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Nicholas W Morrell - One of the best experts on this subject based on the ideXlab platform.
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sildenafil potentiates bone morphogenetic protein signaling in pulmonary arterial smooth muscle cells and in experimental pulmonary hypertension
Arteriosclerosis Thrombosis and Vascular Biology, 2013Co-Authors: Jun Yang, Ralph T Schermuly, Rafia S Allamki, Astrid Weiss, Joachim Berk, Nicholas W MorrellAbstract:Objective— Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable pulmonary arterial hypertension (PAH), and BMPR-II deficiency contributes to idiopathic and experimental forms of PAH. Sildenafil, a potent type-5 nucleotide-dependent phosphodiesterase inhibitor, is an established treatment for PAH, but whether sildenafil affects bone morphogenetic protein (BMP) signaling in the pulmonary circulation remains unknown. Methods and Results— Studies were undertaken in human pulmonary arterial smooth muscle cells (PASMCs) and in vivo in the Monocrotaline rat model of PAH. In PASMCs, sildenafil enhanced BMP4-induced phosphorylation of Smad1/5, Smad nuclear localization, and Inhibitor of DNA binding protein 1 gene and protein expression. This effect was mimicked by 8-bromo-cyclic GMP. Pharmacological inhibition or small interfering RNA knockdown of cyclic GMP-dependent protein kinase I inhibited the effect of sildenafil on BMP signaling. In functional studies, we observed that sildenafil potentiated the antiproliferative effects of BMP4 on PASMC proliferation. Furthermore, sildenafil restored the antiproliferative response to BMP4 in PASMCs harboring mutations in BMPR-II. In the Monocrotaline rat model of PAH, which is characterized by BMPR-II deficiency, sildenafil prevented the development of pulmonary hypertension and vascular remodeling, and partly restored Smad1/5 phosphorylation and Inhibitor of DNA binding protein 1 gene expression in vivo in Monocrotaline exposed rat lungs. Conclusion— Sildenafil enhances canonical BMP signaling via cyclic GMP and cyclic GMP-dependent protein kinase I in vitro and in vivo, and partly restores deficient BMP signaling in BMPR-II mutant PASMCs. Our findings demonstrate a novel mechanism of action of sildenafil in the treatment of PAH and suggest that targeting BMP signaling may be beneficial in this disease.
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altered bone morphogenetic protein and transforming growth factor β signaling in rat models of pulmonary hypertension potential for activin receptor like kinase 5 inhibition in prevention and progression of disease
Circulation, 2009Co-Authors: Lu Long, Alexi Crosby, Xudong Yang, Mark Southwood, Paul D Upton, Daekee Kim, Nicholas W MorrellAbstract:Background— Recent genetic studies have highlighted the role of the bone morphogenetic protein (BMP)/transforming growth factor (TGF)-β signaling pathways in the pathogenesis of familial pulmonary arterial hypertension (PAH). It remains unclear whether alterations in these pathways contribute to other forms of pulmonary hypertension and to what extent these changes can be exploited for therapeutic intervention. Methods and Results— We studied BMP/TGF-β signaling in 2 rat models of PAH due to chronic hypoxia and Monocrotaline. In both models, there was a significant reduction in lung BMP type IA receptor and BMP type II receptor mRNA expression, although these changes were more pronounced in the Monocrotaline model. This was accompanied by a reduction in lung levels of phospho-Smad1/5 and Id (inhibitor of DNA binding) gene expression in the Monocrotaline model. In contrast, we observed increased TGF-β activity, again more marked in the Monocrotaline model, as evidenced by increased phospho-Smad2/3 and incr...
Akira Satoh - One of the best experts on this subject based on the ideXlab platform.
