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Michael Chopp - One of the best experts on this subject based on the ideXlab platform.
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Nitric Oxide Donor up regulation of sdf1 cxcr4 and ang1 tie2 promotes neuroblast cell migration after stroke
Journal of Neuroscience Research, 2009Co-Authors: Jieli Chen, Alex Zacharek, Cynthia Roberts, Yuping Yang, Michael ChoppAbstract:We tested the hypothesis that a Nitric Oxide Donor, DETA-NONOate upregulates Stromal cell-Derived Factor-1 (SDF1) and Angiopoietin 1 (Ang1) in the ischemic brain and their, respective, receptors chemokine CXC motif receptor 4 (CXCR4) and Tie2 in the subventricular zone (SVZ) and thereby promote SVZ neuroblast cell migration after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo) and 24 hours later DETA-NONOate (0.4 mg/kg) or phosphate buffered solution were intravenously administered. Mice were sacrificed at 14 days for histological assessment or sacrificed at 3 days for analysis real-time polymerase chain reaction and migration after MCAo. To elucidate whether SDF1/CXCR4 and Ang1/Tie2 pathways mediate DETA-NONOate induced SVZ migration after stroke, SDF1α, Ang1 peptide and a specific antagonist of CXCR4 (AMD3100) and a neutralizing antibody of Tie2 (anti-Tie2) were used in vitro. DETA-NONOate significantly increased the percent area of doublecortin (a marker of migrating neuroblasts) immunoreactive-cells in the SVZ and ischemic boundary zone. DETA-NONOate significantly increased the expression of SDF1 and Ang1 in the ischemic border and upregulated CXCR4 and Tie2 in the SVZ compared with MCAo control. DCX-positive cell migration from SVZ explants was significantly increased in the DETA-NONOate treatment group compared with MCAo alone animals. In vitro, SDF1α and Ang1 significantly increased SVZ explants cell migration. In addition, inhibition of CXCR4 or Tie2 significantly attenuated DETA-NONOate induced SVZ cell migration. Our data indicated that treatment of stroke with a Nitric Oxide Donor upregulates SDF1/CXCR4 and Ang1/Tie2 pathways and thereby likely increases SVZ neuroblast cell migration.
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Nitric Oxide Donor upregulation of stromal cell derived factor 1 chemokine cxc motif receptor 4 enhances bone marrow stromal cell migration into ischemic brain after stroke
Stem Cells, 2007Co-Authors: Jieli Chen, Alex Zacharek, Cynthia Roberts, Michael Chopp, Yi Li, Alissa Kapke, Smita SavantbhonsaleAbstract:Stromal cell-derived factor-1 (SDF1) and its chemokine (CXC motif) receptor 4 (CXCR4), along with matrix metalloproteinases (MMPs), regulate bone marrow stromal cell (BMSC) migration. We tested the hypothesis that a Nitric Oxide Donor, DETA-NONOate, increases endogenous ischemic brain SDF1 and BMSC CXCR4 and MMP9 expression, which promotes BMSC migration into ischemic brain and thereby enhances functional outcome after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo), and 24 hours later, the following were intravenously administered (n = 9 mice per group): (a) phosphate-buffered saline; (b) BMSCs (5 × 105); (c) 0.4 mg/kg DETA-NONOate; (d) combination of CXCR4-inhibition BMSCs with DETA-NONOate; and (e) combination of BMSCs with DETA-NONOate. To elucidate the mechanisms underlying combination-enhanced BMSC migration, transwell cocultures of BMSC with mouse brain endothelial cells (MBECs) or astrocytes were performed. Combination treatment significantly improved functional outcome after stroke compared with BMSC monotherapy and MCAo control, and it increased SDF1 expression in the ischemic brain compared with DETA-NONOate monotherapy and MCAo control. The number of BMSCs in the ischemic brain was significantly increased after combination BMSC with DETA-NONOate treatment compared with monotherapy with BMSCs. The number of engrafted BMSCs was significantly correlated with functional outcome after stroke. DETA-NONOate significantly increased BMSC CXCR4 and MMP9 expression and promoted BMSC adhesion and migration to MBECs and astrocytes compared with nontreatment BMSCs. Inhibition of CXCR4 or MMPs in BMSCs significantly decreased DETA-NONOate-induced BMSC adhesion and migration. Our data demonstrate that DETA-NONOate enhanced the therapeutic potency of BMSCs, possibly via upregulation of SDF1/CXCR4 and MMP pathways, and increased BMSC engraftment into the ischemic brain. Disclosure of potential conflicts of interest is found at the end of this article.
