The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Kenji Okajima - One of the best experts on this subject based on the ideXlab platform.
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Gabexate Mesilate a synthetic protease inhibitor inhibits lipopolysaccharide induced tumor necrosis factor α production by inhibiting activation of both nuclear factor κb and activator protein 1 in human monocytes
International Congress Series, 2003Co-Authors: Mehtap Yuksel, Kenji Okajima, Mitsuhiro UchibaAbstract:Abstract Gabexate Mesilate, a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation (DIC) in which tumor necrosis factor-α (TNF-α) plays a critical role. We demonstrated that Gabexate Mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-α production in rats. In this study, we analyzed the mechanism(s) by which Gabexate Mesilate inhibits LPS-induced TNF-α production in human monocytes in vitro. Gabexate Mesilate inhibited the production of TNF-α in monocytes stimulated with LPS. Gabexate Mesilate inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of IκBα. Gabexate Mesilate also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase (MAPK) pathways. These observations strongly suggest that Gabexate Mesilate inhibits LPS-induced TNF-α production in human monocytes by inhibiting activation of both NF-κB and AP-1. Inhibition of TNF-α production by Gabexate Mesilate might explain, at least partly, its therapeutic effects in animals given LPS in patients with sepsis.
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Gabexate Mesilate a synthetic anticoagulant inhibits the expression of endothelial leukocyte adhesion molecules in vitro
Critical Care Medicine, 2003Co-Authors: Mitsuhiro Uchiba, Kenji Okajima, Christoph Kaun, Bernd R Binder, Johann WojtaAbstract:Objective Gabexate Mesilate, a synthetic protease inhibitor, has been shown to reduce endotoxin-induced pulmonary vascular injury in an animal model of sepsis by inhibiting leukocyte activation. We examined whether Gabexate Mesilate inhibits tumor necrosis factor-alpha-induced expression of leukocyte adhesion molecules in cultured endothelial cells. Design Prospective, randomized, controlled study. Setting Research laboratory at a university medical center. Subjects Cultured human umbilical vein endothelial cell (HUVECs). Interventions HUVECs were stimulated with tumor necrosis factor-alpha or lipopolysaccharide in the presence or absence of Gabexate Mesilate. Expression of E-selectin and intercellular adhesion molecule-1 was measured by cellular enzyme-linked immunosorbent assay. Messenger RNA levels of E-selectin and intercellular adhesion molecule-1 were determined by reverse transcription-polymerase chain reaction. DNA-binding activity of p65 in the nuclear extracts was evaluated by enzyme-linked immunosorbent assay. Nuclear translocation of nuclear factor-kappaB induced by tumor necrosis factor-alpha was evaluated by immunocytostaining and Western blot analysis. Degradation and phosphorylation of inhibitor of nuclear factor-kappaB (IkappaB) induced by tumor necrosis factor-alpha were evaluated by Western blot analysis. Measurements and main results Gabexate Mesilate inhibited the tumor necrosis factor-alpha-induced increases in the endothelial expression of E-selectin and intercellular adhesion molecule-1 by inhibiting the transcription. Tumor necrosis factor-alpha-induced increase in DNA binding of p65 was inhibited by Gabexate Mesilate through inhibition of the nuclear translocation of p65. Gabexate Mesilate inhibited the tumor necrosis factor-alpha-induced degradation of IkappaBalpha, an inhibitor of nuclear factor-kappaB, by inhibiting phosphorylation of IkappaBalpha in HUVECs. Conclusions Gabexate Mesilate inhibited the expression of leukocyte adhesion molecules by inhibiting the nuclear factor-kappaB-mediated transcription in HUVECs. Inhibition of nuclear factor-kappaB activation by Gabexate Mesilate could be explained by inhibition of degradation of IkappaB. Gabexate Mesilate might reduce lipopolysaccharide-induced pulmonary vascular injury not only by inhibiting monocytic tumor necrosis factor-alpha production but by inhibiting the expression of endothelial leukocyte adhesion molecules.
