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Sample records for circulating plasma endothelin-1

  1. Elevated circulating plasma endothelin-1 concentrations in cirrhosis

    DEFF Research Database (Denmark)

    Møller, S; Emmeluth, C; Henriksen, Jens Henrik Sahl

    1993-01-01

    As endothelin-1 (ET-1), a potent vasoconstricting peptide, may play a role in the circulatory derangement and renal impairment in cirrhosis, the aim of the present study was to investigate plasma concentrations of ET-1 in different vascular beds in relation to clinical and biochemical parameters.......70, P plasma concentration between the liver, renal, or femoral...

  2. Elevated circulating plasma endothelin-1 concentrations in cirrhosis

    DEFF Research Database (Denmark)

    Møller, Søren; Emmeluth, C; Henriksen, Jens Henrik

    1993-01-01

    veins on the one hand and the femoral artery on the other (P > 0.1), indicating no major net elimination or release in the liver, kidney or lower limb. A significant negative correlation was found between systolic and diastolic blood pressures on the one hand and circulating ET-1 on the other (r = -0.......70, P vein catheterization (n = 8), no significant differences were found in ET-1 plasma concentration between the liver, renal, or femoral...

  3. Opposed circulating plasma levels of endothelin-1 and C-type natriuretic peptide in children with Plasmodium falciparum malaria

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    Issifou Saadou

    2008-12-01

    Full Text Available Abstract Background Molecular mechanisms involved in the pathogenesis of severe Plasmodium falciparum malaria (SM, are not yet fully understood. Both endothelin-1 (ET-1 and C-type natriuretic peptide (CNP are produced by vascular endothelium and act locally as paracrine regulators of vascular tone, ET-1 being a potent vasoconstrictor and CNP having strong vasorelaxant properties. Methods Plasma levels of ET-1 and N-terminal fragments of CNP (NT-proCNP were studied on admission and after 24 hours of treatment, using enzyme-linked-immunosorbent-assay (ELISA technique, in Gabonese children with severe falciparum malaria (SM, n = 50, with uncomplicated malaria (UM, n = 39 and healthy controls (HC, n = 25. Results Compared to HC, malaria patients had significantly higher plasma levels of ET-1 and significantly lower levels of NT-proCNP (p p p = 0.034, whereas UM was not significantly different to HC. In the SM group we found a trend towards lower ET-1 levels compared to UM (p = 0.085. Conclusion In the present study, an imbalance between the vasoconstricitve and vasorelaxant endothelium-derived substances ET-1 and CNP in the plasma of children with falciparum malaria is demonstrated, presumably in favor of vasoconstrictive and pro-inflammatory effects. These results may indicate involvement of ET-1 and CNP in malaria pathogenesis. Furthermore, results of lower ET-1 and CNP levels in SM may reflect endothelial cell damage.

  4. Physical activity opposes the age-related increase in skeletal muscle and plasma endothelin-1 levels and normalizes plasma endothelin-1 levels in individuals with essential hypertension

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Mortensen, Stefan Peter; Hellsten, Ylva

    2013-01-01

    AIMS: Endothelin-1 has potent constrictor and proliferative activity in vascular smooth muscle, and essential hypertension and aging are associated with increased endothelin-1-mediated vasoconstrictor tone. The aim of this study was to investigate the effect of physical activity, hypertension...... performed lifelong physical activity had similar plasma and muscle endothelin-1 levels as the young controls and had higher ET(A) receptor levels. CONCLUSION: Our findings suggest that aerobic exercise training opposes the age-related increase in skeletal muscle and plasma endothelin-1 levels and normalizes...... plasma endothelin-1 levels in individuals with essential hypertension. This effect may explain some of the beneficial effects of training on the cardiovascular system in older and hypertensive subjects....

  5. Venous plasma levels of endothelin-1 are not altered immediately after nitroglycerin infusion in healthy subjects

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    Thomsen, L L; Iversen, Helle Klingenberg; Emmeluth, C;

    1995-01-01

    Endothelin-1 and nitric oxide play an important regulatory role in the control of vascular smooth muscle tone. Nitroglycerin (NTG), a nitric oxide donating drug, may inhibit endothelin production. In this double-blind placebo-controlled crossover study, plasma levels of endothelin-1 were measured...

  6. Endothelin-1 concentration in plasma is increased after jogging but decreased after cycling in healthy men.

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    Lewczuk, P; Söhnchen, N; Kele, H; Reimers, C D; Ehrenreich, H

    2003-02-01

    Endothelin-1 plays an important role as a paracrine factor in the regulation of regional blood flow. Plasma levels may represent the net result of spill-over from local stimulation/release and elimination of endothelin-1. In order to compare changes in the concentration of endothelin-1 in the plasma of subjects performing different types of sports exercises we measured immunoreactive endothelin-1 in healthy volunteers ( n=20) performing in random order jogging on a treadmill and cycling on a bicycle ergometer, for 30 min each. Plasma immunoreactive endothelin-1 increased significantly after jogging (2.13+/-0.8 pg/ml versus 2.6+/-0.8 pg/ml, before and after exercise, respectively, Pjogging than during cycling, resulting in a greater increase in plasma endothelin-1, which is too high to be immediately eliminated by the lung despite exercise-induced enhanced pulmonary perfusion. In contrast, similarly enhanced lung perfusion together with a relatively lower stimulation of endothelin-1 compared with jogging, may explain the net decrease in plasma after cycling.

  7. Influence of Circulating Endothelin-1 and Asymmetric Dimethylarginine on Whole Brain Circulation Time in Multiple Sclerosis

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    Lucia Monti

    2017-06-01

    Full Text Available Blood-brain barrier (BBB breakdown, inflammatory and immune cell activation, and chronic cerebral hypoperfusion are features of multiple sclerosis (MS. The aim is to determine the influence of endothelin-1 (ET1 and asymmetric dimethylarginine (ADMA on cerebral circulation time (CCT in patients with MS. In all, 64 patients with MS (39 relapsing-remitting [RR]-MS; 25 secondary progressive [SP]-MS subtype and 37 controls (C were studied. Cerebral circulation time was obtained by angiography. Plasmatic ET1 and ADMA were measured by enzyme-linked immunosorbent assay. Lesion load (LL and brain volume (BV were obtained by magnetic resonance imaging. Cerebral circulation time was correlated to ET1, ADMA, LL, BV, disease duration (DD, and Expanded Disability Status Scale (EDSS. In MS, both ET1 and ADMA were significantly higher than C ( P  < .0001; CCT was approximately 2 times lower than C ( P  < .0001 and significantly slower in SP than in RR-MS ( P  = .0215. Cerebral circulation time significantly correlated with ET1 in SP-MS ( r  = 0.38, whereas in RR-MS CCT significantly correlated with DD ( r  = 0.75. The LL, BV, and EDSS did not correlate with CCT. Endothelin-1 significantly influences CCT delay in SP-MS. Diversely, CCT in RR-MS is independent of ET1 and correlates significantly with DD. We conclude that in RR-MS, DD responds to neurovascular damage accumulation. It is supposed that high ET1 and ADMA levels stem from a protective response to early insults, aimed at opposing nitric oxide overproduction, whereas persistent pathological ET1 and ADMA levels translate into detrimental long-term effects, due to increased brain micro-vessel resistance.

  8. Elimination of intravenously injected endothelin-1 from the circulation of the rat

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    Shiba, R.; Yanagisawa, M.; Miyauchi, T.; Ishii, Y.; Kimura, S.; Uchiyama, Y.; Masaki, T.; Goto, K.

    1989-01-01

    The rate of elimination and the fate of endothelin-1 (ET-1) from the circulating blood was studied in urethane-anesthetized rats by intravenous injection of (125I)-labeled ET-1. The vasoconstrictor activities of the iodinated ET-1 were confirmed to be similar to those of native ET-1. Following i.v. bolus injection of 30 pmol/kg of (125I)-ET-1 into the femoral vein, the total radioactivity of the right atrial blood decayed rapidly, with a half-life of 7 min. At 5 min after the injection, the administered radioactivity distributed chiefly to the parenchyma of the lungs, kidneys, and liver. The analysis of the chemical form of labeled peptides from the plasma by reverse-phase high-performance liquid chromatography (HPLC) demonstrated no appreciable amount of degraded forms of (125I)-ET-1 in the blood for up to 60 min. (125I)-ET-1 was also stable for up to 60 min upon incubation in vitro with heparinized rat blood at 37 degrees C. Even when the same amount of labeled ET-1 was injected together with a pressor dose (1,500 pmol/kg) of cold ET-1, the half-life of the radioactivity in the bloodstream was exactly identical to that for (125I)-ET-1 alone. Nevertheless, the pressor response continued for more than 90 min after i.v. bolus injection of 1500 pmol/kg of ET-1 to the rat. These results clearly indicate that the elimination of ET-1 from circulating blood and the ET-1-induced pressor response are not in parallel, and the relatively rapid disappearance of ET-1 from the bloodstream is mostly due to the removal of the peptide by the parenchymal tissues, in the anesthetized rat. The long-lasting pressor action of ET-1 may be ascribed to our previous finding that the dissociation of ET-1 from its specific binding sites on vascular smooth muscle cells is extremely slow.

  9. Elevated Plasma Endothelin-1 Levels in Normal Tension Glaucoma and Primary Open-Angle Glaucoma: A Meta-Analysis

    Science.gov (United States)

    Li, Shengjie; Zhang, Aiping

    2016-01-01

    Purpose. The aim of this meta-analysis was to clarify the association between the plasma endothelin-1 level and the risks of normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG). Methods. Relevant publications were collected from three databases including PubMed, EMBASE, and the Web of Science through December 31, 2015. In this study, the terms “(endothelin OR ET) AND glaucoma” were searched. Review Manager 5.2 was used to process the data. Results. Seven studies (212 cases, 164 controls) were included for the NTG analysis. The mean plasma endothelin-1 level in the NTG subjects was 0.60 pg/mL (p = 0.02, 95% CI: 0.17–1.04) higher than that of the healthy controls. Six studies (160 cases, 174 controls) were included for the POAG analysis, and the endothelin-1 level was 0.63 pg/mL (p = 0.007, 95% CI: 0.12–1.15) higher in the POAG subjects than in the healthy controls. Additionally, two studies influenced the meta-analysis results regarding the association of plasma endothelin-1 with POAG by sensitivity analysis, and the probability of publication bias was low. Conclusions. The observation that NTG and POAG subjects showed significantly elevated endothelin-1 plasma concentrations suggests that a higher plasma level of endothelin-1 might increase the risk of NTG and POAG development. PMID:27965889

  10. Low levels of plasma endothelin-1 in patients with retinitis pigmentosa

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    Hiroshi Ohguro

    2010-06-01

    Full Text Available Hiroshi Ohguro1, Yukihiko Mashima2, Mitsuru Nakazawa31Department of Ophthalmology, Sapporo Medical University School of Medicine, 2Department of Ophthalmology, Keio University School of Medicine, 3Department of Ophthalmology, Hirosaki University School of Medicine, JapanPurpose: The aim of this study was to elucidate the role of endothelin-1 (ET-1 in the pathophysiology of retinitis pigmentosa (RP.Methods: Plasma ET-1 levels and ophthalmic features in 50 RP patients were compared with those in 20 healthy-eye control subjects. Plasma ET-1 concentrations were determined using a commercially available enzyme-linked immunosorbent assay kit.Results: Mean plasma ET-1 levels of RP patients (1.88 ± 0.56 pg/mL were significantly lower than those of control subjects (2.30 ± 0.30 pg/mL, Mann-Whitney’s U test; P < 0.01. However, ET-1 concentrations varied markedly in each patient. Among RP patients, a significant correlation of ET-1 concentrations was not observed in terms of its hereditary forms or other clinical factors.Conclusion: ET-1 may be important in the pathogenesis of RP, and measurement of its plasma concentrations may also contribute to additional insights into the retinal hemodynamics of RP.Keywords: endothelin-1, retinitis pigmentosa, retinal hemodynamics

  11. Acute effects of inhaled urban particles and ozone: lung morphology, macrophage activity, and plasma endothelin-1.

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    Bouthillier, L; Vincent, R; Goegan, P; Adamson, I Y; Bjarnason, S; Stewart, M; Guénette, J; Potvin, M; Kumarathasan, P

    1998-12-01

    We studied acute responses of rat lungs to inhalation of urban particulate matter and ozone. Exposure to particles (40 mg/m3 for 4 hours; mass median aerodynamic diameter, 4 to 5 microm; Ottawa urban dust, EHC-93), followed by 20 hours in clean air, did not result in acute lung injury. Nevertheless, inhalation of particles resulted in decreased production of nitric oxide (nitrite) and elevated secretion of macrophage inflammatory protein-2 from lung lavage cells. Inhalation of ozone (0.8 parts per million for 4 hours) resulted in increased neutrophils and protein in lung lavage fluid. Ozone alone also decreased phagocytosis and nitric oxide production and stimulated endothelin-1 secretion by lung lavage cells but did not modify secretion of macrophage inflammatory protein-2. Co-exposure to particles potentiated the ozone-induced septal cellularity in the central acinus but without measurable exacerbation of the ozone-related alveolar neutrophilia and permeability to protein detected by lung lavage. The enhanced septal thickening was associated with elevated production of both macrophage inflammatory protein-2 and endothelin-1 by lung lavage cells. Interestingly, inhalation of urban particulate matter increased the plasma levels of endothelin-1, but this response was not influenced by the synergistic effects of ozone and particles on centriacinar septal tissue changes. This suggests an impact of the distally distributed particulate dose on capillary endothelial production or filtration of the vasoconstrictor. Overall, equivalent patterns of effects were observed after a single exposure or three consecutive daily exposures to the pollutants. The experimental data are consistent with epidemiological evidence for acute pulmonary effects of ozone and respirable particulate matter and suggest a possible mechanism whereby cardiovascular effects may be induced by particle exposure. In a broad sense, acute biological effects of respirable particulate matter from ambient air

  12. Effect of breed on plasma endothelin-1 concentration, plasma renin activity, and serum cortisol concentration in healthy dogs

    DEFF Research Database (Denmark)

    Höglund, K.; Lequarré, A.-S.; Ljungvall, I.

    2016-01-01

    BACKGROUND: There are breed differences in several blood variables in healthy dogs. OBJECTIVE: Investigate breed variation in plasma endothelin-1 (ET-1) concentration, plasma renin activity, and serum cortisol concentration. ANIMALS: Five-hundred and thirty-one healthy dogs of 9 breeds examined...... blood pressure measurement, echocardiography, ECG, blood and urine analysis. RESULTS: Median ET-1 concentration was 1.29 (interquartile range [IQR], 0.97-1.82) pg/mL, median cortisol concentration 46.0 (IQR, 29.0-80.8) nmol/L, and median renin activity 0.73 (IQR, 0.48-1.10) ng/mL/h in all dogs. Overall...

  13. Plasma endothelin-1 and tumor necrosis factor-alpha concentrations in pregnant and cyclic rats after low-dose endotoxin infusion

    NARCIS (Netherlands)

    Faas, MM; Bakker, WW; Valkhof, N; Baller, JFW; Schuiling, GA

    1997-01-01

    Plasma endothelin-1 and tumor necrosis factor-alpha were determined in pregnant and cyclic rats after infusion of either endotoxin (1.0 mu g/kg of body weight) or saline solution. After endotoxin, but not after saline solution, administration there was a transient endothelin-1 response in pregnant r

  14. The Correlation between endothelin-1 antibody plasma concentrations in patients with scleroderma and different manifestations of the disease

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    Aghaei M

    2011-03-01

    Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 st1":*{behavior:url(#ieooui } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Systemic scleroderma (SSc is a generalized connective tissue disorder of unknown origin which most notably is characterized by skin thickening and organ damage. Endothelin-1 (ET-1 antibody plays a role in skin fibrosis. The aim of this study was to determine the prevalence and correlation of different manifestations of SSc with ET-1 plasma levels."n"nMethods: This cross-sectional analytical study was conducted on 95 patients (91 women and four men with scleroderma in 2006. The patients had been referred to the Rheumatology Clinic of Shariati Hospital in Tehran, Iran. The demographic data and signs and symptoms were entered in a questionnaire and endothelin-1 concentrations were measured. "n"nResults: The mean age of the patients was 38±12.29 years. Diffuse cutaneous SSc (dcSSc was diagnosed in 52 and limited cutaneous SSc (lcSSc in 43 patients. Raynaud's phenomenon (91% was the most common manifestation in the patients. The relationship between the resorption of terminal phalanges due to fibrosis with the plasma concentration of Endothelin-1 was statistically significant (p=0.001. Pitting ulcers had significant relationships with endothelin-1 concentrations too (p<0

  15. Correlations between plasma endothelin-1 levels and breakthrough pain in patients with cancer

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    Yan XB

    2015-12-01

    Full Text Available Xue-bin Yan, Tuo-chao Peng, Dong Huang Department of Anesthesiologist, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, People’s Republic of China Abstract: Endothelin-1 (ET-1 may be involved in driving pain in patients with advanced cancer. However, a few studies focus on the role of ET-1 in breakthrough pain (BP. The aim of this pivotal study was to explore the correlation between the plasma (ET-1 level and BP intensity. A total of 40 patients were enrolled in the study, and they were divided into two groups: BP group and non-BP group. Moreover, 20 healthy adults were used as the normal control group. Pain intensity was measured using visual analog scale (VAS scores of 1–10. Plasma ET-1 levels were detected by an ET radioimmunoassay kit. Subsequently, the correlation of ET-1 level with the VAS score and cancer types was analyzed by Pearson’s correlation coefficient. The plasma ET-1 level in the BP group (35.31±8.02 pg/mL was higher than that in the non-BP group (29.51±6.78 pg/mL and the normal control group (24.77±10.10 pg/mL, P<0.05. In addition, the VAS score in the BP group (7.45±0.82 was higher than that in the non-BP group (2.80±1.23, P<0.05. The plasma ET-1 level was positively correlated with the VAS score of the BP group (Pearson’s r=0.42. There was no significant correlation between the plasma ET-1 level and VAS score of the non-BP group (Pearson’s r=–0.22 or/and cancer types (P>0.05. The elevated plasma ET-1 levels were positively related to BP, and targeting ET-1 may provide a novel pain-reducing therapeutic treatment in BP. Keywords: visual analog scale, correlation, cancer types, background pain

  16. Correlation between plasma endothelin-1 levels and severity of septic liver failure quantified by maximal liver function capacity (LiMAx test). A prospective study.

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    Kaffarnik, Magnus F; Ahmadi, Navid; Lock, Johan F; Wuensch, Tilo; Pratschke, Johann; Stockmann, Martin; Malinowski, Maciej

    2017-01-01

    To investigate the relationship between the degree of liver dysfunction, quantified by maximal liver function capacity (LiMAx test) and endothelin-1, TNF-α and IL-6 in septic surgical patients. 28 septic patients (8 female, 20 male, age range 35-80y) were prospectively investigated on a surgical intensive care unit. Liver function, defined by LiMAx test, and measurements of plasma levels of endothelin-1, TNF-α and IL-6 were carried out within the first 24 hours after onset of septic symptoms, followed by day 2, 5 and 10. Patients were divided into 2 groups (group A: LiMAx ≥100 μg/kg/h, moderate liver dysfunction; group B: LiMAx <100 μg/kg/h, severe liver dysfunction) for analysis and investigated regarding the correlation between endothelin-1 and the severity of liver failure, quantified by LiMAx test. Group B showed significant higher results for endothelin-1 than patients in group A (P = 0.01, d5; 0.02, d10). For TNF-α, group B revealed higher results than group A, with a significant difference on day 10 (P = 0.005). IL-6 showed a non-significant trend to higher results in group B. The Spearman's rank correlation coefficient revealed a significant correlation between LiMAx and endothelin-1 (-0.434; P <0.001), TNF-α (-0.515; P <0.001) and IL-6 (-0.590; P <0.001). Sepsis-related hepatic dysfunction is associated with elevated plasma levels of endothelin-1, TNF-α and IL-6. Low LiMAx results combined with increased endothelin-1 and TNF-α and a favourable correlation between LiMAx and cytokine values support the findings of a crucial role of Endothelin-1 and TNF-α in development of septic liver failure.

  17. Elevated levels of plasma Big endothelin-1 and its relation to hypertension and skin lesions in individuals exposed to arsenic

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    Hossain, Ekhtear; Islam, Khairul; Yeasmin, Fouzia [Department of Biochemistry and Molecular Biology, Rajshahi University, Rajshahi-6205 (Bangladesh); Karim, Md. Rezaul [Department of Applied Nutrition and Food Technology, Islamic University, Kushtia-7003 (Bangladesh); Rahman, Mashiur; Agarwal, Smita; Hossain, Shakhawoat; Aziz, Abdul; Al Mamun, Abdullah; Sheikh, Afzal; Haque, Abedul; Hossain, M. Tofazzal [Department of Biochemistry and Molecular Biology, Rajshahi University, Rajshahi-6205 (Bangladesh); Hossain, Mostaque [Department of Medicine, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka (Bangladesh); Haris, Parvez I. [Faculty of Health and Life Sciences, De Montfort University, Leicester, LE1 9BH (United Kingdom); Ikemura, Noriaki; Inoue, Kiyoshi; Miyataka, Hideki; Himeno, Seiichiro [Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770–8514 (Japan); Hossain, Khaled, E-mail: khossain69@yahoo.com [Department of Biochemistry and Molecular Biology, Rajshahi University, Rajshahi-6205 (Bangladesh)

    2012-03-01

    Chronic arsenic (As) exposure affects the endothelial system causing several diseases. Big endothelin-1 (Big ET-1), the biological precursor of endothelin-1 (ET-1) is a more accurate indicator of the degree of activation of the endothelial system. Effect of As exposure on the plasma Big ET-1 levels and its physiological implications have not yet been documented. We evaluated plasma Big ET-1 levels and their relation to hypertension and skin lesions in As exposed individuals in Bangladesh. A total of 304 study subjects from the As-endemic and non-endemic areas in Bangladesh were recruited for this study. As concentrations in water, hair and nails were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The plasma Big ET-1 levels were measured using a one-step sandwich enzyme immunoassay kit. Significant increase in Big ET-1 levels were observed with the increasing concentrations of As in drinking water, hair and nails. Further, before and after adjusting with different covariates, plasma Big ET-1 levels were found to be significantly associated with the water, hair and nail As concentrations of the study subjects. Big ET-1 levels were also higher in the higher exposure groups compared to the lowest (reference) group. Interestingly, we observed that Big ET-1 levels were significantly higher in the hypertensive and skin lesion groups compared to the normotensive and without skin lesion counterpart, respectively of the study subjects in As-endemic areas. Thus, this study demonstrated a novel dose–response relationship between As exposure and plasma Big ET-1 levels indicating the possible involvement of plasma Big ET-1 levels in As-induced hypertension and skin lesions. -- Highlights: ► Plasma Big ET-1 is an indicator of endothelial damage. ► Plasma Big ET-1 level increases dose-dependently in arsenic exposed individuals. ► Study subjects in arsenic-endemic areas with hypertension have elevated Big ET-1 levels. ► Study subjects with arsenic

  18. Flavonol-rich dark cocoa significantly decreases plasma endothelin-1 and improves cognitive responses in urban children.

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    Lilian eCalderon-Garciduenas

    2013-08-01

    Full Text Available Air pollution exposures are linked to systemic inflammation, cardiovascular and respiratory morbidity and mortality, neuroinflammation and neuropathology in young urbanites. In particular, most Mexico City Metropolitan Area (MCMA children exhibit subtle cognitive deficits, and neuropathology studies show 40% of them exhibiting frontal tau hyperphosphorylation and 51% amyloid-β diffuse plaques (compared to 0% in low pollution control children. We assessed whether a short cocoa intervention can be effective in decreasing plasma endothelin 1 (ET-1 and/or inflammatory mediators in MCMA children. Thirty g of dark cocoa with 680 mg of total flavonols were given daily for 10.11± 3.4 days (range 9 to 24 days to 18 children (10.55yrs, SD =1.45; 11F/7M. Key metabolite ratios in frontal white matter and in hippocampus pre and during cocoa intervention were quantified by magnetic resonance spectroscopy. ET-1 significantly decreased after cocoa treatment (p=0.0002. Fifteen children (83% showed a marginally significant individual improvement in one or both of the applied simple short memory tasks. Endothelial dysfunction is a key feature of exposure to particulate matter and decreased endothelin-1 bioavailability is likely useful for brain function in the context of air pollution. Our findings suggest that cocoa interventions may be critical for early implementation of neuroprotection of highly exposed urban children. Multi-domain nutraceutical interventions could limit the risk for endothelial dysfunction, cerebral hypoperfusion, neuroinflammation, cognitive deficits, structural volumetric detrimental brain effects, and the early development of the neuropathological hallmarks of Alzheimer’s and Parkinson’s diseases.

  19. Endothelin-1 in systemic sclerosis

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    Mehrdad Aghaei

    2012-01-01

    Full Text Available Introduction: Scleroderma is a systemic disorder with unknown etiology most notably characterized by skin thickening and organ damage. Endothelin-1 (ET-1 plays a role in skin fibrosis. The aim of this study was survey and comparison of ET-1 level in Systemic Sclerosis (SSc patients with and without digital ulcer. Material and Methods: A cross-sectional analytical study conducted among the 95 patients with scleroderma in 2006 who were referred to the Rheumatology clinic in Shariati hospital of Tehran. The questionnaire was completed for every patient. Plasma level of endothelin-1 was also measured in all of them. The data was analyzed using SPSS software and statistical tests. Results: The result indicated, relationship among digital ulcers and digital pitting scars with plasma level of ET-1 were significant (P value < 0.05. We could not find any significant relationship between age and plasma level of ET-1. Conclusion: These data indicate plasma level of ET-1 in scleroderma patients with digital ulcer was higher than patients without digital ulcer. Thus, increase in plasma level of ET-1 could be effective in vascular damage, fibrosis, and skin thickness.

  20. Endothelin-1 in systemic sclerosis

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    Aghaei, Mehrdad; Gharibdost, Farhad; Zayeni, Habib; Akhlaghi, Maryam; Sedighi, Sima; Rostamian, Abduo Rahman; Aghdami, Naser; Shojaa, Mahdieh

    2012-01-01

    Introduction: Scleroderma is a systemic disorder with unknown etiology most notably characterized by skin thickening and organ damage. Endothelin-1 (ET-1) plays a role in skin fibrosis. The aim of this study was survey and comparison of ET-1 level in Systemic Sclerosis (SSc) patients with and without digital ulcer. Material and Methods: A cross-sectional analytical study conducted among the 95 patients with scleroderma in 2006 who were referred to the Rheumatology clinic in Shariati hospital of Tehran. The questionnaire was completed for every patient. Plasma level of endothelin-1 was also measured in all of them. The data was analyzed using SPSS software and statistical tests. Results: The result indicated, relationship among digital ulcers and digital pitting scars with plasma level of ET-1 were significant (P value < 0.05). We could not find any significant relationship between age and plasma level of ET-1. Conclusion: These data indicate plasma level of ET-1 in scleroderma patients with digital ulcer was higher than patients without digital ulcer. Thus, increase in plasma level of ET-1 could be effective in vascular damage, fibrosis, and skin thickness. PMID:23130253

  1. Plasma adrenomedullin and endothelin-1 levels are reduced and Raynaud's phenomenon improved by daily tadalafil administration in male patients with systemic sclerosis.

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    Rosato, E; Letizia, C; Proietti, M; Aversa, A; Menghi, G; Rossi, C; Torella, E; Cotesta, D; Petramala, L; Bruzziches, R; Spera, G; Pisarri, S; Salsano, F

    2009-01-01

    The aim of our study is to evaluate in Systemic Sclerosis (SSc) male patients the tadalafil effects on Raynaud's phenomenon and on AM and ET-1 plasma levels. In an open-label study 20 consecutive male patients with SSc were enrolled and received 10 mg of tadalafil daily for 12 weeks. The primary endpoint was the subjective reduction of frequency and duration of Raynaud's attacks measured with a 10-point Raynaud's Condition Score; the secondary aim was to modify Adrenomedullin (AM) and Endothelin-1 (ET-1) plasma levels. After the treatment Raynaud's phenomenon was improved by once-daily tadalafil (decrease of mean number of Raynaud's attacks and of Raynaud's Condition Score) and plasma AM and ET-1 levels decreased. The results of our study lead us to postulate the beneficial effect of adding long term inhibition of Phosphodiesterase type 5 to Systemic Sclerosis' therapy.

  2. Correlating plasma endothelin-1 and beta-endorphin levels to nine risk factors of acute cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    Daoyou Zhou; Jun Liu; Yingrong Lao; Yigang Xing; Yan Huang

    2008-01-01

    BACKGROUND:Several studies have confirmed that endothelin and endorphin are involved in the occurrence of cerebral vasospasm. However, the correlation of these factors to acute cerebral infarction-related risk factors needs to be confirmed.OBJECTIVE:To detect endothelin-1(ET-1)and beta-endorphin(β-EP)levels in plasma of patients with acute cerebral infarction,and to analyze the correlations of these factors to smoking,alcohol abuse, hypertension,diabetes mellitus,diseased region,diseased degree,gender,and other factors related to acute cerebral infarction. DESIGN:A case-control observation. SETTING:First Department of Neurology,Guangdong Hospital of Traditional Chinese Medicine; Department of Neurology,Second Affiliated Hospital of Sun Yat-sen University.PARTICIPANTS:Sixty-nine inpatients with acute cerebral infarction were admitted to the Department of Neurology,Second Affiliated Hospital of Sun Yat-sen University(March 2003-January 2004)and First Department of Neurology,Guangdong Hospital of Traditional Chinese Medicine(March - July 2004)and recruited for this study.All 69 inpatients corresponded to the diagnosis criteria of acute cerebral infarction,formulated in the National Working Conference of Cerebrovascular Disease in 1998,and were confirmed as acute cerebral infarction by CT/MRI.The patient group consisted of 35 males [(64±12)years old] and 34 females[(67±13 )years old].Among them,9 patients were smokers,7 were alcohol users,48 had a history of hypertension,and 16 had a history of diabetes mellitus.CT/MRI examinations revealed that 35 patients presented with left focus sites,11 with right ones and 23 with bilateral ones.Following attack,24 patients had Barthel Index Scale grading<40 points,21 patients 40-60 points,and 24 patients>60 points.An additional 59 healthy individuals,who received health examinations simultaneously,were included as controls.Among the control subjects,there were 37 males [(62±10)years old] and 22 females [(65±11) years old

  3. Identification of chronic heart failure patients with a high 12-month mortality risk using biomarkers including plasma C-terminal pro-endothelin-1.

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    Ewa A Jankowska

    Full Text Available OBJECTIVES: We hypothesised that assessment of plasma C-terminal pro-endothelin-1 (CT-proET-1, a stable endothelin-1 precursor fragment, is of prognostic value in patients with chronic heart failure (CHF, beyond other prognosticators, including N-terminal pro-B-type natriuretic peptide (NT-proBNP. METHODS: We examined 491 patients with systolic CHF (age: 63±11 years, 91% men, New York Heart Association [NYHA] class [I/II/III/IV]: 9%/45%/38%/8%, 69% ischemic etiology. Plasma CT-proET-1 was detected using a chemiluminescence immunoassay. RESULTS: Increasing CT-proET-1 was a predictor of increased cardiovascular mortality at 12-months of follow-up (standardized hazard ratio 1.42, 95% confidence interval [CI] 1.04-1.95, p = 0.03 after adjusting for NT-proBNP, left ventricular ejection fraction (LVEF, age, creatinine, NYHA class. In receiver operating characteristic curve analysis, areas under curve for 12-month follow-up were similar for CT-proET-1 and NT-proBNP (p = 0.40. Both NT-proBNP and CT-proET-1 added prognostic value to a base model that included LVEF, age, creatinine, and NYHA class. Adding CT-proET-1 to the base model had stronger prognostic power (p<0.01 than adding NT-proBNP (p<0.01. Adding CT-proET-1 to NT-proBNP in this model yielded further prognostic information (p = 0.02. CONCLUSIONS: Plasma CT-proET-1 constitutes a novel predictor of increased 12-month cardiovascular mortality in patients with CHF. High CT-proET-1 together with high NT-proBNP enable to identify patients with CHF and particularly unfavourable outcomes.

  4. The insulinotropic effect of endothelin-1 is mediated by glucagon release from the islet alpha cells

    DEFF Research Database (Denmark)

    Brock, B; Gregersen, Søren; Kristensen, K;

    1999-01-01

    The circulating concentrations of endothelin-1 (ET-1), a peptide derived from endothelium, are increased in hypertension and diabetes. Endothelin-1 has recently been shown to be an insulinotropic agent. The mechanism of action of endothelin-1 on the endocrine pancreas has not yet been clarified....

  5. Perioperative Changes of Plasma Endothelin-1 in Patients Undergoing Coronary Artery bypass Grafting and the Effect of Nitroglycerin

    Institute of Scientific and Technical Information of China (English)

    陈鑫; 蒋英硕; 徐明; 陈振强; 郭子黄

    2002-01-01

    Objectioe To observe the dynamic changes of the plasma ET-1 and the effect of low dose nitroglycerin in patients with coronary artery bypass surgery. Methods Forty patravenous nitroglycerin 1 μg @ kg-1 @ rain-1 perioperatively. RIA was used to assay the plasma ET-1 lev-el. All the hemodynamie parameters were recorded by the Swan-Ganze catheter. Results The preoperative plasma ET-1 level in patients with coronary artery disease was significantly higher than the normal level. Five minutes after cardiopalmouary bypass in these patients the plasma ET-1 level was increased significantly until 6 to 8 h after operation. The increasing plasma ET-1 level in group B was less intense than that in group A. There was a positive correlation between the plasma ET-1 level and the mean pulmonary artery pressure in group A 2 and 8 h after operation. Conclusion In patients undergoing coronary artery bypass surgery, the increased plasma ET-1 level may be due to the influence of cardiopulmonary bypass partly. Low dose nitroglycerin is beneficial to these patients.

  6. Interday variation and effect of transportation on indirect blood pressure measurements, plasma endothelin-1 and serum cortisol in Standardbred and Icelandic horses

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    Söder Josefin

    2012-06-01

    Full Text Available Abstract Background Systemic hypertension is a prominent feature in humans with metabolic syndrome (MS and this is partly caused by an enhanced endothelin-1 (ET-1 mediated vasoconstriction. There are indications that systemic hypertension might be a feature in equine metabolic syndrome (EMS but if ET-1 is involved in the development of hypertension in horses is not known. Increased levels of cortisol have also been found in humans with MS but there are no reports of this in horses. Before blood pressure, plasma ET-1 and serum cortisol can be evaluated in horses with EMS, it is necessary to investigate the interday variation of these parameters on clinically healthy horses. The aims of the present study were therefore to evaluate the interday variation and influence of transportation on systemic blood pressure, plasma ET-1 and serum cortisol in healthy Standardbred and Icelandic horses, and to detect potential breed differences. Methods Nine horses of each breed were included in the study. Blood pressure was measured and blood samples were collected between 6 and 9 am on two separate days. Eight of the horses (four of each breed were transported to a new stable were they stayed overnight. The next morning, the sampling procedure was repeated. Results The interday variation was higher for plasma ET-1 (37% than for indirect pressure measurements (8-21% and serum cortisol (18%. There were no differences in systemic blood pressure between the two breeds. The Icelandic horses had significantly lower serum cortisol and significantly higher plasma ET-1 concentrations compared to the Standardbred horses. Plasma ET-1 was significantly elevated after transportation, but systemic blood pressure and serum cortisol did not differ from the values obtained in the home environment. Conclusions Indirect blood pressure, plasma ET-1 and serum cortisol are of interest as markers for cardiovascular dysfunction in horses with EMS. The elevated plasma ET-1

  7. Endothelin-1 in systemic sclerosis

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    C. Pizzorni

    2011-09-01

    Full Text Available We evaluated endothelin-1 (ET-1 plasma levels in patients affected by primary Raynaud’s phenomenon (PRP, as well as in patients with systemic sclerosis (SSc and secondary Raynaud’s phenomenon (SRP. Furthermore, ET-1 levels were investigated in SSc patients with different patterns of peripheral microvascular damage, as evaluated by nailfold videocapillaroscopy (NVC. Methods: 23 PRP patients, 67 SSc patients according to ACR criteria, and 23 healthy subjects were enrolled. SSc microvascular involvement was classified in three different patterns (Early, Active, and Late by NVC, as previously described. Results: ET-1 was found significantly higher in both PRP and SRP, when compared with controls (median ±IQR: 3.3±2.8, 2.7±2.2, 2.0±2.2, respectively (p=0.05. No statistically significant difference of ET-1 levels was observed between PRP and SRP patients. ET-1 was found higher in patients with Late NVC pattern, when compared with both Active and Early NVC patterns (median±IQR: 3.4±2.5, 2.4±2.2, 2.5±2.1, respectively, but without statistical significance. Patients with Late NVC pattern showed significantly higher ET-1 plasma levels than controls (p=0.03. No correlation was found between ET-1 levels and disease duration in both groups, as well as between ET-1 levels and age of patients. Conclusions: These data support previous studies, reporting increased ET-1 plasma levels in both PRP and SRP patients. Interestingly, patients with the Late NVC pattern of microangiopathy showed higher ET-1 plasma levels than controls. The high levels of ET-1 detected in the Late NVC pattern of microangiopathy might be related to the larger fibrotic involvement typical of the advanced stages of disease.

  8. Elevated Plasma C-Terminal Endothelin-1 Precursor Fragment Concentrations Are Associated with Less Anxiety in Patients with Cardiovascular Risk Factors. Results from the Observational DIAST-CHF Study.

    Directory of Open Access Journals (Sweden)

    Thomas Meyer

    Full Text Available The role of endothelin-1 (ET-1 in the neurobiology of anxiety is unknown, therefore, we assessed in the observational multicenter DIAST-CHF study whether the C-terminal ET-1 precursor fragment (CT-proET-1 is linked to anxiety.Plasma concentrations of CT-proET-1 were measured in a total of 1,410 patients presenting with cardiovascular risk factors (mean age 66.91±8.2 years, 49.3% males, mean left ventricular ejection fraction 60.0±8.2% who had completed the Hospital Anxiety and Depression Scale (HADS questionnaire.Among the total study cohort (n = 1,410, there were 118 subjects (8.4% with an HADS anxiety score above the cut-off level of 11 suggestive of clinically relevant anxiety. Plasma CT-proET-1 levels were significantly lower in the group of anxious patients as compared to non-anxious patients (p = 0.013. In regression models adjusted for sex, age, systolic blood pressure, and diameters of left atrium and ventricle, plasma CT-proET-1 was again linked to anxiety (Exp(β = 0.247, 95%-confidence interval [95%-CI] = 0.067-0.914, p = 0.036. Given the high prevalence of depressive disorders in anxious patients, we additionally included the HADS depression score as an independent variable in the models and found that CT-proET-1 remained a significant predictor of anxiety, independent of comorbid depression (Exp(β = 0.114, 95%-CI = 0.023-0.566, p = 0.008.Our data from a population-based study in outpatients with cardiovascular risk factors revealed that circulating CT-proET-1 levels are negatively associated with anxiety. Further investigations are required to clarify the putative anxiolytic effect of ET-1 or its precursor molecules in humans and to decipher its mechanistic pathways.

  9. [Endothelin-1 in pathogenesis of Raynaud's syndrome].

    Science.gov (United States)

    Knapik-Kordecka, M; Adamiec, R; Ciosek, W

    2001-06-01

    Endothelin is an endogenous vasoconstrictor and plays an important role in pathogenesis of Raynaud's phenomenon. Plasma endothelin-1 (ET-1) and von Willebrand factor (vWF) concentrations following cold exposure in 52 patients with Raynaud's phenomenon were measured. Statistically significant increase of ET-1 and vWF was found in the study group in compare to healthy volunteers. There was positive correlation between ET-1 and vWF in those cases. The dates suggest that ET-changes indicates a vasospastic effect on vascular injury. Treatment with endothelin-receptor antagonist may prevent structural changes in vessel well.

  10. The exercise-induced increase in plasma levels of endothelin-1 is enhanced in patients with atherosclerotic coronary artery disease. Modulation by pentaerithrityltetranitrat (PETN).

    Science.gov (United States)

    Predel, H G; Knigge, H; Prinz, U; Stalleicken, D; Kramer, H J; Rost, R E

    1995-01-01

    Previous studies have suggested that endothelin (ET)-1 with its marked vasoconstrictive potency may play a role in the induction of coronary artery spasms. Furthermore, it was demonstrated using in-vitro vessel preparations that the secretion of ET-1 by the vascular endothelium is enhanced in the presence of atherosclerotic alterations. The objective of the present study was to investigate a) the effects of ergometric exercise on ET-1 plasma concentrations in 10 patients with coronary artery disease (CAD) as compared to an age and sex matched control group and b) the modulatory role of the orally administered organic nitrate, pentaerithrityltetranitrat (PETN), in patients with CAD. 10 male patients with CAD confirmed by coronarography and 10 male healthy controls underwent a bicycle ergometry according to the WHO-standards upt to 125 watts. Venous blood samples for determination of ANP and ET-1 plasma concentrations were drawn in supine position directly before and 5 min after ergometric exercise. Subsequently, patients were randomized and treated for 3 days in a crossover design either with placebo or PETN (150 mg b.i.d.). Basal plasma levels of ET-1 were 6.1 +/- 0.7 pg/ml (patients) and 5.5 +/- 0.6 pg/ml (controls), resp. (n.s.). After ergometric exercise ET-1 plasma concentrations rose significantly (7.3 +/- 0.9 pg/ml; p PETN-treated patient group. Blood pressure and heart rate were not modified by the PETN-treatment. ET-1 plasma levels remained unaffected by ergometric exercise in controls. In contrast to healthy controls ergometric exercise induced an increase in ET-1 plasma concentrations in patients with CAD that may be potentially harmful by promoting coronary vasospasms. The almost complete blunting of the ET-1-increase in the presence of PETN-therapy may result from local-hemodynamic effects of the organic nitrate; it may be hypothesized that the nitrate-induced rise in local NO-concentrations counteracts ET-secretion. The findings of the present study

  11. Direct Action of Endothelin-1 on Podocytes Promotes Diabetic Glomerulosclerosis

    OpenAIRE

    Lenoir, Olivia; Milon, Marine; Virsolvy, Anne; Hénique, Carole; Schmitt, Alain; Massé, Jean-Marc; Kotelevtsev, Yuri; Yanagisawa, Masashi; Webb, David J; Richard, Sylvain; Tharaux, Pierre-Louis

    2014-01-01

    The endothelin system has emerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium tr...

  12. Endothelin-1 as a predictor of impaired glucose tolerance and type 2 diabetes--A longitudinal study in the Vara-Skövde Cohort.

    Science.gov (United States)

    Olausson, Josefin; Daka, Bledar; Hellgren, Margareta I; Larsson, Charlotte A; Petzold, Max; Lindblad, Ulf; Jansson, Per-Anders

    2016-03-01

    We addressed whether endothelin-1, a marker of endothelial dysfunction, predicts impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in a population study in south-western Sweden. Follow-up after 9.7 years showed an association between circulating endothelin-1 levels at baseline and development of IGT/T2DM in women but not in men.

  13. Nitrogen Oxide, Endothelin-1, and Serotonin in the Blood of Immature Spontaneously Hypertensive Rats.

    Science.gov (United States)

    Chibireva, M D; Aflyatumova, G N; Matveeva, V L; Bilalova, D F; Kuz'mina, O I; Sadykova, D I; Nigmatullina, R R

    2017-01-01

    Endothelial function is an early and sensitive marker of subclinical increase of BP in children and adolescents. It is associated with an imbalance of the key vasoactive factors (NO, endothelin-1, and serotonin). Immature spontaneously hypertensive rats (SHR line) are characterized by increased plasma concentrations of NO and endothelin-1 (by 14.7% and 2.9 times, respectively) and increased serotonin content in the plasma and platelets (by 2.7 and 2.3 times, respectively) in comparison with Wistar-Kyoto rats. Platelet count in the blood of SHR rats is by 50% higher than in Wistar-Kyoto rats.

  14. Enhanced endothelin-1-induced contractions in mesenteric arteries from rats with congestive heart failure

    DEFF Research Database (Denmark)

    Bergdahl, A; Valdemarsson, S; Adner, M;

    2001-01-01

    Studies of congestive heart failure (CHF) in man and in experimental CHF have demonstrated elevated circulating levels of endothelin (ET). In order to examine whether there are concomitant ET receptor alterations, the vasomotor effects of endothelin-1 (ET-1) and sarafotoxin 6c (S6c) were examined...

  15. Endothelin-1 stimulates insulin secretion by direct action on the islets of Langerhans in mice

    DEFF Research Database (Denmark)

    Gregersen, S; Thomsen, J L; Brock, B;

    1996-01-01

    Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, is secreted in response to insulin. Elevated circulating ET-1 levels have been found in patients with diabetes mellitus and vascular dysfunction. The question arises whether ET-1 acts as a direct modulator of insulin...

  16. Relationship between endothelin-1 levels and pulmonary arterial hypertension in HIV-infected patients.

    Science.gov (United States)

    Feijoo, Maribel Q; Toro, Rocío; López Vazquez de la Torre, Mariola; Lennie, Vera; Arce, Cristina; Moreno, Victoria; Valencia, Eulalia; Vispo, Eugenia; Almería, Carlos; Mangas, Alipio; Carbonero, Luz M

    2014-11-28

    Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with average survival of less than 3 years if left untreated. It is most common in patients infected with HIV. Although the pathogenesis in this population is not fully understood, it is thought that HIV infection, through the immune response and release of different inflammatory mediators such as endothelin-1, may contribute directly to endothelial damage. Our objective was to quantify endothelin-1 levels in HIV-infected patients and determine whether or not there is an association between this marker and PAH. A case-control study in patients attending an infectious diseases clinic. The sample was composed of 79 patients divided into three groups: 23 HIV patients with PAH (HIV+/PAH+), 45 HIV patients without PAH (HIV+/PAH-) and a control group of 11 healthy individuals. The ratio between the HIV+/PAH- and HIV+/PAH+ groups was 2 : 1. Patients were matched by age, sex, risk group and viral load; the control group by age and sex. All patients had blood taken for endothelin-1 plasma quantification. We found lower endothelin-1 levels in the controls than in the HIV+/PAH- group [0.71 pg/ml (interquartile range, IQR 0.54-0.94) vs. 1.13 pg/ml (IQR 0.87-1.38); P = 0.005] and the HIV+/PAH+ cohort [1.16 pg/ml (IQR 0.86-2.37); P = 0.003]. Patients with severe PAH had higher endothelin-1 levels [2.94 pg/ml (IQR 1.81-6.33)] than patients with mild and moderate PAH. Plasma endothelin-1 levels are higher in HIV patients with PAH than in the HIV-noninfected population and levels increase with the severity of the PAH.

  17. The cardiovascular physiology and pharmacology of endothelin-1.

    Science.gov (United States)

    Thorin, Eric; Clozel, Martine

    2010-01-01

    One year after the discovery in 1980 that the endothelium was obligatory for acetylcholine to relax isolated arteries, it was clearly shown that the endothelium could also promote contraction. In 1988, Dr Yanagisawa's group identified endothelin-1 (ET-1) as the first endothelium-derived contracting factor. The circulating levels of this short (21 amino acids) peptide were quickly determined in humans and it was reported that in most cardiovascular diseases, circulating levels of ET-1 were increased and ET-1 was then recognized as a likely mediator of pathological vasoconstriction in human. The discovery of two receptor subtypes in 1990, ET(A) and ET(B), permitted optimization of bosentan, which entered clinical development in 1993, and was offered to patients with pulmonary arterial hypertension in 2001. In this report, we discuss the physiological and pathophysiological role of endothelium-derived ET-1, the pharmacology of its two receptors, focusing on the regulation of the vascular tone and as much as possible in humans. The coronary bed will be used as a running example, but references to the pulmonary, cerebral, and renal circulation will also be made. Many of the cardiovascular complications associated with aging and cardiovascular risk factors are initially attributable, at least in part, to endothelial dysfunction, particularly dysregulation of the vascular function associated with an imbalance in the close interdependence of NO and ET-1, in which the implication of the ET(B) receptor may be central.

  18. Effects of pulsatile CPB on interleukin-8 and endothelin-1 levels.

    Science.gov (United States)

    Sezai, Akira; Shiono, Motomi; Nakata, Kin-ichi; Hata, Mitsumasa; Iida, Mitsuru; Saito, Akira; Hattori, Tsutomu; Wakui, Shinji; Soeda, Masao; Taoka, Makoto; Umeda, Tomofumi; Negishi, Nanao; Sezai, Yukiyasu

    2005-09-01

    Studies on pulsatile and nonpulsatile perfusion have long been performed. However, investigators have not reached a conclusion on which is more effective. In the present study, pulsatile cardiopulmonary bypass (CPB) was investigated in terms of the effects on cytokines, endothelin, catecholamine, and pulmonary and renal functions. Twenty-four patients who underwent coronary artery bypass grafting were divided into a pulsatile CPB group and a nonpulsatile CPB group. Parameters examined were hemodynamics, interleukin-8 (IL-8), endothelin-1 (ET-1), epinephrine, norepinephrine, lactate, arterial ketone body ratio, urine volume, blood urea nitrogen, creatinine, renin activity, angiotensin-II, lactate dehydrogenase, plasma-free hemoglobin, tracheal intubation time, and respiratory index. The IL-8 at 0.5, 3, and 6 h after CPB, and ET-1 at 3, 6, 9, and 18 h after CPB were significantly lower in the pulsatile group. Both epinephrine and norepinephrine were significantly lower in the pulsatile group. The respiratory index was significantly higher in the pulsatile group. In the present study, inhibitory effects on cytokine activity, edema in pulmonary alveoli, and endothelial damage were shown in addition to the favorable effects on catecholamine level, renal function, and peripheral circulation that have already been documented.

  19. Formation and plasma circulation of solar prominences

    CERN Document Server

    Xia, Chun

    2016-01-01

    Solar prominences are long-lived cool and dense plasma curtains in the hot and rarefied outer solar atmosphere or corona. The physical mechanism responsible for their formation and especially for their internal plasma circulation has been uncertain for decades. The observed ubiquitous down flows in quiescent prominences are difficult to interpret as plasma with high conductivity seems to move across horizontal magnetic field lines. Here we present three-dimensional numerical simulations of prominence formation and evolution in an elongated magnetic flux rope as a result of in-situ plasma condensations fueled by continuous plasma evaporation from the solar chromosphere. The prominence is born and maintained in a fragmented, highly dynamic state with continuous reappearance of multiple blobs and thread structures that move mainly downward dragging along mass-loaded field lines. The prominence plasma circulation is characterized by the dynamic balance between the drainage of prominence plasma back to the chromos...

  20. TIMAP-protein phosphatase 1-complex controls endothelin-1 production via ECE-1 dephosphorylation.

    Science.gov (United States)

    Boratkó, Anita; Veréb, Zoltán; Petrovski, Goran; Csortos, Csilla

    2016-04-01

    Endothelin induced signaling pathways can affect blood pressure and vascular tone, but the influence of endothelins on tumor cells is also significant. We have detected elevated endothelin-1 secretion from TIMAP (TGF-β inhibited membrane associated protein) depleted vascular endothelial cells. The autocrine signaling activated by the elevated endothelin-1 level through the ETB receptors evoked an angiogenic-like phenotype, the cells assumed an elongated morphology, and enhanced tube formation and wound healing abilities. The depleted protein, TIMAP, is a highly specific and abundant protein in the endothelial cells, and it is a regulatory/targeting subunit for the catalytic subunit of protein phosphatase 1 (PP1c). Protein-protein interaction between the TIMAP-PP1c complex and the endothelin converting enzyme-1 (ECE-1) was detected, the latter of which is a transmembrane protein that produces the biologically active 21-amino acid form of endothelin-1 from proendothelin. The results indicate that silencing of TIMAP induces a reduction in TIMAP-PP1c activity connected to ECE-1. This leads to an increase in the amount of ECE-1 protein in the plasma membrane and a consequent increase in endothelin-1 secretion. Similarly, activation of PKC, the kinase responsible for ECE-1 phosphorylation increased ECE-1 protein level in the membrane fraction of the endothelial cells. The elevated ECE-1 level was mitigated in time in normal cells, but was clearly preserved in TIMAP-depleted cells. Overall, our results indicate that PKC-phosphorylated ECE-1 is a TIMAP-PP1c substrate and this phosphatase complex has an important role in endothelin-1 production of EC through the regulation of ECE-1 activity.

  1. FORMATION AND PLASMA CIRCULATION OF SOLAR PROMINENCES

    OpenAIRE

    Xia, Chun; Keppens, Rony

    2016-01-01

    Solar prominences are long-lived cool and dense plasma curtains in the hot and rarefied outer solar atmosphere or corona. The physical mechanism responsible for their formation and especially for their internal plasma circulation has been uncertain for decades. The observed ubiquitous down flows in quiescent prominences are difficult to interpret as plasma with high conductivity seems to move across horizontal magnetic field lines. Here we present three-dimensional numerical simulations of pr...

  2. Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade.

    Science.gov (United States)

    Hathaway, Catherine K; Grant, Ruriko; Hagaman, John R; Hiller, Sylvia; Li, Feng; Xu, Longquan; Chang, Albert S; Madden, Victoria J; Bagnell, C Robert; Rojas, Mauricio; Kim, Hyung-Suk; Wu, Bingruo; Zhou, Bin; Smithies, Oliver; Kakoki, Masao

    2015-04-21

    We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction.

  3. Elevated endothelin-1 expression in dogs with heartworm disease.

    Science.gov (United States)

    Uchide, Tsuyoshi; Saida, Kaname

    2005-11-01

    We explored the involvement of endothelin-1 (ET-1) in the pathophysiology of dog dirofilariasis (heartworm disease caused by Dirofilaria immitis) by analyzing mRNA levels of preproendothelin-1 (PPET-1), the precursor form of ET-1, in cardiopulmonary organs as well as ET-1 peptide levels in plasma. To determine the cDNA sequence and primary protein structure of dog PPET-1, we performed molecular cloning of the full-length cDNA. Based on the determined sequence information, comparative expression analysis of PPET-1 mRNA was carried out by real-time polymerase chain reaction on cardiopulmonary organs from healthy (n=5) and filarial (n=5) dogs. Filarial dogs showed a significantly (p<0.05) higher mRNA expression level in the heart (about one hundred times) and lung (about ten times) than healthy dogs. Analysis of plasma ET-1 levels in healthy (n=10) and filarial (n=10) dogs showed that filarial dogs (6.9+/-2.7 pg/ml) have significantly (p<0.01) increased plasma ET-1 levels compared with healthy dogs (1.4+/-0.3 pg/ml). To assess the pathophysiological significance of ET-1 in dirofilariasis relative to other cardiopulmonary disorders, plasma ET-1 levels determined in dogs diagnosed with mitral regurgitation (n=10), tricuspid regurgitation (n=5), ventricular septal defect (n=5), and patent ductus arteriosus (n=5) were compared to plasma ET-1 levels in filarial dogs. Filarial dogs, which commonly develop serious pulmonary hypertension, exhibited by far the highest ET-1 levels of the disease states examined. Based on the fact that ET-1 is a potent bioactive mediator that induces vasoconstriction and promotes vascular remodeling, these findings suggest that ET-1 plays an important role in the pathophysiology of dog dirofilariasis as an aggravating factor by inducing pulmonary hypertension.

  4. Formation and Plasma Circulation of Solar Prominences

    Science.gov (United States)

    Xia, C.; Keppens, R.

    2016-05-01

    Solar prominences are long-lived cool and dense plasma curtains in the hot and rarefied outer solar atmosphere or corona. The physical mechanism responsible for their formation and especially for their internal plasma circulation has been uncertain for decades. The observed ubiquitous downflows in quiescent prominences are difficult to interpret because plasma with high conductivity seems to move across horizontal magnetic field lines. Here we present three-dimensional numerical simulations of prominence formation and evolution in an elongated magnetic flux rope as a result of in situ plasma condensations fueled by continuous plasma evaporation from the solar chromosphere. The prominence is born and maintained in a fragmented, highly dynamic state with continuous reappearance of multiple blobs and thread structures that move mainly downward, dragging along mass-loaded field lines. The circulation of prominence plasma is characterized by the dynamic balance between the drainage of prominence plasma back to the chromosphere and the formation of prominence plasma via continuous condensation. Plasma evaporates from the chromosphere, condenses into the prominence in the corona, and drains back to the chromosphere, establishing a stable chromosphere-corona plasma cycle. Synthetic images of the modeled prominence with the Solar Dynamics Observatory Atmospheric Imaging Assembly closely resemble actual observations, with many dynamical threads underlying an elliptical coronal cavity.

  5. Herbal Prescription, DSGOST, Prevents Cold-Induced RhoA Activation and Endothelin-1 Production in Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Sung-Gook Cho

    2014-01-01

    Full Text Available Herbal prescription, Danggui-Sayuk-Ga-Osuyu-Saenggang-tang (DSGOST, has long been used to treat Raynaud’s phenomenon (RP in traditional Chinese medicine (TCM. However, a biological mechanism by which DSGOST ameliorates RP is yet deciphered. In this study, we demonstrate that DSGOST inhibits cold-induced activation of RhoA, in both vascular smooth muscle cells (VSMC and endothelial cells (EC, and blocks endothelin-1-mediated paracrine path for cold response on vessels. While cold induced RhoA activity in both cell types, DSGOST pretreatment prevented cold-induced RhoA activation. DSGOST inhibition of cold-induced RhoA activation further blocked α2c-adrenoreceptor translocation to the plasma membrane in VSMC. In addition, DSGOST inhibited endothelin-1-mediated RhoA activation and α2c-adrenoreceptor translocation in VSMC. Meanwhile, DSGOST inhibited cold-induced or RhoA-dependent phosphorylation of FAK, SRC, and ERK. Consistently, DSGOST inhibited cold-induced endothelin-1 expression in EC. Therefore, DSGOST prevents cold-induced RhoA in EC and blocks endothelin-1-mediated paracrine path between EC and VSMC. In conclusion, our data suggest that DSGOST is beneficial for treating RP-like syndrome.

  6. Effects of endothelin-1 eyedrops on the retina in rats.

    Science.gov (United States)

    Masuzawa, Koichi; Miyauchi, Takashi; Takanashi, Masakatsu; Ogata, Takehiro; Yamaguchi, Iwao; Goto, Katsutoshi

    2004-11-01

    Eye disorder accompanied with chronic retinal microvascular obstruction, such as diabetic retinopathy, exists in many diseases. However, it is difficult to produce this model experimentally in the animal eye. Endothelin-1 eyedrops were prepared in order to examine whether the eyedrops affect the rat retina and whether we can produce an obstruction model. Endothelin-1 eyedrops diluted by artificial tears in seven stages from 4 x 10(-5) M to 4 x 10(-11) M were arranged. We administered this solution three times a day in the left eye of male Sprague-Dawley rats. Artificial tears alone were applied to the right eye as a control vehicle. After 2 weeks, rats were sacrificed under anesthesia and the retinal tissues were isolated. As an index to the action of endothelin- 1 eyedrops to the retina, the expressions of endothelin-A (ETA) and endothelin-B (ETB) receptors in the retina were compared in both eyes. Frozen sections of the retina were immunostained to reveal the distribution of the ETA and ETB receptors. We also examined ETA and ETB mRNA expression by quantitative real-time polymerase chain reaction. As a result, the expressions of ETA and ETB receptors are reduced with both immunostaining and the mRNA levels in the left eye, in which endothelin-1 eyedrops were applied at 4 x 10(-5) M. It is suggested that endothelin-1 eyedrops affected the retina and the possibility of producing the experimental model of chronic microvascular obstruction in the rat retina.

  7. NITRIC OXIDE AND ENDOTHELIN-1 IN CHILDREN WITH DIGESTIVE DISORDERS

    Directory of Open Access Journals (Sweden)

    I. V. Panova

    2012-01-01

    Full Text Available The important part in the group of biological compounds, participating in the regulation of the functions of the gastro-intestinal tract, is assigned to endothelial factors because of their impact on the majority of physiological and pathophysiological processes of the digestive system. The article provides information about physiological role of nitric oxide and endothelin-1 and presents a review of scientific data on the participation of nitric oxide and endothelin-1 in the pathogenesis of many digestive system diseases, emphasizing chronic inflammatory disorders of the upper gastrointestinal tract. The authors accentuate the importance of endothelium endocrine function research in children with esophagogastroduodenal disorders at the beginning of puberty, which is the critical period of ontogenesis.

  8. Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

    DEFF Research Database (Denmark)

    Berglund, Lisa M; Lyssenko, Valeriya; Ladenvall, Claes;

    2016-01-01

    Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the pro-atherogenic cytokine osteopontin (OPN) in mouse arteries......, via local release of endothelin-1 (ET-1) and activation of cAMP response element binding protein (CREB). Infusion of GIP increases plasma OPN levels in healthy individuals. Plasma ET-1 and OPN levels are positively correlated in patients with critical limb ischemia. Fasting GIP levels are higher......; and expression associates to parameters characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from human, mouse, rat and pig; remarkable up-regulation...

  9. Endothelin-1 as a master regulator of whole-body Na+ homeostasis.

    Science.gov (United States)

    Speed, Joshua S; Heimlich, J Brett; Hyndman, Kelly A; Fox, Brandon M; Patel, Vivek; Yanagisawa, Masashi; Pollock, Jennifer S; Titze, Jens M; Pollock, David M

    2015-12-01

    The current study was designed to determine whether vascular endothelial-derived endothelin-1 (ET-1) is important for skin Na(+) buffering. In control mice (C57BL/6J), plasma Na(+) and osmolarity were significantly elevated in animals on high- vs. low-salt (HS and LS, respectively) intake. The increased plasma Na(+) and osmolarity were associated with increased ET-1 mRNA in vascular tissue. There was no detectable difference in skin Na(+):H2O in HS fed mice (0.119 ± 0.005 mM vs. 0.127 ± 0.007 mM; LS vs. HS); however, skin Na(+):H2O was significantly increased by blockade of the endothelin type A receptor with ABT-627 (0.116 ± 0.006 mM vs. 0.137 ± 0.007 mM; LS vs. HS; half-maximal inhibitory concentration, 0.055 nM). ET-1 peptide content in skin tissue was increased in floxed control animals on HS (85.9 ± 0.9 pg/mg vs. 106.4 ± 6.8 pg/mg; P < 0.05), but not in vascular endothelial cell endothelin-1 knockout (VEET KO) mice (76.4 ± 5.7 pg/mg vs. 65.7 ± 7.9 pg/mg; LS vs. HS). VEET KO mice also had a significantly elevated skin Na(+):H2O (0.113 ± 0.007 mM vs. 0.137 ± 0.005 mM; LS vs. HS; P < 0.05). Finally, ET-1 production was elevated in response to increasing extracellular osmolarity in cultured human endothelial cells. These data support the hypothesis that increased extrarenal vascular ET-1 production in response to HS intake is mediated by increased extracellular osmolarity and plays a critical role in regulating skin storage of Na(+).

  10. Endothelin-1 and endothelin-3 in cirrhosis: relations to systemic and splanchnic haemodynamics

    DEFF Research Database (Denmark)

    Møller, Søren; Gülberg, V; Henriksen, Jens Henrik;

    1995-01-01

    haemodynamics. METHODS: Endothelin-1 and endothelin-3 were measured in samples from a hepatic vein and the femoral artery in 42 patients with cirrhosis, eight hypertensive controls and 10 normotensive controls. RESULTS: Hepatic venous endothelin-1 was significantly higher in the patients with cirrhosis, mean 21...

  11. Endothelin-1 and Exercise Intensity in Sedentary Adolescents with Obesity

    Directory of Open Access Journals (Sweden)

    Brooke E. Starkoff

    2015-01-01

    Full Text Available Inactivity combined with obesity during adolescence increases the risk of future cardiovascular disease. The study purpose was to compare the influence of differing intensities of exercise on endothelial function in sedentary adolescents with obesity. Participants were randomized to one of two groups in a 6-week exercise intervention: moderate intensity (MOD or high intensity interval exercise (HIIE. Endothelial function was assessed pre- and post-intervention via fasted serum levels of endothelin-1 (ET-1. Pre-measures of ET-1 concentrations were elevated at baseline. No significant differences in ET-1 were found between or within exercise groups. However, in the HIIE group, ET-1 was inversely associated with percentages of age predicted maximal heart rate achieved during the intervention (p=0.035, r=-0.567. The exercise interventions did not positively change ET-1 levels, yet participants who exercised at higher intensities in the HIIE group experienced greater decreases in ET-1. Keywords: childhood obesity, endothelial function, high intensity interval exercise

  12. Association of plasma levels of homocysteine,endothelin-1 and nitric oxide and hypertension with cerebral hemorrhage%高血压性脑出血与血浆同型半胱氨酸、内皮素1和一氧化氮的关系

    Institute of Scientific and Technical Information of China (English)

    王军; 张均

    2011-01-01

    Objective To investigate the relationship of plasma levels of homocysteine(Hcy), endothelin-1 (ET-1) and nitric oxide (NO) and hypertension with cerebral hemorrhage. Methods Plasma levels of Hcy, ET-1 and NO were examined in 62 patients with hypertension (group A), 45 patients with cerebral hemorrhage without hypertension(group B),60 hypertensive patients with cerebral hemorrhage(group C) and 40 healthy volunteers (group D). Results For groups of A,B,C and D,plasma levels of Hcy were (17. 6±6. 6) μmol/L, (18. 2±7. 2) μmol/L, (21. 9±6. 7) μmol/L and (10. 8±4. 6) μmol/L,those of ET-1 were (100. 7±11. 8) μg/L,(101. 2±12.1) μg/L,(120. 8+ 15. 9) μg/L and (44. 7±10. 6) μg/L,and those of NO were (57. 2±11. 7) mg/L,(58. 6±11. 2) mg/L, (41. 8±13. 2) mg/L and (120. 8±12. 6) mg/L,respectively. Compared with group D, plasma levels of Hcy and ET-1 were higher,but NO was lower in groups of A,B and C(P<0. 05). Plasma levels of Hcy and ET-1 were higher, but NO was lower in group C than those in groups of A and B(P<0. 05). The amount of cerebral hemorrhage was positively correlated to Hcy and ET-1, but negatively correlated with NO(P<0. 05). Conclusion The damage and dysfunction of the endothelial cells exist in the patients with hypertensive cerebral hemorrhage.%目的 探讨血浆同型半胱氨酸(Hcy)、内皮素1(ET-1)和一氧化氮(NO)水平与高血压及其合并脑出血的关系.方法 检测62例单纯高血压患者(A组)、45例单纯脑出血患者(B组)、60例高血压性脑出血患者(C组)和40名健康体检者(D组)血浆Hcy、ET-1和NO的水平.结果 A、B、C和D组的血浆Hcy分别为(17.6±6.6) μmol/L、(18.2±7.2)μmol/L、(21.9±6.7)μmol/L和(10.8±4.6)μmol/L;ET-1分别为(100.7±11.8)μg/L、(101.2±12.1)μg/L、(120.8±15.9)μg/L和(44.7±10.6)μg/L;NO分别为(57.2±11.7) mg/L、(58.6±11.2)m g/L、(41.8±13.2) mg/L和(120.8±12.6)mg/L.与D组比较,A、B和C组Hcy和ET-1水平升高,NO水平降低(P<0.05);C组Hcy和ET-1

  13. Assessment of serum endothelin-1 levels in rat appendicitis model and the effects of bosentan.

    Science.gov (United States)

    Sarsu, S B; Sahin, K; Kilincaslan, H; Mirapoglu, S L; Buyukpınarbasili, N; Duz, M E; Aydogdu, I

    2017-04-01

    In this study, the diagnostic value of serum endothelin-1 (ET-1) levels and the therapeutic effects of bosentan have been investigated in an experimental appendicitis rat model. Twenty-one male Sprague-Dawley rats were chosen for the study. The rats were allocated into three groups as follows: Group 1 (control, n = 7), Group 2 (appendicitis, n = 7), and Group 3 (bosentan treatment, n = 7). At the 6th hour of the experiment, Groups 1 and 2 received 2 ml saline, and group 3 received 30 mg/kg bosentan intraperitoneally. At the 24th postoperative hour, all rats were sacrificed and evaluated histopathologically to score the severity of appendicitis. The plasma malondialdehyde, reduced and total glutathione levels, serum, and appendiceal tissue ET-1 levels were evaluated. In this study, we found that the ET-1 levels were significantly increased with appendicitis (p = 0.018). The administration of bosentan can statistically significantly both decrease the histopathologic injury in the inflamed appendix and increase the serum total glutathione levels (p = 0.002). The increase in plasma ET-1 levels may have a diagnostic value of acute appendicitis. We believe that manifestations that occur during the acute phase of appendicitis may be reduced with the administration of bosentan, which may also help prevent complications.

  14. Endothelin-1 and endothelin receptors in the basilar artery of the capybara.

    Science.gov (United States)

    Loesch, Andrzej; Gajkowska, Barbara; Dashwood, Michael R; Fioretto, Emerson T; Gagliardo, Karina M; Lima, Ana R De; Ribeiro, Antonio A C M

    2005-02-01

    Little is known about cerebral vasculature of capybara, which seems may serve as a natural model of studying changes in cerebral circulation due to internal carotid artery atrophy at animal sexual maturation. This is the first study of the light- and electron-immunocytochemical localisation of endothelin-1 (ET-1) and ETA and ETB endothelin receptors in the basilar artery of capybaras (6 to 12-month-old females and males) using an ExtrAvidin detection method. All animals examined showed similar patterns of immunoreactivity. Immunoreactivity for ET-1 was detected in the endothelium and adventitial fibroblasts, whilst immunoreactivity for ETA and ETB receptors was present in the endothelium, vascular smooth muscle, perivascular nerves and fibroblasts. In endothelial cells immunoreactivity to ET-1 was pronounced in the cytoplasm or on the granular endoplasmic reticulum. Similar patterns of immunolabelling were observed for ETA and ETB receptors, though cytoplasmic location of clusters of immunoprecipitate seems dominant. These results suggest that the endothelin system is present throughout the wall of the basilar artery of capybara.

  15. Endothelin-1 downregulates Mas receptor expression in human cardiomyocytes.

    Science.gov (United States)

    Chen, Zhiheng; Tang, Yamei; Yang, Zuocheng; Liu, Shaojun; Liu, Yong; Li, Yan; He, Wei

    2013-09-01

    Endothelin-1 (ET-1) and the renin-angiotensin system (RAS) are involved in the pathogenesis of cardiac dysfunction. The Mas receptor is a functional binding site for angiotensin (Ang)‑(1-7), which is now considered a critical component of the RAS and exerts cardioprotective effects. To the best of our knowledge, the present study aimed to examine, for the first time, the effects of ET-1 on Mas expression in cultured human cardiomyocytes. Human cardiomyocytes were treated with ET-1 at different concentrations (1, 5, 10, 20 and 30 nM) for varied time periods (0.5, 1.5, 3, 4.5 or 6 h) with or without the transcription inhibitor actinomycin D, endothelin A (ETA) receptor blocker BQ123 and ETB receptor blocker BQ788, or different kinase inhibitors. ET-1 decreased the Mas mRNA level in a statistically significant dose- and time-dependent manner within 4.5 h, which was reflected in the dose-dependent downregulation of Mas promoter activity, Mas protein levels and Ang-(1-7) binding on the cell membrane. Actinomycin D (1 mg/ml), BQ123 (1 µM), p38 mitogen-activated protein kinase (MAPK) siRNA and inhibitor PD169316 (25 µM), completely eliminated the inhibitory effects of ET-1 on Mas expression in human cardiomyocytes. In conclusion, the present study demonstrated that ET-1 downregulates Mas expression at the transcription level in human cardiomyocytes via the ETA receptor by a p38 MAPK‑dependent mechanism. This study provides novel insights into the function of ET-1 and the Ang‑(1-7)/Mas axis in cardiac pathophysiology.

  16. Risk Factors in Normal-Tension Glaucoma and High-Tension Glaucoma in relation to Polymorphisms of Endothelin-1 Gene and Endothelin-1 Receptor Type A Gene

    Directory of Open Access Journals (Sweden)

    Dominika Wróbel-Dudzińska

    2015-01-01

    Full Text Available The aim of the research is to analyse the influence of polymorphisms of endothelin-1 gene and endothelin-1 receptor type A gene on the clinical condition of patients with primary open angle glaucoma. Methods. 285 Polish patients took part in the research (160 normal-tension glaucoma and 125 high-tension glaucoma. DNA was isolated by standard methods and genotype distributions of four polymorphisms in genes encoding endothelin-1 (K198N and endothelin-1 receptor type A polymorphisms (C1222T, C70G, and G231A were determined. Genotype distributions were compared between NTG and HTG groups. The clinical condition of participants was examined for association with polymorphisms. Results. A similar frequency of occurrence of the polymorphic varieties of the studied genes was observed in patients with NTG and HTG. There is no relation between NTG risk factors and examined polymorphisms. NTG patients with TT genotype of K198N polymorphism presented with the lowest intraocular pressure in comparison to GG + GT genotype (p=0.03. In NTG patients with CC genotype of C1222T polymorphism (p=0.028 and GG of C70G polymorphism (p=0.03 the lowest values of mean blood pressure were observed. Conclusions. The studied polymorphic varieties (K198N, C1222T do have an influence on intraocular pressure as well as arterial blood pressure in NTG patients.

  17. ADP-ribosylation factor 6 regulates endothelin-1-induced lipolysis in adipocytes.

    Science.gov (United States)

    Davies, Jonathon C B; Bain, Stephen C; Kanamarlapudi, Venkateswarlu

    2014-08-15

    Endothelin-1 (ET-1) induces lipolysis in adipocytes, where ET-1 chronic exposure results in insulin resistance (IR) through suppression of glucose transporter (GLUT)4 translocation to the plasma membrane and consequently glucose uptake. ARF6 small GTPase, which plays a vital role in cell surface receptors trafficking, has previously been shown to regulate GLUT4 recycling and thereby insulin signalling. ARF6 also plays a role in ET-1 promoted endothelial cell migration. However, ARF6 involvement in ET-1-induced lipolysis in adipocytes is unknown. Therefore, we investigated the role of ARF6 in ET-1-induced lipolysis in 3T3-L1 adipocytes. This was achieved by studying the effect of inhibitors for the activation of ARF6 and other signalling proteins on ET-1 induced lipolysis and ARF6 activation in the adipocytes. Our results indicate that ET-1 induces, through endothelin type A receptor (ETAR), lipolysis, the ARF6 activation and extracellular-signal regulated kinase (ERK) phosphorylation in adipocytes, further ET-1 stimulated lipolysis is inhibited by the inhibitors of ARF6 activation, ERK phosphorylation and dynamin, which is essential for endocytosis. Our studies also revealed that ARF6 acts upstream of ERK in ET-1-indcued lipolysis. In summary, we determined that ET-1 activation of ETAR signalled through ARF6, which is crucial for lipolysis. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Influence of noninvasive ventilator in the treatment of plasma C-reactive protein , endothelin-1 and tumor necrosis factor-α in patients with obstructive sleep apneahypopnea syndrome%无创呼吸机治疗对OSAHS患者血清C反应蛋白、内皮素-1及肿瘤坏死因子-α水平的影响

    Institute of Scientific and Technical Information of China (English)

    孟庆华; 李承红; 江城; 孔彬; 冯琼

    2015-01-01

    Objective To investigate the effect of noninvasive ventilator therapy on serum C-reactive protein (CRP), endothelin-1 (ET-1) and tumor necrosis factor-α (TNF-α) levels in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and its clinical significance. Methods One hundred cases of moder-ate and severe OSAHS patients were selected by the method of parallel opening. All of the patients were given health education requirement , quitting smoking and wine , low fat diet and exercise to lose weight and other con-ventional treatment. The patients were randomly divided into the treatment group of 42 cases with noninvasive ventilator treatment , 44 cases treated with conventional treatment , to observe the changes of serum CRP , ET-1 and TNF-α levels and PSG parameters after 12 weeks in two groups. Results Apnea hypopnea index (AHI), oxygen desaturation index (ODI), the lowest oxygen saturation (LSpO2), and the average oxygen saturation MSpO2 in OSAHS patients were significantly improved after treatment (P < 0.01), but the degree of improvement in the two groups after treatment was significantly higher than the control group (P < 0.01). Plasma CRP, ET-1 and TNF-α levels in the two groups after treatment were lower than before treatment (P < 0.05 or P < 0.01), but the treatment group was significantly higher than that of the control group ( P < 0 . 05 or P < 0 . 01 ) . Conclusion Noninvasive ventilator therapy in improving the OSAHS monitoring data of patients with PSG can effectively reduce the serum CRP, TNF-α, ET-1 level, reduce the body′s inflammatory reaction.%目的:探讨无创呼吸机治疗对阻塞性睡眠呼吸暂停低通气综合征( OSAHS )患者血清 C 反应蛋白( CRP )、内皮素-1 ( ET-1 )、肿瘤坏死因子-α( TNF-α)水平的影响及临床意义. 方法:采用平行开放的方法选取中重度 OSAHS 患者 100 例,均予以健康宣教,要求戒烟酒、低脂饮食和运动减肥等常规治疗;随机分为治疗组42

  19. Endothelium-Dependent Contractions: Prostacyclin and Endothelin-1, Partners in Crime?

    Science.gov (United States)

    Baretella, O; Vanhoutte, P M

    2016-01-01

    Both the lipid prostacyclin and the peptide endothelin-1 are endothelium-derived substances. Endothelin-1 is one of the most powerful endogenous vasoconstrictors, while prostacyclin is a potent antiaggregatory and vasodilator mediator upon activation of prostaglandin I2 (IP) receptors. During endothelium-dependent, prostanoid-mediated contractions/constrictions, however, prostacyclin appears to be a major endothelium-derived contracting factor (EDCF). Such cyclooxygenase-dependent responses, whether measured ex vivo or in vivo, are exacerbated by aging, obesity, diabetes, or hypertension. On the background of such cardiovascular risk factors, endothelin-1 may potentiate these contractions by promoting prostacyclin production. The latter is reduced by endothelin-A (ETA) receptor antagonists. This receptor subtype is recognized for mediating contractions of smooth muscle cells to endothelin-1. However, it is present also on endothelial cells, where its activation increases intracellular calcium concentration with subsequent initiation of phospholipase A2 that provides arachidonic acid for metabolism by cyclooxygenases. Thus, endothelin-1 favors cyclooxygenase-dependent vasoconstrictor prostanoid formation, including prostacyclin. Activation of endothelial endothelin-B (ETB) receptors promotes the release of nitric oxide, which opposes both EDCF and endothelin-1. This is less pronounced in disease promoting ETA- and smooth muscle ETB receptor-dependent as well as prostanoid-mediated contractions. In addition, the thromboxane prostanoid (TP) receptors on vascular smooth muscle cells become hyperresponsive to EDCF under pathophysiological conditions, while IP receptor responsiveness diminishes. A better understanding of the interaction between prostacyclin and endothelin-1 and the determination of the roles of the TP and IP receptors involved in prostanoid-mediated contractions in health and during disease will help to define advanced pharmacological strategies for the

  20. Advances on circulating fetal DNA in maternal plasma

    Institute of Scientific and Technical Information of China (English)

    FU Xian-hu; CHEN Han-ping

    2007-01-01

    @@ The discovery of cell-free fetal DNA in maternal plasma in 1997 has opened up new possibilities for noninvasive diagnosis.1 By RT-PCR, circulating fetal DNA can be detected in the plasma of pregnant women,even in the first trimester of pregnancy,2,3 and thus can be used for noninvasive prenatal diagnosis of sex-linked disorders,4-6 the RhD status of fetuses,7 and single gene disorders such as beta-thalassaemia,8,9 congenital adrenal hyperplasia,10 and achondroplasia.11 In addition,quantitative aberrations of circulating fetal DNA may indicate various pregnancy-associated disorders,including1 Preeclampsia,12-14 preterm labor15,16 and fetal trisomy 21.17

  1. Plasma circulating fibrinogen stability and moderate beer consumption.

    Science.gov (United States)

    Gorinstein, Shela; Caspi, Abraham; Zemser, Marina; Libman, Imanuel; Goshev, Ivan; Trakhtenberg, Simon

    2003-12-01

    MODERATE BEER CONSUMPTION (MBC) IS CARDIOPROTECTIVE: it positively influences plasma lipid levels and plasma antioxidant activity in beer-consuming individuals. The connection between MBC and blood coagulation is not clearly defined. Forty-two volunteers were equally divided into experimental (EG) and control (CG) groups following coronary bypass surgery. For 30 consecutive days, only patients of the EG consumed 330 mL of beer per day (about 20 g of alcohol). A comprehensive clinical investigation of 42 patients was done. Blood samples were collected before and after the investigation for a wide range of laboratory tests. The plasma fibrinogen was denatured with 8 M urea and intrinsic fluorescence (IF), hydrophobicity and differential scanning calorimetry (DSC) were used to reveal possible qualitative changes. After 30 days of moderate beer consumption, positive changes in the plasma lipid levels, plasma anticoagulant and plasma antioxidant activities were registered in patients of the EG group. In 17 out of 21 patients of the same group, differences in plasma circulating fibrinogen's (PCF), secondary and tertiary structures were found. The stability of fibrinogen, expressed in thermodynamic parameters, has shown that the loosening of the structure takes place under ethanol and urea denaturation. Also fluorescence stability of PCF was decreased. No changes in the lipid levels, anticoagulant and antioxidant activity or changes in PCF were detected in patients of CG. In conclusion, for the first time after a short term of moderate beer consumption some qualitative changes in the plasma circulating fibrinogen were detected: differences in the emission peak response, fluorescence intensity and all thermodynamic data. Together, with the decrease in the PCF concentration it may lead to an elevation of the blood anticoagulant activity.

