonist, protected endothelial cells against ox-LDL through regulating eNOS activity and LOX-1 signalling. In the present study, rat microvascular endothelial cells (RMVECs) were stimulated by ox-LDL. The impact of Ciglitazone on cell apoptosis and angiogenesis, eNOS expression and phosphorylation, nitric oxide synthesis and related AMPK, Akt and VEGF signalling pathway were observed. Our data showed that both eNOS and Akt phosphorylation, VEGF expression and nitric oxide production were significantly decreased, RMVECs ageing and apoptosis increased after ox-LDL induction for 24 hrs, all of which were effectively reversed by Ciglitazone pre-treatment. Meanwhile, phosphorylation of AMP-activated protein kinase (AMPK) was suppressed by ox-LDL, which was also prevented by Ciglitazone. Of interest, AMPK inhibition abolished Ciglitazone-mediated eNOS function, nitric oxide synthesis and angiogenesis, and increased RMVECs ageing and apoptosis. Further experiments showed that inhibition of PPARγ significantly suppressed AMPK phosphorylation, eNOS expression and nitric oxide production. Ciglitazone-mediated angiogenesis and reduced cell ageing and apoptosis were reversed. Furthermore, LOX-1 protein expression in RMVECs was suppressed by Ciglitazone, but re-enhanced by blocking PPARγ or AMPK. Ox-LDL-induced suppression of eNOS and nitric oxide synthesis were largely prevented by silencing LOX-1. Collectively, these data demonstrate that Ciglitazone-mediated PPARγ activation suppresses LOX-1 and moderates AMPK/eNOS pathway, which contributes to endothelial cell survival and function preservation.
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A protective role of Ciglitazone in ox‐LDL‐induced rat microvascular endothelial cells via modulating PPARγ‐dependent AMPK/eNOS pathway
Journal of Cellular and Molecular Medicine, 2014Co-Authors: Lei Xu, Bingyu Li, Shijun Wang, Junbo GeAbstract:Thiazolidinediones, the antidiabetic agents such as Ciglitazone, has been proved to be effective in limiting atherosclerotic events. However, the underlying mechanism remains elucidative. Ox-LDL receptor-1 (LOX-1) plays a central role in ox-LDL-mediated atherosclerosis via endothelial nitric oxide synthase (eNOS) uncoupling and nitric oxide reduction. Therefore, we tested the hypothesis that Ciglitazone, the PPARγ agonist, protected endothelial cells against ox-LDL through regulating eNOS activity and LOX-1 signalling. In the present study, rat microvascular endothelial cells (RMVECs) were stimulated by ox-LDL. The impact of Ciglitazone on cell apoptosis and angiogenesis, eNOS expression and phosphorylation, nitric oxide synthesis and related AMPK, Akt and VEGF signalling pathway were observed. Our data showed that both eNOS and Akt phosphorylation, VEGF expression and nitric oxide production were significantly decreased, RMVECs ageing and apoptosis increased after ox-LDL induction for 24 hrs, all of which were effectively reversed by Ciglitazone pre-treatment. Meanwhile, phosphorylation of AMP-activated protein kinase (AMPK) was suppressed by ox-LDL, which was also prevented by Ciglitazone. Of interest, AMPK inhibition abolished Ciglitazone-mediated eNOS function, nitric oxide synthesis and angiogenesis, and increased RMVECs ageing and apoptosis. Further experiments showed that inhibition of PPARγ significantly suppressed AMPK phosphorylation, eNOS expression and nitric oxide production. Ciglitazone-mediated angiogenesis and reduced cell ageing and apoptosis were reversed. Furthermore, LOX-1 protein expression in RMVECs was suppressed by Ciglitazone, but re-enhanced by blocking PPARγ or AMPK. Ox-LDL-induced suppression of eNOS and nitric oxide synthesis were largely prevented by silencing LOX-1. Collectively, these data demonstrate that Ciglitazone-mediated PPARγ activation suppresses LOX-1 and moderates AMPK/eNOS pathway, which contributes to endothelial cell survival and function preservation.