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combination therapy of stroke in rats with a Nitric Oxide Donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis
Brain Research, 2004Co-Authors: Jieli Chen, Michael Chopp, Ruilan Zhang, Mark Katakowski, Subhash C Gautam, Zhenggang ZhangAbstract:We tested the hypothesis that intravenous infusion of human marrow stromal cells (hMSC) with a Nitric Oxide Donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate), enhances angiogenesis, neurogenesis and neurological functional recovery after stroke in rats compared to individual therapy. Experimental groups consist of rats subjected to 2 h of middle cerebral artery occlusion (MCAo) and at 24 h after MCAo intravenous injection of (n=10/group): Group 1: phosphate buffered saline (PBS 1 ml) for control. Group 2: NONOate alone (0.4 mg/kg). Group 3: hMSCs (1 x 10(6)) alone. Group 4: hMSCs (1 x 10(6)) with NONOate (0.4 mg/kg). Functional tests and immunohistochemical staining were performed. Marginal functional recovery after treatment of stroke was found with 1 x 10(6) hMSCs alone (p=0.06) and no benefit was detected with NONOate alone (0.4 mg/kg, p=0.64). However, NONOate+hMSCs in combination significantly induced functional recovery (p<0.05). Treatment using hMSC in combination with NONOate significantly increased vessel perimeter and endothelial cell proliferation compared with hMSC or NONOate alone treatment (p<0.05). Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunostaining for cell type-specific markers. Combination treatment promoted increased, BrdU positive cell number in the subventricular zone (SVZ), migrating neuronal doublecortin immunoreactive cells and VEGF and bFGF expression in the ischemic boundary area compared to individual treatment. The functional therapeutic enhancement of combination treatment may be attributed to increased plasticity induced by the combination of a Nitric Oxide Donor and hMSC therapy. These data suggest that pharmacological and cellular therapy may provide an additive therapeutic benefit after stroke.
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a Nitric Oxide Donor induces neurogenesis and reduces functional deficits after stroke in rats
Annals of Neurology, 2001Co-Authors: Ruilan Zhang, Michael Chopp, Zhenggang Zhang, Li Zhang, Ying Wang, Margot C LapointeAbstract:The adult rodent brain is capable of generating neuronal progenitor cells in the subventricular zone, and in the dentate gyrus of the hippocampus, throughout the life of the animal. Signals that regulate progenitor cell proliferation, differentiation, and migration are not well known. We report that administration of a Nitric Oxide Donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio]diazen-1-ium-1,2-diolate (DETA/NONOate), to young adult rats significantly increases cell proliferation and migration in the subventricular zone and the dentate gyrus. Treatment with DETA/ NONOate also increases neurogenesis in the dentate gyrus. Furthermore, administration of DETA/NONOate to rats subjected to embolic middle cerebral artery occlusion significantly increases cell proliferation and migration in the subventricular zone and the dentate gyrus, and these rats exhibit significant improvements of neurological outcome during recovery from ischemic stroke. Administration of DETA/NONOate significantly increases cortical levels of guanosine monophosphate both in ischemic and nonischemic rats, supporting the role of Nitric Oxide in promoting cell proliferation and neurogenesis. Thus, our data indicate that Nitric Oxide is involved in the regulation of progenitor cells and neurogenesis in the adult brain. This suggests that Nitric Oxide delivered to the brain well after stroke may have therapeutic benefits.
Jieli Chen - One of the best experts on this subject based on the ideXlab platform.