  2. IMP 8 observations of a poleward plasma circulation: Evidence of entry into the plasma mantle?

    Science.gov (United States)

    Kolpak, M. A.; Paularena, K. I.; Richardson, J. D.; Siscoe, G. L.

    Plasma data from IMP 8 are used to map the spatial structure of plasma flow in Earth's magnetosheath. Plasma and magnetic field data from instruments on ISEE-3 and WIND are used to normalize the IMP 8 magnetosheath data to upstream solar wind conditions. For the majority of the data, the magnitude and direction of plasma flow inside the magnetosheath agree well with gas-dynamic models. About 8% of the ISEE-3-normalized velocity vectors and 3% of the WIND-normalized velocity vectors exhibit a poleward circulation in the YZ plane. The observed circulation is consistent with predictions for flow within the plasma mantle. The occurrence frequency of these poleward flows increases further down the tail, consistent with predictions that the mantle width increases tailward. Densities are lower where this flow is observed, consistent with expectations for the plasma mantle, but temperatures are higher and the magnetic field magnitudes lower, the opposite of theoretical expectations.

  3. The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke

    DEFF Research Database (Denmark)

    Joseph, Jason P; Mecca, Adam P; Regenhardt, Robert W;

    2014-01-01

    hypothesize that C21 may exert beneficial effects against cerebral damage and neurological deficits produced by ischemic stroke. We determined the effects of central and peripheral administration of C21 on the cerebral damage and neurological deficits in rats elicited by endothelin-1 induced middle cerebral...... artery occlusion (MCAO), a model of cerebral ischemia. Rats infused centrally (intracerebroventricular) with C21 before endothelin-1 induced MCAO exhibited significant reductions in cerebral infarct size and the neurological deficits produced by cerebral ischemia. Similar cerebroprotection was obtained...... in rats injected systemically (intraperitoneal) with C21 either before or after endothelin-1 induced MCAO. The protective effects of C21 were reversed by central administration of an AT2R inhibitor, PD123319. While C21 did not alter cerebral blood flow at the doses used here, peripheral post...

  4. Turnour necrosis factor stimulates endothelin-1 gene expression in cultured bovine endothelial cells

    Directory of Open Access Journals (Sweden)

    Silvia Orisio

    1992-01-01

    Full Text Available We have studied the effect of human recombinant tumour necrosis factor-α (TNF-α on gene expression and production of endothelin-1 in cultured bovine aortic endothelial cells. TNF-α (10 and 100 ng ml−1 increased in a time dependent manner the preproendothelin-1 mRNA levels in respect to unstimulated endothelial cells. TNF-α induced endothelin-1 gene expression was associated with a parallel increase in the release of the corresponding peptide in the culture medium. These findings suggest that the enhanced synthesis and release of endothelin-1 occurring in conditions of increased generation of TNF, may act as a modulatory factor that counteracts the hypotensive effect and the excessive platelet aggregation and adhesion induced by TNF.

  5. 早发型重度子痫前期合并器官功能障碍患者可溶性内皮抑素、内皮素-1与凝血功能的变化及意义%Serum soluble Endoglin, plasma endothelin-1 and coagulation function in early onset severe preeclampsia with organ dysfunction

    Institute of Scientific and Technical Information of China (English)

    张立军; 韩玉环; 韩玉植

    2010-01-01

    Objective To investigate the expression levels of serum soluble Endoglin (sEng), plasma endothelin-1 (ET-1) and coagulation function in patients suffering from early onset severe preeclampsia with organ dysfunction, and to analyze the clinical significance. Methods Forty-nine early onset severe preeclampsia patients were enrolled in the study group, including 26 cases without organ dysfunction (study group Ⅰ) and 23 cases with organ dysfunction (study group Ⅱ). The control group included 30 cases of health pregnant women during the same period of gestation. The serum levels of sEng and plasma ET-1 were analyzed with enzyme-linked immunosorbent assay (ELISA), coagulation function was determined at the same time, and the relationship between the change in levels of sEng, ET-1, coagulation function and organ function, and also outcome of perinatal infants. Results ① The levels of sEng, ET-1, fibrinogen (Fib) and mean platelet volume (MPV) of the study group Ⅰ and I were significantly higher compared with control group (sEng,μg/L:10.96±3.21, 14.17±4.02vs. 7.49±2.73; ET-1, μg/L: 41.54 ± 10. 37, 65.91± 12.46vs. 24.56±6.26; Fib, g/L:4.41±1.02,5.35±1.17vs. 3.69±0.82; MPV, fl:11. 71± 1.21, 13.89±1.76vs. 11.03±0.82, all P< 0.05), and prothrombin time (PT), activated partial thromboplastin time (APTT) and platelet (PLT) were significantly lower compared with control group (PT, s:10.73±1.82, 8.37±1.51vs. 12.95±1.91; APTT, s:26.14±4.32, 22.69±3.77vs. 30.25±4.71; PLT,×109/L; 164.17±50.67, 136.43±51.21vs. 201.63±59.83, all P<0.05). There were also statistical significances in all the values between study group Ⅰ and I (all P<0.05). ②There was positive correlation between the sEng level and systolic pressure, diastolic pressure, Fib, urine protein of 24 hours, serum creatinine (SCr); there was negative correlation between the sEng level and albumin (Alb) content, PT, estriol/creatinine (E/C) of 12-hour urine, fetal birth weight (all P

  6. Relation of improvement in endothelium-dependent flow-mediated vasodilation after rosiglitazone to changes in asymmetric dimethylarginine, endothelin-1, and C-reactive protein in nondiabetic patients with the metabolic syndrome.

    Science.gov (United States)

    Wang, Tzung-Dau; Chen, Wen-Jone; Cheng, Wern-Cherng; Lin, Jong-Wei; Chen, Ming-Fong; Lee, Yuan-Teh

    2006-10-15

    The mechanisms by which thiazolidinediones exert beneficial effects on the endothelium are still not clear. We examined the effects of rosiglitazone on the plasma markers of metabolic control (glucose, insulin, adiponectin, resistin, and lipid profiles), markers of inflammation (high-sensitivity C-reactive protein [CRP], interleukin-6, soluble CD40 ligand, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1), and markers of vasoreactivity (asymmetric dimethylarginine [ADMA] and endothelin-1) and analyzed the relations between changes in endothelium-dependent flow-mediated dilation of the brachial artery and changes in these markers to elucidate their roles in mediating the vascular protective effects of rosiglitazone. Of 70 nondiabetic patients who met a modified National Cholesterol Education Program definition of the metabolic syndrome, 35 were randomized to receive rosiglitazone (4 mg/day) and 35 to receive placebo for 8 weeks. At study end, treatment with rosiglitazone had significantly reduced plasma insulin (-25%, p = 0.004) and resistin (-16%, p flow-mediated dilation (p analysis, changes in ADMA, endothelin-1, and CRP were independent predictors of improved endothelial reactivity with rosiglitazone. In conclusion, we have, for the first time, demonstrated the independent associations between the improvement in flow-mediated dilation and reductions in ADMA, endothelin-1, and CRP after 8 weeks of treatment with rosiglitazone in nondiabetic patients with the metabolic syndrome. These findings suggest that decreases in ADMA, endothelin-1, and CRP may serve as possible mechanisms for the improvement in endothelial function conferred by rosiglitazone treatment.

  7. Role of endothelin-1 in mediating changes in cardiac sympathetic nerve activity in heart failure.

    Science.gov (United States)

    Abukar, Yonis; May, Clive N; Ramchandra, Rohit

    2016-01-01

    Heart failure (HF) is associated with increased sympathetic nerve activity to the heart (CSNA), which is directly linked to mortality in HF patients. Previous studies indicate that HF is associated with high levels of plasma endothelin-1 (ET-1), which correlates with the severity of the disease. We hypothesized that blockade of endothelin receptors would decrease CSNA. The effects of intravenous tezosentan (a nonselective ETA and ETB receptor antagonist) (8 mg·kg(-1)·h(-1)) on resting levels of CSNA, arterial pressure, and heart rate were determined in conscious normal sheep (n = 6) and sheep with pacing-induced HF (n = 7). HF was associated with a significant decrease in ejection fraction (from 74 ± 2% to 38 ± 1%, P < 0.001) and a significant increase in resting levels of CSNA burst incidence (from 56 ± 11 to 87 ± 2 bursts/100 heartbeats, P < 0.01). Infusion of tezosentan for 60 min significantly decreased resting mean aterial pressure (MAP) in both normal and HF sheep (-8 ± 4 mmHg and -4 ± 3 mmHg, respectively; P < 0.05). This was associated with a significant decrease in CSNA (by 25 ± 26% of control) in normal sheep, but there was no change in CSNA in HF sheep. Calculation of spontaneous baroreflex gain indicated significant impairment of the baroreflex control of HR after intravenous tezosentan infusion in normal animals but no change in HF animals. These data suggest that endogenous levels of ET-1 contribute to the baseline levels of CSNA in normal animals, but this effect is absent in HF.

  8. Novel Vasoregulatory Aspects of Hereditary Angioedema: the Role of Arginine Vasopressin, Adrenomedullin and Endothelin-1.

    Science.gov (United States)

    Kajdácsi, Erika; Jani, Péter K; Csuka, Dorottya; Varga, Lilian; Prohászka, Zoltán; Farkas, Henriette; Cervenak, László

    2016-02-01

    The elevation of bradykinin (BK) level during attacks of hereditary angioedema due to C1-Inhibitor deficiency (C1-INH-HAE) is well known. We previously demonstrated that endothelin-1 (ET-1) level also increases during C1-INH-HAE attacks. Although BK and ET-1 are both potent vasoactive peptides, the vasoregulatory aspect of the pathomechanism of C1-INH-HAE has not yet been investigated. Hence we studied the levels of vasoactive peptides in controls and in C1-INH-HAE patients, as well as evaluated their changes during C1-INH-HAE attacks. The levels of arginine vasopressin (AVP), adrenomedullin (ADM) and ET-1 were measured in the plasma of 100 C1-INH-HAE patients in inter-attack periods and of 111 control subjects, using BRAHMS Kryptor technologies. In 18 of the 100 C1-INH-HAE patients, the levels of vasoactive peptides were compared in blood samples obtained during attacks, or in inter-attack periods. AVP, ADM and ET-1 levels were similar in inter-attack samples from C1-INH-HAE patients and in the samples of controls, although cardiovascular risk has an effect on the levels of vasoactive peptides in both groups. The levels of all three vasoactive peptides increased during C1-INH-HAE attacks. Moreover, the levels of ET-1 and ADM as well as their changes during attacks were significantly correlated. This study demonstrated that vascular regulation by vasoactive peptides is affected during C1-INH-HAE attacks. Our results suggest that the cooperation of several vasoactive peptides may be necessary to counterbalance the actions of excess BK, and to terminate the attacks. This may reveal a novel pathophysiological aspect of C1-INH-HAE.

  9. Endothelin 1 levels in relation to clinical presentation and outcome of Henoch Schonlein purpura

    Directory of Open Access Journals (Sweden)

    Moustaki M

    2008-09-01

    Full Text Available Abstract Background Henoch Schonlein purpura (HSP is a common vasculitis of small vessels whereas endothelin-1 (ET-1 is usually reported elevated in vasculities and systematic inflammation. The aim of the present study was to investigate whether ET-1 levels are correlated with the clinical presentation and the outcome of HSP. Methods The study sample consisted of thirty consecutive patients with HSP. An equal number of healthy patients of similar age and the same gender were served as controls. The patients' age range was 2–12.6 years with a mean ± SD = 6.3 ± 3 years. All patients had a physical examination with a renal, and an overall clinical score. Blood and urinary biochemistry, immunology investigation, a skin biopsy and ET-1 measurements in blood and urine samples were made at presentation, 1 month later and 1 year after the appearance of HSP. The controls underwent the same investigation with the exception of skin biopsy. Results ET-1 levels in plasma and urine did not differ between patients and controls at three distinct time points. Furthermore the ET-1 were not correlated with the clinical score and renal involvement was independent from the ET-1 measurements. However, the urinary ET-1 levels were a significant predictor of the duration of the acute phase of HSP (HR = 0.98, p = 0.032, CI0.96–0.99. The ET-1 levels did not correlate with the duration of renal involvement. Conclusion Urinary ET-1 levels are a useful marker for the duration of the acute phase of HSP but not for the length of renal involvement.

  10. Endothelin-1 protects human melanocytes from UV-induced DNA damage by activating JNK and p38 signalling pathways.

    Science.gov (United States)

    von Koschembahr, Anne M; Swope, Viki B; Starner, Renny J; Abdel-Malek, Zalfa A

    2015-04-01

    Endothelin-1 is a paracrine factor with mitogenic, melanogenic and survival effects on cultured human melanocytes. We report that endothelin-1 signalling reduced the generation and enhanced the repair of ultraviolet radiation (UV)-induced DNA photoproducts, and inhibited apoptosis of human melanocytes, without increasing cAMP levels, melanin content or proliferation. Treatment with endothelin-1 activated the MAP kinases JNK and p38, as evidenced by phosphorylation of their target, activating transcription factor-2 (ATF-2). Endothelin-1 also enhanced the phosphorylation of JNK, p38 and ATF-2 by UV. The effects of endothelin-1 were dependent on increasing intracellular calcium mobilization by endothelin B receptor signalling. Activation of both JNK and p38 was required for reducing DNA photoproducts, but only JNK partially contributed to the survival effect of endothelin-1. ATF-2 activation depended mainly on JNK, yet was not sufficient for the effect of endothelin-1 on UV-induced DNA damage, suggesting the requirement for other JNK and p38 targets for this effect. Our results underscore the significance of endothelin-1 and endothelin B receptor signalling in reducing the genotoxic effects of UV via activating JNK and p38, hence restoring genomic stability of melanocytes.

  11. Endothelin-1 increases melanin synthesis in an established sheep skin melanocyte culture.

    Science.gov (United States)

    Pang, Yamiao; Geng, Jianjun; Qin, Yilong; Wang, Haidong; Fan, Ruiwen; Zhang, Ying; Li, Hongquan; Jiang, Shan; Dong, Changsheng

    2016-08-01

    The aims of the study were to establish a culture system for sheep skin melanocytes and uncover the effects of endothelin-1 on melanin synthesis in cultured melanocytes in order to provide an optimal cell system and a theoretical basis for studying the regulatory mechanism of coat color in sheep. In this study, skin punch biopsies were harvested from the dorsal region of 1-3-yr-old sheep, and skin melanocytes were then obtained by the two-step digestion using dispase II and trypsin/ethylene diamine tetraacetic acid (EDTA). The primary cultures of the melanocytes were established and characterized by dopa-staining, immunocytochemical localization of melanocyte markers, and RT-polymerase chain reaction (PCR) analysis of coat color genes. To determine the effect of endothelin-1 on proliferation and melanin synthesis of melanocytes, the cultured cells were treated with different doses of endothelin-1 (10(-7), 10(-8), 10(-9), 10(-10), and 0 mol/L), and the growth rate of melanocytes, production of melanin, expression of related genes, and location of related protein in cultured cells were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), ultraviolet spectrophotometry, qRT-PCR, and immunocytochemical localization, respectively. The results showed that the established melanocyte culture functions properly. Endothelin-1 treatment increased markedly the number of melanocytes and melanin content. In responding to this treatment, expressions of microphthalmia-associated transcription factor (MITF), melanocortin 1 receptor (MC1R), tyrosinase (TYR), and endothelin receptor B (EDNRB) in the melanocytes were significantly up regulated (P skin melanocytes was established successfully in vitro, and endothelin-1 promotes the melanogenesis in sheep skin melanocytes.

  12. Endothelin-1 contributes to the Frank-Starling response in hypertrophic rat hearts.

    Science.gov (United States)

    Piuhola, Jarkko; Szokodi, István; Kinnunen, Pietari; Ilves, Mika; deChâtel, Rudolf; Vuolteenaho, Olli; Ruskoaho, Heikki

    2003-01-01

    Endothelin-1 is involved in mechanical load-induced cardiac growth processes; it also has effects on contractility. The interaction of endothelin-1 and the Frank-Starling response is unknown. The present study aimed to characterize the role of endothelin-1 in the regulation of the Frank-Starling response, one of the major mechanisms regulating cardiac contractile force, in both normal and hypertrophied hearts. Nontransgenic rat hearts and hypertrophic hearts of hypertensive double transgenic rats harboring human angiotensinogen and renin genes were studied in a Langendorff isolated heart setup with a liquid-filled balloon inside the left ventricle used to measure contractile parameters. The rats were studied at compensated phase, before showing any signs of heart failure. Compensated hypertrophy in double transgenic rat hearts resulted in improved contractility at a given level of preload when compared with nontransgenic rat hearts. Hearts of both rat lines showed preserved Frank-Starling responses, that is, increased contractile function in response to increased end-diastolic pressure. The mixed endothelin A/B receptor antagonist bosentan attenuated the Frank-Starling response by 53% (P<0.01) in the double transgenic hearts but not in nontransgenic hearts. The diastolic parameters remained unaffected. The left ventricles of the double transgenic rat hearts showed an 82% higher level of endothelin type A receptor mRNA and a 25% higher level of immunoreactive endothelin-1 compared with nontransgenic rat hearts. The type 1 angiotensin II receptor antagonist CV-11974 had no significant effect on contractile function in response to load in either strain. These results show that endogenous endothelin-1 contributes to the Frank-Starling response in hypertrophied rat hearts by affecting systolic performance.

  13. Exhaled and arterial levels of endothelin-1 are increased and correlate with pulmonary systolic pressure in COPD with pulmonary hypertension

    Directory of Open Access Journals (Sweden)

    Dragonieri Silvano

    2008-09-01

    Full Text Available Abstract Background Endothelin-1 (ET-1 and Nitric Oxide (NO are crucial mediators for establishing pulmonary artery hypertension (PAH. We tested the hypothesis that their imbalance might also occur in COPD patients with PAH. Methods The aims of the study were to measure exhaled breath condensate (EBC and circulating levels of ET-1, as well as exhaled NO (FENO levels by, respectively, a specific enzyme immunoassay kit, and by chemiluminescence analysis in 3 groups of subjects: COPD with PAH (12, COPD only (36, and healthy individuals (15. In order to evaluate pulmonary-artery systolic pressure (PaPs, all COPD patients underwent Echo-Doppler assessment. Results Significantly increased exhaled and circulating levels of ET-1 were found in COPD with PAH compared to both COPD (p 1%, (r = -0.59, p = 0.043, and PaPs negatively correlated to PaO2 (r = -0.618; p = 0.032. Significantly reduced levels of FENO were found in COPD associated with PAH, compared to COPD only (22.92 ± 11.38 vs.35.07 ± 17.53 ppb; p = 0.03. Thus, we observed an imbalanced output in the breath between ET-1 and NO, as expression of pulmonary endothelium and epithelium impairment, in COPD with PAH compared to COPD only. Whether this imbalance is an early cause or result of PAH due to COPD is still unknown and deserves further investigations.

  14. Umbilical cord blood and neonatal endothelin-1 levels in preterm newborns with and without respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    A.C.W. Benjamin

    2005-09-01

    Full Text Available Increased pulmonary vascular resistance in preterm newborn infants with respiratory distress syndrome is suggested, and endothelin-1 plays an important role in pulmonary vascular reactivity in newborns. We determined umbilical cord blood and neonatal (second sample levels of endothelin-1 in 18 preterm newborns with respiratory distress syndrome who had no clinical or echocardiographic diagnosis of pulmonary hypertension and 22 without respiratory distress syndrome (gestational ages: 31.4 ± 1.6 and 29.3 ± 2.3 weeks, respectively. Umbilical cord blood and a second blood sample taken 18 to 40 h after birth were used for endothelin-1 determination by enzyme immunoassay. Median umbilical cord blood endothelin-1 levels were similar in both groups (control: 10.9 and respiratory distress syndrome: 11.4 pg/mL and were significantly higher than in the second sample (control: 1.7 pg/mL and respiratory distress syndrome: 3.5 pg/mL, P < 0.001 for both groups. Median endothelin-1 levels in the second sample were significantly higher in children with respiratory distress syndrome than in control infants (P < 0.001. There were significant positive correlations between second sample endothelin-1 and Score for Neonatal Acute Physiology and Perinatal Extension II (r = 0.36, P = 0.02, and duration of mechanical ventilation (r = 0.64, P = 0.02. A slower decline of endothelin-1 from birth to 40 h of life was observed in newborns with respiratory distress syndrome when compared to controls. A significant correlation between neonatal endothelin-1 levels and some illness-severity signs suggests that endothelin-1 plays a role in the natural course of respiratory distress syndrome in preterm newborns.

  15. Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome.

    Science.gov (United States)

    Lin, Yan-Jie; Juan, Chi-Chang; Kwok, Ching-Fai; Hsu, Yung-Pei; Shih, Kuang-Chung; Chen, Chin-Chang; Ho, Low-Tone

    2015-05-08

    Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ETAR during insulin resistance, ETAR expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ETAR expression, but not ETBR, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ETAR pathway suppressed insulin-induced AKT

  16. Effect of mineralocorticoid treatment in mice with collecting duct-specific knockout of endothelin-1

    OpenAIRE

    Lynch, I. Jeanette; Welch, Amanda K.; Gumz, Michelle L.; Kohan, Donald E.; Cain, Brian D.; Wingo, Charles S.

    2015-01-01

    Aldosterone increases blood pressure (BP) by stimulating sodium (Na) reabsorption within the distal nephron and collecting duct (CD). Aldosterone also stimulates endothelin-1 (ET-1) production that acts within the CD to inhibit Na reabsorption via a negative feedback mechanism. We tested the hypothesis that this renal aldosterone-endothelin feedback system regulates electrolyte balance and BP by comparing the effect of a high-salt (NaCl) diet and mineralocorticoid stimulation in control and C...

  17. Endothelin-1 decreases endothelial PPARγ signaling and impairs angiogenesis after chronic intrauterine pulmonary hypertension

    OpenAIRE

    Wolf, David; Tseng, Nancy; Seedorf, Gregory; Roe, Gates; Abman, Steven H.; Gien, Jason

    2013-01-01

    Increased endothelin-1 (ET-1) disrupts angiogenesis in persistent pulmonary hypertension of the newborn (PPHN), but pathogenic mechanisms are unclear. Peroxisome proliferator activated receptor γ (PPARγ) is decreased in adult pulmonary hypertension, but whether ET-1-PPARγ interactions impair endothelial cell function and angiogenesis in PPHN remains unknown. We hypothesized that increased PPHN pulmonary artery endothelial cell (PAEC) ET-1 production decreases PPARγ signaling and impairs tube ...

  18. Endothelin-1 Induces Proteinuria by Heparanase-Mediated Disruption of the Glomerular Glycocalyx.

    Science.gov (United States)

    Garsen, Marjolein; Lenoir, Olivia; Rops, Angelique L W M M; Dijkman, Henry B; Willemsen, Brigith; van Kuppevelt, Toin H; Rabelink, Ton J; Berden, Jo H M; Tharaux, Pierre-Louis; van der Vlag, Johan

    2016-12-01

    Diabetic nephropathy (DN) is the leading cause of CKD in the Western world. Endothelin receptor antagonists have emerged as a novel treatment for DN, but the mechanisms underlying the protective effect remain unknown. We previously showed that both heparanase and endothelin-1 are essential for the development of DN. Here, we further investigated the role of these proteins in DN, and demonstrated that endothelin-1 activates podocytes to release heparanase. Furthermore, conditioned podocyte culture medium increased glomerular transendothelial albumin passage in a heparanase-dependent manner. In mice, podocyte-specific knockout of the endothelin receptor prevented the diabetes-induced increase in glomerular heparanase expression, consequent reduction in heparan sulfate expression and endothelial glycocalyx thickness, and development of proteinuria observed in wild-type counterparts. Our data suggest that in diabetes, endothelin-1 signaling, as occurs in endothelial activation, induces heparanase expression in the podocyte, damage to the glycocalyx, proteinuria, and renal failure. Thus, prevention of these effects may constitute the mechanism of action of endothelin receptor blockers in DN. Copyright © 2016 by the American Society of Nephrology.

  19. Reproducibility of Circulating MicroRNAs in Stored Plasma Samples.

    Directory of Open Access Journals (Sweden)

    Monica L Bertoia

    Full Text Available Most studies of microRNA (miRNA and disease have examined tissue-specific expression in limited numbers of samples. The presence of circulating miRNAs in plasma samples provides the opportunity to examine prospective associations between miRNA expression and disease in initially healthy individuals. However, little data exist on the reproducibility of miRNAs in stored plasma.We used Real-Time PCR to measure 61 pre-selected microRNA candidates in stored plasma. Coefficients of variation (CVs were used to assess inter-assay reliability (n = 15 and within-person stability over one year (n = 80. Intraclass correlation coefficients (ICCs and polychoric correlation coefficients were used to assess within-person stability and delayed processing reproducibility (whole blood stored at 4°C for 0, 24 and 48 hours; n = 12 samples.Of 61 selected miRNAs, 23 were detected in at least 50% of samples and had average CVs below 20% for inter-assay reproducibility and 31 for delayed processing reproducibility. Ten miRNAs were detected in at least 50% of samples, had average CVs below 20% and had ICCs above 0.4 for within-person stability over 1-2 years, six of which satisfied criteria for both interassay reproducibility and short-term within-person stability (miR-17-5p, -191-5p, -26a-5p, -27b-3p, -320a, and -375 and two all three types of reproducibility (miR-27b-3p and -26a-5p. However, many miRNAs with acceptable average CVs had high maximum CVs, most had low expression levels, and several had low ICCs with delayed processing.About a tenth of miRNAs plausibly related to chronic disease were reliably detected in stored samples of healthy adults.

  20. Umbilical cord blood and neonatal endothelin-1 levels in preterm newborns with and without respiratory distress syndrome

    OpenAIRE

    2005-01-01

    Increased pulmonary vascular resistance in preterm newborn infants with respiratory distress syndrome is suggested, and endothelin-1 plays an important role in pulmonary vascular reactivity in newborns. We determined umbilical cord blood and neonatal (second sample) levels of endothelin-1 in 18 preterm newborns with respiratory distress syndrome who had no clinical or echocardiographic diagnosis of pulmonary hypertension and 22 without respiratory distress syndrome (gestational ages: 31.4 ± 1...

  1. Circulating human B and plasma cells. Age-associated changes in counts and detailed characterization of circulating normal CD138(-) and CD138(+) plasma cells

    NARCIS (Netherlands)

    Caraux, Anouk; Klein, Bernard; Paiva, Bruno; Bret, Caroline; Schmitz, Alexander; Fuhler, Gwenny M.; Bos, Nico A.; Johnsen, Hans E.; Orfao, Alberto; Perez-Andres, Martin

    2010-01-01

    Generation of B and plasma cells involves several organs with a necessary cell trafficking between them. A detailed phenotypic characterization of four circulating B-cell subsets (immature-, naive-, memory- B-lymphocytes and plasma cells) of 106 healthy adults was realized by multiparametric flow cy

  2. High arterial compliance in cirrhosis is related to low adrenaline and elevated circulating calcitonin gene related peptide but not to activated vasoconstrictor systems

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Møller, S; Schifter, S;

    2001-01-01

    , vasoactivity was manipulated by inhalation of oxygen. STUDY POPULATION AND METHODS: In 20 patients with alcoholic cirrhosis and 12 controls we determined COMP(art) (stroke volume relative to pulse pressure), cardiac output, plasma volume, systemic vascular resistance, central circulation time, plasma...... catecholamines, renin activity, endothelin-1, and calcitonin gene related peptide (CGRP) at baseline and during oxygen inhalation. RESULTS: COMP(art) was significantly increased in cirrhotic patients compared with controls (1.32 v 1.06 ml/mm Hg; p

  3. Umbilical cord blood and neonatal endothelin-1 levels in preterm newborns with and without respiratory distress syndrome.

    Science.gov (United States)

    Benjamin, A C W; Silveira, R C; Procianoy, R S

    2005-09-01

    Increased pulmonary vascular resistance in preterm newborn infants with respiratory distress syndrome is suggested, and endothelin-1 plays an important role in pulmonary vascular reactivity in newborns. We determined umbilical cord blood and neonatal (second sample) levels of endothelin-1 in 18 preterm newborns with respiratory distress syndrome who had no clinical or echocardiographic diagnosis of pulmonary hypertension and 22 without respiratory distress syndrome (gestational ages: 31.4 +/- 1.6 and 29.3 +/- 2.3 weeks, respectively). Umbilical cord blood and a second blood sample taken 18 to 40 h after birth were used for endothelin-1 determination by enzyme immunoassay. Median umbilical cord blood endothelin-1 levels were similar in both groups (control: 10.9 and respiratory distress syndrome: 11.4 pg/mL) and were significantly higher than in the second sample (control: 1.7 pg/mL and respiratory distress syndrome: 3.5 pg/mL, P respiratory distress syndrome than in control infants (P newborns with respiratory distress syndrome when compared to controls. A significant correlation between neonatal endothelin-1 levels and some illness-severity signs suggests that endothelin-1 plays a role in the natural course of respiratory distress syndrome in preterm newborns.

  4. Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension

    Energy Technology Data Exchange (ETDEWEB)

    Satwiko, Muhammad Gahan [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Ikeda, Koji [Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe (Japan); Nakayama, Kazuhiko [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Yagi, Keiko [Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe (Japan); Hocher, Berthold [Institute for Nutritional Science, University of Potsdam, Potsdam (Germany); Hirata, Ken-ichi [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Emoto, Noriaki, E-mail: emoto@med.kobe-u.ac.jp [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe (Japan)

    2015-09-25

    Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAH. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. - Highlights: • Role of endothelin-1 in pulmonary arterial hypertension (PAH) was investigated. • The endothelin-1 transgenic (ETTG) and wild type (WT) mice were analyzed. • ETTG mice spontaneously developed PAH under normoxia conditions. • SU5416 further aggravated PAH in ETTG mice. • Enhanced endothelin system activity could be a causative factor in

  5. Confirmation of translatability and functionality certifies the dual endothelin1/VEGFsp receptor (DEspR) protein

    OpenAIRE

    Herrera, Victoria L. M.; Steffen, Martin; Moran, Ann Marie; Tan, Glaiza A.; Khristine A Pasion; Rivera, Keith; Pappin, Darryl J.; Ruiz-Opazo, Nelson

    2016-01-01

    Background In contrast to rat and mouse databases, the NCBI gene database lists the human dual-endothelin1/VEGFsp receptor (DEspR, formerly Dear) as a unitary transcribed pseudogene due to a stop [TGA]-codon at codon#14 in automated DNA and RNA sequences. However, re-analysis is needed given prior single gene studies detected a tryptophan [TGG]-codon#14 by manual Sanger sequencing, demonstrated DEspR translatability and functionality, and since the demonstration of actual non-translatability ...

  6. Correlation of endothelin-1 concentration in aqueous humor with intraocular pressure in primary open angle and pseudoexfoliation glaucoma.

    Science.gov (United States)

    Choritz, Lars; Machert, Maren; Thieme, Hagen

    2012-10-23

    Endothelin-1 (ET-1) has been found in elevated concentrations in the aqueous humor of glaucoma patients. Indirect evidence from animal studies suggests that ET-1 might directly influence intraocular pressure (IOP). The aim of this study was to determine whether ET-1 concentrations in aqueous humor of cataract and glaucoma patients correlate with IOP. Aqueous humor and blood samples from patients with either cataract (control, n = 38), primary open angle glaucoma (POAG, n = 35), or pseudoexfoliation glaucoma (PEXG, n = 21), without other ocular or systemic disease, were collected during routine cataract surgery or trabeculectomy. ET-1 concentration was determined by an ET-1 ELISA kit. IOP was measured preoperatively by standard Goldmann applanation tonometry. All statistical analysis was performed using commercial predictive analytics software. Both IOP and ET-1 concentration in aqueous humor were significantly increased in POAG (23.4 ± 6.8 mm Hg, 5.9 ± 2.9 pg/mL) and PEXG (24.3 ± 8.8 mm Hg, 7.7 ± 2.1 pg/mL) compared with control (15.0 ± 2.9 mm Hg, 4.3 ± 2.4 pg/mL). No difference was detected for plasma ET-1 concentrations. IOP and ET-1 in the aqueous humor were significantly correlated (R = 0.394, R² = 0.155, P < 0.001), although no correlation was found between IOP and ET-1 in blood plasma or between ET-1 in aqueous humor and ET-1 in plasma. In this study, a small but highly significant correlation between IOP and the ET-1 concentration in the aqueous humor was found. Although no causative relationship can be deduced from this, ocular ET-1 effects on IOP control may merit further investigation.

  7. Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Yan-Jie [Institute of Physiology, National Yang-Ming University, Taipei, Taiwan (China); Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan (China); Juan, Chi-Chang [Institute of Physiology, National Yang-Ming University, Taipei, Taiwan (China); Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Kwok, Ching-Fai [Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China); Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Hsu, Yung-Pei [Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan (China); Shih, Kuang-Chung [Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China); Chen, Chin-Chang [Institute of Physiology, National Yang-Ming University, Taipei, Taiwan (China); Ho, Low-Tone, E-mail: ltho@vghtpe.gov.tw [Institute of Physiology, National Yang-Ming University, Taipei, Taiwan (China); Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China); Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan (China)

    2015-05-08

    Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ET{sub A}R during insulin resistance, ET{sub A}R expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ET{sub A}R expression, but not ET{sub B}R, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ET{sub A}R pathway

  8. Formation of native disulfide bonds in endothelin-1. Structural evidence for the involvement of a highly specific salt bridge between the prosequence and the endothelin-1 sequence.

    Science.gov (United States)

    Aumelas, A; Kubo, S; Chino, N; Chiche, L; Forest, E; Roumestand, C; Kobayashi, Y

    1998-04-14

    The [Lys-Arg]-endothelin-1 analogue (KR-ET-1) yields almost selectively the native disulfide pattern (96%), in contrast to endothelin-1 (ET-1) that gives at least 25% of the non-native disulfide pattern. We have previously shown that the carboxylate-state structure of KR-ET-1 is more constrained and stabilized by a salt bridge between Arg(-1) and the Asp8 or Glu10 side chain [Aumelas et al. (1995) Biochemistry 34, 4546-4561]. To identify this salt bridge and its potential involvement in the disulfide bond formation, [E10Q], [D18N], and [D8N] carboxamide analogues were studied, which led to the unambiguous identification of the Arg(-1)-Asp8 salt bridge. Furthermore, while [E10Q] and [D18N] analogues gave a high yield of the native isomer (>/=90%), the [D8N] analogue afforded a ratio of the two isomers close to that observed for ET-1 (68%) [Kubo et al. (1997) Lett. Pept. Sci. 4, 185-192]. Assuming that the formation of disulfide bonds occurs in a thermodynamically controlled step, we have hypothesized that the Arg(-1)-Asp8 salt bridge and concomitant interactions could be responsible for the increase in yield of the native isomer of KR-ET-1. In the present work, we describe the structural studies of the carboxamide analogues and of the minor non-native KR-ET-1 isomer. On the basis of 1H NMR and CD spectra as a function of pH, [E10Q] and [D18N] analogues display a conformational change similar to that of the parent peptide, whereas the structure of the [D8N] analogue is unchanged. For the non-native isomer, we measured a lower helical content than for the native isomer and observed a marked difference in the orientation of the KRCSC backbone. In addition, no salt bridge was experimentally observed. Altogether, these results allow us to hypothesize that the salt bridge between two highly conserved residues, one belonging to the prosequence [Arg(-1)] and the other to the mature sequence [Asp8], is involved in the formation of the native disulfide isomer of ET-1. The

  9. Endothelin 1 and transforming growth factor-β1 correlate with liver function and portal pressure in cirrhotic patients.

    Science.gov (United States)

    Wereszczynka-Siemiatkowska, Urszula; Swidnicka-Siergiejko, Agnieszka; Siemiatkowski, Andrzej; Bondyra, Zofia; Wasielica-Berger, Justyna; Mroczko, Barbara; Janica, Jacek; Dabrowski, Andrzej

    2015-12-01

    The invasive measurement of hepatic venous pressure gradient is the recommended method for the assessment of portal hypertension. We assessed if the mediators that regulate portal hypertension may be used as noninvasive markers of portal hypertension and liver insufficiency. We explored in prospective, observational study the concentration of endothelin-1, nitric oxide, and transforming growth factor-β1/2 in peripheral and hepatic venous blood; their relationship with the values of portal hypertension and liver insufficiency; and their level changes 4-6 months after non-selective beta-blocker therapy in cirrhotic patients with non-bleeding esophageal varices. (1) Cirrhotics have significantly increased peripheral endothelin 1 and decreased transforming growth factor-β1 levels; (2) peripheral levels of all factors correlated significantly with their hepatic levels; (3) after therapy, peripheral endothelin-1 levels significantly increased, but transforming growth factor-β2 levels decreased and were lower in patients with pressure gradient value normalization; (4) before and after therapy, peripheral and hepatic endothelin-1, transforming growth factor-β1/2 levels correlated significantly with liver failure indicators (laboratory parameters, Child-Pough and MELD scores) and pressure gradient values. Peripheral endothelin-1 and transforming growth factor-β1 levels, which strongly correlate with their hepatic levels, reflect the stage of portal hypertension and liver insufficiency in cirrhosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Circulating human B and plasma cells. Age-associated changes in counts and detailed characterization of circulating normal CD138- and CD138+ plasma cells.

    Science.gov (United States)

    Caraux, Anouk; Klein, Bernard; Paiva, Bruno; Bret, Caroline; Schmitz, Alexander; Fuhler, Gwenny M; Bos, Nico A; Johnsen, Hans E; Orfao, Alberto; Perez-Andres, Martin

    2010-06-01

    Generation of B and plasma cells involves several organs with a necessary cell trafficking between them. A detailed phenotypic characterization of four circulating B-cell subsets (immature-, naïve-, memory- B-lymphocytes and plasma cells) of 106 healthy adults was realized by multiparametric flow cytometry. We show that CD10, CD27 and CD38 is the minimal combination of subsetting markers allowing unequivocal identification of immature (CD10(+)CD27(-)CD38(+), 6+/-6 cells/microL), naïve (CD10(-)CD27(-)CD38(-), 125+/-90 cells/microL), memory B lymphocytes (CD10(-)CD27(+)CD38(-), 58+/-42 cells/microL), and plasma cells (CD10(-)CD27(++)CD38(++), 2.1+/-2.1 cells/microL) within circulating CD19(+) cells. From these four subsets, only memory B lymphocytes and plasma cells decreased with age, both in relative and absolute counts. Circulating plasma cells split into CD138(-) (57+/-12%) and CD138(+) (43+/-12%) cells, the latter displaying a more mature phenotypic profile: absence of surface immunoglobulin, lower CD45 positivity and higher amounts of cytoplasmic immunoglobulin, CD38 and CD27. Unlike B lymphocytes, both populations of plasma cells are KI-67(+) and show weak CXCR4 expression.

  11. Alteration of Endothelin 1, MCP-1 and Chromogranin A in patients with atrial fibrillation undergoing pulmonary vein isolation.

    Science.gov (United States)

    Lackermair, K; Clauss, S; Voigt, T; Klier, I; Summo, C; Hildebrand, B; Nickel, T; Estner, H L; Kääb, S; Wakili, R; Wilbert-Lampen, U

    2017-01-01

    The relation between arrhythmias and stress is known. The aim of our current study was to elucidate whether plasma levels of previously described stress parameters are altered in highly symptomatic patients with atrial fibrillation (AF) per se and in patients undergoing ablation therapy by pulmonary vein isolation (PVI). 96 patients with AF undergoing PVI were recruited. Plasma levels of Endothelin-1 (ET-1), MCP-1 and Chromogranin-A (CGA) were measured before and three months after ablation completed with clinical follow-up with respect to AF recurrence. Additionally, we examined 40 healthy age- and sex-matched volunteers as a reference. Symptomatic AF patients showed increased levels of ET-1 compared to healthy controls (2.62pg/ml vs. 1.57pg/ml; pPVI (2.96pg/ml vs. 2.57pg/ml;p = 0.02). The temporal comparison revealed decreased ET-1 levels in patients without (2.57pg/ml vs. 2.33pg/ml; pPVI. Baseline MCP-1 was increased in AF patients vs. controls (268pg/ml vs. 227 pg/ml; p = 0.03). Both groups, with and without AF after PVI, showed an increase of MCP-1 compared to baseline (268pg/ml vs. 349pg/ml;pPVI showed an increase of CGA (14.2ng/ml vs. 20.7ng/ml;pPVI. Our study demonstrated dysregulated levels of ET-1, MCP-1 and CGA in symptomatic AF patients. We could demonstrate an association between ET-1 to presence or absence of AF. Furthermore, we could show that a decrease of ET-1 as well as an increase of CGA after PVI, representing a trend towards control cohort levels, were both associated with restoration of sinus rhythm. These results provide new insights into the role of stress-related biomarkers in AF and AF treatment by ablation therapy.

  12. Effects of age and caloric restriction in the vascular response of renal arteries to endothelin-1 in rats.

    Science.gov (United States)

    Amor, Sara; García-Villalón, Angel Luis; Rubio, Carmen; Carrascosa, Jose Ma; Monge, Luis; Fernández, Nuria; Martín-Carro, Beatriz; Granado, Miriam

    2017-02-01

    Cardiovascular alterations are the most prevalent cause of impaired physiological function in aged individuals with kidney being one the most affected organs. Aging-induced alterations in renal circulation are associated with a decrease in endothelium-derived relaxing factors such as nitric oxide (NO) and with an increase in contracting factors such as endothelin-1(ET-1). As caloric restriction (CR) exerts beneficial effects preventing some of the aging-induced alterations in cardiovascular system, the aim of this study was to analyze the effects of age and caloric restriction in the vascular response of renal arteries to ET-1 in aged rats. Vascular function was studied in renal arteries from 3-month-old Wistar rats fed ad libitum (3m) and in renal arteries from 8-and 24-month-old Wistar rats fed ad libitum (8m and 24m), or subjected to 20% caloric restriction during their three last months of life (8m-CR and 24m-CR). The contractile response to ET-1 was increased in renal arteries from 8m and 24m compared to 3m rats. ET-1-induced contraction was mediated by ET-A receptors in all experimental groups and also by ET-B receptors in 24m rats. Caloric restriction attenuated the increased contraction to ET-1 in renal arteries from 8m but not from 24m rats possibly through NO release proceeding from ET-B endothelial receptors. In 24m rats, CR did not attenuate the aging-increased response of renal arteries to ET-1, but it prevented the aging-induced increase in iNOS mRNA levels and the aging-induced decrease in eNOS mRNA levels in arterial tissue. In conclusion, aging is associated with an increased response to ET-1 in renal arteries that is prevented by CR in 8m but not in 24m rats.

  13. EFFECTS OF MODULATED LDLs ON THE RELEASE OF ENDOTHELIN-1AND PROSTACYCLIN BY ENDOTHELIAL CELLS IN CULTURE

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To study the releases of endothelin-1 and prostacyclin by endothelial cells in culture and to elucidate how these releases were influenced by smoke-treated low density lipoprotein. Methods We exposed endothelial cell cultures to native or oxidized Iow density lipoproteins,low density lipoproteins treated by dimethylsulfoxide-soluble particles from cigarette smoke or dimethylsulfoxide alones. The release of endothelin-1 was assayed by bioassay and the release of prostacyclin was assayed by radioimmunoassay. Results Low density lipoproteins treated by smoke significantly increased the release of endothelin-l (P<0. 025) and decreased the release of prostacyclin (P<0. 02) by endothelial cells in culture, contrast to native or dimethylsulfoxide-treated lipoproteins. Conclusion The main part of vasoconstrictor activity in conditioned medium from bovine aortic EC is endothelin-1.

  14. Endothelin-1 induces a histamine-dependent flare in vivo, but does not activate human skin mast cells in vitro.

    OpenAIRE

    Brain, S D; Thomas, G.; Crossman, D.C.; Fuller, R.; Church, M. K.

    1992-01-01

    The role of the mast cell in endothelin-1 induced flare has been investigated by in vivo and in vitro experiments. The intradermal injection of endothelin-1 (10 pmol) into human skin induced a pallor with surrounding axon-reflex flare which is similar to the flare response to histamine (1 nmol). At these doses, chosen to give identical flare areas, blood flow was increased in the area of the endothelin-induced flare over a longer period. A systemic H1-receptor antagonist significantly inhibit...

  15. High SPARC Expression Starting from Dysplasia, Associated with Breast Carcinoma, Is Predictive for Bone Metastasis without Enhancement of Plasma Levels

    Science.gov (United States)

    Maroni, Paola; Bendinelli, Paola; Morelli, Daniele; Drago, Lorenzo; Luzzati, Alessandro; Perrucchini, Giuseppe; Bonini, Chiara; Matteucci, Emanuela; Desiderio, Maria Alfonsina

    2015-01-01

    In order to become established in the skeleton, metastatic cells disseminating from the breast carcinoma need to acquire organ-specific traits. There are no effective predictors for who will develop bone metastasis to guide long-term predictive therapy. Our purpose was to individuate events critical for bone colonization to make a molecular classification of breast carcinoma useful for bone-metastasis outcome. In dysplasia adjacent to carcinoma and in pair-matched specimens of bone metastasis we examined SPARC expression and localization as well as Endothelin 1/ETAR signals by immunohistochemistry, and the evaluation of plasma levels of SPARC by ELISA was also performed. In patients with breast carcinoma metastasizing to bone, SPARC and Endothelin 1/ETAR axis were highly expressed from dysplasia until bone metastasis, but the SPARC plasma level was as low as that of normal women, in contrast to patients that never develop bone metastasis, suggesting that circulating SPARC was counter adhesive. Altogether, the early identification of SPARC/Endothelin 1/ETAR in dysplastic lesions would be important to devise therapies preventing metastasis engraftment, since often carcinoma cells spread to distant organs at the time or even before patients present with cancer. PMID:26703564

  16. Efecto de la endotelina-1 sobre las arterias tumorales de pacientes con neoplasia colorrectal Effect of endothelin-1 on tumor arteries in patients with colorectal cancer

    Directory of Open Access Journals (Sweden)

    E. Ferrero Herrero

    2008-06-01

    Full Text Available La endotelina-1 es un péptido vasoconstrictor producido por el endotelio vascular, cuyos niveles plasmáticos están aumentados en los pacientes con cáncer colorrectal y que puede participar en la regulación del flujo sanguíneo tumoral. Para estudiar si la respuesta a este péptido está alterada en las arterias tumorales, se obtuvieron, de 13 pacientes intervenidos quirúrgicamente por cáncer colorrectal, arterias mesentéricas irrigando el tumor y arterias mesentéricas de una región alejada del tumor, y asimismo se obtuvieron arterias mesentéricas de pacientes intervenidos por diverticulitis (n = 4 o enfermedad inflamatoria intestinal (n = 3. Las arterias mesentéricas se montaron en una preparación para el registro de la contracción isométrica en un baño de órganos, encontrándose que la endotelina-1 producía contracción en los tres tipos de arterias, pero la sensibilidad a este péptido fue mayor en las arterias irrigando el tumor que en las arterias alejadas del tumor o en las arterias de pacientes sin patología tumoral. Estos resultados indican que la endotelina-1 puede regular el flujo sanguíneo en los tumores colorrectales, produciendo una mayor vasoconstricción en las arterias que irrigan el tumor que en las arterias no tumorales.Endothelin-1 is an endothelium-derived vasoconstrictor peptide whose plasma levels are increased in patients with colorectal cancer, and which may be involved in tumor blood flow regulation. To study whether response to this peptide is altered in tumor arteries, mesenteric arteries supplying blood flow to colorectal tumors, and mesenteric arteries far from said tumors were obtained from 13 patients undergoing colectomy; mesenteric arteries were also obtained from patients with diverticulitis (n = 4 or inflammatory bowel disease (n = 3. Arteries were prepared for isometric tension recording in an organ bath, and in this preparation it was found that endothelin-1 induced contraction in all three

  17. Circulating folic acid in plasma: relation to folic acid fortification

    Science.gov (United States)

    The implementation of folic acid fortification in the United States has resulted in unprecedented amounts of this synthetic form of folate in the American diet. Folic acid in circulation may be a useful measure of physiologic exposure to synthetic folic acid, and there is a potential for elevated co...

  18. Endothelin-1 signalling controls early embryonic heart rate in vitro and in vivo.

    Science.gov (United States)

    Karppinen, S; Rapila, R; Mäkikallio, K; Hänninen, S L; Rysä, J; Vuolteenaho, O; Tavi, P

    2014-02-01

    Spontaneous activity of embryonic cardiomyocytes originates from sarcoplasmic reticulum (SR) Ca(2+) release during early cardiogenesis. However, the regulation of heart rate during embryonic development is still not clear. The aim of this study was to determine how endothelin-1 (ET-1) affects the heart rate of embryonic mice, as well as the pathway through which it exerts its effects. The effects of ET-1 and ET-1 receptor inhibition on cardiac contraction were studied using confocal Ca(2+) imaging of isolated mouse embryonic ventricular cardiomyocytes and ultrasonographic examination of embryonic cardiac contractions in utero. In addition, the amount of ET-1 peptide and ET receptor a (ETa) and b (ETb) mRNA levels were measured during different stages of development of the cardiac muscle. High ET-1 concentration and expression of both ETa and ETb receptors was observed in early cardiac tissue. ET-1 was found to increase the frequency of spontaneous Ca(2+) oscillations in E10.5 embryonic cardiomyocytes in vitro. Non-specific inhibition of ET receptors with tezosentan caused arrhythmia and bradycardia in isolated embryonic cardiomyocytes and in whole embryonic hearts both in vitro (E10.5) and in utero (E12.5). ET-1-mediated stimulation of early heart rate was found to occur via ETb receptors and subsequent inositol trisphosphate receptor activation and increased SR Ca(2+) leak. Endothelin-1 is required to maintain a sufficient heart rate, as well as to prevent arrhythmia during early development of the mouse heart. This is achieved through ETb receptor, which stimulates Ca(2+) leak through IP3 receptors. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  19. Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis.

    NARCIS (Netherlands)

    Dhaun, N.; Lilitkarntakul, P.; Macintyre, I.M.; Muilwijk, E.W.; Johnston, N.R.; Kluth, D.C.; Webb, D.J.; Goddard, J.

    2009-01-01

    Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated

  20. Transcription levels of endothelin-1 and endothelin receptors are associated with age and leaflet location in porcine mitral valves

    DEFF Research Database (Denmark)

    Pedersen, Lotte Gam; Offenberg, Hanne Kjær; Moesgaard, Sophia Gry;

    2007-01-01

    The aim of the study was to investigate the expression levels of endothelin-1 (ET-1) and ETA and ETB receptors (ETA-R and ETB-R) in porcine mitral valves and associate the transcription levels to age, leaflet location and deposition of mucopolysaccharides (MPS). Tissue samples from the chordal an...

  1. Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis.

    NARCIS (Netherlands)

    Dhaun, N.; Lilitkarntakul, P.; Macintyre, I.M.; Muilwijk, E.W.; Johnston, N.R.; Kluth, D.C.; Webb, D.J.; Goddard, J.

    2009-01-01

    Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated t

  2. Low Soluble Fms-Like Tyrosine Kinase-1, Endoglin, and Endothelin-1 Levels in Women With Confirmed or Suspected Preeclampsia Using Proton Pump Inhibitors.

    Science.gov (United States)

    Saleh, Langeza; Samantar, Raaho; Garrelds, Ingrid M; van den Meiracker, Anton H; Visser, Willy; Danser, A H Jan

    2017-09-01

    Patients with preeclampsia display elevated placenta-derived sFlt-1 (soluble Fms-like tyrosine kinase-1) and endoglin levels and decreased placental growth factor levels. Proton pump inhibitors (PPIs) decrease trophoblast sFlt-1 and endoglin secretion in vitro. PPIs are used during pregnancy to combat reflux disease. Here, we investigated whether PPIs affect sFlt-1 in women with confirmed/suspected preeclampsia, making use of a prospective cohort study involving 430 women. Of these women, 40 took PPIs (6 esomeprazole, 32 omeprazole, and 2 pantoprazole) for 8 to 45 (median 29) days before sFlt-1 measurement. Measurements were only made once, at study entry between weeks 20 and 41 (median 33 weeks). PPI use was associated with lower sFlt-1 levels, with no change in placental growth factor levels, both when compared with all non-PPI users and with 80 gestational age-matched controls selected from the non-PPI users. No sFlt-1/placental growth factor alterations were observed in women using ferrous fumarate or macrogol while, as expected, women using antihypertensive medication displayed higher sFlt-1 levels and lower placental growth factor levels. The PPI use-associated decrease in sFlt-1 was independent of the application of antihypertensive drugs and also occurred when restricting our analysis to patients with hypertensive disease of pregnancy at study entry. PPI users displayed more cases with preexisting proteinuria, less gestational hypertension, and a lower number of neonatal sepsis cases. Finally, their plasma endoglin and endothelin-1 levels were lower while sFlt-1 levels correlated positively with both. In conclusion, PPI use associates with low sFlt-1, endoglin, and endothelin-1 levels, warranting prospective trials to investigate the therapeutic potential of PPIs in preeclampsia. © 2017 American Heart Association, Inc.

  3. Chronic administration of phosphodiesterase type 5 inhibitor suppresses renal production of endothelin-1 in dogs with congestive heart failure.

    Science.gov (United States)

    Yamamoto, Takashi; Wada, Atsuyuki; Ohnishi, Masato; Tsutamoto, Takayoshi; Fujii, Masanori; Matsumoto, Takehiro; Takayama, Tomoyuki; Wang, Xinwen; Kurokawa, Kiyoshi; Kinoshita, Masahiko

    2002-08-01

    Endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) play important roles in the regulation of body fluid balance in congestive heart failure (CHF). Renal production of ET-1 increases in CHF and it is a significant independent predictor of sodium excretion. ANP inhibits the ET system through cGMP, a second messenger of ANP. However, in severe CHF, plasma cGMP levels reached a plateau despite the activation of ANP secretion. Thus, ANP does not seem to sufficiently oppose exaggerated ET-1 actions in severe CHF, partially due to the accelerated degradation of cGMP, through phosphodiesterase type 5 (PDE5). We examined the chronic effects of a PDE5 inhibitor, T-1032 (1 mg/kg per day, n=5), on renal function and renal production of ET-1 in dogs with CHF induced by rapid ventricular pacing (270 beats/min). Vehicle dogs were given a placebo (n=5) and normal dogs (n=5) served as normal controls without pacing. In this experimentally produced CHF, plasma levels of ET-1, ANP and cGMP were elevated and renal production of cGMP was increased compared with the normal group, associated with increases in renal expression of preproET-1 mRNA and the number of ET-1-positive cells in glomeruli. In the T-1032 group, systemic and renal production of cGMP were further increased compared with the vehicle group despite no significant difference in plasma ANP levels between the two groups. Subsequently, the agent significantly improved urine flow rate, sodium excretion rate and glomerular filtration rate (GFR) associated with reductions in renal expression of preproET-1 mRNA and the number of ET-1-positive cells compared with the vehicle group. Moreover, there was a significant negative correlation between the number of ET-1-positive cells and GFR (r=-0.802 and Prenal ANP and ET-1 through the cGMP pathway, subsequently preventing renal dysfunction during the progression of CHF.

  4. Association studies suggest a key role for endothelin-1 in the pathogenesis of preeclampsia and the accompanying renin-angiotensin-aldosterone system suppression.

    Science.gov (United States)

    Verdonk, Koen; Saleh, Langeza; Lankhorst, Stephanie; Smilde, J E Ilse; van Ingen, Manon M; Garrelds, Ingrid M; Friesema, Edith C H; Russcher, Henk; van den Meiracker, Anton H; Visser, Willy; Danser, A H Jan

    2015-06-01

    Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomerular filtration. Subcutaneous arteries obtained from patients with preeclampsia displayed an enhanced, AT2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness in preeclampsia involves constrictor AT2 receptors.

  5. Combined exposure to big endothelin-1 and mechanical loading in bovine sternal cores promotes osteogenesis.

    Science.gov (United States)

    Meyer, Luisa A; Johnson, Michael G; Cullen, Diane M; Vivanco, Juan F; Blank, Robert D; Ploeg, Heidi-Lynn; Smith, Everett L

    2016-04-01

    Increased bone formation resulting from mechanical loading is well documented; however, the interactions of the mechanotransduction pathways are less well understood. Endothelin-1, a ubiquitous autocrine/paracrine signaling molecule promotes osteogenesis in metastatic disease. In the present study, it was hypothesized that exposure to big endothelin-1 (big ET1) and/or mechanical loading would promote osteogenesis in ex vivo trabecular bone cores. In a 2×2 factorial trial of daily mechanical loading (-2000με, 120cycles daily, "jump" waveform) and big ET1 (25ng/mL), 48 bovine sternal trabecular bone cores were maintained in bioreactor chambers for 23days. The bone cores' response to the treatment stimuli was assessed with percent change in core apparent elastic modulus (ΔEapp), static and dynamic histomorphometry, and prostaglandin E2 (PGE2) secretion. Two-way ANOVA with a post hoc Fisher's LSD test found no significant treatment effects on ΔEapp (p=0.25 and 0.51 for load and big ET1, respectively). The ΔEapp in the "no load + big ET1" (CE, 13±12.2%, p=0.56), "load + no big ET1" (LC, 17±3.9%, p=0.14) and "load + big ET1" (LE, 19±4.2%, p=0.13) treatment groups were not statistically different than the control group (CC, 3.3%±8.6%). Mineralizing surface (MS/BS), mineral apposition (MAR) and bone formation rates (BFR/BS) were significantly greater in LE than CC (p=0.037, 0.0040 and 0.019, respectively). While the histological bone formation markers in LC trended to be greater than CC (p=0.055, 0.11 and 0.074, respectively) there was no difference between CE and CC (p=0.61, 0.50 and 0.72, respectively). Cores in LE and LC had more than 50% greater MS/BS (p=0.037, p=0.055 respectively) and MAR (p=0.0040, p=0.11 respectively) than CC. The BFR/BS was more than two times greater in LE (p=0.019) and LC (p=0.074) than CC. The PGE2 levels were elevated at 8days post-osteotomy in all groups and the treatment groups remained elevated compared to the CC group on days 15

  6. Prostanoids counterbalance the synergism between endothelin-1 and angiotensin II in mesenteric veins of trained rats.

    Science.gov (United States)

    Chies, Agnaldo Bruno; de Oliveira, Priscilla Bianca; Rossignoli, Patrícia de Souza; Baptista, Rafaela de Fátima Ferreira; de Lábio, Roger William; Payão, Spencer Luiz Marques

    2017-02-01

    Exercise-induced adaptations of the modulating mechanisms that influence the angiotensin (Ang II) responses assume different features depending on the venous bed. In femoral veins, exercise mobilizes vasodilator prostanoids to cooperate with NO in order to maintain reduced Ang II responses. On the other hand, exercise's influence on the Ang II responses in veins that drain blood from the mesenteric region has been poorly described. Therefore, the present study aimed to identify the effects of a single bout of exercise, as well as exercise training, on the Ang II responses in mesenteric veins. The present study also aimed to investigate the involvement of prostanoids, NO and ET-1 in eventual exercise-induced modifications in these veins. To this end, mesenteric veins taken from resting-sedentary, exercised-sedentary, resting-trained and exercised-trained animals were studied in organ baths. In addition, the mRNA expression of prepro-endothelin-1 (ppET-1), as well as that of the ETA and ETB receptors, were quantified by real-time PCR in these veins. The results show that, either in absence or in presence of L-NAME, the Ang II responses were not different between groups. In the presence of indomethacin, higher Ang II responses were observed in the resting-trained animals than in the resting-sedentary animals. This difference, however, disappeared when L-NAME, BQ-123 or BQ-788 were added during incubation. In addition, no differences in ppET-1, ETA or ETB mRNA expression were observed between groups. Furthermore, in the presence of PD123,319, the Ang II responses in the exercised-sedentary animals were higher than those in the resting-sedentary animals. In conclusion, exercise training mobilizes endothelin-1 (ET-1) to reinforce the Ang II-induced responses mainly through ETA activation. On the other hand, vasodilator prostanoids are mobilized to act in parallel with NO in order to counterbalance the Ang II responses that have been potentiated by ET-1 in these trained

  7. Endothelin-1 stimulates human adipocyte lipolysis through the ET A receptor.

    Science.gov (United States)

    Eriksson, A K S; van Harmelen, V; Stenson, B M; Aström, G; Wåhlén, K; Laurencikiene, J; Rydén, M

    2009-01-01

    Levels of the vascular peptide endothelin-1 (ET-1) are significantly elevated in obesity. Adipose tissue-derived ET-1 attenuates insulin-mediated antilipolysis in human visceral adipocytes through the activation of the ET receptor B (ET(B)R), thereby linking ET-1 to insulin resistance. Whether ET-1 has direct effects on lipolysis in human adipocytes is not known. Endothelin-1 receptor (ETR) mRNA expression was determined by quantitative PCR in 130 non-obese and obese subjects. ET-1 mRNA in different adipose tissue regions was also assessed. ETR protein expression was analyzed by western blotting in 37 subjects. The effect of ET-1 on lipolysis was assessed in freshly isolated adipocytes and in vitro differentiated adipocytes from human donors. Freshly isolated human adipocytes incubated with different concentrations of ET-1 showed no acute effect on lipolysis. In contrast, a 24 h incubation in primary cultures of human adipocytes resulted in a significant 50% increase in lipolysis. This effect was concentration dependent and could be mimicked by an agonist of the ET(A) receptor but not with a selective ET(B)R agonist. Adipocyte differentiation was not affected by any of the agonists. In subcutaneous (s.c.) adipose tissue from 19 non-obese and 18 obese subjects, the protein expression of ET(A)R was significantly higher in obese subjects whereas there was no difference in ET(B)R expression. Interestingly, the differences in protein expression were not observed at the mRNA level as ET(A)R expression was similar between lean and obese subjects. Long-term but not acute incubation of human adipocytes with ET-1 results in a significant increase in lipolysis. This appears to be mediated through the activation of ET(A)R, demonstrating a yet another receptor-specific effect of ET-1. In addition, the protein expression of ET(A)R is increased in s.c. adipose tissue in obesity, possibly through post-transcriptional mechanisms. An increased effect of ET-1 could be a mechanism

  8. Inhibition by atrial and brain natriuretic peptides of endothelin-1 secretion after stimulation with angiotensin II and thrombin of cultured human endothelial cells.

    Science.gov (United States)

    Kohno, M; Yasunari, K; Yokokawa, K; Murakawa, K; Horio, T; Takeda, T

    1991-01-01

    We examined the inhibition by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) of endothelin-1 secretion stimulated by angiotensin II (ANGII) and thrombin using cultured human umbilical-vein endothelial cells. ANGII and thrombin dose-dependently stimulated immunoreactive (ir) endothelin-1 secretion. Human ANP(1-28) and human BNP-32 both inhibited such secretion in a dose-dependent way. Inhibition of this secretion by ANP and BNP was paralleled by an increase in the level of cyclic guanosine 5'-monophosphate (GMP). The addition of a cyclic GMP analogue, 8-bromo cyclic GMP, reduced this stimulated secretion. Rat ANP(5-25) was weaker than human ANP(1-28) at inhibiting ir-endothelin-1 secretion and increasing cyclic GMP in the cells. ir-Endothelin-1 in the medium consisted of two components separated by high pressure liquid chromatography; the major one corresponded to endothelin-1(1-21) and the minor one corresponded to big endothelin-1(1-38). Treatment with ANP and BNP did not affect this profile. These findings suggest that human ANP and BNP inhibit endothelin-1 secretion stimulated by ANGII and thrombin in these cells through a cyclic GMP-dependent process. Taken together with endothelin stimulation of ANP and BNP secretion from the heart, our results suggest the existence of a cardiac-endothelium feedback. PMID:1645748

  9. Assessment of Circulating microRNAs in Plasma of Lung Cancer Patients

    Directory of Open Access Journals (Sweden)

    Orazio Fortunato

    2014-03-01

    Full Text Available Lung cancer is the most common cause of cancer deaths worldwide and numerous ongoing research efforts are directed to identify new strategies for its early detection. The development of non-invasive blood-based biomarkers for cancer detection in its preclinical phases is crucial to improve the outcome of this deadly disease. MicroRNAs (miRNAs are a new promising class of circulating biomarkers for cancer detection and prognosis definition, but lack of consensus on data normalization methods for circulating miRNAs and the critical issue of haemolysis, has affected the identification of circulating miRNAs with diagnostic potential. We describe here an interesting approach for profiling circulating miRNAs in plasma samples based on the evaluation of reciprocal miRNA levels measured by quantitative Real-Time PCR. By monitoring changes of plasma miRNA-ratios, it is possible to assess the deregulation of tumor-related miRNAs and identify signatures with diagnostic and prognostic value. In addition, to avoid bias due to the release of miRNAs from blood cells, a miRNA-ratios signature distinguishing haemolyzed samples was identified. The method described was validated in plasma samples of lung cancer patients, but given its reproducibility and reliability, could be potentially applied for the identification of diagnostic circulating miRNAs in other diseases.

  10. The concept of a plasma centrifuge with a high frequency rotating magnetic field and axial circulation

    Science.gov (United States)

    Borisevich, V. D.; Potanin, E. P.

    2017-07-01

    The possibility of using a rotating magnetic field (RMF) in a plasma centrifuge (PC), with axial circulation to multiply the radial separation effect in an axial direction, is considered. For the first time, a traveling magnetic field (TMF) is proposed to drive an axial circulation flow in a PC. The longitudinal separation effect is calculated for a notional model, using specified operational parameters and the properties of a plasma, comprising an isotopic mixture of 20Ne-22Ne and generated by a high frequency discharge. The optimal intensity of a circulation flow, in which the longitudinal separation effect reaches its maximum value, is studied. The optimal parameters of the RMF and TMF for effective separation, as well as the centrifuge performance, are calculated.

  11. Cytokine modulation by endothelin-1 and possible therapeutic implications in systemic sclerosis.

    Science.gov (United States)

    Giordano, N; Papakostas, P; Pecetti, G; Nuti, R

    2011-01-01

    Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disorder characterized by a progressive fibrosis which involves skin and internal organs, caused by microvascular damage. The earliest clinical sign of the disease is Raynauds Phenomenon, a vasospastic response to cold or stress stimuli, followed by the skin and organ involvement over time. This kind of vascular manifestation originates from the microvascular structural alteration, characterized by an abnormal myocyte cell proliferation, intima cell proliferation and adventitia fibrosis. The microvascular damage seems to be the consequence of the autoimmune attack to the endothelium, followed by inflammatory cascade and massive deposition of collagen. From the beginning of the disorder, serum Endothelin-1 (ET- 1) is found in very high concentration: this protein, today, is considered one of the most important mediators of scleroderma vascular alterations. Furthermore, many recent studies have shown that ET-1 is involved in the inflammatory and fibrotic processes, increasing the concentration of pro-fibrotic and pro-inflammatory cytokines. The aim of this review is to clarify the ET-1 role in SSc, in particular the relationship between ET-1 and cytokine expression, adding another element to the understanding of scleroderma disease.

  12. Contribution of transient receptor potential vanilloid subfamily 1 to endothelin-1-induced thermal hyperalgesia.

    Science.gov (United States)

    Kawamata, T; Ji, W; Yamamoto, J; Niiyama, Y; Furuse, S; Namiki, A

    2008-06-26

    Endothelin-1 (ET-1) plays an important role in peripheral pain processing. However, the mechanisms of the nociceptive action of ET-1 have not been fully elucidated. In this study, we investigated the contribution of transient receptor potential vanilloid subfamily 1 (TRPV1) to ET-1-induced thermal hyperalgesia. Intraplantar ET-1-induced thermal hyperalgesia was examined by assessing the paw withdrawal latency to noxious heat stimuli. In electrophysiological study, whole-cell patch-clamp recordings were performed to investigate the interaction of ET-1 and TRPV1 using human embryonic kidney 293 (HEK293) cells expressing endothelin type A receptor (ET(A)) and TRPV1. Intraplantar ET-1 (3, 10 and 30 pmol) produced thermal hyperalgesia in a dose-dependent manner. Thermal hyperalgesia was attenuated by the inhibition of ET(A) and protein kinase C (PKC) but not that of ET(B). ET-1-induced thermal hyperalgesia was significantly attenuated in TRPV1-deficient mice compared with that in wild-type mice. In voltage-clamp experiments, 10 nM capsaicin evoked small inward currents in HEK293 cells expressing TRPV1 and ET(A). In the presence of ET-1, capsaicin produced much larger current responses (Pthermal hyperalgesia.

  13. A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys

    Science.gov (United States)

    Dai, PeiMin; Huang, Hui; Zhang, Lin; He, Jing; Zhao, XuDong; Yang, FuHan; Zhao, Ning; Yang, JianZhen; Ge, LongJiao; Lin, Yu; Yu, HuaLin; Wang, JianHong

    2017-01-01

    Endothelin-1 (ET-1), a vasoconstrictor, has recently been used to induce focal ischemia in rodents and marmoset monkeys. The rhesus monkey, however, has numerous advantages to the rodent and marmoset that make it a superior and irreplaceable animal model for studying stroke in the brain. In the present study, after mapping the preferred hand representation in two healthy male monkeys with intracortical micro-stimulation, ET-1 was microinjected into the contralateral motor cortex (M1) to its preferred hand. The monkeys had been trained in three manual dexterity tasks before the microinjection and were tested for these tasks following the ET-1 injection. Brain Magnetic Resonance Imaging scans were performed 1, 7, 14 and 28 days post ischemia. It was found that ET-1 impaired the manual dexterity of the monkeys in the vertical slot and rotating Brinkman board tasks 3–8 days after the injection. Brain imaging found that severe edema was present 7 days after the focal ischemia. This data suggest that ET-1 can induce transient ischemic stroke in rhesus monkey and that ET-1 induced focal ischemia in non-human primates is a potential model to study the mechanism of stroke and brain repair after stroke. PMID:28358140

  14. HYPOXIA AND ENDOTHELIN-1 STIMULATE DNA SYNTHESIS OF PULMONARY ARTERY SMOOTH MUSCLE CELLS

    Institute of Scientific and Technical Information of China (English)

    冯晓东; 蔡英年

    1996-01-01

    Hypoxia and endothelin-1 (ET-1) are associated with constriction of pulmonary vasculature both in vivo and in vitro. However, the role of hypoxia and ET-1 in the vascular remodelling during the development of pulmonary, hypertension is unciear. This study demonstrated that ET-1 (0.1nmol/L to 100nmol./L)increased the 3H]thymldine uptake in a dose-dependent manner in cuhured bovine pulmonary artery smooth muscle cells(PASMC), which was enhanced by exposing PASMC to hypoxia (2% O2, 93%N2,5%CO2). BQ123, the specific antagonist of endot helin receptor subtype A, eiLmLnated the ET-1 medicated proliferati0n of PASMC and the cooperative effect of hypoxia. Some dilatory drugs could inhibite the mitogenic effect of ET-1. We also observed that hypoxia significantiy increased [3H]thymldine uptake in PASMC without ET-1 and BQ123 could inhibite this effect. Radioimmunoassay suggested that there was an autocrine of ET-1 in cultured PASMC which was enhanced by hypoxia significantly.

  15. Endothelin-1 supports clonal derivation and expansion of cardiovascular progenitors derived from human embryonic stem cells.

    Science.gov (United States)

    Soh, Boon-Seng; Ng, Shi-Yan; Wu, Hao; Buac, Kristina; Park, Joo-Hye C; Lian, Xiaojun; Xu, Jiejia; Foo, Kylie S; Felldin, Ulrika; He, Xiaobing; Nichane, Massimo; Yang, Henry; Bu, Lei; Li, Ronald A; Lim, Bing; Chien, Kenneth R

    2016-03-08

    Coronary arteriogenesis is a central step in cardiogenesis, requiring coordinated generation and integration of endothelial cell and vascular smooth muscle cells. At present, it is unclear whether the cell fate programme of cardiac progenitors to generate complex muscular or vascular structures is entirely cell autonomous. Here we demonstrate the intrinsic ability of vascular progenitors to develop and self-organize into cardiac tissues by clonally isolating and expanding second heart field cardiovascular progenitors using WNT3A and endothelin-1 (EDN1) human recombinant proteins. Progenitor clones undergo long-term expansion and differentiate primarily into endothelial and smooth muscle cell lineages in vitro, and contribute extensively to coronary-like vessels in vivo, forming a functional human-mouse chimeric circulatory system. Our study identifies EDN1 as a key factor towards the generation and clonal derivation of ISL1(+) vascular intermediates, and demonstrates the intrinsic cell-autonomous nature of these progenitors to differentiate and self-organize into functional vasculatures in vivo.

  16. The Matrix Metalloproteases and Endothelin-1 in Infection-Associated Preterm Birth

    Directory of Open Access Journals (Sweden)

    Nicole S. Olgun

    2010-01-01

    Full Text Available Preterm birth (PTB is clinically defined as any delivery which occurs before the completion of 37 weeks of gestation, and is currently the most important problem in obstetrics. In the United States, PTB accounts for 12-13% of all live births, and, with the exception of fetuses suffering from anomalies, is the primary cause of perinatal mortality. While the risk factors for PTB are numerous, the single most common cause is intrauterine infection. As there is currently no FDA-approved therapy for infection-associated PTB, understanding the pathogenesis of preterm labor (PTL and delivery should be given high priority. The matrix metalloproteinases (MMPs are a family of enzymes that have been implicated in normal parturition as well as infection-triggered rupture of membranes and preterm birth. Several lines of evidence also suggest a role for endothelin-1 (ET-1 in infection-associated preterm delivery. This paper focuses on the evidence that the MMPs and ET-1 act in the same molecular pathway in preterm birth.

  17. N-Acetyl Cysteine Inhibits Endothelin-1-Induced ROS Dependent Cardiac Hypertrophy through Superoxide Dismutase Regulation

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    Sobia Mushtaq

    2015-07-01

    Full Text Available Objective: Oxidative stress down regulates antioxidant enzymes including superoxide dismutase (SOD and contributes to the development of cardiac hypertrophy. N-Acetyl cysteine (NAC can enhance the SOD activity, so the aim of this study is to highlight the inhibitory role of NAC against endothelin-1 (ET-1-induced cardiac hypertrophy. Materials and Methods: In this experimental study at QAU from January, 2013 to March, 2013. ET-1 (50 μg/kg and NAC (50 mg/kg were given intraperitoneally to 6-day old neonatal rats in combination or alone. All rats were sacrificed 15 days after the final injection. Histological analysis was carried out to observe the effects caused by both drugs. Reactive oxygen species (ROS analysis and SOD assay were also carried out. Expression level of hypertrophic marker, brain natriuretic peptide (BNP, was detected by western blotting. Results: Our findings showed that ET-1-induced cardiac hypertrophy leading towards heart failure was due to the imbalance of different parameters including free radical-induced oxidative stress and antioxidative enzymes such as SOD. Furthermore NAC acted as an antioxidant and played inhibitory role against ROS-dependent hypertrophy via regulatory role of SOD as a result of oxidative response associated with hypertrophy. Conclusion: ET-1-induced hypertrophic response is associated with increased ROS production and decreased SOD level, while NAC plays a role against free radicals-induced oxidative stress via SOD regulation.

  18. [Effect of endothelin-1 on the proliferation of human lung adenocarcinoma cell SPC-A1].

    Science.gov (United States)

    Ye, Qianjun; Zhou, Juan; Zhang, Weimin

    2007-02-20

    Endothelin-1 (ET-1) is a potent mitogen involved in tumor cell growth and angiogenesis. The aim of this study is to explore the effect of ET-1 on the proliferation of human lung adenocarcinoma cells SPC-A1. Cell number was measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide] assay. Cell cycle was detected by flow cytometry. ET-1 (1×10⁻¹⁵ -1×10⁻⁸ mol/L) enhanced SPC-A1 cell growth in a dose-dependent manner in vitro, with the greatest effect beginning at 1×10⁻¹¹ mol/L. Effect of ET-1 (1×10⁻¹⁰ mol/L) on the proliferation of SPC-A1 cells was completely blocked by BQ123 (1×10⁻⁷ mol/L), a highly selective endothelin receptor A (ETA) antagonist (P SPC-A1 cells (P SPC-A1 cell cycle. ET-1 enhances SPC-A1 cell proliferation by the activation of ETA receptor. Ca(2+) influx from voltage dependent calcium-channel contributes to this process.

  19. Heparin suppresses cyclosporine-induced endothelin-1 synthesis in rat endothelial cells.

    Science.gov (United States)

    Yokokawa, K; Kohno, M; Minami, M; Yasunari, K; Mandal, A K; Yoshikawa, J

    1998-01-01

    Cyclosporine stimulates vasoconstrictor endothelin-1 (ET-1) synthesis. This study examined the effect of heparin on cyclosporine-induced ET-1 synthesis in Wistar rat aortic endothelial cells in culture. Cyclosporine (0.01-5 mumol/L) stimulated ET-1 mRNA expression in a dose-dependent manner. A nitric oxide synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA) (10(-5) mol/L), did not affect cyclosporine-induced ET-1 mRNA expression. Heparin (1-20 U/ml) suppressed cyclosporine-induced ET-1 mRNA expression in a dose-dependent manner. The inhibitory effect of heparin was blunted in the presence of either L-NMMA (10(-5) mol/L) or calmodulin inhibitors such as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) (5 x 10(-5) mol/L) or calmidazolium (5 x 10(-5) mol/L) in the presence of the phosphodiesterase inhibitor 3-isobutyl 1-methylxanthine (0.1 mmol/L). These results suggest that heparin suppresses cyclosporine-induced ET-1 mRNA expression via both NO- and calmodulin-dependent pathways.

  20. Air Pollution-Induced Vascular Dysfunction: Potential Role of Endothelin-1 (ET-1) System.

    Science.gov (United States)

    Finch, Jordan; Conklin, Daniel J

    2016-07-01

    Exposure to air pollution negatively impacts cardiovascular health. Studies show that increased exposure to a number of airborne pollutants increases the risk for cardiovascular disease progression, myocardial events, and cardiovascular mortality. A hypothesized mechanism linking air pollution and cardiovascular disease is the development of systemic inflammation and endothelium dysfunction, the latter of which can result from an imbalance of vasoactive factors within the vasculature. Endothelin-1 (ET-1) is a potent peptide vasoconstrictor that plays a significant role in regulating vascular homeostasis. It has been reported that the production and function of ET-1 and its receptors are upregulated in a number of disease states associated with endothelium dysfunction including hypertension and atherosclerosis. This mini-review surveys epidemiological and experimental air pollution studies focused on ET-1 dysregulation as a plausible mechanism underlying the development of cardiovascular disease. Although alterations in ET-1 system components are observed in some studies, there remains a need for future research to clarify whether these specific changes are compensatory or causally related to vascular injury and dysfunction. Moreover, further research may test the efficacy of selective ET-1 pharmacological interventions (e.g., ETA receptor inhibitors) to determine whether these treatments could impede the deleterious impact of air pollution exposure on cardiovascular health.

  1. Surface Modification of Fine Particle by Plasma Grafting in a Circulating Fluidized Bed Reactor under Reduced Pressure

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sounghee [Woosuk University, Jinchon (Korea, Republic of)

    2015-10-15

    A plasma surface modification of powders has been carried out in a circulating fluidized bed reactor under reduced pressure. Polystyrene (PS) particles treated by plasma are grafted with polyethylene glycol (PEG) on the surface. The virgin, plasma-treated and grafted powders were characterized by DPPH method, FTIR, SEM and contact angle meter. The plasma-treated PS powders have well formed peroxide on the surface, By PEG grafting polymerization, PEG is well grafted and dispersed on the surface of the plasma-treated PS powders. The PEG-g-PS particle was successfully synthesized using the plasma circulating fluidized bed reactor under reduced pressure.