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Ciglitazone inhibits oxidized low density lipoprotein induced immune maturation of dendritic cells
Journal of Cardiovascular Pharmacology, 2004Co-Authors: Chun Liang, Congfeng Xu, Dong Huang, Lianglong Chen, Keqiang Wang, Zonggui Wu, Junbo GeAbstract:Background: The peroxisome proliferator-activated receptor (PPAR) activation has generally been shown to have anti-inflammatory effects and dendritic cells (DCs) are the most efficient antigen presenting cells that play an active role in the development of atherosclerosis. The effects of PPARs on DCs maturation and immune function remain unknown now and we, therefore, studied the influence of PPARγ agonist Ciglitazone on the maturation and immune function of DCs. Methods: Human monocytes were purified and immature DCs derived; Ciglitazone (25 μmol/L) was added to the medium for 24 hours; ox-LDL (50 μg/ml) was then added to the medium for another 24 hours. The immunophenotypic expressions (CD1a, CD40, CD86, and HLA-DR) were analyzed by FACS and endocytosis function by FITC-dextran and the cytokines secretions of culture supernatants (IL-12,IL-10,TNFα, and IL-2) were measured with ELISA. Results: Ciglitazone reduced ox-LDL induced immunophenotypic expressions of DCs (CD40, CD1a, and HLA-DR). Ox-LDL inhibited the endocytosis of DCs, which was prevented by Ciglitazone; Ciglitazone attenuated ox-LDL induced cytokine secretions of DCs (IL-12, 116 ′ 29 versus 34 ′ 3 pg/ml*; IL-10, 49 ′ 1 versus 28 ′ 9 pg/ml*; TNFa, 46 ′ 16 versus 24 ′ 8pg/ml*, *P < 0.05 compared with ox-LDL, respectively). Conclusion: Our study suggested that one of the anti-inflammatory mechanisms of PPAR-γ agonist Ciglitazone was mediated by inhibiting the ox-LDL induced maturation and immune function of DCs.
Lei Xu - One of the best experts on this subject based on the ideXlab platform.
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A protective role of Ciglitazone in ox-LDL-induced rat microvascular endothelial cells via modulating PPARγ-dependent AMPK/eNOS pathway
Journal of Cellular and Molecular Medicine, 2015Co-Authors: Lei Xu, Aijun Sun, Yunzeng Zou, Bingyu Li, Shijun Wang, Junbo GeAbstract:Thiazolidinediones, the antidiabetic agents such as Ciglitazone, has been proved to be effective in limiting atherosclerotic events. However, the underlying mechanism remains elucidative. Ox-LDL receptor-1 (LOX-1) plays a central role in ox-LDL-mediated atherosclerosis via endothelial nitric oxide synthase (eNOS) uncoupling and nitric oxide reduction. Therefore, we tested the hypothesis that Ciglitazone, the PPARγ agonist, protected endothelial cells against ox-LDL through regulating eNOS activity and LOX-1 signalling. In the present study, rat microvascular endothelial cells (RMVECs) were stimulated by ox-LDL. The impact of Ciglitazone on cell apoptosis and angiogenesis, eNOS expression and phosphorylation, nitric oxide synthesis and related AMPK, Akt and VEGF signalling pathway were observed. Our data showed that both eNOS and Akt phosphorylation, VEGF expression and nitric oxide production were significantly decreased, RMVECs ageing and apoptosis increased after ox-LDL induction for 24 hrs, all of which were effectively reversed by Ciglitazone pre-treatment. Meanwhile, phosphorylation of AMP-activated protein kinase (AMPK) was suppressed by ox-LDL, which was also prevented by Ciglitazone. Of interest, AMPK inhibition abolished Ciglitazone-mediated eNOS function, nitric oxide synthesis and angiogenesis, and increased RMVECs ageing and apoptosis. Further experiments showed that inhibition of PPARγ significantly suppressed AMPK phosphorylation, eNOS expression and nitric oxide production. Ciglitazone-mediated angiogenesis and reduced cell ageing and apoptosis were reversed. Furthermore, LOX-1 protein expression in RMVECs was suppressed by Ciglitazone, but re-enhanced by blocking PPARγ or AMPK. Ox-LDL-induced suppression of eNOS and nitric oxide synthesis were largely prevented by silencing LOX-1. Collectively, these data demonstrate that Ciglitazone-mediated PPARγ activation suppresses LOX-1 and moderates AMPK/eNOS pathway, which contributes to endothelial cell survival and function preservation.
