The Experts below are selected from a list of 69 Experts worldwide ranked by ideXlab platform
Pei Fan - One of the best experts on this subject based on the ideXlab platform.
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miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival.
PloS one, 2013Co-Authors: Pei Fan, Zixuan Chen, Peng Tian, Wen Liu, Yan Jiao, Yi Xue, Anindya Bhattacharya, Yuqi GuoAbstract:miRNA biogenesis enzyme Drosha cleaves double-stranded primary miRNA by interacting with double-stranded RNA binding protein DGCR8 and processes primary miRNA into precursor miRNA to participate in the miRNA biogenesis pathway. The role of Drosha in vascular smooth muscle cells (VSMCs) has not been well addressed. We generated Drosha conditional knockout (cKO) mice by crossing VSMC-specific Cre mice, SM22-Cre, with Drosha loxp/loxp mice. Disruption of Drosha in VSMCs resulted in embryonic lethality at E14.5 with severe Liver Hemorrhage in mutant embryos. No obvious developmental delay was observed in Drosha cKO embryos. The vascular structure was absent in the yolk sac of Drosha homozygotes at E14.5. Loss of Drosha reduced VSMC proliferation in vitro and in vivo. The VSMC differentiation marker genes, including αSMA, SM22, and CNN1, and endothelial cell marker CD31 were significantly downregulated in Drosha cKO mice compared to controls. ERK1/2 mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/AKT were attenuated in VSMCs in vitro and in vivo. Disruption of Drosha in VSMCs of mice leads to the dysregulation of miRNA expression. Using bioinformatics approach, the interactions between dysregulated miRNAs and their target genes were analyzed. Our data demonstrated that Drosha is required for VSMC survival by targeting multiple signaling pathways.
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digeorge syndrome critical region 8 dgcr8 protein mediated microrna biogenesis is essential for vascular smooth muscle cell development in mice
Journal of Biological Chemistry, 2012Co-Authors: Zixuan Chen, Pei Fan, Yan Jiao, Chuanhe Yang, Louisa Balazs, Lawrence M Pfeffer, Gabor Tigyi, Junming YueAbstract:DiGeorge Critical Region 8 (DGCR8) is a double-stranded RNA-binding protein that interacts with Drosha and facilitates microRNA (miRNA) maturation. However, the role of DGCR8 in vascular smooth muscle cells (VSMCs) is not well understood. To investigate whether DGCR8 contributes to miRNA maturation in VSMCs, we generated DGCR8 conditional knockout (cKO) mice by crossing VSMC-specific Cre mice (SM22-Cre) with DGCR8(loxp/loxp) mice. We found that loss of DGCR8 in VSMCs resulted in extensive Liver Hemorrhage and embryonic mortality between embryonic days (E) 12.5 and E13.5. DGCR8 cKO embryos displayed dilated blood vessels and disarrayed vascular architecture. Blood vessels were absent in the yolk sac of DGCR8 KOs after E12.5. Disruption of DGCR8 in VSMCs reduced VSMC proliferation and promoted apoptosis in vitro and in vivo. In DGCR8 cKO embryos and knockout VSMCs, differentiation marker genes, including αSMA, SM22, and CNN1, were significantly down-regulated, and the survival pathways of ERK1/2 mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/AKT were attenuated. Knockout of DGCR8 in VSMCs has led to down-regulation of the miR-17/92 and miR-143/145 clusters. We further demonstrated that the miR-17/92 cluster promotes VSMC proliferation and enhances VSMC marker gene expression, which may contribute to the defects of DGCR8 cKO mutants. Our results indicate that the DGCR8 gene is required for vascular development through the regulation of VSMC proliferation, apoptosis, and differentiation.
Daizoh Saitoh - One of the best experts on this subject based on the ideXlab platform.