  2. Effect of endotoxin on the celluar activity and secretion of endothelin-1 in cultured human umbilical vein endothelial cells

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    AIM and METHODS: To investigate the effect of endotoxin on the celluar activity and secretion of endothelin-1 by radioimmunoassay and MTT methods in cultured human umbilical vein endothelial cells stimulated by E coli endotoxin (E coli O55:B5, Sigma) of various concentrations (1 g/L, 100 mg/L, 10 mg/L,1 mg/L,100 μg/L,10 μg/L, 1 μg/L) and at the same time interval (HUVEC stimulated by endotoxin for 6 hours) in vitro.RESULTS:Endotoxin showed a slightly inhibitory effect on the viability of endothelial cells at low doses (1 μg/L, 10 μg/L, 100 μg/L, 1 mg/L). The viabilities were 92.00%±1.45%, 91.81%±2.03%, 89.52%±1.49%, 88.35%±1.88%, respectively, versus control group, P<0.01. The cells were impaired significantly at the higher dose of LPS (100 mg/L), the viability was 80.49%±8.76%, versus control group, P<0.01. The cells were killed evidently at the concentration of LPS (1 g/L), the viability was 73%±8%, versus control group, P<0.01. The secretion of ET-1 increased gradually with the concentration of endotoxin manifolding. The concentration of ET-1 reached its peak at the dose of 100 μg/L, and it was (324.384±17.023) ng/L, versus control group (251.636±17.023) ng/L, P<0.01. Endotoxin was effective in stimulating the endothelial cells to secret ET-1 in a dose dependent manner. CONCLUSION: These findings suggested ET-1 may be one of the important factors in endotoxic shock, and the increase in plasma ET-1 level in endotoxemia may be associated with increase in ET-1 secretion.

  3. The role of the biomarker and the genetic polymorphism of endothelin-1 in pulmonary arterial hypertension among Egyptians

    Directory of Open Access Journals (Sweden)

    Emad Ibrahim

    2012-10-01

    Conclusions: In conclusion, our findings suggest a potential link between endothelin-1 level and specific genotypes in the EDN1 gene and susceptibility for PAH with a worse haemodynamic profile. Further investigations are warranted to understand the molecular basis and to confirm the potential clinical importance of these findings on larger cohorts of patients with PAH. This will impact on the management of PAH of Egyptian patients in the near future.

  4. Endothelin-1 but not Endothelial Nitric Oxide Synthase Gene Polymorphism is Associated with Sickle Cell Disease in Africa.

    Science.gov (United States)

    Thakur, Tanya J; Guindo, Aldiouma; Cullifer, Londyn R; Li, Yi; Imumorin, Ikhide G; Diallo, Dapa A; Thomas, Bolaji N

    2014-01-01

    Sickle cell disease shows marked variability in severity and pathophysiology among individuals, probably linked to differential expression of various adhesion molecules. In this study, we investigated the differential distribution, genomic diversity and haplotype frequency of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) polymorphisms, recently implicated as important in modification of disease severity. One hundred and forty five sickle cell disease patients (HbSS) and 244 adult and pediatric controls, without sickle cell disease (HbAA), were recruited from Mali. Genotypic analysis of the functionally significant eNOS variants (T786C, G894T and intron 4) and endothelin-1 (G5665T) was carried out with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Our results show that the wild type alleles are the most frequent for all eNOS variants between cases and controls. Allelic and genotypic frequencies of eNOS polymorphic groups are not significantly different between cases and controls (P > 0.05). In addition, there is no association between eNOS variants and sickle cell disease, contrary to published reports. On the other hand, we report that endothelin-1 (G5665T) mutant variant had the lowest allelic frequency, and is significantly associated with sickle cell disease in Africa (P haplotype frequencies were the same between cases and controls, except for the haplotype combining all mutant variants (T, C, 4a; P = 0.01). eNOS polymorphic variants are less frequent, with no significance with sickle cell disease in Africa. On the other hand, endothelin-1 is associated with sickle cell disease, and has the capacity to redefine pathophysiology and possibly serve as modulator of disease phenotype.

  5. Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria.

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    Brandi D Freeman

    2016-03-01

    Full Text Available Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

  6. Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria.

    Directory of Open Access Journals (Sweden)

    Brandi D Freeman

    2016-03-01

    Full Text Available Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

  7. Functional measures, inflammatory markers and endothelin-1 as predictors of 360-day survival in centenarians.

    Science.gov (United States)

    Szewieczek, Jan; Francuz, Tomasz; Dulawa, Jan; Legierska, Katarzyna; Hornik, Beata; Włodarczyk, Iwona; Janusz-Jenczeń, Magdalena; Batko-Szwaczka, Agnieszka

    2015-10-01

    Centenarians represent a rapidly growing population. To better characterize this specific age group, we have performed a cross-sectional study to observe associations between functional measures and a range of biochemical markers, including inflammatory markers and their significance as predictors of 360-day survival. Medical history and physical and functional assessment (Mini-Mental State Examination (MMSE), Katz Index (activities of daily living, ADL) and Barthel Index (Barthel Index) of Activities of Daily Living, and Lawton Instrumental Activities of Daily Living Scale (Lawton IADL)) were conducted on 86 101.9 ± 1.2-year-old (mean ± SD) subjects (70 women, 16 men). Blood tests were performed on 84 subjects of whom 43 also had extended biomarker assessment. As a reference group 30 51.8 ± 5.0-year old healthy subjects (20 women, 10 men) were recruited. The centenarians received follow-up phone calls. Fifty-two centenarians (60 %) survived ≥360 days. Longer survival was associated with higher MMSE (hazard ratio, HR = 0.934, 95 % confidence interval (CI) 0.896-0.975, P = .002), ADL (HR = 0.840, 95 % CI 0.716-0.985, P = .032), Barthel Index (HR = 0.988, 95 % CI 0.977-0.999, P = .026), and albumin level (HR .926, 95 % CI 0.870-0.986, P .016) and with lower white blood cell (WBC) (HR = 1.161, 95 % CI 1.059-1.273, P = .001), C-reactive protein (CRP) (HR = 1.032, 95 % CI 1.014-1.050, P Barthel Index ≥15 (P < .001), Lawton IADL ≥10 points (P = .009), WBC <8.3 G/L (P = .039), CRP <10 mg/L (P < .001), IL-6 <6 pg/mL (P .002), and ET-1 <1.1 pg/mL (P .007). Our results indicate that functional measures, inflammatory markers, and endothelin-1 are predictors of 360-day survival in centenarians.

  8. Attenuation of endothelin-1-induced calcium response by tyrosine kinase inhibitors in vascular smooth muscle cells.

    Science.gov (United States)

    Liu, C Y; Sturek, M

    1996-06-01

    Although tyrosine kinases play an important role in cell growth and have been implicated in regulation of smooth muscle contraction, their role in agonist-induced myoplasmic Ca2+ responses is unclear. We examined effects of the tyrosine kinase inhibitors genistein and methyl 2,5-dihydroxycinnamate (MDHC) on the endothelin-1 (ET-1)-induced Ca2+ response and determined underlying mechanisms for the effects. Freshly isolated smooth muscle cells from porcine coronary arteries were loaded with fura 2 ester, and myoplasmic free Ca2+ (Ca2+ (m)) concentration was estimated with fura 2 microfluorometry. Both genistein and MDHC inhibited the initial transient Cam2+ response to ET by 54 and 81%, respectively (P latent period from ET-1 application to the beginning of the Cam2+ response being increased from 1.08 +/- 0.17 to 2.65 +/- 0.52 min (P < 0.05). In the absence of extracellular Ca2+, genistein inhibited the ET-1-induced Cam2+ response by 93% (P < 0.05). The Cam2+ responses to caffeine (5 mM) or inositol trisphosphate (IP3) applied intracellularly via a patch-clamp pipette were not affected by genistein. Both genistein and MDHC also abolished the sustained Cam2+ response to ET-1. However, the Cam2+ response to depolarization by 80 mM K+ was not inhibited by MDHC and only inhibited 22% by genistein (P < 0.05). These results indicate that 1) activation of tyrosine kinases is an important regulatory mechanism for the ET-1-induced Cam2+ response in vascular smooth muscle and 2) tyrosine kinases mediate ET-1-induced Ca2+ release with no direct effect on IP3-mediated Ca2+ release. Thus ET-1-mediated signaling upstream of IP3 interaction with the Ca2+ stores is regulated by tyrosine kinases.

  9. Effect of mineralocorticoid treatment in mice with collecting duct-specific knockout of endothelin-1.

    Science.gov (United States)

    Lynch, I Jeanette; Welch, Amanda K; Gumz, Michelle L; Kohan, Donald E; Cain, Brian D; Wingo, Charles S

    2015-12-15

    Aldosterone increases blood pressure (BP) by stimulating sodium (Na) reabsorption within the distal nephron and collecting duct (CD). Aldosterone also stimulates endothelin-1 (ET-1) production that acts within the CD to inhibit Na reabsorption via a negative feedback mechanism. We tested the hypothesis that this renal aldosterone-endothelin feedback system regulates electrolyte balance and BP by comparing the effect of a high-salt (NaCl) diet and mineralocorticoid stimulation in control and CD-specific ET-1 knockout (CD ET-1 KO) mice. Metabolic balance and radiotelemetric BP were measured before and after treatment with desoxycorticosterone pivalate (DOCP) in mice fed a high-salt diet with saline to drink. CD ET-1 KO mice consumed more high-salt diet and saline and had greater urine output than controls. CD ET-1 KO mice exhibited increased BP and greater fluid retention and body weight than controls on a high-salt diet. DOCP with high-salt feeding further increased BP in CD ET-1 KO mice, and by the end of the study the CD ET-1 KO mice were substantially hypernatremic. Unlike controls, CD ET-1 KO mice failed to respond acutely or escape from DOCP treatment. We conclude that local ET-1 production in the CD is required for the appropriate renal response to Na loading and that lack of local ET-1 results in abnormal fluid and electrolyte handling when challenged with a high-salt diet and with DOCP treatment. Additionally, local ET-1 production is necessary, under these experimental conditions, for renal compensation to and escape from the chronic effects of mineralocorticoids.

  10. Intradermal endothelin-1 excites bombesin-responsive superficial dorsal horn neurons in the mouse.

    Science.gov (United States)

    Akiyama, T; Nagamine, M; Davoodi, A; Iodi Carstens, M; Cevikbas, F; Steinhoff, M; Carstens, E

    2015-10-01

    Endothelin-1 (ET-1) has been implicated in nonhistaminergic itch. Here we used electrophysiological methods to investigate whether mouse superficial dorsal horn neurons respond to intradermal (id) injection of ET-1 and whether ET-1-sensitive neurons additionally respond to other pruritic and algesic stimuli or spinal superfusion of bombesin, a homolog of gastrin-releasing peptide (GRP) that excites spinal itch-signaling neurons. Single-unit recordings were made from lumbar dorsal horn neurons in pentobarbital-anesthetized C57BL/6 mice. We searched for units that exhibited elevated firing after id injection of ET-1 (1 μg/μl). Responsive units were further tested with mechanical stimuli, bombesin (spinal superfusion, 200 μg·ml(-1)·min(-1)), heating, cooling, and additional chemicals [histamine, chloroquine, allyl isothiocyanate (AITC), capsaicin]. Of 40 ET-1-responsive units, 48% responded to brush and pinch [wide dynamic range (WDR)] and 52% to pinch only [high threshold (HT)]. Ninety-three percent responded to noxious heat, 50% to cooling, and >70% to histamine, chloroquine, AITC, and capsaicin. Fifty-seven percent responded to bombesin, suggesting that they participate in spinal itch transmission. That most ET-1-sensitive spinal neurons also responded to pruritic and algesic stimuli is consistent with previous studies of pruritogen-responsive dorsal horn neurons. We previously hypothesized that pruritogen-sensitive neurons signal itch. The observation that ET-1 activates nociceptive neurons suggests that both itch and pain signals may be generated by ET-1 to result in simultaneous sensations of itch and pain, consistent with observations that ET-1 elicits both itch- and pain-related behaviors in animals and burning itch sensations in humans.

  11. Endothelin-1 stimulates catalase activity through the PKCδ-mediated phosphorylation of serine 167.

    Science.gov (United States)

    Rafikov, Ruslan; Kumar, Sanjiv; Aggarwal, Saurabh; Hou, Yali; Kangath, Archana; Pardo, Daniel; Fineman, Jeffrey R; Black, Stephen M

    2014-02-01

    Our previous studies have shown that endothelin-1 (ET-1) stimulates catalase activity in endothelial cells and in lambs with acute increases in pulmonary blood flow (PBF), without altering gene expression. The purpose of this study was to investigate the molecular mechanism by which this occurs. Exposing pulmonary arterial endothelial cells to ET-1 increased catalase activity and decreased cellular hydrogen peroxide (H2O2) levels. These changes correlated with an increase in serine-phosphorylated catalase. Using the inhibitory peptide δV1.1, this phosphorylation was shown to be protein kinase Cδ (PKCδ) dependent. Mass spectrometry identified serine 167 as the phosphorylation site. Site-directed mutagenesis was used to generate a phospho-mimic (S167D) catalase. Activity assays using recombinant protein purified from Escherichia coli or transiently transfected COS-7 cells demonstrated that S167D catalase had an increased ability to degrade H2O2 compared to the wild-type enzyme. Using a phospho-specific antibody, we were able to verify that pS167 catalase levels are modulated in lambs with acute increases in PBF in the presence and absence of the ET receptor antagonist tezosentan. S167 is located on the dimeric interface, suggesting it could be involved in regulating the formation of catalase tetramers. To evaluate this possibility we utilized analytical gel filtration to examine the multimeric structure of recombinant wild-type and S167D catalase. We found that recombinant wild-type catalase was present as a mixture of monomers and dimers, whereas S167D catalase was primarily tetrameric. Further, the incubation of wild-type catalase with PKCδ was sufficient to convert wild-type catalase into a tetrameric structure. In conclusion, this is the first report indicating that the phosphorylation of catalase regulates its multimeric structure and activity.

  12. Altered collecting duct adenylyl cyclase content in collecting duct endothelin-1 knockout mice

    Directory of Open Access Journals (Sweden)

    Kohan Donald E

    2007-05-01

    Full Text Available Abstract Background Endothelin-1 (ET-1 inhibition of vasopressin (AVP-stimulated water reabsorption by the inner medullary collecting duct (IMCD is associated with reduced cAMP accumulation. To determine the effect of ET-1 deficiency, AVP-stimulated cAMP responsiveness was assessed in IMCD from mice with collecting duct-specific deletion of ET-1 (CD ET-1 KO and from control animals. Methods Cyclic AMP production, adenylyl cyclase (AC mRNA, and AC protein were measured in acutely isolated IMCD. Results CD ET-1 KO IMCD had enhanced AVP-stimulated cAMP accumulation. Inhibition of calcium-stimulated AC using BAPTA did not prevent enhanced AVP responsiveness in CD ET-1 KO IMCD. Factors known to be modified by ET-1, including nitric oxide, cyclooxygenase metabolites, and superoxide did not affect the increased AVP responsiveness of CD ET-1 KO IMCD. Differential V2 receptor or G-protein activity was not involved since CD ET-1 KO IMCD had increased cAMP accumulation in response to forskolin and/or cholera toxin. CD ET-1 KO did not affect mRNA or protein levels of AC3, one of the major known collecting duct AC isoforms. However, the other known major collecting duct AC isoform (AC5/6 did have increased protein levels in CD ET-1 KO IMCD, although AC5 (weak signal and 6 mRNA levels were unchanged. Conclusion ET-1 deficiency increases IMCD AC5/6 content, an effect that may synergize with acute ET-1 inhibition of AVP-stimulated cAMP accumulation.

  13. Activation of calcineurin in human failing heart ventricle by endothelin-1, angiotensin II and urotensin II.

    Science.gov (United States)

    Li, Joan; Wang, Jianchun; Russell, Fraser D; Molenaar, Peter

    2005-06-01

    1 The calcineurin (CaN) enzyme-transcriptional pathway is critically involved in hypertrophy of heart muscle in some animal models. Currently there is no information concerning the regulation of CaN activation by endogenous agonists in human heart. 2 Human right ventricular trabeculae from explanted human (14 male/2 female) failing hearts were set up in a tissue bath and electrically paced at 1 Hz and incubated with or without 100 nM endothelin-1 (ET-1), 10 M, angiotensin-II (Ang II) or 20 nM human urotensin-II (hUII) for 30 min. Tissues from four patients were incubated with 200 nM tacrolimus (FK506) for 30 min and then incubated in the presence or absence of ET-1 for a further 30 min. 3 ET-1 increased contractile force in all 13 patients (P0.1). FK506 had no effect on contractile force (P=0.12). 4 ET-1, Ang II and hUII increased calcineurin activity by 32, 71 and 15%, respectively, while FK506 reduced activity by 34%. ET-1 in the presence of FK506 did not restore calcineurin activity (P=0.1). 5 There was no relationship between basal CaN activity and expression levels in the right ventricle. Increased levels of free phosphate were detected in ventricular homogenates that were incubated with PKC(epsilon) compared to samples incubated without PKC(epsilon). 6 Endogenous cardiostimulants which activate G(alpha)q-coupled receptors increase the activity of calcineurin in human heart following acute (30 min) exposure. PKC may contribute to this effect by increasing levels of phosphorylated calcineurin substrate.

  14. Molecular determinants of the profibrogenic effects of endothelin-1 in pancreatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    Anika Jonitz; Brit Fitzner; Robert Jaster

    2009-01-01

    AIM:To gain molecular insights into the expression and functions of endothelin-1 (ET-1) in pancreatic stellate cells (PSC).METHODS: PSCs were isolated from rat pancreas tissue,cultured, and stimulated with ET-1 or other extracellular mediators. Cell proliferation was assessed by measuring the incorporation of 5-bromo-2'-deoxyuridine into DNA and cell migration was studied in a transwell chamber assay. Gene expression at the level of Mrna was quantified by real-time Polymerase chain reaction.Expression and phosphorylation of proteins were monitored by immunoblotting, applying an infrared imaging technology. ET-1 levels in cell culture supernatants were determined by an enzyme immunometric assay.To study DNA binding of individual transcription factors,electrophoretic mobility shift assays were performed.RESULTS: Among several mediators tested, transforming growth factor-β1 and tumour necrosis factor-α displayed the strongest stimulatory effects on ET-1 secretion. The cytokines induced binding of Smad3 and NF-κB, respectively, to oligonucleotides derived from the ET-1 promoter, implicating both transcription factors in the induction of ET-1 gene expression. In accordance with previous studies, ET-1 was found to stimulate migration but not proliferation of PSC. Stimulation of ET-1 receptors led to the activation of two distinct mitogen-activated protein kinases, p38 and extracellular signal-regulated kinases (ERK)1/2, as well as the transcription factor activator protein-1. At the mRNA level, enhanced expression of the PSC activation marker, α-smooth muscle actin and two proinflammatory cytokines, interleukin (IL)-1β and IL-6, was observed.CONCLUSION:This study provides novel lines of evi-dence for profibrgenic and proinflammatory actions of ET-1 in the pancreas,encouraging further studies with ET-1 inhibitors in chronic pancreatitis.

  15. Vascular peptide endothelin-1 links fat accumulation with alterations of visceral adipocyte lipolysis.

    Science.gov (United States)

    van Harmelen, Vanessa; Eriksson, Anna; Aström, Gaby; Wåhlén, Kerstin; Näslund, Erik; Karpe, Fredrik; Frayn, Keith; Olsson, Tommy; Andersson, Jonas; Rydén, Mikel; Arner, Peter

    2008-02-01

    Visceral obesity increases risk of insulin resistance and type 2 diabetes. This may partly be due to a region-specific resistance to insulin's antilipolytic effect in visceral adipocytes. We investigated whether adipose tissue releases the vascular peptide endothelin-1 (ET-1) and whether ET-1 could account for regional differences in lipolysis. One group consisted of eleven obese and eleven nonobese subjects in whom ET-1 levels were compared between abdominal subcutaneous and arterialized blood samples. A second group included subjects undergoing anti-obesity surgery. Abdominal subcutaneous and visceral adipose tissues were obtained to study the effect of ET-1 on differentiated adipocytes regarding lipolysis and gene and protein expression. Adipose tissue had a marked net release of ET-1 in vivo, which was 2.5-fold increased in obesity. In adipocytes treated with ET-1, the antilipolytic effect of insulin was attenuated in visceral but not in subcutaneous adipocytes, which could not be explained by effects of ET-1 on adipocyte differentiation. ET-1 decreased the expression of insulin receptor, insulin receptor substrate-1 and phosphodiesterase-3B and increased the expression of endothelin receptor-B (ET(B)R) in visceral but not in subcutaneous adipocytes. These effects were mediated via ET(B)R with signals through protein kinase C and calmodulin pathways. The effect of ET-1 could be mimicked by knockdown of IRS-1. ET-1 is released from human adipose tissue and links fat accumulation to insulin resistance. It selectively counteracts insulin inhibition of visceral adipocyte lipolysis via ET(B)R signaling pathways, which affect multiple steps in insulin signaling.

  16. Endothelin-1 mediates intermittent hypoxia-induced inflammatory vascular remodeling through HIF-1 activation.

    Science.gov (United States)

    Gras, Emmanuelle; Belaidi, Elise; Briançon-Marjollet, Anne; Pépin, Jean-Louis; Arnaud, Claire; Godin-Ribuot, Diane

    2016-02-15

    Obstructive sleep apnea (OSA) is a major risk factor for cardiovascular mortality, and apnea-induced intermittent hypoxia (IH) is known to promote various cardiovascular alterations such as vascular remodeling. However, the mechanisms that underlie IH remain incompletely investigated. We previously demonstrated that the hypoxia-inducible factor-1 (HIF-1) and endothelin-1 (ET-1) are involved in arterial hypertension and myocardial susceptibility to infarction induced by IH. Thus the objective of the present study was to investigate whether both ET-1 and HIF-1 were also involved in the vascular inflammatory remodeling induced by IH. Mice partially deficient for the Hif1α gene (HIF-1α(+/-)) and their wild-type equivalents, as well as C57BL/6J mice, treated or not with bosentan, a dual endothelin receptor antagonist, were exposed to IH or normoxia for 2 wk, 8 h/day. Splenocyte proliferative and secretory capacities, aortic nuclear factor-κB (NF-κB) and HIF-1 activities, and expression of cytokines and intima-media thickness (IMT) were measured. IH induced a systemic and aortic inflammation characterized by an increase in splenocyte proliferative and secretory capacities, aortic NF-κB activity, and cytokine expression in the aortic wall. This was accompanied by an increase in IMT. These modifications were prevented in HIF-1α(+/-) and bosentan-treated mice. The results of this study suggest that ET-1 is a major contributor to the vascular inflammatory remodeling induced by OSA-related IH, probably through HIF-1-dependent activation of NF-κB.

  17. Modulatory effect of endothelin-1 and -3 on neuronal norepinephrine release in the rat posterior hypothalamus.

    Science.gov (United States)

    Di Nunzio, Andrea S; Legaz, Guillermina; Rodano, Valeria; Bianciotti, Liliana G; Vatta, Marcelo S

    2004-04-15

    Based upon the existence of high density of ET-receptors on catecholaminergic neurons of the hypothalamus, we studied the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on neuronal norepinephrine (NE) release in the rat posterior hypothalamus. The intracellular pathways and receptors involved were also investigated. Neuronal NE release was enhanced by ET-1 and ET-3 (10 etaM). The selective antagonists of subtype A and B ET receptors (ETA, ETB) (100 etaM BQ-610 and 100 etaM BQ-788, respectively) abolished the increase induced by ET-1 but not by ET-3. The PLC inhibitor, U73122 (10 microM), abolished ET-1 and ET-3 response. GF-109203X (100 etaM) (PKC inhibitor) blocked the increase in NE release produced by ET-3 and partially blocked ET-1 response. The inositol 1,4,5-trisphosphate-induced calcium release inhibitor, 42 microM 2-APB, inhibited the stimulatory effect induced by ET-3 but not by ET-1. The PKA inhibitor, 500 etaM H-89, blocked the increase in neuronal NE release evoked by ET-1 but not by ET-3. Our results showed that ET-1 as well as ET-3 displayed an excitatory neuromodulatory effect on neuronal NE release in the rat posterior hypothalamus. ET-1 through an atypical ETA or ETB receptor activated the PLC/PKC signalling pathway as well as the cAMP pathway, whereas ET-3 through a non-ETA/non-ETB receptor activated the phosphoinositide pathway. Both ETs would enhance the sympathoexcitatory response elicited by the posterior hypothalamus and thus participate in cardiovascular regulation.

  18. Circulating human B and plasma cells. Age-associated changes in counts and detailed characterization of circulating normal CD138- and CD138+ plasma cells. : Blood B-lymphocytes and plasma cells in adults

    OpenAIRE

    2010-01-01

    International audience; Generation of B and plasma cells involves several organs with a necessary cell trafficking between them. A detailed phenotypic characterization of four circulating B-cell subsets (immature-, naïve-, memory- B-lymphocytes and plasma cells) of 106 healthy adults was realized by multiparametric flow cytometry. We show that CD10, CD27 and CD38 is the minimal combination of subsetting markers allowing unequivocal identification of immature (CD10(+)CD27(-)CD38(+), 6+/-6 cell...

  19. Circulating plasma cells in multiple myeloma: characterization and correlation with disease stage.

    Science.gov (United States)

    Rawstron, A C; Owen, R G; Davies, F E; Johnson, R J; Jones, R A; Richards, S J; Evans, P A; Child, J A; Smith, G M; Jack, A S; Morgan, G J

    1997-04-01

    The aim of this study was to develop a flow cytometric test to quantitate low levels of circulating myeloma plasma cells, and to determine the relationship of these cells with disease stage. Cells were characterized using five-parameter flow cytometric analysis with a panel of antibodies, and results were evaluated by comparison with fluorescent consensus-primer IgH-PCR. Bone marrow myeloma plasma cells, defined by high CD38 and Syndecan-1 expression, did not express CD10, 23, 30, 34 or 45RO, and demonstrated weak expression of CD37 and CD45. 65% of patients had CD19- 56+ plasma cells, 30% CD19- 56(low), and 5% CD19+ 56+, and these two antigens discriminated myeloma from normal plasma cells, which were all CD19+ 56(low). Peripheral blood myeloma plasma cells had the same composite phenotype, but expressed significantly lower levels of CD56 and Syndecan-1, and were detected in 75% (38/51) of patients at presentation, 92% (11/12) of patients in relapse, and 40% (4/10) of stem cell harvests. Circulating plasma cells were not detectable in patients in CR (n = 9) or normals (n = 10), at a sensitivity of up to 1 in 10,000 cells. There was good correlation between the flow cytometric test and IgH-PCR results: myeloma plasma cells were detectable by flow cytometry in all PCR positive samples, and samples with no detectable myeloma plasma cells were PCR negative. Absolute numbers decreased in patients responding to treatment, remained elevated in patients with refractory disease, and increased in patients undergoing relapse. We conclude that flow cytometry can provide an effective aternative to IgH-PCR that will allow quantitative assessment of low levels of residual disease.

  20. Plasma gelsolin depletion and circulating actin in sepsis: a pilot study.

    Directory of Open Access Journals (Sweden)

    Po-Shun Lee

    Full Text Available BACKGROUND: Depletion of the circulating actin-binding protein, plasma gelsolin (pGSN has been described in septic patients and animals. We hypothesized that the extent of pGSN reduction correlates with outcomes of septic patients and that circulating actin is a manifestation of sepsis. METHODOLOGY/PRINCIPAL FINDINGS: We assayed pGSN in plasma samples from non-surgical septic patients identified from a pre-existing database which prospectively enrolled patients admitted to adult intensive care units at an academic hospital. We identified 21 non-surgical septic patients for the study. Actinemia was detected in 17 of the 21 patients, suggesting actin released into circulation from injured tissues is a manifestation of sepsis. Furthermore, we documented the depletion of pGSN in human clinical sepsis, and that the survivors had significantly higher pGSN levels than the non-survivors (163+/-47 mg/L vs. 89+/-48 mg/L, p = 0.01. pGSN levels were more strongly predictive of 28-day mortality than APACHE III scores. For every quartile reduction in pGSN, the odds of death increased 3.4-fold. CONCLUSION: We conclude that circulating actin and pGSN deficiency are associated with early sepsis. The degree of pGSN deficiency correlates with sepsis mortality. Reversing pGSN deficiency may be an effective treatment for sepsis.

  1. Identification of novel circulating coffee metabolites in human plasma by liquid chromatography-mass spectrometry.

    Science.gov (United States)

    Redeuil, Karine; Smarrito-Menozzi, Candice; Guy, Philippe; Rezzi, Serge; Dionisi, Fabiola; Williamson, Gary; Nagy, Kornél; Renouf, Mathieu

    2011-07-22

    This study reports a liquid chromatography-mass spectrometry method for the detection of polyphenol-derived metabolites in human plasma without enzymatic treatment after coffee consumption. Separation of available standards was achieved by reversed-phase ultra performance liquid chromatography and detection was performed by high resolution mass spectrometry in negative electrospray ionization mode. This analytical method was then applied for the identification and relative quantification of circulating coffee metabolites. A total of 34 coffee metabolites (mainly reduced, sulfated and methylated forms of caffeic acid, coumaric acid, caffeoylquinic acid and caffeoylquinic acid lactone) were identified based on mass accuracy (<4 ppm for most metabolites), specific fragmentation pattern and co-chromatography (when standard available). Among them, 19 circulating coffee metabolites were identified for the first time in human plasma such as feruloylquinic acid lactone, sulfated and glucuronidated forms of feruloylquinic acid lactone and sulfated forms of coumaric acid. Phenolic acid derivatives such as dihydroferulic acid, dihydroferulic acid 4'-O-sulfate, caffeic acid 3'-O-sulfate, dimethoxycinnamic acid, dihydrocaffeic acid and coumaric acid O-sulfate appeared to be the main metabolites circulating in human plasma after coffee consumption. The described method is a sensitive and reliable approach for the identification of coffee metabolites in biological fluids. In future, this analytical method will give more confidence in compound identification to provide a more comprehensive assessment of coffee polyphenol bioavailability studies in humans.

  2. Regulation of the cardiomyocyte transcriptome vs translatome by endothelin-1 and insulin: translational regulation of 5' terminal oligopyrimidine tract (TOP mRNAs by insulin

    Directory of Open Access Journals (Sweden)

    Sugden Peter H

    2010-05-01

    Full Text Available Abstract Background Changes in cellular phenotype result from underlying changes in mRNA transcription and translation. Endothelin-1 stimulates cardiomyocyte hypertrophy with associated changes in mRNA/protein expression and an increase in the rate of protein synthesis. Insulin also increases the rate of translation but does not promote overt cardiomyocyte hypertrophy. One mechanism of translational regulation is through 5' terminal oligopyrimidine tracts (TOPs that, in response to growth stimuli, promote mRNA recruitment to polysomes for increased translation. TOP mRNAs include those encoding ribosomal proteins, but the full panoply remains to be established. Here, we used microarrays to compare the effects of endothelin-1 and insulin on the global transcriptome of neonatal rat cardiomyocytes, and on mRNA recruitment to polysomes (i.e. the translatome. Results Globally, endothelin-1 and insulin (1 h promoted >1.5-fold significant (false discovery rate 1.25-fold significant changes in expression in total and/or polysomal RNA induced by endothelin-1 or insulin, respectively, of which ~35% of endothelin-1-responsive and ~56% of insulin-responsive transcripts were translationally regulated. Of mRNAs for established proteins recruited to polysomes in response to insulin, 49 were known TOP mRNAs with a further 15 probable/possible TOP mRNAs, but 49 had no identifiable TOP sequences or other consistent features in the 5' untranslated region. Conclusions Endothelin-1, rather than insulin, substantially affects global transcript expression to promote cardiomyocyte hypertrophy. Effects on RNA recruitment to polysomes are subtle, with differential effects of endothelin-1 and insulin on specific transcripts. Furthermore, although insulin promotes recruitment of TOP mRNAs to cardiomyocyte polysomes, not all recruited mRNAs are TOP mRNAs.

  3. Regulation of the cardiomyocyte transcriptome vs translatome by endothelin-1 and insulin: translational regulation of 5' terminal oligopyrimidine tract (TOP) mRNAs by insulin

    Science.gov (United States)

    2010-01-01

    Background Changes in cellular phenotype result from underlying changes in mRNA transcription and translation. Endothelin-1 stimulates cardiomyocyte hypertrophy with associated changes in mRNA/protein expression and an increase in the rate of protein synthesis. Insulin also increases the rate of translation but does not promote overt cardiomyocyte hypertrophy. One mechanism of translational regulation is through 5' terminal oligopyrimidine tracts (TOPs) that, in response to growth stimuli, promote mRNA recruitment to polysomes for increased translation. TOP mRNAs include those encoding ribosomal proteins, but the full panoply remains to be established. Here, we used microarrays to compare the effects of endothelin-1 and insulin on the global transcriptome of neonatal rat cardiomyocytes, and on mRNA recruitment to polysomes (i.e. the translatome). Results Globally, endothelin-1 and insulin (1 h) promoted >1.5-fold significant (false discovery rate 1.25-fold significant changes in expression in total and/or polysomal RNA induced by endothelin-1 or insulin, respectively, of which ~35% of endothelin-1-responsive and ~56% of insulin-responsive transcripts were translationally regulated. Of mRNAs for established proteins recruited to polysomes in response to insulin, 49 were known TOP mRNAs with a further 15 probable/possible TOP mRNAs, but 49 had no identifiable TOP sequences or other consistent features in the 5' untranslated region. Conclusions Endothelin-1, rather than insulin, substantially affects global transcript expression to promote cardiomyocyte hypertrophy. Effects on RNA recruitment to polysomes are subtle, with differential effects of endothelin-1 and insulin on specific transcripts. Furthermore, although insulin promotes recruitment of TOP mRNAs to cardiomyocyte polysomes, not all recruited mRNAs are TOP mRNAs. PMID:20509958

  4. Role of nonselective cation channels as Ca2+ entry pathway in endothelin-1-induced contraction and their suppression by nitric oxide.

    Science.gov (United States)

    Zhang, X F; Komuro, T; Miwa, S; Minowa, T; Iwamuro, Y; Okamoto, Y; Ninomiya, H; Sawamura, T; Masaki, T

    1998-07-10

    The present study was carried out to clarify the role of nonselective cation channels as a Ca2+ entry pathway in the contraction and the increase in [Ca2+]i induced by endothelin- in endothelium-denuded rat thoracic aorta rings, and their suppression by nitric oxide (NO). In Ca2+-free medium, the endothelin-1-induced contraction was suppressed to about 20% of control values, although the increase in [Ca2+]i became negligible. The contraction and the increase in [Ca2+]i monitored by fura 2 fluorescence were unaffected by a blocker of L-type voltage-operated Ca2+ channels nifedipine. A blocker of nonselective cation channels 1-[beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl]-1H-imida zole . HCl(SK&F 96365) suppressed the endothelin-1-induced contraction and increase in [Ca2+]i to the level similar to that after removal of extracellular Ca2+. SK&F 96365 had no further effect on the endothelin-1-induced contraction in the absence of extracellular Ca2+. The endothelin-1-induced contraction and increase in [Ca2+]i were abolished by a donor of NO sodium nitroprusside. The effects of another NO donor 3-morpholinosydnonimine (SIN-1) were also tested and yielded essentially similar results to those for sodium nitroprusside on the endothelin-1-induced contraction. Furthermore, the inhibitory effects of sodium nitroprusside could be blocked with a guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) at 30 microM. These findings suggest that Ca2+ entry through nonselective cation channels but not voltage-operated Ca2+ channels plays a critical role in the endothelin-1-induced increase in [Ca2+]i and the resulting contraction and that inhibition by NO of the endothelin-1-induced contraction is mainly the result of blockade of Ca2+ entry through these channels.

  5. Polymorphism of the endothelin-1 gene (rs5370 is a potential contributor to sickle cell disease pathophysiology

    Directory of Open Access Journals (Sweden)

    Kristen G. Navarro

    2016-12-01

    Full Text Available Sickle cell disease has been shown to demonstrate extensive variability in disease severity among and between individuals, the variability highlighted by differing genetic haplotypes. Despite the abundance of reports of functional significance due to polymorphisms of endothelial nitric oxide synthase (eNOS and endothelin-1 (ET-1 genes, the role of these polymorphisms in mediating sickle cell disease pathophysiology among African Americans is presently unclear. To deconvolute their potential significance among African Americans with sickle cell disease, we examined the genetic diversity and haplotype frequency of eNOS and ET-1 polymorphisms in disease (n = 331 and control (n = 379 groups, with a polymerase–chain reaction restriction fragment length polymorphism assay. We report that genotypic and allelic frequencies of eNOS variants are not significantly different between groups. eNOS homozygote mutants, which had been shown to have clinical significance elsewhere, showed no statistical significance in our study. On the other hand, and contrary to previous report among Africans with sickle cell disease, the endothelin-1 homozygous mutant variant showed significant difference in genotypic (p = 2.84E-12 and allelic frequencies (p = 2.20E-16 between groups. The most common haplotype is the combination of T786C homozygote wild-type variant with homozygote mutant variants of G5665T (ET-1 and Glu298Asp (eNOS. These results show that endothelin-1 (rs5370 polymorphism, rather than endothelial nitric oxide synthase polymorphism might play a significant role in disease severity or individual clinical outcomes among African Americans with sickle cell disease. This would have profound implications for designing and/or advancing personalized care for sickle cell patients and relieving disease complications.

  6. Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity

    OpenAIRE

    Lindqvist, D.; Fernström, J; Grudet, C; Ljunggren, L; Träskman-Bendz, L; Ohlsson, L; Westrin, Å

    2016-01-01

    Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samp...

  7. Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity.

    Science.gov (United States)

    Lindqvist, D; Fernström, J; Grudet, C; Ljunggren, L; Träskman-Bendz, L; Ohlsson, L; Westrin, Å

    2016-12-06

    Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samples from 37 suicide attempters, who had undergone a dexamethasone suppression test (DST), and 37 healthy controls. We hypothesized that free circulating mtDNA would be elevated in the suicide attempters and would be associated with hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity. Suicide attempters had significantly higher plasma levels of free-circulating mtDNA compared with healthy controls at different time points (pre- and post-DST; all P-valuesSuicide attempters may have elevated plasma levels of free-circulating mtDNA, which are related to impaired HPA-axis negative feedback. This peripheral index is consistent with an increased cellular or mitochondrial damage. The specific cells and tissues contributing to plasma levels of free-circulating mtDNA are not known, as is the specificity of this finding for suicide attempters. Future studies are needed in order to better understand the relevance of increased free-circulating mtDNA in relation to the pathophysiology underlying suicidal behavior and depression.

  8. Enhanced Endothelin-1 Mediated Vasoconstriction of the Ophthalmic Artery May Exacerbate Retinal Damage after Transient Global Cerebral Ischemia in Rat

    DEFF Research Database (Denmark)

    Blixt, Frank W; Johansson, Sara Ellinor; Johnson, Leif

    2016-01-01

    Cerebral vasculature is often the target of stroke studies. However, the vasculature supplying the eye might also be affected by ischemia. The aim of the present study was to investigate if the transient global cerebral ischemia (GCI) enhances vascular effect of endothelin-1 (ET-1) and 5...... decreased function at 72 hours, but recovered almost completely after 7 days. In conclusion, we propose that the increased contractile response via ET-1 receptors in the ophthalmic artery after 48 hours may elicit negative retinal consequences due to a second ischemic period. This may exacerbate retinal...

  9. Differential expression of circulating miRNAs in maternal plasma in pregnancies with fetal macrosomia.

    Science.gov (United States)

    Ge, Qinyu; Zhu, Yanan; Li, Hailing; Tian, Fei; Xie, Xueying; Bai, Yunfei

    2015-01-01

    Macrosomia is associated with problems at birth and has life-long health implications for the infant. The aim of this study was to profile the plasma microRNAs (miRNAs or miRs) and evaluate the potential of circulating miRNAs to predict fetal macrosomia. The expression levels of miRNAs in plasma samples obtained from pregnant women with fetal macrosomia and from women with normal pregnancies (controls) were analyzed using TaqMan Low-Density Arrays (TLDAs) followed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) validation and analysis. The TLDA data revealed that 143 miRNAs were differentially expressed in the plasma samples from pregnant women with fetal macrosomia compared with the controls (43 upregulated and 100 downregulated miRNAs). Twelve of these miRNAs were selected for RT-qPCR analysis. Receiver operational characteristic (ROC) curve analysis indicated that several miRNAs (e.g., miR‑141-3p and miR-200c-3p) were clearly distinguished between pregnancies with fetal macrosomia and other types of abnormal pregnancy and healthy pregnancies with high sensitivity and specificity (AUC >0.9). The expression of miRNA clusters also showed a similar trend in pregnancies with fetal macrosomia. This study provides a platform for profiling circulating miRNAs in maternal plasma. Our data also suggest that altered levels of maternal plasma miRNAs have great potential to serve as non-invasive biomarkers and as a mechanistic indicator of abnormal pregnancies.

  10. Effects of CPAP therapy on the Concentrations of Endothelin-1 and Nitric Oxide in Blood and Exhaled breath condensate of patients with obstructive sleep apnea%正压通气对OSAHS患者血清和呼出气冷凝液中内皮素-1及一氧化氮水平的影响

    Institute of Scientific and Technical Information of China (English)

    姚苏梅; 陶一江; 朱杰; 何海艳

    2012-01-01

    目的 探讨自动调节持续气道正压通气(auto-CPAP)治疗对OSAHS患者血管内皮功能紊乱的影响.方法 对确诊为OSAHS的实验组进行三个月auto-CPAP治疗,分别测定三个月前后两组血清及EBC中ET-1及NO水平,以及颈动脉内膜中层厚度(IMT).结果 实验组血清和EBC中ET-1水平以及EBC中NO水平均明显下降,IMT较前减少.血清和EBC中ET-1及NO水平与AHI等睡眠监测指标存在相关性.结论 EBC中ET-1及NO水平检测可了解OSAHS患者血管内皮功能紊乱,这种异常可以通过auto-CPAP治疗改善.%Objective To investigate the effect of auto-CPAP therapy on disturbance of vascular endothelium in patients with obstructive sleep apnea/ hypoventilation syndrome( OSAHS ) and the clinical significance of testing Endothelin-1 and Nitric Oxide in exhaled breath condensate( EBC ) of patients with OSAHS. Methods 42 patients with moderate-to-severe OSAHS were randomly allocated to the active group. The active group received the treatments of three months' auto-CPAP. Endothelin-1 and Nitric Oxide levels in plasma and EBC were measured before and after 3 months. Philips iU22 color doppler ultrasound instrument was used to measure intima-medial thick-ness( IMT) of jugular arteries. Results Between before treatment and after the three months, there were significant decrease inAHI, Endothelin-1 levels in plasma and EBC in the active group, and Nitric Oxide levels in EBC were lower. Endothelin-1 levels and Nitric Oxide levels in plasma and EBC were correlated with AHI, LSpO2 , MSpO2 and IMT, but Nitric Oxide levels in EBC showed no correlation with IMT. Conclusion The disturbance of vascular endothelium in patients with OSAHS can be evaluated by testing Endothelin-1 and Nitric Oxide in their EBC, which can be improved by the auto-CPAP treatment.

  11. Circulation control on a rounded trailing-edge wind turbine airfoil using plasma actuators

    Science.gov (United States)

    Baleriola, S.; Leroy, A.; Loyer, S.; Devinant, P.; Aubrun, S.

    2016-09-01

    This experimental study focuses on the implementation via plasma actuators of a circulation control strategy on a wind turbine aerofoil with a rounded trailing-edge with the objective of reducing the aerodynamic load fluctuations on blades. Three sets of multi-DBD (Dielectric Barrier Discharge) actuators with different positions around the trailing-edge are studied. These actuators create a tangential jet that adheres to the blade model wall and diffuses along it. According to the jet direction, lift is increased or decreased. Load and pressure measurements as well as Particle Image Velocimetry (PIV) show respectively the actuation effectiveness in terms of load modification and flow topology alteration.

  12. Fluid Flow Modeling of Arc Plasma and Bath Circulation in DC Electric Arc Furnace

    Institute of Scientific and Technical Information of China (English)

    WANG Feng-hua; JIN Zhi-jian; ZHU Zi-shu

    2006-01-01

    A mathematical model describing the flow field, heat transfer and the electromagnetic phenomenon in a DC electric arc furnace has been developed. First the governing equations in the arc plasma region are solved and the calculated results of heat transfer, current density and shear stresses on the anode surface are used as boundary conditions in a model of molten bath. Then a two-dimensional time-dependent model is used to describe the flow field and electromagnetic phenomenon in the molten bath. Moreover, the effect of bottom electrode diameter on the circulation of molten bath is studied.

  13. Involvement of presynaptic voltage-dependent Kv3 channel in endothelin-1-induced inhibition of noradrenaline release from rat gastric sympathetic nerves.

    Science.gov (United States)

    Nakamura, Kumiko; Shimizu, Takahiro; Tanaka, Kenjiro; Taniuchi, Keisuke; Yokotani, Kunihiko

    2012-11-05

    We previously reported that two types of K(+) channels, the BK type Ca(2+)-activated K(+) channel coupled with phospholipase C (PLC) and the voltage-dependent K(+) channel (Kv channel), are, respectively, involved in the prostanoid TP receptor- and muscarinic M(2) receptor-mediated inhibition of noradrenaline (NA) release from rat gastric sympathetic nerves. In the present study, therefore, we examined whether these K(+) channels are involved in endothelin-1-induced inhibition of NA release, using an isolated, vascularly perfused rat stomach. The gastric sympathetic postganglionic nerves around the left gastric artery were electrically stimulated twice at 2.5 Hz for 1 min, and endothelin-1 was added during the second stimulation. Endothelin-1 (1, 2 and 10 nM) dose-dependently inhibited gastric NA release. Endothelin-1 (2 nM)-induced inhibition of NA release was neither attenuated by PLC inhibitors [U-73122 (3 μM) and ET-18-OCH(3) (3 μM)] nor by Ca(2+)-activated K(+) channel blockers [charybdotoxin (0.1 μM) (a blocker of BK type K(+) channel) and apamin (0.3 μM) (a blocker of SK type K(+) channel)]. The endothelin-1-induced inhibitory response was also not attenuated by α-dendrotoxin (0.1 μM) (a selective inhibitor of Kv1 channel), but abolished by 4-aminopyridine (20 μM) (a selectively inhibitory dose for Kv3 channel). These results suggest the involvement of a voltage-dependent Kv3 channel in the endothelin-1-induced inhibition of NA release from the gastric sympathetic nerves in rats.

  14. Myocardial ischemia-reperfusion enhances transcriptional expression of endothelin-1 and vasoconstrictor ETB receptors via the protein kinase MEK-ERK1/2 signaling pathway in rat

    DEFF Research Database (Denmark)

    Skovsted, Gry Freja; Kruse, Lars Schack; Berchtold, Lukas Adrian

    2017-01-01

    of proteins (pERK1/2, prepro-endothelin-1, endothelin-1, and endothelin ETA and ETB receptors) were analysed by Western blot and immunohistochemistry. We found that pERK1/2 was significantly augmented in the ischemic area 3 hours after ischemia-reperfusion; this correlated with increased ETB receptor and ET-1...... gene expressions in ischemic myocardium and in coronary arteries. ETB receptor-mediated vasoconstriction was observed to be increased in coronary arteries 24 hours after ischemia-reperfusion. Treatment with U0126 reduced pERK1/2, expression of ET-1 and ETB receptor, and ETB receptor...

  15. Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma.

    Science.gov (United States)

    Nowakowski, Grzegorz S; Witzig, Thomas E; Dingli, David; Tracz, Michal J; Gertz, Morie A; Lacy, Martha Q; Lust, John A; Dispenzieri, Angela; Greipp, Philip R; Kyle, Robert A; Rajkumar, S Vincent

    2005-10-01

    We detected circulating plasma cells (PCs) by flow cytometry in 302 patients with newly diagnosed multiple myeloma (MM) by gating on CD38+CD45- cells. The number of circulating PCs per 50 000 mononuclear cells was reported. In 80 (27%) patients, no circulating PC were seen; 106 (35%) patients had 1 to 10 and 115 (38%) patients had more than 10 circulating PCs. Median overall survival for the 302 patients was 47 months. Patients with 10 or fewer circulating PCs had a median survival of 58.7 months, whereas patients with more than 10 circulating PCs had a median survival of 37.3 months (P = .001). On multivariate analysis, the prognostic value of circulating PCs was independent of beta2-microglobulin, albumin, and C-reactive protein. There was only a weak correlation between tumor mass and circulating PCs, suggesting that the appearance of circulating PCs may be a reflection of tumor biology. We conclude that the number of circulating PCs measured by flow cytometry in patients with newly diagnosed MM is an independent predictor of survival.

  16. Influence of plasma processing on recovery and analysis of circulating nucleic acids.

    Directory of Open Access Journals (Sweden)

    Karen Page

    Full Text Available Circulating nucleic acids (CNAs are under investigation as a liquid biopsy in cancer. However there is wide variation in blood processing and methods for isolation of circulating free DNA (cfDNA and microRNAs (miRNAs. Here we compare the extraction efficiency and reproducibility of 4 commercially available kits for cfDNA and 3 for miRNA using spike-in of reference templates. We also compare the effects of increasing time between venepuncture and centrifugation and differential centrifugation force on recovery of CNAs. cfDNA was quantified by TaqMan qPCR and targeted deep sequencing. miRNA profiles were assessed with TaqMan low-density arrays and assays. The QIAamp(® DNA Blood Mini and Circulating nucleic acid kits gave the highest recovery of cfDNA and efficient recovery (>90% of a 564bp spike-in. Moreover, targeted sequencing revealed overlapping cfDNA profiles and variant depth, including detection of HER2 gene amplification, using the Ion AmpliSeq™Cancer Hotspot Panel v2. Highest yields of miRNA and the synthetic Arabidopsis thaliana miR-159a spike-in were obtained using the miRNeasy Serum/Plasma kit, with saturation above 200 µl of plasma. miRNA profiles showed significant variation with increasing time before centrifugation (p 12 years, highlighting the potential for analysis of stored sample biobanks. In the era of the liquid biopsy, standardisation of methods is required to minimise variation, particularly for miRNA.

  17. Increased tissue endothelin-1 and endothelin-B receptor expression in temporal arteries from patients with giant cell arteritis

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Andersson, Christina; Rissler, Pehr;

    2010-01-01

    of temporal arteries using archival formalin-fixed, paraffin-embedded tissue. PARTICIPANTS: The study included 10 patients with GCA and 10 control patients with clinically suspected GCA but diagnosed not to have GCA. METHODS: Immunohistochemistry, with anti ET-1, anti-ET(A), and anti-ET(B) antibodies...... states. High doses of corticosteroids currently are used in the treatment of GCA, whereas other treatments are not as reliably effective. The present study was performed to elucidate the role for ET-1, ET(A), and ET(B) receptors in GCA. DESIGN: Experimental, retrospective immunohistochemical study......, was performed on formalin-fixed and paraffin-embedded temporal arteries. MAIN OUTCOME MEASURES: Endothelin-1, ET(A), and ET(B) receptor immunostaining intensities were quantified. RESULTS: Temporal arteries from the patients with GCA showed the typical histologic features, including intimal thickening...

  18. Preferential recruitment of neutrophils by endothelin-1 in acute lung inflammation induced by lipopolysaccharide or cigarette smoke

    Science.gov (United States)

    Bhavsar, Tapan; Liu, Xing Jian; Patel, Hardik; Stephani, Ralph; Cantor, Jerome O

    2008-01-01

    This study examined the role of endothelin-1 (ET-1) in recruiting inflammatory cells to the lung after induction of injury with either lipopolysaccharide (LPS) or cigarette smoke. Hamsters injected with either ET-1 or its precursor peptide (Big ET-1) prior to treatment with LPS or cigarette smoke had markedly increased concentrations of neutrophils in bronchoalveolar lavage fluid (BALF) despite a reduction in total numbers of BALF leukocytes. Furthermore, the effect of ET-1 on smoke-exposed animals was reversed by addition of an endothelin-A receptor antagonist. These results are consistent with preferential recruitment of neutrophils by ET-1, and suggest that inhibition of this proinflammatory mediator may decrease acute pulmonary inflammation associated with cigarette smoke and other pulmonary toxins. PMID:18990977

  19. Newborn hypoxia/anoxia inhibits cardiomyocyte proliferation and decreases cardiomyocyte endowment in the developing heart: role of endothelin-1.

    Directory of Open Access Journals (Sweden)

    Alexandra N Paradis

    Full Text Available In the developing heart, cardiomyocytes undergo terminal differentiation during a critical window around birth. Hypoxia is a major stress to preterm infants, yet its effect on the development and maturation of the heart remains unknown. We tested the hypothesis in a rat model that newborn anoxia accelerates cardiomyocyte terminal differentiation and results in reduced cardiomyocyte endowment in the developing heart via an endothelin-1-dependent mechanism. Newborn rats were exposed to anoxia twice daily from postnatal day 1 to 3, and hearts were isolated and studied at postnatal day 4 (P4, 7 (P7, and 14 (P14. Anoxia significantly increased HIF-1α protein expression and pre-proET-1 mRNA abundance in P4 neonatal hearts. Cardiomyocyte proliferation was significantly decreased by anoxia in P4 and P7, resulting in a significant reduction of cardiomyocyte number per heart weight in the P14 neonates. Furthermore, the expression of cyclin D2 was significantly decreased due to anoxia, while p27 expression was increased. Anoxia has no significant effect on cardiomyocyte binucleation or myocyte size. Consistently, prenatal hypoxia significantly decreased cardiomyocyte proliferation but had no effect on binucleation in the fetal heart. Newborn administration of PD156707, an ETA-receptor antagonist, significantly increased cardiomyocyte proliferation at P4 and cell size at P7, resulting in an increase in the heart to body weight ratio in P7 neonates. In addition, PD156707 abrogated the anoxia-mediated effects. The results suggest that hypoxia and anoxia via activation of endothelin-1 at the critical window of heart development inhibits cardiomyocyte proliferation and decreases myocyte endowment in the developing heart, which may negatively impact cardiac function later in life.

  20. Cyclic stretch induces upregulation of endothelin-1 with keratinocytes in vitro: Possible role in mechanical stress-induced hyperpigmentation

    Energy Technology Data Exchange (ETDEWEB)

    Kurita, Masakazu, E-mail: masakazukurita@gmail.com [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan); Okazaki, Mutsumi [Department of Plastic and Reconstructive Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Fujino, Takashi [Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan); Takushima, Akihiko; Harii, Kiyonori [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan)

    2011-05-27

    Highlights: {yields} Influence of cyclic stretch on melanogenetic paracrine cytokines was investigated. {yields} Keratinocyte-derived endothelin-1 was upregulated with cyclic stretch. {yields} Degree of upregulation increases dose-dependently. {yields} This upregulation possibly plays a role in the pathogenesis of pigmented disorders. -- Abstract: The aim of this study was to investigate the possible pathological relation between mechanical stress and hyperpigmentation. We did this by investigating the influence of cyclic stretch on the expression of keratinocyte- and fibroblast-derived melanogenetic paracrine cytokines in vitro. Using primary human keratinocytes and fibroblasts, alterations of mRNA expression of melanogenetic paracrine cytokines due to cyclic stretch were investigated using a real-time polymerase chain reaction (PCR). The cytokines included basic fibroblast growth factor (bFGF), stem cell factor (SCF), granulocyte/macrophage colony-stimulating factor, interleukin-1{alpha}, and endothelin-1 (ET-1) for keratinocytes and bFGF, SCF, and hepatocyte growth factor for fibroblasts. The dose dependence of keratinocyte-derived ET-1 upregulation was further investigated using real-time PCR and an enzyme-linked immunosorbent assay. We also investigated the effects of cyclic stretch on the proliferation and differentiation of keratinocytes. Among the melanogenetic paracrine cytokines investigated, keratinocyte-derived ET-1 was consistently upregulated in all four cell lines. The degree of upregulation increased with the degree of the length and frequency of the stretch; in contrast, cell number and differentiation markers showed no obvious alterations with cyclic stretch. Keratinocyte-derived ET-1 upregulation possibly plays a significant role in the pathogenesis of pigmented disorders, such as friction melanosis, caused by mechanical stress.

  1. Selective over-expression of endothelin-1 in endothelial cells exacerbates inner retinal edema and neuronal death in ischemic retina.

    Directory of Open Access Journals (Sweden)

    Simon S F Cheung

    Full Text Available The level of endothelin-1 (ET-1, a potent vasoconstrictor, was associated with retinopathy under ischemia. The effects of endothelial endothelin-1 (ET-1 over-expression in a transgenic mouse model using Tie-1 promoter (TET-1 mice on pathophysiological changes of retinal ischemia were investigated by intraluminal insertion of a microfilament up to middle cerebral artery (MCA to transiently block the ophthalmic artery. Two-hour occlusion and twenty-two-hour reperfusion were performed in homozygous (Hm TET-1 mice and their non-transgenic (NTg littermates. Presence of pyknotic nuclei in ganglion cell layer (GCL was investigated in paraffin sections of ipsilateral (ischemic and contralateral (non-ischemic retinae, followed by measurement of the thickness of inner retinal layer. Moreover, immunocytochemistry of glial fibrillary acidic protein (GFAP, glutamine synthetase (GS and aquaporin-4 (AQP4 peptides on retinal sections were performed to study glial cell reactivity, glutamate metabolism and water accumulation, respectively after retinal ischemia. Similar morphology was observed in the contralateral retinae of NTg and Hm TET-1 mice, whereas ipsilateral retina of NTg mice showed slight structural and cellular changes compared with the corresponding contralateral retina. Ipsilateral retinae of Hm TET-1 mice showed more significant changes when compared with ipsilateral retina of NTg mice, including more prominent cell death in GCL characterized by the presence of pyknotic nuclei, elevated GS immunoreactivity in Müller cell bodies and processes, increased AQP-4 immunoreactivity in Müller cell processes, and increased inner retinal thickness. Thus, over-expression of endothelial ET-1 in TET-1 mice may contribute to increased glutamate-induced neurotoxicity on neuronal cells and water accumulation in inner retina leading to edema.

  2. Prolonging the plasma circulation of proteins by nano-encapsulation with phosphorylcholine-based polymer

    Institute of Scientific and Technical Information of China (English)

    Linlin Zhang; Yang Liu; Gan Liu; Duo Xu; Sheng Liang; Xinyuan Zhu; Yunfeng Lu

    2016-01-01

    Short in vivo circulation is a major hindrance to the widespread adoption of protein therapeutics.Protein nanocapsules generated by encapsulating proteins with a thin layer of phosphorylcholine-based polymer via a two-step encapsulation process exhibited significantly prolonged plasma half-life.Furthermore,by constructing nanocapsules with similar sizes but different surface charges and chemistry,we demonstrated a generic strategy for prolonging the plasma half-life of therapeutic proteins.In an in vitro experiment,four types of bovine serum albumin (BSA) nanocapsules were incubated with fetal bovine serum (FBS) in phosphate buffer saline (PBS);the cell uptake by HeLa cells was monitored to systematically evaluate the characteristics of the surface chemistry during drculation.Single positron emission tomography-computed tomography (SPECT)was employed to allow real-time observation of the BSA nanoparticle distribution in vivo,as well as quantification of the plasma concentration after intravenous administration.This study offers a practical method for translating a broad range of proteins for clinical use.

  3. Effects of CPU 86017 (chlorobenzyltetrahydroberberine chloride) and its enantiomers on thyrotoxicosis-induced overactive endothelin-1 system and oxidative stress in rat testes.

    Science.gov (United States)

    Tang, XiaoYun; Qi, MinYou; Dai, DeZai; Zhang, Can

    2006-08-01

    To study the effects of CPU 86017, a berberine derivative, and its four enantiomers on thyrotoxicosis-induced oxidative stress and the excessive endothelin-1 system in rat testes. Adult male SD rats were given high-dose L-thyroxin (0.2 mg/kg subcutaneously) once daily for 10 days to develop thyrotoxicosis. Subsets of the rats were treated with CPU 86017 or its four enantiomers (SR, SS, RS, and RR) once daily from day 6 to day 10. The alterations of redox, nitric oxide synthase, and endothelin-1 system in testes were examined by spectrophotometry and reverse transcriptase-polymerase chain reaction assay. After 10 days of high-dose L-thyroxin administration, increased mRNA expression of prepro-endothelin-1 and endothelin-converting enzyme was observed in the rat testes, accompanied by an elevated inducible nitric oxide synthase activity and oxidative stress. CPU 86017 and its enantiomer SR significantly improved these abnormalities. High-dose L-thyroxin results in an overactive endothelin-1 system and oxidative stress in adult rat testis. CPU 86017 and its enantiomer SR suppressed the excessive ET-1 system by improving oxidative stress, and SR exhibited more potent efficacy than CPU 86017 and other enantiomers.

  4. A flow cytometric method for characterization of circulating cell-derived microparticles in plasma

    DEFF Research Database (Denmark)

    Nielsen, Morten Hjuler; Beck-Nielsen, Henning; Andersen, Morten Nørgaard;

    2014-01-01

    BACKGROUND AND AIM: Previous studies on circulating microparticles (MPs) indicate that the majority of MPs are of a size below the detection limit of most standard flow cytometers. The objective of the present study was to establish a method to analyze MP subpopulations above the threshold...... of detection of a new generation BD FACSAria™ III digital flow cytometer. METHODS: We analyzed MP subpopulations in plasma from 24 healthy individuals (9 males and 15 females). MPs were identified according to their size (.... The sensitivity of the flow cytometer was tested against that of a previous-generation instrument FC500. Reproducibility of the FACSAria and our set-up was investigated, and the percentage of phosphatidylserine (PS) exposing MPs binding Lactadherin was determined. RESULTS: By using a flow cytometric approach we...

  5. Ionospheric Plasma Circulation Associated with Polar Cap Arcs Detached from the Auroral Oval

    Science.gov (United States)

    Yakymenko, K.; Koustov, A. V.; Hosokawa, K.; Shiokawa, K.

    2015-12-01

    Joint observations of the OMTI all-sky camera at Resolute Bay, NWT (Canada), the SuperDARN radars and Swarm satellites are considered to investigate horizontal plasma flows and vertical field-aligned currents (FACs) associated with polar cap arcs "detached" from the auroral oval but not penetrated deep into the polar cap. All cases are for the near winter solstice, positive IMF Bz and mostly dominating IMF By. We show that the arcs are usually co-exist with strong flow shears driven by electric fields of the converging type. The shears, being added to the background flow, produce unusual convection patterns, for example reverse (sunward) flows on the nightside, several MLT hours away from the noon-midnight line. We also investigate the distribution of FACs in the arcs' vicinity, both duskward and dawnward, for several Swarm passes. Electron density data onboard Swarm satellites are used to identify the arc and auroral oval boundaries, along with the ground-based optics. The data suggest that the arcs correspond to a separate current system excited in addition to the background plasma circulation governed by the reconnection processes.Joint observations of the OMTI all-sky camera at Resolute Bay, NWT (Canada), the SuperDARN radars and Swarm satellites are considered to investigate horizontal plasma flows and vertical field-aligned currents (FACs) associated with polar cap arcs "detached" from the auroral oval but not penetrated deep into the polar cap. All cases are for the near winter solstice, positive IMF Bz and mostly dominating IMF By. We show that the arcs are usually co-exist with strong flow shears driven by electric fields of the converging type. The shears, being added to the background flow, produce unusual convection patterns, for example reverse (sunward) flows on the nightside, several MLT hours away from the noon-midnight line. We also investigate the distribution of FACs in the arcs' vicinity, both duskward and dawnward, for several Swarm passes

  6. Plasma macrophage colony-stimulating factor levels during cardiopulmonary bypass with extracorporeal circulation

    Directory of Open Access Journals (Sweden)

    Y. Denizot

    1996-01-01

    Full Text Available Leukocytosis and thrombocytopenia occur during cardiopulmonary bypass (CPB with extracorporeal circulation (ECC. Elevated circulating concentrations of macrophage colony-stimulating factor (M-CSF are reported during thrombocytopenia and leukopenia of different origins. We have assessed M-CSF concentrations in 40 patients undergoing CPB with ECC. Plasma M-CSF concentrations were stable during ECC and increased at the 6th (7.3 ± 0.7 IU/μg protein and 24th (8.6 ± 0.8 IU/μg protein postoperative hour compared with pre-ECC values (4.9 ± 0.5 IU/μg protein. A deep thrombocytopenia was found during ECC and until the 24th postoperative hour. A drop of leukocyte counts was found during ECC followed by an increase after ECC weaning. While no correlation was found between M-CSF concentrations and the leukocyte counts, M-CSF values were positively correlated with platelet counts only before and during ECC. Thus, M-CSF is not implicated in the thrombocytopenia and the leukopenia generated during CPB with ECC. However the elevated levels of M-CSFa few hours after the end of ECC might play a role in the inflammatory process often observed after CPB.

  7. Application of circulating plasma/serum EBV DNA in the clinical management of nasopharyngeal carcinoma.

    Science.gov (United States)

    Yip, Timothy T C; Ngan, Roger K C; Fong, Alvin H W; Law, Stephen C K

    2014-06-01

    Elevated levels of circulating cell-free Epstein-Barr virus (EBV) DNA have been detected in plasma and serum samples from nasopharyngeal cancer (NPC) patients by quantitative real time PCR (qPCR) test. This qPCR test for circulating EBV DNA was found to be useful in the clinical management of NPC patients. For instance, EBV DNA qPCR test has good sensitivity and specificity in the detection of NPC at disease onset. Increase of the viral DNA load was found in NPC patients at late stages of disease. High EBV DNA load at disease onset or detectable viral load post-treatment was associated with poor survival or frequent relapse in NPC patients. Residual EBV DNA load after primary treatment could be a useful indicator to justify adjuvant chemotherapy. The qPCR test might also be applied to define a poor prognostic group in patients at early stage (I/II) for implementing concurrent chemo-radiotherapy (chemo-RT) to improve patients' outcome. The test is also useful to monitor distant metastases or response to radiotherapy, chemo-RT or surgery. Supplementary tests, however, are needed to pick up EBV negative WHO type I NPC and test improvement is needed to increase sensitivity in detecting stage I disease and local recurrence.

  8. Circulating nucleic acids in plasma and serum (CNAPS: applications in oncology

    Directory of Open Access Journals (Sweden)

    González-Masiá JA

    2013-07-01

    Full Text Available José A González-Masiá,1 Damián García-Olmo,2 Dolores C García-Olmo31General Surgery Service, General University Hospital of Albacete, Albacete, 2Department of Surgery, Universidad Autónoma de Madrid and La Paz University Hospital, IdiPaz, Madrid, 3Experimental Research Unit, General University Hospital of Albacete, Albacete, SpainAbstract: The presence of small amounts of circulating nucleic acids in plasma and serum (CNAPS is not a new finding. The verification that such amounts are significantly increased in cancer patients, and that CNAPS might carry a variety of genetic and epigenetic alterations related to cancer development and progression, has aroused great interest in the scientific community in the last decades. Such alterations potentially reflect changes that occur during carcinogenesis, and include DNA mutations, loss of heterozygosity, viral genomic integration, disruption of microRNA, hypermethylation of tumor suppressor genes, and changes in the mitochondrial DNA. These findings have led to many efforts toward the implementation of new clinical biomarkers based on CNAPS analysis. In the present article, we review the main findings related to the utility of CNAPS analysis for early diagnosis, prognosis, and monitoring of cancer, most of which appear promising. However, due to the lack of harmonization of laboratory techniques, the heterogeneity of disease progression, and the small number of recruited patients in most of those studies, there has been a poor translation of basic research into clinical practice. In addition, many aspects remain unknown, such as the release mechanisms of cell-free nucleic acids, their biological function, and the way by which they circulate in the bloodstream. It is therefore expected that in the coming years, an improved understanding of the relationship between CNAPS and the molecular biology of cancer will lead to better diagnosis, management, and treatment.Keywords: plasma, cancer, clinical

  9. Effects of Shehuang Paste(麝黄膏) on Hemodynamics, Endotoxin,Nitric Oxide and Endothelin-1 in Patients with Refractory Cirrhotic Ascites

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective: To explore the influence of Shehuang Paste (麝黄膏 ,SHP) to the hemodynamics,endotoxin, nitric oxide (NO), and endothelin-1 (ET-1) in patients with refractory cirrhotic ascites. Methods:Fifty-nine cases of refractory cirrhotic ascites were randomly assigned to two groups, 32 cases in the treatment group and 27 cases in the control group. The basic treatment was the same for both groups, including liver protecting medicines, diuretics and supportive drugs, but SHP navel sticking was applied for the treatment group additionally once a day. A course of one month of treatment was applied and the general efficacy on ascites was observed by the end of the therapeutic course. Before and after the treatment, examinations by limulus lysate chromogenic test was conducted to measure plasma endotoxin content; colorimetry to measure plasma content of NO indirectly, radioimmunoassay to measure plasma ET-1 content; and color Doppler ultrasonography to measure the blood flow of portal vein and splenic vein. The relationship between the blood flow of portal vein and splenic vein and endotoxin, NO and ET-1 in the treatment group was analyzed as well.Results: The total effective rate on ascites was 84.4% in the treatment group, and 48. 1% in the control group, with significant difference shown between them ( P<0.01 ). In the treatment group the blood flow of portal vein and splenic vein, contents of endotoxin, NO and ET-1 all got significantly reduced after treatment ( P<0.05 or P<0.01 ); while these indexes in the control group were not significantly changed ( P>0.05).Moreover, it was found that in the treatment group, the blood flow of portal vein and splenic vein had a positive correlation to the levels of NO, ET-1, and endotoxin, either before or after treatment. Conclusion: Application of SHP navel sticking could clearly reduce the blood flow of portal vein and splenic vein, and lower the content of endotoxin, NO and ET-1. The blood flow of portal vein and

  10. A Fall in Plasma Free Fatty Acid (FFA) Level Activates the Hypothalamic-Pituitary-Adrenal Axis Independent of Plasma Glucose: Evidence for Brain Sensing of Circulating FFA

    Science.gov (United States)

    Oh, Young Taek; Oh, Ki-Sook; Kang, Insug

    2012-01-01

    The brain responds to a fall in blood glucose by activating neuroendocrine mechanisms for its restoration. It is unclear whether the brain also responds to a fall in plasma free fatty acids (FFA) to activate mechanisms for its restoration. We examined whether lowering plasma FFA increases plasma corticosterone or catecholamine levels and, if so, whether the brain is involved in these responses. Plasma FFA levels were lowered in rats with three independent antilipolytic agents: nicotinic acid (NA), insulin, and the A1 adenosine receptor agonist SDZ WAG 994 with plasma glucose clamped at basal levels. Lowering plasma FFA with these agents all increased plasma corticosterone, but not catecholamine, within 1 h, accompanied by increases in plasma ACTH. These increases in ACTH or corticosterone were abolished when falls in plasma FFA were prevented by Intralipid during NA or insulin infusion. In addition, the NA-induced increases in plasma ACTH were completely prevented by administration of SSR149415, an arginine vasopressin receptor antagonist, demonstrating that the hypothalamus is involved in these responses. Taken together, the present data suggest that the brain may sense a fall in plasma FFA levels and activate the hypothalamic-pituitary-adrenal axis to increase plasma ACTH and corticosterone, which would help restore FFA levels. Thus, the brain may be involved in the sensing and control of circulating FFA levels. PMID:22669895

  11. Site-Specific Zwitterionic Polymer Conjugates of a Protein Have Long Plasma Circulation.

    Science.gov (United States)

    Bhattacharjee, Somnath; Liu, Wenge; Wang, Wei-Han; Weitzhandler, Isaac; Li, Xinghai; Qi, Yizhi; Liu, Jinyao; Pang, Yan; Hunt, Donald F; Chilkoti, Ashutosh

    2015-11-01

    Many proteins suffer from suboptimal pharmacokinetics (PK) that limit their utility as drugs. The efficient synthesis of polymer conjugates of protein drugs with tunable PK to optimize their in vivo efficacy is hence critical. We report here the first study of the in vivo behavior of a site-specific conjugate of a zwitterionic polymer and a protein. To synthesize the conjugate, we first installed an initiator for atom-transfer radical polymerization (ATRP) at the N terminus of myoglobin (Mb-N-Br). Subsequently, in situ ATRP was carried out in aqueous buffer to grow an amine-functionalized polymer from Mb-N-Br. The cationic polymer was further derivatized to two zwitterionic polymers by treating the amine groups of the cationic polymer with iodoacetic acid to obtain poly(carboxybetaine methacrylate) with a one-carbon spacer (PCBMA; C1 ), and sequentially with 3-iodopropionic acid and iodoacetic acid to obtain PCBMA(mix) with a mixture of C1 and C2 spacers. The Mb-N-PCBMA polymer conjugates had a longer in vivo plasma half-life than a PEG-like comb polymer conjugate of similar molecular weights (MW). The structure of the zwitterion plays a role in controlling the in vivo behavior of the conjugate, as the PCBMA conjugate with a C1 spacer had significantly longer plasma circulation than the conjugate with a mixture of C1 and C2 spacers.

  12. Catabolism of circulating enzymes: plasma clearance, endocytosis, and breakdown of lactate dehydrogenase-1 in rabbits

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    Smit, M.J.; Beekhuis, H.; Duursma, A.M.; Bouma, J.M.; Gruber, M.

    1988-12-01

    Lactate dehydrogenase-1, intravenously injected into rabbits, was cleared with first-order kinetics (half-life 27 min), until at least 80% of the injected activity had disappeared from plasma. Radioactivity from injected SVI-labeled enzyme disappeared at this same rate. Trichloroacetic-acid-soluble breakdown products started to appear in the circulation shortly after injection of the labeled enzyme. Body scans of the rabbits for 80 min after injection of T I-labeled enzyme revealed rapid accumulation of label in the liver, peaking 10-20 min after injection. Subsequently, activity in the liver declined and radioactivity (probably labeled breakdown products of low molecular mass) steadily accumulated in the bladder. Tissue fractionation of liver, 19 min after injection of labeled enzyme, indicated that the radioactivity was present both in endosomes and in lysosomes, suggesting uptake by endocytosis, followed by breakdown in the lysosomes. Measurements of radioactivity in liver and plasma suggest that the liver is responsible for the breakdown of at least 75% of the injected enzyme. Radioautography of tissue sections of liver and spleen showed accumulated radioactivity in sinusoidal liver cells and red pulpa, respectively. These results are very similar to those for lactate dehydrogenase-5, creatine kinase MM, and several other enzymes that we have previously studied in rats.

  13. Catabolism of circulating enzymes: plasma clearance, endocytosis, and breakdown of lactate dehydrogenase-1 in rabbits.

    Science.gov (United States)

    Smit, M J; Beekhuis, H; Duursma, A M; Bouma, J M; Gruber, M

    1988-12-01

    Lactate dehydrogenase-1 (EC 1.1.1.27), intravenously injected into rabbits, was cleared with first-order kinetics (half-life 27 min), until at least 80% of the injected activity had disappeared from plasma. Radioactivity from injected 125I-labeled enzyme disappeared at this same rate. Trichloroacetic-acid-soluble breakdown products started to appear in the circulation shortly after injection of the labeled enzyme. Body scans of the rabbits for 80 min after injection of 131I-labeled enzyme revealed rapid accumulation of label in the liver, peaking 10-20 min after injection. Subsequently, activity in the liver declined and radioactivity (probably labeled breakdown products of low molecular mass) steadily accumulated in the bladder. Tissue fractionation of liver, 19 min after injection of labeled enzyme, indicated that the radioactivity was present both in endosomes and in lysosomes, suggesting uptake by endocytosis, followed by breakdown in the lysosomes. Measurements of radioactivity in liver and plasma suggest that the liver is responsible for the breakdown of at least 75% of the injected enzyme. Radioautography of tissue sections of liver and spleen showed accumulated radioactivity in sinusoidal liver cells and red pulpa, respectively. These results are very similar to those for lactate dehydrogenase-5, creatine kinase MM, and several other enzymes that we have previously studied in rats.

  14. Space weather circulation model of plasma clouds as background radiation medium of space environment.

    Science.gov (United States)

    Kalu, A. E.

    A model for Space Weather (SW) Circulation with Plasma Clouds as background radiation medium of Space Environment has been proposed and discussed. Major characteristics of the model are outlined and the model assumes a baroclinic Space Environment in view of observed pronounced horizontal electron temperature gradient with prevailing weak vertical temperature gradient. The primary objective of the study is to be able to monitor and realistically predict on real- or near real-time SW and Space Storms (SWS) affecting human economic systems on Earth as well as the safety and Physiologic comfort of human payload in Space Environment in relation to planned increase in human space flights especially with reference to the ISS Space Shuttle Taxi (ISST) Programme and other prolonged deep Space Missions. Although considerable discussions are now available in the literature on SW issues, routine Meteorological operational applications of SW forecast data and information for Space Environment are still yet to receive adequate attention. The paper attempts to fill this gap in the literature of SW. The paper examines the sensitivity and variability in 3-D continuum of Plasmas in response to solar radiation inputs into the magnetosphere under disturbed Sun condition. Specifically, the presence of plasma clouds in the form of Coronal Mass Ejections (CMEs) is stressed as a major source of danger to Space crews, spacecraft instrumentation and architecture charging problems as well as impacts on numerous radiation - sensitive human economic systems on Earth. Finally, the paper considers the application of model results in the form of effective monitoring of each of the two major phases of manned Spaceflights - take-off and re-entry phases where all-time assessment of spacecraft transient ambient micro-incabin and outside Space Environment is vital for all manned Spaceflights as recently evidenced by the loss of vital information during take-off of the February 1, 2003 US Columbia

  15. Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers.

    Science.gov (United States)

    Perkins, Geraldine; Yap, Timothy A; Pope, Lorna; Cassidy, Amy M; Dukes, Juliet P; Riisnaes, Ruth; Massard, Christophe; Cassier, Philippe A; Miranda, Susana; Clark, Jeremy; Denholm, Katie A; Thway, Khin; Gonzalez De Castro, David; Attard, Gerhardt; Molife, L Rhoda; Kaye, Stan B; Banerji, Udai; de Bono, Johann S

    2012-01-01

    Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical 'hot-spot' mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid

  16. Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers.

    Directory of Open Access Journals (Sweden)

    Geraldine Perkins

    Full Text Available Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE archival tumor tissue (primary and/or metastatic and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600; this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS hazard ratio of 2.4 (95% CI 1.4, 4.2 for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical 'hot-spot' mutations (KRAS, BRAF, PIK3CA in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic

  17. Endothelin-1 Overexpression Improves Renal Function in eNOS Knockout Mice

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    Oleg Tsuprykov

    2015-10-01

    Full Text Available Background/Aims: To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+, endothelial nitric oxide synthase knockout (eNOS-/- and ET+/+eNOS-/- mice. Methods: We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics. Results: eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpine1, TIMP1, Col1a1, CCL2 were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice. Conclusion: eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET-1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in β-oxidation of fatty acids and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels.

  18. Circulating tumour-derived microvesicles in plasma of gastric cancer patients.

    Science.gov (United States)

    Baran, Jaroslaw; Baj-Krzyworzeka, Monika; Weglarczyk, Kazimierz; Szatanek, Rafal; Zembala, Maria; Barbasz, Jakub; Czupryna, Antoni; Szczepanik, Antoni; Zembala, Marek

    2010-06-01

    Cell membrane microfragments called microvesicles (MV) originating from different cells are circulating in the blood of healthy subjects and their elevated numbers are found in different diseases, including cancer. This study was designed to characterise MV present in plasma of gastric cancer patients. Since majority of MV in blood are platelets-derived (PMV), plasma samples deprived of PMV were used. In comparison to control, the number of MV in patients was significantly elevated in all stages, higher in more advanced disease. Patients' MV showed an increased membrane expression of CCR6 and HER-2/neu. The proportion of MV carrying some leucocyte determinants was low and similar in patients and control. Transmission electron microscopy showed their substantial heterogeneity in size and shape. The size determined by dynamic light scattering analysis confirmed this heterogeneity. The MV size distribution in patients was broader within the range of 10-800 nm, while in control MV showed 3-mode distribution within the range of 10-400 nm. Atomic force microscopy confirmed MV size heterogeneity with implication that larger objects represented aggregates of smaller microparticles. Patients' MV exhibited increased absolute values of zeta potential, indicating a higher surface charge. Tumour markers HER-2/neu, MAGE-1, c-MET and EMMPRIN were detected both in control and patients' samples with stronger expression in the latter. Significantly higher expression of MAGE-1 and HER-2/neu mRNA was observed in individual patients. All together, it suggests that at least some MV in plasma of gastric cancer patients are tumour-derived. However, their role in cancer requires further studies.