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Gabexate Mesilate a synthetic protease inhibitor inhibits lipopolysaccharide induced tumor necrosis factor α production by inhibiting activation of both nuclear factor κb and activator protein 1 in human monocytes
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Mehtap Yuksel, Mitsuhiro Uchiba, Kenji Okajima, Hiroaki OkabeAbstract:Gabexate Mesilate, a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation in which tumor necrosis factor-α (TNF-α) plays a critical role. We demonstrated that Gabexate Mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-α production in rats. In the present study, we analyzed the mechanism(s) by which Gabexate Mesilate inhibits LPS-induced TNF-α production in human monocytes in vitro. Gabexate Mesilate inhibited the production of TNF-α in monocytes stimulated with LPS. Gabexate Mesilate inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of inhibitory κBα. Gabexate Mesilate also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that Gabexate Mesilate inhibited LPS-induced TNF-α production in human monocytes by inhibiting activation of both NF-κB and AP-1. Inhibition of TNF-α production by Gabexate Mesilate might explain at least partly its therapeutic effects in animals given LPS and those in patients with sepsis.
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Gabexate Mesilate a synthetic protease inhibitor reduces ischemia reperfusion injury of rat liver by inhibiting leukocyte activation
Critical Care Medicine, 1999Co-Authors: Naoaki Harada, Kenji Okajima, Shigeki KushimotoAbstract:Objective:To investigate whether Gabexate Mesilate, a synthetic protease inhibitor with anticoagulant properties, prevents hepatic damage by inhibiting leukocyte activation, we examined its effect on ischemia/reperfusion injury of rat liver in which activated leukocytes play a critical role.Design:P
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Gabexate Mesilate a synthetic protease inhibitor prevents compression induced spinal cord injury by inhibiting activation of leukocytes in rats
Critical Care Medicine, 1997Co-Authors: Yuji Taoka, Mitsuhiro Uchiba, Kenji Okajima, Hiroaki Okabe, Kazunori Murakami, Shigeki Kushimoto, Masayoshi Johno, Masakuni Naruo, Kiyoshi TakatsukiAbstract:Objective: Gabexate Mesilate is a synthetic protease inhibitor capable of inhibiting both coagulation and cytokine production by monocytes. To investigate whether Gabexate Mesilate is useful for the prevention of posttraumatic spinal cord injury, we examined its effect on compression trauma-induced spinal cord injury in rats. Design: Prospective, randomized, blinded, controlled study. Setting: Research laboratory at a university medical center. Subjects: Male Wistar rats weighing 300 to 350 g. Interventions: Spinal cord injury was induced by applying a 20-g weight extradurally to the spinal cord at the level of the 12th thoracic vertebra for 20 mins. Spinal cord injury was evaluated by assessing the motor function of the rats 24 hrs posttrauma. The accumulation of leukocytes and histologic changes in the injured spinal cord tissue also were examined. Rats received Gabexate Mesilate (10 or 20 mglkg ip) 30 mins before or after the compressive trauma. The effects of heparin or an inactive derivative of activated factor X (a selective inhibitor of thrombin generation) on compressive trauma-induced spinal cord injury also were examined. Leukocytopenia was induced by the administration of nitrogen mustard. Measurements and Main Results: The motor disturbances observed following traumatic spinal cord compression, evaluated by Tarlov's score, and the accumulation of leukocytes in the injured tissue, evaluated by measuring tissue myeloperoxidase activity, were markedly reduced by leukocyte depletion induced by nitrogen mustard and by pre- or posttreatment of animals with Gabexate Mesilate. Neither heparin nor the inactive derivative of activated factor X prevented the motor disturbances and the accumulation of leukocytes. Histologic examination demonstrated that intramedullary hemorrhages observed 24 hrs after trauma at the 12th thoracic vertebra were significantly attenuated by nitrogen mustard-induced leukocytopenia and the administration of Gabexate Mesilate. Conclusions: The compression trauma-induced spinal cord injury demonstrated by this model was mainly mediated by leukocytes. Gabexate Mesilate prevented spinal cord injury not by inhibiting coagulation, but by inhibiting the activation of leukocytes.
Mitsuhiro Uchiba - One of the best experts on this subject based on the ideXlab platform.