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treatment with fibrinogen γ chain peptide coated adenosine 5 diphosphate encapsulated liposomes as an infusible hemostatic agent against active Liver bleeding in rabbits with acute thrombocytopenia
Transfusion, 2015Co-Authors: Kousuke Hagisawa, Kahoko Nishikawa, Manabu Kinoshita, Mami Doi, Rempei Yanagawa, Hidenori Suzuki, Keiichi Iwaya, Daizoh Saitoh, Shuhji Seki, Shinji TakeokaAbstract:Background We evaluated the hemostatic efficacy of H12-(adenosine 5′-diphosphate [ADP])-liposomes in the setting of active Liver bleeding in rabbits with dilutional thrombocytopenia after massive transfusion. Study Design and Methods Acute thrombocytopenia (platelet [PLT] count < 50 × 109/L) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed red blood cells. Liver Hemorrhage was initiated by a penetrating Liver injury. Subsequently, the animals received tamponade treatment for the Liver Hemorrhage for 5 minutes and were intravenously administered H12-(ADP)-liposomes with PLT-poor plasma (PPP), PLT-rich plasma (PRP), PPP alone, H12-(phosphate-buffered saline [PBS])-liposome/PPP, or H12-(ADP)-liposomes/PPP plus fibrinogen concentrate during the tamponade. Results Administration of H12-(ADP)-liposomes/PPP rescued 60% of the rabbits from the Liver Hemorrhage; PRP administration rescued 50%. In contrast, rabbits receiving PPP or H12-(PBS)-liposome/PPP achieved only 10 or 17% survival, respectively, for the first 24 hours. H12-(ADP)-liposomes/PPP as well as PRP consistently reduced bleeding volumes and shortened clotting times (CTs) in comparison to PPP administration. Specifically, bleeding volumes in the initial 5 minutes averaged 11 mL (H12-(ADP)-liposomes/PPP) and 17 mL (PRP) versus 30 mL (PPP; p < 0.05); CTs averaged 270 and 306 seconds versus 401 seconds (p < 0.05). H12-(ADP)-liposomes were observed at the bleeding site with thrombus formation, suggesting an induction of thrombi. Neither macro- nor microthrombi were detected in the lung, kidney, spleen, or Liver in rabbits treated with H12-(ADP)-liposomes. Supplementation of fibrinogen to H12-(ADP)-liposomes/PPP did not significantly improve rabbit survival. Conclusions H12-(ADP)-liposomes might be a safe and effective therapeutic tool during damage control surgery for trauma patients with acute thrombocytopenia and massive bleeding.
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fibrinogen γ chain peptide coated adp encapsulated liposomes rescue thrombocytopenic rabbits from non compressible Liver Hemorrhage
Journal of Thrombosis and Haemostasis, 2012Co-Authors: Kahoko Nishikawa, Kousuke Hagisawa, Manabu Kinoshita, Satoshi Shono, S Katsuno, Mami Doi, Rempei Yanagawa, Hidenori Suzuki, Keiichi Iwaya, Daizoh SaitohAbstract:Summary. Background: We developed a fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV [H12])-coated, ADP-encapsulated liposome (H12-[ADP]-liposome) that accumulates at bleeding sites via interaction with activated platelets via glycoprotein IIb–IIIa and augments platelet aggregation by releasing ADP. Objective: To evaluate the efficacy of H12-(ADP)-liposomes for treating Liver Hemorrhage in rabbits with acute thrombocytopenia. Methods: Thrombocytopenia (platelets < 50 000 μL−1) was induced in rabbits by repeated blood withdrawal (100 mL kg−1 in total) and isovolemic transfusion of autologous washed red blood cells. H12-(ADP)-liposomes with platelet-poor plasma (PPP), platelet-rich plasma (PRP), PPP, ADP liposomes with PPP or H12-(PBS)-liposomes/PPP, were administered to the thrombocytopenic rabbits, and Liver Hemorrhage was induced by penetrating Liver injury. Results: Administration of H12-(ADP)-liposomes and of PRP rescued all thrombocytopenic rabbits from Liver Hemorrhage as a result of potent hemostasis at the Liver bleeding site, although rabbits receiving PPP or ADP liposomes showed 20% survival in the first 24 h. Administration of H12-(ADP)-liposomes and of PRP suppressed both bleeding volume and time from the site of Liver injury. H12-(phosphate-buffered saline)-liposomes lacking ADP also improved rabbit survival after Liver Hemorrhage, although their hemostatic effect was weaker. In rabbits with severe thrombocytopenia (25 000 platelets μL−1), the hemostatic effects of H12-(ADP)-liposomes tended to be attenuated as compared with those of PRP treatment. Histologic examination revealed that H12-(ADP)-liposomes accumulated at the bleeding site in the Liver. Notably, neither macrothombi nor microthrombi were detected in the lung, kidney or Liver in rabbits treated with H12-(ADP)-liposomes. Conclusions: H12-(ADP)-liposomes appear to be a safe and effective therapeutic tool for acute thrombocytopenic trauma patients with massive bleeding.
Kahoko Nishikawa - One of the best experts on this subject based on the ideXlab platform.