  19. Exposure to fipronil elevates systolic blood pressure and disturbs related biomarkers in plasma of rats.

    Science.gov (United States)

    Chaguri, Joao Leandro; Godinho, Antonio Francisco; Horta, Daniel França; Gonçalves-Rizzi, Victor Hugo; Possomato-Vieira, Jose Sergio; Nascimento, Regina Aparecida; Dias-Junior, Carlos Alan

    2016-03-01

    Recent reports show that fipronil affects non-target organisms, including environmental species populations and potentially humans. We aimed to examine if fipronil exposure affects the systolic blood pressure and related biomarkers. Thus, fipronil was orally administered to rats (30 mg/kg/day) during 15 days (Fipronil group) or physiological solution (Control group). While fipronil increased significantly the systolic blood pressure (158±13 mmHg), no significant changes were observed in Control group (127±3 mmHg). Significantly, higher levels of fipronil in plasma were observed in Fipronil group (0.46±0.09 μg/mL versus 0.17±0.11 μg/mL in Control group). Fipronil group showed lower weight gain compared with Control group. While fipronil resulted in higher concentrations of endothelin-1, reduced antioxidant capacity and lower levels of circulating matrix metalloproteinase 2 (MMP-2) and nitric oxide (NO) metabolites compared to Control group, no alteration was observed in serum biomarkers of renal and hepatic/biliary functional abilities. Therefore, this study suggests that fipronil causes hypertension and endothelin-1 plays a key role. Also, these findings suggest that reductions of both MMP-2 and NO may contribute with the elevation of systolic blood pressure observed with fipronil.

  20. 单纯性肥胖儿童血浆内皮素-1水平及影响因素分析%Analysis of endothelin-1 level and influence factors in simple obese children

    Institute of Scientific and Technical Information of China (English)

    金咏梅; 都鹏飞

    2015-01-01

    Objective:To investigate plasma endothelin-1(ET-1) level and influence factors in simple obese children. Methods:28 cases of simple obese children as obesity group, and 30 healthy children as control group, the plasma ET-1 were measured by radioimmunoassay. Results: The plasma ET-1 increased in the simple obesity group compared with the control group, and positively correlated (r=0.41, P<0.05) with waist circumference and negative correlation (r=-0.37, P<0.05) with high density lipoprotein cholesterol(HDL-C). Conclusion:In simple obese children, there was dysfunctions of endothelial dysfunction, associated with the increase of plasma ET-1, the later was correlated with the increase of waist circumference and the decrease of HDL-C.%目的:探讨单纯性肥胖儿童血浆内皮素-1(endothelin-1, ET-1)的水平及影响因素。方法:28例单纯性肥胖儿童为肥胖组,30例健康儿童作为对照组。放射免疫法检测血浆ET-1水平。结果:与对照组比较,单纯性肥胖儿童血浆ET-1升高,与腰围呈正相关(r=0.41,P<0.05),与高密度脂蛋白胆固醇(high density lipoprotein cholesterol, HDL-C)呈负相关(r=-0.37,P<0.05)。结论:单纯性肥胖儿童存在血管内皮功能紊乱,与血浆ET-1升高有关,后者与腰围升高及体内HDL-C水平下降有关。

  1. Circulating Plasma microRNAs can differentiate Human Sepsis and Systemic Inflammatory Response Syndrome (SIRS).

    Science.gov (United States)

    Caserta, Stefano; Kern, Florian; Cohen, Jonathan; Drage, Stephen; Newbury, Sarah F; Llewelyn, Martin J

    2016-06-20

    Systemic inflammation in humans may be triggered by infection, termed sepsis, or non-infective processes, termed non-infective systemic inflammatory response syndrome (SIRS). MicroRNAs regulate cellular processes including inflammation and may be detected in blood. We aimed to establish definitive proof-of-principle that circulating microRNAs are differentially affected during sepsis and non-infective SIRS. Critically ill patients with severe (n = 21) or non-severe (n = 8) intra-abdominal sepsis; severe (n = 23) or non-severe (n = 21) non-infective SIRS; or no SIRS (n = 16) were studied. Next-generation sequencing and qRT-PCR were used to measure plasma microRNAs. Detectable blood miRNAs (n = 116) were generally up-regulated in SIRS compared to no-SIRS patients. Levels of these 'circulating inflammation-related microRNAs' (CIR-miRNAs) were 2.64 (IQR: 2.10-3.29) and 1.52 (IQR: 1.15-1.92) fold higher for non-infective SIRS and sepsis respectively (p SIRS. Six CIR-miRNAs (miR-30d-5p, miR-30a-5p, miR-192-5p, miR-26a-5p, miR-23a-5p, miR-191-5p) provided good-to-excellent discrimination of severe sepsis from severe SIRS (0.742-0.917 AUC of ROC curves). CIR-miRNA levels inversely correlated with pro-inflammatory cytokines (IL-1, IL-6 and others). Thus, among critically ill patients, sepsis and non-infective SIRS are associated with substantial, differential changes in CIR-miRNAs. CIR-miRNAs may be regulators of inflammation and warrant thorough evaluation as diagnostic and therapeutic targets.

  2. Bone-marrow-derived mesenchymal stem cells attenuate cognitive deficits in an endothelin-1 rat model of stroke.

    Science.gov (United States)

    Lowrance, S A; Fink, K D; Crane, A; Matyas, J; Dey, N D; Matchynski, J J; Thibo, T; Reinke, T; Kippe, J; Hoffman, C; Sandstrom, M; Rossignol, J; Dunbar, G L

    2015-01-01

    Stroke is the third leading cause of death and permanent disability in the United States, often producing long-term cognitive impairments, which are not easily recapitulated in animal models. The goals of this study were to assess whether: (1) the endothelin-1 (ET-1) model of chronic stroke produced discernable cognitive deficits; (2) a spatial operant reversal task (SORT) would accurately measure memory deficits in this model; and (3) bone-marrow-derived mesenchymal stem cells (BMMSCs) could reduce any observed deficits. Rats were given unilateral intracerebral injections of vehicle or ET-1, a stroke-inducing agent, near the middle cerebral artery. Seven days later, they were given intrastriatal injections of BMMSCs or vehicle, near the ischemic penumbra. The cognitive abilities of the rats were assessed on a novel SORT, which was designed to efficiently distinguish cognitive deficits from potential motoric confounds. Rats given ET-1 had significantly more cognitive errors at six weeks post-stroke on the SORT, and that these deficits were attenuated by BMMSC transplants. These findings indicate that: (1) the ET-1 model produces chronic cognitive deficits; (2) the SORT efficiently measures cognitive deficits that are not confounded by motoric impairment; and (3) BMMSCs may be a viable treatment for stroke-induced cognitive dysfunction.

  3. The Association of Endothelin-1 with Markers of Arterial Stiffness in Black South African Women: The SABPA Study

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    Christine Susara du Plooy

    2015-01-01

    Full Text Available Background. Limited data exist regarding endothelin-1 (ET-1, a vasoactive contributor in vascular tone, in a population subjected to early vascular deterioration. We compared ET-1 levels and explored its association with markers of arterial stiffness in black and white South Africans. Methodology. This cross-sectional substudy included 195 black (men: n=99; women: n=95 and 197 white (men: n=99; women: n=98 South Africans. Serum ET-1 levels were measured as well as markers of arterial stiffness (blood pressure, pulse wave velocity, and arterial compliance. ET-1 levels were higher in black men and white women compared to their counterparts after adjusting for C-reactive protein. In both single and partial (adjusting for body mass index and gamma glutamyl transferase regression analyses ET-1 correlated with age, interleukin-6, high density lipoprotein cholesterol, systolic blood pressure, pulse pressure, and pulse wave velocity in black women. In multivariate regression analyses the independent association of ET-1 with systolic blood pressure (Adj. R2=0.13; β=0.28, p<0.01 and pulse pressure (Adj. R2=0.11; β=0.27, p<0.01 was confirmed in black women only. ET-1 additionally associated with interleukin-6 in black women (p<0.01. Conclusion. Our result suggests that ET-1 and its link with subclinical arteriosclerosis are potentially driven by low-grade inflammation as depicted by the association with interleukin-6 in the black female cohort.

  4. The Lipid Moiety of Haemozoin (Malaria Pigment and P. falciparum Parasitised Red Blood Cells Bind Synthetic and Native Endothelin-1

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    Nicoletta Basilico

    2010-01-01

    Full Text Available Endothelin1 (ET-1 is a 21-amino acid peptide produced by the vascular endothelium under hypoxia, that acts locally as regulator of vascular tone and inflammation. The role of ET-1 in Plasmodium falciparum malaria is unknown, although tissue hypoxia is frequent as a result of the cytoadherence of parasitized red blood cell (pRBC to the microvasculature. Here, we show that both synthetic and endothelial-derived ET-1 are removed by parasitized RBC (D10 and W2 strains, chloroquine sensitive, and resistant, resp. and native haemozoin (HZ, malaria pigment, but not by normal RBC, delipidized HZ, or synthetic beta-haematin (BH. The effect is dose dependent, selective for ET-1, but not for its precursor, big ET-1, and not due to the proteolysis of ET-1. The results indicate that ET-1 binds to the lipids moiety of HZ and membranes of infected RBCs. These findings may help understanding the consequences of parasite sequestration in severe malaria.

  5. Endothelial dysfunction in high fructose containing diet fed rats: Increased nitric oxide and decreased endothelin-1 levels in liver tissue

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    Zeki Arı

    2010-09-01

    Full Text Available Objectives: Dietary high fructose consumption which is closely associated with endothelial dysfunction via insulin re-sistance has recently increased in developed countries. Insulin resistance has a promoter effect on many metabolic disorders such as syndrome X, polycystic ovary syndrome, Type 2 diabetes mellitus etc. Our aim in this study is to understand the impact of increased fructose intake on metabolisms of glucose, insulin and endothelial dysfunction by measuring nitric oxide (NO and endothelin-1 (ET-1 levels in hepatic tissue which is crucial in fructose metabolism.Materials and Methods: We designed an animal study to understand increased fructose intake on hepatic endothe-lium. Twenty adult male albino rats were divided into two groups; the study group (group 1, n=10 received isocaloric fructose enriched diet (fructose-fed rats, containing 18.3% protein, 60.3% fructose and 5.2% fat while the control group received purified regular chow (group 2, n=10 for 2 weeks. After feeding period, blood and hepatic tissue samples were collected and glucose, insulin, NO and ET-1 levels were analysed.Results: We found increased fasting glucose and insulin levels and impaired glucose tolerance in fructose fed rats. Higher NO and lower ET–1 levels were also detected in hepatic tissue samples of the group 1.Conclusion: Increased fructose consumption has deleterious effects on glucose tolerance, insulin resistance and may cause to endothelial dysfunction.

  6. Status epilepticus induces vasogenic edema via tumor necrosis factor-α/ endothelin-1-mediated two different pathways.

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    Ji-Eun Kim

    Full Text Available Status epilepticus (SE induces vasogenic edema in the piriform cortex with disruptions of the blood-brain barrier (BBB. However, the mechanisms of vasogenic edema formation following SE are still unknown. Here we investigated the endothelin B (ETB receptor-mediated pathway of SE-induced vasogenic edema. Following SE, the release of tumor necrosis factor-α (TNF-α stimulated endothelin-1 (ET-1 release and expression in neurons and endothelial cells. In addition, TNF-α-induced ET-1 increased BBB permeability via ETB receptor-mediated endothelial nitric oxide synthase (eNOS activation in endothelial cells. ETB receptor activation also increased intracellular reactive oxygen species by NADPH oxidase production in astrocytes. These findings suggest that SE results in BBB dysfunctions via endothelial-astroglial interactions through the TNF-α-ET-1-eNOS/NADPH oxidase pathway, and that these ETB receptor-mediated interactions may be an effective therapeutic strategy for vasogenic edema in various neurological diseases.

  7. Cooperation of endothelin-1 signaling with melanosomes plays a role in developing and/or maintaining human skin hyperpigmentation

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    Daiki Murase

    2015-10-01

    Full Text Available Skin hyperpigmentation is characterized by increased melanin synthesis and deposition that can cause significant psychosocial and psychological distress. Although several cytokine-receptor signaling cascades contribute to the formation of ultraviolet B-induced cutaneous hyperpigmentation, their possible involvement in other types of skin hyperpigmentation has never been clearly addressed. Since our continuous studies using skin specimens from more than 30 subjects with ethnic skin diversity emphasized a consistent augmentation in the expression of endothelin-1 (ET-1 and its receptor (Endothelin B receptor, ET-B in hyperpigmented lesions, including senile lentigos (SLs, the precise function of ET-1 signaling was investigated in the present study. In line with previous studies, ET-1 significantly induced melanogenesis followed by increases in melanosome transport in melanocytes and in its transfer to keratinocytes while inhibition of ET-B function substantially depressed melanogenic ability in tissue-cultured SLs. Additionally, in agreement with a previous report that the formation of autophagosomes rather than melanosomes is stimulated according to starvation or defective melanosome production, ET-1 was found to remarkably augment the expression of components necessary for early melanosome formation, indicating its counteraction against autophagy-targeting melanosome degradation in melanocytes. Despite the lack of substantial impact of ET-1 on keratinocyte melanogenic functions, the expression of ET-1 was enhanced following melanosome uptake by keratinocytes. Taken together, our data suggest that ET-1 plays a substantial role in the development and/or maintenance of skin hyperpigmentation in reciprocal cooperation with increased melanosome incorporation.

  8. Hydrostatic pressure and shear stress affect endothelin-1 and nitric oxide release by endothelial cells in bioreactors.

    Science.gov (United States)

    Vozzi, Federico; Bianchi, Francesca; Ahluwalia, Arti; Domenici, Claudio

    2014-01-01

    Abundant experimental evidence demonstrates that endothelial cells are sensitive to flow; however, the effect of fluid pressure or pressure gradients that are used to drive viscous flow is not well understood. There are two principal physical forces exerted on the blood vessel wall by the passage of intra-luminal blood: pressure and shear. To analyze the effects of pressure and shear independently, these two stresses were applied to cultured cells in two different types of bioreactors: a pressure-controlled bioreactor and a laminar flow bioreactor, in which controlled levels of pressure or shear stress, respectively, can be generated. Using these bioreactor systems, endothelin-1 (ET-1) and nitric oxide (NO) release from human umbilical vein endothelial cells were measured under various shear stress and pressure conditions. Compared to the controls, a decrease of ET-1 production by the cells cultured in both bioreactors was observed, whereas NO synthesis was up-regulated in cells under shear stress, but was not modulated by hydrostatic pressure. These results show that the two hemodynamic forces acting on blood vessels affect endothelial cell function in different ways, and that both should be considered when planning in vitro experiments in the presence of flow. Understanding the individual and synergic effects of the two forces could provide important insights into physiological and pathological processes involved in vascular remodeling and adaptation.

  9. The effect of serum magnesium levels and serum endothelin-1 levels on bone mineral density in protein energy malnutrition.

    Science.gov (United States)

    Ozturk, C F; Karakelleoglu, C; Orbak, Z; Yildiz, L

    2012-06-01

    An inadequate and imbalanced intake of protein and energy results in protein-energy malnutrition (PEM). It is known that bone mineral density and serum magnesium levels are low in malnourished children. However, the roles of serum magnesium and endothelin-1 (ET-1) levels in the pathophysiology of bone mineralization are obscure. Thus, the relationships between serum magnesium and ET-1 levels and the changes in bone mineral density were investigated in this study. There was a total of 32 subjects, 25 of them had PEM and seven were controls. While mean serum ET-1 levels of the children with kwashiorkor and marasmus showed no statistically significant difference, mean serum ET-1 levels of both groups were significantly higher than that of the control group. Serum magnesium levels were lower than normal value in 9 (36%) of 25 malnourished children. Malnourished children included in this study were divided into two subgroups according to their serum magnesium levels. While mean serum ET-1 levels in the group with low magnesium levels were significantly higher than that of the group with normal magnesium levels (p malnutrition. Our study suggested that lower magnesium levels and higher ET-1 levels might be important factors in changes of bone mineral density in malnutrition. We recommend that the malnourished patients, especially with hypomagnesaemia, should be treated with magnesium early.

  10. Which Aspects of Stroke Do Animal Models Capture? A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1.

    Science.gov (United States)

    Schirrmacher, Ralf; Dea, Melvin; Heiss, Wolf-Dieter; Kostikov, Alexey; Funck, Thomas; Quessy, Stephan; Bedell, Barry; Dancause, Numa; Thiel, Alexander

    2016-01-01

    Cortical injections of the vasoconstrictor endothelin-1 (ET1) have widely been used to induce focal circumscribed ischemic lesions in the motor cortex of rodents in the context of stroke recovery studies. In order to apply this model correctly, it is essential to understand the time course of regional flow changes and of the development of penumbra and infarction. Multitracer micro-PET of ET1 focal ischemia in rats was performed using [11C]-flumazenil ([11C]FMZ) as a flow- and viability tracer and [18F]-fluoromisonidazole ([18F]FMISO) as hypoxia marker in order to characterize the physiological time-course of this model. Nine adult Sprague-Dawley rats received stereotaxic injections of ET1 into the right primary motor cortex, 3 served as controls. PET imaging was started 2, 3 and 20 h after the last ET1 injection. Histology was obtained at the end of the scans. Standardized uptake value ratios reflecting cerebral blood flow (CBF), [11C]FMZ-binding and [18F]FMISO-retention were calculated for the region of hypoperfusion and the normoperfused cortex. CBF in the hypoperfused cortex was significantly reduced (p ischemic core that later turned into infarct. ET1 injections yield reproducible, slowly developing ischemic lesions with constant levels of hypoperfusion. This multitracer micro-PET study suggests that the ET1 model is appropriate for inducing chronic circumscribed ischemic lesions but seems to be less suited for studying acute stroke pathophysiology. © 2016 S. Karger AG, Basel.

  11. Hemodynamic changes in a rat parietal cortex after endothelin-1-induced middle cerebral artery occlusion monitored by optical coherence tomography

    Science.gov (United States)

    Liu, Jian; Ma, Yushu; Dou, Shidan; Wang, Yi; La, Dongsheng; Liu, Jianghong; Ma, Zhenhe

    2016-07-01

    A blockage of the middle cerebral artery (MCA) on the cortical branch will seriously affect the blood supply of the cerebral cortex. Real-time monitoring of MCA hemodynamic parameters is critical for therapy and rehabilitation. Optical coherence tomography (OCT) is a powerful imaging modality that can produce not only structural images but also functional information on the tissue. We use OCT to detect hemodynamic changes after MCA branch occlusion. We injected a selected dose of endothelin-1 (ET-1) at a depth of 1 mm near the MCA and let the blood vessels follow a process first of occlusion and then of slow reperfusion as realistically as possible to simulate local cerebral ischemia. During this period, we used optical microangiography and Doppler OCT to obtain multiple hemodynamic MCA parameters. The change trend of these parameters from before to after ET-1 injection clearly reflects the dynamic regularity of the MCA. These results show the mechanism of the cerebral ischemia-reperfusion process after a transient middle cerebral artery occlusion and confirm that OCT can be used to monitor hemodynamic parameters.

  12. Reoxygenation, but neither hypoxia nor intermittent ischemia, increases ( sup 125 I)endothelin-1 binding to rat cardiac membranes

    Energy Technology Data Exchange (ETDEWEB)

    Liu, J.J.; Gu, X.H.; Casley, D.J.; Nayler, W.G. (Univ. of Melbourne, Heidelberg, Victoria (Australia))

    1990-03-01

    Standard binding techniques were used to establish whether either hypoxia, reoxygenation, perfusion under acidotic conditions, or stunning of the myocardium resembles ischemia and postischemic reperfusion in increasing cardiac membrane ({sup 125}I)endothelin-1 (ET-1) binding site density (Bmax). Membranes from aerobically perfused rat hearts bound ({sup 125}I)ET-1 to a single population of sites, with an affinity (KD) of 0.093 +/- 0.004 nM and a Bmax of 98.8 +/- 5.2 fmol/mg of protein. Bmax was increased (p less than 0.01) after 30 min of global ischemia, and further increased upon reperfusion, without changes in KD or selectivity. Neither three 10 min episodes of ischemia separated by 15 min of perfusion, nor perfusion at pH 6.8 instead of 7.4, nor 60 min of hypoxia altered Bmax, KD, or selectivity. Reoxygenation after 60 min of hypoxia increased Bmax (p less than 0.01) and KD (p less than 0.01) without changing selectivity. These results are interpreted to mean that the ischemia-induced increase in Bmax for ({sup 125}I)ET-1 cannot be explained simply in terms of the ischemia-induced acidosis, or the accompanying reduction in tissue adenosine triphosphate and creatine phosphate.

  13. Preferential recruitment of neutrophils by endothelin-1 in acute lung inflammation induced by lipopolysaccharide or cigarette smoke

    Directory of Open Access Journals (Sweden)

    Tapan Bhavsar

    2008-10-01

    Full Text Available Tapan Bhavsar, Xing Jian Liu, Hardik Patel, Ralph Stephani, Jerome O CantorSt John’s University, School of Pharmacy and Allied Health Sciences, New York, USAAbstract: This study examined the role of endothelin-1 (ET-1 in recruiting inflammatory cells to the lung after induction of injury with either lipopolysaccharide (LPS or cigarette smoke. Hamsters injected with either ET-1 or its precursor peptide (Big ET-1 prior to treatment with LPS or cigarette smoke had markedly increased concentrations of neutrophils in bronchoalveolar lavage fluid (BALF despite a reduction in total numbers of BALF leukocytes. Furthermore, the effect of ET-1 on smoke-exposed animals was reversed by addition of an endothelin-A receptor antagonist. These results are consistent with preferential recruitment of neutrophils by ET-1, and suggest that inhibition of this proinfl ammatory mediator may decrease acute pulmonary inflammation associated with cigarette smoke and other pulmonary toxins.Keywords: endothelin, lipopolysaccahride, cigarette smoke, neutrophils, lung

  14. Levels of plasma circulating cell free nuclear and mitochondrial DNA as potential biomarkers for breast tumors

    Directory of Open Access Journals (Sweden)

    Diesch Claude

    2009-11-01

    Full Text Available Abstract Background With the aim to simplify cancer management, cancer research lately dedicated itself more and more to discover and develop non-invasive biomarkers. In this connection, circulating cell-free DNA (ccf DNA seems to be a promising candidate. Altered levels of ccf nuclear DNA (nDNA and mitochondrial DNA (mtDNA have been found in several cancer types and might have a diagnostic value. Methods Using multiplex real-time PCR we investigated the levels of ccf nDNA and mtDNA in plasma samples from patients with malignant and benign breast tumors, and from healthy controls. To evaluate the applicability of plasma ccf nDNA and mtDNA as a biomarker for distinguishing between the three study-groups we performed ROC (Receiver Operating Characteristic curve analysis. We also compared the levels of both species in the cancer group with clinicopathological parameters. Results While the levels of ccf nDNA in the cancer group were significantly higher in comparison with the benign tumor group (P P P P = 0.022. The level of ccf nDNA was also associated with tumor-size (2 cmP = 0.034. Using ROC curve analysis, we were able to distinguish between the breast cancer cases and the healthy controls using ccf nDNA as marker (cut-off: 1866 GE/ml; sensitivity: 81%; specificity: 69%; P P Conclusion Our data suggests that nuclear and mitochondrial ccf DNA have potential as biomarkers in breast tumor management. However, ccf nDNA shows greater promise regarding sensitivity and specificity.

  15. INTRACELLULAR REDISTRIBUTION OF CARDIAC ENDOTHELIN-1 RECEPTOR IN RAT DURING MYOCARDIAL HYPERTROPHY

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. In a model of rat cardiac hypertrophy, the changes in the distribution of ET-1 receptors in two subcellular fractions, the sarcolemma and the light vesicles during myocardial hypertrophy were studied. Methods. Cardiac hypertrophy was produced by placing a constricting clip around the suprarenal abdominal aorta of rats, and ET-1 receptor was assayed with radioactive analysis method. Results. It was found that plasma and ventricular ET-1 levels increased significantly on week 2 and week 4 of pressure overload. ET-1 binding studies showed that during myocardial hypertrophy, the maximum binding capacity (Bmax) was increased by 41% (P<0.01) and 65% (P< 0.01) in sarcolemma in H-2 week and H-4 week groups, but was decreased by 24% (P< 0.01) and 21% (P< 0.01) in light vesicles. The sum of Bmax of sarcolemmal and light vesicle fractions was increased by 33% (P< 0.01) and 57% (P< 0.01) in group H-2 week and H-4 week, respectively. ? Conclusion. ET-1 receptors in rat heart were externalized from light vesicles to sarcolemma, which may contribute to the development of myocardial hypertrophy.

  16. INTRACELLULAR REDISTRIBUTION OF CARDIAC ENDOTHELIN-1 RECEPTOR IN RAT DURING MYOCARDIAL HYPERTROPHYA

    Institute of Scientific and Technical Information of China (English)

    王晓红; 齐永芬; 杨军; 佟利家; 庞永正; 唐朝枢

    2001-01-01

    Objective. In a model of rat cardiac hypertrophy, the changes in the distribution of ET-1 receptors in two subcellular fractions, the sarcolemma and the light vesicles during myocardial hypertrophy were studied. Methods. Cardiac hypertrophy was produced by placing a constricting clip around the suprarenal abdominalaorta of rats, and ET-1 receptor was assayed with radioactive analysis method. Results. It was found that plasma and ventricular ET-1 levels increased significantly on week 2 and week 4 ofpressure overload. ET-1 binding studies showed that during myocardial hypertrophy, the maximum binding capaci-ty (Bmax) was increased by 41% ( P < 0. 01) and 65% ( P < 0. 01) in sarcolemma in H-2 week and H-4 weekgroups, but was decreased by 24% (P <0.01) and 21% (P <0.01) in light vesicles. The sum of Bmax ofsarcolemmal and light vesicle fractions was increased by 33% ( P < 0. 01 ) and 57% ( P < 0.01 ) in group H-2 week and H-4 week, respectively. Conclusion. ET-1 receptors in rat heart were externalized from light vesicles to sarcolemma, which may contribute to the development of myocardial hypertrophy.

  17. Cerebrovascular endothelin-1 hyper-reactivity is associated with transient receptor potential canonical channels 1 and 6 activation and delayed cerebral hypoperfusion after forebrain ischaemia in rats

    DEFF Research Database (Denmark)

    Johansson, S E; Andersen, X E D R; Hansen, R H;

    2015-01-01

    AIM: In this study, we aimed to investigate whether changes in cerebrovascular voltage-dependent calcium channels and non-selective cation channels contribute to the enhanced endothelin-1-mediated vasoconstriction in the delayed hypoperfusion phase after experimental transient forebrain ischaemia....... METHODS: Experimental forebrain ischaemia was induced in Wistar male rats by a two-vessel occlusion model, and the cerebral blood flow was measured by magnetic resonance imaging two days after reperfusion. In vitro vasoreactivity studies, immunofluorescence and quantitative PCR were performed on cerebral...... arteries from ischaemic or sham-operated rats to evaluate changes in vascular voltage-dependent calcium channels, transient receptor potential canonical channels as well as endothelin-1 receptor function and expression. RESULTS: The expression of transient receptor potential canonical channels 1 and 6...

  18. EFFECTS OF NOVEL PHOSPHODIESTERASE 4 INHIBITORS,ARIFLO AND SB242126A, ON ENDOTHELIN-1-INDUCED CONTRACTILITY OF ISOLATED HUMAN MYOMETRIUM

    Institute of Scientific and Technical Information of China (English)

    QI Hong(祁红); ZHANG Yong(张勇); CHEN Hong-zhuan(陈红专); Marie Jo LEROY; Charles ADVENIER

    2005-01-01

    Objective To investigate the effects of novel selective phosphodiesterase4 ( PDE4) inhibitors,Ariflo and SB242126A, on the endothelin-1 ( ET-1 ) - induced contractility occurring in nonpregnant human myometrium specimens. Methods Contractile responses to Ariflo and SB242126A were recorded cumulatively on isolated human longitudinal myometrium specimens obtained through surgical operations. Results Ariflo and SB242126A could inhibit both the frequency and amplitude of spontaneous contractions of myometrium (pD2 =8.6and 7. 6,n =4) and ET-1-induced contractions in a concentration-dependent manner (pD2 =7. 7 and 8. 1 ,n =5),with a potency similar to that of Rolipram. Conclusion Ariflo and SB242126A have an obvious inhibitory effect on endothelin-1-induced contractility of isolated human myometrium. The finding suggested that PDE4 inhibitors might have clinical potential in treating preterm labour and dysmenorrhoea.

  19. Over, and Underexpression of Endothelin 1 and TGF-Beta Family Ligands and Receptors in Lung Tissue of Broilers with Pulmonary Hypertension

    Science.gov (United States)

    Dominguez-Avila, Norma; Ruiz-Castañeda, Gabriel; González-Ramírez, Javier; Fernandez-Jaramillo, Nora; Escoto, Jorge; Sánchez-Muñoz, Fausto; Marquez-Velasco, Ricardo; Bojalil, Rafael; Espinosa-Cervantes, Román; Sánchez, Fausto

    2013-01-01

    Transforming growth factor beta (TGFβ) is a family of genes that play a key role in mediating tissue remodeling in various forms of acute and chronic lung disease. In order to assess their role on pulmonary hypertension in broilers, we determined mRNA expression of genes of the TGFβ family and endothelin 1 in lung samples from 4-week-old chickens raised either under normal or cold temperature conditions. Both in control and cold-treated groups of broilers, endothelin 1 mRNA expression levels in lungs from ascitic chickens were higher than levels from healthy birds (P 0.05). BAMBI mRNA gene expression was lowest in birds with ascites only in the control group as compared with the values from healthy birds (P < 0.05). PMID:24286074

  20. Effect of varying doses of tamoxifen on ovarian histopathology, serum VEGF, and endothelin 1 levels in ovarian hyperstimulation syndrome: an experimental study.

    Science.gov (United States)

    Pala, Şehmus; Atilgan, Remzi; Ozkan, Zehra Sema; Kavak, Salih Burçin; Ilhan, Nevin; Akpolat, Nusret; Sapmaz, Ekrem

    2015-01-01

    To examine the effects of low-to-high doses of tamoxifen on ovarian histopathology, serum VEGF, and endothelin 1 levels in ovarian hyperstimulation syndrome (OHSS) in an experimental setting. A total of 20 female Wistar albino rats, 22 days of age, were randomly divided into four groups. Follicle-stimulating hormone 10 IU was administered subcutaneously in 15 rats on 4 consecutive days, with OHSS induction on day 5 by 30 IU of human chorionic gonadotropin. Group 1 (n=5) comprised 35-day-old control rats, group 2 (n=5) 35-day-old OHSS rats, group 3 (n=5) 27-day-old OHSS rats receiving 1 mg/kg of oral tamoxifen for 7 days, group 4 (n=5) 27-day-old OHSS rats receiving 3 mg/kg of oral tamoxifen for 7 days. All rats were decapitated on day 35. Serum VEGF, endothelin 1, and ovarian follicular reserve were assessed in all rats. Kruskal-Wallis variance analysis and the Mann-Whitney U-test were used for statistical comparisons. A Bonferroni correction was performed to control the inflation of significance, with a significance level set at a P-value of less than 0.025. Despite higher serum VEGF, endothelin 1, follicular reserve, and angiogenesis and fibrosis of the corpus luteum in the OHSS group compared to controls, these differences were not significant (P>0.025, Mann-Whitney U-test). There was a significant reduction in the ovarian follicular reserve in tamoxifen groups compared to controls (Ptamoxifen (Ptamoxifen group in comparison with rats in the high-dose tamoxifen group (P0.025, Mann-Whitney U-test). Tamoxifen 1 g and 3 g resulted in a dose-dependent increase in VEGF and endothelin 1 levels, and ovarian follicle reserves were significantly reduced in our experimental model.

  1. In-depth characterization of viral isolates from plasma and cells compared with plasma circulating quasispecies in early HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Judith Dalmau

    Full Text Available BACKGROUND: The use of in vitro models to unravel the phenotypic characteristics of circulating viral variants is key to understanding HIV-1 pathogenesis but limited by the availability of primary viral isolates from biological samples. However, overall in vivo genetic variability of HIV-1 within a subject may not be reflected in the viable viral population obtained after isolation. Although several studies have tried to determine whether viral populations expanded in vitro are representative of in vivo findings, the answer remains unclear due to the reduced number of clonal sequences analyzed or samples compared. In order to overcome previous experimental limitations, here we applied Deep Pyrosequencing (DPS technology in combination with phenotypic experiments to analyze and compare with unprecedented detail the composition of viral isolates and in vivo quasispecies. METHODOLOGY/PRINCIPAL FINDINGS: We amplified by DPS HIV-1 genomic regions covering gag, protease, integrase and env-V3 to characterize paired isolates from plasma and peripheral blood mononuclear cells and compare them with total plasma viral RNA in four recently HIV-1 infected subjects. Our study demonstrated the presence of unique haplotypes scattered between sample types with conservation of major variants. In addition, no differences in intra- and inter-population encoded protein variability were found between the different types of isolates or when these were compared to plasma viral RNA within subjects. Additionally, in vitro experiments demonstrated phenotypic similarities in terms of replicative capacity and co-receptor usage between viral isolates and plasma viral RNA. CONCLUSION: This study is the first in-depth comparison and characterization of viral isolates from different sources and plasma circulating quasispecies using DPS in recently HIV-1 infected subjects. Our data supports the use of primary isolates regardless of their plasma or cellular origin to define

  2. Association of left atrial endothelin-1 with atrial rhythm, size, and fibrosis in patients with structural heart disease.

    Science.gov (United States)

    Mayyas, Fadia; Niebauer, Mark; Zurick, Andrew; Barnard, John; Gillinov, A Marc; Chung, Mina K; Van Wagoner, David R

    2010-08-01

    Atrial fibrillation (AF) promotes atrial remodeling and can develop secondary to heart failure or mitral valve disease. Cardiac endothelin-1 (ET-1) expression responds to wall stress and can promote myocyte hypertrophy and interstitial fibrosis. We tested the hypothesis that atrial ET-1 is elevated in AF and is associated with AF persistence. Left atrial appendage tissue was studied from coronary artery bypass graft, valve repair, and/or Maze procedure in patients in sinus rhythm with no history of AF (SR, n=21), with history of AF but in SR at surgery (AF/SR, n=23), and in AF at surgery (AF/AF, n=32). The correlation of LA size with atrial protein and mRNA expression of ET-1 and ET-1 receptors (ETAR and ETBR) was evaluated. LA appendage ET-1 content was higher in AF/AF than in SR, but receptor levels were similar. Immunostaining revealed that ET-1 and its receptors were present both in atrial myocytes and in fibroblasts. ET-1 content was positively correlated with LA size, heart failure, AF persistence, and severity of mitral regurgitation. Multivariate analysis confirmed associations of ET-1 with AF, hypertension, and LA size. LA size was associated with ET-1 and MR severity. ET-1 mRNA levels were correlated with genes involved in cardiac dilatation, hypertrophy, and fibrosis. Elevated atrial ET-1 content is associated with increased LA size, AF rhythm, hypertension, and heart failure. ET-1 is associated with atrial dilatation, fibrosis, and hypertrophy and probably contributes to AF persistence. Interventions that reduce atrial ET-1 expression and/or block its receptors may slow AF progression.

  3. Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow: role of skeletal muscle NO synthase and endothelin-1.

    Science.gov (United States)

    Reynolds, Leryn J; Credeur, Daniel P; Manrique, Camila; Padilla, Jaume; Fadel, Paul J; Thyfault, John P

    2017-01-01

    Increased endothelin-1 (ET-1) and reduced endothelial nitric oxide phosphorylation (peNOS) are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), but studies examining these links in humans are limited. We sought to assess basal and insulin-stimulated endothelial signaling proteins (ET-1 and peNOS) in skeletal muscle from T2D patients. Ten obese T2D [glucose disposal rate (GDR): 6.6 ± 1.6 mg·kg lean body mass (LBM)(-1)·min(-1)] and 11 lean insulin-sensitive subjects (Lean GDR: 12.9 ± 1.2 mg·kg LBM(-1)·min(-1)) underwent a hyperinsulinemic-euglycemic clamp with vastus lateralis biopsies taken before and 60 min into the clamp. Basal biopsies were also taken in 11 medication-naïve, obese, non-T2D subjects. ET-1, peNOS (Ser1177), and eNOS protein and mRNA were measured from skeletal muscle samples containing native microvessels. Femoral artery blood flow was assessed by duplex Doppler ultrasound. Insulin-stimulated blood flow was reduced in obese T2D (Lean: +50.7 ± 6.5% baseline, T2D: +20.8 ± 5.2% baseline, P 0.05). Obese non-T2D subjects tended to also display elevated basal ET-1 (P = 0.06). In summary, higher basal skeletal muscle expression of ET-1 and reduced peNOS/eNOS may contribute to a reduced insulin-stimulated leg blood flow response in obese T2D patients.

  4. Endothelin-1 activation of ETB receptors leads to a reduced cellular proliferative rate and an increased cellular footprint

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Jamie L.; Taylor, Linda; Polgar, Peter, E-mail: peterp@bu.edu

    2012-06-10

    Endothelin-1 (ET-1) is a vasoactive peptide which signals through two G-protein coupled receptors, endothelin receptor A (ETA) and B (ETB). We determined that ET-1 activation of its ETB receptor in stably cDNA transfected CHO cells leads to a 55% reduction in cell number by end-point cell counting and a 35% decrease in cell growth by a real-time cell-substrate impedance-based assay after 24 h of cell growth. When CHO ETB cells were synchronized in the late G1 cell cycle phase, ET-1 delayed their S phase progression compared to control by 30% as determined by [{sup 3}H]-thymidine incorporation. On the other hand, no such delay was observed during late G2/M to G1 transit when cells were treated with ET-1 after release from mitotic arrest. Using the cell-substrate impedance-based assay, we observed that ET-1 induces opposing morphological changes in CHO ETA and CHO ETB cells with ETB causing an increase in the cell footprint and ETA a decrease. Likewise, in pulmonary artery smooth muscle cells, which express both ETA and ETB receptors, ET-1 induces an ETA-dependent contraction and an ETB dependent dilation. These results are shedding light on a possible beneficial role for ETB in diseases involving ET-1 dysfunction such as pulmonary hypertension. -- Highlights: Black-Right-Pointing-Pointer ET- hinders cell proliferation in CHO cells transfected with ETB. Black-Right-Pointing-Pointer ET-1 also decreases the rate of DNA synthesis in CHO ETB cells. Black-Right-Pointing-Pointer JNK and PI3K appear to be involved in this reduction of DNA synthesis. Black-Right-Pointing-Pointer ETB activation in CHO ETB cells and hSMCs leads to dilatory morphological changes. Black-Right-Pointing-Pointer In CHO ETA and hSMCs, ETA activation leads to constrictive morphological changes.

  5. Vascular endothelium derived endothelin-1 is required for normal heart function after chronic pressure overload in mice.

    Directory of Open Access Journals (Sweden)

    Susi Heiden

    Full Text Available BACKGROUND: Endothelin-1 participates in the pathophysiology of heart failure. The reasons for the lack of beneficial effect of endothelin antagonists in heart failure patients remain however speculative. The anti-apoptotic properties of ET-1 on cardiomyocytes could be a reasonable explanation. We therefore hypothesized that blocking the pro-apoptotic TNF-α pathway using pentoxifylline could prevent the deleterious effect of the lack of ET-1 in a model for heart failure. METHODS: We performed transaortic constriction (TAC in vascular endothelial cells specific ET-1 deficient (VEETKO and wild type (WT mice (n = 5-9 and treated them with pentoxifylline for twelve weeks. RESULTS: TAC induced a cardiac hypertrophy in VEETKO and WT mice but a reduction of fractional shortening could be detected by echocardiography in VEETKO mice only. Cardiomyocyte diameter was significantly increased by TAC in VEETKO mice only. Pentoxifylline treatment prevented cardiac hypertrophy and reduction of fractional shortening in VEETKO mice but decreased fractional shortening in WT mice. Collagen deposition and number of apoptotic cells remained stable between the groups as did TNF-α, caspase-3 and caspase-8 messenger RNA expression levels. TAC surgery enhanced ANP, BNP and bcl2 expression. Pentoxifylline treatment reduced expression levels of BNP, bcl2 and bax. CONCLUSIONS: Lack of endothelial ET-1 worsened the impact of TAC-induced pressure overload on cardiac function, indicating the crucial role of ET-1 for normal cardiac function under stress. Moreover, we put in light a TNF-α-independent beneficial effect of pentoxifylline in the VEETKO mice suggesting a therapeutic potential for pentoxifylline in a subpopulation of heart failure patients at higher risk.

  6. Big-endothelin 1 (big ET-1) and homocysteine in the serum of dogs with chronic kidney disease.

    Science.gov (United States)

    Rossi, Gabriele; Giordano, Alessia; Breda, Sara; Lisi, Chiara; Roura, Xavier; Zatelli, Andrea; Paltrinieri, Saverio

    2013-10-01

    This study was aimed at determining the serum concentration of homocysteine (Hcy) and big endothelin-1 (big ET-1, the precursor of endothelin) in dogs with chronic kidney disease (CKD) with and without hypertension, proteinuria and inflammation, in order to explore their role as biomarkers of hypertension associated with CKD. Hcy and big ET-1 were measured using an enzyme-linked immunosorbent assay and an enzymatic cyclic reaction, respectively, in dogs with CKD staged, as proposed by the International Renal Interest Society (IRIS), using serum creatinine, urinary protein to creatinine (UPC) ratio and systolic blood pressure, and classified as affected or not by inflammation based on the serum concentration of C-reactive protein (CRP). Serum Hcy was significantly higher in dogs of IRIS stages II, III and IV compared with controls and in proteinuric compared with non-proteinuric dogs. No differences relating to the degree of hypertension or to the CRP concentration were found. Serum big ET-1 significantly increased in dogs of IRIS stage IV compared with controls, in proteinuric compared with non-proteinuric dogs, in dogs with severe hypertension compared with those without hypertension, and in dogs with increased CRP compared to those with normal CRP concentrations. Hcy only correlated with serum creatinine but big ET-1 significantly correlated with serum creatinine, UPC ratio, systolic blood pressure, and increased CRP. In conclusion, both Hcy and big ET-1 increase in dogs with CKD. Although further research is needed, big ET-1, but not Hcy, may also be considered as a biomarker of hypertension.

  7. [The effect and mechanism of endothelin-1-induced intracellular free calcium in human lung adenocarcinoma cells SPC-A1.].

    Science.gov (United States)

    Zhou, Juan; Zhang, Weimin; Ye, Qianjun; Jia, Gang

    2008-08-20

    Endothelin-1 (ET-1) is a potent mitogen involved in cell growth in human lung adenocarcinoma cells SPC-A1. The increase in intracellular free calcium ([Ca(2+)]i) plays a great role in this process. The aim of this study is to investigate the ET-1-induced [Ca(2+)]i responses in SPC-A1 cells and to explore its cellular mechanism. [Ca(2+)]i was measured by Fura-2/AM fluorescent assay. Endothelin receptors antagonists, calcium channel blockers and intracellular signal transduction blockers were used to study the underlying mechanism of ET-1-induced [Ca(2+)]i responses in SPC-A1 cells. At the concentration of 1*10(-15) mol/L-1*10(-8) mol/L, ET-1 caused a dose-dependent increase of [Ca(2+)]i in SPC-A1 cells (P 0.05), a highly selective endothelin receptor B (ETBR) antagonist. Depletion of extracellular Ca(2+) with free Ca(2+) solution and 0.1mmol/L ethyleneglycol bis (2-aminoethyl ether) tetraacetic acid (EGTA) or blockade of voltage dependent calcium channel with nifedipine at 1*10(-6) mol/L significantly reduced the ET-1-induced increase of [Ca(2+)]i. The ET-1-induced (1*10(-10) mol/L) increase of [Ca(2+)]i was also significantly attenuated by U73122 at 1*10(-5) mol/L (P <0.05), a phospholipase C inhibitor, and by Ryanodine at 50*10(-6) mol/L. However, Staurosporine (2*10(-9) mol/L), a protein kinas C inhibitor, exerted no significant effect on the ET-1-induced (1*10(-10) mol/L) increase of [Ca(2+)]i. ET-1 elevates [Ca(2+)]i via activation of ETA receptor. Both phospholipase C/Ca(2+) pathway and Ca(2+) influx through voltage dependent Ca(2+) channel activate by ETAR contribute to this process.

  8. Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis.

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    Hanyin Cheng

    Full Text Available BACKGROUND: Colorectal cancer (CRC remains one of the major cancer types and cancer related death worldwide. Sensitive, non-invasive biomarkers that can facilitate disease detection, staging and prediction of therapeutic outcome are highly desirable to improve survival rate and help to determine optimized treatment for CRC. The small non-coding RNAs, microRNAs (miRNAs, have recently been identified as critical regulators for various diseases including cancer and may represent a novel class of cancer biomarkers. The purpose of this study was to identify and validate circulating microRNAs in human plasma for use as such biomarkers in colon cancer. METHODOLOGY/PRINCIPAL FINDINGS: By using quantitative reverse transcription-polymerase chain reaction, we found that circulating miR-141 was significantly associated with stage IV colon cancer in a cohort of 102 plasma samples. Receiver operating characteristic (ROC analysis was used to evaluate the sensitivity and specificity of candidate plasma microRNA markers. We observed that combination of miR-141 and carcinoembryonic antigen (CEA, a widely used marker for CRC, further improved the accuracy of detection. These findings were validated in an independent cohort of 156 plasma samples collected at Tianjin, China. Furthermore, our analysis showed that high levels of plasma miR-141 predicted poor survival in both cohorts and that miR-141 was an independent prognostic factor for advanced colon cancer. CONCLUSIONS/SIGNIFICANCE: We propose that plasma miR-141 may represent a novel biomarker that complements CEA in detecting colon cancer with distant metastasis and that high levels of miR-141 in plasma were associated with poor prognosis.

  9. Circulating Plasma MiR-141 Is a Novel Biomarker for Metastatic Colon Cancer and Predicts Poor Prognosis

    Science.gov (United States)

    Cogdell, David E.; Zheng, Hong; Schetter, Aaron J.; Nykter, Matti; Harris, Curtis C.; Chen, Kexin; Hamilton, Stanley R.; Zhang, Wei

    2011-01-01

    Background Colorectal cancer (CRC) remains one of the major cancer types and cancer related death worldwide. Sensitive, non-invasive biomarkers that can facilitate disease detection, staging and prediction of therapeutic outcome are highly desirable to improve survival rate and help to determine optimized treatment for CRC. The small non-coding RNAs, microRNAs (miRNAs), have recently been identified as critical regulators for various diseases including cancer and may represent a novel class of cancer biomarkers. The purpose of this study was to identify and validate circulating microRNAs in human plasma for use as such biomarkers in colon cancer. Methodology/Principal Findings By using quantitative reverse transcription-polymerase chain reaction, we found that circulating miR-141 was significantly associated with stage IV colon cancer in a cohort of 102 plasma samples. Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of candidate plasma microRNA markers. We observed that combination of miR-141 and carcinoembryonic antigen (CEA), a widely used marker for CRC, further improved the accuracy of detection. These findings were validated in an independent cohort of 156 plasma samples collected at Tianjin, China. Furthermore, our analysis showed that high levels of plasma miR-141 predicted poor survival in both cohorts and that miR-141 was an independent prognostic factor for advanced colon cancer. Conclusions/Significance We propose that plasma miR-141 may represent a novel biomarker that complements CEA in detecting colon cancer with distant metastasis and that high levels of miR-141 in plasma were associated with poor prognosis. PMID:21445232

  10. Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol.

    Science.gov (United States)

    Pare, Guillaume; Serre, David; Brisson, Diane; Anand, Sonia S; Montpetit, Alexandre; Tremblay, Gerald; Engert, James C; Hudson, Thomas J; Gaudet, Daniel

    2007-04-01

    Coronary artery disease (CAD) is a major health concern in both developed and developing countries. With a heritability estimated at ~50%, there is a strong rationale to better define the genetic contribution to CAD. This project involves the analysis of 884 individuals from 142 families (with average sibships of 5.7) as well as 558 case and control subjects from the Saguenay Lac St-Jean region of northeastern Quebec, with the use of 1,536 single-nucleotide polymorphisms (SNPs) in 103 candidate genes for CAD. By use of clusters of SNPs to generate multiallelic haplotypes at candidate loci for segregation studies within families, suggestive linkage for high-density lipoprotein (HDL) cholesterol is observed on chromosome 1p36.22. Furthermore, several associations that remain significant after Bonferroni correction are observed with lipoprotein-related traits as well as plasma concentrations of adiponectin. Of note, HDL cholesterol levels are associated with an amino acid substitution (lysine/asparagine) at codon 198 (rs5370) of endothelin-1 (EDN1) in a sex-specific manner, as well as with a SNP (rs2292318) located 7.7 kb upstream of lecithin cholesterol acyl-transferase (LCAT). Whereas the other observed associations are described in the current literature, these two are new. Using an independent validation sample of 806 individuals, we confirm the EDN1 association (P<.005), whereas the LCAT association was nonsignificant (P=.12).

  11. Endothelin-1-induced modulation of contractile responses elicited by an alpha 1-adrenergic agonist on human corpus cavernosum smooth muscle.

    Science.gov (United States)

    Kim, D C; Gondré, C M; Christ, G J

    1996-03-01

    The goal of these studies was to examine endothelin-1 (ET-1)-induced modulation of contractile responses elicited by the selective alpha 1-adrenergic agonist, phenylephrine (PE), on isolated human corporal tissue strips. Pharmacological studies were conducted on human corporal tissue strips obtained from 22 patients undergoing implantation of penile prostheses for erectile dysfunction. For the purposes of statistical analysis, the patients were stratified into two age groups: A, age or = 60 y (n = 12). The patients were further sub-divided into two diagnostic categories, diabetics (DM, n = 9) and nondiabetics (ND, n = 13). Cumulative concentration-response curves (CRCs) were constructed to the alpha 1-adrenergic agonist, PE, prior to constructing a CRC to a single mixture of PE and ET-1 on the same tissue. A previously described fixed molar ratio (FMR) protocol was used to generate CRCs to mixtures of PE and ET-1. In all cases, for the PE:ET-1 FMRs of 90:10, 80:20 and 70:30, the partial substitution of PE with ET-1 resulted in an approx 3-fold leftward shift in the EC50 of the PE alone CRC with an approx 4% concomitant increase in Emax and a decrease in the slope factor value. There were no significant age- or disease-related differences in any of the logistic parameter estimates that describe the FMR CRC, indicating that there are no detectable age- or disease-related alterations in ET-1-induced amplification of alpha 1-adrenergic-mediated contractions in these studies. In addition, the location of the FMR CRC was precisely predicted by the theoretical CRC for simple additivity of agonist effects. In conclusion, since relatively small increases in ET-1 concentrations were associated with significant increases in alpha 1-adrenergic-mediated contractile responses, these data provide further testimony to the importance of ET-1 in modulating corporal smooth muscle tone, and moreover, establish a conceptual framework for understanding the mechanism of its action(s).

  12. Pivotal role of mouse mast cell protease 4 in the conversion and pressor properties of Big-endothelin-1.

    Science.gov (United States)

    Houde, Martin; Jamain, Marc-David; Labonté, Julie; Desbiens, Louisane; Pejler, Gunnar; Gurish, Michael; Takai, Shinji; D'Orléans-Juste, Pedro

    2013-07-01

    The serine protease chymase has been reported to generate intracardiac angiotensin-II (Ang-II) from Ang-I as well as an intermediate precursor of endothelin-1 (ET-1), ET-1 (1-31) from Big-ET-1. Although humans possess only one chymase, several murine isoforms are documented, each with its own specific catalytic activity. Among these, mouse mast cell protease 4 (mMCP-4) is the isoform most similar to the human chymase for its activity. The aim of this study was to characterize the capacity of mMCP-4 to convert Big-ET-1 into its bioactive metabolite, ET-1, in vitro and in vivo in the mouse model. Basal mean arterial pressure did not differ between wild-type (WT) and mMCP-4(-/-) mice. Systemic administration of Big-ET-1 triggered pressor responses and increased blood levels of immunoreactive (IR) ET-1 (1-31) and ET-1 that were reduced by more than 50% in mMCP-4 knockout (-/-) mice compared with WT controls. Residual responses to Big-ET-1 in mMCP-4(-/-) mice were insensitive to the enkephalinase/neutral endopeptidase inhibitor thiorphan and the specific chymase inhibitor TY-51469 {2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl]thiazole-4-carboxylic acid}. Soluble fractions from the lungs, left cardiac ventricle, aorta, and kidneys of WT but not mMCP-4(-/-) mice generated ET-1 (1-31) from exogenous Big-ET-1 in a TY-51469-sensitive fashion as detected by high-performance liquid chromatography/ matrix-assisted laser desorption/ionization-mass spectrometry. Finally, pulmonary endogenous levels of IR-ET-1 were reduced by more than 40% in tissues derived from mMCP-4(-/-) mice compared with WT mice. Our results show that mMCP-4 plays a pivotal role in the dynamic conversion of systemic Big-ET-1 to ET-1 in the mouse model.

  13. Modulation by endothelin-1 of spontaneous activity and membrane currents of atrioventricular node myocytes from the rabbit heart.

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    Stéphanie C Choisy

    Full Text Available BACKGROUND: The atrioventricular node (AVN is a key component of the cardiac pacemaker-conduction system. Although it is known that receptors for the peptide hormone endothelin-1 (ET-1 are expressed in the AVN, there is very little information available on the modulatory effects of ET-1 on AVN electrophysiology. This study characterises for the first time acute modulatory effects of ET-1 on AVN cellular electrophysiology. METHODS: Electrophysiological experiments were conducted in which recordings were made from rabbit isolated AVN cells at 35-37°C using the whole-cell patch clamp recording technique. RESULTS: Application of ET-1 (10 nM to spontaneously active AVN cells led rapidly (within ~13 s to membrane potential hyperpolarisation and cessation of spontaneous action potentials (APs. This effect was prevented by pre-application of the ET(A receptor inhibitor BQ-123 (1 µM and was not mimicked by the ET(B receptor agonist IRL-1620 (300 nM. In whole-cell voltage-clamp experiments, ET-1 partially inhibited L-type calcium current (I(Ca,L and rapid delayed rectifier K(+ current (I(Kr, whilst it transiently activated the hyperpolarisation-activated current (I(f at voltages negative to the pacemaking range, and activated an inwardly rectifying current that was inhibited by both tertiapin-Q (300 nM and Ba(2+ ions (2 mM; each of these effects was sensitive to ET(A receptor inhibition. In cells exposed to tertiapin-Q, ET-1 application did not produce membrane potential hyperpolarisation or immediate cessation of spontaneous activity; instead, there was a progressive decline in AP amplitude and depolarisation of maximum diastolic potential. CONCLUSIONS: Acutely applied ET-1 exerts a direct modulatory effect on AVN cell electrophysiology. The dominant effect of ET-1 in this study was activation of a tertiapin-Q sensitive inwardly rectifying K(+ current via ET(A receptors, which led rapidly to cell quiescence.

  14. Endothelin-1 Induces Contraction of Female Rat Internal Pudendal and Clitoral Arteries through ETA Receptor and Rho-Kinase Activation

    Science.gov (United States)

    Allahdadi, Kyan J.; Hannan, Johanna L.; Tostes, Rita C.; Webb, R. Clinton

    2011-01-01

    Introduction Endothelin-1 (ET-1), a potent vasoconstrictor peptide, acts mainly through the Gprotein-coupled ETA receptor (ETAR). Increased vascular ET-1 production and constrictor sensitivity have been observed in various cardiovascular diseases, including hypertension, as well as erectile dysfunction. The internal pudendal artery (IPA) supplies blood to the vagina and clitoris. Inadequate blood flow through the IPA may lead to insufficient vaginal engorgement and clitoral tumescence. Aim Characterize the effects of ET-1 on the IPA and clitoral artery (CA). Methods IPA and CA from female Sprague Dawley rats (225–250 g) were mounted in myograph chambers. Arterial segments were submitted to increasing concentrations of ET-1 (10-10-10-6 M). Segments were incubated with the ETAR antagonist, atrasentan (10-8 M) or the Rho-kinase inhibitor, Y-27632 (10-6 M) 30 minutes prior to agonist exposure. All Emax values are expressed as % KCl-induced maximal contraction. ETAR, RhoA, and Rho-kinase expression from IPA was evaluated by Western blot. mRNA of preproET-1, ETAR, ETBR, RhoA, and Rho-kinase were measured by real time PCR. Main Outcome Measures ET-1 constrictor sensitivity in IPA and CA, protein expression and messenger RNA levels of ET-1-mediated constriction components. Results ET-1 concentration-dependently contracted IPA (% Contraction and pD2, respectively: 156 ± 18, 8.2 ± 0.1) and CA (163 ± 12, 8.8 ± 0.08), while ETAR antagonism reduced ET-1-mediated contraction (IPA: 104 ± 23, 6.4 ± 0.2; CA: 112 ± 17, 6.6 ± 0.08). Pretreatment with Y-27632 significantly shifted ET-1 pD2 in IPA (108 ± 24, 7.9 ± 0.1) and CA (147 ± 58 and 8.0 ± 0.25). Protein expression of ETAR, ETBR, RhoA, and Rho-kinase were detected in IPA. IPA and CA contained preproET-1, ETAR, ETBR, RhoA, and Rho-kinase message. Conclusion We observed that the IPA and CA are sensitive to ET-1, signaling through the ETAR and Rho-kinase pathway. These data indicate that ET-1 may play a role in vaginal

  15. HIF-1 and c-Src mediate increased glucose uptake induced by endothelin-1 and connexin43 in astrocytes.

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    José Carlos Valle-Casuso

    Full Text Available In previous work we showed that endothelin-1 (ET-1 increases the rate of glucose uptake in astrocytes, an important aspect of brain function since glucose taken up by astrocytes is used to supply the neurons with metabolic substrates. In the present work we sought to identify the signalling pathway responsible for this process in primary culture of rat astrocytes. Our results show that ET-1 promoted an increase in the transcription factor hypoxia-inducible factor-1α (HIF-1α in astrocytes, as shown in other cell types. Furthermore, HIF-1α-siRNA experiments revealed that HIF-1α participates in the effects of ET-1 on glucose uptake and on the expression of GLUT-1, GLUT-3, type I and type II hexokinase. We previously reported that these effects of ET-1 are mediated by connexin43 (Cx43, the major gap junction protein in astrocytes. Indeed, our results show that silencing Cx43 increased HIF-1α and reduced the effect of ET-1 on HIF-1α, indicating that the effect of ET-1 on HIF-1α is mediated by Cx43. The activity of oncogenes such as c-Src can up-regulate HIF-1α. Since Cx43 interacts with c-Src, we investigated the participation of c-Src in this pathway. Interestingly, both the treatment with ET-1 and with Cx43-siRNA increased c-Src activity. In addition, when c-Src activity was inhibited neither ET-1 nor silencing Cx43 were able to up-regulate HIF-1α. In conclusion, our results suggest that ET-1 by down-regulating Cx43 activates c-Src, which in turn increases HIF-1α leading to the up-regulation of the machinery required to take up glucose in astrocytes. Cx43 expression can be reduced in response not only to ET-1 but also to various physiological and pathological stimuli. This study contributes to the identification of the signalling pathway evoked after Cx43 down-regulation that results in increased glucose uptake in astrocytes. Interestingly, this is the first evidence linking Cx43 to HIF-1, which is a master regulator of glucose metabolism.

  16. Intracortical injection of endothelin-1 induces cortical infarcts in mice: effect of neuronal expression of an adenosine transporter

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    Soylu Hanifi

    2012-03-01

    Full Text Available Abstract Background Activation of adenosine A1 receptors has neuroprotective effects in animal stroke models. Adenosine levels are regulated by nucleoside transporters. In vitro studies showed that neuron-specific expression of human equilibrative nucleoside transporter 1 (hENT1 decreases extracellular adenosine levels and adenosine A1 receptor activity. In this study, we tested the effect of hENT1 expression on cortical infarct size following intracerebral injection of the vasoconstrictor endothelin-1 (ET-1 or saline. Methods Mice underwent stereotaxic intracortical injection of ET-1 (1 μl; 400 pmol or saline (1 μl. Some mice received the adenosine receptor antagonist caffeine (25 mg/kg, intraperitoneal 30 minutes prior to ET-1. Perfusion and T2-weighted magnetic resonance imaging (MRI were used to measure cerebral blood flow (CBF and subsequent infarct size, respectively. Results ET-1 reduced CBF at the injection site to 7.3 ± 1.3% (n = 12 in hENT1 transgenic (Tg and 12.5 ± 2.0% (n = 13 in wild type (Wt mice. At 48 hours following ET-1 injection, CBF was partially restored to 35.8 ± 4.5% in Tg and to 45.2 ± 6.3% in Wt mice; infarct sizes were significantly greater in Tg (9 ± 1.1 mm3 than Wt (5.4 ± 0.8 mm3 mice. Saline-treated Tg and Wt mice had modest decreases in CBF and infarcts were less than 1 mm3. For mice treated with caffeine, CBF values and infarct sizes were not significantly different between Tg and Wt mice. Conclusions ET-1 produced greater ischemic injury in hENT1 Tg than in Wt mice. This genotype difference was not observed in mice that had received caffeine. These data indicate that hENT1 Tg mice have reduced ischemia-evoked increases in adenosine receptor activity compared to Wt mice.

  17. Effects of endothelin- 1 on hepatic stellate cell proliferation, collagen synthesis and secretion, intracellular free calcium concentration

    Institute of Scientific and Technical Information of China (English)

    Chuan-Yong Guo; Jian-Ye Wu; Yun-Bin Wu; Min-Zhang Zhong; Han-Ming Lu

    2004-01-01

    AIM: To explore the effects of endothelin-1(ET-1) on hepatic stellate cells (HSCs) DNA uptake, DNA synthesis, collagen synthesis and secretion, inward whole-cell calcium concentration ([Ca2+]i) as well as the blocking effect of verapamil on ET-1-stimulated release of inward calcium (Ca2+) of HSC in vitro.METHODS: Rat hepatic stellate cells (HSCs) were isolated and cultivated. 3H-TdR and 3H-proline incorporation used for testing DNA uptake and synthesis, collagen synthesis and secretion of HSCs cultured in vitro; Fluorescent calciumindicator Fura-2/AM was used to measure [Ca2+]i inward HSCs.RESULTS: ET-1 at the concentration of 5×10-8 mol/L,caused significant increase both in HSC DNA synthesis(2 247±344 cpm, P<0.05) and DNA uptake (P<0.05) whencompared with the control group. ET-1 could also increase collagen synthesis (P<0.05 vs control group) and collagen secretion (P<0.05 vs control group). Besides, inward HSC [Ca2+]i reached a peak concentration (422±98 mol/L, P<0.001)at 2 min and then went down slowly to165±51 mol/L(P<0.01) at 25 min from resting state (39±4 mol/L)aftertreated with ET-1. Verapamil (5 mol/L) blocked ET-1activated [Ca2+]i inward HSCs compared with control group(P<0.05). Fura-2/AM loaded HSC was suspended in no Ca2+ buffer containing 1 mol/L EGTA, 5 min later, 10-8 mol/Lof ET-1 was added, [Ca2+]i inward HSCs rose from restingstate to peak 399±123 mol/L, then began to come downby the time of 20 min. It could also raise [Ca2+]i inwardHSCs even without Ca2+ in extracellular fluid, and had a remarkable dose-effect relationship(P<0.05). Meanwhile, verapamil could restrain the action of ET-1(P<0.05). CONCLUSION: Actions of ET-1 on collagen metabolism of HSCs may depend on the transportation of inward wholecell calcium.

  18. A zebrafish screen for craniofacial mutants identifies wdr68 as a highly conserved gene required for endothelin-1 expression

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    Amsterdam Adam

    2006-06-01

    Full Text Available Abstract Background Craniofacial birth defects result from defects in cranial neural crest (NC patterning and morphogenesis. The vertebrate craniofacial skeleton is derived from cranial NC cells and the patterning of these cells occurs within the pharyngeal arches. Substantial efforts have led to the identification of several genes required for craniofacial skeletal development such as the endothelin-1 (edn1 signaling pathway that is required for lower jaw formation. However, many essential genes required for craniofacial development remain to be identified. Results Through screening a collection of insertional zebrafish mutants containing approximately 25% of the genes essential for embryonic development, we present the identification of 15 essential genes that are required for craniofacial development. We identified 3 genes required for hyomandibular development. We also identified zebrafish models for Campomelic Dysplasia and Ehlers-Danlos syndrome. To further demonstrate the utility of this method, we include a characterization of the wdr68 gene. We show that wdr68 acts upstream of the edn1 pathway and is also required for formation of the upper jaw equivalent, the palatoquadrate. We also present evidence that the level of wdr68 activity required for edn1 pathway function differs between the 1st and 2nd arches. Wdr68 interacts with two minibrain-related kinases, Dyrk1a and Dyrk1b, required for embryonic growth and myotube differentiation, respectively. We show that a GFP-Wdr68 fusion protein localizes to the nucleus with Dyrk1a in contrast to an engineered loss of function mutation Wdr68-T284F that no longer accumulated in the cell nucleus and failed to rescue wdr68 mutant animals. Wdr68 homologs appear to exist in all eukaryotic genomes. Notably, we found that the Drosophila wdr68 homolog CG14614 could substitute for the vertebrate wdr68 gene even though insects lack the NC cell lineage. Conclusion This work represents a systematic

  19. Long-lasting physiological antagonism of calcitonin gene-related peptide towards endothelin-1 in rat mesenteric arteries and human coronary arteries

    DEFF Research Database (Denmark)

    Labruijere, Sieneke; Compeer, Matthijs G; van den Bogaerdt, Antoon J;

    2013-01-01

    Endothelin-1 causes long-lasting contraction via endothelin type A receptor (ETAR) in isolated rat mesenteric arteries (RMA) that cannot be readily terminated by removing the agonist, or by adding the ETAR antagonist BQ123 or the NO donor sodium nitroprusside. It could be terminated by adding cal......-lasting non-selective arterial smooth muscle relaxation that may add to the neuropeptide being a physiological antagonist of arterial effects of ET-1. Long-lasting, washout-resistant ET-1/ETAR interaction does not occur in HCMAs....

  20. Amino acids protects against renal ischemia-reperfusion injury and attenuates renal endothelin-1 disorder in rats

    Institute of Scientific and Technical Information of China (English)

    谢立平; 郑祥毅; 秦杰; 童炎岳

    2004-01-01

    Objective: To investigate nephroprotective effects of a mixture of 8 L-amino acids on renal ischemia-reperfusion injury and its effects on renal endothelin-1 (ET-1). Methods: The mixture of 8 L-amino acids includes glycine, alanine, threonine, serine, valine, leucine, isoleucine and proline. Acute ischemic renal injury was induced by clamping renal pedicle for 45 minutes in rats. Sixty male Sprague-Dawiey rats were randomly divided into 3 groups: a sham-operated group ( Group A, n = 8), a control group (Group B, n = 26 ) and an amino acid- treated group (Group C, n = 26 ). Amino acids were infused at a rate of 1 mi · 100g-1 · h-1 I hour before ischemia and during 3 hours of the whole reperfusion. The serum creatinine values, BUN levels, creatiulne clearance, urine sodium & potassium excretion, urine lactate dehydrogenase (LDH),the rate of urine flow and histological examination were measured. Renal ET-1 levels were assayed with radioimmunological assay (RIA) Results: The creatinine clearance was 471.0 μl/min ± 121.5 pi/main in Group C and 227.0 μl/min ± 27.0 μl/min in Group B 3 hours after reperfnsion, P < 0.01 ). The urine flow rate was 63.6 pi/min ± 15.2 μl/min in Group C and 24.3 μl/min ± 7.7 μl/minin Group B, P < 0.01 ) 1.5 hours after reperfusion. The serum creatinine was 85.0 μl/min ± 7.7 μmol/L and BUN oncentration11.4 mmol/L ±3.9 mmol/L in Group C and 112.7 μmol/L ± 19.5 μmol/L and 20.7 mmol/L ± 6.6 mmol/L respectively in Group B after 24 hours of reperfusion (P < 0.05) . The mean histological score by standards of Paller in kidneys was 108.7 ± 15.7 in Group C, and 168.8 ± 14.8 in Group B (P < 0.01 ). The renal ET-1 levels 15 minute and 3 hours after reperfusion were 7.2 pg/mg ± 0.8 pg/mg and 9.6 pg/ml ± 1.0 pg/ml in Group C , and 10.1 pg/ml ± 2.8 pg/ml and 13.0 pg/ml ± 2.7 pg/mi in Group B ( P < 0.01). Conclusions: The mixture of 8 L-amino acids can provide remarkable protection against renal isehemia- reperfusion injury

  1. Differential modulation of bradykinin-induced relaxation of endothelin-1 and phenylephrine contractions of rat aorta by antioxidants

    Institute of Scientific and Technical Information of China (English)

    Ogechukwu ANOZIE; Richonda ROSS; Adebayo O OYEKAN; Momoh A YAKUBU

    2007-01-01

    Aim: We tested the hypothesis that bradykinin (BK)-induced relaxation of phenylephrine (PE) and endothelin-1 (ET-1) contractions can be differentially modulated by reactive oxygen species (ROS). Methods: Aortic rings isolated from Sprague-Dawley rats were used for the study. The contribution of ROS to PE(1×10-9-1×10-5 mol/L)- and ET-1 (1×10-10-1×10-8 mol/L)-induced contractions and the influence of ROS in B K (1×10-9-1×10mol/L) relaxation of PE (1×10-7 mol/L) or ET-1 (1×10-9 mol/L)-induced tension was evaluated in the aorta in the presence or absence of the following antioxidants: catalase (CAT, 300 U/mL), superoxide dismutase (SOD, 300 U/mL), and vitamin C (1×10-4 mol/L). Results: Tension generated by ET-1 (1 × 10-9 mol/L) or PE (1 × 10-7 mol/L) was differentially relaxed by BK(1 × 10-5 mol/L), producing a maximal relaxation of 75 %±5 % and 35±4%, respectively.The BK (1×10-5 mol/L)-induced relaxation of PE (1×10-7 mol/L) tension was signifi-cantly enhanced from 35%±4% (control) to 56%±9%, 60%±5%, and 49%±6% by SOD, CAT, and vitamin C, respectively (P<0.05, n=8). However, the relaxation of ET-1 (1×10-9 mol/L) tension was significantly attenuated from 75%±5% (control)to 37%±9%, 63%±4%, and 39%±7% by SOD, CAT, and vitamin C, respectively(P<0.05, n=8). On the other hand, CAT had no effect on PE-induced tension, while SOD enhanced PE-induced tension (36%,P<0.05, n=10) and vitamin C attenuated(66%, P<0.05, n=8) the tension induced by PE. By contrast, SOD or vitamin C had no effect, but CAT attenuated (44%, P<0.05, n=9) the tension induced by ET-1.Conclusion: We have demonstrated that O2- and H2O2 differentially modulate BK relaxation in an agonist-specific manner. O2- attenuates BK-induced relaxation of PE contraction, but contributes to the relaxation of ET-1 contraction. O2- seems to inhibit PE contraction, while H2O2 contributes to ET-1-induced contraction. Thus,ROS differentially modulate vascular tone depending on the vasoactive agent that

  2. Isolation of Circulating Plasma Cells in Multiple Myeloma Using CD138 Antibody-Based Capture in a Microfluidic Device

    Science.gov (United States)

    Qasaimeh, Mohammad A.; Wu, Yichao C.; Bose, Suman; Menachery, Anoop; Talluri, Srikanth; Gonzalez, Gabriel; Fulciniti, Mariateresa; Karp, Jeffrey M.; Prabhala, Rao H.; Karnik, Rohit

    2017-04-01

    The necessity for bone marrow aspiration and the lack of highly sensitive assays to detect residual disease present challenges for effective management of multiple myeloma (MM), a plasma cell cancer. We show that a microfluidic cell capture based on CD138 antigen, which is highly expressed on plasma cells, permits quantitation of rare circulating plasma cells (CPCs) in blood and subsequent fluorescence-based assays. The microfluidic device is based on a herringbone channel design, and exhibits an estimated cell capture efficiency of ~40-70%, permitting detection of <10 CPCs/mL using 1-mL sample volumes, which is difficult using existing techniques. In bone marrow samples, the microfluidic-based plasma cell counts exhibited excellent correlation with flow cytometry analysis. In peripheral blood samples, the device detected a baseline of 2-5 CD138+ cells/mL in healthy donor blood, with significantly higher numbers in blood samples of MM patients in remission (20-24 CD138+ cells/mL), and yet higher numbers in MM patients exhibiting disease (45-184 CD138+ cells/mL). Analysis of CPCs isolated using the device was consistent with serum immunoglobulin assays that are commonly used in MM diagnostics. These results indicate the potential of CD138-based microfluidic CPC capture as a useful ‘liquid biopsy’ that may complement or partially replace bone marrow aspiration.

  3. Over, and Underexpression of Endothelin 1 and TGF-Beta Family Ligands and Receptors in Lung Tissue of Broilers with Pulmonary Hypertension

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    Norma Dominguez-Avila

    2013-01-01

    Full Text Available Transforming growth factor beta (TGFβ is a family of genes that play a key role in mediating tissue remodeling in various forms of acute and chronic lung disease. In order to assess their role on pulmonary hypertension in broilers, we determined mRNA expression of genes of the TGFβ family and endothelin 1 in lung samples from 4-week-old chickens raised either under normal or cold temperature conditions. Both in control and cold-treated groups of broilers, endothelin 1 mRNA expression levels in lungs from ascitic chickens were higher than levels from healthy birds (, whereas levels in animals with cardiac failure were intermediate. Conversely, TGFβ2 and TGFβ3 gene expression in lungs were higher in healthy animals than in ascitic animals in both groups (. TGFβ1, TβRI, and TβRII mRNA gene expression among healthy, ascitic, and chickens with cardiac failure showed no differences (. BAMBI mRNA gene expression was lowest in birds with ascites only in the control group as compared with the values from healthy birds (.

  4. Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension

    Science.gov (United States)

    Steven, Sebastian; Oelze, Matthias; Brandt, Moritz; Ullmann, Elisabeth; Kröller-Schön, Swenja; Heeren, Tjebo; Tran, Lan P.; Daub, Steffen; Dib, Mobin; Stalleicken, Dirk; Wenzel, Philip; Münzel, Thomas

    2017-01-01

    Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined. Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d) and reduced by oral PETN (10 mg/kg, 24 d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved endothelium-dependent relaxation in pulmonary arteries and inhibited endothelin-1-induced oxidative burst in whole blood and the expression of adhesion molecule (ICAM-1) in endothelial cells. Conclusion. MCT-induced PAH impairs endothelial function (aorta and pulmonary arteries) and increases oxidative stress whereas PETN markedly attenuates these adverse effects. Thus, PETN therapy improves pulmonary hypertension beyond its known cardiac preload reducing ability.

  5. Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension

    Directory of Open Access Journals (Sweden)

    Sebastian Steven

    2017-01-01

    Full Text Available Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH. The role of the nitrovasodilator pentaerythritol tetranitrate (PETN on endothelial function and oxidative stress in PAH has not yet been defined. Methods and Results. PAH was induced by monocrotaline (MCT, i.v. in Wistar rats. Low (30 mg/kg; MCT30, middle (40 mg/kg; MCT40, or high (60 mg/kg; MCT60 dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d and reduced by oral PETN (10 mg/kg, 24 d therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1. PETN therapy improved endothelium-dependent relaxation in pulmonary arteries and inhibited endothelin-1-induced oxidative burst in whole blood and the expression of adhesion molecule (ICAM-1 in endothelial cells. Conclusion. MCT-induced PAH impairs endothelial function (aorta and pulmonary arteries and increases oxidative stress whereas PETN markedly attenuates these adverse effects. Thus, PETN therapy improves pulmonary hypertension beyond its known cardiac preload reducing ability.

  6. Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension.

    Science.gov (United States)

    Steven, Sebastian; Oelze, Matthias; Brandt, Moritz; Ullmann, Elisabeth; Kröller-Schön, Swenja; Heeren, Tjebo; Tran, Lan P; Daub, Steffen; Dib, Mobin; Stalleicken, Dirk; Wenzel, Philip; Münzel, Thomas; Daiber, Andreas

    2017-01-01

    Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined. Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d) and reduced by oral PETN (10 mg/kg, 24 d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved endothelium-dependent relaxation in pulmonary arteries and inhibited endothelin-1-induced oxidative burst in whole blood and the expression of adhesion molecule (ICAM-1) in endothelial cells. Conclusion. MCT-induced PAH impairs endothelial function (aorta and pulmonary arteries) and increases oxidative stress whereas PETN markedly attenuates these adverse effects. Thus, PETN therapy improves pulmonary hypertension beyond its known cardiac preload reducing ability.

  7. Effect of varying doses of tamoxifen on ovarian histopathology, serum VEGF, and endothelin 1 levels in ovarian hyperstimulation syndrome: an experimental study

    Directory of Open Access Journals (Sweden)

    Pala S

    2015-03-01

    Full Text Available Sehmus Pala,1 Remzi Atilgan,1 Zehra Sema Ozkan,1 Salih Burçin Kavak,1 Nevin Ilhan,2 Nusret Akpolat,3 Ekrem Sapmaz1 1Department of Obstetrics and Gynecology, 2Department of Biochemistry, 3Department of Pathology, Firat University School of Medicine, Elazig, Turkey Objective: To examine the effects of low-to-high doses of tamoxifen on ovarian histopathology, serum VEGF, and endothelin 1 levels in ovarian hyperstimulation syndrome (OHSS in an experimental setting.Materials and methods: A total of 20 female Wistar albino rats, 22 days of age, were randomly divided into four groups. Follicle-stimulating hormone 10 IU was administered subcutaneously in 15 rats on 4 consecutive days, with OHSS induction on day 5 by 30 IU of human chorionic gonadotropin. Group 1 (n=5 comprised 35-day-old control rats, group 2 (n=5 35-day-old OHSS rats, group 3 (n=5 27-day-old OHSS rats receiving 1 mg/kg of oral tamoxifen for 7 days, group 4 (n=5 27-day-old OHSS rats receiving 3 mg/kg of oral tamoxifen for 7 days. All rats were decapitated on day 35. Serum VEGF, endothelin 1, and ovarian follicular reserve were assessed in all rats. Kruskal–Wallis variance analysis and the Mann–Whitney U-test were used for statistical comparisons. A Bonferroni correction was performed to control the inflation of significance, with a significance level set at a P-value of less than 0.025.Results: Despite higher serum VEGF, endothelin 1, follicular reserve, and angiogenesis and fibrosis of the corpus luteum in the OHSS group compared to controls, these differences were not significant (P>0.025, Mann–Whitney U-test. There was a significant reduction in the ovarian follicular reserve in tamoxifen groups compared to controls (P<0.025, Mann–Whitney U-test, while angiogenesis of the corpus luteum, number of atretic follicles, fibrosis, and serum VEGF were significantly higher in rats receiving tamoxifen (P<0.025, Mann–Whitney U-test. Also, significantly lower follicular reserve and

  8. Circulating FGF23 levels in response to acute changes in plasma Ca(2+).

    Science.gov (United States)

    Gravesen, Eva; Mace, Maria L; Hofman-Bang, Jacob; Olgaard, Klaus; Lewin, Ewa

    2014-07-01

    The regulation of fibroblast growth factor 23 (FGF23) synthesis and secretion is still incompletely understood. FGF23 is an important regulator of renal phosphate excretion and has regulatory effects on the calciotropic hormones calcitriol and parathyroid hormone (PTH). Calcium (Ca) and phosphate homeostasis are closely interrelated, and it is therefore likely that Ca is involved in FGF23 regulation. It has recently been reported that dietary Ca influenced FGF23 levels, with high Ca increasing FGF23. The mechanism remains to be clarified. It remains unknown whether acute changes in plasma Ca influence FGF23 levels and whether a close relationship, similar that known for Ca and PTH, exists between Ca and FGF23. Thus, the aim of the present study was to examine whether acute hypercalcemia and hypocalcemia regulate FGF23 levels in the rat. Acute hypercalcemia was induced by an intravenous Ca infusion and hypocalcemia by infusion of ethylene glycol tetraacetic acid (EGTA) in normal and acutely parathyroidectomized rats. Intact plasma FGF23 and intact plasma PTH and plasma Ca(2+) and phosphate were measured. Acute hypercalcemia and hypocalcemia resulted as expected in adequate PTH secretory responses. Plasma FGF23 levels remained stable at all plasma Ca(2+) levels; acute parathyroidectomy did not affect FGF23 secretion. In conclusion, Ca is not a regulator of acute changes in FGF23 secretion.

