The Experts below are selected from a list of 231 Experts worldwide ranked by ideXlab platform
Jwu Lai Yeh - One of the best experts on this subject based on the ideXlab platform.
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data supporting the effects of Xanthine Derivative kmup 3 on vascular smooth muscle cell calcification and abdominal aortic aneurysm in mice
Data in Brief, 2020Co-Authors: Chao Han Lai, Ching Wen Chang, Fang Tzu Lee, Cheng Hsiang Kuo, Jong Hau Hsu, Chung Pin Liu, Jwu Lai YehAbstract:No pharmacotherapy in the clinical setting has been available to alter the natural history of abdominal aortic aneurysm (AAA). Targeting vascular smooth muscle cell (VSMC) dysfunction during the pathogenesis of AAA, including phenotypic switch and apoptosis, could be a potential strategy to limit AAA growth. Here, we provide additional information regarding materials, methods and data related to our recent study published in Atherosclerosis [1]. The therapeutic potential of a self-developed Xanthine Derivative KMUP-3 was evaluated in VSMC calcification and abdominal aortic aneurysm (AAA). In vitro VSMC calcification was induced using β-glycerophosphate, and AAA was induced using angiotensin II infusion for 4 weeks in apolipoprotein E-deficient mice. The data contained in this article support the effects of KMUP-3 on VSMC calcification and AAA.
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targeting vascular smooth muscle cell dysfunction with Xanthine Derivative kmup 3 inhibits abdominal aortic aneurysm in mice
Atherosclerosis, 2020Co-Authors: Chao Han Lai, Ching Wen Chang, Fang Tzu Lee, Cheng Hsiang Kuo, Jong Hau Hsu, Chung Pin Liu, Jwu Lai YehAbstract:Abstract Background and aims Inflammation, oxidative stress, matrix degradation, medial calcification and vascular smooth muscle cell (VSMC) loss are prominent features in abdominal aortic aneurysm (AAA). VSMC phenotypic switch to a proinflammatory state and VSMC apoptosis could be targetable mechanisms implicated in the pathogenesis of AAA formation. Herein, we investigated the hypothesis that a Xanthine Derivative (KMUP-3) might suppress AAA through inhibition of VSMC phenotypic switch and apoptosis. Methods In vitro, VSMC calcification was induced using β-glycerophosphate. In vivo, AAA was induced using angiotensin II (1000 ng/kg per minute) infusion for 4 weeks in apolipoprotein E-deficient mice. Results As determined by alizarin red S staining and calcium content measurements, KMUP-3 suppressed VSMC calcification. During VSMC calcification, KMUP-3 inhibited mTOR and β-catenin upregulation, essential for VSMC phenotypic switch, while it enhanced AMP-activated protein kinase (AMPK) activation that protects against VSMC phenotypic switch. Moreover, KMUP-3 attenuated VSMC apoptosis with an increased Bcl-2/Bax ratio and reduced activated caspase-3 expression. During AAA formation, treatment with KMUP-3 inhibited phosphorylated mTOR expression and increased phosphorylated AMPK expression in the medial layer. In addition, KMUP-3 treatment suppressed aortic dilatation together with reduction in proinflammatory cytokines and infiltrating macrophages, attenuation of medial VSMC apoptosis and mitigation of reactive oxygen species generation, matrix-degrading proteinase activities, elastin breakdown and vascular calcification. Conclusions Treatment with KMUP-3 inhibits aneurysm growth possibly through its interference with signaling pathways involved in VSMC phenotypic switch and apoptosis. These findings provide a proof-of-concept validation for VSMC dysfunction as a potential therapeutic target in AAA.