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treatment with fibrinogen γ chain peptide coated adenosine 5 diphosphate encapsulated liposomes as an infusible hemostatic agent against active Liver bleeding in rabbits with acute thrombocytopenia
Transfusion, 2015Co-Authors: Kousuke Hagisawa, Kahoko Nishikawa, Manabu Kinoshita, Mami Doi, Rempei Yanagawa, Hidenori Suzuki, Keiichi Iwaya, Daizoh Saitoh, Shuhji Seki, Shinji TakeokaAbstract:Background We evaluated the hemostatic efficacy of H12-(adenosine 5′-diphosphate [ADP])-liposomes in the setting of active Liver bleeding in rabbits with dilutional thrombocytopenia after massive transfusion. Study Design and Methods Acute thrombocytopenia (platelet [PLT] count < 50 × 109/L) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed red blood cells. Liver Hemorrhage was initiated by a penetrating Liver injury. Subsequently, the animals received tamponade treatment for the Liver Hemorrhage for 5 minutes and were intravenously administered H12-(ADP)-liposomes with PLT-poor plasma (PPP), PLT-rich plasma (PRP), PPP alone, H12-(phosphate-buffered saline [PBS])-liposome/PPP, or H12-(ADP)-liposomes/PPP plus fibrinogen concentrate during the tamponade. Results Administration of H12-(ADP)-liposomes/PPP rescued 60% of the rabbits from the Liver Hemorrhage; PRP administration rescued 50%. In contrast, rabbits receiving PPP or H12-(PBS)-liposome/PPP achieved only 10 or 17% survival, respectively, for the first 24 hours. H12-(ADP)-liposomes/PPP as well as PRP consistently reduced bleeding volumes and shortened clotting times (CTs) in comparison to PPP administration. Specifically, bleeding volumes in the initial 5 minutes averaged 11 mL (H12-(ADP)-liposomes/PPP) and 17 mL (PRP) versus 30 mL (PPP; p < 0.05); CTs averaged 270 and 306 seconds versus 401 seconds (p < 0.05). H12-(ADP)-liposomes were observed at the bleeding site with thrombus formation, suggesting an induction of thrombi. Neither macro- nor microthrombi were detected in the lung, kidney, spleen, or Liver in rabbits treated with H12-(ADP)-liposomes. Supplementation of fibrinogen to H12-(ADP)-liposomes/PPP did not significantly improve rabbit survival. Conclusions H12-(ADP)-liposomes might be a safe and effective therapeutic tool during damage control surgery for trauma patients with acute thrombocytopenia and massive bleeding.
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fibrinogen γ chain peptide coated adp encapsulated liposomes rescue thrombocytopenic rabbits from non compressible Liver Hemorrhage
Journal of Thrombosis and Haemostasis, 2012Co-Authors: Kahoko Nishikawa, Kousuke Hagisawa, Manabu Kinoshita, Satoshi Shono, S Katsuno, Mami Doi, Rempei Yanagawa, Hidenori Suzuki, Keiichi Iwaya, Daizoh SaitohAbstract:Summary. Background: We developed a fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV [H12])-coated, ADP-encapsulated liposome (H12-[ADP]-liposome) that accumulates at bleeding sites via interaction with activated platelets via glycoprotein IIb–IIIa and augments platelet aggregation by releasing ADP. Objective: To evaluate the efficacy of H12-(ADP)-liposomes for treating Liver Hemorrhage in rabbits with acute thrombocytopenia. Methods: Thrombocytopenia (platelets < 50 000 μL−1) was induced in rabbits by repeated blood withdrawal (100 mL kg−1 in total) and isovolemic transfusion of autologous washed red blood cells. H12-(ADP)-liposomes with platelet-poor plasma (PPP), platelet-rich plasma (PRP), PPP, ADP liposomes with PPP or H12-(PBS)-liposomes/PPP, were administered to the thrombocytopenic rabbits, and Liver Hemorrhage was induced by penetrating Liver injury. Results: Administration of H12-(ADP)-liposomes and of PRP rescued all thrombocytopenic rabbits from Liver Hemorrhage as a result of potent hemostasis at the Liver bleeding site, although rabbits receiving PPP or ADP liposomes showed 20% survival in the first 24 h. Administration of H12-(ADP)-liposomes and of PRP suppressed both bleeding volume and time from the site of Liver injury. H12-(phosphate-buffered saline)-liposomes lacking ADP also improved rabbit survival after Liver Hemorrhage, although their hemostatic effect was weaker. In rabbits with severe thrombocytopenia (25 000 platelets μL−1), the hemostatic effects of H12-(ADP)-liposomes tended to be attenuated as compared with those of PRP treatment. Histologic examination revealed that H12-(ADP)-liposomes accumulated at the bleeding site in the Liver. Notably, neither macrothombi nor microthrombi were detected in the lung, kidney or Liver in rabbits treated with H12-(ADP)-liposomes. Conclusions: H12-(ADP)-liposomes appear to be a safe and effective therapeutic tool for acute thrombocytopenic trauma patients with massive bleeding.