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Gabexate Mesilate a synthetic protease inhibitor inhibits lipopolysaccharide induced tumor necrosis factor α production by inhibiting activation of both nuclear factor κb and activator protein 1 in human monocytes
International Congress Series, 2003Co-Authors: Mehtap Yuksel, Kenji Okajima, Mitsuhiro UchibaAbstract:Abstract Gabexate Mesilate, a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation (DIC) in which tumor necrosis factor-α (TNF-α) plays a critical role. We demonstrated that Gabexate Mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-α production in rats. In this study, we analyzed the mechanism(s) by which Gabexate Mesilate inhibits LPS-induced TNF-α production in human monocytes in vitro. Gabexate Mesilate inhibited the production of TNF-α in monocytes stimulated with LPS. Gabexate Mesilate inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of IκBα. Gabexate Mesilate also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase (MAPK) pathways. These observations strongly suggest that Gabexate Mesilate inhibits LPS-induced TNF-α production in human monocytes by inhibiting activation of both NF-κB and AP-1. Inhibition of TNF-α production by Gabexate Mesilate might explain, at least partly, its therapeutic effects in animals given LPS in patients with sepsis.
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Gabexate Mesilate a synthetic anticoagulant inhibits the expression of endothelial leukocyte adhesion molecules in vitro
Critical Care Medicine, 2003Co-Authors: Mitsuhiro Uchiba, Kenji Okajima, Christoph Kaun, Bernd R Binder, Johann WojtaAbstract:Objective Gabexate Mesilate, a synthetic protease inhibitor, has been shown to reduce endotoxin-induced pulmonary vascular injury in an animal model of sepsis by inhibiting leukocyte activation. We examined whether Gabexate Mesilate inhibits tumor necrosis factor-alpha-induced expression of leukocyte adhesion molecules in cultured endothelial cells. Design Prospective, randomized, controlled study. Setting Research laboratory at a university medical center. Subjects Cultured human umbilical vein endothelial cell (HUVECs). Interventions HUVECs were stimulated with tumor necrosis factor-alpha or lipopolysaccharide in the presence or absence of Gabexate Mesilate. Expression of E-selectin and intercellular adhesion molecule-1 was measured by cellular enzyme-linked immunosorbent assay. Messenger RNA levels of E-selectin and intercellular adhesion molecule-1 were determined by reverse transcription-polymerase chain reaction. DNA-binding activity of p65 in the nuclear extracts was evaluated by enzyme-linked immunosorbent assay. Nuclear translocation of nuclear factor-kappaB induced by tumor necrosis factor-alpha was evaluated by immunocytostaining and Western blot analysis. Degradation and phosphorylation of inhibitor of nuclear factor-kappaB (IkappaB) induced by tumor necrosis factor-alpha were evaluated by Western blot analysis. Measurements and main results Gabexate Mesilate inhibited the tumor necrosis factor-alpha-induced increases in the endothelial expression of E-selectin and intercellular adhesion molecule-1 by inhibiting the transcription. Tumor necrosis factor-alpha-induced increase in DNA binding of p65 was inhibited by Gabexate Mesilate through inhibition of the nuclear translocation of p65. Gabexate Mesilate inhibited the tumor necrosis factor-alpha-induced degradation of IkappaBalpha, an inhibitor of nuclear factor-kappaB, by inhibiting phosphorylation of IkappaBalpha in HUVECs. Conclusions Gabexate Mesilate inhibited the expression of leukocyte adhesion molecules by inhibiting the nuclear factor-kappaB-mediated transcription in HUVECs. Inhibition of nuclear factor-kappaB activation by Gabexate Mesilate could be explained by inhibition of degradation of IkappaB. Gabexate Mesilate might reduce lipopolysaccharide-induced pulmonary vascular injury not only by inhibiting monocytic tumor necrosis factor-alpha production but by inhibiting the expression of endothelial leukocyte adhesion molecules.