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a protective role of Ciglitazone in ox ldl induced rat microvascular endothelial cells via modulating pparγ dependent ampk enos pathway
Journal of Cellular and Molecular Medicine, 2015Co-Authors: Lei Xu, Bingyu Li, Shijun Wang, Junbo GeAbstract:Thiazolidinediones, the antidiabetic agents such as Ciglitazone, has been proved to be effective in limiting atherosclerotic events. However, the underlying mechanism remains elucidative. Ox-LDL receptor-1 (LOX-1) plays a central role in ox-LDL-mediated atherosclerosis via endothelial nitric oxide synthase (eNOS) uncoupling and nitric oxide reduction. Therefore, we tested the hypothesis that Ciglitazone, the PPARγ agonist, protected endothelial cells against ox-LDL through regulating eNOS activity and LOX-1 signalling. In the present study, rat microvascular endothelial cells (RMVECs) were stimulated by ox-LDL. The impact of Ciglitazone on cell apoptosis and angiogenesis, eNOS expression and phosphorylation, nitric oxide synthesis and related AMPK, Akt and VEGF signalling pathway were observed. Our data showed that both eNOS and Akt phosphorylation, VEGF expression and nitric oxide production were significantly decreased, RMVECs ageing and apoptosis increased after ox-LDL induction for 24 hrs, all of which were effectively reversed by Ciglitazone pre-treatment. Meanwhile, phosphorylation of AMP-activated protein kinase (AMPK) was suppressed by ox-LDL, which was also prevented by Ciglitazone. Of interest, AMPK inhibition abolished Ciglitazone-mediated eNOS function, nitric oxide synthesis and angiogenesis, and increased RMVECs ageing and apoptosis. Further experiments showed that inhibition of PPARγ significantly suppressed AMPK phosphorylation, eNOS expression and nitric oxide production. Ciglitazone-mediated angiogenesis and reduced cell ageing and apoptosis were reversed. Furthermore, LOX-1 protein expression in RMVECs was suppressed by Ciglitazone, but re-enhanced by blocking PPARγ or AMPK. Ox-LDL-induced suppression of eNOS and nitric oxide synthesis were largely prevented by silencing LOX-1. Collectively, these data demonstrate that Ciglitazone-mediated PPARγ activation suppresses LOX-1 and moderates AMPK/eNOS pathway, which contributes to endothelial cell survival and function preservation.