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activation of endothelial no synthase by a Xanthine Derivative ameliorates hypoxia induced apoptosis in endothelial progenitor cells
Journal of Pharmacy and Pharmacology, 2016Co-Authors: Jong Hau Hsu, Jwu Lai Yeh, Ingjun Chen, Zenkong Dai, Shufen LiouAbstract:Objectives Endothelial damage is strongly associated with cardiovascular diseases such as atherosclerosis, thrombosis and hypertension. Endothelial progenitor cells (EPCs) are primitive bone marrow (BM) cells that possess the capacity to mature into endothelial cells and play a role in neovascularization and vascular remodelling. This study aimed to investigate whether KMUP-1, a synthetic Xanthine-based Derivative, atorvastatin and simvastatin, can prevent endothelial dysfunction and apoptosis induced by hypoxia and to elucidate the underlying mechanisms. Methods Mononuclear cells were separated and were induced to differentiate into EPCs. KMUP-1, atorvastatin or simvastatin were administered prior to hypoxia. Key findings We found that EPCs exposed to hypoxia increased apoptosis as well as diminished proliferation. Pretreatment with KMUP-1, atorvastatin and simvastatin significantly prevented hypoxia-induced EPCs death and apoptosis, with associated increased of the Bcl-2/Bax ratio, and reduced caspase-3 and caspase-9 expression. We also assessed the nitrite production and Ser(1177)-phospho-eNOS expression and found that KMUP-1, atorvastatin and simvastatin not only increased the secretion of NO compared with the hypoxia group but also upregulated the eNOS activation. Conclusions KMUP-1 inhibited hypoxia-induced dysfunction and apoptosis in EPCs, which may be mediated through suppressing oxidative stress, upregulating eNOS and downregulating the caspase-3 signalling pathway.
Jong Hau Hsu - One of the best experts on this subject based on the ideXlab platform.
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data supporting the effects of Xanthine Derivative kmup 3 on vascular smooth muscle cell calcification and abdominal aortic aneurysm in mice
Data in Brief, 2020Co-Authors: Chao Han Lai, Ching Wen Chang, Fang Tzu Lee, Cheng Hsiang Kuo, Jong Hau Hsu, Chung Pin Liu, Jwu Lai YehAbstract:No pharmacotherapy in the clinical setting has been available to alter the natural history of abdominal aortic aneurysm (AAA). Targeting vascular smooth muscle cell (VSMC) dysfunction during the pathogenesis of AAA, including phenotypic switch and apoptosis, could be a potential strategy to limit AAA growth. Here, we provide additional information regarding materials, methods and data related to our recent study published in Atherosclerosis [1]. The therapeutic potential of a self-developed Xanthine Derivative KMUP-3 was evaluated in VSMC calcification and abdominal aortic aneurysm (AAA). In vitro VSMC calcification was induced using β-glycerophosphate, and AAA was induced using angiotensin II infusion for 4 weeks in apolipoprotein E-deficient mice. The data contained in this article support the effects of KMUP-3 on VSMC calcification and AAA.
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targeting vascular smooth muscle cell dysfunction with Xanthine Derivative kmup 3 inhibits abdominal aortic aneurysm in mice
Atherosclerosis, 2020Co-Authors: Chao Han Lai, Ching Wen Chang, Fang Tzu Lee, Cheng Hsiang Kuo, Jong Hau Hsu, Chung Pin Liu, Jwu Lai YehAbstract:Abstract Background and aims Inflammation, oxidative stress, matrix degradation, medial calcification and vascular smooth muscle cell (VSMC) loss are prominent features in abdominal aortic aneurysm (AAA). VSMC phenotypic switch to a proinflammatory state and VSMC apoptosis could be targetable mechanisms implicated in the pathogenesis of AAA formation. Herein, we investigated the hypothesis that a Xanthine Derivative (KMUP-3) might suppress AAA through inhibition of VSMC phenotypic switch and apoptosis. Methods In vitro, VSMC calcification was induced using β-glycerophosphate. In vivo, AAA was induced using angiotensin II (1000 ng/kg per minute) infusion for 4 weeks in apolipoprotein E-deficient mice. Results As determined by alizarin red S staining and calcium content measurements, KMUP-3 suppressed VSMC calcification. During VSMC calcification, KMUP-3 inhibited mTOR and β-catenin upregulation, essential for VSMC phenotypic switch, while it enhanced AMP-activated protein kinase (AMPK) activation that protects against VSMC phenotypic switch. Moreover, KMUP-3 attenuated VSMC apoptosis with an increased Bcl-2/Bax ratio and reduced activated caspase-3 expression. During AAA formation, treatment with KMUP-3 inhibited phosphorylated mTOR expression and increased phosphorylated AMPK expression in the medial layer. In addition, KMUP-3 treatment suppressed aortic dilatation together with reduction in proinflammatory cytokines and infiltrating macrophages, attenuation of medial VSMC apoptosis and mitigation of reactive oxygen species generation, matrix-degrading proteinase activities, elastin breakdown and vascular calcification. Conclusions Treatment with KMUP-3 inhibits aneurysm growth possibly through its interference with signaling pathways involved in VSMC phenotypic switch and apoptosis. These findings provide a proof-of-concept validation for VSMC dysfunction as a potential therapeutic target in AAA.