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3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension
2015Co-Authors: Mitsutoshi Satoh, Akira SatohAbstract:ABSTRACT- Purpose. We examined the inhibitory effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, a prostacyclin analogue and a phosphodiesterase type V inhibitor on hemodynamic function and cardiac remodeling in rats with Monocrotaline-induced pulmonary hypertension. Methods. The rat model of pulmonary hypertension was created by administration of Monocrotaline (70 mg/kg, s.c.) to male Wistar rats. A polyethylene tube was introduced into a left carotid artery for measurement of mean arterial pressure (MAP), another into the right ventricle via the right jugular vein for measurement of right ventricular systolic pressure (RVSP). Results. Repeated administration of atorvastatin (2 mg/kg/day, p.o. 0- 28 days) an
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3 hydroxy 3 methylglutaryl coa reductase inhibitors and phosphodiesterase type v inhibitors attenuate right ventricular pressure and remodeling in a rat model of pulmonary hypertension
Journal of Pharmacy and Pharmaceutical Sciences, 2009Co-Authors: Mitsutoshi Satoh, Akira SatohAbstract:PURPOSE. We examined the inhibitory effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors and a phosphodiesterase type V inhibitor on hemodynamic function and cardiac remodeling in rats with Monocrotaline-induced pulmonary hypertension. METHODS. The rat model of pulmonary hypertension was created by administration of Monocrotaline (70 mg/kg, s.c.) to male Wistar rats. A polyethylene tube was introduced into a femoral artery for measurement of mean arterial pressure, another into the right ventricle via the right jugular vein for measurement of right ventricular systolic pressure (RVSP), and another into a femoral vein for administration of test drugs. RESULTS. Repeated administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) and simvastatin (2 mg/kg/day, p.o. 0 - 28 days) significantly reduced RVSP and right ventricular weight (RV)/left ventricular + septum weight (LV + S) without a change in heart rate. However, repeated administration of pravastatin (4 mg/kg/day, p.o. 0 - 28 days) did not reduce the Monocrotaline-induced elevation of RVSP and RV/(LV + S) significantly. The reduction of RVSP and RV/(LV + S)) induced by a combination of a prostacyclin analogue, beraprost (100 mg/kg/day, 0 - 28 days) and simvastatin (2 mg/kg/day, 0 - 28 days), was more potent than the effect induced by each drug alone. Sildenafil (5 mg/kg/day, 0 - 28 days) tended to reduce RVSP and RV/(LV + S). Repeated combined administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) + sildenafil (5 mg/kg/day, p.o. 0 - 28 days) significantly reduced Lung/BW. CONCLUSION. Our present results suggest that repeated administration of the lipophilic HMG-CoA reductase inhibitors, atorvastatin and simbastatin, selectively attenuates the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with Monocrotaline-induced pulmonary hypertension, and that a combination of HMG-CoA reductase inhibitor and beraprost has a more potent effect than each agent alone.
Jun Tang - One of the best experts on this subject based on the ideXlab platform.
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The chemical structures of senecionine, seneciphylline, Monocrotaline and clivorine.
2017Co-Authors: Wenju Liu, Bo Zhou, Shoucai Fang, Hui Chen, Hao Liang, Jun TangAbstract:The chemical structures of senecionine, seneciphylline, Monocrotaline and clivorine.
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Cytotoxic effects of senecionine, seneciphylline, Monocrotaline and clivorine increase with the increase of their concentrations in Huh-7.5 cells as determined by MTT.
2017Co-Authors: Wenju Liu, Bo Zhou, Shoucai Fang, Hui Chen, Hao Liang, Jun TangAbstract:Cells were incubated with indicated concentrations of senecionine (closed rectangle), seneciphylline (closed diamond), Monocrotaline (closed triangle) and clivorine (open circle) for 48 h, respectively. Cell viability was measured by MTT assay as described in Materials and Methods. Values are shown as mean ± SD (n = 3), of which the solvent control are at 0 μM; Δ, #P < 0.05, **P < 0.01, ***, ΔΔΔ, ###P < 0.001, comparing clivorine with senecionine (*), seneciphylline (Δ), and Monocrotaline (#), respectively, at the corresponding concentrations.
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Transmission electron micrographs of autophagosome induced by senecionine, seneciphylline, clivorine and Monocrotaline in Huh-7.5 cells.
2017Co-Authors: Wenju Liu, Bo Zhou, Shoucai Fang, Hui Chen, Hao Liang, Jun TangAbstract:(a) The untreated Huh-7.5 cells (Control); (b) The senecionine -treated cells (6.25 μM), (c) The seneciphylline-treated cells (6.25 μM), (d) The clivorine-treated cells (6.25 μM), (e) The Monocrotaline-treated cells (6.25 μM). Huh-7.5 cells were cultured in the presence of senecionine, seneciphylline, clivorine and Monocrotaline for 24 h, respectively. As indicated by black arrows, the autophagic vacuoles with double-membrane structures were observed in cytoplasm. Asterisks indicate mature autophagosomes containing highly degraded contents. N, nucleus. Scale bar, 500 nm.