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A protective role of Ciglitazone in ox‐LDL‐induced rat microvascular endothelial cells via modulating PPARγ‐dependent AMPK/eNOS pathway
Journal of Cellular and Molecular Medicine, 2014Co-Authors: Lei Xu, Bingyu Li, Shijun Wang, Junbo GeAbstract:Thiazolidinediones, the antidiabetic agents such as Ciglitazone, has been proved to be effective in limiting atherosclerotic events. However, the underlying mechanism remains elucidative. Ox-LDL receptor-1 (LOX-1) plays a central role in ox-LDL-mediated atherosclerosis via endothelial nitric oxide synthase (eNOS) uncoupling and nitric oxide reduction. Therefore, we tested the hypothesis that Ciglitazone, the PPARγ agonist, protected endothelial cells against ox-LDL through regulating eNOS activity and LOX-1 signalling. In the present study, rat microvascular endothelial cells (RMVECs) were stimulated by ox-LDL. The impact of Ciglitazone on cell apoptosis and angiogenesis, eNOS expression and phosphorylation, nitric oxide synthesis and related AMPK, Akt and VEGF signalling pathway were observed. Our data showed that both eNOS and Akt phosphorylation, VEGF expression and nitric oxide production were significantly decreased, RMVECs ageing and apoptosis increased after ox-LDL induction for 24 hrs, all of which were effectively reversed by Ciglitazone pre-treatment. Meanwhile, phosphorylation of AMP-activated protein kinase (AMPK) was suppressed by ox-LDL, which was also prevented by Ciglitazone. Of interest, AMPK inhibition abolished Ciglitazone-mediated eNOS function, nitric oxide synthesis and angiogenesis, and increased RMVECs ageing and apoptosis. Further experiments showed that inhibition of PPARγ significantly suppressed AMPK phosphorylation, eNOS expression and nitric oxide production. Ciglitazone-mediated angiogenesis and reduced cell ageing and apoptosis were reversed. Furthermore, LOX-1 protein expression in RMVECs was suppressed by Ciglitazone, but re-enhanced by blocking PPARγ or AMPK. Ox-LDL-induced suppression of eNOS and nitric oxide synthesis were largely prevented by silencing LOX-1. Collectively, these data demonstrate that Ciglitazone-mediated PPARγ activation suppresses LOX-1 and moderates AMPK/eNOS pathway, which contributes to endothelial cell survival and function preservation.
John J Bright - One of the best experts on this subject based on the ideXlab platform.
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pparγ antagonists reverse the inhibition of neural antigen specific th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15 deoxy δ12 14 prostaglandin j2
Journal of Neuroimmunology, 2006Co-Authors: Himanshu P Raikwar, Gladson Muthian, Johnson Rajasingh, Caroline Johnson, John J BrightAbstract:Abstract Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARγ agonists have been used to treat obesity, diabetes, cancer and inflammation and recent studies have shown the protective effects of PPARγ agonists on experimental allergic encephalomyelitis (EAE), a Th 1 cell-mediated autoimmune disease model of multiple sclerosis (MS). Our studies have further demonstrated that the PPARγ agonists, 15d-PGJ 2 and Ciglitazone, inhibit EAE through blocking IL-12 signaling leading to Th 1 differentiation and the PPARγ deficient heterozygous mice (PPARγ +/− ) or those treated with PPARγ antagonists develop an exacerbated EAE in association with an augmented Th 1 response. In this study, we show that the PPARγ antagonists, Bisphenol A diglycidyl ether (BADGE) and 2-chloro-5-nitro- N -(4-pyridyl)benzamide (T0070907), reverse the inhibition of EAE by the PPARγ agonists, Ciglitazone and 15-Deoxy-Δ 12,14 -Prostaglandin J 2 , in C57BL/6 wild-type and PPARγ +/− mice. The reversal of EAE by BADGE and T0070907 was associated with restoration of neural antigen-induced T cell proliferation, IFNγ production and Th 1 differentiation inhibited by Ciglitazone and 15d-PGJ 2 . These results suggest that Ciglitazone and 15d-PGJ 2 ameliorate EAE through PPARγ-dependent mechanisms and further confirm a physiological role for PPARγ in the regulation of CNS inflammation and demyelination in EAE.
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PPARgamma antagonists reverse the inhibition of neural antigen-specific Th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-deoxy-Delta12,14-prostaglandin J2.