Kousuke Hagisawa - One of the best experts on this subject based on the ideXlab platform.
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treatment with fibrinogen γ chain peptide coated adenosine 5 diphosphate encapsulated liposomes as an infusible hemostatic agent against active Liver bleeding in rabbits with acute thrombocytopenia
Transfusion, 2015Co-Authors: Kousuke Hagisawa, Kahoko Nishikawa, Manabu Kinoshita, Mami Doi, Rempei Yanagawa, Hidenori Suzuki, Keiichi Iwaya, Daizoh Saitoh, Shuhji Seki, Shinji TakeokaAbstract:Background We evaluated the hemostatic efficacy of H12-(adenosine 5′-diphosphate [ADP])-liposomes in the setting of active Liver bleeding in rabbits with dilutional thrombocytopenia after massive transfusion. Study Design and Methods Acute thrombocytopenia (platelet [PLT] count < 50 × 109/L) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed red blood cells. Liver Hemorrhage was initiated by a penetrating Liver injury. Subsequently, the animals received tamponade treatment for the Liver Hemorrhage for 5 minutes and were intravenously administered H12-(ADP)-liposomes with PLT-poor plasma (PPP), PLT-rich plasma (PRP), PPP alone, H12-(phosphate-buffered saline [PBS])-liposome/PPP, or H12-(ADP)-liposomes/PPP plus fibrinogen concentrate during the tamponade. Results Administration of H12-(ADP)-liposomes/PPP rescued 60% of the rabbits from the Liver Hemorrhage; PRP administration rescued 50%. In contrast, rabbits receiving PPP or H12-(PBS)-liposome/PPP achieved only 10 or 17% survival, respectively, for the first 24 hours. H12-(ADP)-liposomes/PPP as well as PRP consistently reduced bleeding volumes and shortened clotting times (CTs) in comparison to PPP administration. Specifically, bleeding volumes in the initial 5 minutes averaged 11 mL (H12-(ADP)-liposomes/PPP) and 17 mL (PRP) versus 30 mL (PPP; p < 0.05); CTs averaged 270 and 306 seconds versus 401 seconds (p < 0.05). H12-(ADP)-liposomes were observed at the bleeding site with thrombus formation, suggesting an induction of thrombi. Neither macro- nor microthrombi were detected in the lung, kidney, spleen, or Liver in rabbits treated with H12-(ADP)-liposomes. Supplementation of fibrinogen to H12-(ADP)-liposomes/PPP did not significantly improve rabbit survival. Conclusions H12-(ADP)-liposomes might be a safe and effective therapeutic tool during damage control surgery for trauma patients with acute thrombocytopenia and massive bleeding.
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fibrinogen γ chain peptide coated adp encapsulated liposomes rescue thrombocytopenic rabbits from non compressible Liver Hemorrhage
Journal of Thrombosis and Haemostasis, 2012Co-Authors: Kahoko Nishikawa, Kousuke Hagisawa, Manabu Kinoshita, Satoshi Shono, S Katsuno, Mami Doi, Rempei Yanagawa, Hidenori Suzuki, Keiichi Iwaya, Daizoh SaitohAbstract:Summary. Background: We developed a fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV [H12])-coated, ADP-encapsulated liposome (H12-[ADP]-liposome) that accumulates at bleeding sites via interaction with activated platelets via glycoprotein IIb–IIIa and augments platelet aggregation by releasing ADP. Objective: To evaluate the efficacy of H12-(ADP)-liposomes for treating Liver Hemorrhage in rabbits with acute thrombocytopenia. Methods: Thrombocytopenia (platelets < 50 000 μL−1) was induced in rabbits by repeated blood withdrawal (100 mL kg−1 in total) and isovolemic transfusion of autologous washed red blood cells. H12-(ADP)-liposomes with platelet-poor plasma (PPP), platelet-rich plasma (PRP), PPP, ADP liposomes with PPP or H12-(PBS)-liposomes/PPP, were administered to the thrombocytopenic rabbits, and Liver Hemorrhage was induced by penetrating Liver injury. Results: Administration of H12-(ADP)-liposomes and of PRP rescued all thrombocytopenic rabbits from Liver Hemorrhage as a result of potent hemostasis at the Liver bleeding site, although rabbits receiving PPP or ADP liposomes showed 20% survival in the first 24 h. Administration of H12-(ADP)-liposomes and of PRP suppressed both bleeding volume and time from the site of Liver injury. H12-(phosphate-buffered saline)-liposomes lacking ADP also improved rabbit survival after Liver Hemorrhage, although their hemostatic effect was weaker. In rabbits with severe thrombocytopenia (25 000 platelets μL−1), the hemostatic effects of H12-(ADP)-liposomes tended to be attenuated as compared with those of PRP treatment. Histologic examination revealed that H12-(ADP)-liposomes accumulated at the bleeding site in the Liver. Notably, neither macrothombi nor microthrombi were detected in the lung, kidney or Liver in rabbits treated with H12-(ADP)-liposomes. Conclusions: H12-(ADP)-liposomes appear to be a safe and effective therapeutic tool for acute thrombocytopenic trauma patients with massive bleeding.