  9. Effects of lactation upon circulating plasma metabolites in cafeteria-fed rats

    OpenAIRE

    Salvadó, J.; Segués Piqué, Teresa; Alemany, Marià; Arola i Ferrer, Lluís

    1986-01-01

    1. The effects of "cafeteria feeding" on primiparous Wistar rats during lactation have been studied by measuring circulating levels of glucose, amino acids, lactate, urea and ammonia as well as glycogen levels in liver and muscle. 2. No significant changes in glucose levels were observed despite alterations in blood glucose compartmentation. 3. Compared with controls, the dams given the cafeteria diet had higher liver glycogen stores which were more easily mobilized at the peak of lactation. ...

  10. The Concentrations of Circulating Plasma Oxytocin and the Pattern of Oxytocin Release in Mare during Oestrus and after Ovulation

    Science.gov (United States)

    Bae, Sung Eun

    Mares susceptible to persistent mating-induced endometritis (PMIE) accumulate intrauterine fluid after mating. One of the factors causing delayed uterine clearance is thought to be impaired uterine contractility. Oxytocin is central in controlling myometrial contractility. The objective of the present study was to describe peripheral oxytocin release during estrus and in the early postovulatory period in reproductively-normal mares and to compare the baseline circulating oxytocin concentrations in reproductively-normal mares and mares with PMIE. Blood samples were collected from reproductively-normal mares (n=5) from day -5 of estrus to day 2 postovulation and every 5 min for 30 min from reproductively-normal mares (n=5) and mares with PMIE (n=5) on day 3 of estrus. Pulsatile secretion of oxytocin was observed in all mares. Mean plasma oxytocin concentrations were significantly higher (Poxytocin concentrations tended to increase. On day 3 of estrus, plasma oxytocin concentrations were significantly higher (Poxytocin concentrations between mares to PMIE. The low plasma oxytocin concentrations in mares with PMIE may contribute to predisposing factors in their poor uterine clearance in these mares.

  11. Kinetics of Circulating Plasma Cell-Free DNA in Paediatric Classical Hodgkin Lymphoma

    Science.gov (United States)

    Primerano, Simona; Burnelli, Roberta; Carraro, Elisa; Pillon, Marta; Elia, Caterina; Farruggia, Piero; Sala, Alessandra; Vinti, Luciana; Buffardi, Salvatore; Basso, Giuseppe; Mascarin, Maurizio; Mussolin, Lara

    2016-01-01

    Levels of plasma cell-free DNA (cfDNA) of a large series of children with classical Hodgkin lymphoma (cHL) were evaluated and analyzed at diagnosis and during chemotherapy treatment in relation with clinical characteristics. CfDNA levels in cHL patients were significantly higher compared with controls (p=0.002). CfDNA at diagnosis was correlated with presence of B symptoms (p=0.027) and high erythrocyte sedimentation rate (p=0.049). We found that the increasing of plasma cfDNA after first chemotherapy cycle seems to be associated with a worse prognosis (p=0.049). Levels of plasma cfDNA might constitute an interesting non-invasive tool in cHL patients' management. PMID:26918050

  12. Impairment of endothelial and subendothelial sites by a circulating plasma factor associated with minimal change disease

    NARCIS (Netherlands)

    Cheung, PK; Baller, JFW; Bakker, WW

    1996-01-01

    Background. The pathogenesis of albuminuria in minimal change disease (MCD) is unknown. A human plasma factor (denoted as 100KF) is able to induce minimal change-like glomerular alterations, i.e. loss of glomerular sialoglycoproteins and decreased expression of glomerular ecto-ATPase, following in v

  13. Impairment of endothelial and subendothelial sites by a circulating plasma factor associated with minimal change disease

    NARCIS (Netherlands)

    Cheung, PK; Baller, JFW; Bakker, WW

    1996-01-01

    Background. The pathogenesis of albuminuria in minimal change disease (MCD) is unknown. A human plasma factor (denoted as 100KF) is able to induce minimal change-like glomerular alterations, i.e. loss of glomerular sialoglycoproteins and decreased expression of glomerular ecto-ATPase, following in

  14. Impairment of endothelial and subendothelial sites by a circulating plasma factor associated with minimal change disease

    NARCIS (Netherlands)

    Cheung, PK; Baller, JFW; Bakker, WW

    1996-01-01

    Background. The pathogenesis of albuminuria in minimal change disease (MCD) is unknown. A human plasma factor (denoted as 100KF) is able to induce minimal change-like glomerular alterations, i.e. loss of glomerular sialoglycoproteins and decreased expression of glomerular ecto-ATPase, following in v

  15. Plasma in Saturn's nightside magnetosphere and the implications for global circulation

    Energy Technology Data Exchange (ETDEWEB)

    Mcandrews, Hazel J [Los Alamos National Laboratory; Wilson, R J [Los Alamos National Laboratory; Henderson, M G [Los Alamos National Laboratory; Tokar, R L [Los Alamos National Laboratory; Jackman, C M [IMPERIAL COLLEGE; Khurana, K K [UNIV OF CAL; Sittler, E C [NASA/GSFC; Coates, A J [MSSL; Dougherty, M K [IMPERIAL COLLEGE

    2009-01-01

    We present a bulk ion flow map from the nightside equatorial region of Saturn's magnetosphere derived from the Cassini CAPS ion mass spectrometer data. The map clearly demonstrates the dominance of corotation flow over radial flow and suggests that the flux tubes sampled are still closed and attached to the planet up to distances of 50 R{sub s}. The plasma characteristics in the near-midnight region are described and indicate a transition between the region of the magnetosphere containing plasma on closed drift paths and that containing flux tubes which may not complete a full rotation around the planet. Data from the electron spectrometer reveal two plasma states of high and low density. These are attributed either to the sampling of mass-loaded and depleted flux tubes, respectively, or to the latitudinal structure of the plasma sheet Depleted, returning flux tubes are not, in general, directly observed in the ions, although the electron observations suggest that such a process must take place in order to produce the low density population. Flux tube content is conserved below a limIt defined by the mass-loading and magnetic field strength and indicates that the flux tubes sampled may survive their passage through the tail. The conditions for mass release are evaluated using measured densities, angular velocities and magnetic field strength, The results suggest that for the relatively dense ion populations detectable by IMS, the condition for flux-tube breakage has not yet been exceeded, However, the low-density regimes observed in the electron data suggest that loaded flux tubes at greater distances do exceed the threshold for mass loss and subsequently return to the inner magnetosphere significantly depleted of plasma.

  16. Plasma in Saturn's nightside magnetosphere and the implications for global circulation

    Energy Technology Data Exchange (ETDEWEB)

    Mcandrews, Hazel J [Los Alamos National Laboratory; Thomsen, Michelle F [Los Alamos National Laboratory; Wilson, Robert J [Los Alamos National Laboratory; Henderson, Michael G [Los Alamos National Laboratory; Tokar, Robert L [Los Alamos National Laboratory; Arridge, Chris S [MSSL/UCL; Jackman, Caitriona M [IMPERIAL COLLEGE; Khurana, Krishan K [UCLA; Sittler, Edward C [GSFC; Coates, Andrew J [MSSL; Dougherty, Michele K [IMPERIAL COLLEGE

    2008-01-01

    We present a bulk ion flow map from the nightside, equatorial region of Saturn's magnetosphere derived from the Cassini CAPS ion mass spectrometer data. The map clearly demonstrates the dominance of corotation flow over radial flow and suggests that the flux tubes sampled are still closed and attached to the planet up to distances of 50 RS. The plasma characteristics in the near-midnight region are described and indicate a transition between the region of the magnetosphere containing plasma on closed drift paths and that containing flux tubes which may not complete a full rotation around the planet. Data from the electron spectrometer reveal two plasma states of high and low density. These are attributed either to the sampling of mass-loaded and depleted flux tubes, respectively, or to the latitudinal structure of the plasma sheet. Depleted, returning flux tubes are not, in general, directly observed in the ions, although the electron observations suggest that such a process must take place in order to produce the low density population. An example of such a low-density interval containing hot electrons with a dipolarised, swept-forward field configuration is described and strongly suggests that reconnection must have occurred planetward of Cassini. Flux tube content is conserved below a limit defined by the mass-loading and magnetic field strength and indicates that the flux tubes sampled may survive their passage through the tail. The conditions for mass release are evaluated using measured densities, angular velocities and magnetic field strength. The results suggest that for the relatively dense ion populations detectable by IMS, the condition for flux-tube breakage has not yet been exceeded. However, the low-density regimes observed in the electron data suggest that loaded flux tubes at greater distances do exceed the threshold for mass loss and subsequently return to the inner magnetosphere significantly depleted of plasma.

  17. Expression of Endothelial Nitric Oxide Synthase and Endothelin-1 in Skin Tissue from Amputated Limbs of Patients with Complex Regional Pain Syndrome

    Directory of Open Access Journals (Sweden)

    J. George Groeneweg

    2008-01-01

    Full Text Available Background and Objectives. Impaired microcirculation during the chronic stage of complex regional pain syndrome (CRPS is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Endothelial dysfunction is suggested to be the main cause of diminished blood flow. The aim of this study was to examine the distribution of endothelial nitric oxide synthase (eNOS and endothelin-1(ET-1 relative to vascular density represented by the endothelial marker CD31-immunoreactivity in the skin tissue of patients with chronic CRPS. Methods. We performed immunohistochemical staining on sections of skin specimens obtained from the amputated limbs (one arm and one leg of two patients with CRPS. Results. In comparison to proximal specimens we found an increased number of migrated endothelial cells as well as an increase of eNOS activity in distal dermis specimens. Conclusions. We found indications that endothelial dysfunction plays a role in chronic CRPS.

  18. Distributed computing and NMR constraint-based high-resolution structure determination: applied for bioactive Peptide endothelin-1 to determine C-terminal folding.

    Science.gov (United States)

    Takashima, Hiroyuki; Mimura, Norio; Ohkubo, Tadayasu; Yoshida, Takuya; Tamaoki, Haruhiko; Kobayashi, Yuji

    2004-04-14

    Distributed computing has been implemented to the solution structure determination of endothelin-1 to evaluate efficiency of the method for NMR constraint-based structure calculations. A key target of the investigation was determination of the C-terminal folding of the peptide, which had been dispersed in previous studies of NMR, despite its pharmacological significances. With use of tens of thousands of random initial structures to explore the conformational space comprehensively, we determined high-resolution structures with good convergences of C-terminal as well as previously defined N-terminal structures. The previous studies had missed the C-terminal convergence because of initial structure dependencies trapped in localized folding of the N-terminal region, which are strongly constricted by two disulfide bonds.

  19. Endothelin-1 shifts the mediator of bradykinin-induced relaxation from NO to H2 O2 in resistance arteries from patients with cardiovascular disease

    DEFF Research Database (Denmark)

    Leurgans, Thomas M; Bloksgaard, Maria; Brewer, Jonathan R

    2016-01-01

    compared to K(+) and U46619. BK-induced relaxation was i) abolished by N(ω) -nitro L-arginine methyl ester (L-NAME) in K(+) -contracted arteries, ii) partly inhibited by L-NAME in presence of U46619, iii) not altered by indomethacin, L-NAME plus inhibitors of small and intermediate conductance calcium-activated...... patients were studied by myography and imaging techniques. Segments were sub-maximally contracted by K(+) , the thromboxane A2 analogue U46619 or endothelin-1 (ET-1). KEY RESULTS: Relaxing effects of Na-nitroprusside were comparable but those of bradykinin (BK) were more potent in the presence of ET-1...... K(+) -channels, but markedly blunted by catalase during ET-1-induced contraction. This catalase-sensitive relaxation was not modified by inhibitors of NADPH oxidases or allopurinol. Exogenous H2 O2 caused significantly larger relaxation of ET-1- than K(+) - or U46619-induced contraction...

  20. Blockade of Endothelin-1 with a Novel Series of 1,3,6-Trisubstituted-2-Carboxy-Quinol-4-Ones Controls Infection-Associated Preterm Birth

    Science.gov (United States)

    Olgun, Nicole S.; Patel, Hardik J.; Stephani, Ralph; Lengyel, Istvan; Reznik, Sandra E.

    2010-01-01

    Preterm birth (PTB) currently accounts for 13% of all births in the United States, with the leading cause of PTB being maternal infection. Endothelin-1, an extremely potent vasoconstrictor capable of increasing myometrial smooth muscle tone, has been shown to be up-regulated in the setting of infection in pregnancy, ultimately leading to PTB. In previous work, we have shown that infection-associated PTB is controlled in our murine model by using phospharamidon, an endothelin-converting enzyme-1 inhibitor; knocking down endothelin-converting enzyme-1 mRNA; or blocking the binding of endothelin-1 to the endothelin-A (ETA) receptor with either BQ-123 or with HJP-272, the 6-OH compound of our series of novel synthetic (ETA) receptor antagonists. In the current study, we show that HJP-272, a highly selective ETA receptor antagonist with an IC50 of 70.1 nmol/L, binds in a noncompetitive manner to the ETA receptor. Additionally, we introduce n-propyl (HJP-286) and n-butyl (HJP-278) analogs of HJP-272. We find that the LD50 of HJP-272, the analog in the series most effective in controlling preterm birth, is more than 20-fold higher than its therapeutic dose. Acute exposure to high doses of these compounds produces no histological changes in any organ, while chronic exposure produces only a rare hepatotoxic effect. These findings may be of clinical significance, as there is currently no FDA-approved therapy for women presenting with threatened preterm delivery. PMID:20802183

  1. Circulating nucleic acids in plasma and serum: applications in diagnostic techniques for noninvasive prenatal diagnosis

    Directory of Open Access Journals (Sweden)

    Gahan PB

    2013-04-01

    Full Text Available Peter B Gahan Anatomy and Human Sciences Department, King's College London, London Bridge, London, UK Abstract: The analysis of fetal nucleic acids in maternal blood 13 years ago has led to the initiation of noninvasive methods for the early determination of fetal gender, rhesus D status, and a number of aneuploid disorders and hemoglobinopathies. Subsequently, a comparatively large quantity of fetal DNA and RNA has been demonstrated in amniotic fluid as well as small amounts in premature infant saliva. The DNA and RNA in amniotic fluid has permitted an analysis of core transcriptomes, whilst the DNA and RNA in saliva allows the early detection and treatment monitoring of fetal developmental problems. These aspects are discussed together with the methodology and limits of analysis for noninvasive prenatal diagnosis in predictive, preventive, and personalized medicine. Keywords: fetal circulating DNA/RNA, amniotic fluid, saliva, aneuploidy, thalassemias

  2. Prediagnostic circulating concentrations of plasma insulin-like growth factor-I and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition

    NARCIS (Netherlands)

    Perez-Cornago, Aurora; Appleby, Paul N.; Tipper, Sarah; Key, Timothy J.; Allen, Naomi E.; Nieters, Alexandra; Vermeulen, Roel; Roulland, Sandrine; Casabonne, Delphine; Kaaks, Rudolf; Fortner, Renee T.; Boeing, Heiner; Trichopoulou, Antonia; La Vecchia, Carlo; Klinaki, Eleni; Hansen, Louise; Tjønneland, Anne; Bonnet, Fabrice; Fagherazzi, Guy; Boutron-Ruault, Marie Christine; Pala, Valeria; Masala, Giovanna; Sacerdote, Carlotta; Peeters, Petra H.; Bueno-de-Mesquita, H. Bas; Weiderpass, Elisabete; Dorronsoro, Miren; Quirós, J. Ramón; Barricarte, Aurelio; Gavrila, Diana; Agudo, Antonio; Borgquist, Signe; Rosendahl, Ann H.; Melin, Beatrice; Wareham, Nick; Khaw, Kay Tee; Gunter, Marc; Riboli, Elio; Vineis, Paolo; Travis, Ruth C.

    2017-01-01

    Insulin-like growth factor (IGF)-I has cancer promoting activities. However, the hypothesis that circulating IGF-I concentration is related to risk of lymphoma overall or its subtypes has not been examined prospectively. IGF-I concentration was measured in pre-diagnostic plasma samples from a nested

  3. Astaxanthin and withaferin A block paracrine cytokine interactions between UVB-exposed human keratinocytes and human melanocytes via the attenuation of endothelin-1 secretion and its downstream intracellular signaling.

    Science.gov (United States)

    Niwano, Takao; Terazawa, Shuko; Nakajima, Hiroaki; Wakabayashi, Yuki; Imokawa, Genji

    2015-06-01

    Paracrine interactions between keratinocytes and melanocytes via cytokines play an essential role in regulating pigmentation in epidermal hyperpigmentary disorders. There is an urgent need for a human epidermal model in which melanogenic paracrine interactions between UVB-exposed keratinocytes and melanocytes can be precisely evaluated because human epidermal equivalents consisting of multilayered keratinocytes and melanocytes have significant limitations in this respect. To resolve this challenge, we established a co-culture system with cell inserts using human keratinocytes and human melanocytes that serves as an appropriate new model for UVB-induced hyperpigmentation. Using that new model, we examined the blocking effects of two natural chemicals, astaxanthin and withaferin A, on paracrine cytokine interactions between UVB-exposed keratinocytes and melanocytes and characterized their mechanisms of action. RT-PCR analysis showed that co-culture of human keratinocytes that had been exposed to UVB significantly stimulated human melanocytes to increase their expression of genes encoding microphthalmia-associated transcription factor, tyrosinase and tyrosinase-related protein 1. The catalytic activity of tyrosinase was also increased. ELISA assays revealed that UVB significantly increased the secretion of interleukin-1α, interleukin-6/8, granulocyte macrophage stimulatory factor and endothelin-1 but not α-melanocyte stimulating hormone. The addition of an endothelin-1 neutralizing antibody significantly abrogated the increase of tyrosinase activity. Post-irradiation treatment with astaxanthin or withaferin A significantly abolished the up-regulation of tyrosinase activity induced by UVB. Treatment with astaxanthin or withaferin A significantly reduced the increased levels of interleukin-1α, interleukin-6/8, granulocyte macrophage stimulatory factor and endothelin-1. Withaferin A but not astaxanthin also significantly abrogated the endothelin-1-stimulated activity

  4. DOES SINGLE INTRAMUSCULAR APPLICATION OF AUTOLOGOUS CONDITIONED PLASMA INFLUENCE SYSTEMIC CIRCULATING GROWTH FACTORS?

    Directory of Open Access Journals (Sweden)

    Gert Schippinger

    2012-09-01

    Full Text Available Platelet-rich plasma (PRP has been employed to treat sports injuries to possibly accelerate healing and regeneration. This method offers some potential, especially for athletes. Growth factors are generally prohibited by the World Anti Doping Agency with exception to PRP which may induce adverse effects. The aim of this study was to evaluate any systemic increase of growth factors such as Insulin Like Growth Factor-1, Endothelial Growth Factors, Platelet-Derived Growth Factors, Fibroblast Growth Factors, Vascular-Endothelial Growth Factor and Transforming Growth Factors after local intramuscular administration of PRP in young, healthy male subjects keeping in mind adverse treatment effects. Enriched plasma from centrifuged blood samples was injected into the gluteus muscle. Venous blood was collected and serum prepared before as well as 0.5, 3 and 24 hours after PRP administration. Growth factors were analyzed using ELISA test kits. No significant systemic increase of growth factor levels was found after PRP injection except TGF-ß2. For that reason the PRP method may be applied for muscle injury treatment in elite athletes although further studies are necessary to clarify the response to the unspecific increased TGF-ß2 blood levels, which could increase the risk for local fibrosis

  5. INFLUENCE OF INTRAMUSCULAR APPLICATION OF AUTOLOGOUS CONDITIONED PLASMA ON SYSTEMIC CIRCULATING IGF-1

    Directory of Open Access Journals (Sweden)

    Gert Schippinger

    2011-09-01

    Full Text Available Platelet-rich plasma (PRP to increase levels of platelets and growth factors has been used for the treatment of sports injuries suggesting to improve healing and regeneration. This method offers some potential especially for elite athletes. However, the insulin like growth factor-1 (IGF-1 is prohibited by the World Anti Doping Agency and, in addition, there may be a possible link between increased levels of IGF-1 and cancer risk. Aim of the study was to evaluate a systemic increase of IGF-1 after local intramuscular administration of PRP in young healthy moderately trained male subjects. Blood samples were drawn and PRP preparation was performed by means of centrifugation. Enriched plasma was injected into the gluteus muscle. Venous blood was collected and serum prepared before as well as after 0.5, 3 and 24 hours after PRP administration. IGF-1 analysis was performed applying an ELISA test kit. No significant systemic increase of mean IGF-1 was found after the PRP injection. Only one subject showed an increase after 24 h, but all IGF-1 values were found within reference limits. We conclude that a single intramuscular application of PRP does not significantly increase systemic IGF-1 levels. Therefore, a single application of PRP is safe with respect to systemic IGF-1 response and cancer risk and this should be allowed for treatment of muscle injuries in elite athletes

  6. Peroxisome proliferator-activated receptor-α-mediated transcription of miR-301a and miR-454 and their host gene SKA2 regulates endothelin-1 and PAI-1 expression in sickle cell disease.

    Science.gov (United States)

    Gonsalves, Caryn S; Li, Chen; Malik, Punam; Tahara, Stanley M; Kalra, Vijay K

    2015-10-12

    Endothelin-1 (ET-1) and plasminogen activator inhibitor-1 (PAI-1) play important roles in pulmonary hypertension (PH) in sickle cell disease (SCD). Our previous studies show higher levels of placenta growth factor (PlGF) in SCD correlate with increased plasma levels of ET-1, PAI-1, and other physiological markers of PH. PlGF-mediated ET-1 and PAI-1 expression occurs via activation of hypoxia-inducible factor-1α (HIF-1α). However, relatively little is understood regarding post-transcriptional regulation of PlGF-mediated expression of ET-1 and PAI-1. Herein, we show PlGF treatment of endothelial cells reduced levels of miR-301a and miR-454 from basal levels. In addition, both miRNAs targeted the 3'-UTRs of ET-1 and PAI-1 mRNAs. These results were corroborated in the mouse model of SCD [Berkeley sickle mice (BK-SS)] and in SCD subjects. Plasma levels of miR-454 in SCD subjects were significantly lower compared with unaffected controls, which correlated with higher plasma levels of both ET-1 and PAI-1. Moreover, lung tissues from BK-SS mice showed significantly reduced levels of pre-miR-301a and concomitantly higher levels of ET-1 and PAI-1. Furthermore, we show that miR-301a/miR-454 located in the spindle and kinetochore-associated protein-2 (SKA2) transcription unit was co-transcriptionally regulated by both HIF-1α and peroxisome proliferator-activated receptor-α (PPAR-α) as demonstrated by SKA2 promoter mutational analysis and ChIP. Finally we show that fenofibrate, a PPAR-α agonist, increased the expression of miR-301a/miR-454 and SKA2 in human microvascular endothelial cell line (HMEC) cells; the former were responsible for reduced expression of ET-1 and PAI-1. Our studies provide a potential therapeutic approach whereby fenofibrate-induced miR-301a/miR-454 expression can ameliorate PH and lung fibrosis by reduction in ET-1 and PAI-1 levels in SCD.

  7. Circulating plasma cells in newly diagnosed symptomatic multiple myeloma as a possible prognostic marker for patients with standard-risk cytogenetics.

    Science.gov (United States)

    Vagnoni, Davide; Travaglini, Fosco; Pezzoni, Valerio; Ruggieri, Miriana; Bigazzi, Catia; Dalsass, Alessia; Mestichelli, Francesca; Troiani, Emanuela; Falcioni, Sadia; Mazzotta, Serena; Natale, Annalisa; Angelini, Mario; Ferretti, Silvia; Angelini, Stefano; Galieni, Piero

    2015-08-01

    Detection of circulating plasma cells (PCs) in multiple myeloma (MM) patients is a well-known prognostic factor. We evaluated circulating PCs by flow cytometry (FC) in 104 patients with active MM at diagnosis by gating on CD38(+)  CD45(-) cells and examined their relationship with cytogenetic risk. Patients had an average follow-up of 36 months. By using a receiver operating characteristics analysis, we estimated the optimal cut-off of circulating PCs for defining poor prognosis to be 41. Patients with high-risk cytogenetics (n = 24) had poor prognosis, independently of circulating PC levels [PC cytogenetics (n = 65) showed a better prognosis when associated with a lower number of circulating PCs (PC cytogenetics confirmed that the co-presence of circulating PCs ≥ 41, older age, Durie-Salmon stage >I and lack of maintenance adversely affected PFS, while OS was adversely affected only by lactate dehydrogenase, older age and lack of maintenance. Our results indicate that the quantification of circulating PCs by a simple two-colour FC analysis can provide useful prognostic information in newly diagnosed MM patients with standard-risk cytogenetics.

  8. Circulating FGF23 levels in response to acute changes in plasma Ca(2+)

    DEFF Research Database (Denmark)

    Gravesen, E; Mace, M.L.; Hofman-Bang, J.

    2014-01-01

    The regulation of fibroblast growth factor 23 (FGF23) synthesis and secretion is still incompletely understood. FGF23 is an important regulator of renal phosphate excretion and has regulatory effects on the calciotropic hormones calcitriol and parathyroid hormone (PTH). Calcium (Ca) and phosphate...... homeostasis are closely interrelated, and it is therefore likely that Ca is involved in FGF23 regulation. It has recently been reported that dietary Ca influenced FGF23 levels, with high Ca increasing FGF23. The mechanism remains to be clarified. It remains unknown whether acute changes in plasma Ca influence...... FGF23 levels and whether a close relationship, similar that known for Ca and PTH, exists between Ca and FGF23. Thus, the aim of the present study was to examine whether acute hypercalcemia and hypocalcemia regulate FGF23 levels in the rat. Acute hypercalcemia was induced by an intravenous Ca infusion...

  9. Rapid Changes in Circulating Tumor DNA in Serially Sampled Plasma During Treatment of Breast Cancer: A Case Report

    Science.gov (United States)

    Nakagomi, Hiroshi; Hirotsu, Yosuke; Amemiya, Kenji; Nakada, Haruka; Inoue, Masayuki; Mochizuki, Hitoshi; Oyama, Toshio; Omata, Masao

    2017-01-01

    Patient: Female, 45 Final Diagnosis: Breast cancer Symptoms: Breast tumor Medication: — Clinical Procedure: Analysis of circulating tumor DNA Specialty: Oncology Objective: Unusual setting of medical care Background: The analysis of circulating tumor DNA (ctDNA) is expected to be a modality to determine the status of cancer in real time. This case indicated utilities and issues in measuring the ctDNA in cancer patients. Case Report: A 45-year-old woman with metastatic breast cancer was treated with bevacizumab and paclitaxel. The lung metastases were decreased but the meningitis carcinoma developed rapidly and she died. During the treatment with bevacizumab and paclitaxel, blood samples were taken serially and ctDNA was analyzed using a next-generation sequencer. TP53 frameshift mutation (TP53; p.Arg158fs with 7 nucleotides deletion) was identified in the tumor, and dynamic change in this mutation in ctDNA was observed in serially sampled plasma in this patient. We observed a rapid decrease of TP53 mutation at the beginning of treatment, then it increased as a sign of relapse. However, the high allelic fraction value of TP53 mutation was not consistent during the progression of cancer, suggesting that several factors affected the value of ctDNA. Conclusions: Although this is a single-case experience, it strongly suggests ctDNA could be a modality to determine the cancer status in real time. However, we found that several factors affected the value of ctDNA. Further investigations are needed to reveal the significance of these very high-sensitivity changes. PMID:28065930

  10. The effect of clomethiazole on plasma concentrations of interleukin-6, -8, -1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation.

    LENUS (Irish Health Repository)

    Harmon, D

    2012-02-03

    Clomethiazole (CMZ), a neuroprotective drug, has antiinflammatory actions. We investigated the effects of CMZ administration on plasma concentrations of interleukin (IL)-6, IL-8, IL-1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation. Five healthy volunteers each donated 500 mL of blood, which was subsequently divided into equal portions. Identical extracorporeal circuits were simultaneously primed with donated blood (250 mL) and circulated for 2 h at 37 degrees C. CMZ was added to 1 of the circuits of each pair to achieve a total plasma concentration of 40 micro mol\\/L. Blood samples were withdrawn at (i) donation, (ii) immediately after addition of CMZ, and at (iii) 30, 60, 90, and 120 min after commencing circulation. Plasma concentrations of IL-6, IL-8, and tumor necrosis factor-alpha were less in the CMZ group compared with control after 60 min of circulation (2.2 [0.3] versus 3.2 [0.4], 14.9 [4.8] versus 21.9 [18.4], 63.3 [43.5] versus 132.2 [118.9] pg\\/mL, respectively, P < 0.05). After 120 min of circulation, neutrophils from CMZ-treated circuits showed significantly less CD18 expression compared with control (237.5 [97.4] versus 280.5 [111.5], P = 0.03). The addition of CMZ to experimental extracorporeal circuits decreases the inflammatory response. This effect may be of clinical benefit by decreasing inflammatory-mediated neurological injury during cardiopulmonary bypass. IMPLICATIONS: Enhancement of gamma-aminobutyric acid(A)-mediated effects by clomethiazole (CMZ) and associated neuroprotection has been established in animal models of cerebral ischemia. In an ex vivo study, we demonstrated antiinflammatory activity of CMZ in experimental extracorporeal circulation. This represents a potential neuroprotective mechanism of CMZ in patients undergoing coronary artery bypass surgery.

  11. Detection of free circulating Epstein-Barr virus DNA in plasma of patients with Hodgkin’s disease

    Directory of Open Access Journals (Sweden)

    Juliane Garcez Musacchio

    Full Text Available CONTEXT AND OBJECTIVE: Free circulating Epstein-Barr virus (EBV DNA is often present in the plasma of Hodgkin’s disease patients. The aim here was to evaluate the prevalence of this finding, its correlation with the immunohistochemical expression of LMP-1 (latent membrane protein 1 and the influence of other clinical factors. DESIGN AND SETTING: Prospective study in two public tertiary institutions: Hematology Service, Universidade Federal do Rio de Janeiro, and Oncology Service, Instituto Nacional do Câncer, Rio de Janeiro. METHODS: A cohort of 30 patients with newly diagnosed Hodgkin’s disease was studied. The control group consisted of 13 healthy adult volunteers. EBV DNA was determined by conventional polymerase chain reaction (PCR. RESULTS: The median age was 28 years, and 16 patients were women. Advanced disease was present in 19 patients, and six were HIV-positive. EBV DNA was present in the plasma of 13 patients and one control (43% versus 8%, p = 0.03. EBV DNA prevalence was higher in HIV-positive patients (100% versus 29%, p = 0.0007 and those with advanced disease (63% versus 9%, p = 0.006. Among HIV-negative patients alone, EBV DNA prevalence remained higher in those with advanced disease. EBV DNA was found in 10/11 patients with LMP-1 expression in the lymph nodes, and in 3/19 without LMP-1 expression (kappa coefficient = 0.72. CONCLUSION: EBV DNA was present in 91% of patients with EBV-associated Hodgkin’s disease, and in all patients with HIV-associated Hodgkin’s disease. EBV DNA prevalence was higher in patients with advanced disease, irrespective of HIV status.

  12. Contractile effect of endothelin - 1 on isolated artery and the antagonistic effect of vasodilators%内皮素 - 1对离体动脉的收缩作用及舒张药物的对抗效应

    Institute of Scientific and Technical Information of China (English)

    王涛; 顾玉东; 沈忆文

    2001-01-01

    Objective To observe the characteristics of vasoconstriction caused by endothelin - 1 and determine the antagonistic effect of vasodilators. Methods Vasomotory test of the isolated rat common carotid artery was done to compare the influence of endothelin - 1 (ET - 1) and noradrenaline (NE)on artery tension in vitro, and detect the antagonistic effects of vasodilators on ET - 1 induced vasoconstriction. Results Endothelin - 1 resulted in a constant constriction which was concentration - dependent in isolated rat common carotid arteries. The median effective concentration (EC50) of endothelin - 1 and noradrenaline were 1.8 × 10-9mol/L and 3.4 × 10-8mol/L respectively. The EC50 of noradrenaline was 18.9 times of that of endothelin - 1. Lidocaine, nifedipine, papaverine, sodium nitroprusside, and anisodamine all relaxed endothelin - 1 - induced vasoconstriction. The strongest among those vasodilators was sodium nitroprusside, whereas lidocaine and anisodamine weaker. Conclusions Endothelin - 1 induces potent and persistent vasoconstriction of isolated arteries. Vasodilators can reduce endothelin - 1 - induced vasoconstriction.%目的 研究内皮素 - 1(Endothelin - 1,ET - 1)收缩血管的特性及显微血管外科常用舒张药物的对抗效应。方法 采用离体血管舒缩功能的实验技术比较ET - 1与去甲肾上腺素(noradrenaline,NE)对离体动脉张力的影响,同时检测舒张药物对ET - 1收缩血管的拮抗作用。结果 ET - 1使离体大鼠颈总动脉环产生浓度依赖性的恒定收缩,ET - 1与NE的半数有效浓度(median effective concentration,EC50)分别为1.8 × 10-9 mol/L和3.4 × 10-8 mol/L,NE的EC50值为ET - 1的18.9倍。血管舒张药如利多卡因、硝苯啶、罂粟硷、硝普钠、山莨菪硷,能有效对抗ET - 1的缩血管作用。其中以硝普钠最强,利多卡因与山莨菪硷较弱。结论 ET - 1对离体动脉具有强大而持久的收缩效应。

  13. Morphological changes of Endothelin-1 innervation in cerebral arteries of scald rats%烫伤大鼠脑底动脉壁内含内皮素-1能神经纤维的形态学变化

    Institute of Scientific and Technical Information of China (English)

    林雪群; 祝高春; 薛国勇; 唐讯

    2012-01-01

    目的 探讨烫(烧)伤损伤时大鼠脑血管内皮素-1能神经纤维分布与脑血管神经源性调节的关系,以及烫(烧)伤对脑血管损伤的影响.方法应用免疫组织化学技术观察烫(烧)伤大鼠脑底动脉(包括大脑前动脉、大脑中动脉、大脑后动脉和基底动脉)内皮素-1能神经纤维的分布.结果 烫(烧)伤大鼠和正常大鼠脑底动脉均可见棕褐色的内皮素-1能免疫反应阳性神经纤维,似细线状,攀附于血管壁上,烫(烧)伤大鼠脑底动脉各主要分支内皮素-1能免疫反应阳性纤维密度较正常大鼠明显增加,纤维走行大多呈网状.结论 烫(烧)伤可引起大鼠脑底动脉内皮素-1能免疫反应阳性神经纤维增加,增加的内皮素-1能神经纤维可能诱发脑血管痉挛和脑血液循环紊乱.提示内皮素-1能神经纤维在烫(烧)伤后在脑血管的神经源性调节中可能起重要的作用.%Objective To investigate the relationship between ET - 1 innervation and neurogenic regulation of cerebral vessels during scald, and to detect the effect of scald-induced cerebrovascular injury. Methods Immunohistochemical technique was used to measure the density of endothelin-1 nerve fibers in cerebral arteries of scald rat. Results The density of ET - 1 nerve fibers in cerebral arteries of scald rats was obviously higher than that of the control group. Conclusion Scald may cause an increase in the density of ET-1 nerve fibers in cerebral arteries. The elevated ET - 1 innervation may induce cerebral vasospasm and promote the disorder of cerebral blood circulation. It is suggested that ET-1 innervation may play an important role in the neurogenic regulation of cerebral vessels after scald.

  14. The evaluation of the impact of age, skin tags, metabolic syndrome, body mass index, and smoking on homocysteine, endothelin-1, high-sensitive C-reactive protein, and on the heart

    Directory of Open Access Journals (Sweden)

    Omar Soliman El Safoury

    2013-01-01

    Full Text Available Background: Skin tags (STs are small, pedunculated skin-colored or brown papules that occur around any site where skin folds occur. The literature is short of comprehensive and controlled clinical studies aimed to evaluate the atherogenic risk factors in patients with STs. Aim of Work: The aim of this study is to evaluate the impact of age, STs, metabolic syndrome (METs, body mass index (BMI, and smoking on homocysteine (Hcy, endothelin-1 (ET-1, high-sensitive C-reactive protein (Hs-CRP, and on cardiovascular diseases. Materials and Methods: This study included 30 cardiac patients with STs, 30 non-cardiac patients with STs, and 30 healthy controls with neither heart disease nor STs. History of smoking, measurement of height, weight, BMI, waist circumference (WC, blood pressure, STs number, color, acanthosis nigricans, estimation of serum level of fasting glucose, triglycerides (TGs, cholesterol, high-dense lipoproteins (HDL, Hcy, ET-1, Hs-CRP, and the presence of the METs were elicited in the three groups. Results: Regarding the Hcy, ET-1, and Hs-CRP, the cardiac-STs group showed the highest levels and the control group showed the least ( P < 0.001. The percents of patients with METs were 56.7% in the cardiac-STs, 40% in the non-cardiac-STs, and 0% in the control group ( P < 0.001. Mean BMI exceeded the limit of obesity in the cardiac-STs group (30.9 ± 3.9 and the non-cardiac-STs group (32.6 ± 6 and was normal in the control group (24.7 ± 2.8. Hyperpigmented STs were present in 66.7% of the cardiac-STs group. Multivariate regression analysis for the independent effectors on Hcy level were the presence of STs ( P < 0.001, METs ( P = 0.001, and BMI ( P = 0.024. Regarding ET-1, the effectors were the presence of STs and METs ( P = 0.032. For Hs-CRP, effectors were the presence of STs ( P < 0.001 and smoking ( P = 0.040. Multivariate logistic regression of the predictors of cardiac disease showed that the independent predictors of the occurrence

  15. High-resolution X-ray structure of the unexpectedly stable dimer of the [Lys(-2)-Arg(-1)-des(17-21)]endothelin-1 peptide.

    Science.gov (United States)

    Hoh, François; Cerdan, Rachel; Kaas, Quentin; Nishi, Yoshinori; Chiche, Laurent; Kubo, Shigeru; Chino, Naoyoshi; Kobayashi, Yuji; Dumas, Christian; Aumelas, André

    2004-12-07

    Previous structural studies on the [Lys((-2))-Arg((-1))]endothelin-1 peptide (KR-ET-1), 540-fold less potent than ET-1, strongly suggested the presence of an intramolecular Arg(-1)-Asp(8) (R(-1)-D(8)) salt bridge that was also observed in the shorter [Lys((-2))-Arg((-1))-des(17-21)]endothelin-1 derivative (KR-CSH-ET). In addition, for these two analogues, we have shown that the Lys-Arg dipeptide, which belongs to the prosequence, significantly improves the formation of the native disulfide bonds (>or=96% instead of approximately 70% for ET-1). In contrast to what was inferred from NMR data, molecular dynamics simulations suggested that such an intramolecular salt bridge would be unstable. The KR-CSH-ET peptide has now been crystallized at pH 5.0 and its high-resolution structure determined ab initio at 1.13 A using direct methods. Unexpectedly, KR-CSH-ET was shown to be a head-to-tail symmetric dimer, and the overall interface involves two intermolecular R(-1)-D(8) salt bridges, a two-stranded antiparallel beta-sheet, and hydrophobic contacts. Molecular dynamics simulations carried out on this dimer clearly showed that the two intermolecular salt bridges were in this case very stable. Sedimentation equilibrium experiments unambiguously confirmed that KR-ET-1 and KR-CSH-ET also exist as dimers in solution at pH 5.0. On the basis of the new dimeric structure, previous NMR data were reinterpreted. Structure calculations were performed using 484 intramolecular and 38 intermolecular NMR-derived constraints. The solution and the X-ray structures of the dimer are very similar (mean rmsd of 0.85 A). Since the KR dipeptide at the N-terminus of KR-CSH-ET is present in the prosequence, it can be hypothesized that similar intermolecular salt bridges could be involved in the in vivo formation of the native disulfide bonds of ET-1. Therefore, it appears to be likely that the prosequence does assist the ET-1 folding in a chaperone-like manner before successive cleavages that

  16. Evaluation of endothelin-1 and MMPs-2, -9, -14 in cerebrospinal fluid as indirect indicators of blood-brain barrier dysfunction in chronic canine hypothyroidism.

    Science.gov (United States)

    Pancotto, Theresa E; Rossmeisl, John H; Huckle, William R; Inzana, Karen D; Zimmerman, Kurt L

    2016-04-01

    Chronic canine hypothyroidism is associated with blood-brain barrier (BBB) disruption. We hypothesized that this change is mediated by endothelin-1(ET-1) and matrix metalloproteinases (MMP) -2, -9, and -14, as evidenced by increased concentrations of these proteins in cerebrospinal fluid (CSF) compared to controls. CSF from 18 dogs, 9 controls and 9 with experimentally induced hypothyroidism was collected before and 6, 12, and 18 months after induction of hypothyroidism. Concentrations of ET-1 using an ELISA kit, and for MMP-2, -9, and -14 using gelatinase zymography were measured in CSF. ET-1 was undetectable in CSF of control and hypothyroid dogs at all time-points. Constitutively expressed MMP-2 was detectable in CSF samples in all dogs at all time-points. No other MMPs were detectable in CSF. No differences in CSF concentrations of ET-1 and MMP-2, 9, and 14 were found between hypothyroid and euthyroid dogs. Therefore, ET-1 and MMP-2, 9, and 14 are unlikely to be primary mediators of BBB damage in chronically hypothyroid dogs.

  17. Differential Impact of Stress Reduction Programs upon Ambulatory Blood Pressure among African American Adolescents: Influences of Endothelin-1 Gene and Chronic Stress Exposure

    Directory of Open Access Journals (Sweden)

    Mathew J. Gregoski

    2012-01-01

    Full Text Available Stress-activated gene × environment interactions may contribute to individual variability in blood pressure reductions from behavioral interventions. We investigated effects of endothelin-1 (ET-1 LYS198ASN SNP and discriminatory stress exposure upon impact of 12-week behavioral interventions upon ambulatory BP (ABP among 162 prehypertensive African American adolescents. Following genotyping, completion of questionnaire battery, and 24-hour ABP monitoring, participants were randomized to health education control (HEC, life skills training (LST, or breathing awareness meditation (BAM. Postintervention ABP was obtained. Significant three-way interactions on ABP changes indicated that among ET-1 SNP carriers, the only group to show reductions was BAM from low chronic stress environments. Among ET-1 SNP noncarriers, under low chronic stress exposure, all approaches worked, especially BAM. Among high stress exposure noncarriers, only BAM resulted in reductions. If these preliminary findings are replicated via ancillary analyses of archival databases and then via efficacy trials, selection of behavioral prescriptions for prehypertensives will be edging closer to being guided by individual's underlying genetic and environmental factors incorporating the healthcare model of personalized preventive medicine.

  18. Pharmacological reversal of endothelin-1 mediated constriction of the spiral modiolar artery: a potential new treatment for sudden sensorineural hearing loss

    Directory of Open Access Journals (Sweden)

    Arnold Wolfgang

    2005-11-01

    Full Text Available Abstract Background Vasospasm of the spiral modiolar artery (SMA may cause ischemic stroke of the inner ear. Endothelin-1 (ET-1 induces a strong, long-lasting constriction of the SMA by increasing contractile apparatus Ca2+ sensitivity via Rho-kinase. We therefore tested several Rho-kinase inhibitors and a cell-permeable analogue of cAMP (dbcAMP for their ability to reverse ET-1-induced constriction and Ca2+-sensitization. Methods The present study employed SMA isolated from gerbil temporal bones. Ca2+sensitivity was evaluated by correlating vascular diameter and smooth muscle cell [Ca2+]i, measured by fluo-4-microfluorometry and videomicroscopy. Results The Rho-kinase inhibitors Y-27632, fasudil, and hydroxy-fasudil reversed ET-1-induced vasoconstriction with an IC50 of 3, 15, and 111 μmol/L, respectively. DbcAMP stimulated a dose-dependent vasodilation (Ec50 = 1 mmol/L and a reduction of [Ca2+]i (EC50 = 0.3 μmol/L of ET-1-preconstricted vessels (1 nmol/L. Fasudil and dbcAMP both reversed the ET-1-induced increase in Ca2+ sensitivity. Conclusion Rho-kinase inhibition and dbcAMP reversed ET-1-induced vasoconstriction and Ca2+-sensitization. Therefore, Rho-kinase inhibitors or cAMP modulators could possess promise as pharmacological tools for the treatment of ET-1-induced constriction, ischemic stroke and sudden hearing loss.

  19. Effect of low-intensity focused ultrasound on endothelin-1, nitrogen monoxide and oxytocin receptor in the uterine tissues of Sprague-Dawley rats following abortion.

    Science.gov (United States)

    Zhang, Yanxia; Guo, Jufang; Lin, Chuan; Lu, L U; Li, Chengzhi

    2016-03-01

    The aim of the present study was to investigate the effect of low-intensity focused ultrasound on endothelin-1 (ET-1), nitrogen monoxide (NO) and oxytocin receptor (OXTR) levels in the uterine tissues of Sprague-Dawley (SD) rats following abortion. A total of 30 SD rats undergoing complete abortion were randomly divided into ultrasound irradiation and sham irradiation groups (15 rats per group). The rats in the ultrasound irradiation group were treated with low-intensity ultrasound (sound intensity, 2 W/cm(2); frequency, 0.8 MHz) for 30 min daily for 5 consecutive days, and those in the sham irradiation group received sham treatment. The uterine tissue was removed to measure the levels of ET-1, NO and OXTR using the enzyme-linked immunosorbent assay and immunohistochemistry, respectively. The ET-1 level in the uterine tissues was significantly higher in the ultrasound irradiation group compared to the sham irradiation group (P0.05). In the uterine myometrium and endometrium, the strong positive expression of OXTR was observed in the ultrasound irradiation group, which was significantly higher compared to the sham irradiation group (Pultrasound could promote uterine involution by increasing ET-1 levels, modifying the balance of ET-1 and NO, and enhancing the expression of OXTR in the uterine myometrium and endometrium.

  20. Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1

    Directory of Open Access Journals (Sweden)

    Niehof Sjoerd

    2006-11-01

    Full Text Available Abstract Background In complex regional pain syndrome type 1 (CRPS1 pro-inflammatory mediators and vascular changes play an important role in the sustained development and outcome of the disease. The aim of this study was to determine the involvement of vasoactive substances endothelin-1 (ET-1 and nitric oxide (NO during early chronic CRPS1. Methods Included were 29 patients with CRPS 1 who were diagnosed during the acute stage of their disease and observed during follow-up visits. Disease activity and impairment were determined and artificial suction blisters were made on the CRPS1 and the contralateral extremities for measurements of IL-6, TNF-α, ET-1 and nitrate/nitrite (NOx. Results The levels of IL-6, TNF-α and ET-1 in blister fluid in the CRPS1 extremity versus the contralateral extremity were significantly increased and correlated with each other, whereas NOx levels were decreased. Conclusion The NOx/ET-1 ratio appears to be disturbed in the intermediate stage of CRPS, resulting in vasoconstriction and consequently in a diminished tissue blood distribution.

  1. Role of epidermal growth factor receptor transactivation in endothelin-1-induced enhanced expression of Gi protein and proliferation in A10 vascular smooth muscle cells.

    Science.gov (United States)

    Gomez Sandoval, Yessica-Haydee; Lévesque, Louis-Olivier; Li, Yuan; Anand-Srivastava, Madhu B

    2013-03-01

    We have recently shown that vasoactive peptides such as angiotensin II (Ang II) and endothelin-1 (ET-1) increase the expression of Gi proteins and the proliferation of A10 vascular smooth muscle cells (VSMC) through mitogen-activated protein (MAP) kinase-phosphoinositide (PI) 3-kinase pathways. This study was intended to examine the implication of epidermal growth factor receptor (EGFR) activation in ET-1-induced enhanced expression of Gi proteins and proliferation of A10 VSMC, and to further investigate the underlying mechanisms responsible for these increases. Cell proliferation was determined by [(3)H]thymidine incorporation and the expression of Gi proteins; extracellular signal-regulated kinases 1 and 2 (ERK1/2) and EGFR phosphorylation was determined by Western blotting. Treatment of A10 VSMC with ET-1 enhanced the expression of Gi proteins, which was attenuated by BQ123 and BQ788, antagonists of ET(A) and ET(B) receptor respectively. In addition, ET-1 enhanced the phosphorylation of EGFR in A10 VSMC, which was restored to the control levels by EGFR inhibitor and ETA and ETB receptor antagonists. Furthermore, ET-1 also augmented the proliferation and ERK1/2 phosphorylation of A10 VSMC, which were restored to the control levels by inhibition of EGFR. These data suggest that ET-1 transactivates EGFR, which, through MAP kinase signaling, may contribute to the enhanced expression of Gi proteins and thus increased proliferation of A10 VSMC.

  2. Stimuli of sensory-motor nerves terminate arterial contractile effects of endothelin-1 by CGRP and dissociation of ET-1/ET(A-receptor complexes.

    Directory of Open Access Journals (Sweden)

    Merlijn J P M T Meens

    Full Text Available BACKGROUND: Endothelin-1 (ET-1, a long-acting paracrine mediator, is implicated in cardiovascular diseases but clinical trials with ET-receptor antagonists were not successful in some areas. We tested whether the quasi-irreversible receptor-binding of ET-1 (i limits reversing effects of the antagonists and (ii can be selectively dissociated by an endogenous counterbalancing mechanism. METHODOLOGY/PRINCIPAL FINDINGS: In isolated rat mesenteric resistance arteries, ET(A-antagonists, endothelium-derived relaxing factors and synthetic vasodilators transiently reduced contractile effects of ET-1 but did not prevent persistent effects of the peptide. Stimuli of peri-vascular vasodilator sensory-motor nerves such as capsaicin not only reduced but also terminated long-lasting effects of ET-1. This was prevented by CGRP-receptor antagonists and was mimicked by exogenous calcitonin gene-related peptide (CGRP. Using 2-photon laser scanning microscopy in vital intact arteries, capsaicin and CGRP, but not ET(A-antagonism, were observed to promote dissociation of pre-existing ET-1/ET(A-receptor complexes. CONCLUSIONS: Irreversible binding and activation of ET(A-receptors by ET-1 (i occur at an antagonist-insensitive site of the receptor and (ii are selectively terminated by endogenously released CGRP. Hence, natural stimuli of sensory-motor nerves that stimulate release of endogenous CGRP can be considered for therapy of diseases involving ET-1.

  3. Xanthoangelol D isolated from the roots of Angelica keiskei inhibits endothelin-1 production through the suppression of nuclear factor-kappaB.

    Science.gov (United States)

    Sugii, Masato; Ohkita, Mamoru; Taniguchi, Masahiko; Baba, Kimiye; Kawai, Yu; Tahara, Chiyoko; Takaoka, Masanori; Matsumura, Yasuo

    2005-04-01

    Transcription factor nuclear factor-kappa B (NF-kappaB) has been demonstrated to be important in regulating various gene expressions such as cytokines, adhesion molecules, and endothelin-1 (ET-1) in vascular endothelial cells. In the present study, we show the effects of xanthoangelol, xanthoangelol D, E, and F, which isolated from the root of Angelica keiskei KOIDZUMI (Umbelliferae), on NF-kappaB activation and ET-1 gene expression in cultured porcine aortic endothelial cells (PAECs). Treatments of xanthoangelol D but not xanthoangelol, xanthoangelol E and F markedly suppressed both of basal and tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activation in PAECs. To clarify the mechanism of xanthoangelol D-induced suppression on NF-kappaB activation, we evaluated the effects of xanthoangelol D on phosphorylation and degradation of IkappaBalpha, an inhibitory protein bound to NF-kappaB, and obtained evidence that xanthoangelol D selectively suppresses the phosphorylation of IkappaBalpha rather than the degradation of phosphorylated IkappaBalpha. In addition, xanthoangelol D significantly attenuated basal and TNF-alpha-induced prepro ET-1 mRNA expression in PAECs. These results suggest that xanthoangelol D may be useful for the treatment of various vascular diseases involved NF-kappaB activation.

  4. Genetic Polymorphisms in Endothelin-1 as Predictors for Long-Term Survival and the Cardiac Index in Patients Undergoing On-Pump Cardiac Surgery.

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    Ashham Mansur

    Full Text Available Genetic variants within the endothelin-1 gene (EDN1 have been associated with several cardiovascular diseases and may act as genetic prognostic markers. Here, we explored the overall relevance of EDN1 polymorphisms for long-term survival in patients undergoing on-pump cardiac surgery. A prospectively collected cohort of 455 Caucasian patients who underwent cardiac surgery with cardiopulmonary bypass was followed up for 5 years. The obtained genotypes and inferred haplotypes were analyzed for their associations with the five-year mortality rate (primary endpoint. The EDN1 T-1370G and K198N genotype distributions did not deviate from Hardy-Weinberg equilibrium and the major allele frequencies were 83% and 77%, respectively. The cardiovascular risk factors were equally distributed in terms of the different genotypes and haplotypes associated with the two polymorphisms. The five-year mortality rate did not differ among the different EDN1 T-1370G and K198N genotypes and haplotypes. Haplotype analysis revealed that carriers of the G-T (compound EDN1 T-1370G G/K198N T haplotype had a higher cardiac index than did non-carriers (p = 0.0008; however, this difference did not reach significance after adjusting for multiple testing. The results indicate that common variations in EDN1 do not act as prognostic markers for long-term survival in patients undergoing on-pump cardiac surgery.

  5. Endothelin-1 induces proliferation of human lung fibroblasts and IL-11 secretion through an ET(A) receptor-dependent activation of MAP kinases.

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    Gallelli, Luca; Pelaia, Girolamo; D'Agostino, Bruno; Cuda, Giovanni; Vatrella, Alessandro; Fratto, Donatella; Gioffrè, Vincenza; Galderisi, Umberto; De Nardo, Marilisa; Mastruzzo, Claudio; Salinaro, Elisa Trovato; Maniscalco, Mauro; Sofia, Matteo; Crimi, Nunzio; Rossi, Francesco; Caputi, Mario; Costanzo, Francesco S; Maselli, Rosario; Marsico, Serafino A; Vancheri, Carlo

    2005-11-01

    Endothelin-1 (ET-1) is implicated in the fibrotic responses characterizing interstitial lung diseases, as well as in the airway remodeling process occurring in asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal human lung fibroblasts (NHLFs), the ET-1 receptor subtypes, and the intracellular signal transduction pathways involved in the proliferative effects of this peptide. Therefore, cells were exposed to ET-1 in the presence or absence of an overnight pre-treatment with either ET(A) or ET(B) selective receptor antagonists. After cell lysis, immunoblotting was performed using monoclonal antibodies against the phosphorylated, active forms of mitogen-activated protein kinases (MAPK). ET-1 induced a significant increase in MAPK phosphorylation pattern, and also stimulated fibroblast proliferation and IL-6/IL-11 release into cell culture supernatants. All these effects were inhibited by the selective ET(A) antagonist BQ-123, but not by the specific ET(B) antagonist BQ-788. The stimulatory influence of ET-1 on IL-11, but not on IL-6 secretion, was prevented by MAPK inhibitors. Therefore, such results suggest that in human lung fibroblasts ET-1 exerts a profibrogenic action via an ET(A) receptor-dependent, MAPK-mediated induction of IL-11 release and cell proliferation.

  6. Peroxisome Proliferator-Activated Receptor α Reduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin

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    Hsu-Lung Jen

    2016-01-01

    Full Text Available Peroxisome proliferator-activated receptor α (PPARα plays a role in the pathogenesis of cardiac hypertrophy, although its underlying mechanism remains unclear. The purpose of this study was to evaluate the effect of PPARα activation on endothelin-1- (ET-1- caused cardiomyocyte hypertrophy and explore its underlying mechanisms. Human cardiomyocytes (HCMs were cultured with or without ET-1, whereafter the inhibitory effects of fenofibrate, a PPARα activator, on cell size and adiponectin protein were tested. We examined the activation of extracellular signal-regulated kinase (ERK and p38 proteins caused by ET-1 and the inhibition of the ERK and p38 pathways on ET-1-induced cell size and adiponectin expression. Moreover, we investigated the interaction of PPARα with adiponectin and nuclear factor-κB (NF-κB by electrophoretic mobility shift assays and coimmunoprecipitation. ET-1 treatment significantly increased cell size, suppressed PPARα expression, and enhanced the expression of adiponectin. Pretreatment with fenofibrate inhibited the increase in cell size and enhancement of adiponectin expression. ET-1 significantly activated the ERK and p38 pathways, whereas PD98059 and SB205380, respectively, inhibited them. Our results suggest that activated PPARα can decrease activation of adiponectin and NF-κB and inhibit ET-1-induced cardiomyocyte hypertrophy.

  7. Endothelial Nitric Oxide Synthase (−786T>C) and Endothelin-1 (5665G>T) Gene Polymorphisms as Vascular Dysfunction Risk Factors in Sickle Cell Anemia

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    Vilas-Boas, Wendell; Figueiredo, Camylla V. B.; Pitanga, Thassila N.; Carvalho, Magda O. S.; Santiago, Rayra P.; Santana, Sânzio S.; Guarda, Caroline C.; Zanette, Angela M. D.; Cerqueira, Bruno A. V.; Gonçalves, Marilda S.

    2016-01-01

    Sickle cell anemia (SCA) patients have vascular complications, and polymorphisms in endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) genes were associated with ET-1 and nitric oxide disturbance. We investigate the association of ET-1 5665G>T and eNOS −786T>C polymorphisms with soluble adhesion molecules (sVCAM-1 and sICAM-1), biochemical markers, and medical history. We studied 101 SCA patients; carriers of eNOS minor allele (C) had the highest levels of sVCAM-1, and carriers of ET-1 minor allele had more occurrence of acute chest syndrome (ACS). The multivariate analysis suggested the influence of the ET-1 gene on ACS outcome and an association of the eNOS gene with upper respiratory tract infection. We suggest that eNOS and ET-1 gene polymorphisms can influence SCA pathophysiology and that eNOS variant in SCA patients might be important to nitric oxide activity and vascular alteration. We found an association of the ET-1 minor allele in ACS, showing the importance of genetic screening in SCA. PMID:27486304

  8. Evaluation of C-Reactive Protein, Endothelin-1, Adhesion Molecule(s, and Lipids as Inflammatory Markers in Type 2 Diabetes Mellitus Patients

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    Hala El-Mesallamy

    2007-01-01

    Full Text Available This study compared lipids, the product of lipid peroxidation malondialdehyde (MDA, the acute phase reactant high sensitive C-reactive protein (hsCRP, endothelin-1 (ET-1, P-selectin, intercellular adhesion molecule-1 (ICAM-1, and vascular cell adhesion molecule-1 (VCAM-1 between healthy controls, subjects with ischemic heart disease (IHD and type 2 diabetes mellitus (DM subjects who did not perform coronary artery bypass graft (CABG surgery as well as type 2 DM subjects who performed CABG. HbA1c, lipids, MDA, hsCRP, ET-1, P-selectin, ICAM-1, and VCAM-1 levels were significantly higher in the diabetic groups than in either healthy controls or IHD subjects. In the diabetic groups, there was a negative association among hsCRP and HDL-C. ET-1, ICAM-1 levels and TAG were positively correlated, as do the association between P-selectin, VCAM-1 and HbA1c%. Also a positive relation was found among hsCRP levels and ICAM-1, as well as MDA and ET-1. P-selectin and ICAM-1 were significantly positively correlated. This study indicates that increased level of oxidative stress marker, proinflammatory markers and their downstream effectors adhesion molecules occurs in type 2 DM.

  9. Polyphenol fraction of extra virgin olive oil protects against endothelial dysfunction induced by high glucose and free fatty acids through modulation of nitric oxide and endothelin-1

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    Carolina Emilia Storniolo

    2014-01-01

    Full Text Available Epidemiological and clinical studies have reported that olive oil reduces the incidence of cardiovascular disease. However, the mechanisms involved in this beneficial effect have not been delineated. The endothelium plays an important role in blood pressure regulation through the release of potent vasodilator and vasoconstrictor agents such as nitric oxide (NO and endothelin-1 (ET-1, respectively, events that are disrupted in type 2 diabetes. Extra virgin olive oil contains polyphenols, compounds that exert a biological action on endothelial function. This study analyzes the effects of olive oil polyphenols on endothelial dysfunction using an in vitro model that simulates the conditions of type 2 diabetes. Our findings show that high glucose and linoleic and oleic acids decrease endothelial NO synthase phosphorylation, and consequently intracellular NO levels, and increase ET-1 synthesis by ECV304 cells. These effects may be related to the stimulation of reactive oxygen species production in these experimental conditions. Hydroxytyrosol and the polyphenol extract from extra virgin olive oil partially reversed the above events. Moreover, we observed that high glucose and free fatty acids reduced NO and increased ET-1 levels induced by acetylcholine through the modulation of intracellular calcium concentrations and endothelial NO synthase phosphorylation, events also reverted by hydroxytyrosol and polyphenol extract. Thus, our results suggest a protective effect of olive oil polyphenols on endothelial dysfunction induced by hyperglycemia and free fatty acids.

  10. Clinical Observation on Influence of Chinese Medicines for Promoting Blood Circulation to Remove Blood Stasis on FIB and DD in Plasma of Patients with Cerebral Thrombosis

    Institute of Scientific and Technical Information of China (English)

    梁晖; 陈甦; 陈少芳

    2002-01-01

    Objective: to study the influence of Chinese medicines for promoting blood circulation to remove blood stasis on fibrinogen (FIB) and D-dimer (DD) in plasma of patients with cerebral thrombosis. Method: 73 inpatients with acute cerebral thrombosis were randomly divided into a control group of 34 cases and a treatment group of 39 cases. The content of FIB and DD in plasma was detected before treatment and on the 7th and 14th days after treatment. Result: FIB content in plasma after treatment was lower than that before treatment in the control group (P<0.01) and more remarkable in the treatment group (P<0.001). There was an obvious difference in DD content before and after treatment in both groups. DD content on the 7th and 14th days after treatment in the treatment group was obviously higher than that in the control group (P<0.01 and P<0.05 respectively). Conclusion: Chinese medicines for promoting blood circulation to remove blood stasis can reduce the FIB content in plasma of patients with cerebral thrombosis, raise the DD content in plasma, cause the peak of DD content appear earlier and obviously improve hypercoagulability of blood in patients with cerebral thrombosis.

  11. Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: meta-analysis of 9 studies in the CHARGE consortium

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    Smith, Caren E.; Follis, Jack L.; Nettleton, Jennifer A.; Foy, Millennia; Wu, Jason H.Y.; Ma, Yiyi; Tanaka, Toshiko; Manichakul, Ani W.; Wu, Hongyu; Chu, Audrey Y.; Steffen, Lyn M.; Fornage, Myriam; Mozaffarian, Dariush; Kabagambe, Edmond K.; Ferruci, Luigi; da Chen, Yii-Der I; Rich, Stephen S.; Djoussé, Luc; Ridker, Paul M.; Tang, Weihong; McKnight, Barbara; Tsai, Michael Y.; Bandinelli, Stefania; Rotter, Jerome I.; Hu, Frank B.; Chasman, Daniel I.; Psaty, Bruce M.; Arnett, Donna K.; King, Irena B.; Sun, Qi; Wang, Lu; Lumley, Thomas; Chiuve, Stephanie E.; Siscovick, David S; Ordovás, José M.; Lemaitre, Rozenn N.

    2015-01-01

    Scope Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. Objective We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). Methods and Results We conducted meta-analyses (N to 11,668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein) and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma vs. erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary ALA and linoleic acid for DHA and DPA. Conclusion Our findings reinforce earlier reports that genetically-based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes. PMID:25626431

  12. Circulating levels of maternal plasma cell-free pregnancy-associated placenta-specific microRNAs are associated with placental weight.

    Science.gov (United States)

    Miura, K; Morisaki, S; Abe, S; Higashijima, A; Hasegawa, Y; Miura, S; Tateishi, S; Mishima, H; Yoshiura, K; Masuzaki, H

    2014-10-01

    The aim of this study was to investigate the relationship between plasma concentration of cell-free pregnancy-associated placenta-specific microRNAs and clinical variables (placental weight, maternal body mass index, and neonatal birth weight). Circulating levels of cell-free pregnancy-associated placenta-specific microRNAs (miR-515-3p, miR-517a, miR-517c and miR-518b) in maternal plasma were measured by quantitative real-time RT-PCR in sixty-two pregnant women. The levels of cell-free pregnancy-associated placenta-specific microRNAs were significantly associated with placental weight, but not associated with body mass index or birth weight. Therefore, the measurement of cell-free pregnancy-associated placenta-specific miRNAs levels in maternal plasma may reflect the pregnancy status related to placenta volume.

  13. Obligatory Role of Intraluminal O2− in Acute Endothelin-1 and Angiotensin II Signaling to Mediate Endothelial Dysfunction and MAPK Activation in Guinea-Pig Hearts

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    Emilia Wojtera

    2014-10-01

    Full Text Available We hypothesized that, due to a cross-talk between cytoplasmic O2−-sources and intraluminally expressed xanthine oxidase (XO, intraluminal O2− is instrumental in mediating intraluminal (endothelial dysfunction and cytosolic (p38 and ERK1/2 MAPKs phosphorylation manifestations of vascular oxidative stress induced by endothelin-1 (ET-1 and angiotensin II (AT-II. Isolated guinea-pig hearts were subjected to 10-min agonist perfusion causing a burst of an intraluminal O2−. ET-1 antagonist, tezosentan, attenuated AT-II-mediated O2−, indicating its partial ET-1 mediation. ET-1 and Ang-T (AT-II + tezosentan triggered intraluminal O2−, endothelial dysfunction, MAPKs and p47phox phosphorylation, and NADPH oxidase (Nox and XO activation. These effects were: (i prevented by blocking PKC (chelerythrine, Nox (apocynin, mitochondrial ATP-dependent K+ channel (5-HD, complex II (TTFA, and XO (allopurinol; (ii mimicked by the activation of Nox (NADH; and mitochondria (diazoxide, 3-NPA and (iii the effects by NADH were prevented by 5-HD, TTFA and chelerythrine, and those by diazoxide and 3-NPA by apocynin and chelerythrine, suggesting that the agonists coactivate Nox and mitochondria, which further amplify their activity via PKC. The effects by ET-1, Ang-T, NADH, diazoxide, and 3-NPA were opposed by blocking intraluminal O2− (SOD and XO, and were mimicked by XO activation (hypoxanthine. Apocynin, TTFA, chelerythrine, and SOD opposed the effects by hypoxanthine. In conclusion, oxidative stress by agonists involves cellular inside-out and outside-in signaling in which Nox-mitochondria-PKC system and XO mutually maintain their activities via the intraluminal O2−.

  14. Role of the 3'-untranslated region of human endothelin-1 in vascular endothelial cells. Contribution to transcript lability and the cellular heat shock response.

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    Mawji, Imtiaz A; Robb, G Brett; Tai, Sharon C; Marsden, Philip A

    2004-03-05

    Endothelin-1 (ET-1) is a potent vasoconstrictor peptide expressed in the vascular endothelium. Stringent control over ET-1 expression is achieved through a highly regulated promoter and rapid mRNA turnover. Since little is known about mechanisms governing ET-1 post-transcriptional regulation, and changes in ET-1 mRNA stability are implicated in disease processes, we characterized these pathways using a variety of functional approaches. We expressed human ET-1 and luciferase transcripts with or without a wild type ET-1 3'-untranslated region (3'-UTR) and found that the 3'-UTR had potent mRNA destabilizing activity. Deletion analysis localized this activity to two domains of the 3'-UTR we have termed destabilizing elements 1 and 2 (DE1 and DE2). Mutational studies revealed that DE1 functions as an AU-rich element (ARE) dependent on a 100-nucleotide region. This activity was further localized to a 10-nucleotide region at position 978-987 of the 3'-UTR. Depletion of AUF1 by RNA interference up-regulated ET-1 in endothelial cells suggesting AUF1-dependent regulation. Since AUF1 functions through the ubiquitin-proteasome pathway, we disrupted this pathway with heat shock and proteasome inhibitor in endothelial cells and observed stabilization of endogenous ET-1 mRNA. Chimeric transcripts bearing wild type ET-1 3'-UTRs were also stabilized in response to proteasome inhibition whereas DE1 mutants failed to respond. Taken together, these findings suggest a complex model of ARE-mediated mRNA turnover dependent on two 3'-UTR domains, DE1 and DE2. Furthermore, DE1 functions as an ARE directing mRNA half-life through the proteasome. Finally, this data provides evidence for a novel pathway of ET-1 mRNA stabilization by heat shock.

  15. Endothelin-1 and macrophage colony-stimulating factor are co-localized in human amnion membrane cells and secreted into amniotic fluid.

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    Fried, Gabriel; Sand, Anna; Ostlund, Eva; Andersson, Eva; Byström, Birgitta; Ståbi, Berit

    2003-11-01

    We have examined the cellular localization and human amniotic fluid content of endothelin-1 (ET-1) and macrophage colony-stimulating factor (M-CSF). The study material consisted of amniotic fluid from 20 patients referred for amniocentesis, and placental samples from normal deliveries. ET-1 and M-CSF were analysed by radioimmunoassay and enzyme-linked immunosorbent assay respectively. The cellular localization of ET-1 and M-CSF in the amnion membranes was analysed by double-labelling immunocytochemistry using fluorescein isothiocyanate- and Cy3-labelled secondary antibodies. Release of ET-1 and M-CSF was studied in cultured amniocytes. We found that the mean +/- SD concentrations of ET-1 and M-CSF in fetal amniotic fluid were 45.6 +/- 17.3 pmol/l (range 16.8-85.5) and 7323 +/- 3415 ng/l (range 2640-12 110) respectively. Double-labelling immunocytochemistry showed that both M-CSF and ET-1 were co-localized in the same cells to a high extent. Further analysis revealed that levels of M-CSF, but not ET-1, were significantly correlated with pregnancy length. Both M-CSF and ET-1 were released from cultured amniocytes in response to interleukin-1. These findings show that ET-1 and M-CSF are partly co-localized to specific cells in the human amniotic membrane. As both M-CSF and ET-1 were released from cultured amniocytes in vitro, this suggests that they both may be secreted into fetal amniotic fluid in vivo as well.

  16. The first Russian experience with the endothelin 1 receptor inhibitor traclir used in patients with pulmonary hypertension associated with systemic connective tissue diseases

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    Aleksandr Vitalyevich Volkov

    2011-01-01

    Full Text Available Objective: to study the efficacy and safety of the endothelin 1 receptor inhibitor traclir in patients with pulmonary hypertension (PH asso ciated with systemic connective tissue diseases. Subjects and methods. The study included 4 patients: 3 with scleroderma systematica and 1 with exanthematous lupus erythematosus. The diagnosis of PH was established on the basis of right heart catheterization data and after exclusion of all its other causes of HP. In addition to hemodynamic evaluation, the female patients underwent echocardiography (EchoCG, lung function tests, 6-minute walk test, and blood biochemical study (determination of uric acid levels. Traclir was given in a dose of 62.5 mg twice in the first 4 weeks of the study and then in a dose of 125 mg twice for the subsequent 12 weeks. Every 4 weeks, the levels of transaminases were monitored and a pregnancy test was carried out in patients of fertile age. Results. After 16-week intake of the drug, all the female patients were found to have obvious positive changes as a longer 6-min walk test distance and two female patients had improvement in the functional class of PH. Estimation of hemodynamic parameters suggested a posi tive effect in all the female patients, as confirmed primarily by an increase in cardiac index and a reduction in pulmonary vascular resist ance. According to EchoCG data, there was a substantial increase in tricuspid annular plane systolic excursion; other parameters had no informative value. During traclir therapy, there was also an increase in lung diffusion capacity and a reduction in uric acid levels. There were no adverse events throughout the trial. Conclusion. Thus, the experience with traclir used in patients with PH associated with systemic autoimmune diseases suggests its high effi cacy and safety.

  17. Up-regulation of COX-2/PGE2 by endothelin-1 via MAPK-dependent NF-κB pathway in mouse brain microvascular endothelial cells

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    Lin Chih-Chung

    2013-01-01

    Full Text Available Abstract Background Endothelin-1 (ET-1 is a proinflammatory mediator and elevated in the regions of several brain injury and inflammatory diseases. The deleterious effects of ET-1 on endothelial cells may aggravate brain inflammation mediated through the regulation of cyclooxygenase-2 (COX-2/prostaglandin E2 (PGE2 system in various cell types. However, the signaling mechanisms underlying ET-1-induced COX-2 expression in brain microvascular endothelial cells remain unclear. Herein we investigated the effects of ET-1 in COX-2 regulation in mouse brain microvascular endothelial (bEnd.3 cells. Results The data obtained with Western blotting, RT-PCR, and immunofluorescent staining analyses showed that ET-1-induced COX-2 expression was mediated through an ETB-dependent transcriptional activation. Engagement of Gi- and Gq-protein-coupled ETB receptors by ET-1 led to phosphorylation of ERK1/2, p38 MAPK, and JNK1/2 and then activated transcription factor NF-κB. Moreover, the data of chromatin immunoprecipitation (ChIP and promoter reporter assay demonstrated that the activated NF-κB was translocated into nucleus and bound to its corresponding binding sites in COX-2 promoter, thereby turning on COX-2 gene transcription. Finally, up-regulation of COX-2 by ET-1 promoted PGE2 release in these cells. Conclusions These results suggested that in mouse bEnd.3 cells, activation of NF-κB by ETB-dependent MAPK cascades is essential for ET-1-induced up-regulation of COX-2/PGE2 system. Understanding the mechanisms of COX-2 expression and PGE2 release regulated by ET-1/ETB system on brain microvascular endothelial cells may provide rationally therapeutic interventions for brain injury or inflammatory diseases.

  18. The Role of Calcium-Sensing Receptors in Endothelin-1-Dependent Effects on Adult Rat Ventricular Cardiomyocytes: Possible Contribution to Adaptive Myocardial Hypertrophy.

    Science.gov (United States)

    Dyukova, Elena; Schreckenberg, Rolf; Arens, Christoph; Sitdikova, Guzel; Schlüter, Klaus-Dieter

    2017-09-01

    Nitric oxide (NO)-deficiency as it occurs during endothelial dysfunction activates the endothelin-1 (ET-1) system and increases the expression of receptor activity modifying protein (RAMP)-1 that acts as a chaperon for calcium-sensing receptors (CaR) that have recently been identified to improve cardiac function. Here, we hypothesized that ET-1 increases the cardiac expression of CaR and thereby induces an adaptive type of hypertrophy. Expressions of RAMP-1, endothelin receptors, and CaR were analyzed by RT-PCR in left ventricular tissues of L-NAME-treated rats. Effects of ET-1 on CaR expression and cell function (load free cell shortening) were analyzed in adult rat ventricular cardiomyocytes. siRNA directed against CaR and RAMP-1 was used to investigate a causal relationship. PD142893 and BQ788 were used to dissect the contribution of ETB1 , ETB2 , and ETA receptors. Non-specific NO synthase inhibition with L-Nitro arginine methyl ester (L-NAME) caused a cardiac upregulation of ETB receptors and CaR suggesting a paracrine effect of ET-1 on cardiomyocytes. Indeed, ET-1 induced the expression of CaR in cultured cardiomyocytes. Under these conditions, cardiomyocytes increased cell size (hypertrophy) but maintained normal function. Inhibition of ETA and ETB1 receptors led to ET-1-dependent reduction in cell shortening and attenuated up-regulation of CaR. Down-regulation of RAMP-1 reduced CaR responsiveness. In conclusion, ET-1 causes an adaptive type of hypertrophy by up-regulation of CaR in cardiomyocytes via ETA and/or ETB1 receptors. J. Cell. Physiol. 232: 2508-2518, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Relaxation of endothelin-1-induced pulmonary arterial constriction by niflumic acid and NPPB: mechanism(s) independent of chloride channel block.

    Science.gov (United States)

    Kato, K; Evans, A M; Kozlowski, R Z

    1999-03-01

    We investigated the effects of the Cl- channel blockers niflumic acid, 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and 4, 4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) on endothelin-1 (ET-1)-induced constriction of rat small pulmonary arteries (diameter 100-400 microm) in vitro, following endothelium removal. ET-1 (30 nM) induced a sustained constriction of rat pulmonary arteries in physiological salt solution. Arteries preconstricted with ET-1 were relaxed by niflumic acid (IC50: 35.8 microM) and NPPB (IC50: 21.1 microM) in a reversible and concentration-dependent manner. However, at concentrations known to block Ca++-activated Cl- channels, DIDS (

  20. G-231A and G+70C polymorphisms of endothelin receptor type-A gene could affect the psoriasis area and severity index score and endothelin 1 levels

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    Gökhan Okan

    2015-01-01

    Full Text Available Background: The etiopathogenesis of psoriasis has not been clearly elucidated although the role of chronic inflammation, imbalance between pro- and anti-inflammatory cytokines, and many immunological events have been established. Endothelin 1 (EDN1 and endothelin receptor type-A (EDNRA are implicated in the inflammatory process. The relationships between EDN1 and EDNRA polymorphisms with several diseases have been found. Aims and Objectives: This study examined the possible association of EDN1 (G5665T and T-1370G and EDNRA (G-231A and G + 70C single nucleotide polymorphisms (SNPs with the occurence of psoriasis, and evaluated the relationship between genotypes and clinical/laboratory manifestation of psoriasis. Materials and Methods: We analyzed genotype and allele distributions of the above-mentioned polymorphisms in 151 patients with psoriasis and 152 healthy controls by real-time PCR combined with melting curve analysis. Results: We did not find significant differences in the genotype and allele distributions of EDN1 T-1370G, EDNRA G-231A, and EDNRA G+70C polymorphisms between patients with psoriasis and healthy controls. Psoriasis area and severity index (PASI score of EDNRA -231 polymorphic A allele carrying subjects (AA and AA + AG was higher than that of wild homozygotes (P = 0.044 and P = 0.027, respectively. In addition, EDN1 levels in EDNRA+70 polymorphic C allele carriers (CC + CG were elevated when compared with GG genotype; however, the difference was at borderline significance (P = 0.05. Conclusion: Although there were no associations between studied polymorphisms and psoriasis susceptibility, the PASI score and EDN1 levels seem to be affected by EDNRA G-231A and G + 70C polymorphisms.

  1. Human recombinant erythropoietin alters the flow-dependent vasodilatation of in vitro perfused rat mesenteric arteries with unbalanced endothelial endothelin-1 / nitric oxide ratio.

    Science.gov (United States)

    Barhoumi, Tlili; Jallat, Isabelle; Berthelot, Alain; Laurant, Pascal

    2011-06-01

    Chronic use of human recombinant erythropoietin (r-HuEPO) is accompanied by serious vascular side effects related to the rise in blood viscosity and shear stress. We investigated the direct effects of r-HuEPO on endothelium and nitric oxide (NO)-dependent vasodilatation induced by shear stress of cannulated and pressurized rat mesenteric resistance arteries. Intravascular flow was increased in the presence or absence of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 10(-4) mol/L). In the presence of r-HuEPO, the flow-dependent vasodilatation was attenuated, while L-NAME completely inhibited it. The association of r-HuEPO and L-NAME caused a vasoconstriction in response to the rise in intravascular flow. Bosentan (10(-5) mol/L), an inhibitor of endothelin-1 (ET-1) receptors, corrected the attenuated vasodilatation observed with r-HuEPO and inhibited the vasoconstriction induced by flow in the presence of r-HuEPO and L-NAME. r-HuEPO and L-NAME exacerbated ET-1 vasoconstriction. At shear stress values of 2 and 14 dyn/cm(2) (1 dyn = 10(-5) N), cultured EA.hy926 endothelial cells incubated with r-HuEPO, L-NAME, or both released greater ET-1 than untreated cells. In conclusion, r-HuEPO diminishes flow-induced vasodilatation. This inhibitory effect seems to implicate ET-1 release. NO withdrawal exacerbates the vascular effects of ET-1 in the presence of r-HuEPO. These findings support the importance of a balanced endothelial ET-1:NO ratio to avoid the vasopressor effects of r-HuEPO.

  2. Effects of adrenomedullin on tumour necrosis factor alpha, interleukins, endothelin-1, leptin, and adiponectin in the epididymal fat and soleus muscle of the rat.