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Gabexate Mesilate a synthetic protease inhibitor inhibits lipopolysaccharide induced tumor necrosis factor α production by inhibiting activation of both nuclear factor κb and activator protein 1 in human monocytes
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Mehtap Yuksel, Mitsuhiro Uchiba, Kenji Okajima, Hiroaki OkabeAbstract:Gabexate Mesilate, a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation in which tumor necrosis factor-α (TNF-α) plays a critical role. We demonstrated that Gabexate Mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-α production in rats. In the present study, we analyzed the mechanism(s) by which Gabexate Mesilate inhibits LPS-induced TNF-α production in human monocytes in vitro. Gabexate Mesilate inhibited the production of TNF-α in monocytes stimulated with LPS. Gabexate Mesilate inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of inhibitory κBα. Gabexate Mesilate also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that Gabexate Mesilate inhibited LPS-induced TNF-α production in human monocytes by inhibiting activation of both NF-κB and AP-1. Inhibition of TNF-α production by Gabexate Mesilate might explain at least partly its therapeutic effects in animals given LPS and those in patients with sepsis.
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Gabexate Mesilate a synthetic protease inhibitor prevents compression induced spinal cord injury by inhibiting activation of leukocytes in rats
Critical Care Medicine, 1997Co-Authors: Yuji Taoka, Mitsuhiro Uchiba, Kenji Okajima, Hiroaki Okabe, Kazunori Murakami, Shigeki Kushimoto, Masayoshi Johno, Masakuni Naruo, Kiyoshi TakatsukiAbstract:Objective: Gabexate Mesilate is a synthetic protease inhibitor capable of inhibiting both coagulation and cytokine production by monocytes. To investigate whether Gabexate Mesilate is useful for the prevention of posttraumatic spinal cord injury, we examined its effect on compression trauma-induced spinal cord injury in rats. Design: Prospective, randomized, blinded, controlled study. Setting: Research laboratory at a university medical center. Subjects: Male Wistar rats weighing 300 to 350 g. Interventions: Spinal cord injury was induced by applying a 20-g weight extradurally to the spinal cord at the level of the 12th thoracic vertebra for 20 mins. Spinal cord injury was evaluated by assessing the motor function of the rats 24 hrs posttrauma. The accumulation of leukocytes and histologic changes in the injured spinal cord tissue also were examined. Rats received Gabexate Mesilate (10 or 20 mglkg ip) 30 mins before or after the compressive trauma. The effects of heparin or an inactive derivative of activated factor X (a selective inhibitor of thrombin generation) on compressive trauma-induced spinal cord injury also were examined. Leukocytopenia was induced by the administration of nitrogen mustard. Measurements and Main Results: The motor disturbances observed following traumatic spinal cord compression, evaluated by Tarlov's score, and the accumulation of leukocytes in the injured tissue, evaluated by measuring tissue myeloperoxidase activity, were markedly reduced by leukocyte depletion induced by nitrogen mustard and by pre- or posttreatment of animals with Gabexate Mesilate. Neither heparin nor the inactive derivative of activated factor X prevented the motor disturbances and the accumulation of leukocytes. Histologic examination demonstrated that intramedullary hemorrhages observed 24 hrs after trauma at the 12th thoracic vertebra were significantly attenuated by nitrogen mustard-induced leukocytopenia and the administration of Gabexate Mesilate. Conclusions: The compression trauma-induced spinal cord injury demonstrated by this model was mainly mediated by leukocytes. Gabexate Mesilate prevented spinal cord injury not by inhibiting coagulation, but by inhibiting the activation of leukocytes.