Zixuan Chen - One of the best experts on this subject based on the ideXlab platform.
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miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival.
PloS one, 2013Co-Authors: Pei Fan, Zixuan Chen, Peng Tian, Wen Liu, Yan Jiao, Yi Xue, Anindya Bhattacharya, Yuqi GuoAbstract:miRNA biogenesis enzyme Drosha cleaves double-stranded primary miRNA by interacting with double-stranded RNA binding protein DGCR8 and processes primary miRNA into precursor miRNA to participate in the miRNA biogenesis pathway. The role of Drosha in vascular smooth muscle cells (VSMCs) has not been well addressed. We generated Drosha conditional knockout (cKO) mice by crossing VSMC-specific Cre mice, SM22-Cre, with Drosha loxp/loxp mice. Disruption of Drosha in VSMCs resulted in embryonic lethality at E14.5 with severe Liver Hemorrhage in mutant embryos. No obvious developmental delay was observed in Drosha cKO embryos. The vascular structure was absent in the yolk sac of Drosha homozygotes at E14.5. Loss of Drosha reduced VSMC proliferation in vitro and in vivo. The VSMC differentiation marker genes, including αSMA, SM22, and CNN1, and endothelial cell marker CD31 were significantly downregulated in Drosha cKO mice compared to controls. ERK1/2 mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/AKT were attenuated in VSMCs in vitro and in vivo. Disruption of Drosha in VSMCs of mice leads to the dysregulation of miRNA expression. Using bioinformatics approach, the interactions between dysregulated miRNAs and their target genes were analyzed. Our data demonstrated that Drosha is required for VSMC survival by targeting multiple signaling pathways.
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digeorge syndrome critical region 8 dgcr8 protein mediated microrna biogenesis is essential for vascular smooth muscle cell development in mice
Journal of Biological Chemistry, 2012Co-Authors: Zixuan Chen, Pei Fan, Yan Jiao, Chuanhe Yang, Louisa Balazs, Lawrence M Pfeffer, Gabor Tigyi, Junming YueAbstract:DiGeorge Critical Region 8 (DGCR8) is a double-stranded RNA-binding protein that interacts with Drosha and facilitates microRNA (miRNA) maturation. However, the role of DGCR8 in vascular smooth muscle cells (VSMCs) is not well understood. To investigate whether DGCR8 contributes to miRNA maturation in VSMCs, we generated DGCR8 conditional knockout (cKO) mice by crossing VSMC-specific Cre mice (SM22-Cre) with DGCR8(loxp/loxp) mice. We found that loss of DGCR8 in VSMCs resulted in extensive Liver Hemorrhage and embryonic mortality between embryonic days (E) 12.5 and E13.5. DGCR8 cKO embryos displayed dilated blood vessels and disarrayed vascular architecture. Blood vessels were absent in the yolk sac of DGCR8 KOs after E12.5. Disruption of DGCR8 in VSMCs reduced VSMC proliferation and promoted apoptosis in vitro and in vivo. In DGCR8 cKO embryos and knockout VSMCs, differentiation marker genes, including αSMA, SM22, and CNN1, were significantly down-regulated, and the survival pathways of ERK1/2 mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/AKT were attenuated. Knockout of DGCR8 in VSMCs has led to down-regulation of the miR-17/92 and miR-143/145 clusters. We further demonstrated that the miR-17/92 cluster promotes VSMC proliferation and enhances VSMC marker gene expression, which may contribute to the defects of DGCR8 cKO mutants. Our results indicate that the DGCR8 gene is required for vascular development through the regulation of VSMC proliferation, apoptosis, and differentiation.