    Science.gov (United States)

    Liao, S B; Wong, P F; Cheung, B M Y; Tang, F

    2013-01-01

    Adrenomedullin (ADM) is a peptide hormone, which participates in the development of metabolic syndrome. In this study, we have investigated the interaction of ADM and cytokines, endothelin-1 (EDN-1) and adipokines in the epididymal fat and the soleus muscle. Epididymal fat and soleus muscles from adult male Sprague-Dawley rat were incubated with ADM at concentration of 100 nM for the study of the gene expression and secretion of tumour necrosis factor (TNF-α), EDN-1, leptin, adiponectin, interleukin 1β (IL-1β), and IL-6. The effects of TNF-α and EDN-1 on ADM gene expression and secretion were also investigated. The results showed that ADM decreased the gene expression and protein secretion of TNF-α in both the epididymal fat and the soleus muscle and decreased IL-1β gene expression and secretion in the soleus muscle. It also decreased endothelin gene expression and adiponectin gene expression and release and increased IL-6 and leptin gene expression and secretion in the epididymal fat. These effects were effectively blocked by the calcitonin gene-related peptide (CGRP) receptor antagonist, hCGRP8-37, but not by the ADM receptor antagonist, hADM22-52. The reduction of inflammatory cytokines and EDN-1 may help to decrease insulin resistance and increase glucose uptake. As TNF-α also increases ADM levels in the epididymal fat and the soleus muscle and EDN-1 also increases ADM levels in the epididymal fat, they may form a feedback loop with ADM in these tissues. The increase in leptin and the decrease in adiponectin by ADM in the epididymal fat may have opposite effects on metabolism. © Georg Thieme Verlag KG Stuttgart · New York.

  3. The neuroprotective effect of post ischemic brief mild hypothermic treatment correlates with apoptosis, but not with gliosis in endothelin-1 treated rats

    Directory of Open Access Journals (Sweden)

    Zgavc Tine

    2012-08-01

    Full Text Available Abstract Background Stroke remains one of the most common diseases with a serious impact on quality of life but few effective treatments exist. Mild hypothermia (33°C is a promising neuroprotective therapy in stroke management. This study investigated whether a delayed short mild hypothermic treatment is still beneficial as neuroprotective strategy in the endothelin-1 (Et-1 rat model for a transient focal cerebral ischemia. Two hours of mild hypothermia (33°C was induced 20, 60 or 120 minutes after Et-1 infusion. During the experiment the cerebral blood flow (CBF was measured via Laser Doppler Flowmetry in the striatum, which represents the core of the infarct. Functional outcome and infarct volume were assessed 24 hours after the insult. In this sub-acute phase following stroke induction, the effects of the hypothermic treatment on apoptosis, phagocytosis and astrogliosis were assessed as well. Apoptosis was determined using caspase-3 immunohistochemistry, phagocytic cells were visualized by CD-68 expression and astrogliosis was studied by glial fibrillary acidic protein (GFAP staining. Results Cooling could be postponed up to 1 hour after the onset of the insult without losing its positive effects on neurological deficit and infarct volume. These results correlated with the caspase-3 staining. In contrast, the increased CD-68 expression post-stroke was reduced in the core of the insult with all treatment protocols. Hypothermia also reduced the increased levels of GFAP staining, even when it was delayed up to 2 hours after the insult. The study confirmed that the induction of the hypothermia treatment in the Et-1 model does not affect the CBF. Conclusions These data indicate that in the Et-1 rat model, a short mild hypothermic treatment delayed for 1 hour is still neuroprotective and correlates with apoptosis. At the same time, hypothermia also establishes a lasting inhibitory effect on the activation of astrogliosis.

  4. Involvement of nitric oxide pathways in short term modulation of tyrosine hydroxylase activity by endothelins 1 and 3 in the rat anterior hypothalamus.

    Science.gov (United States)

    Morgazo, Carolina; Perfume, Guadalupe; Legaz, Guillermina; di Nunzio, Andrea; Hope, Sandra I; Bianciotti, Liliana G; Vatta, Marcelo S

    2005-09-02

    The ability of endothelins 1 and 3 (ET-1 and ET-3) to reduce neuronal norepinephrine release through ETB receptor activation involving nitric oxide (NO) pathways in the rat anterior hypothalamus region (AHR) was previously reported. In the present work, we studied the effects of ET-1 and -3 on tyrosine hydroxylase (TH) activity and the possible involvement of NO pathways. Results showed that ET-1 and -3 (10 nM) diminished TH activity in AHR and this effect was blocked by a selective ETB receptor antagonist (100 nM BQ-788), but not by a ET(A) receptor antagonist (BQ-610). To confirm these results, 1 microM IRL-1620 (ET(B) agonist) reduced TH activity whereas 300 nM sarafotoxin S6b falled to modify it. N(omega)-Nitro-L-arginine methyl ester (10 microM), 7-nitroindazole (10 microM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-ona (10 microM), KT5823 (2 microM), inhibitors of nitric oxide synthase, neuronal nitric oxide synthase, NO-sensitive-guanylyl cyclase, and protein kinase G, respectively, did not modify the reduction of TH activity produced by ETs. In addition, both 100 microM sodium nitroprusside and 50 microM 8-bromoguanosine-3',5'-cyclic monophosphate (NO donor and guanosine-3',5'-cyclic monophosphate analog, respectively) diminished TH activity. Present results showed that ET-1 and ET-3 diminished TH activity through the activation of ET(B) receptors involving the NO/guanosine-3',5'-cyclic monophosphate/protein kinase G pathway. Taken jointly present and previous results it can be concluded that both ETs play an important role as modulators of norepinephrine neurotransmission in the rat AHR.

  5. Serum Interleukin-18, Fetuin-A, Soluble Intercellular Adhesion Molecule-1, and Endothelin-1 in Ankylosing Spondylitis, Psoriatic Arthritis, and SAPHO Syndrome.

    Science.gov (United States)

    Przepiera-Będzak, Hanna; Fischer, Katarzyna; Brzosko, Marek

    2016-08-03

    To examine serum interleukin 18 (IL-18), fetuin-A, soluble intercellular adhesion molecule-1 (sICAM-1), and endothelin-1 (ET-1) levels in ankylosing spondylitis (AS), psoriatic arthritis (PsA), and Synovitis Acne Pustulosis Hyperostosis Osteitis syndrome (SAPHO). We studied 81 AS, 76 PsA, and 34 SAPHO patients. We measured serum IL-18, fetuin-A, sICAM-1, ET-1, IL-6, IL-23, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). IL-18 levels were higher in AS (p = 0.001), PsA (p = 0.0003), and SAPHO (p = 0.01) than in controls, and were positively correlated with CRP (p = 0.03), VEGF (p = 0.03), and total cholesterol (TC, p = 0.006) in AS and with IL-6 (p = 0.03) in PsA. Serum fetuin-A levels were lower in AS (p = 0.001) and PsA (p = 0.001) than in controls, and negatively correlated with C-reactive protein (CRP) in AS (p = 0.04) and SAPHO (p = 0.03). sICAM-1 positively correlated with CRP (p = 0.01), erythrocyte sedimentation rate (ESR, p = 0.01), and IL-6 (p = 0.008) in AS, and with IL-6 (p = 0.001) in SAPHO. Serum ET-1 levels were lower in AS (p = 0.0005) than in controls. ET-1 positively correlated with ESR (p = 0.04) and Disease Activity Score 28 (DAS28, p = 0.003) in PsA. In spondyloarthritis, markers of endothelial function correlated with disease activity and TC.

  6. Serum Interleukin-18, Fetuin-A, Soluble Intercellular Adhesion Molecule-1, and Endothelin-1 in Ankylosing Spondylitis, Psoriatic Arthritis, and SAPHO Syndrome

    Directory of Open Access Journals (Sweden)

    Hanna Przepiera-Będzak

    2016-08-01

    Full Text Available To examine serum interleukin 18 (IL-18, fetuin-A, soluble intercellular adhesion molecule-1 (sICAM-1, and endothelin-1 (ET-1 levels in ankylosing spondylitis (AS, psoriatic arthritis (PsA, and Synovitis Acne Pustulosis Hyperostosis Osteitis syndrome (SAPHO. We studied 81 AS, 76 PsA, and 34 SAPHO patients. We measured serum IL-18, fetuin-A, sICAM-1, ET-1, IL-6, IL-23, vascular endothelial growth factor (VEGF, and epidermal growth factor (EGF. IL-18 levels were higher in AS (p = 0.001, PsA (p = 0.0003, and SAPHO (p = 0.01 than in controls, and were positively correlated with CRP (p = 0.03, VEGF (p = 0.03, and total cholesterol (TC, p = 0.006 in AS and with IL-6 (p = 0.03 in PsA. Serum fetuin-A levels were lower in AS (p = 0.001 and PsA (p = 0.001 than in controls, and negatively correlated with C-reactive protein (CRP in AS (p = 0.04 and SAPHO (p = 0.03. sICAM-1 positively correlated with CRP (p = 0.01, erythrocyte sedimentation rate (ESR, p = 0.01, and IL-6 (p = 0.008 in AS, and with IL-6 (p = 0.001 in SAPHO. Serum ET-1 levels were lower in AS (p = 0.0005 than in controls. ET-1 positively correlated with ESR (p = 0.04 and Disease Activity Score 28 (DAS28, p = 0.003 in PsA. In spondyloarthritis, markers of endothelial function correlated with disease activity and TC.

  7. Characterization of the gp120 of circulating HIV type 1 in a group of infected Chinese blood/plasma donors with asymptomatic and symptomatic stages of the disease.

    Science.gov (United States)

    Chen, Yue; Craigo, Jodi K; Ding, Ming; Guo, Yan; Shen, Shengli; Zhou, Yushen; Wu, Hao; Gupta, Phalguni

    2006-11-01

    The C2-V5 regions of the HIV envelope gene were cloned and sequenced from DNA samples of four asymptomatic and five AIDS patients from a cohort of HIV-1-infected Chinese plasma and blood donors. Sequence analysis revealed that regardless of the stage of disease, all the patient's HIV-1 belonged to either clade B' or circulating recombinant form 15 (CRF15) subtype. However, since these blood donors were infected at a time when circulating CRF15 was not known in that region, it is likely these HIV-1 types belong to clade B'. However, the C2-V5 sequences from AIDS patients clustered differently in the phylogenetic tree than those present in asymptomatic patients and showed a significantly higher divergence and lower diversity compared to those from asymptomatic patients. In addition, more syncytia-inducing viral genotypes were present in AIDS patients than in asymptomatic patients. These results contribute to a better understanding of the pathogenesis of circulating HIV-1 in infected Chinese plasma and blood donors, warrant additional investigation of the possible presence of CRF15 in Chinese blood donors, and may have important implications in the future design of therapeutic strategies for treating these infected patients.

  8. Circulating microparticles and plasma levels of soluble E- and P-selectins in patients with systemic sclerosis

    DEFF Research Database (Denmark)

    Iversen, Lars; Østergaard, O; Ullman, S

    2013-01-01

    Microparticles (MPs) may be involved in the pathogenesis of systemic sclerosis (SSc), which includes vasculopathy, endothelial cell activation, and coagulation activation. Circulating MPs from SSc patients were characterized and their relationship with soluble markers of vascular activation...

  9. Circulating intestine-derived exosomal miR-328 in plasma, a possible biomarker for estimating BCRP function in the human intestines.

    Science.gov (United States)

    Gotanda, Keisuke; Hirota, Takeshi; Saito, Jumpei; Fukae, Masato; Egashira, Yu; Izumi, Noritomo; Deguchi, Mariko; Kimura, Miyuki; Matsuki, Shunji; Irie, Shin; Ieiri, Ichiro

    2016-08-30

    A variant in the breast cancer resistance protein (BCRP) gene, 421C> A is a useful biomarker for describing large inter-individual differences in the pharmacokinetics of sulfasalazine (SASP), a BCRP substrate. However, large intra-genotypic variability still exists in spite of the incorporation of this variant into the pharmacokinetics of SASP. Since miR-328 negatively regulates BCRP expression in human tissues, we hypothesized that exosomal miR-328 in plasma, which leaks from the intestines, is a possible biomarker for estimating BCRP activity in the human intestines. We established an immunoprecipitation-based quantitative method for circulating intestine-derived miR-328 in plasma using an anti-glycoprotein A33 antibody. A clinical study was conducted with an open-label, non-randomized, and single-arm design involving 33 healthy participants. Intestine-derived exosomal miR-328 levels positively correlated (P intestinal BCRP activity, resulting in the high AUC of SASP. Circulating intestine-derived exosomal miR-328 in plasma has potential as a possible biomarker for estimating BCRP function in the human intestines.

  10. The prognostic value of clonal heterogeneity and quantitative assessment of plasma circulating clonal IG-VDJ sequences at diagnosis in patients with follicular lymphoma

    Science.gov (United States)

    Sarkozy, Clémentine; Huet, Sarah; Carlton, Victoria E.H; Fabiani, Bettina; Delmer, Alain; Jardin, Fabrice; Delfau-Larue, Marie-Helene; Hacini, Maya; Ribrag, Vincent; Guidez, Stéphanie; Faham, Malek; Salles, Gilles

    2017-01-01

    Recent advances in next-generation sequencing (NGS) have enabled the quantitation of circulating tumour DNA (ctDNA) encoding the clonal rearranged V(D)J immunoglobulin locus. We aimed to evaluate the clonal heterogeneity of follicular lymphoma (FL) in the tumour and the plasma at diagnosis and to assess the prognostic value of the ctDNA level. Plasma samples at diagnosis were available for 34 patients registered in the PRIMA trial (NCT00140582). One tumour clonotype or more could be detected for 29 (85%) and 25 (74%) patients, respectively, in the tumour or plasma samples. In 18 patients, several subclones were detected in the tumour (2 to 71 subclones/cases) and/or in the plasma (2 to 20 subclones/cases). In more than half of the cases, the distribution of subclones differed between the tumour and plasma samples, reflecting high clonal heterogeneity and diversity in lymphoma subclone dissemination. In multivariate analysis, a high level of ctDNA was the only independent factor associated with patients’ progression-free survival (HR 4, IC 95 (1.1-37), p=.039). In conclusion, an NGS-based immunosequencing method reveals the marked clonal heterogeneity of follicular lymphoma in patients with FL, and quantification of ctDNA at diagnosis represents a potential powerful prognostic biomarker that needs to be investigated in larger cohorts. PMID:28060738

  11. Effect of Lycium barbarum Polysaccharides on the expression of endothelin-1 and its receptors in an ocular hypertension model of rat glaucoma

    Institute of Scientific and Technical Information of China (English)

    Xue-Song Mi; Kin Chiu; Geoffrey Van; Justin Wai Chung Leung; Amy Cheuk Yin; Sookja Kim Chung; Raymond Chuen-Chung Chang; Kwok-Fai So

    2012-01-01

    Lycium barbarum, a traditional Chinese anti-aging herb, has been shown to protect retinal ganglion cells (RGCs) in a rat chronic ocular hypertension (COH) model.Here, we investigated the expression of endothelin-1 (ET-1), a strong vasoconstrictor, and its receptors, ETA and ETB, in the COH model and assessed the effects of Lycium barbarum on the ET-1 axis.Elevated intraocular pressure (IOP) was induced in the right eye of SD rats using argon laser photocoagulation.(1) The expression of ET-1, ETA and ETB in normal and COH retinas was studied.(2) Some COH rats were fed daily with Lycium barbarum Polysaccharides (LBP) using 1 mg/kg or phosphate-buffered saline (PBS) for 3 weeks (started 1 week before photocoagulation).The effects of LBP on the expression of ET-1 and its receptors, ETA and ETB, in COH retina were evaluated.A semi-quantitative analysis of staining intensity was used to evaluate the expression levels of ET-1, ETA and ETB in retinal vasculature.We found that (1) Under COH condition, the immunoreactivity of ET-1 was increased in retina associated with an increase of ETB receptor immunoreactivity and a decrease of ETA receptor immunoreactivity.(2) After feeding COH rats with LBP, the expression of ET-1 was decreased with an increase of ETA expression and a decrease of ETB expression in the retina, especially in RGCs.(3) By comparing the staining intensity in the vasculature of COH retina in LBP-fed group with PBS-fed group, there was a decrease in the expression of ET-1 and ETA and an increase in ETB.In summary, ET-1 expression was up-regulated in the retina in COH model.LBP could decrease the expression of ET-1 and modulate the expression of its receptors, ETA and ETB, under the condition of COH.The neuroprotective effect of LBP on RGCs might be related to its ability to regulate the ET-1-mediated biological effects on RGCs and retinal vasculature.

  12. Human circulating plasma DNA significantly decreases while lymphocyte DNA damage increases under chronic occupational exposure to low-dose gamma-neutron and tritium β-radiation

    Energy Technology Data Exchange (ETDEWEB)

    Korzeneva, Inna B., E-mail: inna.korzeneva@molgen.vniief.ru [Russian Federal Nuclear Center – All-Russian Research Institute of Experimental Physics (RFNC-VNIIEF) 607190, Sarov, 37 Mira ave., Nizhniy Novgorod Region (Russian Federation); Kostuyk, Svetlana V.; Ershova, Liza S. [Research Centre for Medical Genetics, Russian Academy of Medical Sciences, 115478 Moscow, 1 Moskvorechye str. (Russian Federation); Osipov, Andrian N. [Federal Medial and Biological Center named after Burnazyan of the Federal Medical and Biological Agency (FMBTz named after Burnazyan of FMBA), Moscow (Russian Federation); State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Zhivopisnaya, 46, Moscow, 123098 (Russian Federation); Zhuravleva, Veronika F.; Pankratova, Galina V. [Russian Federal Nuclear Center – All-Russian Research Institute of Experimental Physics (RFNC-VNIIEF) 607190, Sarov, 37 Mira ave., Nizhniy Novgorod Region (Russian Federation); Porokhovnik, Lev N.; Veiko, Natalia N. [Research Centre for Medical Genetics, Russian Academy of Medical Sciences, 115478 Moscow, 1 Moskvorechye str. (Russian Federation)

    2015-09-15

    Highlights: • The chronic exposure to low-dose IR induces DSBs in human lymphocytes (TM index). • Exposure to IR decreases the level of human circulating DNA (cfDNA index). • IR induces an increase of DNase1 activity (DNase1 index) in plasma. • IR induces an increase of the level of antibodies to DNA (Ab DNA index) in plasma. • The ratio cfDNA/(DNase 1 × Ab DNA × TM) is a potential marker of human exposure to IR. - Abstract: The blood plasma of healthy people contains cell-fee (circulating) DNA (cfDNA). Apoptotic cells are the main source of the cfDNA. The cfDNA concentration increases in case of the organism’s cell death rate increase, for example in case of exposure to high-dose ionizing radiation (IR). The objects of the present research are the blood plasma and blood lymphocytes of people, who contacted occupationally with the sources of external gamma/neutron radiation or internal β-radiation of tritium N = 176). As the controls (references), blood samples of people, who had never been occupationally subjected to the IR sources, were used (N = 109). With respect to the plasma samples of each donor there were defined: the cfDNA concentration (the cfDNA index), DNase1 activity (the DNase1 index) and titre of antibodies to DNA (the Ab DNA index). The general DNA damage in the cells was defined (using the Comet assay, the tail moment (TM) index). A chronic effect of the low-dose ionizing radiation on a human being is accompanied by the enhancement of the DNA damage in lymphocytes along with a considerable cfDNA content reduction, while the DNase1 content and concentration of antibodies to DNA (Ab DNA) increase. All the aforementioned changes were also observed in people, who had not worked with the IR sources for more than a year. The ratio cfDNA/(DNase1 × Ab DNA × TM) is proposed to be used as a marker of the chronic exposure of a person to the external low-dose IR. It was formulated the assumption that the joint analysis of the cfDNA, DNase1, Ab

  13. Blood Volume, Plasma Volume and Circulation Time in a High-Energy-Demand Teleost, the Yellowfin Tuna (Thunnus Albacares)

    DEFF Research Database (Denmark)

    Brill, R.W.; Cousins, K.L.; Jones, D.R.

    1998-01-01

    tuna, circulation time is approximately 0.4 min (47 ml kg-1/115 ml min-1 kg- 1) compared with 1.3 min (46 ml kg-1/35 ml min-1 kg-1) in yellowtail (Seriola quinqueradiata) and 1.9 min (35 ml kg-1/18 ml min-1 kg-1) in rainbow trout (Oncorhynchus mykiss). In air-breathing vertebrates, high metabolic rates...... are necessarily correlated with short circulation times. Our data are the first to imply that a similar relationship occurs in fishes....

  14. Effects of fresh frozen plasma, Ringer's acetate and albumin on plasma volume and on circulating glycocalyx components following haemorrhagic shock in rats

    DEFF Research Database (Denmark)

    Nelson, Axel; Statkevicius, Svajunas; Schött, Ulf;

    2016-01-01

    and syndecan-1. Hemodynamic effects of resuscitation were evaluated by measuring lactate and mean arterial pressure (MAP). RESULTS: Resuscitation with FFP or albumin resulted in plasma volume expansion equalling the blood loss (to 55 ± 5 ml/kg and 54 ± 4 ml/kg (mean ± S.D.), respectively), whereas plasma...

  15. Differential regulation of self-reactivity discriminates between IgG+ human circulating memory B cells and bone marrow plasma cells.

    Science.gov (United States)

    Scheid, Johannes F; Mouquet, Hugo; Kofer, Juliane; Yurasov, Sergey; Nussenzweig, Michel C; Wardemann, Hedda

    2011-11-01

    Long-term humoral immunity is maintained by the formation of high-affinity class-switched memory B cells and long-lived antibody-secreting plasma cells. In healthy humans, a substantial fraction of IgG-positive memory B cells express self-reactive and polyreactive IgG antibodies that frequently develop by somatic mutations. Whether self- and polyreactive IgG-secreting B cells are also tolerated in the long-lived plasma cell pool is not known. To address this question, we cloned and expressed the Ig genes from 177 IgG-producing bone marrow plasma cells of four healthy donors. All antibodies were highly mutated but the frequency of self- and polyreactive IgG antibodies was significantly lower than that found in circulating memory B cells. The data suggest that in contrast to the development of memory B cells, entry into the bone marrow plasma cell compartment requires previously unappreciated selective regulation by mechanisms that limit the production of self- and polyreactive serum IgG antibodies.

  16. Plasma ghrelin in anorexia, bulimia, and binge-eating disorder: relations with eating patterns and circulating concentrations of cortisol and thyroid hormones.

    Science.gov (United States)

    Troisi, Alfonso; Di Lorenzo, Giorgio; Lega, Ilaria; Tesauro, Manfredi; Bertoli, Aldo; Leo, Roberto; Iantorno, Micaela; Pecchioli, Chiara; Rizza, Stefano; Turriziani, Mario; Lauro, Renato; Siracusano, Alberto

    2005-01-01

    The present study was designed to investigate the relations between plasma ghrelin concentrations, eating patterns, and circulating concentrations of cortisol and thyroid hormones in women with anorexia nervosa, bulimia nervosa, and binge-eating disorder. The patterns of disordered eating behavior were assessed using the Eating Attitudes Test (EAT-26) and the Bulimia Test-Revised (BULIT-R). In women with eating disorders, but not in healthy control women, plasma ghrelin concentrations were negatively correlated with body mass index (BMI) and plasma concentrations of thyreotropin (TSH), free T3 and free T4, and positively correlated with plasma concentrations of cortisol. The ghrelin concentrations of women with binge-eating and purging behavior were significantly lower than those of women with anorexia nervosa, restricting type, and there was a negative relation between the frequency and severity of binge-eating and purging behavior, as measured by the BULIT-R total score, and ghrelin concentrations. In a multivariate regression model controlling for the confounding effects of body mass index (BMI) and age, higher ghrelin concentrations were correlated with lower BULIT-R total scores. The results of this study did not confirm the hypothesis advanced in previous studies that ghrelin concentrations are higher in patients with binge-eating/purging forms of eating disorders. Based on these data, we suggest that, in women with eating disorders, ghrelin concentrations best reflect nutritional status rather than specific patterns of disordered eating behavior.

  17. The [Lys(-2)-Arg(-1)-des(17-21)]-endothelin-1 peptide retains the specific Arg(-1)-Asp8 salt bridge but reveals discrepancies between NMR data and molecular dynamics simulations.

    Science.gov (United States)

    Kaas, Quentin; Aumelas, André; Kubo, Shigeru; Chino, Naoyoshi; Kobayashi, Yuji; Chiche, Laurent

    2002-09-17

    The [des(17-21)]-endothelin-1 (CSH-ET) and [Lys(-)(2)-Arg(-)(1)-des(17-21)]-endothelin-1 (KR-CSH-ET) peptides, designed by removing the five-residue hydrophobic tail from the endothelin-1 (ET-1) and [Lys(-)(2)-Arg(-)(1)]-endothelin-1 (KR-ET-1) peptides, respectively, were synthesized. Previous studies on KR-ET-1 showed that, in contrast to ET-1, this engineered compound displays a pH-dependent conformational change related to the formation of a stabilizing salt bridge between the Arg(-)(1) and Asp(8) side chains. CD and NMR spectra indicate that CSH-ET and KR-CSH-ET display conformational behavior similar to those of ET-1 and KR-ET-1, respectively. The short salt bridge-stabilized KR-CSH-ET peptide therefore appears to be an attractive elementary scaffold for drug design. The solution structure of the salt-bridged form of KR-CSH-ET was determined by NMR at pH 4.5 and is very similar to the corresponding form of the parent KR-ET-1 peptide. Molecular dynamics simulations of the salt-bridged form of KR-CSH-ET were performed using both the GB/SA implicit solvation scheme or an explicit solvation and the particle-mesh Ewald method for long-range electrostatic calculation. Unexpectedly, the Arg(-)(1)-Asp(8) salt bridge does not display in the simulation the stability that could be expected from the experimental data. The cooperative involvement of a cation-pi interaction in formation of the salt bridge has been hypothesized. Difficulties in accurately simulating cation-pi interactions might be responsible for the lack of stability in the simulation. At this time, however, no definitive explanation for the observed discrepancy between experiments and simulations is available, and further experimental studies appear to be necessary to fully understand in atomic detail the pH-dependent conformational change observed in the KR-ET-1 series.

  18. Evidence of cell damages caused by circulating bubbles: high level of free mitochondrial DNA in plasma of rats.

    Science.gov (United States)

    Vallée, Nicolas; Gaillard, Sandrine; Peinnequin, André; Risso, Jean-Jacques; Blatteau, Jean-Eric

    2013-11-01

    Bubble formation can occur in the vascular system after diving, leading to decompression sickness (DCS). DCS signs and symptoms range from minor to death. Too often, patients are admitted to a hyperbaric center with atypical symptoms, as bubbles cannot be detected anymore. In the absence of a relevant biomarker for humans, the therapeutic management remains difficult. As circulating DNA was found in the blood of healthy humans and animals, our study was made to correlate the extracellular mitochondrial DNA (mDNA) concentration with the occurrence of clinical DCS symptoms resulting from initial bubble-induced damages. Therefore, 109 rats were subjected to decompression from a simulated 90-m sea water dive, after which, 78 rats survived (71.6%). Among the survivors, 15.6% exhibited typical DCS symptoms (DCS group), whereas the remaining 56% showed no detectable symptoms (noDCS group). Here, we report that the symptomatic rats displayed both a circulating mDNA level (DNADCS → 2.99 ± 2.62) and a bubble grade (median Spencer score = 3) higher than rats from the noDCS group (DNAnoDCS → 1.49 ± 1.27; Spencer score = 1). These higher levels could be correlated with the platelet and leukocyte consumption induced by the pathogenic decompression. Rats with no detectable bubble had lower circulating mDNA than those with higher bubble scores. We determined that in rats, a level of circulating mDNA >1.91 was highly predictive of DCS with a positive-predictive value of 87.3% and an odds ratio of 4.57. Thus circulating mDNA could become a relevant biomarker to diagnose DCS and should be investigated further to confirm its potential application in humans.

  19. Modification of pLL/DNA complexes with a multivalent hydrophilic polymer permits folate-mediated targeting in vitro and prolonged plasma circulation in vivo.

    Science.gov (United States)

    Ward, Christopher M; Pechar, Michal; Oupicky, David; Ulbrich, Karel; Seymour, Leonard W

    2002-01-01

    Gene delivery vectors based on poly(L-lysine) and DNA (pLL/DNA complexes) have limited use for targeted systemic application in vivo since they bind cells and proteins non-specifically. In this study we have attempted to form folate-targeted vectors with extended systemic circulation by surface modification of pLL/DNA complexes with hydrophilic polymers. pLL/DNA complexes were stabilised by surface modification with a multivalent reactive polymer based on alternating segments of poly(ethylene glycol) and tripeptides bearing reactive ester groups. Folate moieties were incorporated into the vectors either by direct attachment of folate to the polymer or via intermediate poly(ethylene glycol) spacers of 800 and 3400 Da. Polymer-coated complexes show similar morphology to uncoated complexes, their zeta potential is decreased towards zero, serum protein binding is inhibited and aqueous solubility is substantially increased. Intravenous (i.v.) administration to mice of coated complexes produced extended systemic circulation, with up to 2000-fold more DNA measured in the bloodstream after 30 min compared with simple pLL/DNA complexes. In further contrast to simple pLL/DNA complexes, coated complexes do not bind blood cells in vivo. Folate receptor targeting is shown to mediate targeted association with HeLa cells in vitro, leading to increased transgene expression. We demonstrate for the first time that DNA uptake via the folate receptor is dependent on pEG spacer length, with the transgene expression relatively independent of the level of internalised DNA. We show increased systemic circulation, decreased blood cell and protein binding, and folate-targeted transgene expression using pLL/DNA complexes surface-modified with a novel multireactive hydrophilic polymer. This work provides the basis for the development of plasma-circulating targeted vectors for in vivo applications. Copyright 2002 John Wiley & Sons, Ltd.

  20. Circulating MicroRNAs in Plasma of Hepatitis B e Antigen Positive Children Reveal Liver-Specific Target Genes

    DEFF Research Database (Denmark)

    Winther, Thilde Nordmann; Jacobsen, Kari Stougaard; Mirza, Aashiq Hussain

    2014-01-01

    Background and Aim. Hepatitis B e antigen positive (HBeAg-positive) children are at high risk of severe complications such as hepatocellular carcinoma and cirrhosis. Liver damage is caused by the host immune response to infected hepatocytes, and we hypothesise that specific microRNAs play a role...... with chronic hepatitis B (CHB) and in healthy controls, candidate microRNAs with aberrant plasma expressions in HBeAg-positive children were identified. MicroRNAs targeting liver-specific genes were selected based on bioinformatics analysis and validated by qRT-PCR using plasma samples from 34 HBe...... in this complex interaction between virus and host. The study aimed to identify microRNAs with aberrant plasma expressions in HBeAg-positive children and with liver-specific target genes. Methods. By revisiting our previous screen of microRNA plasma levels in HBeAg-positive and HBeAg-negative children...

  1. Altered expression of circulating microRNA in plasma of patients with primary osteoarthritis and in silico analysis of their pathways.

    Directory of Open Access Journals (Sweden)

    Verónica M Borgonio Cuadra

    Full Text Available OBJECTIVE: To analyze a set of circulating microRNA (miRNA in plasma from patients with primary Osteoarthritis (OA and describe the biological significance of altered miRNA in OA based on an in silico analysis of their target genes. METHODS: miRNA expression was analyzed using TaqMan Low Density Arrays and independent assays. The search for potential messenger RNA (mRNA targets of the differentially expressed miRNA was performed by means of the miRWalk and miRecords database; we conducted the biological relevance of the predicted miRNA targets by pathway analysis with the Reactome and DAVID databases. RESULTS: We measured the expression of 380 miRNA in OA; 12 miRNA were overexpressed under the OA condition (p value, ≤0.05; fold change, >2. These results were validated by the detection of some selected miRNA by quantitative PCR (qPCR. In silico analysis showed that target messenger RNA (mRNA were potentially regulated by these miRNA, including genes such as SMAD1, IL-1B, COL3A, VEGFA, and FGFR1, important in chondrocyte maintenance and differentiation. Some metabolic pathways affected by the miRNA: mRNA ratio are signaling Bone morphogenetic proteins (BMP, Platelet-derived growth factor (PDGF, and Nerve growth factor (NGF, these latter two involved in the process of pain. CONCLUSIONS: We identified 12 miRNA in the plasma of patients with primary OA. Specific miRNA that are altered in the disease could be released into plasma, either due to cartilage damage or to an inherent cellular mechanism. Several miRNA could regulate genes and pathways related with development of the disease; eight of these circulating miRNA are described, to our knowledge, for first time in OA.

  2. ENO1 Protein Levels in the Tumor Tissues and Circulating Plasma Samples of Non-small Cell Lung Cancer Patients

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    Ying ZHANG

    2010-12-01

    Full Text Available Background and objective Proper tumor markers are useful to diagnosis, prognosis and treatment for lung cancer. The aim of this study is to examine the levels of alpha-enolase (ENO1 protein in the tumor tissues and peripheral plasma samples obtained from non-small cell lung cancer (NSCLC patients, and evaluate its potential clinical significance. Methods The ENO1 protein levels in the tumor tissues and corresponding normal tissues from 16 cases of lung squamous cell carcinoma were analyzed by Western blot. The ENO1 protein levels in the plasma samples from 42 healthy individuals, 34 patients with lung benign disease and 84 patients with NSCLC were measured by double antibody sandwich enzyme-linked immunosorbent assay. Results For 87.5% (14/16 of the patients with lung squamous cell carcinoma, the ENO1 protein level in the tumor tissues was higher than that in the corresponding normal lung tissues. The ENO1 protein level in the plasma of NSCLC patients was significantly higher than that in the plasma of healthy individuals (P=0.031 and patients with lung benign disease (P=0.019. Furthermore, the ENO1 protein level was significantly higher in the plasma of patients with lung adenocarcinoma than that of patients with lung squamous cell carcinoma. Conclusion The elevated levels of ENO1 protein in the tumor tissues and the plasma samples from NSCLC patients indicate ENO1 may be a candidate biomarker of lung cancer.

  3. Alpha-tocotrienol is the most abundant tocotrienol isomer circulated in plasma and lipoproteins after postprandial tocotrienol-rich vitamin E supplementation

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    Fairus Syed

    2012-01-01

    Full Text Available Abstract Background Tocotrienols (T3 and tocopherols (T, both members of the natural vitamin E family have unique biological functions in humans. T3 are detected in circulating human plasma and lipoproteins, although at concentrations significantly lower than α-tocopherol (α-T. T3, especially α-T3 is known to be neuropotective at nanomolar concentrations and this study evaluated the postprandial fate of T3 and α-T in plasma and lipoproteins. Methods Ten healthy volunteers (5 males and 5 females were administered a single dose of vitamin E [526 mg palm tocotrienol-rich fraction (TRF or 537 mg α-T] after 7-d pre-conditioning on a T3-free diet. Blood was sampled at baseline (fasted and 2, 4, 5, 6, 8, and 24 h after supplementation. Concentrations of T and T3 isomers in plasma, triacylglycerol-rich particles (TRP, LDL, and HDL were measured at each postprandial interval. Results After TRF supplementation, plasma α-T3 and γ-T3 peaked at 5 h (α-T3: 4.74 ± 1.69 μM; γ-T3: 2.73 ± 1.27 μM. δ-T3 peaked earlier at 4 h (0.53 ± 0.25 μM. In contrast, α-T peaked at 6 h (30.13 ± 2.91 μM and 8 h (37.80 ± 3.59 μM following supplementation with TRF and α-T, respectively. α-T was the major vitamin E isomer detected in plasma, TRP, LDL, and HDL even after supplementation with TRF (composed of 70% T3. No T3 were detected during fasted states. T3 are detected postprandially only after TRF supplementation and concentrations were significantly lower than α-T. Conclusions Bio-discrimination between vitamin E isomers in humans reduces the rate of T3 absorption and affects their incorporation into lipoproteins. Although low absorption of T3 into circulation may impact some of their physiological functions in humans, T3 have biological functions well below concentration noted in this study.

  4. Plasma L-cystine/L-glutamate imbalance increases tumor necrosis factor-alpha from CD14+ circulating monocytes in patients with advanced cirrhosis.

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    Eiji Kakazu

    Full Text Available BACKGROUND AND AIMS: The innate immune cells can not normally respond to the pathogen in patients with decompensated cirrhosis. Previous studies reported that antigen-presenting cells take up L-Cystine (L-Cys and secrete substantial amounts of L-Glutamate (L-Glu via the transport system Xc- (4F2hc+xCT, and that this exchange influences the immune responses. The aim of this study is to investigate the influence of the plasma L-Cys/L-Glu imbalance observed in patients with advanced cirrhosis on the function of circulating monocytes. METHODS: We used a serum-free culture medium consistent with the average concentrations of plasma amino acids from patients with advanced cirrhosis (ACM, and examined the function of CD14+ monocytes or THP-1 under ACM that contained 0-300 nmol/mL L-Cys with LPS. In patients with advanced cirrhosis, we actually determined the TNF-alpha and xCT mRNA of monocytes, and evaluated the correlation between the plasma L-Cys/L-Glu ratio and TNF-alpha. RESULTS: The addition of L-Cys significantly increased the production of TNF alpha from monocytes under ACM. Monocytes with LPS and THP-1 expressed xCT and a high level of extracellular L-Cys enhanced L-Cys/L-Glu antiport, and the intracellular GSH/GSSG ratio was decreased. The L-Cys transport was inhibited by excess L-Glu. In patients with advanced cirrhosis (n = 19, the TNF-alpha and xCT mRNA of monocytes were increased according to the Child-Pugh grade. The TNF-alpha mRNA of monocytes was significantly higher in the high L-Cys/L-Glu ratio group than in the low ratio group, and the plasma TNF-alpha was significantly correlated with the L-Cys/L-Glu ratio. CONCLUSIONS: A plasma L-Cys/L-Glu imbalance, which appears in patients with advanced cirrhosis, increased the TNF-alpha from circulating monocytes via increasing the intracellular oxidative stress. These results may reflect the immune abnormality that appears in patients with decompensated cirrhosis.

  5. Isolation and characterization of circulating micro(nano)vesicles in the plasma of colorectal cancer patients and their interactions with tumor cells.

    Science.gov (United States)

    Stec, Małgorzata; Baj-Krzyworzeka, Monika; Baran, Jarosław; Węglarczyk, Kazimierz; Zembala, Maria; Barbasz, Jakub; Szczepanik, Antoni; Zembala, Marek

    2015-11-01

    Micro(nano)vesicles (MV) are regarded as important messengers in cell-to-cell communication. There is also evidence for their pivotal role in cancer progression. Circulating MV are of different body cells origin, including tumor cell‑derived MV (TMV) in cancer patients. Determination of circulating TMV is of importance because of their potential diagnostic and therapeutic applications. In the present study, an analysis of circulating MV in colorectal cancer (CRC) patients was undertaken. Plasma from healthy donors was used as the control. In order to define MV characteristics, two plasma fractions: obtained by sequential centrifugation at 15,000 x g (MV15) and 50,000 x g (MV50) were used for analysis. The two fractions possessed a large range of sizes: 70(80)-1,300(1,400) nm and the most common particles with sizes 70-90 nm, both in patients and controls. Atomic force microscopy images of MV50 revealed a heterogeneous population of particles with different shapes and sizes. MV15 contained an increased level of CD41+ and CD61+ particles, suggesting their platelet origin. No difference between patients and controls was observed. A more precise analysis of MV50 showed the increased level of particles expressing EGFR (HER-1/Erb B1), HER-2/neu and Mucin1 (MUC1), suggesting their tumor origin. The total level of MV50‑expressing EGFR, HER-2/neu and MUC1 was enhanced in CRC patients. MV50 both of patients and controls attached to a colon cancer cell line (SW480) and to isolated blood monocytes at 2 h and were engulfed at 24 h. This uptake showed the lack of specificity. Thus, apart from the direct delivery of MV to the tumor site by plasma, monocytes carrying MV may also be involved in their transportation. Taken together, the presented data indicate that MV15 contain mainly platelet‑derived particles, while MV50 from CRC patients are enriched in TMV. Interaction of MV with cancer cells may pin-point their role in communication between tumor cells, resulting

  6. Circulating cytokines and chemokines associated with plasma leakage and hepatic dysfunction in Brazilian children with dengue fever.

    Science.gov (United States)

    Ferreira, Ralph Antonio Xavier; de Oliveira, Solange Artimos; Gandini, Mariana; Ferreira, Laura da Cunha; Correa, Gladys; Abiraude, Fernanda Mattos; Reid, Mariana Mancebo; Cruz, Oswaldo Gonçalves; Kubelka, Claire Fernandes

    2015-09-01

    Dengue fever is usually a benign acute viral infection transmitted by arthropods but may evolve to severe clinical manifestations such as coagulation and/or hemodynamic disorders, caused mainly by an increase of vascular permeability. Deregulated circulating immunological factors have been associated with severity. In Brazil severe cases appeared in children only recently and we evaluated the profile of cytokine/chemokine kinetics in 134 hospitalized young patients during the epidemic in Rio de Janeiro in 2008. Inflammatory cytokines TNF and IFNγ were found elevated during the acute phase in children as well as the anti-inflammatory IL10 and chemokines MIF and CXCL10/IP10, all last three persisting longer during the recovery phase. Severe disease fitting the dengue hemorrhagic fever pattern (WHO, 1997) was associated with higher IL10 and CXCL10/IP10 circulating levels (peak levels at seven days with P<0.01 and P<0.001 respectively as compared to DF). These factors were higher in patients pulmonary effusion or ascites (P<0.05 for IL10 and P<0.01 for CXCL10/IP10). Both factors were also associated with liver changes such as AST increase correlated with CXCL10/IP10 (r=0.4300 with P<0.0001) and patients presenting painful hepatomegaly showed higher circulating levels of IL10 (P<0.01, at 7-9 days) and of CXCL10/IP10 (P<0.05, 4-6 days and P<0.001, 7-9 days) when compared to patients without apparent liver alterations. Most cases presented a history of prior infection (93%). This is the first study demonstrating cytokine and chemokine association with severity during dengue fever in Brazilian children. IL10 and CXCL10/IP10 play a role in the disease severity associated with induction of vascular leakage and a novel association with changes in liver dysfunction.

  7. Circulating MicroRNAs in Plasma of Hepatitis B e Antigen Positive Children Reveal Liver-Specific Target Genes

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    Thilde Nordmann Winther

    2014-01-01

    Full Text Available Background and Aim. Hepatitis B e antigen positive (HBeAg-positive children are at high risk of severe complications such as hepatocellular carcinoma and cirrhosis. Liver damage is caused by the host immune response to infected hepatocytes, and we hypothesise that specific microRNAs play a role in this complex interaction between virus and host. The study aimed to identify microRNAs with aberrant plasma expressions in HBeAg-positive children and with liver-specific target genes. Methods. By revisiting our previous screen of microRNA plasma levels in HBeAg-positive and HBeAg-negative children with chronic hepatitis B (CHB and in healthy controls, candidate microRNAs with aberrant plasma expressions in HBeAg-positive children were identified. MicroRNAs targeting liver-specific genes were selected based on bioinformatics analysis and validated by qRT-PCR using plasma samples from 34 HBeAg-positive, 26 HBeAg-negative, and 60 healthy control children. Results. Thirteen microRNAs showed aberrant plasma expressions in HBeAg-positive children and targeted liver-specific genes. In particular, three microRNAs were upregulated and one was downregulated in HBeAg-positive children compared to HBeAg-negative and healthy control children, which showed equal levels. Conclusion. The identified microRNAs might impact the progression of CHB in children. Functional studies are warranted, however, to elucidate the microRNAs’ role in the immunopathogenesis of childhood CHB.

  8. Prediagnostic circulating concentrations of plasma insulin-like growth factor-I and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition.

    Science.gov (United States)

    Perez-Cornago, Aurora; Appleby, Paul N; Tipper, Sarah; Key, Timothy J; Allen, Naomi E; Nieters, Alexandra; Vermeulen, Roel; Roulland, Sandrine; Casabonne, Delphine; Kaaks, Rudolf; Fortner, Renee T; Boeing, Heiner; Trichopoulou, Antonia; La Vecchia, Carlo; Klinaki, Eleni; Hansen, Louise; Tjønneland, Anne; Bonnet, Fabrice; Fagherazzi, Guy; Boutron-Ruault, Marie-Christine; Pala, Valeria; Masala, Giovanna; Sacerdote, Carlotta; Peeters, Petra H; Bueno-de-Mesquita, H B As; Weiderpass, Elisabete; Dorronsoro, Miren; Quirós, J Ramón; Barricarte, Aurelio; Gavrila, Diana; Agudo, Antonio; Borgquist, Signe; Rosendahl, Ann H; Melin, Beatrice; Wareham, Nick; Khaw, Kay-Tee; Gunter, Marc; Riboli, Elio; Vineis, Paolo; Travis, Ruth C

    2017-03-01

    Insulin-like growth factor (IGF)-I has cancer promoting activities. However, the hypothesis that circulating IGF-I concentration is related to risk of lymphoma overall or its subtypes has not been examined prospectively. IGF-I concentration was measured in pre-diagnostic plasma samples from a nested case-control study of 1,072 cases of lymphoid malignancies and 1,072 individually matched controls from the European Prospective Investigation into Cancer and Nutrition. Odds ratios (ORs) and confidence intervals (CIs) for lymphoma were calculated using conditional logistic regression. IGF-I concentration was not associated with overall lymphoma risk (multivariable-adjusted OR for highest versus lowest third = 0.77 [95% CI = 0.57-1.03], ptrend  = 0.06). There was no statistical evidence of heterogeneity in this association with IGF-I by sex, age at blood collection, time between blood collection and diagnosis, age at diagnosis, or body mass index (pheterogeneity for all  ≥ 0.05). There were no associations between IGF-I concentration and risk for specific BCL subtypes, T-cell lymphoma or Hodgkin lymphoma, although number of cases were small. In this European population, IGF-I concentration was not associated with risk of overall lymphoma. This study provides the first prospective evidence on circulating IGF-I concentrations and risk of lymphoma. Further prospective data are required to examine associations of IGF-I concentrations with lymphoma subtypes.

  9. Fetal RHD Genotyping from Circulating Cell-Free Fetal DNA in Plasma of Rh Negative Pregnant Women in Iran.

    Science.gov (United States)

    Ahmadi, Mohammad Hossein; Hantuoshzadeh, Sedigheh; Okhovat, Mohammad Ali; Nasiri, Nahid; Azarkeivan, Azita; Amirizadeh, Naser

    2016-12-01

    The prenatal determination of the fetal Rh genotype could lead to a substantial reduction in the use of anti-D immunoglobulin and prevention of unnecessary exposure of pregnant women carrying RhD negative fetus. The aim of this study was fetal RHD genotyping through the analysis of cffDNA in plasma samples of RhD negative pregnant women by real-time PCR technique. In this experiment, 30 plasma samples were collected from RhD negative pregnant women. DNA were extracted and real-time PCR reactions were done by specific primers for RHD, SRY and beta-globin (GLO) genes. The Rh phenotypes of mothers and their babies were determined by agglutination method and specific anti-serums. From the 30 maternal plasma samples considered for SRY genotyping, 16 samples revealed the presence of the SRY gene. Regarding the fetal RHD genotyping, 26 samples were positive for RhD and 4 samples were negative. In all cases, the predicted RhD and SRY genotypes were in concordance with the serologically determined phenotypes. The sensitivity, specificity and precision of the fetal RHD and SRY genotyping test were calculated 100 % (p value <0.0005; K = 100 %). The present study confirms the precision of fetal RHD and SRY genotyping in maternal plasma by real-time PCR technique. This method helps RhD negative pregnant women about the appropriate use of anti-D immunoglobulin and also on the management and prevention of HDFN. However, superior and confirmatory studies are recommended before fetal RHD genotyping by real-time PCR is introduced as a non-invasive prenatal screening test.

  10. Characterization of inactive renin from human kidney and plasma. Evidence of a renal source of circulating inactive renin.

    OpenAIRE

    Hsueh, W A; Carlson, E J; Dzau, V J

    1983-01-01

    An inactive form of renin has been isolated from human plasma. It has been suggested that this may represent renin precursor secreted from the kidney. However, early studies failed to isolate inactive renin from human renal tissue. In this investigation, rapid processing of human kidney cortex at temperatures below 4 degrees C in the presence of protease inhibitors followed by cibacron-blue affinity chromatography allowed us to extract a totally inactive form of renal renin. Furthermore, we f...

  11. Human circulating plasma DNA significantly decreases while lymphocyte DNA damage increases under chronic occupational exposure to low-dose gamma-neutron and tritium β-radiation.

    Science.gov (United States)

    Korzeneva, Inna B; Kostuyk, Svetlana V; Ershova, Liza S; Osipov, Andrian N; Zhuravleva, Veronika F; Pankratova, Galina V; Porokhovnik, Lev N; Veiko, Natalia N

    2015-09-01

    The blood plasma of healthy people contains cell-fee (circulating) DNA (cfDNA). Apoptotic cells are the main source of the cfDNA. The cfDNA concentration increases in case of the organism's cell death rate increase, for example in case of exposure to high-dose ionizing radiation (IR). The objects of the present research are the blood plasma and blood lymphocytes of people, who contacted occupationally with the sources of external gamma/neutron radiation or internal β-radiation of tritium N = 176). As the controls (references), blood samples of people, who had never been occupationally subjected to the IR sources, were used (N = 109). With respect to the plasma samples of each donor there were defined: the cfDNA concentration (the cfDNA index), DNase1 activity (the DNase1 index) and titre of antibodies to DNA (the Ab DNA index). The general DNA damage in the cells was defined (using the Comet assay, the tail moment (TM) index). A chronic effect of the low-dose ionizing radiation on a human being is accompanied by the enhancement of the DNA damage in lymphocytes along with a considerable cfDNA content reduction, while the DNase1 content and concentration of antibodies to DNA (Ab DNA) increase. All the aforementioned changes were also observed in people, who had not worked with the IR sources for more than a year. The ratio cfDNA/(DNase1×Ab DNA × TM) is proposed to be used as a marker of the chronic exposure of a person to the external low-dose IR. It was formulated the assumption that the joint analysis of the cfDNA, DNase1, Ab DNA and TM values may provide the information about the human organism's cell resistivity to chronic exposure to the low-dose IR and about the development of the adaptive response in the organism that is aimed, firstly, at the effective cfDNA elimination from the blood circulation, and, secondly - at survival of the cells, including the cells with the damaged DNA. Copyright © 2015. Published by Elsevier B.V.

  12. Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients.

    Science.gov (United States)

    Hertz, Daniel L; Speth, Kelly A; Kidwell, Kelley M; Gersch, Christina L; Desta, Zeruesenay; Storniolo, Anna Maria; Stearns, Vered; Skaar, Todd C; Hayes, Daniel F; Henry, N Lynn; Rae, James M

    2017-06-22

    The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05). Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

  13. 血浆大内皮素1对心脏再同步治疗反应性的预测价值%Predictive value of big endothelin-1 to responsiveness to cardiac resynchronization therapy

    Institute of Scientific and Technical Information of China (English)

    杨新玮; 华伟; 王靖; 丁立刚; 刘志敏; 李崇强; 陈柯萍; 张澍

    2013-01-01

    Objective To assess the predictive potency of big endothelin-1 (big ET-1) to response to cardiac resynchronization therapy (CRT).Methods We retrospectively analyzed the data of patients who underwent CRT-P/D implantation from Jan 2009 to Dec 2011.Big ET-1 and NT-proBNP were tested by ELISA kit at baseline.NYHA functional class,echocardiography were evaluated both at baseline and follow-up.Simpson method was applied to measure left ventricular ejection fraction (LVEF).Improvement of LVEF by 0.05 and reduction in NYHA class ≥ 1 grade was defined as responder.Improvement of LVEF by twice or the absolute level ≥ 0.50 with NYHA class Ⅰ or Ⅱ grade was defined as super-responder.Results Overall 93 patients aged (60.8 ± 11.0) years old included in this observational study.During 12 ~ 50 (27 ± 11.0) months follow-up,there were 34 non-responders,24 responders and 35 super-responders.Level of plasma big ET-1 in three groups were (1.2±0.9) pmol/L、(0.8±0.4) pmol/L and (0.8±0.6) pmol/L(P =0.003),respectively.Correlation between big ET-1 and NT-proBNP and between big ET-1 and response to CRT was r =0.469 (P =0.001) and r =-0.237(P=0.022),respectively.Conclusion Plasma big ET-1 correlated with the severity of heart failure.It could serve as a response predictor to CRT.High level of big ET-1 indicated non-responder.%目的 评价血浆大内皮素l(big ET-1)预测心脏再同步治疗(CRT)反应性的临床价值.方法 本研究回顾性分析了2009年1月至2011年12月间在阜外心血管病医院植入心脏再同步治疗起搏器和/或心脏再同步治疗除颤器(CRT-P/D)的患者.酶联免疫吸附试验(ELISA)测定基线big ET-1及氨基末端B型脑钠肽前体(NT-proBNP)水平,采集基线及随访期心功能(NYHA分级)和超声心动图指标,用Simpson法测定左心室射血分数(LVEF).心功能降低Ⅰ级同时LVEF提高≥0.05定义为有反应;LVEF提高2倍或绝对值≥0.50同时心功能改善至Ⅰ或

  14. Steroid-induced polycystic ovaries in rats: effect of electro-acupuncture on concentrations of endothelin-1 and nerve growth factor (NGF, and expression of NGF mRNA in the ovaries, the adrenal glands, and the central nervous system

    Directory of Open Access Journals (Sweden)

    Aloe Luigi

    2003-04-01

    Full Text Available Abstract Previous studies on the effect of repeated electro-acupuncture (EA treatments in rats with steriod-induced polycystic ovaries (PCO, EA has been shown to modulate nerve growth factor (NGF concentration in the ovaries as well as corticotropin releasing factor (CRF in the median eminence (ME. In the present study we tested the hypothesis that repeated EA treatments modulates sympathetic nerve activity in rats with PCO. This was done by analysing endothelin-1 (ET-1, a potent vasoconstrictor involved in ovarian functions, as well as NGF and NGF mRNA expression involved in the pathophysiological process underlying steroid-induced PCO. The main result in the present study was that concentrations of ET-1 in the ovaries were significantly lower in the PCO group receiving EA compared with the healthy control group (p p p p

  15. A Novel Algorithm for the Assessment of Blood-Brain Barrier Permeability Suggests That Brain Topical Application of Endothelin-1 Does Not Cause Early Opening of the Barrier in Rats

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    D. Jorks

    2011-01-01

    Full Text Available There are a number of different experimental methods for ex vivo assessment of blood-brain barrier (BBB opening based on Evans blue dye extravasation. However, these methods require many different steps to prepare the brain and need special equipment for quantification. We here report a novel, simple, and fast semiquantitative algorithm to assess BBB integrity ex vivo. The method is particularly suitable for cranial window experiments, since it keeps the spatial information about where the BBB opened. We validated the algorithm using sham controls and the established model of brain topical application of the bile salt dehydrocholate for early BBB disruption. We then studied spreading depolarizations in the presence and the absence of the vasoconstrictor endothelin-1 and found no evidence of early BBB opening (three-hour time window. The algorithm can be used, for example, to assess BBB permeability ex vivo in combination with dynamic in vivo studies of BBB opening.

  16. Prediagnostic circulating concentrations of plasma insulin‐like growth factor‐I and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition

    Science.gov (United States)

    Appleby, Paul N.; Tipper, Sarah; Key, Timothy J.; Allen, Naomi E.; Nieters, Alexandra; Vermeulen, Roel; Roulland, Sandrine; Casabonne, Delphine; Kaaks, Rudolf; Fortner, Renee T.; Boeing, Heiner; Trichopoulou, Antonia; La Vecchia, Carlo; Klinaki, Eleni; Hansen, Louise; Tjønneland, Anne; Bonnet, Fabrice; Fagherazzi, Guy; Boutron‐Ruault, Marie‐Christine; Pala, Valeria; Masala, Giovanna; Sacerdote, Carlotta; Peeters, Petra H.; Bueno‐de‐Mesquita, H. B(as); Weiderpass, Elisabete; Dorronsoro, Miren; Quirós, J. Ramón; Barricarte, Aurelio; Gavrila, Diana; Agudo, Antonio; Borgquist, Signe; Rosendahl, Ann H.; Melin, Beatrice; Wareham, Nick; Khaw, Kay‐Tee; Gunter, Marc; Riboli, Elio; Vineis, Paolo; Travis, Ruth C.

    2016-01-01

    Insulin‐like growth factor (IGF)‐I has cancer promoting activities. However, the hypothesis that circulating IGF‐I concentration is related to risk of lymphoma overall or its subtypes has not been examined prospectively. IGF‐I concentration was measured in pre‐diagnostic plasma samples from a nested case–control study of 1,072 cases of lymphoid malignancies and 1,072 individually matched controls from the European Prospective Investigation into Cancer and Nutrition. Odds ratios (ORs) and confidence intervals (CIs) for lymphoma were calculated using conditional logistic regression. IGF‐I concentration was not associated with overall lymphoma risk (multivariable‐adjusted OR for highest versus lowest third = 0.77 [95% CI = 0.57–1.03], p trend = 0.06). There was no statistical evidence of heterogeneity in this association with IGF‐I by sex, age at blood collection, time between blood collection and diagnosis, age at diagnosis, or body mass index (p heterogeneity for all ≥ 0.05). There were no associations between IGF‐I concentration and risk for specific BCL subtypes, T‐cell lymphoma or Hodgkin lymphoma, although number of cases were small. In this European population, IGF‐I concentration was not associated with risk of overall lymphoma. This study provides the first prospective evidence on circulating IGF‐I concentrations and risk of lymphoma. Further prospective data are required to examine associations of IGF‐I concentrations with lymphoma subtypes. PMID:27870006

  17. Taoren-Honghua herb pair and its main components promoting blood circulation through influencing on hemorheology, plasma coagulation and platelet aggregation.

    Science.gov (United States)

    Liu, Li; Duan, Jin-ao; Tang, Yuping; Guo, Jianming; Yang, Nianyun; Ma, Hongyue; Shi, Xuqin

    2012-01-31

    Persicae Semen (Taoren) and Carthami Flos (Honghua) used in pair which is named as Taoren-Honghua (TH) herb pair has been used in traditional Chinese medicine (TCM) for promoting blood circulation to dissipate blood stasis for many years in China. This paper investigated the effects of TH and its main components amygdalin and hydroxysafflor yellow A (HSYA) on hemorheological disorders of blood stasis in rats. Rats were randomly divided into seven groups (control group, model group, TH group, amygdalin group, HSYA group, amygdalin+HSYA group, and aspirin group) with eight animals in each, whose gender was equally distributed throughout groups. All treatments were performed by gavage and administered seven times with an interval of 12h. After the fifth administration, the model rats except those in control group with blood stasis were established by being placed in ice-cold water during the interval between two injections of adrenaline hydrochloride (Adr); and blood samples were collected 30min after the last administration on the following day. TH could significantly decrease whole blood viscosity (WBV), plasma viscosity (PV) and packed cell volume (PCV). It also significantly prolonged thrombin time (TT) and thromboplastin time (APTT), increased prothrombin time (PT) and lowered fibrinogen content (FIB). HSYA which significantly decreased WBV and PV had no effect on plasma coagulation parameters. Amygdalin could significantly decrease PV, prolong APTT and decrease FIB, showing few effects on WBV. TH and its main components amygdalin and HSYA could significantly reduce platelet aggregation and protect vascular endothelial cells. Based on the above results, amygdalin and HSYA were responsible for the main curative effects of TH and usually had synergetic effects, such as decreasing PV and platelet aggregation percentage. The study may provide scientific information to further understanding of the mechanism(s) of TH and its main components in activating blood

  18. Fetal Circulation

    Science.gov (United States)

    ... Peripheral Artery Disease Venous Thromboembolism Aortic Aneurysm More Fetal Circulation Updated:Oct 18,2016 click to enlarge The ... fetal heart. These two bypass pathways in the fetal circulation make it possible for most fetuses to survive ...

  19. Analysis of plasma cytokines and angiogenic factors in patients with pretreated urothelial cancer receiving Pazopanib: the role of circulating interleukin-8 to enhance the prognostic accuracy

    Science.gov (United States)

    Necchi, A; Pennati, M; Zaffaroni, N; Landoni, E; Giannatempo, P; Raggi, D; Schwartz, L H; Morosi, C; Crippa, F; Farè, E; Nicolai, N; Lanocita, R; Sava, T; Sacco, C; Messina, C; Ortega, C; De Braud, F G; Salvioni, R; Daidone, M G; Gianni, A M; Mariani, L

    2014-01-01

    Background: Pazopanib achieved the end point of clinical activity in pretreated patients with urothelial cancer in a single-group, phase 2 trial. The objective was to identify biological predictors of clinical benefit to pazopanib in these patients. Methods: EDTA blood samples were collected at baseline (T0) and after 4 weeks (T1) of treatment, together with radiological imaging in all 41 patients to analyse plasma circulating angiogenic factor levels by multiplex ELISA plates. Changes from T0 to T1 in marker levels were matched with response with the covariance analysis. Univariable and multivariable analyses evaluated the association with overall survival (OS), adjusted for prespecified clinical variables. Net reclassification improvement (NRI) tested the performance of the recognised Cox model. Results: Increasing IL8T1 level associated with lower response probability at covariance analysis (P=0.010). Both IL8T0 (P=0.019) and IL8T1 (P=0.004) associated with OS and the prognostic model, including clinical variables and IL8T1 best-predicted OS after backward selection. The NRI for this model was 39%. When analysed as a time-varying covariate, IL8T1 level<80 pg ml−1 portended significantly greater response (∼80%) and 6-month OS (∼60%) probability than level⩾80. Conclusion: IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability. PMID:24231947

  20. Perbedaan Kadar Endotelin-1 Plasma pada Penderita Preeklampsia dengan Kehamilan Normotensif

    Directory of Open Access Journals (Sweden)

    Susi Hartati

    2015-09-01

    Full Text Available Abstrak Endotelin-1 merupakan derivat endotelium yang ampuh sebagai vasokontriksi  paling kuat yang memiliki 21 asam amino. Kerusakan lapisan endotel mengaktivasikan peningkatan vasokontriksi yaitu endotelin-1. Peningkatan endotelin-1 ini menyebabkan terjadinya resistensi diseluruh sistem vaskuler maternal yang memiliki lapisan endotel sehingga menimbulkan manifestasi klinis preeklampsia. Tujuan penelitian ini adalah menentukan perbedaan kadar endotelin-1 plasma pada penderita preeklampsia dan kehamilan normotensif. Penelitian bersifat observasional dengan desaincross sectional comparative. Penelitian ini dilakukan di RSUP Dr.M.Djamil Padang dan RS Tk.III Reksodiwiryo Padang. Sampel penelitian ini terdiri dari dua kelompok yaitu 16 penderita preeklampsia dan 16 kehamilan normotensifdengan waktu penelitian dari  Juni sampai Agustus 2014. Analisis sampel dilakukan di Laboratorium Biomedik Universitas Andalas Padang. Pemeriksaan kadar endotelin-1 menggunakan metode ELISA. Analisa statistik mengunakan univariat dan bivariat. Analisa bivariat mengunakan uji t tidak berpasangan yang telah dilakukan uji normalitas dan uji homogenitas. Hasil penelitian ini diperoleh bahwa rerata kadar endotelin-1 plasma pada penderita preeklampsia yaitu 0,73 ± 0,15 pg/ml, rerata kadar endotelin-1 plasma pada kehamilan normotensif yaitu 0,56 ±0,13 pg/ml dengan nilai p<0,05 (0,002. Kesimpulan penelitian ini adalah terdapat perbedaan kadar endotelin-1 yang signifikan rerata kadar endotelin-1 plasma pada penderita preeklampsia dengan kehamilan normotensif.Kata kunci: preeklampsia, endotelin-1, normotensifAbstract  Endothelin-1 is potent endothelium derived as the strongest vasocontrictor that has 21 amino acids. Damage of endothelial layer activated the increasing of vasoconstriction which is endothelin-1. The increasing of endothelin-1 caused a resistence across the maternal vascular system that has endothelial layer make a clinical manifestations of preeclampsia. The

  1. High arterial compliance in cirrhosis is related to low adrenaline and elevated circulating calcitonin gene related peptide but not to activated vasoconstrictor systems

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik; Møller, Søren; Schifter, S

    2001-01-01

    catecholamines, renin activity, endothelin-1, and calcitonin gene related peptide (CGRP) at baseline and during oxygen inhalation. RESULTS: COMP(art) was significantly increased in cirrhotic patients compared with controls (1.32 v 1.06 ml/mm Hg; padrenaline levels (r=-0.......001) and central circulation time (r=-0.49; padrenaline (-16%; p... to COMP(art) disappeared. The relation of COMP(art) to CGRP and circulatory variables remained unchanged. CONCLUSION: Elevated arterial compliance in cirrhosis is related to low adrenaline, high CGRP, and systemic hyperdynamics but not to indicators of the activated vasoconstrictor systems (noradrenaline...

  2. Role of endothelin in uteroplacental circulation and fetal vascular function.

    Science.gov (United States)

    Paradis, Alexandra; Zhang, Lubo

    2013-09-01

    Endothelins are 21-amino acid peptides involved in vascular homeostasis. Three types of peptide have been identified, with endothelin-1 (ET-1) being the most potent vasoconstrictor currently known. Two endothelin receptor subtypes are found in various tissues, including the brain, heart, blood vessel, lung, and placenta. The ETA-receptor is associated with vasoconstriction in vascular smooth muscle. Conversely, the ETB-receptor can elicit a vasoconstrictor effect in vascular smooth muscle and a vasodilator effect via its action in endothelial cells. Both receptors play a key role in maintaining circulatory homeostasis and vascular function. Changes in ET-1 expression are found in various disease states, and overexpression of ET-1 is observed in hypertension and preeclampsia in pregnancy. Placental localization of ET-1 implies a key role in regulating the uteroplacental circulation. Additionally, ET-1 is important in the fetal circulation and is involved in the pulmonary circulation and closure of the ductus arteriosus after birth, as well as fetal growth constriction in utero. ET receptor antagonists and nitric oxide donors may provide therapeutic potential in treating conditions associated with overexpression of ET and hypertension.

  3. Endothelin-1 induces intracellular [Ca2+] increase via Ca2+ influx through the L-type Ca2+ channel, Ca2+-induced Ca2+ release and a pathway involving ETA receptors, PKC, PKA and AT1 receptors in cardiomyocytes

    Institute of Scientific and Technical Information of China (English)

    ZENG QingHua; LI XingTing; ZHONG GuoGan; ZHANG WenJie; SUN ChengWen

    2009-01-01

    Using fura-2-acetoxymethyl eater (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca2+]1) in a dose-dependent manner and activated the L-type Ca2+ channel in cardiomyocytes isolated from rats.The effect of ET-1 on [Ca2+]1 elevation was abolished in the presence of the ETA receptor blocker BQ123,but was not affected by the ETa receptor blocker BQ788. ET-1-induced an increase in [Ca2+]1, which was inhibited 46.7% by pretreatment with a high concentration of ryanodine (10 μmol/L), a blocker of the ryanodine receptor. The ET-1-induced [Ca2+]i increase was also inhibited by the inhibltors of protein kinase A (PKA), protein kinase C (PKC) and angiotensin type 1 receptor (AT1 receptor). We found that ET-1 induced an enhancement of the amplitude of the whole cell L-type Ca2+ channel current and an Increase of open-state probability (NPo) of an L-type single Ca2+ channel. BQ123 completely blocked the ET-1-induced increase in calcium channel open-state probability. In this study we demonstrated that ET-1 regulates calcium overload through a series of mechanisms that include L-type Ca2+ channel activation and Ca2+-induced Ca2+ release (CICR). ETa receptors, PKC, PKA and AT1 receptors may also contribute to this pathway.

  4. Endothelin-1 induces intracellular [Ca2+] increase via Ca2+ influx through the L-type Ca2+ channel, Ca2+-induced Ca2+ release and a pathway involving ETA receptors, PKC, PKA and AT1 receptors in cardiomyocytes

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca2+]i) in a dose-dependent manner and activated the L-type Ca2+ channel in cardiomyocytes isolated from rats. The effect of ET-1 on [Ca2+]i elevation was abolished in the presence of the ETA receptor blocker BQ123, but was not affected by the ETB receptor blocker BQ788. ET-1-induced an increase in [Ca2+]i, which was inhibited 46.7% by pretreatment with a high concentration of ryanodine (10 μmol/L), a blocker of the ryanodine receptor. The ET-1-induced [Ca2+]i increase was also inhibited by the inhibitors of protein kinase A (PKA), protein kinase C (PKC) and angiotensin type 1 receptor (AT1 receptor). We found that ET-1 induced an enhancement of the amplitude of the whole cell L-type Ca2+ channel current and an increase of open-state probability (NPo) of an L-type single Ca2+ channel. BQ123 completely blocked the ET-1-induced increase in calcium channel open-state probability. In this study we demonstrated that ET-1 regulates calcium overload through a series of mechanisms that include L-type Ca2+ channel activation and Ca2+-induced Ca2+ release (CICR). ETA receptors, PKC, PKA and AT1 receptors may also contribute to this pathway.

  5. Nearshore circulation

    NARCIS (Netherlands)

    Battjes, J.A.; Sobey, R.J.; Stive, M.J.F.

    1990-01-01

    Shelf circulation is driven primarily by wind- and tide-induced forces. It is laterally only weakly constrained so that the geostrophic (Coriolis) acceleration is manifest in the response. Nearshore circulation on the other hand is dominated by wave-induced forces associated with shallow-water. wave

  6. Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise Garm; Pallisgaard, Niels; Appelt, Ane Lindegaard

    2015-01-01

    by an in-house qPCR method. Results are presented according to REMARK. RESULTS: One-hundred-and-forty patients were included. Thirty-four percent had detectable KRAS mutations in the tumour, compared to 23% in plasma. KRAS detection in archival tumour tissue showed no correlation to survival, whereas...... in patients from metastatic colorectal cancer (mCRC) prior to anti-epidermal growth factor receptor (anti-EGFR) therapy. Secondly, we investigated the concentration of total cfDNA in relation to clinical outcome. PATIENTS AND METHODS: Patients were resistant to 5-FU, oxaliplatin and irinotecan and treated......BACKGROUND: Circulating cell-free DNA (cfDNA) in plasma is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumour specific mutations e.g. KRAS. We investigated the clinical value of KRAS mutations when detected in plasma compared to tumour...

  7. Landiolol hydrochloride ameliorates acute lung injury in a rat model of early sepsis through the suppression of elevated levels of pulmonary endothelin-1.

    Science.gov (United States)

    Matsuishi, Yujiro; Jesmin, Subrina; Kawano, Satoru; Hideaki, Sakuramoto; Shimojo, Nobutake; Mowa, Chishimba Nathan; Akhtar, Shila; Zaedi, Sohel; Khatun, Tanzila; Tsunoda, Yoshiya; Kiwamoto, Takumi; Hizawa, Nobuyuki; Inoue, Yoshiaki; Mizutani, Taro

    2016-12-01

    Among the dysfunctions and pathologies associated with sepsis, the underlying molecular mechanisms of sepsis-induced acute lung injury (ALI) are poorly understood. Endothelin (ET)-1, a potent vasoconstrictor and pro-inflammatory peptide, is known to be involved in the pathogenesis of ALI in a rat model of sepsis. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting β-blocker, plays a crucial role in ameliorating and attenuating LPS-induced ALI through modulation of the ET-1 system. Male Wistar rats at 8weeks of age were administered with either saline or lipopolysaccharide (LPS) for three hours (3h) and some of the LPS-administered rats were continuously treated with landiolol for 3h. ALI was induced by LPS, including levels of both circulatory and pulmonary TNF-α and IL-6 but [PaO2] was significantly decreased. LPS also induced a significant increase in levels of pulmonary ET-1 and ET-A receptor, but levels of ET-B receptor, which has vasodilating effects, were remarkably diminished. Further, LPS administration upregulated the pulmonary expression of HIF-1α. Finally, the treatment of LPS-administered rats with landiolol for 3h ameliorated and prevented ALI, normalized the altered levels of pulmonary ET-1 and ET-A receptors. Landiolol also induced significant down-regulation of ET-B receptor in lung tissues in the early hours (phase) of sepsis. However, Landiolol treatment had no effect on the up-regulated inflammatory mediators (TNF-α, IL-6) in both plasma and lung tissues during sepsis, and expression of pulmonary HIF-1α also remained unchanged after landiolol treatment. Collectively, these data led us to conclude that landiolol may ameliorate sepsis-induced ALI via the pulmonary ET system. Copyright © 2016. Published by Elsevier Inc.

  8. Effect of Micronized Purified Flavonoid Fraction Therapy on Endothelin-1 and TNF-α Levels in Relation to Antioxidant Enzyme Balance in the Peripheral Blood of Women with Varicose Veins.

    Science.gov (United States)

    Pietrzycka, Agata; Kózka, Mariusz; Urbanek, Tomasz; Stpniewski, Marek; Kucharzewski, Marek

    2015-01-01

    The aetiology of varicose veins involves various factors and pathomechanisms including endothelial cell activation or dysfunction, venous hypertension, vein wall hypoxia, shear stress disturbances, inflammatory reaction activation or free radical production. To improve our understanding of the mechanisms of potential pharmacological interventions for chronic venous disease, we evaluated the influence of micronized purified flavonoid fraction (MPFF) on the relationship between antioxidant enzyme balance, endothelin-1 (ET-1) and tumour necrosis factor-α (TNF-α) levels. Blood samples were obtained from 89 women with primary varicose veins; 34 were treated with MPFF and 55 did not receive any phlebotropic drug treatment. For the evaluation of the blood antioxidant enzyme balance, catalase (CAT) and superoxide dismutase (SOD) activity was assessed and the CAT/SOD ratio was calculated. Patients taking MPFF had significantly lower ET-1 levels than those not taking MPFF [median (25-75th quartile): 24.2 (22.30-27.87) vs 37.62 (24.9-44.58) pg.ml-1; p -1; plevels increased with the CAT/SOD ratio. In those taking MPFF, the ET-1 level was stable at approximately 25.0 pg.ml-1¬ up to a CAT/SOD ratio of 100. TNF-α level increased continuously with an increasing CAT/SOD ratio; however, the highest levels of TNF-α were observed in women not taking MPFF. We demonstrate the ability of MPFF to effectively lower the levels of ET-1 and TNF-α in patients with chronic venous disease. Further investigations are needed to define the therapeutic potential of MPFF including the potential effect on chronic subclinical inflammation, antioxidant imbalance and vascular dysfunction during the development of chronic venous disease.

  9. Mexico City normal weight children exposed to high concentrations of ambient PM2.5 show high blood leptin and endothelin-1, vitamin D deficiency, and food reward hormone dysregulation versus low pollution controls. Relevance for obesity and Alzheimer disease.

    Science.gov (United States)

    Calderón-Garcidueñas, Lilian; Franco-Lira, Maricela; D'Angiulli, Amedeo; Rodríguez-Díaz, Joel; Blaurock-Busch, Eleonore; Busch, Yvette; Chao, Chih-kai; Thompson, Charles; Mukherjee, Partha S; Torres-Jardón, Ricardo; Perry, George

    2015-07-01

    Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1±3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (pchildren. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin DMexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer disease.

  10. Lycopene inhibits cyclic strain-induced endothelin-1 expression through the suppression of reactive oxygen species generation and induction of heme oxygenase-1 in human umbilical vein endothelial cells.

    Science.gov (United States)

    Sung, Li-Chin; Chao, Hung-Hsing; Chen, Cheng-Hsien; Tsai, Jen-Chen; Liu, Ju-Chi; Hong, Hong-Jye; Cheng, Tzu-Hurng; Chen, Jin-Jer

    2015-06-01

    Lycopene is the most potent active antioxidant among the major carotenoids, and its use has been associated with a reduced risk for cardiovascular disease (CVD). Endothelin-1 (ET-1) is a powerful vasopressor synthesized by endothelial cells and plays a crucial role in the pathophysiology of CVD. However, the direct effects of lycopene on vascular endothelial cells have not been fully described. This study investigated the effects of lycopene on cyclic strain-induced ET-1 gene expression in human umbilical vein endothelial cells (HUVECs) and identified the signal transduction pathways that are involved in this process. Cultured HUVECs were exposed to cyclic strain (20% in length, 1 Hz) in the presence or absence of lycopene. Lycopene inhibited strain-induced ET-1 expression through the suppression of reactive oxygen species (ROS) generation through attenuation of p22(phox) mRNA expression and NAD(P)H oxidase activity. Furthermore, lycopene inhibited strain-induced ET-1 secretion by reducing ROS-mediated extrace-llular signal-regulated kinase (ERK) phosphorylation. Conversely, lycopene treatment enhanced heme oxygenase-1 (HO-1) gene expression through the activation of phosphoinositide 3-kinase (PI3K)/Akt pathway, followed by induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation; in addition, HO-1 silencing partially inhibited the repressive effects of lycopene on strain-induced ET-1 expression. In summary, our study showed, for the first time, that lycopene inhibits cyclic strain-induced ET-1 gene expression through the suppression of ROS generation and induction of HO-1 in HUVECs. Therefore, this study provides new valuable insight into the molecular pathways that may contribute to the proposed beneficial effects of lycopene on the cardiovascular system.

  11. KMUP-1 Attenuates Endothelin-1-Induced Cardiomyocyte Hypertrophy through Activation of Heme Oxygenase-1 and Suppression of the Akt/GSK-3β, Calcineurin/NFATc4 and RhoA/ROCK Pathways.

    Science.gov (United States)

    Liou, Shu-Fen; Hsu, Jong-Hau; Chen, You-Ting; Chen, Ing-Jun; Yeh, Jwu-Lai

    2015-06-05

    The signaling cascades of the mitogen activated protein kinase (MAPK) family, calcineurin/NFATc4, and PI3K/Akt/GSK3, are believed to participate in endothelin-1 (ET-1)-induced cardiac hypertrophy. The aim of this study was to investigate whether KMUP-1, a synthetic xanthine-based derivative, prevents cardiomyocyte hypertrophy induced by ET-1 and to elucidate the underlying mechanisms. We found that in H9c2 cardiomyocytes, stimulation with ET-1 (100 nM) for 4 days induced cell hypertrophy and enhanced expressions of hypertrophic markers, including atrial natriuretic peptide and brain natriuretic peptide, which were all inhibited by KMUP-1 in a dose-dependent manner. In addition, KMUP-1 prevented ET-1-induced intracellular reactive oxygen species generation determined by the DCFH-DA assay in cardiomyocytes. KMUP-1 also attenuated phosphorylation of ERK1/2 and Akt/GSK-3β, and activation of calcineurin/NFATc4 and RhoA/ROCK pathways induced by ET-1. Furthermore, we found that the expression of heme oxygenase-1 (HO-1), a stress-response enzyme implicated in cardio-protection, was up-regulated by KMUP-1. Finally, KMUP-1 attenuated ET-1-stimulated activator protein-1 DNA binding activity. In conclusion, KMUP-1 attenuates cardiomyocyte hypertrophy induced by ET-1 through inhibiting ERK1/2, calcineurin/NFATc4 and RhoA/ROCK pathways, with associated cardioprotective effects via HO-1 activation. Therefore, KMUP-1 may have a role in pharmacological therapy of cardiac hypertrophy.

  12. Progress in Study on Endothelin-1 in Pathogenesis of Inflammatory Bowel Disease%内皮素-1在炎症性肠病发病中作用的研究进展

    Institute of Scientific and Technical Information of China (English)

    安博然; 祝斌

    2016-01-01

    炎症性肠病(IBD)是一种病因尚未完全明确的慢性非特异性肠道炎性疾病,包括克罗恩病(CD)和溃疡性结肠炎(UC)。内皮素-1(ET-1)是一种由21个氨基酸残基组成的活性多肽,具有较强的收缩力,可通过活化血管平滑肌的电位依赖性钙离子通道发挥收缩血管作用。研究显示 ET-1在 IBD 的发生、发展中发挥重要作用。本文就 ET-1在 IBD 发病中作用的研究进展作一综述。%Inflammatory bowel disease(IBD)is a kind of chronic and non-specific inflammatory disease comprising Crohn’s disease(CD)and ulcerative colitis(UC),the etiology has not yet been clarified. Endothelin-1(ET-1)is an active polypeptide composed of 21 amino acid residues,which can constrict blood vessels by activating voltage-dependent Ca2 + channels in vascular smooth muscle cells. Studies have shown that ET-1 plays an important role in the pathogenesis of IBD. This article reviewed the progress in study on ET-1 in the pathogenesis of IBD.