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Gabexate Mesilate a synthetic protease inhibitor attenuates endotoxin induced pulmonary vascular injury by inhibiting tumor necrosis factor production by monocytes
Critical Care Medicine, 1996Co-Authors: Kazunori Murakami, Mitsuhiro Uchiba, Kenji Okajima, Hiroaki Okabe, Kiyoshi TakatsukiAbstract:Objective In order to determine whether Gabexate Mesilate, a synthetic protease inhibitor with anticoagulant properties, is useful for the treatment of adult respiratory distress syndrome, we examined its effect on endotoxin-induced pulmonary vascular injury in rats. Design Prospective, randomized, controlled study. Setting Research laboratory at a university medical center. Subjects Male Wistar rats (180 to 220 g). Interventions Animals received intravenous infusions of endotoxin (5 mg/kg iv) or saline (control). Pulmonary vascular injury was assessed 6 hrs after administration of endotoxin in terms of the increase in vascular permeability. Rats received Gabexate Mesilate (10 mg/kg ip), heparin, antithrombin III, an inactive derivative of activated factor X (a selective inhibitor of thrombin generation), or N-[2-[4-(2,2-dimethyl-propionyloxy) phenyl-sulfonylamino] benzoyl] aminoacetic acid (ONO-5046) (a potent granulocyte elastase inhibitor) 30 mins before endotoxin administration. Leukocytopenia was induced by administration of methotrexate. The effects of Gabexate Mesilate on the function of activated neutrophils and the production of tumor necrosis factor-alpha (TNF-alpha) by endotoxin-stimulated monocytes were examined in vitro using neutrophils and monocytes prepared from healthy human volunteers. Measurements and Main Results Pulmonary vascular permeability was determined by measuring the vascular leakage of intravenously administered125 I-labeled bovine serum albumin. Intravenous administration of endotoxin significantly increased pulmonary vascular permeability. Gabexate Mesilate significantly inhibited pulmonary vascular injury observed 6 hrs after the administration of endotoxin. Pulmonary vascular injury was not attenuated by the administration of heparin, heparin plus antithrombin III, or the inactive derivative of activated factor X, but pulmonary vascular injury was significantly attenuated in animals with methotrexate-induced leukocytopenia and in those animals treated with N-[2-[4-(2,2-dimethyl-propionyloxy) phenylsulfonylamino] benzoyl] aminoacetic acid. Gabexate Mesilate in concentrations of 10minus 4 to 10minus 3 M inhibited the release of granulocyte elastase and leukocyte aggregation stimulated by N-formyl-methionyl-leucyl-phenylalanine and the opsonized zymosan-activated production of superoxide radical by neutrophils in vitro. Gabexate Mesilate significantly inhibited the endotoxin-induced increase in the serum concentration of TNF-alpha in vivo and, at a concentration of 10minus 8 M, the production of TNF-alpha by endotoxin-stimulated monocytes in vitro. Conclusion Our findings suggest that Gabexate Mesilate attenuated endotoxin-induced pulmonary vascular injury mainly by inhibiting TNF-alpha production by monocytes, which may play a central role in sepsis-related lung injury.
Hiroaki Okabe - One of the best experts on this subject based on the ideXlab platform.
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Gabexate Mesilate a synthetic protease inhibitor inhibits lipopolysaccharide induced tumor necrosis factor α production by inhibiting activation of both nuclear factor κb and activator protein 1 in human monocytes
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Mehtap Yuksel, Mitsuhiro Uchiba, Kenji Okajima, Hiroaki OkabeAbstract:Gabexate Mesilate, a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation in which tumor necrosis factor-α (TNF-α) plays a critical role. We demonstrated that Gabexate Mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-α production in rats. In the present study, we analyzed the mechanism(s) by which Gabexate Mesilate inhibits LPS-induced TNF-α production in human monocytes in vitro. Gabexate Mesilate inhibited the production of TNF-α in monocytes stimulated with LPS. Gabexate Mesilate inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of inhibitory κBα. Gabexate Mesilate also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that Gabexate Mesilate inhibited LPS-induced TNF-α production in human monocytes by inhibiting activation of both NF-κB and AP-1. Inhibition of TNF-α production by Gabexate Mesilate might explain at least partly its therapeutic effects in animals given LPS and those in patients with sepsis.