Journal of neuroimmunology, 2006Co-Authors: Himanshu P Raikwar, Gladson Muthian, Johnson Rajasingh, Caroline N Johnson, John J BrightAbstract:Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARgamma agonists have been used to treat obesity, diabetes, cancer and inflammation and recent studies have shown the protective effects of PPARgamma agonists on experimental allergic encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). Our studies have further demonstrated that the PPARgamma agonists, 15d-PGJ2 and Ciglitazone, inhibit EAE through blocking IL-12 signaling leading to Th1 differentiation and the PPARgamma deficient heterozygous mice (PPARgamma+/-) or those treated with PPARgamma antagonists develop an exacerbated EAE in association with an augmented Th1 response. In this study, we show that the PPARgamma antagonists, Bisphenol A diglycidyl ether (BADGE) and 2-chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907), reverse the inhibition of EAE by the PPARgamma agonists, Ciglitazone and 15-Deoxy-Delta(12,14)-Prostaglandin J2, in C57BL/6 wild-type and PPARgamma+/- mice. The reversal of EAE by BADGE and T0070907 was associated with restoration of neural antigen-induced T cell proliferation, IFNgamma production and Th1 differentiation inhibited by Ciglitazone and 15d-PGJ2. These results suggest that Ciglitazone and 15d-PGJ2 ameliorate EAE through PPARgamma-dependent mechanisms and further confirm a physiological role for PPARgamma in the regulation of CNS inflammation and demyelination in EAE.
Basilia Zingarelli - One of the best experts on this subject based on the ideXlab platform.
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Ciglitazone a novel inhibitor of lung apoptosis following hemorrhagic shock
International Journal of Clinical and Experimental Medicine, 2010Co-Authors: Ranjit S Chima, Paul W Hake, Giovanna Piraino, Prajakta Mangeshkar, Michael Oconnor, Basilia ZingarelliAbstract:Apoptosis or programmed cell death has been demonstrated to play a role in the development of lung injury following hemorrhagic shock. A major pathway modulating the apoptotic response is the phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) pathway. Ciglitazone, a peroxisome proliferator-activated receptor-y (PPARy) ligand has previously been shown to attenuate lung inflammation following hemorrhagic shock. In vivo similar ligands have demonstrated anti-apoptotic effects with a reduction in organ injury in models of acute illness. In this study we examined the effect of Ciglitazone on apoptosis and PI3K/Akt signaling in the lung following severe hemorrhage and resuscitation. Hemorrhagic shock was induced in male Wistar rats by withdrawing blood from the femoral artery to a mean arterial pressure of 50 mmHg. Animals were kept in shock for 3h at which time they were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, groups of animals received Ciglitazone (10mg/kg) or DMSO intraperitoneally. Vehicle-treated rats had increased lung apoptosis following hemorrhage and resuscitation by Tunel staining. This was associated with increased activity of caspase-3. Ciglitazone treatment reduced lung apoptosis with a significant reduction in caspase-3 activity. This was associated with increased phosphorylation of the pro-survival kinase Akt. Thus, our data suggest that Ciglitazone, a PPARy ligand, promotes cell survival in the lung following hemorrhagic shock.
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Ciglitazone ameliorates lung inflammation by modulating the inhibitor κb protein kinase nuclear factor κb pathway after hemorrhagic shock
Critical Care Medicine, 2008Co-Authors: Ranjit S Chima, Paul W Hake, Giovanna Piraino, Prajakta Mangeshkar, Alvin Denenberg, Basilia ZingarelliAbstract:Objective Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor. Ciglitazone a PPARγ ligand, has been shown to provide beneficial effects in experimental models of sepsis and ischemia/reperfusion injury. We investigated the effects of Ciglitazone on lung inflammation following severe hemorrhage.
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Ciglitazone ameliorates lung inflammation by modulating the inhibitor κB protein kinase/nuclear factor-κB pathway after hemorrhagic shock
Critical Care Medicine, 2008Co-Authors: Ranjit S Chima, Paul W Hake, Giovanna Piraino, Prajakta Mangeshkar, Alvin Denenberg, Basilia ZingarelliAbstract:Objective Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor. Ciglitazone a PPARγ ligand, has been shown to provide beneficial effects in experimental models of sepsis and ischemia/reperfusion injury. We investigated the effects of Ciglitazone on lung inflammation following severe hemorrhage.