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Nitric Oxide Donor up regulation of sdf1 cxcr4 and ang1 tie2 promotes neuroblast cell migration after stroke
Journal of Neuroscience Research, 2009Co-Authors: Jieli Chen, Alex Zacharek, Cynthia Roberts, Yuping Yang, Michael ChoppAbstract:We tested the hypothesis that a Nitric Oxide Donor, DETA-NONOate upregulates Stromal cell-Derived Factor-1 (SDF1) and Angiopoietin 1 (Ang1) in the ischemic brain and their, respective, receptors chemokine CXC motif receptor 4 (CXCR4) and Tie2 in the subventricular zone (SVZ) and thereby promote SVZ neuroblast cell migration after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo) and 24 hours later DETA-NONOate (0.4 mg/kg) or phosphate buffered solution were intravenously administered. Mice were sacrificed at 14 days for histological assessment or sacrificed at 3 days for analysis real-time polymerase chain reaction and migration after MCAo. To elucidate whether SDF1/CXCR4 and Ang1/Tie2 pathways mediate DETA-NONOate induced SVZ migration after stroke, SDF1α, Ang1 peptide and a specific antagonist of CXCR4 (AMD3100) and a neutralizing antibody of Tie2 (anti-Tie2) were used in vitro. DETA-NONOate significantly increased the percent area of doublecortin (a marker of migrating neuroblasts) immunoreactive-cells in the SVZ and ischemic boundary zone. DETA-NONOate significantly increased the expression of SDF1 and Ang1 in the ischemic border and upregulated CXCR4 and Tie2 in the SVZ compared with MCAo control. DCX-positive cell migration from SVZ explants was significantly increased in the DETA-NONOate treatment group compared with MCAo alone animals. In vitro, SDF1α and Ang1 significantly increased SVZ explants cell migration. In addition, inhibition of CXCR4 or Tie2 significantly attenuated DETA-NONOate induced SVZ cell migration. Our data indicated that treatment of stroke with a Nitric Oxide Donor upregulates SDF1/CXCR4 and Ang1/Tie2 pathways and thereby likely increases SVZ neuroblast cell migration.
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Nitric Oxide Donor upregulation of stromal cell derived factor 1 chemokine cxc motif receptor 4 enhances bone marrow stromal cell migration into ischemic brain after stroke
Stem Cells, 2007Co-Authors: Jieli Chen, Alex Zacharek, Cynthia Roberts, Michael Chopp, Yi Li, Alissa Kapke, Smita SavantbhonsaleAbstract:Stromal cell-derived factor-1 (SDF1) and its chemokine (CXC motif) receptor 4 (CXCR4), along with matrix metalloproteinases (MMPs), regulate bone marrow stromal cell (BMSC) migration. We tested the hypothesis that a Nitric Oxide Donor, DETA-NONOate, increases endogenous ischemic brain SDF1 and BMSC CXCR4 and MMP9 expression, which promotes BMSC migration into ischemic brain and thereby enhances functional outcome after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo), and 24 hours later, the following were intravenously administered (n = 9 mice per group): (a) phosphate-buffered saline; (b) BMSCs (5 × 105); (c) 0.4 mg/kg DETA-NONOate; (d) combination of CXCR4-inhibition BMSCs with DETA-NONOate; and (e) combination of BMSCs with DETA-NONOate. To elucidate the mechanisms underlying combination-enhanced BMSC migration, transwell cocultures of BMSC with mouse brain endothelial cells (MBECs) or astrocytes were performed. Combination treatment significantly improved functional outcome after stroke compared with BMSC monotherapy and MCAo control, and it increased SDF1 expression in the ischemic brain compared with DETA-NONOate monotherapy and MCAo control. The number of BMSCs in the ischemic brain was significantly increased after combination BMSC with DETA-NONOate treatment compared with monotherapy with BMSCs. The number of engrafted BMSCs was significantly correlated with functional outcome after stroke. DETA-NONOate significantly increased BMSC CXCR4 and MMP9 expression and promoted BMSC adhesion and migration to MBECs and astrocytes compared with nontreatment BMSCs. Inhibition of CXCR4 or MMPs in BMSCs significantly decreased DETA-NONOate-induced BMSC adhesion and migration. Our data demonstrate that DETA-NONOate enhanced the therapeutic potency of BMSCs, possibly via upregulation of SDF1/CXCR4 and MMP pathways, and increased BMSC engraftment into the ischemic brain. Disclosure of potential conflicts of interest is found at the end of this article.
