Impact of ticagrelor on P2Y1 and P2Y12 localization and on cholesterol levels in platelet plasma membrane.

Science.gov (United States)

Rabani, Vahideh; Montange, Damien; Meneveau, Nicolas; Davani, Siamak

2017-10-11

Ticagrelor is an antiplatelet agent that inhibits platelet activation via P2Y12 antagonism. There are several studies showing that P2Y12 needs lipid rafts to be activated, but there are few data about how ticagrelor impacts lipid raft organization. Therefore, we aimed to investigate how ticagrelor could impact the distribution of cholesterol and consequently alter the organization of lipid rafts on platelet plasma membranes. We identified cholesterol-enriched raft fractions in platelet membranes by quantification of their cholesterol levels. Modifications in cholesterol and protein profiles (Flotillin 1, Flotillin 2, CD36, P2Y1, and P2Y12) were studied in platelets stimulated by ADP, treated by ticagrelor, or both. In ADP-stimulated and ticagrelor-treated groups, we found a decreased level of cholesterol in raft fractions of platelet plasma membrane compared to the control group. In addition, the peak of cholesterol in different experimental groups changed its localization on membrane fractions. In the control group, it was situated on fraction 2, while in ADP-stimulated platelets, it was located in fractions 3 to 5, and in fraction 4 in ticagrelor-treated group. The proteins studied also showed changes in their level of expression and localization in fractions of plasma membrane. Cholesterol levels of plasma membranes have a direct role in the organization of platelet membranes and could be modified by stimulation or drug treatment. Since ticagrelor and ADP both changed lipid composition and protein profile, investigating the lipid and protein composition of platelet membranes is of considerable importance as a focus for further research in anti-platelet management.

Doubly excited 2s2p 1,3Po resonance states of helium in dense plasmas

International Nuclear Information System (INIS)

Kar, Sabyasachi; Ho, Y.K.

2005-01-01

We have made an investigation on the 2s2p 1,3 P o resonance states of helium embedded in dense plasma environments. A screened Coulomb potential obtained from the Debye model is used to represent the interaction between the charge particles. A correlated wave function consisting of a generalized exponential expansion has been used to represent the correlation effect. Resonance energies and widths for the doubly excited He embedded in plasmas with various Debye lengths are determined using the stabilization method by calculating the density of resonance states. The resonance energies and widths for various Debye parameters ranging from infinity to a small value for the lowest 1,3 P o resonance states are reported

A lifetime measurement of the 1s2p 3P1 level in helium-like Mg and Al

International Nuclear Information System (INIS)

Armour, I.A.; Silver, J.D.; Traebert, E.; Oxford Univ.

1981-01-01

The lifetimes of the 1s2p 3 P 1 levels of helium-like magnesium and aluminium have been measured by the beam-foil decay curve technique. The 1s 2 -1s2p transitions were observed with a curved-crystal x-ray spectrometer. Decay curves taken under systematically varied conditions have been evaluated using several techniques including a cascade model. The results are in agreement with most of the theoretical predictions. (author)

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization[S

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Lee, Mi-Hye; Appleton, Kathryn M.; El-Shewy, Hesham M.; Sorci-Thomas, Mary G.; Thomas, Michael J.; Lopes-Virella, Maria F.; Luttrell, Louis M.; Hammad, Samar M.; Klein, Richard L.

2017-01-01

HDL normally transports about 50–70% of plasma sphingosine 1-phosphate (S1P), and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDL-stimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay and confocal microscopy. In both primary rat aortic vascular smooth muscle cells and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration, which was mediated by S1PR1. Mechanistic studies performed in HEK293 cells showed that incubation of cells with HDL led to an increase in the physical interaction between the SR-BI and S1PR1 receptors that mainly occurred on the plasma membrane. Model recombinant HDL (rHDL) particles formed in vitro with S1P incorporated into the particle initiated the internalization of S1PR1, whereas rHDL without supplemented S1P did not, suggesting that S1P transported in HDL can selectively activate S1PR1. In conclusion, these data suggest that S1P in HDL stimulates the transient interaction between SR-BI and S1PRs that can activate S1PRs and induce an elevation in intracellular calcium concentration. PMID:27881715

Uncleaved ApoM signal peptide is required for formation of large ApoM/sphingosine 1-phosphate (S1P)-enriched HDL particles.