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PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR γ IS REQUIRED FOR THE INHIBITORY EFFECT OF Ciglitazone BUT NOT 15-DEOXY-Δ12,14-PROSTAGLANDIN J2 ON THE NFκB PATHWAY IN HUMAN ENDOTHELIAL CELLS
Shock, 2007Co-Authors: Jennifer M. Kaplan, James A. Cook, Michael O'connor, Basilia ZingarelliAbstract:Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated nuclear receptor with effects on inflammation, atherosclerosis, and apoptosis. The endogenous PPARgamma ligand, 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2), and the synthetic ligand, Ciglitazone, have anti-inflammatory properties in endothelial cells. In addition to PPARgamma-dependent effects on the anti-inflammatory process, it has been proposed that PPARgamma ligands may also inhibit the nuclear transcription factor kappaB (NFkappaB) pathway in a PPARgamma-independent manner. The purpose of this study was to compare the effects of 15d-PGJ2 and Ciglitazone on the cytokine-induced activation of the NFkappaB pathway. Human umbilical vein endothelial cells (HUVECs) were transiently transfected with NFkappaB-luciferase or PPARgamma elements-luciferase reporter constructs for 48 h. The HUVECs were pretreated with 15d-PGJ2 or Ciglitazone (30 microM) for 1 h, followed by a 4-h stimulation with tumor necrosis factor alpha (100 U/mL). Luciferase assay was performed to determine reporter activity. Additionally, HUVECs were transiently transfected with a dominant-negative mutant, which retains ligand and DNA binding but exhibits markedly reduced transactivation. Stimulation of HUVEC with tumor necrosis factor alpha increased NFkappaB activation while decreasing PPARgamma activity. Overexpression of a dominant-negative PPARgamma mutant prevented the inhibitory effect of Ciglitazone on cytokine-induced NFkappaB activation in transfected human endothelial cells. Conversely, 15d-PGJ2 inhibited the cytokine-induced NFkappaB activation even in the absence of PPARgamma. Our data suggest that 15d-PGJ2 exerts direct inhibitory effects on the NFkappaB pathway through a PPARgamma-independent mechanism. On the contrary, the inhibitory effect of Ciglitazone on the NFkappaB pathway seems to require PPARgamma activation.
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diverse cardioprotective signaling mechanisms of peroxisome proliferator activated receptor gamma ligands 15 deoxy delta12 14 prostaglandin j2 and Ciglitazone in reperfusion injury role of nuclear factor kappab heat shock factor 1 and akt
Shock, 2007Co-Authors: Basilia Zingarelli, Paul W Hake, Giovanna Piraino, Prajakta Mangeshkar, Alvin Denenberg, Michael Oconnor, Timothy J Burroughs, Hector R WongAbstract:Abstract Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear receptor that regulates diverse biological functions including inflammation. The PPARgamma ligands have been reported to exert cardioprotective effects and attenuate myocardial reperfusion injury. Here, we examined the molecular mechanisms of their anti-inflammatory effects. Male Wistar rats were subjected to myocardial ischemia and reperfusion and were treated with the PPAR-gamma ligands, 15-deoxy-Delta-prostaglandin J2 (15d-PGJ2) or Ciglitazone, or with vehicle only, in the absence or presence of the selective PPAR-gamma antagonist GW-9662. In vehicle-treated rats, myocardial injury was associated with elevated tissue activity of myeloperoxidase, indicating infiltration of neutrophils, and elevated plasma levels of creatine kinase and tumor necrosis factor-alpha. These events were preceded by activation of the nuclear factor-kappaB pathway. The PPAR-gamma DNA binding was also increased in the heart after reperfusion. Treatment with Ciglitazone or 15d-PGJ2 reduced myocardial damage and neutrophil infiltration and blunted creatine kinase levels and cytokine production. The beneficial effects of both ligands were associated with enhancement of PPAR-gamma DNA binding and reduction of nuclear factor-kappaB activation. Treatment with 15d-PGJ2, but not Ciglitazone, enhanced DNA binding of heat shock factor 1 and upregulated the expression of the cardioprotective heat shock protein 70. Treatment with 15d-PGJ2, but not Ciglitazone, also induced a significant increase in nuclear phosphorylation of the prosurvival kinase Akt. The cardioprotection afforded by Ciglitazone was attenuated by the PPAR-gamma antagonist GW-9662. In contrast, GW-9662 did not affect the beneficial effects afforded by 15d-PGJ2. Thus, our data suggest that treatment with these chemically unrelated PPAR-gamma ligands results in diverse anti-inflammatory mechanisms.