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activation of endothelial no synthase by a Xanthine Derivative ameliorates hypoxia induced apoptosis in endothelial progenitor cells
Journal of Pharmacy and Pharmacology, 2016Co-Authors: Jong Hau Hsu, Jwu Lai Yeh, Ingjun Chen, Zenkong Dai, Shufen LiouAbstract:Objectives Endothelial damage is strongly associated with cardiovascular diseases such as atherosclerosis, thrombosis and hypertension. Endothelial progenitor cells (EPCs) are primitive bone marrow (BM) cells that possess the capacity to mature into endothelial cells and play a role in neovascularization and vascular remodelling. This study aimed to investigate whether KMUP-1, a synthetic Xanthine-based Derivative, atorvastatin and simvastatin, can prevent endothelial dysfunction and apoptosis induced by hypoxia and to elucidate the underlying mechanisms. Methods Mononuclear cells were separated and were induced to differentiate into EPCs. KMUP-1, atorvastatin or simvastatin were administered prior to hypoxia. Key findings We found that EPCs exposed to hypoxia increased apoptosis as well as diminished proliferation. Pretreatment with KMUP-1, atorvastatin and simvastatin significantly prevented hypoxia-induced EPCs death and apoptosis, with associated increased of the Bcl-2/Bax ratio, and reduced caspase-3 and caspase-9 expression. We also assessed the nitrite production and Ser(1177)-phospho-eNOS expression and found that KMUP-1, atorvastatin and simvastatin not only increased the secretion of NO compared with the hypoxia group but also upregulated the eNOS activation. Conclusions KMUP-1 inhibited hypoxia-induced dysfunction and apoptosis in EPCs, which may be mediated through suppressing oxidative stress, upregulating eNOS and downregulating the caspase-3 signalling pathway.
Chao Han Lai - One of the best experts on this subject based on the ideXlab platform.
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data supporting the effects of Xanthine Derivative kmup 3 on vascular smooth muscle cell calcification and abdominal aortic aneurysm in mice
Data in Brief, 2020Co-Authors: Chao Han Lai, Ching Wen Chang, Fang Tzu Lee, Cheng Hsiang Kuo, Jong Hau Hsu, Chung Pin Liu, Jwu Lai YehAbstract:No pharmacotherapy in the clinical setting has been available to alter the natural history of abdominal aortic aneurysm (AAA). Targeting vascular smooth muscle cell (VSMC) dysfunction during the pathogenesis of AAA, including phenotypic switch and apoptosis, could be a potential strategy to limit AAA growth. Here, we provide additional information regarding materials, methods and data related to our recent study published in Atherosclerosis [1]. The therapeutic potential of a self-developed Xanthine Derivative KMUP-3 was evaluated in VSMC calcification and abdominal aortic aneurysm (AAA). In vitro VSMC calcification was induced using β-glycerophosphate, and AAA was induced using angiotensin II infusion for 4 weeks in apolipoprotein E-deficient mice. The data contained in this article support the effects of KMUP-3 on VSMC calcification and AAA.