  13. Study on the antiulcer effects of Veronicastrum axillare on gastric ulcer in rats induced by ethanol based on tumor necrosis factor-α (TNF-α) and endothelin-1 (ET-1)

    Institute of Scientific and Technical Information of China (English)

    Yong Du; Weichun Zhao; Leilei Lu; Jiayan Zheng; Xishi Hu; Zhehan Yu; Lixin Zhu

    2013-01-01

    Objective:To assess whether Veronicastrum axillare (V. axillare) can ameliorate ethanol-induced gastric mucosal lesions in rats, reduce the production of pro-inflammatory cytokines, suppress apoptosis and improve local microcirculation disturbances. Methods:Totally 48 male Sprague-Dawley rats were randomly divided into six groups, eight rats in each group. Rats in the normal group and the model group were administered with 0.9%normal saline respectively. Rats in the positive group and ranitidine group were administered with 0.18% ranitidine suspension by intragastric administration respectively. Those in the high dose V. axillare group, the medium dose V. axillare group and the low dose V. axillare group were administrated with V. axillare at the daily dose of 2.8 g/kg, 1.4 g/kg and 0.7 g/kg by intragastric administration. Gastric mucosal lesions were produced by intragastric administration of absolute ethanol. Water extract of V. axillare was successively injected for 14 d and last day was injected 1 h before ethanol administration. Gastric mucosal ulcer index and ulcer inhibitory rate were counted by improved Guth methods. The tissue sections were made for pathological histology analysis. Also, we measured the concentrations of tumor necrosis factor-α (TNF-α) and endothelin-1 (ET-1) in gastric mucosal, as an index of the pro-inflammatory cytokines, apoptosis and local microcirculation. Besides, the mRNA contents of TNF-αand ET-1 were measured to verify effects on gene expression by real-time fluorescent quantitative PCR. Results: Water extract of V. axillare significantly ameliorated the gastric mucosal lesions induced by ethanol administration (P Conclusion: Current evidences show water extract of V. axillare is effective for defending against ethanol-induced gastric mucosal lesions, significantly inhibiting the production of pro-inflammatory cytokines and the expressions of TNF-αand ET-1 mRNA, which may be useful for inhibiting apoptosis and improving local

  14. Study on the antiulcer effects of Veronicastrum axillare on gastric ulcer in rats induced by ethanol based on tumor necrosis factor-α (TNF-α) and endothelin-1 (ET-1).

    Science.gov (United States)

    Du, Yong; Zhao, Weichun; Lu, Leilei; Zheng, Jiayan; Hu, Xishi; Yu, Zhehan; Zhu, Lixin

    2013-12-01

    To assess whether Veronicastrum axillare (V. axillare) can ameliorate ethanol-induced gastric mucosal lesions in rats, reduce the production of pro-inflammatory cytokines, suppress apoptosis and improve local microcirculation disturbances. Totally 48 male Sprague-Dawley rats were randomly divided into six groups, eight rats in each group. Rats in the normal group and the model group were administered with 0.9% normal saline respectively. Rats in the positive group and ranitidine group were administered with 0.18% ranitidine suspension by intragastric administration respectively. Those in the high dose V. axillare group, the medium dose V. axillare group and the low dose V. axillare group were administrated with V. axillare at the daily dose of 2.8 g/kg, 1.4 g/kg and 0.7 g/kg by intragastric administration. Gastric mucosal lesions were produced by intragastric administration of absolute ethanol. Water extract of V. axillare was successively injected for 14 d and last day was injected 1 h before ethanol administration. Gastric mucosal ulcer index and ulcer inhibitory rate were counted by improved Guth methods. The tissue sections were made for pathological histology analysis. Also, we measured the concentrations of tumor necrosis factor-α (TNF-α) and endothelin-1 (ET-1) in gastric mucosal, as an index of the pro-inflammatory cytokines, apoptosis and local microcirculation. Besides, the mRNA contents of TNF-α and ET-1 were measured to verify effects on gene expression by real-time fluorescent quantitative PCR. Water extract of V. axillare significantly ameliorated the gastric mucosal lesions induced by ethanol administration (Pgastric mucosal lesions, significantly inhibiting the production of pro-inflammatory cytokines and the expressions of TNF-α and ET-1 mRNA, which may be useful for inhibiting apoptosis and improving local microcirculation. Copyright © 2013 Asian Pacific Tropical Biomedical Magazine. Published by Elsevier B.V. All rights reserved.

  15. KMUP-1 Attenuates Endothelin-1-Induced Cardiomyocyte Hypertrophy through Activation of Heme Oxygenase-1 and Suppression of the Akt/GSK-3β, Calcineurin/NFATc4 and RhoA/ROCK Pathways

    Directory of Open Access Journals (Sweden)

    Shu-Fen Liou

    2015-06-01

    Full Text Available The signaling cascades of the mitogen activated protein kinase (MAPK family, calcineurin/NFATc4, and PI3K/Akt/GSK3, are believed to participate in endothelin-1 (ET-1-induced cardiac hypertrophy. The aim of this study was to investigate whether KMUP-1, a synthetic xanthine-based derivative, prevents cardiomyocyte hypertrophy induced by ET-1 and to elucidate the underlying mechanisms. We found that in H9c2 cardiomyocytes, stimulation with ET-1 (100 nM for 4 days induced cell hypertrophy and enhanced expressions of hypertrophic markers, including atrial natriuretic peptide and brain natriuretic peptide, which were all inhibited by KMUP-1 in a dose-dependent manner. In addition, KMUP-1 prevented ET-1-induced intracellular reactive oxygen species generation determined by the DCFH-DA assay in cardiomyocytes. KMUP-1 also attenuated phosphorylation of ERK1/2 and Akt/GSK-3β, and activation of calcineurin/NFATc4 and RhoA/ROCK pathways induced by ET-1. Furthermore, we found that the expression of heme oxygenase-1 (HO-1, a stress-response enzyme implicated in cardio-protection, was up-regulated by KMUP-1. Finally, KMUP-1 attenuated ET-1-stimulated activator protein-1 DNA binding activity. In conclusion, KMUP-1 attenuates cardiomyocyte hypertrophy induced by ET-1 through inhibiting ERK1/2, calcineurin/NFATc4 and RhoA/ROCK pathways, with associated cardioprotective effects via HO-1 activation. Therefore, KMUP-1 may have a role in pharmacological therapy of cardiac hypertrophy.

  16. Enhanced expression of Gqα and PLC-β1 proteins contributes to vascular smooth muscle cell hypertrophy in SHR: role of endogenous angiotensin II and endothelin-1.

    Science.gov (United States)

    Atef, Mohammed Emehdi; Anand-Srivastava, Madhu B

    2014-07-01

    Vascular Gqα signaling has been shown to contribute to cardiac hypertrophy. In addition, angiotensin II (ANG II) was shown to induce vascular smooth muscle cell (VSMC) hypertrophy through Gqα signaling; however, the studies on the role of Gqα and PLC-β1 proteins in VSMC hypertrophy in animal model are lacking. The present study was therefore undertaken to examine the role of Gqα/PLC-β1 proteins and the signaling pathways in VSMC hypertrophy using spontaneously hypertensive rats (SHR). VSMC from 16-wk-old SHR and not from 12-wk-old SHR exhibited enhanced levels of Gqα/PLC-β1 proteins compared with age-matched Wistar-Kyoto (WKY) rats as determined by Western blotting. However, protein synthesis as determined by [(3)H]leucine incorporation was significantly enhanced in VSMC from both 12- and 16-wk-old SHR compared with VSMC from age-matched WKY rats. Furthermore, the knockdown of Gqα/PLC-β1 in VSMC from 16-wk-old SHR by antisense and small interfering RNA resulted in attenuation of protein synthesis. In addition, the enhanced expression of Gqα/PLC-β1 proteins, enhanced phosphorylation of ERK1/2, and enhanced protein synthesis in VSMC from SHR were attenuated by the ANG II AT1 and endothelin-1 (ET-1) ETA receptor antagonists losartan and BQ123, respectively, but not by the ETB receptor antagonist BQ788. In addition, PD98059 decreased the enhanced expression of Gqα/PLC-β1 and protein synthesis in VSMC from SHR. These results suggest that the enhanced levels of endogenous ANG II and ET-1 through the activation of AT1 and ETA receptors, respectively, and MAP kinase signaling, enhanced the expression of Gqα/PLC-β1 proteins in VSMC from 16-wk-old SHR and result in VSMC hypertrophy. Copyright © 2014 the American Physiological Society.

  17. Regulation of the pulmonary circulation in the fetus and newborn.

    Science.gov (United States)

    Gao, Yuansheng; Raj, J Usha

    2010-10-01

    During the development of the pulmonary vasculature in the fetus, many structural and functional changes occur to prepare the lung for the transition to air breathing. The development of the pulmonary circulation is genetically controlled by an array of mitogenic factors in a temporo-spatial order. With advancing gestation, pulmonary vessels acquire increased vasoreactivity. The fetal pulmonary vasculature is exposed to a low oxygen tension environment that promotes high intrinsic myogenic tone and high vasocontractility. At birth, a dramatic reduction in pulmonary arterial pressure and resistance occurs with an increase in oxygen tension and blood flow. The striking hemodynamic differences in the pulmonary circulation of the fetus and newborn are regulated by various factors and vasoactive agents. Among them, nitric oxide, endothelin-1, and prostaglandin I(2) are mainly derived from endothelial cells and exert their effects via cGMP, cAMP, and Rho kinase signaling pathways. Alterations in these signaling pathways may lead to vascular remodeling, high vasocontractility, and persistent pulmonary hypertension of the newborn.

  18. The Alterations of Plasma ET-l, NO Post Laser Treatment in Patients with Primary Deep Venous Insufficiency%原发性下肢深静脉瓣膜功能不全激光微创治疗术后血浆ET-1、NO水平的变化

    Institute of Scientific and Technical Information of China (English)

    王春喜; 牛磊; 顾瑛; 韩丽娜; 曾晶; 周静

    2011-01-01

    目的:探讨原发性深静脉瓣膜功能不全患者血浆内皮素-1(endothelin-1,ET-1)、一氧化氮(nitric oxide,NO)水平的变化及与病情轻重和临床治疗的关系.方法:分别选择495例原发性深静脉瓣膜功能不全住院患者和495例同期同龄同性别健康查体者,分别抽取空腹静脉血,制备相关标本,采用放射免疫分析和Griss方法测定血浆ET-1、NO,利用密度梯度法测定血液循环血管内皮细胞计数(circulating endothelial cells counting,CEC)同时测定手术后临床治愈时血浆CEC、ET-1、NO水平.结果:495例病人血浆ET-1水平和血中CEC水平均高于正常对照组,而NO水平则低于正常人水平,且以重症患者最明显.术后2周均达到临床治愈时,其血浆ET-1水平和血中CEC水平明显降低,而NO水平则明显升高,恢复正常或接近正常人水平.结论:检测血液中CEC、ET-1和NO水平有助于了解病情轻重,了解疾病进程,动态观察血液中CEC、ET-1和NO水平有助于了解临床治疗效果.%Objectivo To investigate the alterations of plasma endothelin-1 ( ET-1 ), nitric oxide( NO ), circulating endothelial cells counting ( CEC ) in patienrts with primary deep venous insufficiency, and to investigate the relationship between such alteration and illness. Methods The plasma samples were obtained from 495 cases with primary deep venous insufficiency and from 495 healthcontrols, and the levels of ET-l, NO, CEC were determined by radialmmtmoassay, Gress method and density gradient method respectively. Results The level of plasma ET-1 and blood CEC in 495 patients with primary deep venous insufficiency wine significantly higher than those in contrals. The level of plasma NO was significantly lower than that in controls. Two weeks after operation, the level of plasma ET-1 and blood CEC were significantly decreased and the plasma NO contents was significantly increased, which was closely returned to nomal levels. Conclusion It is hallpflul to

  19. [Haemodynamic role of blood-plasma circulating cell-free DNA and contained therein high-molecular-weight CpG-rich fraction in pathogenesis of arterial hypertension and atherosclerosis obliterans of carotid arteries].

    Science.gov (United States)

    Konorova, I L; Veĭko, N N; Ershova, E S; Antelava, A L; Chechetkin, A O

    2009-01-01

    The hydrodynamic resistance (HR) of blood is one of the components of the total peripheral resistance. High-molecular-weight DNA appears to decrease the HR in accordance with the Toms's effect. The present study was undertaken to investigate the HR and properties of cell-free DNA circulating in the blood plasma (hereinafter referred to as pDNA) of the control donors, patients suffering from either arterial hypertension (AH) alone or that combined with atherosclerotic lesions of the carotid arteries (CAs). Within the normal concentrations of pDNA, we revealed an inverse dependence of the HR thereupon and upon the content in pDNA of the high-molecular-weight CpG-rich fraction (CpG-DNA), i. e., a transcribed region of the ribosomal repeat (rDNA). A decrease or an increase in the pDNA concentration in all the patients examined was accompanied by an elevation of the rDNA concentration in the blood plasma. Exceeding a certain level thereof appeared to give rise to an increase in both the HR and arterial pressure (AP). Patients presenting with degree I essential AH were found to have a decreased endonuclease activity of the blood plasma, with the pDNA concentration being more than two-fold higher with no change in the rDNA content. Their HR appeared to be increased (parteries were typically revealed on the background of a lowered HR (parterial intima. In some of them, the pDNA concentration does not differ from the normal values, but in its composition, there is an increased content of rDNA, elevating as obliteration of the vessels' lumen increases, with the HR being decreased. The majority of them have degree II AH. In others, the pDNA concentration is by an order of magnitude higher than the normal values, while the rDNA content in pDNA is decreased, with the HR being elevated. Most of them have degree III AH. Pronounced and rough stenoses take an asymptomatic course in patients with decreased values of the HR and a slightly elevated level of pDNA and/or rDNA in the

  20. Effect of endothelin-1 receptor antagonists on histological and ultrastructural changes in the pancreas and trypsinogen activation in the early course of caerulein-induced acute pancreatitis in rats

    Institute of Scientific and Technical Information of China (English)

    Anna Andrzejewska; Jan W. Dlugosz; Albert Augustynowicz

    2005-01-01

    AIM: To assess the effect of non-selective ETA/B (LU 302872)and selective ETA (LU 302146) antagonist on pancreatic histology and ultrastructure of acinar cells in connection with trypsinogen activation in early caerulein-induced AP.METHODS: Male Wistar rats with caerulein-induced AP,lasting 4 h, were treated i.p. with 10 and 20 mg/kg b.w.of each antagonist. Edema, inflammatory infiltration,necrosis and vacuolization of acinar cells in the pancreas were scored at 0-3 scale. Free active trypsin (FAT), total potential trypsin (TPT) after activation with enterokinase,and index of trypsinogen activation (%FAT/TPT) were assayed in pancreatic homogenates.RESULTS: In untreated AP, the edema, inflammatory infiltration, necrosis and vacuolization increased as compared to control healthy rats (P<0.01). None of the treatment exerted any meaningful effect on the edema and inflammatory infiltration. The selective antagonist increased slightly the necrosis score to 0.82±0.06 at higher dose (P<0.05) vs 0.58±0.06 in untreated AP. The nonselective antagonist increased slightly the vacuolization score to 2.41±0.07 at higher dose (P<0.01) vs 1.88±0.08in untreated AP. The decrease in the number of zymogen granules, disorganization of endoplasmic reticulum,autophagosomes and cytoplasmic vacuoles were more prominent in treated AP than in untreated AP groups.%FAT/TPT in untreated AP increased about four times (18.4±3.8 vs4.8±1.3 in control group without AP, P<0.001).Treatment of AP with both antagonists did not affect significantly augmented trypsinogen activation.CONCLUSION: The treatment with endothelin-1 receptors (non-selective ETA/B and selective ETA) antagonists has essential effect neither on the edema and inflammatory infiltration nor on trypsinogen activation observed in the early course of caerulein-induced AP. Nevertheless a slight increase of the necrosis and vacuolization score and some of the ultrastructural data could suggest the possibility of their undesired

  1. [Lys(-2)-Arg(-1)]endothelin-1 solution structure by two-dimensional 1H-NMR: possible involvement of electrostatic interactions in native disulfide bridge formation and in biological activity decrease.

    Science.gov (United States)

    Aumelas, A; Chiche, L; Kubo, S; Chino, N; Tamaoki, H; Kobayashi, Y

    1995-04-11

    Addition of the Lys(-2)-Arg(-1) dipeptide, present in the precursor protein, to the N-terminus of endothelin-1 (ET-1), to form a 23-residue peptide (KR-ET-1) has been shown to greatly improve formation of native disulfide bridges and to dramatically decrease biological activity. Conformational analysis was carried out on this peptide. During protonation of the carboxyl groups, CD spectra showed a decrease in the helical contribution, and NMR spectra displayed strong chemical shift modifications, suggesting the importance of electrostatic interactions in the KR-ET-1 conformation. CD spectra and two-dimensional NMR experiments were performed to investigate the KR-ET-1 three-dimensional structure in water in the carboxylic acid and carboxylate states. Distance and angle constraints were used as input for distance geometry calculations. The KR-ET-1 carboxylic acid conformation was found to be very similar to ET-1, with a helix spanning residues 9-15 and an unconstrained C-terminal part. In contrast, in the carboxylate state, large changes in Arg(-1) and Phe14 chemical shifts and long-range NOEs were consistent with a conformation characterized by a helix extension to Leu17 and a stabilized C-terminal section folded back toward the N-terminus. In addition, thanks to NOEs with Cys11 and Phe14, the Arg(-1) side chain appeared well-defined. Simulated annealing and molecular dynamics calculations, supported an Arg(-1)-Glu10 salt bridge and an electrostatic network involving the charged groups of Trp21, Asp18, and Lys(-2). Moreover, stabilization of the KR-ET-1 C-terminal part is probably reinforced by hydrophobic interactions involving the Val12, Tyr13, Phe14, Leu17, Ile19, Ile20, and Trp21 side chains. In vitro, native disulfide bond formation improvement observed for KR-ET-1 could be ascribed to electrostatic interactions and more specifically to the Arg(-1)-Glu10 salt bridge. In vivo, similar interactions could play an important role in the native folding of the ET-1

  2. Effects on plasma angiotensin-converting enzyme activity and circulating renin of lisinopril and enalapril alone and in combination with propranolol in healthy volunteers

    DEFF Research Database (Denmark)

    Hansen, EF; Bendtsen, F; Henriksen, Jens Henrik Sahl

    1999-01-01

    The effects on plasma angiotensin-converting enzyme activity and renin activity of the two long-acting angiotensin-converting enzyme inhibitors, lisinopril and enalapril, alone and in combination with propranolol were studied. In an open, randomised, cross-over design 12 healthy volunteers received...... orally enalapril 20 mg alone, enalapril 20 mg in combination with propranolol 80 mg, lisinopril 20 mg alone, and lisinopril 20 mg in combination with propranolol 80 mg. Plasma angiotensin-converting enzyme activity and plasma renin activity were measured for 24 h after each treatment period. Lisinopril...... and enalapril reduced plasma angiotensin converting enzyme activity substantially and equally at six hr (-70%, Penzyme activity remained significantly suppressed only after lisinopril (-60%, P

  3. Effects on plasma angiotensin-converting enzyme activity and circulating renin of lisinopril and enalapril alone and in combination with propranolol in healthy volunteers

    DEFF Research Database (Denmark)

    Hansen, Erik Feldager; Bendtsen, Flemming; Henriksen, Jens Henrik

    1999-01-01

    The effects on plasma angiotensin-converting enzyme activity and renin activity of the two long-acting angiotensin-converting enzyme inhibitors, lisinopril and enalapril, alone and in combination with propranolol were studied. In an open, randomised, cross-over design 12 healthy volunteers received...... orally enalapril 20 mg alone, enalapril 20 mg in combination with propranolol 80 mg, lisinopril 20 mg alone, and lisinopril 20 mg in combination with propranolol 80 mg. Plasma angiotensin-converting enzyme activity and plasma renin activity were measured for 24 h after each treatment period. Lisinopril...... and enalapril reduced plasma angiotensin converting enzyme activity substantially and equally at six hr (-70%, Penzyme activity remained significantly suppressed only after lisinopril (-60%, P

  4. Glucagon-like peptide-1 (GLP-1) increases in plasma and colon tissue prior to estrus and circulating levels change with increasing age in reproductively competent Wistar rats.

    Science.gov (United States)

    Johnson, Michelle L; Saffrey, M Jill; Taylor, Victoria J

    2017-02-22

    There is a well-documented association between cyclic changes to food intake and the changing ovarian hormone levels of the reproductive cycle in female mammals. Limited research on appetite-controlling gastrointestinal peptides has taken place in females, simply because regular reproductive changes in steroid hormones present additional experimental factors to account for. This study focussed directly on the roles that gastrointestinal-secreted peptides may have in these reported, naturally occurring, changes to food intake during the rodent estrous cycle and aimed to determine whether peripheral changes occurred in the anorexigenic (appetite-reducing) hormones peptide-YY (PYY) and glucagon-like peptide-1 (GLP-1) in female Wistar rats (32-44 weeks of age). Total forms of each peptide were measured in matched fed and fasted plasma and descending colon tissue samples for each animal during the dark (feeding) phase. PYY concentrations did not significantly change between defined cycle stages, in either plasma or tissue samples. GLP-1 concentrations in fed plasma and descending colon tissue were significantly increased during proestrus, just prior to a significant reduction in fasted stomach contents at estrus, suggesting increased satiety and reduced food intake at this stage of the cycle. Increased proestrus GLP-1 concentrations could contribute to the reported reduction in food intake during estrus and may also have biological importance in providing the optimal nutritional and metabolic environment for gametes at the potential point of conception. Additional analysis of the findings demonstrated significant interactions of ovarian cycle stage and fed/fasted status with age on GLP-1, but not PYY plasma concentrations. Slightly older females had reduced fed plasma GLP-1 suggesting that a relaxation of regulatory control of this incretin hormone may also take place with increasing age in reproductively competent females.

  5. 内皮素对Oddi括约肌功能影响的实验研究%Study on the effect of endothelin-1 on the contraction of Oddi sphincter

    Institute of Scientific and Technical Information of China (English)

    葛春林; 罗晓光; 李智; 孙树

    2007-01-01

    目的 研究ET对离体Oddi括约肌收缩的直接影响,并对其传导通路进行初步的了解.方法 按累积加药法在K-H液中加入各浓度(0.1nM~100nM)的ET-1,观察Oddi括约肌收缩频率及振幅的变化;加入ET-1抗血清、Nicardipine、BQ-123,再加入ET-1,测定三者对Oddi括约肌收缩的影响;并检测Oddi括约肌PKC的活性.结果 ET能收缩静息状态下的Oddi括约肌,其作用强度随ET浓度的增加而增强.Nicardipine对ET所致的Oddi括约肌收缩反应无明显抑制作用,ET抗血清及ET受体拮抗剂显著抑制了Oddi括约肌的收缩.随着ET-1浓度增高,Oddi括约肌细胞胞浆PKC活性也呈增高趋势,并伴随有Oddi括约肌收缩的增强.结论 ET-1能明显收缩离体Oddi括约肌,且与其收缩强度存在量效关系.ET抗血清与ET受体拮抗剂对ET-1有较强的拮抗作用.PKC参与了ET-1引起的Oddi括约肌收缩的信号传导.%[Objective] To investigate the direct effect of endothelin-1 on the contraction of Oddi sphincter, the signal transduction pathway was also explored. [Methods] Accumulated ET-1 were given in K-H solution to made a final concentration (0.1nM~100nM), the contraction amplitude and frequency of Oddi sphincter were observed,Anti-ET serum, Nicardipine, BQ-123 were added to detect their effects on the contraction of Oddi sphincter, and PKC activities in Oddi sphincter were also detected. [Results] ET addition resulted in the contraction of resting Oddi sphincter, and the contraction intensity increased with the rising ET concentration. No obvious inhibition effect on Oddi sphincter contraction was induced by Nicardipine, while anti-ET serum and ET receptor antagonist reduced the Oddi sphincter contraction significantly. The PKC activity in cytoplasm of Oddi sphincter enhanced with the rising ET-1 concentration, and the contraction of Oddi sphincter increased at the same time. [Conclusion] ET-1 addition results in the significant contraction of the ex vivo Oddi

  6. Relationships between expression of Heparanase and Endothelin-1 and neovaseularization in breast cancer%乳腺癌HPA、ET-1表达和肿瘤血管生成关系

    Institute of Scientific and Technical Information of China (English)

    陆晔; 潘湘涛; 杨育生

    2009-01-01

    Objective To study expression of heparanase (HPA) and endothelin-1(ET-1) and the rela-tionships between HPA and ET-1 with neovascularization in breast cancer, Methods The expression of HPA and ET-1 and microvascular density (MVD) were detected by immunohistochemistry in 60 patients with breast cancer. Results (1) The rate of MVD, HPA and ET-1 were(25.40±8.91),(56.30±24.16)%and(67.53±18.98)% respectively. (2) The expression of HPA and ET-1 were positive correlated with the MVD (P<0.005, P<0.05, respectively).(3)The MVD were positive correlated with metastasis, but were no significantly correlated with the size and clinical staging. (4)The expression of HPA and ET-1 were positive correlated with metastasis and clinical staging, but were no significantly correlated with the size. Conclusion The expression of HPA and ET-1 in breast cancer was correlation with MVD, and HPA and ET-1 may be the valuable markers to evaluate biological behavior of breast cancer.%目的 研究乳腺癌患者内皮素-1(ET-1)和乙酰肝素酶(HPA)的表达及其与肿瘤血管生成的关系.方法 应用免疫组化方法检测60例乳腺癌患者的ET-1和HPA的表达,同时检测肿瘤微血管密度(MVD),并分析与临床病理之间的关系.结果 ①60例MVD平均计数为(25.40±8.91),59例表达ET-1平均阳性率为(67.53±18.98)%,57例表达HPA平均阳性率为(56.30±24.16)%.②MVD与HPA呈正相关(r=0.3961、t=3.2899、P<0.005);MVD与ET-1呈正相关(r=0.3170、t=2.5462、P<0.05).③MVD与有无转移有关,与分期及肿块大小无关.④HPA和ET-1均与分期及转移有关,但与肿块大小均无关.结论 乳腺癌患者高表达HPA和ET-1,并与MVD呈正相关关系.HPA、ET-1和MVD均与转移有关,而与肿块大小无关;HPA和ET-1与分期有关.

  7. 血浆循环microRNA-126在非小细胞肺癌诊断中的应用%Application of plasma circulation microRNA - 126 to diagnosis of non - small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    刘沙; 杨季云

    2011-01-01

    目的 探讨血浆循环microRNA - 126浓度与非小细胞肺癌(NSCLC)的相关性及其诊断价值.方法 采用实时荧光定量PCR方法检测130例NSCLC患者和作为对照的170例健康人的血浆循环microRNA - 126浓度.结果 对照组血浆循环microRNA - 126浓度显著高于NSCLC组(P<0.01).血浆循环microRNA - 126浓度ROC曲线下面积(area under the ROC curve,AUC)为0.758,95%CI为0.704~0.811(P<0.01).当血浆microRNA - 126浓度为1051 fmol/L时,血浆microRNA - 126对NSCLC诊断的特异度为90.0%,灵敏度为46.4%.其浓度与患者的年龄、性别、吸烟,病理分型和分期均无显著的相关性(P>0.05).结论 血浆循环microRNA - 126浓度对NSCLC有一定的临床诊断意义,联合其他血浆microRNA或肿瘤标志物,如神经元特异性烯醇化酶、癌胚抗原和细胞角蛋白片段21 - 1,可以弥补单一检测的局限性,以提高肺癌的阳性检出率,为临床提供可靠的依据.%Objective To discuss the correlation between the concentration of plasma circulation microRNA - 126 and the non - small cell lung cancer( NSCLC ), and to study its diagnostic value. Methods The concentration of plasma circulation micro RNA - 126 in 130 patients with NSCLC( NSCLC group )and 170 healthy people( control group )was detected through the method of real time fluorescent quantitation PCR. Results The concentration of microRNA - 126 in the control group was significantly higher than that in the NSCLC group( P < 0. 01 ). The area under the receiver operating characteristic curve of the concentration was 0. 758, and the 95% CI was 0. 704 - 0. 81l( P < 0. 01 ). When the concentration of plasma microRNA - 126 was 1051 fmol/L, its specificity in the diagnosis of NSCLC was 90% ,and its sensitivity was 46. 4%. There were not obvious correlations between the concentration and age, gender, smoking, pathological typing and staging of the 130 patients. Conclusion The concentration of plasma circulation microRNA -126 has

  8. Circulation economics

    DEFF Research Database (Denmark)

    Ingebrigtsen, Stig; Jakobsen, Ove

    2006-01-01

    Purpose - This paper is an attempt to advance the critical discussion regarding environmental and societal responsibility in economics and business. Design/methodology/approach - The paper presents and discusses as a holistic, organic perspective enabling innovative solutions to challenges...... concerning the responsible and efficient use of natural resources and the constructive interplay with culture. To reach the goal of sustainable development, the paper argues that it is necessary to make changes in several dimensions in mainstream economics. This change of perspective is called a turn towards...... presupposes a perspective integrating economic, natural and cultural values. Third, to organize the interplay between all stakeholders we introduce an arena for communicative cooperation. Originality/value - The paper concludes that circulation economics presupposes a change in paradigm, from a mechanistic...

  9. Circulating miR-145 is associated with plasma high-sensitivity C-reactive protein in acute ischemic stroke patients.

    Science.gov (United States)

    Jia, Lihua; Hao, Fang; Wang, Weihua; Qu, Yang

    2015-07-01

    Stroke is a major cerebrovascular disease threatening human health and life with high morbidity, disability and mortality. We aimed to find effective biomarkers for the early diagnosis on stroke. Nine previously reported stroke-associated miRNAs (miR-21, miR-23a, miR-29b, miR-124, miR-145, miR-210, miR-221, miR-223 and miR-483-5p) were measured by quantitative real time-PCR, and plasma high-sensitivity C-reactive protein (hs-CRP) and serum interleukin 6 (IL-6), the pro-inflammation markers in brain injury, were examined by enzyme-linked immunosorbent assay in 146 acute ischemic stroke patients and 96 healthy blood donors. We found that serum miR-145 was significantly increased within 24 h after stroke onset and serum miR-23a and miR-221 were decreased in patients. Moreover, serum miR-145 was strong positively correlated with plasma hs-CRP and moderate positively correlated with serum IL-6. Meanwhile, serum miR-23a and miR-221 were moderate negatively correlated with plasma hs-CRP but not serum IL-6. Importantly, the combination of hs-CRP and serum miR-145 gained a better sensitivity/spectivity for prediction of acute ischemia stroke (area under receiver operating characteristic curve from 0.794 to 0.896). Conclusively, our preliminary findings indicate that serum miR-145 upregulated in acute ischemic stroke might be a new biomarker for acute ischemia stroke evaluation. Copyright © 2015 John Wiley & Sons, Ltd.

  10. Genomic characterisation of brain malignancies through liquid biopsies: The cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma

    OpenAIRE

    Arruda,Letícia de Mattos

    2016-01-01

    Los recientes avances en la secuenciación masiva en paralelo y en las técnicas genómicas digitales apoyan la validez clínica del ADN libre tumoral circulante (ctDNA) como una "biopsia líquida" en el cáncer humano. La presencia de ctDNA en el plasma puede ser útil para identificar alteraciones genómicas, monitorizar la respuesta al tratamiento, identificar la resistencia terapéutica, y potencialmente caracterizar la heterogeneidad del tumor. El estudio de prueba de concepto en el campo de las ...

  11. A blood circulation model for reference man

    Energy Technology Data Exchange (ETDEWEB)

    Leggett, R.W.; Eckerman, K.F. [Oak Ridge National Lab., TN (United States). Health Sciences Research Div.; Williams, L.R. [Indiana Univ., South Bend, IN (United States). Div. of Liberal Arts and Sciences

    1999-01-01

    This paper describes a dynamic blood circulation model that predicts the movement and gradual dispersal of a bolus of material in the circulation after its intravascular injection into an adult human. The main purpose of the model is to improve the dosimetry of internally deposited radionuclides that decay in the circulation to a significant extent. The total blood volume is partitioned into the blood contents of 24 separate organs or tissues, right heart chambers, left heart chambers, pulmonary circulation, arterial outflow to the systemic tissues (aorta and large arteries), and venous return from the systemic tissues (large veins). As a compromise between physical reality and computational simplicity, the circulation of blood is viewed as a system of first-order transfers between blood pools, with the delay time depending on the mean transit time across the pool. The model allows consideration of incomplete, tissue-dependent extraction of material during passage through the circulation and return of material from tissues to plasma.

  12. Circulating human IgG reactive to apoptotic cells are masked by plasma proteins%血浆蛋白可屏蔽人类循环中IgG抗体对凋亡细胞的反应活性

    Institute of Scientific and Technical Information of China (English)

    荣春书; 连鑫; 王伟刚; 郑宗宇; 高宝山

    2016-01-01

    Objective To confirm the influence of plasma proteins on the reactivity of circulating IgG to apoptotic cells and to develop an optimal methodology for studying these antibodies.Methods IgG reactivity to apoptotic cells was assessed before and after purification.The following sources of IgG were used:(1)Plasma specimens from 10 kid-ney transplant recipients with AMR;(2)purified IgG from the same 10 AMR patients;(3)supernatant from IgG-pro-ducing immortalized B cell clones;(4)purified IgG from the same B cell clone supernatants.Results Results Plasma IgG reactivity to apoptotic cells was dramatically increased following purification.We observed that reactivity to apop-totic cells could only be detected after purification for some monoclonal IgG produced by B cell clones.Fetal calf serum (FCS)partially reversed the apoptotic-binding potential of purified IgG.Conclusion The reactivity of circulating IgG to apoptotic cells is modified in the presence of plasma proteins.These antibodies must first be purified to remove plasma proteins in order to accurately assess their reactivity.%目的:明确血浆蛋白影响循环中 IgG抗体对凋亡细胞的反应性,并探索检测此类抗体活性的最佳条件。方法分别检测纯化前及纯化后的 IgG抗体对凋亡细胞的反应性。检测所用样本来源于:(1)10例发生移植肾抗体介导排异反应(AMR)患者的血浆样本;(2)从以上10例患者血浆中纯化的IgG抗体;(3)分泌IgG抗体的永生化B淋巴细胞克隆培养上清液;(4)从同一永生化B淋巴细胞克隆培养上清液中纯化的 IgG抗体。结果当 IgG从血浆中纯化出来时,其对凋亡细胞的反应性显著增强。对于某些单克隆 B细胞分泌的 IgG抗体,只有将此抗体从细胞培养上清液中纯化,才能检测到其对凋亡细胞的反应性。而胎牛血清(FCS)可部分阻滞纯化 IgG抗体对凋亡细胞的反应性。结论当血

  13. Biological significance and variation of endothelin-1 in the penis of rat model with abnormal phlegmatic syndrome%维医异常黏液质型阳痿病证大鼠模型阴茎组织中ET-1的改变及其生物学意义

    Institute of Scientific and Technical Information of China (English)

    毛吾兰·买买提依明; 张盼盼; 刘凤霞; 阿地力江·伊明; 木萨·艾麦尔; 薛志琴; 陈胜国

    2016-01-01

    目的:研究维医异常黏液质型阳痿病证大鼠模型阴茎组织中 ET-1的改变及其生物学意义。方法100只 SD大鼠经实验确认具有正常性功能后,10只作为正常对照组,其余90只作为造模组,采用湿寒性饲料和湿寒性环境条件下建立异常黏液质证候模型。造模20 w以后,通过交配和勃起实验从证候模型中筛选出阳痿病证模型,并将其分为病证模型组和病证药物反证组,未成阳痿的证候模型再随机分为证候模型组与证候药物反证组。药物干预2周后,取材,并对阴茎组织进行免疫组化染色,光镜下观察。结果证候模型组、病证模型组大鼠阴茎组织中 ET-1的表达均较正常对照组显著增高(P <0.05),各组织间差异均无统计学意义(P >0.05),而证候药物反证组和病证药物反证组 ET-1较证候模型组和病证模型组明显降低,但无统计学差异(P >0.05)。结论 ET-1表达水平升高可能是异常黏液质型阳痿病证重要的发病机制之一。%Objective To study the biological significance and variation of endothelin-1 expression in the pe-nis of rat model with impotence disease.Methods A total of 100 normal mature male SD rats were en-rolled in the study,and 10 of them were randomly chosen as the control group,the other 90 were treated with spinach and coriander diet in a cold and humid environment until the model of abnormal phlegmatic syndrome was established.After 20 weeks of diet treatment,they were divided into abnormal phlegmatic syndrome model group and pharmacological intervention group by APO erectile experiments and mating experiments.After 2 weeks of recovery treatment to the pharmacological intervention group,immunohis-tochemical stainingwas conducted in the penile tissue of all groups.Results Compared withthe control group,the level of endothelin-1 expression in the impotence model group,medication group of impotence model

  14. Amplificação dos genes que codificam a endotelina-1 e seus receptores em valvas mitrais reumáticas Amplificación de los genes que codifican la endotelina-1 y sus receptores en válvulas mitrales reumáticas Amplification of the genes that codify endothelin-1 and its receptors in rheumatic mitral valves

    Directory of Open Access Journals (Sweden)

    Edmilson Bastos de Moura

    2010-07-01

    receptors in the mitral valve itself - promoting pulmonary vascular changes, with increased rheumatic valvular deformation - has not been discussed in the literature. OBJECTIVE: To determine the expression of endothelin gene and its receptors in rheumatic mitral valves through techniques of molecular genetics. METHODS: Twenty-seven patients submitted to mitral valve replacement had their valvular tissue examined to determine the presence of ET-1 genes and their A and B receptors. Histological and molecular analysis of the valves was performed (divided into M1, M2 and M3 fragments, with patients' clinical and epidemiological data collected. Patients were divided into 3 groups (mitral valvopathy, mitroaortic valvopathy, and reoperation patients. RESULTS: The study showed endothelin-1 gene expression in 40.7% specimens and A receptor in all samples; receptor gene B had lower expression (22.2%. CONCLUSION: All patients showed A receptor gene expression. No statistically significant difference was observed in regard to condition severity, expressed according to functional class, and subgroups (mitral valvopathy, mitroaortic valvopathy, and reoperation patients.

  15. Degradation of circulating thyroglobulin

    Energy Technology Data Exchange (ETDEWEB)

    Taura, M.; Yamashita, S.; Kubo, I.; Izumi, M.; Nagataki, S.

    1985-10-01

    In order to elucidate whether the derivatives of rat Tg in the peripheral circulation affect the results of kinetic studies of Tg, the present study was performed to investigate kinetics of rat Tg after separation of 19S Tg from its derivatives using gel-filtration. Radiolabeled Tg was obtained from thyroids of rats injected with SVI 24 hours before death, and subsequently purified by ammonium sulfate precipitation. The plasma samples obtained at varying time intervals after intravenous injection of SVI-rat Tg were fractionated on a Sephacryl S-300 column. As determined by sucrose density gradient, 99% of in vivo radiolabeled Tg was 19S. On gel-filtration, the injected labeled Tg and plasma samples obtained within two hours after injection showed a single peak in an identical area. A second peak in an area corresponding to a molecular weight of 60,000 to 70,000 appeared within six hours, and became as high as the first within 24 hours. In the second peak, 22.8% radioactivity was precipitated by anti-rat Tg antibody, and 14.4% of radioactivity of its TCA precipitate was not extracted by n-butanol. Thus, the second peak could affect the results of Tg kinetic studies which utilize TCA precipitation, n-butanol extraction or RIA procedures. The half life of rat Tg in the present study was calculated from the disappearance curves of radioactivity of 19S Tg separated from other radioactive substances.

  16. The effect of endothelin-1 on the phagocytic function of human trabecular meshwork cells in vitro%内皮素-1对人小梁细胞吞噬功能的影响

    Institute of Scientific and Technical Information of China (English)

    向艳; 李贵刚; 徐林娟; 陈志祺; 王瑞林; 张虹

    2010-01-01

    目的 观察内皮素-1(ET-1)对人小梁细胞(TMCs)吞噬功能的影响及作用机制.方法 取培养第3代人TMCs,与直径0.5μm荧光标记的乳胶微粒共孵育0、4、8、12、24、48、72h,荧光显微镜下动态定量观察人TMCs吞噬动力学.取6孔板培养3代人TMCs,随机分为4组,观察不同浓度ET-1对人TMCs吞噬功能的影响:对照组(0mol/L ET-1)、低剂量组(10~(-9)mol/L ET-1)、中剂量组(10~(-8)mol/L ET-1)、高剂量组(10~(-7)mol/L ET-1),分别与乳胶颗粒共孵育后观察各组细胞吞噬乳胶颗粒数.取6孔板培养人TMCs随机分为4组,观察内皮素受体对吞噬功能的影响:对照组(0mol/L ET-1)、ET-1组(10~(-8)mol/L ET-1)、ETA受体拮抗剂组(10~(-8)mol/L ET-1+10~(-7)mol/L BQ123)、ETB受体拮抗剂组(10~(-8)mol/L ET-1+10~(-7)mol/L BQ788),并分别与乳胶颗粒共孵育,观察各组人TMCs吞噬乳胶颗粒数.结果 人TMCs免疫组织化学鉴定纤维连接蛋白(FN)、层粘连蛋白(LN)、神经元特异性烯醇酶(NSE)染色均呈阳性;Ⅷ因子相关抗原(FⅧRAg)染色阴性;人TMCs吞噬动力学观察示,人TMCs与乳胶颗粒共孵育4h后可见明显的吞噬颗粒,随时间延长吞噬微粒数明显增多,24h吞噬微粒密度最佳,48h吞噬微粒达到饱和,细胞形态改变;加入ET-1干预后,细胞内吞噬乳胶微球数明显减少,其吞噬抑制效果呈ET-1浓度依赖性(F=28.91,P<0.05);ET-1组吞噬颗粒数较对照组减少(q=13.7228,P<0.05),而ETA受体拮抗剂组吞噬颗粒较ET-1组明显增多(q=9.4312,P<0.05),ETB受体拮抗剂组与ET-1组相比差异无统计学意义(q=1.1600,P>0.05).结论 ET-1能抑制体外培养人TMCs的吞噬能力;ET-1主要通过ETA受体发挥抑制人TMCs吞噬功能的作用.%Background Endothelin-1 (ET-1) is an active regulator of intraocular pressure.The ET-1 level in aqueous humor is elevated in primary open-angle glaucoma,normal intraocular tension glaucoma and the animal model of glaucoma.There is now

  17. Correlation between Saliva and Plasma Levels of Endothelin Isoforms ET-1, ET-2, and ET-3

    Directory of Open Access Journals (Sweden)

    Roma Gurusankar

    2015-01-01

    Full Text Available Although saliva endothelins are emerging as valuable noninvasive cardiovascular biomarkers, reports on the relationship between isoforms in saliva and plasma remain scarce. We measured endothelins in concurrent saliva and plasma samples (n=30 males; age 18–63 by HPLC-fluorescence. Results revealed statistically significant positive correlations among all isoforms between saliva and plasma: big endothelin-1 (BET-1, 0.55 ± 0.27 versus 3.35 ± 1.28 pmol/mL; r=0.38, p=0.041, endothelin-1 (ET-1, 0.52 ± 0.21 versus 3.45 ± 1.28 pmol/mL; r=0.53, p=0.003, endothelin-2 (ET-2, 0.21 ± 0.07 versus 1.63 ± 0.66 pmol/mL; r=0.51, p=0.004, and endothelin-3 (ET-3, 0.39 ± 0.19 versus 2.32 ± 1.44 pmol/mL; r=0.75, p<0.001. Correlations of BET-1, ET-1, and ET-3 within each compartment were positive in both plasma (p<0.05 and saliva (p≤0.1, whereas ET-2 was not significantly correlated with other isoforms in either plasma or saliva. For all isoforms, concentrations varied on average fivefold between individuals (90th/10th percentiles; individuals with high plasma endothelin levels generally had high saliva endothelin levels. Our results reveal that salivary ET isoform profiles portray the plasmatic profiles and support the view of coordinated regulation of ET-1 and ET-3, but distinct regulatory pathways for ET-2.

  18. Bioactive factors in uteroplacental and systemic circulation link placental ischemia to generalized vascular dysfunction in hypertensive pregnancy and preeclampsia.

    Science.gov (United States)

    Shah, Dania A; Khalil, Raouf A

    2015-06-15

    Preeclampsia is a pregnancy-associated disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality; however, the pathophysiological mechanisms involved are unclear. Predisposing demographic, genetic and environmental risk factors could cause localized abnormalities in uteroplacental cytoactive factors such as integrins, matrix metalloproteinases, cytokines and major histocompatibility complex molecules leading to decreased vascular remodeling, uteroplacental vasoconstriction, trophoblast cells apoptosis, and abnormal development of the placenta. Defective placentation and decreased trophoblast invasion of the myometrium cause reduction in uteroplacental perfusion pressure (RUPP) and placental ischemia/hypoxia, an important event in preeclampsia. RUPP could stimulate the release of circulating bioactive factors such as the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin that cause imbalance with the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or cause the release of inflammatory cytokines, reactive oxygen species, hypoxia-induced factor-1 and AT1 angiotensin receptor agonistic autoantibodies. The circulating bioactive factors target endothelial cells causing generalized endotheliosis, endothelial dysfunction, decreased vasodilators such as nitric oxide and prostacyclin and increased vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction. The bioactive factors also stimulate the mechanisms of VSM contraction including Ca(2+), protein kinase C, and Rho-kinase and induce extracellular matrix remodeling leading to further vasoconstriction and hypertension. While therapeutic options are currently limited, understanding the underlying mechanisms could help design new interventions for management of preeclampsia.

  19. Effects of a novel phosphodiesterase IV inhibitor Ariflo on endothelin-1-induced contractility of isolated human uterine myometrium%新型磷酸二酯酶Ⅳ抑制剂Ariflo对内皮素-1诱发离体人子宫平滑肌收缩的影响

    Institute of Scientific and Technical Information of China (English)

    祁红; Leroy MJ; Advenier C; 张勇; Emmanuel N; 陈红专

    2004-01-01

    目的:研究选择性磷酸二酯酶 (phosphodiesterase,PDE) Ⅳ抑制剂Ariflo对内皮素-1 (endothelin-1,ET-1) 诱发的非妊娠人子宫平滑肌收缩的影响.方法:累积给药法观察药物对离体平滑肌收缩的作用.结果:Ariflo可降低子宫平滑肌自主收缩的收缩频率及收缩幅度 (pD2=7.90),且对ET-1 (3×10-8 mol*L-1)诱发的子宫平滑肌收缩具有浓度依赖性抑制作用(pD2=7.40),作用强度与Rolipram相似.结论:Ariflo对ET-1诱发的离体人子宫平滑肌的收缩具有显著抑制作用,提示在临床上有缓解痛经的作用.

  20. Microwave circulator design

    CERN Document Server

    Linkhart, Douglas K

    2014-01-01

    Circulator design has advanced significantly since the first edition of this book was published 25 years ago. The objective of this second edition is to present theory, information, and design procedures that will enable microwave engineers and technicians to design and build circulators successfully. This resource contains a discussion of the various units used in the circulator design computations, as well as covers the theory of operation. This book presents numerous applications, giving microwave engineers new ideas about how to solve problems using circulators. Design examples are provided, which demonstrate how to apply the information to real-world design tasks.

  1. 冠心病患者血浆循环miR-126的表达及其对血管内皮细胞的影响%Plasma circulating miR-126 in patients with coronary artery heart disease and its effect on vascular endothelial cells

    Institute of Scientific and Technical Information of China (English)

    郑志伟; 劳海燕; 余细勇; 陈纪言; 林秋雄; 麦丽萍; 钟诗龙

    2011-01-01

    AIM: To investigate the role of plasma circulating miR - 126 and miR - 16 in the patients with coronary artery heart disease and to explore the influence of miR - 126 on vascular endothelial cells. METHODS: Plasma total RNA was isolated from 52 patients with stable coronary artery disease and 52 healthy volunteers. The circulating miR -126 and miR -16 in those people were detected using specific primers. Endothelial cell line EA. Hy926 was transfected with a miR - 126 inhibitor, and total RNA of the cells was isolated 30 h after transfection to detect the expression level of vascular endothelial growth factor ( VEGF ). RESULTS: The expression of plasma circulating miR - 126 was significantly decreased in the patients with coronary artery heart disease compared with healthy controls ( P 0. 05 ). The expression of VEGF in the endothelial cell line EA. Hy926 transfected with miR - 126 inhibitor was 2.08 times higher than that in negative control cells 30 h after transfection ( P 0.05);(2)内皮细胞株EA.hy926中miR-126被抑制后,血管内皮生长因子的表达为对照组的2.08倍(P<0.05).结论:血浆循环miR-126在冠心病患者表达下降,血浆循环miR-16在人群中的表达较稳定;miR-126通过负性调节血管内皮生长因子的表达,对血管内皮细胞产生调节作用.

  2. Mountains and Tropical Circulation

    Science.gov (United States)

    Naiman, Z.; Goodman, P. J.; Krasting, J. P.; Malyshev, S.; Russell, J. L.; Stouffer, R. J.

    2015-12-01

    Observed tropical convection exhibits zonal asymmetries that strongly influence spatial precipitation patterns. The drivers of changes to this zonally-asymmetric Walker circulation on decadal and longer timescales have been the focus of significant recent research. Here we use two state-of-the-art earth system models to explore the impact of earth's mountains on the Walker circulation. When all land-surface topography is removed, the Walker circulation weakens by 33-59%. There is a ~30% decrease in global, large-scale upward vertical wind velocities in the middle of the troposphere, but only minor changes in global average convective mass flux, precipitation, surface and sea-surface temperatures. The zonally symmetric Hadley circulation is also largely unchanged. Following the spatial pattern of changes to large-scale vertical wind velocities, precipitation becomes less focused over the tropics. The weakening of the Walker circulation, but not the Hadley circulation, is similar to the behavior of climate models during radiative forcing experiments: in our simulations, the weakening is associated with changes in vertical wind velocities, rather than the hydrologic cycle. These results indicate suggest that mountain heights may significantly influence the Walker circulation on geologic time scales, and observed changes in tropical precipitation over millions of years may have been forced by changes in tropical orography.

  3. On circulating power of steady state tokamaks

    Energy Technology Data Exchange (ETDEWEB)

    Itoh, Kimitaka [National Inst. for Fusion Science, Nagoya (Japan); Itoh, Sanae; Fukuyama, Atsushi; Yagi, Masatoshi

    1996-03-01

    Circulating power for the sustenance and profile control of the steady state tokamak plasmas is discussed. The simultaneous fulfillment of the MHD stability at high beta value, the improved confinement and the stationary equilibrium requires the rotation drive as well as the current drive. In addition to the current drive efficiency, the efficiency for the rotation drive is investigated. The direct rotation drive by the external torque, such as the case of beam injection, is not efficient enough. The mechanism and the magnitude of the spontaneous plasma rotation are studied. (author)

  4. 内皮素1受体拮抗剂在先天性心脏病相关肺动脉高压治疗中的应用研究进展%Application Progress of Endothelin-1 Receptor Antagonists in Treatment of Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

    Institute of Scientific and Technical Information of China (English)

    郭耀磊

    2013-01-01

    Endothelin-1( ET-1) is a powerful vasoconstrictor and mitogen for smooth muscle and plays an important role in the development of pulmonary arterial hypertension( PAH ).An activation of the ET-1 system has been demonstrated in PAH patients as well as in animal models of PAH.The most efficient way to antagonize the ET-1 system is the use of ET-1 receptor antagonists which mainly include bosentan, sitaxsentan and ambrisentan.Lots of researches have showed ET-1 receptor antagonists can significantly reduce pulmonary artery pressure of patients with idiopathic PAH.Recently,the use of ET-1 receptor antagonists in the treatment of PAH associated with congenital heart disease has made some progress.%内皮素1(ET-1)是一种强效的血管收缩剂和促平滑肌细胞分裂剂,在肺动脉高压(PAH)的发展中扮演着重要角色.研究显示,PAH患者和动物模型中的ET-1系统是激活的.阻断ET-1系统最有效的方法就是使用ET-1受体拮抗剂.目前,临床常用的ET-1受体拮抗剂主要有波生坦、西他生坦和安立生坦.研究表明,ET-1受体拮抗剂可明显降低特发性PAH患者的肺血管阻力.近年来,ET-1受体拮抗剂在先天性心脏病相关PAH的治疗中也取得一些进展.

  5. Learning Circulant Sensing Kernels

    Science.gov (United States)

    2014-03-01

    learned dictionaries. Examples of analytic dictionaries include the discrete cosine basis, various wavelets bases , as well as tight frames. Some of them...Compressive sensing based high resolution channel estimation for OFDM system. To appear in IEEE Journal of Selected Topics in Signal Processing, Special...theoretical and computational properties to a (partial) circulant matrix of the same size, our discussions below are based exclusively on the circulant

  6. Circulating CXCL16 in Diabetic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Usama Elewa

    2016-09-01

    Full Text Available Background/Aims: Chronic kidney disease and, specifically, diabetic kidney disease, is among the fastest increasing causes of death worldwide. A better understanding of the factors contributing to the high mortality may help design novel monitoring and therapeutic approaches. CXCL16 is both a cholesterol receptor and a chemokine with a potential role in vascular injury and inflammation. We aimed at identifying predictors of circulating CXCL16 levels in diabetic patients with chronic kidney disease. Methods: We have now studied plasma CXCL16 in 134 European patients with diabetic kidney disease with estimated glomerular filtration rate (eGFR categories G1-G4 and albuminuria categories A1-A3, in order to identify factors influencing plasma CXCL16 in this population. Results: Plasma CXCL16 levels were 4.0±0.9 ng/ml. Plasma CXCL16 increased with increasing eGFR category from G1 to G4 (that is, with decreasing eGFR values and with increasing albuminuria category. Plasma CXCL16 was higher in patients with prior cardiovascular disease (4.33±1.03 vs 3.88±0.86 ng/ml; p=0.013. In multivariate analysis, eGFR and serum albumin had an independent and significant negative correlation with plasma CXCL16. Conclusion: In diabetic kidney disease patients, GFR and serum albumin independently predicted plasma CXCL16 levels.

  7. Endothelin-1 induces connective tissue growth factor expression in cardiomyocytes.

    Science.gov (United States)

    Recchia, Anna Grazia; Filice, Elisabetta; Pellegrino, Daniela; Dobrina, Aldo; Cerra, Maria Carmela; Maggiolini, Marcello

    2009-03-01

    Endothelin (ET)-1 is a vasoconstrictor involved in cardiovascular diseases. Connective tissue growth factor/CCN2 (CTGF) is a fibrotic mediator overexpressed in human atherosclerotic lesions, myocardial infarction, and hypertension. In different cell types CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation and plays important roles in angiogenesis, chondrogenesis, osteogenesis, tissue repair, cancer and fibrosis. In the present study, we investigated the ET-1 signaling which triggers CTGF expression in cultured adult mouse atrial-muscle HL-1 cells used as a model system. ET-1 activated the CTGF promoter and induced CTGF expression at both mRNA and protein levels. Real-time PCR analysis revealed CTGF induction also in isolated rat heart preparations perfused with ET-1. Several intracellular signals elicited by ET-1 via ET receptors and even Epidermal Growth Factor Receptor (EGFR) contributed to the up-regulation of CTGF, including ERK activation and induction of the AP-1 components c-fos and c-jun, as also evaluated by ChIP analysis. Moreover, in cells treated with ET-1 the expression of ECM component decorin was abolished by CTGF silencing, indicating that CTGF is involved in ET-1 induced ECM accumulation not only in a direct manner but also through downstream effectors. Collectively, our data indicate that CTGF could be a mediator of the profibrotic effects of ET-1 in cardiomyocytes. CTGF inhibitors should be considered in setting a comprehensive pharmacological approach towards ET-1 induced cardiovascular diseases.

  8. Gaussian Fibonacci Circulant Type Matrices

    Directory of Open Access Journals (Sweden)

    Zhaolin Jiang

    2014-01-01

    Full Text Available Circulant matrices have become important tools in solving integrable system, Hamiltonian structure, and integral equations. In this paper, we prove that Gaussian Fibonacci circulant type matrices are invertible matrices for n>2 and give the explicit determinants and the inverse matrices. Furthermore, the upper bounds for the spread on Gaussian Fibonacci circulant and left circulant matrices are presented, respectively.

  9. Ocean circulation using altimetry

    Science.gov (United States)

    Minster, Jean-Francois; Brossier, C.; Gennero, M. C.; Mazzega, P.; Remy, F.; Letraon, P. Y.; Blanc, F.

    1991-01-01

    Our group has been very actively involved in promoting satellite altimetry as a unique tool for observing ocean circulation and its variability. TOPEX/POSEIDON is particularly interesting as it is optimized for this purpose. It will probably be the first instrument really capable of observing the seasonal and interannual variability of subtropical and polar gyres and the first to eventually document the corresponding variability of their heat flux transport. The studies of these phenomena require data of the best quality, unbiased extraction of the signal, mixing of these satellite data with in situ measurements, and assimilation of the whole set into a dynamic description of ocean circulation. Our group intends to develop responses to all these requirements. We will concentrate mostly on the circulation of the South Atlantic and Indian Oceans: This will be done in close connection with other groups involved in the study of circulation of the tropical Atlantic Ocean, in the altimetry measurements (in particular, those of the tidal issue), and in the techniques of data assimilation in ocean circulation models.

  10. Circulant Double Coverings of a Circulant Graph of Valency Five

    Institute of Scientific and Technical Information of China (English)

    Rong Quan FENG; Jin Ho KWAK

    2007-01-01

    Enumerating the isomorphism classes of several types of graph covering projections is one of the central research topics in enumerative topological graph theory. A covering of G is called circulant if its covering graph is circulant. Recently, the authors [Discrete Math., 277, 73-85 (2004)]enumerated the isomorphism classes of circulant double coverings of a certain type, called a typicalcovering, and showed that no double covering of a circulant graph of valency three is circulant. Also, in [Graphs and Combinatorics, 21, 386-400 (2005)], the isomorphism classes of circulant double coverings of a circulant graph of valency four are enumerated. In this paper, the isomorphism classes of circulant double coverings of a circulant graph of valency five are enumerated.

  11. Kernels in circulant digraphs

    Directory of Open Access Journals (Sweden)

    R. Lakshmi

    2014-06-01

    Full Text Available A kernel $J$ of a digraph $D$ is an independent set of vertices of $D$ such that for every vertex $w,in,V(D,setminus,J$ there exists an arc from $w$ to a vertex in $J.$ In this paper, among other results, a characterization of $2$-regular circulant digraph having a kernel is obtained. This characterization is a partial solution to the following problem: Characterize circulant digraphs which have kernels; it appeared in the book {it Digraphs - theory, algorithms and applications}, Second Edition, Springer-Verlag, 2009, by J. Bang-Jensen and G. Gutin.

  12. Influence of advanced glycation end products on prostacyclin and endothelin-1 secretion from human vascular endothelial cells%糖基化终末产物对人内皮细胞分泌前列环素和内皮素-1的影响

    Institute of Scientific and Technical Information of China (English)

    赵保明; 李凤良; 宋喜明

    2011-01-01

    Objective To investigate the influence of advanced glycation end products (AGES) on prostacyclin (PGI2) and endothelin-1 ( ET-1) secretion from human umbilical vein endothelial cells (HUVEC), and the effect of a-lipoic acid(a-LPA) on it. Methods HUVEC were obtained by enzyme digestion and primary culture, and divided into the normal control group, the AGES group, the normal + AGES group, and the AGES + a-LPA group. PGI2 and ET-1 in culture media were assayed by radioimmunoassay( RIA) when HUVEC were cultured for 24,48 and 72 hours. Results ①The content of PGI2 in the AGES group was lower than that in the normal control group( P < 0.05), while the content of ET-1 was higher(p <0.05). ②The content of PGI2 in the AGES + a-LPA group was higher than that in the AGES group (P < 0.05), while the content of ET-1 was lower( P < 0.01). Conclusion AGES can injure vascular endothelial cells, while a-LPA can diminish the injury, which indicates that antioxidants can protect vascular endothelial cells.%目的 了解糖基化终末产物(AGEs)对人内皮细胞分泌前列环素(PGI2)和内皮素-1(ET-1)的影响,以及α-硫辛酸(α-LPA)对其的影响.方法 采用酶消化法收集人脐静脉内皮细胞,经原代培养后随机分为4组:正常对照组、AGEs组、正常+AGEs组和AGEs+α-LPA组;放免法测定培养24、48、72 h时培养基中的PGI2和ET-1含量.结果 ①AGEs组较正常对照组PGI2显著下降(P<0.05),ET-1显著升高(P<0.05);②AGEs+α-LPA组较AGEs组PGI2显著升高(P<0.05),ET-1显著下降(P<0.01).结论 AGEs对血管内皮细胞有损伤作用,α-LPA可减轻这种损伤,提示抗氧化剂可用于保护血管内皮细胞.

  13. Evaluation of the serum endothelin-1 level and sleep architecture change in patients with obstructive sleep apnea hypopnea syndrome accompanied hypertension%阻塞性睡眠呼吸暂停低通气综合征合并高血压患者睡眠结构分析及血清内皮素-1的测定

    Institute of Scientific and Technical Information of China (English)

    李延忠; 王廷础; 卢红霞; 王欣; 王岩; 张丙峰

    2004-01-01

    目的探讨内皮素-1(endothelin-1,ET-1)在阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea hypopnea syndrome,OSAHS)合并高血压发病中的作用.方法对30例OSAHS合并高血压患者及30例OSAHS血压正常患者的睡眠结构、呼吸暂停、低氧血症及唤醒程度进行分析,同时应用ET-1酶免疫测定试剂盒测定其血清中ET-1的含量.结果 OSAHS合并高血压组及OSAHS血压正常组与单纯鼾症对照组比较觉醒时间、浅睡眠(1期)明显增多,中度睡眠(2期)明显减少(P<0.01);而OSAHS合并高血压组与OSAHS血压正常组比较无明显差异.OSAHS合并高血压与OSAHS血压正常组血清ET-1质量浓度(±s,下同)分别是(42.5±8.4)和(38.6±4.7) ng/L明显高于正常对照组(33.1±5.4) ng/L(P<0.01);同时OSAHS合并高血压组与OSAHS血压正常组比较血清ET-1质量浓度也明显增高(P<0.05).血清ET-1水平与AHI呈明显的正相关(r=0.334,P<0.01),与最低血氧饱和度呈明显的负相关(r=-0.230,P<0.05).结论 OSAHS患者存在着明显的睡眠结构紊乱,但合并高血压者并没有特异性改变.ET-1可能在OSAHS合并高血压的发病中起一定作用.

  14. Expression of endothelin-1 and endothelin receptors in villi and its relation to unexplained recurrent spontaneous abortion%ET-1及受体在不明原因复发性流产绒毛中的表达及其对滋养细胞迁移的调节

    Institute of Scientific and Technical Information of China (English)

    周红娣; 宗姗姗; 罗成凤; 王凯; 周倩

    2015-01-01

    目的 通过检测内皮素-1(endothelin-1,ET-1)及受体(endothelin receptors,ETR)在不明原因复发性流产(unexplained recurrent spontaneous abortion,URSA)绒毛组织中的表达,探讨其与URSA的关系.方法 不明原因复发性流产患者30例(RSA组)及正常早孕人流妇女30例(正常组,即CTL组),采用实时荧光定量PCR(Real-Time PCR)及Western印迹法检测两组绒毛组织中ET-1、ETR-A、ETR-B mRNA及蛋白的表达.取体外培养的妊娠早期绒毛外滋养细胞Transwell迁移实验法检测ET-1、ETR-A阻断剂BQ-123及ETR-B阻断剂BQ-788受体对绒毛外滋养细胞迁移能力的影响.结果 RSA组较正常组绒毛组织中ETR-B mRNA及蛋白表达降低,差异有统计学意义(P<0.05),而ET-1、ETR-A mRNA及蛋白在二组绒毛组织中的表达差异无统计学意义(P>0.05).ET-1促进HTR-8细胞迁移,ETR-B阻断剂阻断ET-1的促迁移作用.结论 ET-1可能通过ETR-B受体促进妊娠早期绒毛外滋养细胞迁移,URSA患者较正常组绒毛中ETR-B mRNA及蛋白表达降低可能与URSA相关.

  15. Global Circulation and Impact of Plasmaspheric Plumes

    Science.gov (United States)

    Moore, Thomas E.; Fok, Mei-Ching; Chen, Sheng-Hsiem; Delcourt, Dominique C.; Fedder, Joel A.; Slinker, Steven P.

    2008-01-01

    We report results from the global circulation model of Lyon, Fedder, and Mobarry with an embedded model of the inner magnetosphere including the plasmasphere. The combination is used to initiate large numbers of representative protons on the geosynchronous orbit L shell, to assign particle weightings, to track their: subsequent trajectories in the 3D fields. This permits us to study the global circulation of plasmaspheric plumes and to compare these with Polar observations from the dayside magnetopause region . A range of events is studied from an isolated period of SBz in the solar wind,to a large storm sequence. We consider effects on circulating plasma reaching the dayside reconnection X-line, the population of the plasma sheet with ionospheric protons and the generation of ring current pressure from this source, compared with solar wind, polar wind, and auroral wind sources. We find that the transient plasmaspheric plume source is large in terms of total fluence, but of modest proportions in terms of contribution to the ring current. Implications of this and other results for improved space weather modeling and prediction will be discussed.

  16. Transpulmonary plasma ET-1 and nitrite differences in high altitude pulmonary hypertension.

    Science.gov (United States)

    Berger, Marc M; Dehnert, Christoph; Bailey, Damian M; Luks, Andrew M; Menold, Elmar; Castell, Christian; Schendler, Guido; Faoro, Vitalie; Mairbäurl, Heimo; Bärtsch, Peter; Swenson, Erik R

    2009-01-01

    Berger, Marc M., Christoph Dehnert, Damian M. Bailey, Andrew M. Luks, Elmar Menold, Christian Castell, Guido Schendler, Vitalie Faoro, Heimo Mairbäurl, Peter Bärtsch, and Eric R. Swenson. Transpulmonary plasma ET-1 and nitrite differences in high altitude pulmonary hypertension. High Alt. Med. Biol. 10:17-24, 2009.- Thirty-four mountaineers were studied at low (110 m) and high altitude (4559 m) to evaluate if increased pulmonary artery systolic pressure (PASP) at high altitude is associated with increased pulmonary endothelin-1 (ET-1) availability and alterations in nitrite metabolism across the lung. Blood samples were obtained using central venous and radial artery catheters for plasma ET-1 and nitrite. Pulmonary blood flow was measured by inert gas rebreathing to calculate transpulmonary exchange of plasma ET-1 and nitrite, and PASP was assessed by transthoracic Doppler echocardiography. After ascent to high altitude, PASP increased from 23 +/- 4 to 39 +/- 10 mmHg. Arterial and central venous plasma ET-1 increased, while plasma nitrite did not change significantly. At low altitude there was a transpulmonary loss of plasma ET-1, but a transpulmonary gain at high altitude. In contrast was a transpulmonary gain of plasma nitrite at low altitude and a transpulmonary loss at high altitude. PASP positively correlated with a transpulmonary gain of plasma ET-1 and negatively correlated with a transpulmonary loss of plasma nitrite. These results suggest that a transpulmonary gain of plasma ET- 1 is associated with higher PASP at high altitude. Transpulmonary loss of plasma nitrite indicates either less pulmonary nitric oxide (NO) production, which contributes to higher PASP, or increased NO bioavailability arising from nitrite reduction, which may oppose ET-1-mediated vasoconstriction.

  17. 前循环短暂性脑缺血发作患者血浆纤维蛋白原水平与ABCD2评分的关系%Relationship between the level of plasma fibrinogen and ABCD2 score in patients with anterior circulation transient ischemic attack

    Institute of Scientific and Technical Information of China (English)

    叶子明; 刘莹; 秦超; 邓晓; 陈相任; 林翠婷

    2013-01-01

    目的 探讨前循环短暂性脑缺血发作(TIA)患者血浆纤维蛋白原(Fg)水平与ABCD2评分的关系.方法 采用ABCD2评分对133例前循环TIA患者进行评估,并根据评分分为低危亚组、中危亚组和高危亚组.检测TIA患者及128名正常对照者的血浆Fg水平,并比较.结果 根据ABCD2评分将患者分为低危亚组32例,中危亚组72例,高危亚组29例.TIA组血浆Fg水平显著高于正常对照组(P<0.01).中危及高危亚组的血浆Fg水平显著高于低危亚组;高危亚组显著高于中危亚组(均P<0.05).Kruskal-Wallis H检验显示,高危亚组、中危亚组、低危亚组的血浆Fg水平差异有统计学意义(P<0.01).经Spearmen秩相关系数检验,血浆Fg平均水平与ABCD2评分呈正相关(r=0.548,P<0.001).结论 前循环TIA患者血浆Fg水平与ABCD2评分呈正相关.%Objective To investigate the relationship between the level of plasma fibrinogen (Fg) and ABCD2 score in patients with anterior circulation transient ischemic attack (TIA).Methods One hundred and thirty-three patients were evaluated by ABCD2 score,and they were divided into low-risk subgroup,mid-risk subgroup and high-risk subgroup.The level of plasma Fg was detected in TIA patients and 128 normal controls,and the results were compared.Results According to ABCD2 score,patients were divided into low-risk subgroup (32 cases),mid-risk subgroup (72 cases) and high-risk subgroup (29 cases).The level of plasma Fg in TIA group was significantly higher than that in normal control group (P < 0.01).The level of plasma Fg in mid-risk subgroup and high-risk subgroup were significantly higher than that in low-risk subgroup; and the level of plasma Fg in high-risk subgroup was significantly higher than that in mid-risk subgroup (all P < 0.05).Kruskal-Wallis H test demonstrated that there were significant differences of plasma Fg level among low-risk subgroup,mid-risk subgroup and high-risk subgroup (P <0.01).Spearman rank

  18. Periodontitis and increase in circulating oxidative stress

    Directory of Open Access Journals (Sweden)

    Takaaki Tomofuji

    2009-05-01

    Full Text Available Reactive oxygen species (ROS are products of normal cellular metabolism. However, excessive production of ROS oxidizes DNA, lipids and proteins, inducing tissue damage. Studies have shown that periodontitis induces excessive ROS production in periodontal tissue. When periodontitis develops, ROS produced in the periodontal lesion diffuse into the blood stream, resulting in the oxidation of blood molecules (circulating oxidative stress. Such oxidation may be detrimental to systemic health. For instance, previous animal studies suggested that experimental periodontitis induces oxidative damage of the liver and descending aorta by increasing circulating oxidative stress. In addition, it has been revealed that clinical parameters in chronic periodontitis patients showed a significant improvement 2 months after periodontal treatment, which was accompanied by a significant reduction of reactive oxygen metabolites in plasma. Improvement of periodontitis by periodontal treatment could reduce the occurrence of circulating oxidative stress. Furthermore, recent studies indicate that the increase in circulating oxidative stress following diabetes mellitus and inappropriate nutrition damages periodontal tissues. In such cases, therapeutic approaches to systemic oxidative stress might be necessary to improve periodontal health.

  19. Circulating microparticles, protein C, free protein S and endothelial vascular markers in children with sickle cell anaemia

    Directory of Open Access Journals (Sweden)

    Andrea Piccin

    2015-11-01

    Full Text Available Introduction: Circulating microparticles (MP have been described in sickle cell anaemia (SCA; however, their interaction with endothelial markers remains unclear. We investigated the relationship between MP, protein C (PC, free protein S (PS, nitric oxide (NO, endothelin-1 (ET-1 and adrenomedullin (ADM in a large cohort of paediatric patients. Method: A total of 111 children of African ethnicity with SCA: 51 in steady state; 15 in crises; 30 on hydroxyurea (HU therapy; 15 on transfusion; 17 controls (HbAA of similar age/ethnicity. MP were analysed by flow cytometry using: Annexin V (AV, CD61, CD42a, CD62P, CD235a, CD14, CD142 (tissue factor, CD201 (endothelial PC receptor, CD62E, CD36 (TSP-1, CD47 (TSP-1 receptor, CD31 (PECAM, CD144 (VE-cadherin. Protein C, free PS, NO, pro-ADM and C-terminal ET-1 were also measured. Results: Total MP AV was lower in crisis (1.26×106 ml−1; 0.56–2.44×106 and steady state (1.35×106 ml−1; 0.71–3.0×106 compared to transfusion (4.33×106 ml−1; 1.6–9.2×106, p0.9, p<0.05 between total numbers of AV-positive MP (MP AV and platelet MP expressing non-activation platelet markers. There was a lower correlation between MP AV and MP CD62P (R=0.73, p<0.05 (platelet activation marker, and also a lower correlation between percentage of MP expressing CD201 (%MP CD201 and %MP CD14 (R=0.627, p<0.001. %MP CD201 was higher in crisis (11.6% compared with HbAA (3.2%, p<0.05; %MP CD144 was higher in crisis (7.6% compared with transfusion (2.1%, p<0.05; %CD14 (0.77% was higher in crisis compared with transfusion (0.0%, p<0.05 and steady state (0.0%, p<0.01; MP CD14 was detectable in a higher number of samples (92% in crisis compared with the rest (40%; %MP CD235a was higher in crisis (17.9% compared with transfusion (8.9%, HU (8.7% and steady state (9.9%, p<0.05; %CD62E did not differ significantly across the groups and CD142 was undetectable. Pro-ADM levels were raised in chest crisis: 0.38 nmol L−1 (0.31–0

  20. Role of the heme oxygenases in abnormalities of the mesenteric circulation in cirrhotic rats.

    Science.gov (United States)

    Sacerdoti, David; Abraham, Nader G; Oyekan, Adebayo O; Yang, Liming; Gatta, Angelo; McGiff, John C

    2004-02-01

    Carbon monoxide (CO), a product of heme metabolism by heme-oxygenase (HO), has biological actions similar to those of nitric oxide (NO). The role of CO in decreasing vascular responses to constrictor agents produced by experimental cirrhosis induced by carbon tetrachloride was evaluated before and after inhibition of HO with tin-mesoporphyrin (SnMP) in the perfused superior mesenteric vasculature (SMV) of cirrhotic and normal rats and in normal rats transfected with the human HO-1 (HHO-1) gene. Perfusion pressure and vasoconstrictor responses of the SMV to KCl, phenylephrine (PE), and endothelin-1 (ET-1) were decreased in cirrhotic rats. SnMP increased SMV perfusion pressure and restored the constrictor responses of the SMV to KCl, PE, and ET-1 in cirrhotic rats. The relative roles of NO and CO in producing hyporeactivity of the SMV to PE in cirrhotic rats were examined. Vasoconstrictor responses to PE were successively augmented by stepwise inhibition of CO and NO production, suggesting a complementary role for these gases in the regulation of reactivity of the SMV. Expression of constitutive but not of inducible HO (HO-1) was increased in the SMV of cirrhotic rats as was HO activity. Administration of adenovirus containing HHO-1 gene produced detection of HHO-1 RNA and increased HO activity in the SMV within 7 days. Rats transfected with HO-1 demonstrated reduction in both perfusion pressure and vasoconstrictor responses to PE in the SMV. We propose that HO is an essential component in mechanisms that modulate reactivity of the mesenteric circulation in experimental hepatic cirrhosis in rats.

  1. Ocean circulation studies

    Science.gov (United States)

    Koblinsky, C. J.

    1984-01-01

    Remotely sensed signatures of ocean surface characteristics from active and passive satellite-borne radiometers in conjunction with in situ data were utilized to examine the large scale, low frequency circulation of the world's oceans. Studies of the California Current, the Gulf of California, and the Kuroshio Extension Current in the western North Pacific were reviewed briefly. The importance of satellite oceanographic tools was emphasized.

  2. The fetal circulation.

    Science.gov (United States)

    Kiserud, Torvid; Acharya, Ganesh

    2004-12-30

    Accumulating data on the human fetal circulation shows the similarity to the experimental animal physiology, but with important differences. The human fetus seems to circulate less blood through the placenta, shunt less through the ductus venosus and foramen ovale, but direct more blood through the lungs than the fetal sheep. However, there are substantial individual variations and the pattern changes with gestational age. The normalised umbilical blood flow decreases with gestational age, and, at 28 to 32 weeks, a new level of development seems to be reached. At this stage, the shunting through the ductus venosus and the foramen ovale reaches a minimum, and the flow through the lungs a maximum. The ductus venosus and foramen ovale are functionally closely related and represent an important distributional unit for the venous return. The left portal branch represents a venous watershed, and, similarly, the isthmus aorta an arterial watershed. Thus, the fetal central circulation is a very flexible and adaptive circulatory system. The responses to increased afterload, hypoxaemia and acidaemia in the human fetus are equivalent to those found in animal studies: increased ductus venosus and foramen ovale shunting, increased impedance in the lungs, reduced impedance in the brain, increasingly reversed flow in the aortic isthmus and a more prominent coronary blood flow.

  3. Correlation between level of plasma SDF-1 and coronary collateral circulation in patients with CHD complicating diabetes mellitus%冠心病合并糖尿病患者血浆SDF-1水平及与冠状动脉侧支循环的相关性研究

    Institute of Scientific and Technical Information of China (English)

    赵亚珍; 浦奎; 徐娅楠

    2012-01-01

    目的 探讨冠心病合并糖尿病(DM)患者血浆基质细胞衍生因子-1(SDF-1)水平及与冠状动脉侧支循环的关系.方法 纳入79例拟诊冠心病并行冠状动脉造影(CAG)的患者.根据CAG结果分为:正常对照组(n=26)及冠心病组(n=53).冠心病组又根据患者是否合并DM分为:合并DM亚组(n=21)与未合并DM亚组(n=32).采用ELISA法检测患者血浆中SDF-1的水平;用Rentrop分级系统对冠状动脉侧支血管形成进行评级.比较各组患者血浆SDF-1的水平,并对冠心病患者SDF-1的水平与Rentrop分级进行直线相关分析.结果 冠心病组患者血浆SDF-1水平低于对照组,两组差异有统计学意义(P<0.05);冠心病合并DM亚组SDF-1水平低于未合并DM亚组,两亚组间差异亦有统计学意义(P<0.05).合并DM亚组冠脉侧支循环形成率为33.3%,低于未合并DM亚组冠脉侧支循环的形成率(75.0%),两亚组侧支循环形成率有统计学差异(P<0.05).冠心病组患者SDF-1水平与Rentrop的分级呈正相关(r=0.508,P<0.01).结论 冠心病合并DM患者血浆中SDF-1水平及侧支循环形成的能力降低,SDF-1水平与冠状动脉侧支循环形成的能力呈正相关.%Objective To investigate the relationship between the level of plasma SDF-1 and coronary collateral circulation in patients with coronary heart disease ( CHD ) complicating diabetes mellitus ( DM ). Methods The patients ( n = 79 ) with suspected CHD and having coronary angiography ( CAG ) were selected and divided into control group ( n = 26 ) and CHD group ( n = 53 ) according to CAG results. The CHD group was then divided into subgroup complicating DM ( DM subgroup,n =21 ) and subgroup without DM ( non-DM subgroup ). The level of plasma SDF-1 was detected by using ELISA, and the angiopoiesis of coronary collateral vessels was graded by applying Rentrop grading system. The level of plasma SDF-1 was compared among all groups and the linear correlation analysis was carried out

  4. Semicarbazide-sensitive amine oxidase (SSAO): from cell to circulation

    NARCIS (Netherlands)

    F. Boomsma (Frans); H. Hut; U. Bagghoe; A.H. van den Meiracker (Anton)

    2005-01-01

    textabstractSemicarbazide-sensitive amine oxidase (SSAO) is a multi-functional enzyme widely present in nature. It converts primary amines into their corresponding aldehydes, while generating H(2)O(2) and NH(3). In mammals, SSAO circulates in plasma, while a membrane-bound form (of

  5. Semicarbazide-sensitive amine oxidase (SSAO): from cell to circulation

    NARCIS (Netherlands)

    F. Boomsma (Frans); H. Hut; U. Bagghoe; A.H. van den Meiracker (Anton)

    2005-01-01

    textabstractSemicarbazide-sensitive amine oxidase (SSAO) is a multi-functional enzyme widely present in nature. It converts primary amines into their corresponding aldehydes, while generating H(2)O(2) and NH(3). In mammals, SSAO circulates in plasma, while a membrane-bound form

  6. The synergistic effect of endothelin- 1 and basic fibroblast growth factor on rat vascular smooth muscle cell proliferation%ET-1和bFGF促进大鼠血管平滑肌细胞增殖的协同作用及其机制研究

    Institute of Scientific and Technical Information of China (English)

    潘晓宏; 单江; 罗建红

    2000-01-01

    AIM: The synergistic effect of basic fibroblast growth factor (bFGF) and endothelin- 1 (ET-1 ) on rat aortic vascular smooth muscle cells(VSMC) proliferation was observed. The possible mechanism of the synergism was also investigated. METHODS: BrdU incorporation and cell counting method were adopted to value the pro - proliferative effect of VSMC. Western- blotting was used to observe the variation of bFGF and FGFR - 1 isoforms expression. RESULTS: bFGF and ET- 1 could promote VSMC proliferation separately, and synergistically in combination. The synergism was dose - and time - dependent. ET- 1 increased all the three bFGF isoforms and FGFR - 1 protein level in dose - and time- dependent manner. In addition, after exhaustion of intracellular PKC, the upregulation effects of ET- 1 on bFGF and FGFR - 1 expressions in VSMC both inclined. CONCLUSION: bFGF and ET- 1 had synergistic effect on VSMC proliferation. ET- 1 may increase the responsiveness of VSMC to bFGF through modulation of bFGF isoforms together with FGFR - 1, which was PKC - dependent.%目的:观察碱性成纤维细胞生长因子(bFGF)和内皮素-1(ET-1)促进血管平滑肌细胞(VSMC)增殖的协同作用,并进一步研究可能的机制。方法:5-溴-2'-脱氧尿嘧啶(BrdU)掺入法和细胞计数法观察对VsMC增殖的影响,westem免疫印迹法观察ET-1对VSMC bFCF和成纤维细胞生长因子受体-1(FGFR-1)蛋白表达的影响。结果:bFGF和ET-1能协同促进VsMC BrdU掺入和细胞增多,并且在一定剂量和时间范围内呈量效、时效关系。同时ET-1剂量依赖性上调bFGF和FGFR-1蛋白,表达高峰分别为24和48 h,二丁酸佛波脂(PDBU)预耗竭细胞内蛋白激酶C(PKC)后该上调作用显著下降。结论:bFGF和ET-1对VSMC增殖具有协同作用,与ET-1上调bFGF和FGFR-1蛋白有关,上调作用呈PKC依赖性。

  7. 呼吸窘迫新生儿血浆内皮素-1和转化生长因子-β的变化及其意义%Clinical significance of endothelin-1 and transforming growth factor-β in the newborns with respiratory distress.