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Gabexate Mesilate a synthetic protease inhibitor prevents compression induced spinal cord injury by inhibiting activation of leukocytes in rats
Critical Care Medicine, 1997Co-Authors: Yuji Taoka, Mitsuhiro Uchiba, Kenji Okajima, Hiroaki Okabe, Kazunori Murakami, Shigeki Kushimoto, Masayoshi Johno, Masakuni Naruo, Kiyoshi TakatsukiAbstract:Objective: Gabexate Mesilate is a synthetic protease inhibitor capable of inhibiting both coagulation and cytokine production by monocytes. To investigate whether Gabexate Mesilate is useful for the prevention of posttraumatic spinal cord injury, we examined its effect on compression trauma-induced spinal cord injury in rats. Design: Prospective, randomized, blinded, controlled study. Setting: Research laboratory at a university medical center. Subjects: Male Wistar rats weighing 300 to 350 g. Interventions: Spinal cord injury was induced by applying a 20-g weight extradurally to the spinal cord at the level of the 12th thoracic vertebra for 20 mins. Spinal cord injury was evaluated by assessing the motor function of the rats 24 hrs posttrauma. The accumulation of leukocytes and histologic changes in the injured spinal cord tissue also were examined. Rats received Gabexate Mesilate (10 or 20 mglkg ip) 30 mins before or after the compressive trauma. The effects of heparin or an inactive derivative of activated factor X (a selective inhibitor of thrombin generation) on compressive trauma-induced spinal cord injury also were examined. Leukocytopenia was induced by the administration of nitrogen mustard. Measurements and Main Results: The motor disturbances observed following traumatic spinal cord compression, evaluated by Tarlov's score, and the accumulation of leukocytes in the injured tissue, evaluated by measuring tissue myeloperoxidase activity, were markedly reduced by leukocyte depletion induced by nitrogen mustard and by pre- or posttreatment of animals with Gabexate Mesilate. Neither heparin nor the inactive derivative of activated factor X prevented the motor disturbances and the accumulation of leukocytes. Histologic examination demonstrated that intramedullary hemorrhages observed 24 hrs after trauma at the 12th thoracic vertebra were significantly attenuated by nitrogen mustard-induced leukocytopenia and the administration of Gabexate Mesilate. Conclusions: The compression trauma-induced spinal cord injury demonstrated by this model was mainly mediated by leukocytes. Gabexate Mesilate prevented spinal cord injury not by inhibiting coagulation, but by inhibiting the activation of leukocytes.
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Gabexate Mesilate a synthetic protease inhibitor attenuates endotoxin induced pulmonary vascular injury by inhibiting tumor necrosis factor production by monocytes
Critical Care Medicine, 1996Co-Authors: Kazunori Murakami, Mitsuhiro Uchiba, Kenji Okajima, Hiroaki Okabe, Kiyoshi TakatsukiAbstract:Objective In order to determine whether Gabexate Mesilate, a synthetic protease inhibitor with anticoagulant properties, is useful for the treatment of adult respiratory distress syndrome, we examined its effect on endotoxin-induced pulmonary vascular injury in rats. Design Prospective, randomized, controlled study. Setting Research laboratory at a university medical center. Subjects Male Wistar rats (180 to 220 g). Interventions Animals received intravenous infusions of endotoxin (5 mg/kg iv) or saline (control). Pulmonary vascular injury was assessed 6 hrs after administration of endotoxin in terms of the increase in vascular permeability. Rats received Gabexate Mesilate (10 mg/kg ip), heparin, antithrombin III, an inactive derivative of activated factor X (a selective inhibitor of thrombin generation), or N-[2-[4-(2,2-dimethyl-propionyloxy) phenyl-sulfonylamino] benzoyl] aminoacetic acid (ONO-5046) (a potent granulocyte elastase inhibitor) 30 mins before endotoxin administration. Leukocytopenia was induced by administration of methotrexate. The effects of Gabexate Mesilate on the function of activated neutrophils and the production of tumor necrosis factor-alpha (TNF-alpha) by endotoxin-stimulated monocytes were examined in vitro using neutrophils and monocytes prepared from healthy human volunteers. Measurements and Main Results Pulmonary vascular permeability was determined by measuring the vascular leakage of intravenously administered125 I-labeled bovine serum albumin. Intravenous administration of endotoxin significantly increased pulmonary vascular permeability. Gabexate Mesilate significantly inhibited pulmonary vascular injury observed 6 hrs after the administration of endotoxin. Pulmonary vascular injury was not attenuated by the administration of heparin, heparin plus antithrombin III, or the inactive derivative of activated factor X, but pulmonary vascular injury was significantly attenuated in animals with methotrexate-induced leukocytopenia and in those animals treated with N-[2-[4-(2,2-dimethyl-propionyloxy) phenylsulfonylamino] benzoyl] aminoacetic acid. Gabexate Mesilate in concentrations of 10minus 4 to 10minus 3 M inhibited the release of granulocyte elastase and leukocyte aggregation stimulated by N-formyl-methionyl-leucyl-phenylalanine and the opsonized zymosan-activated production of superoxide radical by neutrophils in vitro. Gabexate Mesilate significantly inhibited the endotoxin-induced increase in the serum concentration of TNF-alpha in vivo and, at a concentration of 10minus 8 M, the production of TNF-alpha by endotoxin-stimulated monocytes in vitro. Conclusion Our findings suggest that Gabexate Mesilate attenuated endotoxin-induced pulmonary vascular injury mainly by inhibiting TNF-alpha production by monocytes, which may play a central role in sepsis-related lung injury.