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Evaluation of senecionine, seneciphylline, Monocrotaline and clivorine-induced apoptosis of Huh-7.5 cells by flow cytometry analysis.
2017Co-Authors: Wenju Liu, Bo Zhou, Shoucai Fang, Hui Chen, Hao Liang, Jun TangAbstract:Cells were treated by four concentrations of senecionine, seneciphylline, Monocrotaline and clivorine for 24 h, respectively. Afterwards, the cells were collected and stained with Annexin V-kFluor488 and PI. The flow cytometry analysis was performed. The percentages of apoptotic cells at both the early and late periods were shown as Q1-LR and Q1-UR, respectively, in the form of scatter plots (a-1 to a-4). The results in the representative of three independent experiments were marked in each diagram and summarized in the histograms (b-1 to b-4). a-1 and b-1 show the results from senecionine-treated cells; a-2 and b-2, from seneciphylline-treated cells; a-3 and b-3, from Monocrotaline-treated cells; a-4 and b-4, from clivorine-treated cells. N0, F0, M0 and C0, negative controls; N6.25, N25, N100 and N400 represent senecionine-treated cells at the concentrations of 6.25 μM, 25 μM, 100 μM and 400 μM; F6.25, F25, F100 and F400 represent seneciphylline-treated cells at the concentrations of 6.25 μM, 25 μM, 100 μM and 400 μM; M6.25, M25, M100 and M400 represent Monocrotaline-treated cells at the concentrations of 6.25 μM, 25 μM, 100 μM and 400 μM; and C6.25, C25, C100, and C400 represent clivorine-treated cells at the concentrations of 6.25 μM, 25 μM, 100 μM and 400 μM, respectively. *P
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in vitro metabolism of isoline a pyrrolizidine alkaloid from ligularia duciformis by rodent liver microsomal esterase and enhanced hepatotoxicity by esterase inhibitors
Drug Metabolism and Disposition, 2007Co-Authors: Jun Tang, Zhengtao Wang, Teruaki Akao, Norio Nakamura, Kiyoshi Takagawa, Masakiyo Sasahara, Masao HattoriAbstract:Isoline, a major retronecine-type pyrrolizidine alkaloid (PA) from the Chinese medicinal herb Ligularia duciformis, was suggested to be the most toxic known PA. Its in vitro metabolism was thus examined in rat and mouse liver microsomes, and its toxicity was compared with that of clivorine and Monocrotaline after i.p. injection in mice. Isoline was more rapidly metabolized by both microsomes than clivorine and Monocrotaline and converted to two polar metabolites M1 and M2, which were spectroscopically determined to be bisline (a deacetylated metabolite of isoline) and bisline lactone, respectively. Both metabolites were formed in the presence or absence of an NADPH-generating system with liver microsomes but not cytosol. Their formation was completely inhibited by the esterase inhibitors, triorthocresyl phosphate (TOCP) and phenylmethylsulfonyl fluoride, but not at all or partially by cytochrome P450 (P450) inhibitors, α-naphthoflavone and proadifen (SKF 525A), respectively. These results demonstrated that both metabolites were produced by microsomal esterase(s) but not P450 isozymes. The esterase(s) involved showed not only quite different activities but also responses to different inhibitors in rat and mouse liver microsomes, suggesting that different key isozyme(s) or combinations might be responsible for the deacetylation of isoline. Isoline injected i.p. into mice induced liver-specific toxicity that was much greater than that with either clivorine or Monocrotaline, as judged by histopathology as well as serum alanine aminotransferase and aspartate aminotransferase levels. Isoline-induced hepatotoxicity was remarkably enhanced by the esterase inhibitor TOCP but was reduced by the P450 inhibitor SKF 525A, indicating that rodent hepatic esterase(s) played a principal role in the detoxification of isoline via rapid deacetylation in vivo.
Lamiaa A Ahmed - One of the best experts on this subject based on the ideXlab platform.