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combination therapy of stroke in rats with a Nitric Oxide Donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis
Brain Research, 2004Co-Authors: Jieli Chen, Michael Chopp, Ruilan Zhang, Mark Katakowski, Subhash C Gautam, Zhenggang ZhangAbstract:We tested the hypothesis that intravenous infusion of human marrow stromal cells (hMSC) with a Nitric Oxide Donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate), enhances angiogenesis, neurogenesis and neurological functional recovery after stroke in rats compared to individual therapy. Experimental groups consist of rats subjected to 2 h of middle cerebral artery occlusion (MCAo) and at 24 h after MCAo intravenous injection of (n=10/group): Group 1: phosphate buffered saline (PBS 1 ml) for control. Group 2: NONOate alone (0.4 mg/kg). Group 3: hMSCs (1 x 10(6)) alone. Group 4: hMSCs (1 x 10(6)) with NONOate (0.4 mg/kg). Functional tests and immunohistochemical staining were performed. Marginal functional recovery after treatment of stroke was found with 1 x 10(6) hMSCs alone (p=0.06) and no benefit was detected with NONOate alone (0.4 mg/kg, p=0.64). However, NONOate+hMSCs in combination significantly induced functional recovery (p<0.05). Treatment using hMSC in combination with NONOate significantly increased vessel perimeter and endothelial cell proliferation compared with hMSC or NONOate alone treatment (p<0.05). Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunostaining for cell type-specific markers. Combination treatment promoted increased, BrdU positive cell number in the subventricular zone (SVZ), migrating neuronal doublecortin immunoreactive cells and VEGF and bFGF expression in the ischemic boundary area compared to individual treatment. The functional therapeutic enhancement of combination treatment may be attributed to increased plasticity induced by the combination of a Nitric Oxide Donor and hMSC therapy. These data suggest that pharmacological and cellular therapy may provide an additive therapeutic benefit after stroke.
Philip M W Bath - One of the best experts on this subject based on the ideXlab platform.
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baseline characteristics of the 1149 patients recruited into the rapid intervention with glyceryl trinitrate in hypertensive stroke trial 2 right 2 randomized controlled trial
International Journal of Stroke, 2019Co-Authors: Philip M W Bath, Mark Dixon, Jason P Appleton, Polly Scutt, Lisa J Woodhouse, Nikola Sprigg, Joanna M WardlawAbstract:BackgroundHigh blood pressure is common in acute stroke and associated with a worse functional outcome. Glyceryl trinitrate, a Nitric Oxide Donor, lowers blood pressure in acute stroke and may impr...
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statistical analysis plan for the rapid intervention with glyceryl trinitrate in hypertensive stroke trial 2 right 2
European Stroke Journal, 2018Co-Authors: Polly Scutt, Mark Dixon, Jason P Appleton, Alan A Montgomery, Stuart J Pocock, Lisa J Woodhouse, Nikola Sprigg, Joanna M Wardlaw, Philip M W BathAbstract:Rationale:Glyceryl trinitrate, a Nitric Oxide Donor, is a candidate treatment for acute stroke; it lowers blood pressure, does not alter cerebral blood flow or platelet function and is neuroprotect...
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rapid intervention with glyceryl trinitrate in hypertensive stroke trial 2 right 2 safety and efficacy of transdermal glyceryl trinitrate a Nitric Oxide Donor
Emergency Medicine Journal, 2016Co-Authors: Philip M W Bath, Mark Dixon, Jason P Appleton, Polly Scutt, Timothy J England, Hayley Foster, Harriet Howard, Malcolm Jarvis, Alan A Montgomery, Stuart J PocockAbstract:Rationale High blood pressure (BP) is common in acute stroke and is associated with poor outcome. Previous hospital-based trials testing the effects of BP lowering on functional outcome have been inconclusive. The PIL-FAST and RIGHT pilot trials confirmed the feasibility of performing single-centre ambulance-based stroke trials in the UK. In both RIGHT and a subgroup of patients recruited within 6 hours into the large ENOS trial, transdermal glyceryl trinitrate (GTN), a Nitric Oxide Donor, lowered BP and reduced death or disability. Based on these results, RIGHT-2 aims to test the safety and efficacy of transdermal GTN in the pre-hospital setting. Methods Paramedics from 7 UK ambulance services serving 40 comprehensive or primary stroke care centres will screen, consent, randomise and treat 850 patients presenting within 4 hours of FAST-positive stroke and with systolic BP >120 mm Hg. Treatment will comprise GTN or similar sham patch, and will be continued in hospital for 3 days. The primary outcome will be the modified Rankin Scale at day 90. Secondary outcomes include vascular events, disability, quality of life, mood and cognition. Neuroimaging and biomarkers will examine potential mechanisms of action. Status Recruitment commenced in October 2015. Challenges with the trial and baseline characteristics of the first recruited patients will be presented. Funding British Heart Foundation.