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targeting vascular smooth muscle cell dysfunction with Xanthine Derivative kmup 3 inhibits abdominal aortic aneurysm in mice
Atherosclerosis, 2020Co-Authors: Chao Han Lai, Ching Wen Chang, Fang Tzu Lee, Cheng Hsiang Kuo, Jong Hau Hsu, Chung Pin Liu, Jwu Lai YehAbstract:Abstract Background and aims Inflammation, oxidative stress, matrix degradation, medial calcification and vascular smooth muscle cell (VSMC) loss are prominent features in abdominal aortic aneurysm (AAA). VSMC phenotypic switch to a proinflammatory state and VSMC apoptosis could be targetable mechanisms implicated in the pathogenesis of AAA formation. Herein, we investigated the hypothesis that a Xanthine Derivative (KMUP-3) might suppress AAA through inhibition of VSMC phenotypic switch and apoptosis. Methods In vitro, VSMC calcification was induced using β-glycerophosphate. In vivo, AAA was induced using angiotensin II (1000 ng/kg per minute) infusion for 4 weeks in apolipoprotein E-deficient mice. Results As determined by alizarin red S staining and calcium content measurements, KMUP-3 suppressed VSMC calcification. During VSMC calcification, KMUP-3 inhibited mTOR and β-catenin upregulation, essential for VSMC phenotypic switch, while it enhanced AMP-activated protein kinase (AMPK) activation that protects against VSMC phenotypic switch. Moreover, KMUP-3 attenuated VSMC apoptosis with an increased Bcl-2/Bax ratio and reduced activated caspase-3 expression. During AAA formation, treatment with KMUP-3 inhibited phosphorylated mTOR expression and increased phosphorylated AMPK expression in the medial layer. In addition, KMUP-3 treatment suppressed aortic dilatation together with reduction in proinflammatory cytokines and infiltrating macrophages, attenuation of medial VSMC apoptosis and mitigation of reactive oxygen species generation, matrix-degrading proteinase activities, elastin breakdown and vascular calcification. Conclusions Treatment with KMUP-3 inhibits aneurysm growth possibly through its interference with signaling pathways involved in VSMC phenotypic switch and apoptosis. These findings provide a proof-of-concept validation for VSMC dysfunction as a potential therapeutic target in AAA.
Masayuki Nadai - One of the best experts on this subject based on the ideXlab platform.
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alterations in renal uptake kinetics of the Xanthine Derivative enprofylline in endotoxaemic mice
Journal of Pharmacy and Pharmacology, 1996Co-Authors: Masayuki Nadai, Toshiki Okasaka, Soheila Haghgoo, Takaaki Hasegawa, Li Wang, Toshitaka Nabeshima, Nobuo KatoAbstract:: The pharmacokinetics and renal uptake of enprofylline, which is primarily excreted into the urine by an active tubular secretion mechanism, were investigated in endotoxaemic mice by lipopolysaccharide isolated from Klebsiella pneumoniae. Lipopolysaccharide (1 mg kg-1) was infused 2 h before starting the examination, thereby inducing a decrease in the systemic clearance and an increase in the steady-state volume of distribution of enprofylline while inducing no changes in the urinary recovery (> 90%). The protein binding of enprofylline significantly decreased in the presence of lipopolysaccharide. Both the systemic clearance for unbound enprofylline and glomerular filtration rate decreased in the treated mice. A nonlinear relationship was found in both groups between the steady-state unbound plasma concentration and renal uptake of enprofylline after constant infusion for 1 h. The renal uptake rate of enprofylline decreased in the treated mice. Lipopolysaccaharide caused increases in the apparent maximum capacity for renal uptake (Vmax) from 17.3 to 32.2 micrograms h-1 g-1 of kidney and in the Michaelis-Menten constant (Km) from 2.7 to 21.7 micrograms mL-1 and decrease in the nonsaturable uptake rate constant (K4) from 0.87 to 0.43 mL h-1 g-1 of kidney. These results indicate that lipopolysaccharide decreases the renal tubular secretion of enprofylline by inducing a decrease in the renal uptake ability.