Ryozo Oishi - One of the best experts on this subject based on the ideXlab platform.
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characteristics of Gabexate Mesilate induced cell injury in porcine aorta endothelial cells
Journal of Pharmacological Sciences, 2008Co-Authors: Tomoko Aki, Nobuaki Egashira, Mika Hama, Yui Yamauchi, Takahisa Yano, Yoshinori Itoh, Ryozo OishiAbstract:Abstract Gabexate Mesilate (GM), a serine protease inhibitor, often causes severe vascular injury, when injected in high concentration. In the present study, we investigated the mechanisms for the cytotoxicity of GM on porcine aorta endothelial cells (PAECs). GM (0.5 –5.0 mM) decreased cell viability in a dose-dependent manner and caused cell injury, whilst nafamostat Mesilate (NM), another serine protease inhibitor, or Mesilate itself had no effect on cell viability. zVAD-fmk, a pancaspase inhibitor, or zDEVD-fmk, a caspase-3 inhibitor, did not affect the GM (1.5 mM)-induced decrease of cell viability. Apoptotic cells or DNA fragmentation were also not observed after GM treatment. Moreover, Ca2+chelators, a nitric oxide (NO) synthase inhibitor, antioxidants, and radical scavengers had no effect on the GM-induced cell injury. On the other hand, cellular ATP content was decreased in the GM (2.0 mM)-treated cells. Surprisingly, GM (2.0 mM) immediately increased cellular uptake of propidium iodine. These findings suggest that GM induces necrotic cell death via injury of the cell membrane.
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protective effects of amino acids against Gabexate Mesilate induced cell injury in porcine aorta endothelial cells
Journal of Pharmacological Sciences, 2008Co-Authors: Tomoko Aki, Nobuaki Egashira, Mika Hama, Yui Yamauchi, Takahisa Yano, Yoshinori Itoh, Takaaki Yamada, Ryozo OishiAbstract:Gabexate Mesilate (GM), a serine protease inhibitor, often causes severe vascular injury. We previously reported that GM induced necrotic cell death via injury of the cell membrane in porcine aorta endothelial cells (PAECs). In the present study, we investigated the protective effects of amino acids against this GM-induced cell injury in PAECs. L-Cysteine (Cys), glycine (Gly), L-serine, L-glutamine (Gln), L-glutamate (Glu), L-proline, L-methionine, L-threonine, and L-isoleucine significantly inhibited the GM-induced decrease of cell viability. Gly showed the most potent effect among these amino acids. Gly, L-Cys, L-Glu, and L-Gln also inhibited the GM-induced increase in the number of necrotic cells stained by propidium iodide (PI). However, these amino acids had no effect on the GM-induced inhibition of trypsin activity. Strychnine, MK-801, or dichlorokynurenic acid did not affect the protective effect of Gly. Gly completely suppressed the GM-induced increase in PI uptake, which occurred immediately after exposure to GM. These findings suggest that Gly exerts protection against GM-induced cellular membrane injury, and several amino acids such as Gly may be useful for prophylaxis of the GM-induced severe vascular injury.
Guido Biasco - One of the best experts on this subject based on the ideXlab platform.