    Institute of Scientific and Technical Information of China (English)

    邢莉; 黄志伟; 孙冬冬

    2010-01-01

    Objective To measure the serum levels of endothelin-1 (ET-1) and transforming growth factor-β(TGF-β) in the newborns with respiratory distress and investigate its clinical significance. Methods Newborns with respiratory distress hospitalized into the Newborn Intensive Care Unit were included. The serum levels of ET-1 and TGF-β were all detected with ELISA in the first six hours,3,7,14 and 28 days after birth. Results The highest levels of ln ( 1 + ET-1 ) and ln ( 1 + TGF-β) were obtained from newborns with diagnosis as meconium aspiration syndrome ( 1.95 ± 1.02) ng/L and ( 1.51 ±0.99) ng/L,respectively) in the samples obtained in the first six hours after birth, and these were statistically different from those of the control group ( P < 0. 05 ). Following were obtained for newborns with respiratory distress syndrome ( ( 1.52 ± 0.74 ) ng/L and ( 1.13 ± 0. 48 ) ng/L, t = 2.28,2. 13,respectively). After oxygen treatment, ET-1 levels obtained in the first six hours of life decreased gradually in the following days (P <0.05 ). Conclusions The measurements of ET-1 and TGF-β levels will help in differentiating diagnosis of the respiratory distress of newborns. The ET-1 levels will help to assess the therapy effectiveness and prognosis.%目的 检测呼吸窘迫新生儿血浆内皮素-1(ET-1)和转化生长因子-β(TGF-β)水平并探讨其临床意义.方法 呼吸窘迫新生儿100例,其中呼吸窘迫综合征62例,胎粪吸入综合征14例,暂时性呼吸窘迫24例,分别于生后6 h采用ELISA法进行血浆ET-1和TGF-β检测,取对数ln(1+X)转为正态分布后统计学分析数据结果.结果 胎粪吸入综合征患儿生后6 h内血浆ln(1+ET-1)和ln(1+TGF-β)水平最高,分别为(1.95±1.02)、(1.51±0.99)ng/L,与健康对照组[(0.48±0.21)、(0.11±0.09)ng/L]相比差异有统计学意义(P均<0.05),呼吸窘迫综合征患儿分别为(1.52±0.74)、(1.13±0.48)ng/L(t=2.28、2.13,P均<0.05).结论 血浆ET-1和TGF-β水平在不同

  8. Effect of Radiation-induced Heart Injury on Content of Cardiac Troponion Ⅰ and Endothelin-1 in SD Rats%大鼠心脏放射损伤对内皮素-1和心肌肌钙蛋白Ⅰ表达水平的影响

    Institute of Scientific and Technical Information of China (English)

    徐久宏; 高耀明; 张军宁; 李新莉

    2011-01-01

    Objective To investigate the the effect of radiation-induced heart injury (RIHD) on cardiac endothelin-1 ( ET-1) and cardiac troponin I (cTnI) in SD rats, and the possibility regarding ET-1 and cTnI as biomarker of RIHD was also explored. Methods Healthy female SD rats were randomly divided into two groups; the control group(C) and irradiation group(R). The rats in R group were irradiated with linear accelerator at a single dose of 25Gy. Five milliliters blood was collected from the inferior vena cava on the 5th, 15th, 30th, 60th day after radiation. Blood was centrifuged and serum was collected. Content of ET-1 and cTnI in blood serum were detected by ELISA kits. Results The content of ET1 in the R group was always higher than that in the C group (P <0.01) during the whole process, and the difference between two groups had statistical significance only on the 5th day (P <0. 01) and 15th day (P <0.05) after radiation. However, the content of cTnI in R group was higher than that in the C group withtin 30 days after radiation, then decreased, and only on the 15th day (P<0. 05) and the 30th day (P <0.01) after radiation, there was statistical difference between two groups. Conclusion The content of ET-1 and cTnl in blood serum increase obviously after receiving RIHD, so these two indicators can be used as markers to diagnose early RIHD sensitively and specifically.%目的:观察SD大鼠心脏放射损伤时血清内皮素-1(ET-1)和心肌肌钙蛋白Ⅰ(cTn-Ⅰ)表达水平的变化,以及将ET-1和cTnⅠ作为放射性心肌损伤诊断指标的可行性.方法 采用随机数字表法,将健康雌性SD大鼠30只分为对照组和照射组.照射组大鼠采用直线加速器心前区照射,单次剂量25 Gy.照射后第5、15、30、60天经下腔静脉取血5ml,离心后取血清,采用ELlSA试剂盒,分别测定血清ET-1和cTnⅠ含量.结果 照射组大鼠血清ET-1含量均高于对照组,但只有在照射第5天和第15天时与对照组的差

  9. 三参汤对早期糖尿病肾病大鼠血清血管紧张素Ⅱ、VEGF和尿ET-1含量的影响%Influence of Sanshen Decoction on the levels of angio tensin Ⅱ,Endothelin-1,Vascular endothelial growth factor in rats with early diabetic nephropathy

    Institute of Scientific and Technical Information of China (English)

    陈贵海; 陈娟; 唐爱华; 夏猛; 蓝丽霞; 连利军; 何清平

    2015-01-01

    Objective It is to observe the influence of Sanshen Decoction on angio tensin Ⅱ( ATⅡ),Endothelin-1( ET-1),Vascular endothelial growth factor(VEGF)levels of rats with early diabetic nephropathy,and investigate the mecha-nism in treatment of early diabetic nephropathy. Methods The rat models of type 2 diabetic nephropathy were duplicated by u-sing high-fat diet and streptozotocin and divided into model group,control group and treatment group with 10 cases in each. Other 10 rats by tail vein injected with saline were selected as the blank group. The animals were treated by intragastric admin-istration for equal volume of saline in model group and blank group,irbesartan in control group and Sanshen Decoction in treat-ment group,the treatment kept for 3 weeks. Before and after treatment,the levels of ATⅡ,ET-1,and VEGF were detected by ELISA method,and the levels of urine micro albumin and blood sugar were detected by chemical turbidimetry. Results Af-ter the treatment of Sanshen Decoction,the levels of ATⅡ,ET-1 and VEGF were decreased,and the level of blood sugar and urine micro albumin were reduced,there were significant differences between treatment group and model group( all P ﹤0. 05). Conclusion Sanshen Decoction might play the therapeutic role on diabetic nephropathy through regulating the renin-angiotensin system.%目的:观察三参汤对早期糖尿病肾病大鼠血清血管紧张素Ⅱ( ATⅡ)、血管内皮生长因子(VEGF)、血浆和尿内皮素-1(ET -1)的影响,探讨三参汤治疗早期糖尿病肾病的作用机制。方法采用高脂饲养+链脲佐菌素注射方法复制2型糖尿病肾病大鼠模型,造模成功大鼠随机分为模型组、对照组和治疗组各10只,另选10只尾静脉注射等量生理盐水大鼠作为空白组。模型组和空白组灌胃等体积生理盐水,对照组灌胃厄贝沙坦,治疗组灌胃三参汤,灌胃3周。治疗前后酶免法检测4组大鼠血清 AT

  10. Modelled Circulation In Storfjorden

    Science.gov (United States)

    Skogseth, R.; Asplin, L.

    The model area Storfjorden is situated between the islands Spitsbergen, Barentsöya and Edgeöya at the Svalbard Archipelago. The entrance of Storfjorden is defined by a shallow bank Storfjordbanken and some small islands Tusenöyane in southeast, and by an 115m deep sill at about 76 45' N in the south. Maximum depth in Storfjorden is 190m, which is surrounded by gradually shallower shelves in the north, the east and southeast. A steep bottom slope is present on the western side of Storfjorden. He- leysundet and Freemansundet, two sounds between respectively Spitsbergen and Bar- entsöya, and Barentsöya and Edgeöya, define two narrow and shallow entrances in the north and northeast connecting Storfjorden with the northwestern Barents Sea. Strong tidal currents exist in Heleysundet (4-5ms-1) and Freemansundet (2-3ms-1), but the general circulation in Storfjorden is not well known. The coastal current in Storfjor- den is cyclonic directed into Storfjorden south of Edgeöya from the East Spitsbergen Current and out of Storfjorden south of Spitsbergen where it is called Sørkappstrøm- men. A three-dimensional sigma layered numerical ocean model called Bergen Ocean Model (BOM) was used to simulate the circulation in Storfjorden with Freemansundet opened. Two simulations were carried out, one with heat flux (100 Wm-2) and one without heat flux from the ocean to the atmosphere. The heat flux was applied only in the proper fjord area north of the sill and not outside as a crude approximation of the effects of a polynya in the sea ice cover during winter. Both simulations had a 4km horizontal resolution and 21 sigma layers. The model is forced by winds (from the NCEP reanalyzed fields) and tides. Initial fields are from the DNMI/IMR climatol- ogy. The model simulation without heat flux gave a circulation heavily dependent on tidal forcing, showing strong tidal currents up to 2ms-1 in Freemansundet, between Tusenöyane and on Storfjordbanken southwest of Edgeöya. Earlier

  11. Cereral Circulation in Preeclampsia

    Directory of Open Access Journals (Sweden)

    A. A. Ivshin

    2008-01-01

    Full Text Available Objective: to evaluate the possibilities of using transcranial Doppler study in pregnant women and pueperas with preeclamp-sia. Subjects and methods. Two hundred and thirty-two pregnant women diagnosed as having varying preeclampsia were prospectively studied. A comparison group comprised 90 apparently healthy women in the third trimester of pregnancy. All the respondents underwent transcranial duplex scanning of the medial cerebral artery with the linear velocity values being determined. A number of the values reflecting the level of perfusion and intracranial pressures, hydrodynamic resistance in the system, cerebrovascular responsiveness and the state of the vascular wall were calculated. Correlation analysis was made between the parameters of cerebral circulation and the severity of preeclampsia, proteinuria, the severity of hydrops, and the parameters of central and peripheral hemodynamics. Results. The findings suggest that there is impaired cerebral perfusion in pregnant women and puerperas with varying preeclampsia, the severity of cerebral circulatory disorders being in proportion with that of preeclampsia. There is a close correlation between cerebral circulation and the individual criteria determining the severity of preeclampsia. The linear values of the Doppler spectrum, namely linear flow characteristics, are prognos-tically most significant. Conclusion. The introduction of transcranial Doppler study into obstetric care has permitted the authors not only to study cerebral circulatory disorders in healthy and pregnant women and puerperas with preeclampia in detail, but also to establish a number of highly significant prognostic criteria for the severity of this life-threatening complication of gestation. The results of transcranial Doppler study assist practitioners in timely and accurately solving the problems in the diagnosis of preeclampsia and in evaluating its severity. Cerebral circulatory values may be successfully used to

  12. Plasma resistin is increased in patients with unstable angina

    Institute of Scientific and Technical Information of China (English)

    HU Wen-lan; QIAO Shu-bin; HOU Qing; YUAN Jian-song

    2007-01-01

    Background Resistin, a novel adipokine linked to insulin resistance and obesity in rodents, which is derived mainly from macrophages and identified in atheromas in human, has been shown to play a potential role in atherosclerosis.Resistin levels were reported to increase in coronary artery disease (CAD), while data concerning resistin in different stages of CAD in Chinese people are lacking. The aim of this study was to assess whether plasma concentrations of resistin differed between patients with unstable and stable angina pectoris.Methods Plasma resistin levels were determined by means of enzyme-linked immunosorbent assay (ELISA) in 46 patients with unstable angina (UAP), 37 with stable angina (SAP) and 31 control subjects.Results Plasma concentrations of resistin were significantly increased in UAP group (geometric mean (interquartile range) 12.09 ng/ml (8.40, 18.08)) in comparison with SAP (9.04 ng/ml (7.09, 11.44)) and control groups (8.71 ng/ml (6.58,11.56)). No differences in resistin levels were found between patients with SAP and controls. We also found that plasma resistin positively correlated with leukocyte counts (r=0.21, P=0.027), high sensitive C-reactive protein (hs-CRP) (r=0.25,P=0.008), and endothelin-1 (r=0.21, P=0.025) after adjustment for age, sex and BMI.Conclusion Resistin may be involved in the development of CAD by influencing systemic inflammation and endothelial activation.

  13. World Ocean Circulation Experiment

    Science.gov (United States)

    Clarke, R. Allyn

    1992-01-01

    The oceans are an equal partner with the atmosphere in the global climate system. The World Ocean Circulation Experiment is presently being implemented to improve ocean models that are useful for climate prediction both by encouraging more model development but more importantly by providing quality data sets that can be used to force or to validate such models. WOCE is the first oceanographic experiment that plans to generate and to use multiparameter global ocean data sets. In order for WOCE to succeed, oceanographers must establish and learn to use more effective methods of assembling, quality controlling, manipulating and distributing oceanographic data.

  14. Resolvability in Circulant Graphs

    Institute of Scientific and Technical Information of China (English)

    Muhammad SALMAN; Imran JAVAID; Muhammad Anwar CHAUDHRY

    2012-01-01

    A set W of the vertices of a connected graph G is called a resolving set for G if for every two distinct vertices u,v ∈ V(G) there is a vertex w ∈ W such that d(u,w) ≠ d(v,w).A resolving set of minimum cardinality is called a metric basis for G and the number of vertices in a metric basis is called the metric dimension of G,denoted by dim(G).For a vertex u of G and a subset S of V(G),the distance between u and S is the number mins∈s d(u,s).A k-partition H ={S1,S2,...,Sk} of V(G) is called a resolving partition if for every two distinct vertices u,v ∈ V(G) there is a set Si in Π such that d(u,Si) ≠ d(v,Si).The minimum k for which there is a resolving k-partition of V(G) is called the partition dimension of G,denoted by pd(G).The circulant graph is a graph with vertex set Zn,an additive group ofintegers modulo n,and two vertices labeled i and j adjacent if and only if i - j (mod n) ∈ C,where C C Zn has the property that C =-C and 0(∈) C.The circulant graph is denoted by Xn,△ where A =|C|.In this paper,we study the metric dimension of a family of circulant graphs Xn,3 with connection set C ={1,-n/2,n - 1} and prove that dim(Xn,3) is independent of choice of n by showing that 3 for all n =0 (mod 4),dim(X,n,3) ={ 4 for all n =2 (mod 4).We also study the partition dimension of a family of circulant graphs Xn,4 with connection set C ={±1,±2} and prove that pd(Xn,4) is independent of choice of n and show that pd(X5,4) =5 and 3 forall odd n≥9,pd(Xn,4) ={ 4 for all even n ≥ 6 and n =7.

  15. Oxidative stress and antioxidant status in fetal circulation in preeclampsia.

    Science.gov (United States)

    Braekke, Kristin; Harsem, Nina K; Staff, Anne C

    2006-11-01

    Preeclampsia is associated with oxidative stress in maternal circulation. The purpose of this study was to explore oxidative stress and antioxidants in the fetal circulation in preeclampsia. Women with preeclampsia (n = 19) or uncomplicated pregnancies (n = 33) delivered by cesarean section were included. Blood was sampled separately from the umbilical vein and artery. 8-Iso-prostaglandin F(2alpha) (8-isoprostane), a stable product of lipid peroxidation, is a reliable marker of oxidative stress. Concentration of total 8-isoprostane in cord plasma was analyzed by gas chromatography-mass spectrometry. Antioxidant status was evaluated measuring ferric reducing ability of plasma and vitamin E. There was no difference between preeclampsia and control groups regarding median plasma concentration of 8-isoprostane in umbilical vein (955 versus 780 pg/mL, p = 0.41) or in umbilical artery (233 versus 276 pg/mL, p = 0.65). Concentration of 8-isoprostane was much higher in plasma from the umbilical vein than artery, suggesting placenta as the source of 8-isoprostane. Median ferric reducing ability of plasma concentration was higher in preeclampsia than in controls, both in the umbilical vein and artery. Median vitamin E concentration in the umbilical vein was higher in preeclampsia, but no difference was found in the umbilical artery. In conclusion, no evidence of increased oxidative stress, evaluated by 8-isoprostane concentration, was found in fetal circulation in preeclampsia.

  16. Remove MPO-ANCA from circulation of patients with vasculitides by a novel double-filtration plasmapheresis therapy using selective plasma separators combination%选择性血浆分离器行双重血浆置换对抗中性粒细胞胞质抗体清除的研究

    Institute of Scientific and Technical Information of China (English)

    龚德华; 季大玺; 朱冬冬; 徐斌; 崔俊; 刘志红

    2011-01-01

    Objective; To investigate the ability to remove different plasma proteins by double-filtration plasmapheresis (DFPP) using various primary separator and secondary separator combinations; based on it, to propose a novel DFPP therapy, and test its ability to eliminate MPO-ANCA from circulation of patients with vasculitides. Methodology;Fifteen patients with serum MPO-ANCA positive diagnosed as vaseulitides were enrolled and received 44 sessions DFPP. Three kinds of plasma filters were used to serve as primary and secondary filter, one plasma separator MPS07 and two plasma fraction separators EC50W, EC20W. There were three combinations; MPS07/EC50W, MPS07/ EC20W, and EC50W/EC20W combination; in each combination, the former was used as primary filter, and the latter was used as secondary filter. Double volume of plasma was processed, and 30 ~40g human albumin was supplemented during each session. One received 3 sessions DFPP using MPS07/EC50W, 9 received 27 sessions DFPP using MPS07/EC20W, and the other 5 patients received 14 sessions DFPP using EC50W/EC20W. During DFPP, waste plasma was discarded in intermittent way.When the pressure pre-secondary filter reached the threshold value to discard plasma, 800ml normalsaline was flushing the secondary filter to force filtration of plasma proteins accumulated in filter, before waste plasma was discarded. Sieving coefficients (SC) of albumin, IgA, IgG and IgM were measured for 3 filters, as well as reduction percentage of plasma proteins concentrations, MPO-ANCA titer by single session DFPP. Results: MPS07 filter was well permeable for all above-mentioned plasma proteins ( SC > 0. 6 ) ; while EC50W filter was well permeable for albumin and IgG, less permeable for IgA, and little permeable for IgM ( SC 0. 06) ; EC20W filter was permeable for only small proportion of albumin and IgG, much less for IgA, and impermeable for IgM ( SC 0. 03 ). Single session of DFPP had no effect on serum albumin level, but had diverse effects on

  17. Elevated circulating somatostatin levels in acromegaly.

    Science.gov (United States)

    Arosio, M; Porretti, S; Epaminonda, P; Giavoli, C; Gebbia, C; Penati, C; Beck-Peccoz, P; Peracchi, M

    2003-06-01

    GH increases hypothalamic somatostatin (SS) synthesis and secretion but it is unknown if chronic GH excess, as found in acromegaly, may influence circulating SS levels, that are mainly of enteropancreatic source and affect several gastrointestinal functions, including motility. Circulating SS occurs in several post-translational forms including somatostatin-14 (SS-14), somatostatin-28 (SS-28) and other small peptides. The aim of the present study was to characterize the fasting and postprandial pattern of plasma circulating somatostatin in normal subjects and patients with acromegaly. Fasting total SS and SS-28 levels were measured in 32 subjects, 16 acromegalic patients with a new diagnosis (A) (8 F, 8 M, median age 48) and 16 matched healthy volunteers (C) (8 F, 8 M, median age 45). SS was also determined after a standard solid-liquid meal (550 kCal) in 24 of the subjects (12 C and 12 A). Fasting SS and SS-28 were significantly higher in acromegalic patients as compared to healthy subjects. In the former, a positive correlation was found between IGF-I and SS levels (r = 0.525 p acromegaly. Excess GH/IGF-I could be a causal factor in somatostatin hypersecretion. Conceivably this abnormality might play a role in some alterations of gastrointestinal function of acromegalic patients such as prolonged bowel transit.

  18. Circulation of Stars

    Science.gov (United States)

    Boitani, P.

    2016-01-01

    Since the dawn of man, contemplation of the stars has been a primary impulse in human beings, who proliferated their knowledge of the stars all over the world. Aristotle sees this as the product of primeval and perennial “wonder” which gives rise to what we call science, philosophy, and poetry. Astronomy, astrology, and star art (painting, architecture, literature, and music) go hand in hand through millennia in all cultures of the planet (and all use catasterisms to explain certain phenomena). Some of these developments are independent of each other, i.e., they take place in one culture independently of others. Some, on the other hand, are the product of the “circulation of stars.” There are two ways of looking at this. One seeks out forms, the other concentrates on the passing of specific lore from one area to another through time. The former relies on archetypes (for instance, with catasterism), the latter constitutes a historical process. In this paper I present some of the surprising ways in which the circulation of stars has occurred—from East to West, from East to the Far East, and from West to East, at times simultaneously.

  19. North Atlantic Circulation

    Science.gov (United States)

    Molinari, R.; Bryan, K.; Schott, F.

    The intensity of the North Atlantic winddriven and thermohaline circulation and the close proximity of many oceanographic installations make the North Atlantic a particularly favored region of the world ocean from the standpoint of research in ocean circulation. Recent increases in available data and advances in numerical modeling techniques served as the impetus to convene a joint workshop of modelers and observers working on the North Atlantic with the Scientific Committee on Oceanic Research (SCOR) Working Group (WG) 68 (“North Atlantic Circulation”). Goals of the workshop were to provide an update on data sets and models and to discuss the poleward heat flux problem and possible monitoring strategies. The joint Workshop/SCOR WG-68 meeting was convened by F. Schott (chairman of the working group; Rosenstiel School of Marine and Atmospheric Science, Miami, Fla.), K. Bryan (National Oceanic and Atmospheric Administration/ Geophysical Fluid Dynamics Laboratory (NOAA/GFDL)), and R. Molinari (NOAA/Atlantic Oceanographic and Meteorological Laboratory (NOAA/AOML)).

  20. Efficient quantum circuits for dense circulant and circulant like operators

    Science.gov (United States)

    Zhou, S. S.; Wang, J. B.

    2017-05-01

    Circulant matrices are an important family of operators, which have a wide range of applications in science and engineering-related fields. They are, in general, non-sparse and non-unitary. In this paper, we present efficient quantum circuits to implement circulant operators using fewer resources and with lower complexity than existing methods. Moreover, our quantum circuits can be readily extended to the implementation of Toeplitz, Hankel and block circulant matrices. Efficient quantum algorithms to implement the inverses and products of circulant operators are also provided, and an example application in solving the equation of motion for cyclic systems is discussed.

  1. 动脉压力感受性反射受损后血浆血管紧张素Ⅱ和内皮素1水平的明亮-黑暗周期变化%Plasma Levels of Angiotensin Ⅱ and Endothelin-1 During Light-Dark Period in Sinoaortic Denervated Rats

    Institute of Scientific and Technical Information of China (English)

    李慧; 孙宁玲

    2006-01-01

    目的 研究去窦弓神经(SAD)大鼠血浆血管紧张素Ⅱ和内皮素1水平的明亮-黑暗周期变化模式,探讨其与血压异常波动的联系.方法 72只12周龄Sprague-Dawley大鼠随机分为手术去除窦弓神经组和假手术组,各36只,术后4周测定两组大鼠24 h血压和血压波动性(BPV).在光照-黑暗交替(LD)光制下适应10 d后,再将两组大鼠各自随机分为6组,每组各6只,明亮-黑暗周期内每隔4 h采集1组血标本,采用放射免疫分析技术测定不同人工明亮-昼夜周期时点(ZT)血浆血管紧张素Ⅱ(Ang Ⅱ)和内皮素1(ET-1)水平.结果 SAD大鼠术后4周,24 h平均收缩压(SBP)和舒张压(DBP)与假手术对照组比较无显著差异,24 h SBPV和DBPV均显著高于对照组大鼠[(SBPV:13.8±4.2 vs对照组:6.4±1.1),(DBPV:11.5±3.1 vs对照组:5.3±0.8)mm Hg,P均<0.01].血浆Ang Ⅱ和ET-1水平均呈现明显的明亮-黑暗周期节律性变化,假手术大鼠血浆Ang Ⅱ水平呈明亮-黑暗周期双峰模式(F=2.82,P<0.05,ANOVA),光照期峰值位于ZT8(776.9±189.5)pg/mL,黑暗期峰值位于ZT16(689.5±199.6)pg/mL;血浆ET-1变化呈昼(明亮)低夜(黑暗)高模式(F=2.749,P<0.05,ANOVA),其峰值和谷值分别位于ZT20(峰值:193.7±28.5)pg/mL和ZT4(谷值:131.1±26.5)pg/mL;而SAD大鼠血浆Ang Ⅱ为昼(明亮)高夜(黑暗)低模式(F=5.29,P<0.01,ANOVA),其峰值和谷值分别位于ZT4(峰值:1014.6±130.9)pg/mL和ZT16(谷值:220.4±147.6)pg/mL;血浆ET-1变化呈明亮-黑暗周期双峰模式(F=2.68,P<0.05,ANOVA),峰值分别位于ZT4(峰值:228.3±54.0)pg/mL和ZT20(谷值:213.7±54.6)pg/mL.结论 SAD大鼠血浆血管紧张素Ⅱ和内皮素1的明亮-黑暗周期分泌节律异常,并对血压波动性的调节可能有一定作用.

  2. Construction of a Sequencing Library from Circulating Cell-Free DNA.

    Science.gov (United States)

    Fang, Nan; Löffert, Dirk; Akinci-Tolun, Rumeysa; Heitz, Katja; Wolf, Alexander

    2016-04-01

    Circulating DNA is cell-free DNA (cfDNA) in serum or plasma that can be used for non-invasive prenatal testing, as well as cancer diagnosis, prognosis, and stratification. High-throughput sequence analysis of the cfDNA with next-generation sequencing technologies has proven to be a highly sensitive and specific method in detecting and characterizing mutations in cancer and other diseases, as well as aneuploidy during pregnancy. This unit describes detailed procedures to extract circulating cfDNA from human serum and plasma and generate sequencing libraries from a wide concentration range of circulating DNA.

  3. Global ocean circulation by altimetry

    Science.gov (United States)

    Wunsch, Carl; Haidvogel, D.

    1991-01-01

    The overall objectives of this project are to determine the general circulation of the oceans and many of its climate and biochemical consequences through the optimum use of altimetry data from TOPEX/POSEIDON and related missions. Emphasis is on the global-scale circulation, as opposed to the regional scale, but some more local studies will be carried out. Because of funding limitations, the primary initial focus will be on the time-dependent global-scale circulation rather than the mean; eventually, the mean circulation must be dealt with as well.

  4. Percutaneous interventions in Fontan circulation

    Directory of Open Access Journals (Sweden)

    Eduardo Franco

    2015-09-01

    Conclusions: Interventional catheterization procedures are often necessary to reach and maintain the fragile Fontan circulation, mainly in patients with right morphology systemic ventricles and fenestrated Fontan conduits.

  5. Lost circulation technology development status

    Energy Technology Data Exchange (ETDEWEB)

    Glowka, D.A.; Schafer, D.M.; Loeppke, G.E.; Scott, D.D.; Wernig, M.D.; Wright, E.K.

    1992-07-01

    Lost circulation is the loss of drilling fluid from the wellbore to fractures or pores in the rock formation. In geothermal drilling, lost circulation is often a serious problem that contributes greatly to the cost of the average geothermal well. The Lost Circulation Technology Development Program is sponsored at Sandia National Laboratories by the US Department of Energy. The goal of the program is to reduce lost circulation costs by 30--50% through the development of mitigation and characterization technology. This paper describes the technical progress made in this program during the period April 1991--March 1992. 8 refs.

  6. Trypanosoma cruzi: circulating antigens

    Directory of Open Access Journals (Sweden)

    V. Bongertz

    1981-03-01

    Full Text Available Circulating antigens were detected in sera of mice experimentally infected with a high close of Trypanosoma cruzi by reaction with sera from chronically infected mice. The immunodiffusion reaction between homologous acute and chronic sera produced four precipitation lines. By reaction with chronic mouse serum, circulating antingens were detected in sera from heavily infected hamsters, dogs, rabbits and in sera from chagasic patients. A reaction was also found in urine from acutely infected mice and dogs. Trypanosoma cruzi exoantigen was detected in trypanosome culture medium and in the supernatant of infected cell cultures. Attempts to isolate the antigens are described.Antígenos circulantes foram detectados em soros de camundongos infectados experimentalmente com elevadas doses de Trypanosoma cruzi pela reação com soros obtidos de camundongos em fase crônica de infecção. A reação de imunodifusão entre soros homólogos agudo e crônico produziu quatro linhas de precipitação. Por reação com soro crônico de camundongo antígenos circulantes foram detectados em soros de crícetos, cães e coelhos infectados com doses elevadas de Trypanosoma cruzi e em soros de pacientes chagásicos. Uma reação foi também observada com urina de camundongos e cães infectados de forma aguda. Exoantígeno de Trypanosoma cruzi foi detectado em meio de cultura de tripanosomas e em sobrenadantes de culturas de células infectadas. Tentativas de isolamento dos antigenos são descritas.

  7. Circulating levels of vasoactive peptides in patients with acute bacterial meningitis

    DEFF Research Database (Denmark)

    Berg, Ronan Martin Griffen; Strauss, Gitte Irene; Tofteng, Flemming

    2009-01-01

    PURPOSE: The underlying mechanisms for cerebral blood flow (CBF) abnormalities in acute bacterial meningitis (ABM) are largely unknown. Putative mediators include vasoactive peptides, e.g. calcitonin-gene related peptide (CGRP), vasoactive intestinal peptide (VIP), and endothelin-1 (ET-1), all of...

  8. Increased circulating calcitonin in cirrhosis. Relation to severity of disease and calcitonin gene-related peptide

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Schifter, S; Møller, S

    2000-01-01

    circulating plasma concentrations of CT in patients with cirrhosis in relation to the severity of disease and the plasma level of CGRP. Moreover, the kinetics of CT was evaluated for different organ systems by determination of arteriovenous extraction. Thirty-nine patients with cirrhosis (Child-Turcotte...... control (12.1 v 6.9 pmol/L, P Turcotte score was found (P

  9. Change of level of plasma mitochondrial coupling factor-6 in coronary circulation of patients with coronary heart disease%血浆线粒体偶联因子-6在冠心病患者冠脉循环中浓度的变化

    Institute of Scientific and Technical Information of China (English)

    马健; 庞继恩

    2011-01-01

    目的:研究不同类型冠心病(CHD)[稳定型心绞痛(SAP)、不稳定型心绞痛(UAP)],以及急性心肌梗塞(AMI)]患者血浆线粒体偶联因子-6(MCF-6)在冠脉循环中浓度的变化.方法:用放免法分别测定不同类型心绞痛的冠心病患者与正常对照组外周、冠状静脉窦与主动脉根部血浆中MCF-6浓度,计算心脏局部分泌的MCF-6浓度(冠状静脉窦-主动脉根部浓度的差值).结果:与正常对照组比较,CHD患者MCF-6浓度:外周[(294±40)pg/ml∶(265±40) pg/ml]、主动脉根部[(310±47) pg/ml∶(259±43) pg/ml]、冠状静脉窦[(384±42) pg/ml∶(271±37) pg/ml]、心脏局部分泌(74 pg/ml∶12pg/ml)的明显升高 (P均<0.01),冠状静脉窦MCF-6浓度明显高于主动脉根部及外周循环的(P均<0.01);且在CHD患者,外周、主动脉根部与冠状静脉窦血浆中MCF-6浓度随CHD严重程度增加而明显升高,以AMI组患者最高(P均<0.01),分别为[(358±51)pg/ml,(366±48)pg/ml,(420±56)pg/ml].结论:结果提示血浆线粒体偶联因子-6参与了冠心病的病理生理过程,在冠心病的发展过程中有可能是一种较为重要的血管活性物质.%Objective: To investigate changes of level of plasma mitochondrial coupling factor 6 (MCF- 6) in coronary circulation of patients with coronary heart disease (CHD) [ contain stable angina pectoris (SAP), unstable angina pec toris (UAP) and acute myocardial infarction (AMI)]. Methods: Radioimmunoassay was used to measure concentra tions of CF- 6 in peripheral circulation, aortic root (Ao) and coronary sinus (CS) of CHD patients and normal control group. The CS-Ao difference of MCF 6 was regarded as concentration of MCF- 6 secreted by local heart. Results:Concentrations of MCF- 6 in CHD patients were significantly higher than those in normal control group in peripheral circulation [ (294±40) pg/mlvs. (265±40) pg/ml], Ao [ (310±47) pg/mlvs. (259±43) pg/ml], CS[ (384±42) pg/mlvs. (271±37) pg/ml] andlocal heart (74 pg

  10. 妊娠高血压患者血清淀粉样蛋白 A、血浆内皮素1和一氧化氮水平变化及其相互关系%Significance of serum amyloid A,endothelin-1 and nitric oxide in patients with pregnancy-induced hypertension

    Institute of Scientific and Technical Information of China (English)

    李峻; 王小娟

    2015-01-01

    Objective To observe the significance of serum amyloid A (SAA),endothelin-1 (ET-1)and nitric oxide (NO)in patients with pregnancy-induced hypertension and their relationship.Methods A total of 65 patients with pregnancy-induced hypertension were selected as pregnancy-induced hypertension group,including 24 cases with solely pregnancy-induced hypertension, 1 9 cases with mild preeclampsia and 22 cases with severe preeclampsia according to disease severity.At the same period,30 healthy pregnant women and 20 healthy women were selected as normal pregnancy control group and healthy control group,respectively.The levels of SAA,ET-1 and NO in pregnancy-induced hypertension group,normal pregnancy group and healthy control group were detected and their relationship with disease severity was observed.Results ① The levels of SAA and ET-1 in pregnancy-induced hypertension group and normal pregnancy group were significantly higher than those of healthy control group,and the levels of SAA and ET-1 were significantly higher in pregnancy-induced hypertension group than in normal pregnancy group (P <0.01);while the level of NO was significantly decreased,and the level of NO was significantly decreased in pregnancy-induced hypertension group than in normal pregnancy group (P <0.01).②The levels of SAA and ET-1 in severe preeclampsia and mild preeclampsia group were significantly higher than in pregnancy-induced hypertension group,and the indexes in severe preeclampsia group were significantly higher than those of mild preeclampsia group;while NO level was significantly decreased,and NO level was significantly decreased in severe preeclampsia group than in mild preeclampsia group (P < 0.05 ).③ The SAA level in patients with pregnancy-induced hypertension was positively correlated with ET-1 (r =0.876,P <0.05),while the SAA level was negatively correlated with NO (r =-0.761,P <0.05).Conclusion Endothelial dysfunction is found in pregnancy-induced hypertension,the markers of SAA

  11. Sino-Danish Brain Circulation

    DEFF Research Database (Denmark)

    Bertelsen, Rasmus Gjedssø; Du, Xiangyun; Søndergaard, Morten Karnøe

    2014-01-01

    China is faced with urgent needs to develop an economically and environmentally sustainable economy based on innovation and knowledge. Brain circulation and research and business investments from the outside are central for this development. Sino-American brain circulation and research...... and investment by overseas researchers and entrepreneurs are well described. In that case, the US is the center of global R&D and S&T. However, the brain circulation and research and investments between a small open Scandinavian economy, such as Denmark, and the huge developing economy of China are not well...... understood. In this case, Denmark is very highly developed, but a satellite in the global R&D and S&T system. With time and the growth of China as a R&D and S&T power house, both Denmark and China will benefit from brain circulation between them. Such brain circulation is likely to play a key role in flows...

  12. TROPICAL METEOROLOGY & Climate: Hadley Circulation

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Jian; Vecchi, Gabriel A.

    2015-01-30

    The Hadley circulation, a prominent circulation feature characterized by rising air near the Equator and sinking air in the subtropics, defines the position of dry subtropical areas and is a fundamental regulator of the earth’s energy and momentum budgets. The character of the Hadley circulation, and its related precipitation regimes, exhibits variation and change in response to both climate variability and radiative forcing changes. The strength and position of the Hadley circulation change from year to year paced by El Niño and La Niña events. Over the last few decades of the twentieth century, the Hadley cell has expanded poleward in both hemispheres, with changes in atmospheric composition (including stratospheric ozone depletion and greenhouse gas increases) thought to have contributed to its expansion. This article introduces the basic phenomenology and driving mechanism of the Hadley circulation and discusses its variations under both natural and anthropogenic climate forcings.

  13. Plasma cell leukemia

    DEFF Research Database (Denmark)

    Fernández de Larrea, C; Kyle, R A; Durie, B G M

    2013-01-01

    Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic......-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds...... regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding...

  14. Circulating Vitamin D and Risk of Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Alan A. Arslan

    2009-01-01

    Full Text Available We conducted a nested case-control study within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Health and Disease Study, to examine the association between prediagnostic circulating levels of 25-hydroxy vitamin D (25(OHD and the risk of subsequent invasive epithelial ovarian cancer (EOC. The 25(OHD levels were measured in serum or plasma from 170 incident cases of EOC and 373 matched controls. Overall, circulating 25(OHD levels were not associated with the risk of EOC in combined cohort analysis: adjusted OR for the top tertile versus the reference tertile, 1.09 (95% CI, 0.59–2.01. In addition, there was no evidence of an interaction effect between VDR SNP genotype or haplotype and circulating 25(OHD levels in relation to ovarian cancer risk, although more complex gene-environment interactions may exist.

  15. Circulating somatostatin after food and glucose in man.

    Science.gov (United States)

    Wass, J A; Penman, E; Dryburgh, J R; Tsiolakis, D; Goldberg, P L; Dawson, A M; Besser, G M; Rees, L H

    1980-06-01

    Using a recently validated radioimmunoassay, changes in circulating somatostatin have been measured in normal subjects after food (a standard breakfast), and oral and intravenous glucose. After the standard breakfast, a clear and sustained rise in plasma somatostatin was seen in all subjects from a mean value (+/-1 SE) of 28 +/- 7 pg/ml to a mean peak value, at 60 min of 57 +/- 11 pg/ml. When glucose was taken by mouth a significant but smaller rise was seen, but intravenous glucose caused no significant change in plasma somatostatin. A rise in circulating somatostatin after feeding has not previously been demonstrated in normal man and it is suggested that somatostatin may have an important endocrine role in the gut.

  16. Plasma turbulence

    Energy Technology Data Exchange (ETDEWEB)

    Horton, W. [Univ. of Texas, Austin, TX (United States). Inst. for Fusion Studies; Hu, G. [Globalstar LP, San Jose, CA (United States)

    1998-07-01

    The origin of plasma turbulence from currents and spatial gradients in plasmas is described and shown to lead to the dominant transport mechanism in many plasma regimes. A wide variety of turbulent transport mechanism exists in plasmas. In this survey the authors summarize some of the universally observed plasma transport rates.

  17. Combined Influence of EGF+61G>A and TGFB+869T>C Functional Polymorphisms in Renal Cell Carcinoma Progression and Overall Survival: The Link to Plasma Circulating MiR-7 and MiR-221/222 Expression

    Science.gov (United States)

    Teixeira, Ana L.; Dias, Francisca; Ferreira, Marta; Gomes, Mónica; Santos, Juliana I.; Lobo, Francisco; Maurício, Joaquina; Machado, José Carlos; Medeiros, Rui

    2015-01-01

    The epidermal growth factor (EGF) is responsible for the activation of intracellular signal transducers that act on cell-cycle progression, cell motility, angiogenesis and inhibition of apoptosis. However, cells can block these effects activating opposite signaling pathways, such as the transforming growth factor beta 1 (TGFβ1) pathway. Thus changes in expression levels of EGF and TGFB1 in renal cells might modulate the renal cell carcinoma (RCC) development, in consequence of changes in regulatory elements of signaling networks such as the microRNAs (miRNAs). Our purpose was to investigate the synergic role of EGF+61G>A and TGFB1+869T>C polymorphisms in RCC development. Genetic polymorphisms were studied by allelic discrimination using real-time PCR in 133 RCC patients vs. 443 healthy individuals. The circulating EGF/EGFR-MAPK-related miR-7, miR-221 and miR-222 expression was analyzed by a quantitative real-time PCR in plasma from 22 RCC patients vs. 27 healthy individuals. The intermediate/high genetic proliferation profile patients carriers present a significantly reduced time-to-progression and a higher risk of an early relapse compared with the low genetic proliferation profile carriers (HR = 8.8, P = 0.038) with impact in a lower overall survival (Log rank test, P = 0.047). The RCC patients presented higher circulating expression levels of miR-7 than healthy individuals (6.1-fold increase, P<0.001). Moreover, the intermediate/high genetic proliferation profile carriers present an increase in expression levels of miR-7, miR-221 and miR-222 during the RCC development and this increase is not observed in low genetic proliferation profile (P<0.001, P = 0.004, P<0.001, respectively). The stimulus to angiogenesis, cell-cycle progression and tumoral cells invasion, through activation of EGFR/MAPK signaling pathway in intermediate/high proliferation profile carriers is associated with an early disease progression, resulting in a poor overall survival. We also

  18. The origin of circulating CD36 in type 2 diabetes

    OpenAIRE

    2013-01-01

    Objective: Elevated plasma levels of the fatty acid transporter, CD36, have been shown to constitute a novel biomarker for type 2 diabetes mellitus (T2DM). We recently reported such circulating CD36 to be entirely associated with cellular microparticles (MPs) and aim here to determine the absolute levels and cellular origin(s) of these CD36+MPs in persons with T2DM. Design: An ex vivo case-control study was conducted using plasma samples from 33 obese individuals with T2DM (body mass index (B...

  19. Plasma lactoferrin level as a predictor to endothelial dysfunction in patients with obstructive sleep apnea

    Directory of Open Access Journals (Sweden)

    Abir Zakaria

    2013-01-01

    Conclusion The present study showed that low circulating plasma lactoferrin levels in OSA patients independently predict endothelial dysfunction as assessed by FMD%. High BMI in OSA patients negatively influences plasma lactoferrin levels unrelated to other OSA severity predictors.

  20. Big endothelin-1 and long-term clinical outcomes in heart failure patients receiving cardiac resynchroni-zation therapy%大内皮素1对心脏再同步治疗患者临床预后的评估作用

    Institute of Scientific and Technical Information of China (English)

    糜家睿; 刘志敏; 杨绳文; 华伟; 陈柯萍; 丁立刚; 张澍

    2015-01-01

    目的探讨大内皮素1(big ET-1)对接受心脏再同步治疗(CRT)的心力衰竭(心衰)患者全因死亡和心衰再住院的风险评估作用。方法回顾性调查阜外医院心律失常中心2010年1月至2014年12月行首次CRT植入的249例心衰患者临床资料,对所有患者行电话随访。定义随访终点为全因死亡(包括心脏移植)和心衰再住院。以1年内全因死亡为因变量绘制受试者工作特征( ROC)曲线,根据Youden指数(敏感度+特异度-1)最大值找到big ET-1的最佳诊断界值。将患者分为big ET-1≥界值组与big ET-1<界值组,比较两组患者基线资料并行相关性分析;对随访结果做生存分析和Cox回归分析以评价big ET-1对各临床终点的风险评估作用。结果相关性分析显示,big ET-1与超敏C反应蛋白(hsCRP)、N末端脑钠肽前体对数值(LgNT-proBNP)、左心房内径(LAD)和左心室舒张末期内径(LVEDD)呈正相关(r=0Â.207,P=0ö.001;r=06.337,P<0ÿ.0001;r=0°.275,P<0 C.0001;r=0?.131,P=0æ.038)。 ROC曲线分析显示,预测患者1年内全因死亡的big ET-1最佳诊断界值为0?.565 pmol/L,(P<0æ.0001,曲线下面积0˝.722,敏感度0 i.750,特异度0÷.620)。 Kaplan-Meier 生存分析显示 big ET-1≥0?.565 pmol/L组在全因死亡和心衰再入院方面均劣于 big ET-1<0|.565 pmol/L 组( P=0.002, P<0æ.0001)。单因素及多因素 Cox 回归分析显示, big ET-1≥0?.565 pmol/L 是CRT 患者全因死亡( HR 2?.331,95%CI 1.060~5 Q.125,P=0Ë.035)和心衰再住院( HR 2˜.662,95%CI 1 N.599~4å.432,P<0.0001)的独立危险因素。结论 big ET-1与CRT患者的心衰严重程度相关。基线big ET-1≥0Ê.565 pmol/L提示患者接受CRT的全因死亡率和心衰再住院风险增加。%Objective The goal of this study was to evaluate the role of big endothelin-1

  1. Circulating Biomarker Panels in Alzheimer's Disease.

    Science.gov (United States)

    Zafari, Sachli; Backes, Christina; Meese, Eckart; Keller, Andreas

    2015-01-01

    The early diagnosis of diseases frequently represents an important unmet clinical need supporting in-time treatment of pathologies. This also applies to neurodegenerative diseases such as Alzheimer's disease (AD), the most common form of dementia, estimated to affect millions of individuals worldwide. The respective diagnostic and prognostic markers, especially for the preclinical stages of AD, are expected to improve patients' outcome significantly. In the last decades, many approaches to detecting AD have been developed, including markers to discover changes in amyloid-β levels [from cerebrospinal fluid (CSF) or using positron emission tomography] or other brain imaging technologies such as structural magnetic resonance imaging (MRI), functional-connectivity MRI or task-related functional MRI. A major challenge is the detection of AD using minimally or even noninvasive biomarkers from body fluids such as plasma or serum. Circulating biomarker candidates based on mRNAs or proteins measured from blood cells, plasma or serum have been proposed for various pathologies including AD. As for other diseases, there is a tendency to use marker signatures obtained by high-throughput approaches, which allow the generation of profiles of hundreds to thousands of biomarkers simultaneously [microarrays, mass spectrometry or next-generation sequencing (NGS)]. Beyond mRNAs and proteins, recent approaches have measured small noncoding RNA (so-called microRNA) profiles in AD patients' blood samples using NGS or array-based technologies. Generally, the development of marker panels is in its early stages and requires further, substantial clinical validation. In this review, we provide an overview of different circulating AD biomarkers, starting with a brief summary of CSF markers and focusing on novel biomarker signatures such as small noncoding RNA profiles.

  2. Inhibition of Progenitor Dendritic Cell Maturation by Plasma from Patients with Peripartum Cardiomyopathy: Role in Pregnancy-associated Heart Disease

    Directory of Open Access Journals (Sweden)

    Jane E. Ellis

    2005-01-01

    Full Text Available Dendritic cells (DCs play dual roles in innate and adaptive immunity based on their functional maturity, and both innate and adaptive immune responses have been implicated in myocardial tissue remodeling associated with cardiomyopathies. Peripartum cardiomyopathy (PPCM is a rare disorder which affects women within one month antepartum to five months postpartum. A high occurrence of PPCM in central Haiti (1 in 300 live births provided the unique opportunity to study the relationship of immune activation and DC maturation to the etiology of this disorder. Plasma samples from two groups (n = 12 of age- and parity-matched Haitian women with or without evidence of PPCM were tested for levels of biomarkers of cardiac tissue remodeling and immune activation. Significantly elevated levels of GM-CSF, endothelin-1, proBNP and CRP and decreased levels of TGF- were measured in PPCM subjects relative to controls. Yet despite these findings, in vitro maturation of normal human cord blood derived progenitor dendritic cells (CBDCs was significantly reduced (p < 0.001 in the presence of plasma from PPCM patients relative to plasma from post-partum control subjects as determined by expression of CD80, CD86, CD83, CCR7, MHC class II and the ability of these matured CBDCs to induce allo-responses in PBMCs. These results represent the first findings linking inhibition of DC maturation to the dysregulation of normal physiologic cardiac tissue remodeling during pregnancy and the pathogenesis of PPCM.

  3. The circulation physiology of agroecosystems

    Institute of Scientific and Technical Information of China (English)

    Cao Zhiping; Richard Dawson

    2007-01-01

    This paper represents an effort to enlarge the understanding of the biophysical foundation of agroecosystems by using an analogy with the circulation of the blood in the human body. The circulation function in the human body can be represented as arterial pressure. The factors affecting arterial pressure in the human body have direct counterparts in the cultivation-husbandry system. The relationship between circulation pressure and the factors affecting that pressure in the cultivation-husbandry system are similar to the relationship between the arterial pressure and factors affecting arterial pressure in the human body. Furthermore, circulation resistance in the cultivation-husbandry system can be shown to be analogous to the calculation of peripheral resistance in the human body by Poiseuille's formula.

  4. Plasma harmonics

    CERN Document Server

    Ganeev, Rashid A

    2014-01-01

    Preface; Why plasma harmonics? A very brief introduction Early stage of plasma harmonic studies - hopes and frustrations New developments in plasma harmonics studies: first successes Improvements of plasma harmonics; Theoretical basics of plasma harmonics; Basics of HHG Harmonic generation in fullerenes using few-cycle pulsesVarious approaches for description of observed peculiarities of resonant enhancement of a single harmonic in laser plasmaTwo-colour pump resonance-induced enhancement of odd and even harmonics from a tin plasmaCalculations of single harmonic generation from Mn plasma;Low-o

  5. Modulation of circulating vasoactive peptides and extracellular matrix proteins are two novel mechanisms in the cardioprotective action of acarbose.

    Science.gov (United States)

    Rudovich, Natalia; Pivovarova, Olga; Bernigau, Wolfgang; Sparwasser, Andrea; Tacke, Christopher; Murahovshi, Veronica; Mertes, Gabriele; Birkenfeld, Andreas L; Bergmann, Andreas; Weickert, Martin O; Pfeiffer, Andreas F

    2016-12-01

    Acarbose, an alpha-glucosidase inhibitor, unexpectedly reduced the incidence of hypertension and cardiovascular endpoints in the STOP-NIDDM study. Based on the growing evidence of a link between vasoregulatory peptides and metabolic traits, we hypothesized that changes of the Glycemic Index by acarbose may modulate vasoregulatory peptide levels via regulation of postprandial metabolism. Subjects with type 2 diabetes and with metabolic syndrome were treated with acarbose (12 weeks, 300mg/d) in a double-blind, placebo-controlled, cross-over intervention. Changes in fasting and postprandial levels of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1) and midregional pro-adrenomedullin (MR-proADM), WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as well as fasting and postprandial glucose/insulin levels in the liquid meal test were assessed. Acarbose strongly decreased postprandial insulin concentrations in subjects with metabolic syndrome (P=0.004), and postprandial glucose excursions in both groups. Postprandial MR-proANP and CT-proET-1 levels increased after acarbose treatment (P<0.01 and P<0.05, respectively) in subjects with metabolic syndrome only. No effect of acarbose treatment on MR-prADM was observed in both groups. All three peptides were correlated with each over, but neither with insulin sensitivity in euglycemic clamps, nor with adiponectin levels. WISP1 decreased after acarbose treatment in subjects with metabolic syndrome. Plasma MR- proANP and CT-proET-1 concentrations, but not MR-prADM concentrations, were affected by treatment with acarbose over 12 weeks. Our findings provide new possible mechanisms of acarbose action in diabetes and metabolic syndrome.

  6. Circulating and Brain BDNF Levels in Stroke Rats. Relevance to Clinical Studies

    OpenAIRE

    Yannick Béjot; Claude Mossiat; Maurice Giroud; Anne Prigent-Tessier; Christine Marie

    2011-01-01

    BACKGROUND: Whereas brain-derived neurotrophic factor (BDNF) levels are measured in the brain in animal models of stroke, neurotrophin levels in stroke patients are measured in plasma or serum samples. The present study was designed to investigate the meaning of circulating BDNF levels in stroke patients. METHODS AND RESULTS: Unilateral ischemic stroke was induced in rats by the injection of various numbers of microspheres into the carotid circulation in order to mimic the different degrees o...

  7. Seasonal overturning circulation in the Red Sea: 2. Winter circulation

    KAUST Repository

    Yao, Fengchao

    2014-04-01

    The shallow winter overturning circulation in the Red Sea is studied using a 50 year high-resolution MITgcm (MIT general circulation model) simulation with realistic atmospheric forcing. The overturning circulation for a typical year, represented by 1980, and the climatological mean are analyzed using model output to delineate the three-dimensional structure and to investigate the underlying dynamical mechanisms. The horizontal model circulation in the winter of 1980 is dominated by energetic eddies. The climatological model mean results suggest that the surface inflow intensifies in a western boundary current in the southern Red Sea that switches to an eastern boundary current north of 24N. The overturning is accomplished through a cyclonic recirculation and a cross-basin overturning circulation in the northern Red Sea, with major sinking occurring along a narrow band of width about 20 km along the eastern boundary and weaker upwelling along the western boundary. The northward pressure gradient force, strong vertical mixing, and horizontal mixing near the boundary are the essential dynamical components in the model\\'s winter overturning circulation. The simulated water exchange is not hydraulically controlled in the Strait of Bab el Mandeb; instead, the exchange is limited by bottom and lateral boundary friction and, to a lesser extent, by interfacial friction due to the vertical viscosity at the interface between the inflow and the outflow. Key Points Sinking occurs in a narrow boundary layer along the eastern boundary Surface western boundary current switches into an eastern boundary current Water exchange in the Strait of Bab el Mandeb is not hydraulically controlled © 2014. American Geophysical Union. All Rights Reserved.

  8. The Invertibility, Explicit Determinants, and Inverses of Circulant and Left Circulant and g-Circulant Matrices Involving Any Continuous Fibonacci and Lucas Numbers

    Directory of Open Access Journals (Sweden)

    Zhaolin Jiang

    2014-01-01

    Full Text Available Circulant matrices play an important role in solving delay differential equations. In this paper, circulant type matrices including the circulant and left circulant and g-circulant matrices with any continuous Fibonacci and Lucas numbers are considered. Firstly, the invertibility of the circulant matrix is discussed and the explicit determinant and the inverse matrices by constructing the transformation matrices are presented. Furthermore, the invertibility of the left circulant and g-circulant matrices is also studied. We obtain the explicit determinants and the inverse matrices of the left circulant and g-circulant matrices by utilizing the relationship between left circulant, g-circulant matrices and circulant matrix, respectively.

  9. Dusty plasmas

    Energy Technology Data Exchange (ETDEWEB)

    Fortov, Vladimir E; Khrapak, Aleksei G; Molotkov, Vladimir I; Petrov, Oleg F [Institute for High Energy Densities, Associated Institute for High Temperatures, Russian Academy of Sciences, Moscow (Russian Federation); Khrapak, Sergei A [Max-Planck-Institut fur Extraterrestrische Physik, Garching (Germany)

    2004-05-31

    The properties of dusty plasmas - low-temperature plasmas containing charged macroparticles - are considered. The most important elementary processes in dusty plasmas and the forces acting on dust particles are investigated. The results of experimental and theoretical investigations of different states of strongly nonideal dusty plasmas - crystal-like, liquid-like, gas-like - are summarized. Waves and oscillations in dusty plasmas, as well as their damping and instability mechanisms, are studied. Some results on dusty plasma investigated under microgravity conditions are presented. New directions of experimental research and potential applications of dusty plasmas are discussed. (reviews of topical problems)

  10. Circulating Fibronectin Controls Tumor Growth

    Directory of Open Access Journals (Sweden)

    Anja von Au

    2013-08-01

    Full Text Available Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.

  11. Circulating docosahexaenoic acid levels are associated with fetal insulin sensitivity.

    Directory of Open Access Journals (Sweden)

    Jin-Ping Zhao

    Full Text Available BACKGROUND: Arachidonic acid (AA; C20∶4 n-6 and docosahexaenoic acid (DHA; C22∶6 n-3 are important long-chain polyunsaturated fatty acids (LC-PUFA in maintaining pancreatic beta-cell structure and function. Newborns of gestational diabetic mothers are more susceptible to the development of type 2 diabetes in adulthood. It is not known whether low circulating AA or DHA is involved in perinatally "programming" this susceptibility. This study aimed to assess whether circulating concentrations of AA, DHA and other fatty acids are associated with fetal insulin sensitivity or beta-cell function, and whether low circulating concentrations of AA or DHA are involved in compromised fetal insulin sensitivity in gestational diabetic pregnancies. METHODS AND PRINCIPAL FINDINGS: In a prospective singleton pregnancy cohort, maternal (32-35 weeks gestation and cord plasma fatty acids were assessed in relation to surrogate indicators of fetal insulin sensitivity (cord plasma glucose-to-insulin ratio, proinsulin concentration and beta-cell function (proinsulin-to-insulin ratio in 108 mother-newborn pairs. Cord plasma DHA levels (in percentage of total fatty acids were lower comparing newborns of gestational diabetic (n = 24 vs. non-diabetic pregnancies (2.9% vs. 3.5%, P = 0.01. Adjusting for gestational age at blood sampling, lower cord plasma DHA levels were associated with lower fetal insulin sensitivity (lower glucose-to-insulin ratio, r = 0.20, P = 0.036; higher proinsulin concentration, r = -0.37, P <0.0001. The associations remained after adjustment for maternal and newborn characteristics. Cord plasma saturated fatty acids C18∶0 and C20∶0 were negatively correlated with fetal insulin sensitivity, but their levels were not different between gestational diabetic and non-diabetic pregnancies. Cord plasma AA levels were not correlated with fetal insulin sensitivity. CONCLUSION: Low circulating DHA levels are associated with

  12. Atmospheric Circulation of Terrestrial Exoplanets

    CERN Document Server

    Showman, Adam P; Merlis, Timothy M; Kaspi, Yohai

    2013-01-01

    The investigation of planets around other stars began with the study of gas giants, but is now extending to the discovery and characterization of super-Earths and terrestrial planets. Motivated by this observational tide, we survey the basic dynamical principles governing the atmospheric circulation of terrestrial exoplanets, and discuss the interaction of their circulation with the hydrological cycle and global-scale climate feedbacks. Terrestrial exoplanets occupy a wide range of physical and dynamical conditions, only a small fraction of which have yet been explored in detail. Our approach is to lay out the fundamental dynamical principles governing the atmospheric circulation on terrestrial planets--broadly defined--and show how they can provide a foundation for understanding the atmospheric behavior of these worlds. We first survey basic atmospheric dynamics, including the role of geostrophy, baroclinic instabilities, and jets in the strongly rotating regime (the "extratropics") and the role of the Hadle...

  13. Circulation in blast driven instabilities

    Science.gov (United States)

    Henry de Frahan, Marc; Johnsen, Eric

    2016-11-01

    Mixing in many natural phenomena (e.g. supernova collapse) and engineering applications (e.g. inertial confinement fusion) is often initiated through hydrodynamic instabilities. Explosions in these systems give rise to blast waves which can interact with perturbations at interfaces between different fluids. Blast waves are formed by a shock followed by a rarefaction. This wave profile leads to complex time histories of interface acceleration. In addition to the instabilities induced by the acceleration field, the rarefaction from the blast wave decompresses the material at the interface, further increasing the perturbation growth. After the passage of the wave, circulation circulation generated by the blast wave through baroclinic vorticity continues to act upon the interface. In this talk, we provide scaling laws for the circulation and amplitude growth induced by the blast wave. Numerical simulations of the multifluid Euler equations solved using a high-order accurate Discontinuous Galerkin method are used to validate the theoretical results.

  14. Circulating DNG level is negatively associated with the long-term survival of hepatocellular carcinoma patients

    Institute of Scientific and Technical Information of China (English)

    Ning Ren; Qing-Hai Ye; Lun-Xiu Qin; Bo-Heng Zhang; Yin-Kun Liu; Zhao-You Tang

    2006-01-01

    AIM: To quantify the circulating DNA in plasma from patients with hepatocellular carcinoma (HCC) and to evaluate its prognostic value.METHODS: Blood samples were collected from 79patients with HCC before operation, 20 patients with liver cirrhosis, and 20 healthy volunteers. Circulating DNA was extracted from plasma and quantified. The association between circulating DNA level and prognosis of HCC patients was evaluated.RESULTS: Compared with the healthy volunteers (17.6± 9.5 ng/mL), a significant higher circulating DNA level was found in the patients with HCC (47.1±43.7 ng/mL, P = 0.000) or with liver cirrhosis (30.0 ± 13.3 ng/mL, P = 0.002). The circulating DNA level was closely associated with tumor size (P = 0.008) and TNM stage (P = 0.040), negatively associated with the 3-year diseasefree survival (DFS) (P = 0.017) and overall survival (OS) (P = 0.001).CONCLUSION: Large or invasive tumor may release more circulating DNA, and higher level of circulating DNA may be associated with poor prognosis of HCC patients.

  15. Predictive ability of circulating osteoprotegerin as a novel biomarker for early detection of acute kidney injury induced by sepsis.

    Science.gov (United States)

    Schaalan, Mona; Mohamed, Waleed

    2017-06-01

    Though significant progress has been made towards new diagnostic approaches for early detection of acute kidney injury (AKI) induced by different factors, there is still an urgent demand for a more specific and predictive biomarker for each type. The aim of this study is to unravel the potential diagnostic utility of circulating osteoprotegerin (OPG) in septic patients who developed AKI in the ICU, compared to cystatin C (a renal function maker) and KIM-1 (a kidney damage marker). Eighty patients (male = 43, female = 37) with ages ranging from 42 to 46 years and with sepsis, 40 of whom developed AKI, and 30 healthy controls were enrolled in this prospective study. Results revealed significant progressive elevation of OPG, along with cystatin C and KIM-1, among sepsis, severe sepsis, and sepsis-AKI patients. The progression of OPG levels paralleled the deterioration of kidney and endothelial functions from sepsis to sepsis-AKI, revealed as progressively increased levels of serum E-selectin (15.3%), endothelin-1 (ET-1) (19.6%), and decreased nitric oxide (NO) (29.7%), associated with elevations of TNF-α (25.5%) and TGF-β (18%). Their comparative prognostic validity of sepsis-AKI was assessed using ROC analysis, which revealed that OPG, KIM-1, and cystatin C showed similar AUCs (0.827-0.83) but with different sensitivities, viz., 84%, 88%, and 92%, respectively. Although cystatin showed 82% specificity, OPG showed a higher, similar specificity to KIM-1 of 85%, indicating its potential function as a marker of renal damage such as KIM-1. This study revealed a significant elevation of circulating OPG in septic patients with different levels of severity and those who progressed to AKI. Moreover, OPG showed a significant correlation to KIM-1 and cystatin, as well as conventional renal, inflammatory, and endothelial markers. Having a similar specificity to KIM-1, as evidenced by the ROC analysis, OPG has the potential to serve as a reliable biomarker of kidney damage

  16. Variety of RNAs in Peripheral Blood Cells, Plasma, and Plasma Fractions

    Directory of Open Access Journals (Sweden)

    Anna V. Savelyeva

    2017-01-01

    Full Text Available Human peripheral blood contains RNA in cells and in extracellular membrane vesicles, microvesicles and exosomes, as well as in cell-free ribonucleoproteins. Circulating mRNAs and noncoding RNAs, being internalized, possess the ability to modulate vital processes in recipient cells. In this study, with SOLiD sequencing technology, we performed identification, classification, and quantification of RNAs from blood fractions: cells, plasma, plasma vesicles pelleted at 16,000g and 160,000g, and vesicle-depleted plasma supernatant of healthy donors and non-small cell lung cancer (NSCLC patients. It was determined that 16,000g blood plasma vesicles were enriched with cell-free mitochondria and with a set of mitochondrial RNAs. The variable RNA set of blood plasma 160,000g pellets reflected the prominent contribution of U1, U5, and U6 small nuclear RNAs’ fragments and at the same time was characterized by a remarkable depletion of small nucleolar RNAs. Besides microRNAs, the variety of fragments of mRNAs and snoRNAs dominated in the set of circulating RNAs differentially expressed in blood fractions of NSCLC patients. Taken together, our data emphasize that not only extracellular microRNAs but also circulating fragments of messenger and small nuclear/nucleolar RNAs represent prominent classes of circulating regulatory ncRNAs as well as promising circulating biomarkers for the development of disease diagnostic approaches.

  17. Variety of RNAs in Peripheral Blood Cells, Plasma, and Plasma Fractions.

    Science.gov (United States)

    Savelyeva, Anna V; Kuligina, Elena V; Bariakin, Dmitry N; Kozlov, Vadim V; Ryabchikova, Elena I; Richter, Vladimir A; Semenov, Dmitry V

    2017-01-01

    Human peripheral blood contains RNA in cells and in extracellular membrane vesicles, microvesicles and exosomes, as well as in cell-free ribonucleoproteins. Circulating mRNAs and noncoding RNAs, being internalized, possess the ability to modulate vital processes in recipient cells. In this study, with SOLiD sequencing technology, we performed identification, classification, and quantification of RNAs from blood fractions: cells, plasma, plasma vesicles pelleted at 16,000g and 160,000g, and vesicle-depleted plasma supernatant of healthy donors and non-small cell lung cancer (NSCLC) patients. It was determined that 16,000g blood plasma vesicles were enriched with cell-free mitochondria and with a set of mitochondrial RNAs. The variable RNA set of blood plasma 160,000g pellets reflected the prominent contribution of U1, U5, and U6 small nuclear RNAs' fragments and at the same time was characterized by a remarkable depletion of small nucleolar RNAs. Besides microRNAs, the variety of fragments of mRNAs and snoRNAs dominated in the set of circulating RNAs differentially expressed in blood fractions of NSCLC patients. Taken together, our data emphasize that not only extracellular microRNAs but also circulating fragments of messenger and small nuclear/nucleolar RNAs represent prominent classes of circulating regulatory ncRNAs as well as promising circulating biomarkers for the development of disease diagnostic approaches.

  18. Circulating MicroRNAs and Life Expectancy Among Identical Twins.

    Science.gov (United States)

    Wu, Shenghui; Kim, Taek-Kyun; Wu, Xiaogang; Scherler, Kelsey; Baxter, David; Wang, Kai; Krasnow, Ruth E; Reed, Terry; Dai, Jun

    2016-09-01

    Human life expectancy is influenced not only by longevity assurance mechanisms and disease susceptibility loci but also by the environment, gene-environment interactions, and chance. MicroRNAs (miRNAs) are a class of small noncoding RNAs closely related to genes. Circulating miRNAs have been shown as promising noninvasive biomarkers in the development of many pathophysiological conditions. However, the concentration of miRNA in the circulation may also be affected by environmental factors. We used a next-generation sequencing platform to assess the association of circulating miRNA with life expectancy, for which deaths are due to all causes independent of genes. In addition, we showed that miRNAs are present in 41-year archived plasma samples, which may be useful for both life expectancy and all-cause mortality risk assessment. Plasma miRNAs from nine identical male twins were profiled using next-generation sequencing. The average absolute difference in the minimum life expectancy was 9.68 years. Intraclass correlation coefficients were above 0.4 for 50% of miRNAs. Comparing deceased twins with their alive co-twin brothers, the concentrations were increased for 34 but decreased for 30 miRNAs. Identical twins discordant in life expectancy were dissimilar in the majority of miRNAs, suggesting that environmental factors are pivotal in miRNAs related to life expectancy.

  19. Plasma waves

    CERN Document Server

    Swanson, DG

    1989-01-01

    Plasma Waves discusses the basic development and equations for the many aspects of plasma waves. The book is organized into two major parts, examining both linear and nonlinear plasma waves in the eight chapters it encompasses. After briefly discussing the properties and applications of plasma wave, the book goes on examining the wave types in a cold, magnetized plasma and the general forms of the dispersion relation that characterize the waves and label the various types of solutions. Chapters 3 and 4 analyze the acoustic phenomena through the fluid model of plasma and the kinetic effects. Th

  20. Plasma astrophysics

    CERN Document Server

    Kaplan, S A; ter Haar, D

    2013-01-01

    Plasma Astrophysics is a translation from the Russian language; the topics discussed are based on lectures given by V.N. Tsytovich at several universities. The book describes the physics of the various phenomena and their mathematical formulation connected with plasma astrophysics. This book also explains the theory of the interaction of fast particles plasma, their radiation activities, as well as the plasma behavior when exposed to a very strong magnetic field. The text describes the nature of collective plasma processes and of plasma turbulence. One author explains the method of elementary

  1. 冠心病患者冠脉循环中血浆线粒体偶联因子-6含量与冠脉狭窄程度的相关性%Correlation between plasma mitochondrial coupling factor-6 level in coronary circulation and coronary stenotic degree in CHD patients

    Institute of Scientific and Technical Information of China (English)

    马健; 成强

    2014-01-01

    目的:研究冠心病(CHD)患者冠脉循环中血浆线粒体偶联因子-6(MCF-6)含量与冠脉狭窄程度的相关性。方法:选择冠心病患者64例(冠心病组),根据冠脉病变程度分为单支、双支、多支病变组;另选冠脉正常者20例作为正常对照组,用放免方法分别测定各组外周、冠状窦、冠状窦与主动脉根部血浆 MCF-6浓度,并用多元线性逐步回归分析分析冠脉循环血浆MCF-6含量与冠脉狭窄程度的相关性。结果:冠心病患者外周、主动脉根部、冠状窦血浆MCF-6浓度较正常对照组均显著升高(P<0.05);冠心病组冠状窦血浆 MCF-6浓度较主动脉根部及外周血的均显著升高[(402±56)pg/ml比(348±48)pg/ml比(340±51)pg/ml,P<0.01];多支病变组的血浆MCF-6浓度较单支、双支病变组的显著升高(P<0.05~0.01);多元线性逐步回归分析显示冠状窦及主动脉根部血浆MCF-6浓度与 Gensini积分均呈明显正相关(r=0.650,P<0.01;r=0.711,P<0.01)。结论:线粒体偶联因子-6参与了冠心病的病理生理过程,在冠心病的发病过程中可能是一种较为重要的血管活性物质。%Objective:To study correlation betWeen plasma mitochondrial coupling factor-6 (MCF-6)level in coro-nary circulation and coronary stenotic degree in CHD patients.Methods:A total of 64 CHD patients Were selected as CHD group,and they Were further divided into single-vessel group,double-vessel group and multi-vessel coronary disease group;another 20 cases With normal coronary artery Were enrolled as normal control group.Radioimmuno-assay method Was used to measure plasma MCF-6 concentration in peripheral,coronary sinus and aortic root in each group.Multivariant linear gradual regressive analysis Was used to analyze above-mentioned correlation.Results:Compared With normal control group,there Was significant increase in plasma MCF-6 concentration in peripheral

  2. 急性肺损伤/急性呼吸窘迫综合征患者呼出气冷凝液和血清一氧化氮及内皮素检测的意义%The clinical significance of nitric oxide and endothelin-1 in exhaled breath condensate and serum of patients with acute lung injury/acute respiratory distress syndrome

    Institute of Scientific and Technical Information of China (English)

    顾言; 陈建荣; 邵峰

    2014-01-01

    Objective To observe the level of the nitric oxide (NO) and endothelin-1 (ET-1) in the exhaled breath condensate(EBC)and serum of the patients with ALI /ARDS, and investigate its clinical significance. Methods The study group included 52 mechanical ventilation patients with ALI/ARDS in ICU , which were divided into the survival and death group, while 30 healthy volunteers were recruited as healthy control. EBC samples of the healthy control and the study group on the 1st day and 5st day were collected by EcoScreen condenser with the synchronous collection of the venous blood. The concentrations of NO and ET-1 in the EBC and serum were measured by EIA. Results The levels of NO and ET-1 in EBC and serum of the patients with ALI /ARDS were all significantly higher than those of the healthy control. After treatment , the levels of NO and ET-1 in EBC and serum of the patients all decreased significantly compared with before treatment. After treatment , The levels of NO in EBC and serum of the survival group were significantly lower than those of the death group. After treatment , the levels of ET-1 in serum of the survival group was significantly lower than that of the death group. Conclusions Detecting the levels of NO and ET-1 in the EBC and serum can reflect oxidative stress , inflammatory reaction and endothelial injury in lung of patients with ALI/ARDS.%目的:研究急性肺损伤/急性呼吸窘迫综合征(acute lung injury/acute respiratory distress syndrome, ALI/ARDS)患者呼出气冷凝液(exhaled breath condensate, EBC)和血清中一氧化氮(nitric oxide, NO)和内皮素(endothelin-1, ET-1)改变与病情变化及预后的关系。方法:研究组为南通大学第二附属医院重症监护病房(intensive care unit,ICU)行机械通气的52例ALI/ARDS患者,根据预后分为存活组和病死组;健康对照组为30例健康体检者。采用Ecoscreen呼出气冷凝液收集器收集健康对

  3. Fragment Length of Circulating Tumor DNA.

    Directory of Open Access Journals (Sweden)

    Hunter R Underhill

    2016-07-01

    Full Text Available Malignant tumors shed DNA into the circulation. The transient half-life of circulating tumor DNA (ctDNA may afford the opportunity to diagnose, monitor recurrence, and evaluate response to therapy solely through a non-invasive blood draw. However, detecting ctDNA against the normally occurring background of cell-free DNA derived from healthy cells has proven challenging, particularly in non-metastatic solid tumors. In this study, distinct differences in fragment length size between ctDNAs and normal cell-free DNA are defined. Human ctDNA in rat plasma derived from human glioblastoma multiforme stem-like cells in the rat brain and human hepatocellular carcinoma in the rat flank were found to have a shorter principal fragment length than the background rat cell-free DNA (134-144 bp vs. 167 bp, respectively. Subsequently, a similar shift in the fragment length of ctDNA in humans with melanoma and lung cancer was identified compared to healthy controls. Comparison of fragment lengths from cell-free DNA between a melanoma patient and healthy controls found that the BRAF V600E mutant allele occurred more commonly at a shorter fragment length than the fragment length of the wild-type allele (132-145 bp vs. 165 bp, respectively. Moreover, size-selecting for shorter cell-free DNA fragment lengths substantially increased the EGFR T790M mutant allele frequency in human lung cancer. These findings provide compelling evidence that experimental or bioinformatic isolation of a specific subset of fragment lengths from cell-free DNA may improve detection of ctDNA.

  4. Fragment Length of Circulating Tumor DNA.

    Science.gov (United States)

    Underhill, Hunter R; Kitzman, Jacob O; Hellwig, Sabine; Welker, Noah C; Daza, Riza; Baker, Daniel N; Gligorich, Keith M; Rostomily, Robert C; Bronner, Mary P; Shendure, Jay

    2016-07-01

    Malignant tumors shed DNA into the circulation. The transient half-life of circulating tumor DNA (ctDNA) may afford the opportunity to diagnose, monitor recurrence, and evaluate response to therapy solely through a non-invasive blood draw. However, detecting ctDNA against the normally occurring background of cell-free DNA derived from healthy cells has proven challenging, particularly in non-metastatic solid tumors. In this study, distinct differences in fragment length size between ctDNAs and normal cell-free DNA are defined. Human ctDNA in rat plasma derived from human glioblastoma multiforme stem-like cells in the rat brain and human hepatocellular carcinoma in the rat flank were found to have a shorter principal fragment length than the background rat cell-free DNA (134-144 bp vs. 167 bp, respectively). Subsequently, a similar shift in the fragment length of ctDNA in humans with melanoma and lung cancer was identified compared to healthy controls. Comparison of fragment lengths from cell-free DNA between a melanoma patient and healthy controls found that the BRAF V600E mutant allele occurred more commonly at a shorter fragment length than the fragment length of the wild-type allele (132-145 bp vs. 165 bp, respectively). Moreover, size-selecting for shorter cell-free DNA fragment lengths substantially increased the EGFR T790M mutant allele frequency in human lung cancer. These findings provide compelling evidence that experimental or bioinformatic isolation of a specific subset of fragment lengths from cell-free DNA may improve detection of ctDNA.

  5. VanderLaan Circulant Type Matrices

    Directory of Open Access Journals (Sweden)

    Hongyan Pan

    2015-01-01

    Full Text Available Circulant matrices have become a satisfactory tools in control methods for modern complex systems. In the paper, VanderLaan circulant type matrices are presented, which include VanderLaan circulant, left circulant, and g-circulant matrices. The nonsingularity of these special matrices is discussed by the surprising properties of VanderLaan numbers. The exact determinants of VanderLaan circulant type matrices are given by structuring transformation matrices, determinants of well-known tridiagonal matrices, and tridiagonal-like matrices. The explicit inverse matrices of these special matrices are obtained by structuring transformation matrices, inverses of known tridiagonal matrices, and quasi-tridiagonal matrices. Three kinds of norms and lower bound for the spread of VanderLaan circulant and left circulant matrix are given separately. And we gain the spectral norm of VanderLaan g-circulant matrix.

  6. Conservation of Circulation in Magnetohydrodynamics

    CERN Document Server

    Bekenstein, J D; Bekenstein, Jacob D.; Oron, Asaf

    2000-01-01

    We demonstrate, both at the Newtonian and (general) relativistic levels, theexistence of a generalization of Kelvin's circulation theorem (for pure fluids)which is applicable to perfect magnetohydrodynamics. The argument is based onthe least action principle for magnetohydrodynamic flow. Examples of the newconservation law are furnished. The new theorem should be helpful inidentifying new kinds of vortex phenomena distinct from magnetic ropes or fluidvortices.

  7. Circulating Fibrocytes Are Increased in Neonates with Bronchopulmonary Dysplasia

    Science.gov (United States)

    Li, Chun; Li, Xiaoyu; Deng, Chun; Guo, Chunbao

    2016-01-01

    Background Bronchopulmonary dysplasia (BPD) is characterized by the aberrant remodeling of the lung parenchyma, resulting from accumulation of fibroblasts or myofibroblasts. Circulating fibrocytes are implied in pulmonary fibrosis, but whether these cells are associated with the development of BPD or the progressive fibrosis is unknown. The aim of the present study was to investigate the occurrence of fibrocytes in peripheral venous blood and explore whether these cells might be associated with severity of BPD. Methods We investigated circulating fibrocytes in 66 patients with BPD, 23 patients with acute respiratory distress syndrome(ARDS) and 11 normal subjects. Circulating fibrocytes were defined and quantified as cells positive for CD45 andcollagen-1 by flow cytometry. Furthermore, serum SDF-1/CXCL12 and TGF-β1 were evaluated using ELISA methods. We also investigated the clinical value of fibrocyte counts by comparison with standard clinical parameters. Results The patients with BPD had significantly increased numbers of fibrocytes compared to the controls (p fibrocytes and pulmonary hypertension or oxygen saturation (p Fibrocyte numbers were not correlated with other clinical or functional variables or radiologic severity scores. The fibrocyte attractant chemokine CXCL12 increased in plasma (p fibrocytes are increased in patients with BPD and may contribute to pulmonary fibrosis in BPD. Circulating fibrocytes, likely recruited through the CXCR4/CXCL12 axis, might contribute to the production of TGF-β1 for the expansion of fibroblast/myofibroblast population in BPD. PMID:27309347

  8. Circulating levels of GH-releasing hormone and GH during human pregnancy.