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time dependent changes in the pharmacokinetics and renal excretion of Xanthine Derivative enprofylline induced by bacterial endotoxin in rats
Biological & Pharmaceutical Bulletin, 1995Co-Authors: Masayuki Nadai, Soheila Haghgoo, Takaaki Hasegawa, Li Wang, Toshitaka Nabeshima, Nobuo KatoAbstract:Time-dependent changes in the pharmacokinetics and renal handling of enprofylline induced by bacterial endotoxin (Klebsiella pneumoniae LPS) were investigated in rats. To evaluate the early effect of LPS on kidney functions and the renal excretion of enprofylline, which is an organic anion drug excreted primarily by an active tubular secretion, LPS (250μg/kg) was infused for 5 min under constant infusion at rates of 2.3 and 23 μg/min/kg for inulin and enprofylline, respectively. LPS caused a drop in the glomerular filtration rate (GFR), estimated as the renal clearance of inulin, to 65-75% of that observed in the control rats within 30 min after the LPS treatment. The renal clearance (CLr) of enprofylline decreased in conjunction with GFR, while the percentage of decrease in the CLr was slightly greater than that in GFR. LPS-induced decreases in the CLr for enprofylline and GFR continued over the testing period of 120min. The time-dependent effect of LPS on the pharmacokinetics of enprofylline was examined by a single injection of enprofylline (2.5 mg/kg) to rats pretreated 2, 10 or 24h earlier with or without LPS. The pharmacokinetic parameters of enprofylline were determined by a model-independent method. Significant changes in the systemic clearance for enprofylline were observed in rats pretreated 2 and 10h earlier with LPS. but no such changes were observed in rats pretreated 24h earlier with LPS. These findings indicate the existence of a time-dependent effect of LPS on the pharmacokinetics of enprofylline, and suggest that LPS at a dose of 250 μg/kg, at least, does not induce cytotoxicity to kidney cells.
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Protein Binding of Xanthine Derivatives to Guinea Pig Serum Albumin
Journal of pharmaceutical sciences, 1991Co-Authors: Takaaki Hasegawa, Kenzo Takagi, Masayuki Nadai, Kenichi MiyamotoAbstract:Binding of the bronchodilators N3-alkylXanthine and N3-alkyl-N1-methylXanthine Derivatives to guinea pig serum albumin was investigated in vitro using the ultrafiltration method. A marked difference in the binding parameters of Xanthine Derivatives was observed, and binding was shown to be concentration dependent. Significant relations were observed among their binding parameter, dissociation constant (Kd), and hydrophobicity (log PC). The extent of binding of Xanthine Derivatives was increased both when a N3-methyl group was replaced by a longer alkyl chain and when a N3-alkylXanthine molecule was additionally replaced by a methyl group. Reversed-phase HPLC retention, as an index of hydrophobicity of Xanthine Derivatives, was also determined. Significant relationships were found between the adjusted retention time data for each Xanthine Derivative and their hydrophobicity or biological activities, such as their abilities to cause muscle relaxation and cyclic AMP phosphodiesterase (PDE) inhibition. These findings indicate that the difference in the extent of binding among Xanthine Derivatives is related to hydrophobicity, which is an important determinant of their biological activities.
Takaaki Hasegawa - One of the best experts on this subject based on the ideXlab platform.
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alterations in renal uptake kinetics of the Xanthine Derivative enprofylline in endotoxaemic mice
Journal of Pharmacy and Pharmacology, 1996Co-Authors: Masayuki Nadai, Toshiki Okasaka, Soheila Haghgoo, Takaaki Hasegawa, Li Wang, Toshitaka Nabeshima, Nobuo KatoAbstract:: The pharmacokinetics and renal uptake of enprofylline, which is primarily excreted into the urine by an active tubular secretion mechanism, were investigated in endotoxaemic mice by lipopolysaccharide isolated from Klebsiella pneumoniae. Lipopolysaccharide (1 mg kg-1) was infused 2 h before starting the examination, thereby inducing a decrease in the systemic clearance and an increase in the steady-state volume of distribution of enprofylline while inducing no changes in the urinary recovery (> 90%). The protein binding of enprofylline significantly decreased in the presence of lipopolysaccharide. Both the systemic clearance for unbound enprofylline and glomerular filtration rate decreased in the treated mice. A nonlinear relationship was found in both groups between the steady-state unbound plasma concentration and renal uptake of enprofylline after constant infusion for 1 h. The renal uptake rate of enprofylline decreased in the treated mice. Lipopolysaccaharide caused increases in the apparent maximum capacity for renal uptake (Vmax) from 17.3 to 32.2 micrograms h-1 g-1 of kidney and in the Michaelis-Menten constant (Km) from 2.7 to 21.7 micrograms mL-1 and decrease in the nonsaturable uptake rate constant (K4) from 0.87 to 0.43 mL h-1 g-1 of kidney. These results indicate that lipopolysaccharide decreases the renal tubular secretion of enprofylline by inducing a decrease in the renal uptake ability.