Sung Hee Hong - One of the best experts on this subject based on the ideXlab platform.
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combined treatment with the cox 2 inhibitor niflumic acid and pparγ ligand Ciglitazone induces er stress caspase 8 mediated apoptosis in human lung cancer cells
Cancer Letters, 2011Co-Authors: Kyungah Maeng, Sung Hee HongAbstract:Abstract The present study was performed to investigate the possible combined use of the Cox-2 inhibitor niflumic acid and the PPARγ ligand Ciglitazone and to elucidate the mechanisms underlying enhanced apoptosis by this combination treatment in human lung cancer cells. Combined niflumic acid–Ciglitazone treatment synergistically induced apoptotic cell death, activated caspase-9, caspase-3, and induced caspase-3-mediated PARP cleavage. The combination treatment also triggered apoptosis through caspase-8/Bid/Bax activation, and the inhibition of caspase-8 suppressed caspase-8/Bid activation, caspase-3-mediated PARP cleavage, and concomitant apoptosis. In addition, combined niflumic acid–Ciglitazone treatment significantly induced ER stress responses, and suppression of CHOP expression significantly attenuated the combined niflumic acid–Ciglitazone treatment-induced activation of caspase-8 and caspase-3, and the subsequent apoptotic cell death, indicating a role of ER stress in caspase-8 activation and apoptosis. Interestingly, the pro-apoptotic effects of combined niflumic acid–Ciglitazone treatment were realized through Cox-2- and PPARγ-independent mechanisms. Taken together, these results suggest that sequential ER stress and caspase-8 activation are critical in combined niflumic acid–Ciglitazone treatment-induced apoptosis in human lung cancer cells.
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Combined treatment with the Cox-2 inhibitor niflumic acid and PPARγ ligand Ciglitazone induces ER stress/caspase-8-mediated apoptosis in human lung cancer cells
Cancer Letters, 2010Co-Authors: Kyungah Maeng, Sung Hee HongAbstract:Abstract The present study was performed to investigate the possible combined use of the Cox-2 inhibitor niflumic acid and the PPARγ ligand Ciglitazone and to elucidate the mechanisms underlying enhanced apoptosis by this combination treatment in human lung cancer cells. Combined niflumic acid–Ciglitazone treatment synergistically induced apoptotic cell death, activated caspase-9, caspase-3, and induced caspase-3-mediated PARP cleavage. The combination treatment also triggered apoptosis through caspase-8/Bid/Bax activation, and the inhibition of caspase-8 suppressed caspase-8/Bid activation, caspase-3-mediated PARP cleavage, and concomitant apoptosis. In addition, combined niflumic acid–Ciglitazone treatment significantly induced ER stress responses, and suppression of CHOP expression significantly attenuated the combined niflumic acid–Ciglitazone treatment-induced activation of caspase-8 and caspase-3, and the subsequent apoptotic cell death, indicating a role of ER stress in caspase-8 activation and apoptosis. Interestingly, the pro-apoptotic effects of combined niflumic acid–Ciglitazone treatment were realized through Cox-2- and PPARγ-independent mechanisms. Taken together, these results suggest that sequential ER stress and caspase-8 activation are critical in combined niflumic acid–Ciglitazone treatment-induced apoptosis in human lung cancer cells.