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pinocembrin ex vivo preconditioning improves the therapeutic efficacy of endothelial progenitor cells in Monocrotaline induced pulmonary hypertension in rats
Biochemical Pharmacology, 2017Co-Authors: Lamiaa A Ahmed, Sherine M Rizk, Shohda A ElmaraghyAbstract:Pulmonary hypertension is still not curable and the available current therapies can only alleviate symptoms without hindering the progression of disease. The present study was directed to investigate the possible modulatory effect of pinocembrin on endothelial progenitor cells transplanted in Monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of Monocrotaline (60mg/kg). Endothelial progenitor cells were in vitro preconditioned with pinocembrin (25mg/L) for 30min before being i.v. injected into rats 2weeks after Monocrotaline administration. Four weeks after Monocrotaline administration, blood pressure, electrocardiography and right ventricular systolic pressure were recorded. Rats were sacrificed and serum was separated for determination of endothelin-1 and asymmetric dimethylarginine levels. Right ventricles and lungs were isolated for estimation of tumor necrosis factor-alpha and transforming growth factor-beta contents as well as caspase-3 activity. Moreover, protein expression of matrix metalloproteinase-9 and endothelial nitric oxide synthase in addition to myocardial connexin-43 was assessed. Finally, histological analysis of pulmonary arteries, cardiomyocyte cross-sectional area and right ventricular hypertrophy was performed and cryosections were done for estimation of cell homing. Preconditioning with pinocembrin provided a significant improvement in endothelial progenitor cells' effect towards reducing Monocrotaline-induced elevation of inflammatory, fibrogenic and apoptotic markers. Furthermore, preconditioned cells induced a significant amelioration of endothelial markers and cell homing and prevented Monocrotaline-induced changes in right ventricular function and histological analysis compared with native cells alone. In conclusion, pinocembrin significantly improves the therapeutic efficacy of endothelial progenitor cells in Monocrotaline-induced pulmonary hypertension in rats.
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role of oxidative stress inflammation nitric oxide and transforming growth factor beta in the protective effect of diosgenin in Monocrotaline induced pulmonary hypertension in rats
European Journal of Pharmacology, 2014Co-Authors: Lamiaa A Ahmed, Al Arqam Z Obaid, Hala F Zaki, Azza M AghaAbstract:Pulmonary hypertension is a progressive disease of various origins that is associated with right ventricular dysfunction. In the present study, the protective effect of diosgenin was investigated in Monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of Monocrotaline (60 mg/kg). Diosgenin (100 mg/kg) was given by oral administration once daily for 3 weeks. At the end of the experiment, mean arterial blood pressure, electrocardiography and echocardiography were recorded. Rats were then sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta contents. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Diosgenin treatment provided a significant improvement toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by Monocrotaline in rats. Furthermore, diosgenin therapy prevented Monocrotaline-induced changes in nitric oxide production, endothelial and inducible nitric oxide synthase protein expression as well as histological analysis. These findings support the beneficial effect of diosgenin in pulmonary hypertension induced by Monocrotaline in rats.
Ming W. Chou - One of the best experts on this subject based on the ideXlab platform.
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formation of dhp derived dna adducts from metabolic activation of the prototype heliotridine type pyrrolizidine alkaloid heliotrine
Toxicology Letters, 2008Co-Authors: Qingsu Xia, Jian Yan, Ming W. ChouAbstract:Abstract Pyrrolizidine alkaloid-containing plants are widespread in the world and may be the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids require metabolism to exert their genotoxicity and tumorigenicity. Our mechanistic studies have determined that metabolism of the retronecine-type (riddelliine, retrorsine, and Monocrotaline), heliotridine-type (lasiocarpine), and otonecine-type (clivorine) tumorigenic pyrrolizidine alkaloids in vivo and/or in vitro all generates a common set of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts responsible for tumor induction. All the pyrrolizidine alkaloids studied previously are diesters with an ester linkage at the C7 and C9 positions of the necine base. In this study, we report that F344 rat liver microsomal metabolism of heliotrine, a tumorigenic monoester bearing a hydroxyl group at the C7 of the necine base, resulted in the formation of the dehydroheliotridine (DHH) metabolite. When incubations of heliotrine were carried out in the presence of calf thymus DNA, the same set of DHP-derived DNA adducts was formed. These results support that DHP-derived DNA adducts are potential common biomarkers of pyrrolizidine alkaloid exposure and tumorigenicity. For comparison, the dehydroretronecine (DHR)-derived DNA adducts formed from metabolism of riddleiine, retrorsine, Monocrotaline, riddelleiine N-oxide, and retrorsine N-oxide were measured in parallel; the levels of DHP-derived DNA adduct formation were in the order: riddelliine ≈ retrorsine > Monocrotaline > retrorsine N-oxide ≥ riddelliine N-oxide > heliotrine.