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time dependent changes in the pharmacokinetics and renal excretion of Xanthine Derivative enprofylline induced by bacterial endotoxin in rats
Biological & Pharmaceutical Bulletin, 1995Co-Authors: Masayuki Nadai, Soheila Haghgoo, Takaaki Hasegawa, Li Wang, Toshitaka Nabeshima, Nobuo KatoAbstract:Time-dependent changes in the pharmacokinetics and renal handling of enprofylline induced by bacterial endotoxin (Klebsiella pneumoniae LPS) were investigated in rats. To evaluate the early effect of LPS on kidney functions and the renal excretion of enprofylline, which is an organic anion drug excreted primarily by an active tubular secretion, LPS (250μg/kg) was infused for 5 min under constant infusion at rates of 2.3 and 23 μg/min/kg for inulin and enprofylline, respectively. LPS caused a drop in the glomerular filtration rate (GFR), estimated as the renal clearance of inulin, to 65-75% of that observed in the control rats within 30 min after the LPS treatment. The renal clearance (CLr) of enprofylline decreased in conjunction with GFR, while the percentage of decrease in the CLr was slightly greater than that in GFR. LPS-induced decreases in the CLr for enprofylline and GFR continued over the testing period of 120min. The time-dependent effect of LPS on the pharmacokinetics of enprofylline was examined by a single injection of enprofylline (2.5 mg/kg) to rats pretreated 2, 10 or 24h earlier with or without LPS. The pharmacokinetic parameters of enprofylline were determined by a model-independent method. Significant changes in the systemic clearance for enprofylline were observed in rats pretreated 2 and 10h earlier with LPS. but no such changes were observed in rats pretreated 24h earlier with LPS. These findings indicate the existence of a time-dependent effect of LPS on the pharmacokinetics of enprofylline, and suggest that LPS at a dose of 250 μg/kg, at least, does not induce cytotoxicity to kidney cells.
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Protein Binding of Xanthine Derivatives to Guinea Pig Serum Albumin
Journal of pharmaceutical sciences, 1991Co-Authors: Takaaki Hasegawa, Kenzo Takagi, Masayuki Nadai, Kenichi MiyamotoAbstract:Binding of the bronchodilators N3-alkylXanthine and N3-alkyl-N1-methylXanthine Derivatives to guinea pig serum albumin was investigated in vitro using the ultrafiltration method. A marked difference in the binding parameters of Xanthine Derivatives was observed, and binding was shown to be concentration dependent. Significant relations were observed among their binding parameter, dissociation constant (Kd), and hydrophobicity (log PC). The extent of binding of Xanthine Derivatives was increased both when a N3-methyl group was replaced by a longer alkyl chain and when a N3-alkylXanthine molecule was additionally replaced by a methyl group. Reversed-phase HPLC retention, as an index of hydrophobicity of Xanthine Derivatives, was also determined. Significant relationships were found between the adjusted retention time data for each Xanthine Derivative and their hydrophobicity or biological activities, such as their abilities to cause muscle relaxation and cyclic AMP phosphodiesterase (PDE) inhibition. These findings indicate that the difference in the extent of binding among Xanthine Derivatives is related to hydrophobicity, which is an important determinant of their biological activities.