Takafumi Kudo - One of the best experts on this subject based on the ideXlab platform.
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A long-term transdermal Nitric Oxide Donor improves uteroplacental circulation in women with preeclampsia.
Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 2002Co-Authors: Mikiya Nakatsuka, Toshihiro Habara, Kazuo Asagiri, Soichi Noguchi, Masayo Takata, Katsuhiko Tada, Takafumi KudoAbstract:OBJECTIVE To determine the effects of long-term transdermal administration (range, 4-30 days; mean +/- SD, 11.1+/-7.2 days) of isosorbide dinitrate, a Nitric Oxide Donor, in preeclamptic women. METHODS We studied uterine and fetoplacental circulation of 12 preeclamptic women with oligohydramnios and an elevated pulsatility index in the uterine arteries. RESULTS Transdermal isosorbide dinitrate significantly suppressed the blood pressure of patients. Pulsed Doppler ultrasonography revealed that the average pulsatility index in the uterine arteries was significantly reduced by treatment with isosorbide dinitrate (P < .003). The average pulsatility index in the umbilical artery was also significantly reduced (P < .004). Furthermore, the size of the amniotic fluid pocket increased approximately 4-fold by treatment with isosorbide dinitrate. CONCLUSIONS Long-term transdermal administration of isosorbide dinitrate improves fetoplacental circulation and may be effective therapy for avoiding maternal hypertension and oligohydramnios in some preeclamptic women.
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Effect of a Nitric Oxide Donor on the ophthalmic artery flow velocity waveform in preeclamptic women
Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 2002Co-Authors: Mikiya Nakatsuka, Masayo Takata, Katsuhiko Tada, Takafumi KudoAbstract:Objective. To evaluate the effects of an antihypertensive agent on the orbital circulation of preeclamptic women. Methods. We studied the ophthalmic arteries of 10 healthy pregnant women and 10 women with severe preeclampsia by pulsed Doppler ultrasonography and evaluated the effect of transdermal isosorbide dinitrate, a Nitric Oxide Donor, on preeclamptic women. Results. The average pulsatility index and resistive index were significantly lower, whereas the average end-diastolic velocity, time-averaged mean peak velocity, and peak ratio, which quantifies characteristic changes in the ophthalmic artery flow velocity waveform, were higher in preeclamptic women. Transdermal isosorbide dinitrate significantly reduced the average end-diastolic velocity (P
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Clinical Experience of Long-Term Transdermal Treatment with Nitric Oxide Donor for Women with Preeclampsia
Gynecologic and obstetric investigation, 1999Co-Authors: Mikiya Nakatsuka, Kazuo Asagiri, Masayo Takata, Katsuhiko Tada, Yoshihiro Kimura, Yasuhiko Kamada, Takakimi Nakata, Nanako Inoue, Takafumi KudoAbstract:Isosorbide dinitrate (ISDN), a Nitric Oxide Donor, was applied transdermally for 4–16 days to 4 preeclamptic women with oligohydramnios, intrauterine fetal growth retardation (IUGR), and elevated resi
Peng George Wang - One of the best experts on this subject based on the ideXlab platform.
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Sialated diazeniumdiolate: a new sialidase-activated Nitric Oxide Donor.
Organic letters, 2004Co-Authors: T Bill Cai, Megan Landerholm, Peng George WangAbstract:A new sialated diazeniumdiolate has been synthesized, and the glycosylation product was exclusively an α anomer. This new Nitric Oxide Donor exhibited significantly improved stability as compared t...
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The synthesis and cytotoxicity of fructose-1-SNAP, a novel fructose conjugated S-nitroso Nitric Oxide Donor
Tetrahedron Letters, 2001Co-Authors: Xuejun Wu, Paul G. Braunschweiger, Peng George WangAbstract:Abstract An efficient synthetic strategy has been developed for the synthesis of a novel fructose conjugated S -nitroso Nitric Oxide Donor, fructose-1- S -nitroso- N -acetylpenicillamine. This compound showed similar cytotoxicity as the first generation fructose-SNAP, fructose-2-SNAP. A 5- and 26-fold increased cytotoxicity was observed compared to glucose-2-SNAP and SNAP against DU-145 human prostate cancer cells in vitro.