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Antitumoral Efficacy of the Protease Inhibitor Gabexate Mesilate in Colon Cancer Cells Harbouring KRAS, BRAF and PIK3CA Mutations
2016Co-Authors: Simona Tavolari, Francesco De Rosa, Stefania Di Girolamo, Valentina Agostini, Maria Aurelia Barbera, Giorgio Frega, Guido BiascoAbstract:The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor Gabexate Mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that Gabexate Mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of Gabexate Mesilate and cetuximab in combination was found to be not superior than that observed with Gabexate Mesilate as single agent. Overall, these preliminary findings suggest that Gabexate Mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as mono-therapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexat
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Effect of Gabexate Mesilate and cetuximab, alone and in combination, on CRC invasive potential.
2013Co-Authors: Giovanni Brandi, Simona Tavolari, Francesco De Rosa, Stefania Di Girolamo, Valentina Agostini, Maria Aurelia Barbera, Giorgio Frega, Guido BiascoAbstract:Evaluation by Boyden chamber invasion assay of CACO-2, SW48, HT-29, Colo205, SW480, SW620, RKO, LS174T and HCT-116 invasive potential after 6 hrs of treatment with cetuximab 100 µg/ml and Gabexate Mesilate 1 mM, alone and in combination. For each cell line, the mean value of untreated samples was assumed as 100% and mean values of treated cells were plotted as percentages with respect to their matched controls. Photographs of invading cells are representative of three independent experiments with similar findings. Cetux: cetuximab; GM: Gabexate Mesilate. Scale bar: 50 µm. *p
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Effect of Gabexate Mesilate and cetuximab, alone and in combination, on CRC cell viability.
2013Co-Authors: Giovanni Brandi, Simona Tavolari, Francesco De Rosa, Stefania Di Girolamo, Valentina Agostini, Maria Aurelia Barbera, Giorgio Frega, Guido BiascoAbstract:Evaluation by MTT assay of CACO-2, SW48, HT-29, Colo205, SW480, SW620, RKO, LS174T and HCT-116 cell viability after 24 and 48 h of treatment with cetuximab 100 µg/ml and Gabexate Mesilate 0.1–1 mM, alone and in combination. Three independent experiments were performed. For each cell line, the mean value of untreated samples was assumed as 100% and mean values of treated cells were plotted as percentages with respect to their matched controls. Cetux: cetuximab; GM: Gabexate Mesilate. *p
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Effect of Gabexate Mesilate and cetuximab, alone and in combination, on CRC conditioned medium-induced angiogenesis.
2013Co-Authors: Giovanni Brandi, Simona Tavolari, Francesco De Rosa, Stefania Di Girolamo, Valentina Agostini, Maria Aurelia Barbera, Giorgio Frega, Guido BiascoAbstract:Evaluation by in vitro Matrigel angiogenesis assay of EA.hy926 endothelial cell differentiation in capillary-like structures after 24 hrs incubation with the conditioned medium of CACO-2, SW48, HT-29, Colo205, SW480, SW620, RKO, LS174T and HCT-116 cells, previously treated for 6 hrs with cetuximab 100 µg/ml and Gabexate Mesilate 1 mM, alone and in combination. Tube formation index was assessed as described in Material and Methods section. For each cell line, the mean value of untreated samples was assumed as 100% and mean values of treated cells were plotted as percentages with respect to their matched controls. Photographs are representative of three independent experiments with similar findings. Cetux: cetuximab; GM: Gabexate Mesilate. Scale bar: 50 µm. *p
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antitumoral efficacy of the protease inhibitor Gabexate Mesilate in colon cancer cells harbouring kras braf and pik3ca mutations
PLOS ONE, 2012Co-Authors: Giovanni Brandi, Simona Tavolari, Francesco De Rosa, Stefania Di Girolamo, Valentina Agostini, Maria Aurelia Barbera, Giorgio Frega, Guido BiascoAbstract:The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor Gabexate Mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that Gabexate Mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of Gabexate Mesilate and cetuximab in combination was found to be not superior than that observed with Gabexate Mesilate as single agent. Overall, these preliminary findings suggest that Gabexate Mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as mono-therapy or in addition to standard chemotherapy regimens. Further studies to better elucidate Gabexate Mesilate mechanism of action in CRC cells are therefore warranted.