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Liu, Mingxia; Allegood, Jeremy; Zhu, Xuewei; Seo, Jeongmin; Gebre, Abraham K; Boudyguina, Elena; Cheng, Dongmei; Chuang, Chia-Chi; Shelness, Gregory S; Spiegel, Sarah; Parks, John S

2015-03-20

Apolipoprotein M (apoM), a plasma sphingosine 1-phosphate (S1P) carrier, associates with plasma HDL via its uncleaved signal peptide. Hepatocyte-specific apoM overexpression in mice stimulates formation of both larger nascent HDL in hepatocytes and larger mature apoM/S1P-enriched HDL particles in plasma by enhancing hepatic S1P synthesis and secretion. Mutagenesis of apoM glutamine 22 to alanine (apoM(Q22A)) introduces a functional signal peptidase cleavage site. Expression of apoM(Q22A) in ABCA1-expressing HEK293 cells resulted in the formation of smaller nascent HDL particles compared with wild type apoM (apoM(WT)). When apoM(Q22A) was expressed in vivo, using recombinant adenoviruses, smaller plasma HDL particles and decreased plasma S1P and apoM were observed relative to expression of apoM(WT). Hepatocytes isolated from both apoM(WT)- and apoM(Q22A)-expressing mice displayed an equivalent increase in cellular levels of S1P, relative to LacZ controls; however, relative to apoM(WT), apoM(Q22A) hepatocytes displayed more rapid apoM and S1P secretion but minimal apoM(Q22A) bound to nascent lipoproteins. Pharmacologic inhibition of ceramide synthesis increased cellular sphingosine and S1P but not medium S1P in both apoM(WT) and apoM(Q22A) hepatocytes. We conclude that apoM secretion is rate-limiting for hepatocyte S1P secretion and that its uncleaved signal peptide delays apoM trafficking out of the cell, promoting formation of larger nascent apoM- and S1P-enriched HDL particles that are probably precursors of larger apoM/S1P-enriched plasma HDL. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

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

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization.

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Lee, Mi-Hye; Appleton, Kathryn M; El-Shewy, Hesham M; Sorci-Thomas, Mary G; Thomas, Michael J; Lopes-Virella, Maria F; Luttrell, Louis M; Hammad, Samar M; Klein, Richard L

2017-02-01

HDL normally transports about 50-70% of plasma sphingosine 1-phosphate (S1P), and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDL-stimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay and confocal microscopy. In both primary rat aortic vascular smooth muscle cells and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration, which was mediated by S1PR1. Mechanistic studies performed in HEK293 cells showed that incubation of cells with HDL led to an increase in the physical interaction between the SR-BI and S1PR1 receptors that mainly occurred on the plasma membrane. Model recombinant HDL (rHDL) particles formed in vitro with S1P incorporated into the particle initiated the internalization of S1PR1, whereas rHDL without supplemented S1P did not, suggesting that S1P transported in HDL can selectively activate S1PR1. In conclusion, these data suggest that S1P in HDL stimulates the transient interaction between SR-BI and S1PRs that can activate S1PRs and induce an elevation in intracellular calcium concentration.

Paradoxical Association of Postoperative Plasma Sphingosine-1-Phosphate with Breast Cancer Aggressiveness and Chemotherapy

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Rajesh Ramanathan

2017-01-01

Full Text Available Sphingosine-1-phosphate (S1P is a bioactive lipid mediator that has been shown to serve an important regulatory function in breast cancer progression. This study analyzes plasma S1P levels in breast cancer patients undergoing adjuvant therapy as compared to healthy control volunteers. 452 plasma S1P samples among 158 breast cancer patients, along with 20 healthy control volunteers, were analyzed. Mean S1P levels did not significantly differ between cancer patients and controls. Smoking was associated with higher S1P levels in cancer patients. Baseline S1P levels had weak inverse correlation with levels of the inflammatory mediator interleukin- (IL- 17 and CCL-2 and positive correlation with tumor necrosis factor alpha (TNF-α. Midpoint S1P levels during adjuvant therapy were lower than baseline, with near return to baseline after completion, indicating a relationship between chemotherapy and circulating S1P. While stage of disease did not correlate with plasma S1P levels, they were lower among patients with Her2-enriched and triple-negative breast cancer as compared to luminal-type breast cancer. Plasma S1P levels are paradoxically suppressed in aggressive breast cancer and during adjuvant chemotherapy, which raises the possibility that postoperative plasma S1P levels do not reflect S1P secretion from resected breast cancer.

Obesity-stimulated aldosterone release is not related to an S1P-dependent mechanism.

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Werth, Stephan; Müller-Fielitz, Helge; Raasch, Walter

2017-12-01

Aldosterone has been identified as an important factor in obesity-associated hypertension. Here, we investigated whether sphingosine-1-phosphate (S1P), which has previously been linked to obesity, increases aldosterone release. S1P-induced aldosterone release was determined in NCI H295R cells in the presence of S1P receptor (S1PR) antagonists. In vivo release of S1P (100-300 µg/kg bw ) was investigated in pithed, lean Sprague Dawley (SD) rats, diet-obese spontaneous hypertensive rats (SHRs), as well as in lean or obese Zucker rats. Aldosterone secretion was increased in NCI H295R cells by S1P, the selective S1PR1 agonist SEW2871 and the selective S1PR2 antagonist JTE013. Treatment with the S1PR1 antagonist W146 or fingolimod and the S1PR1/3 antagonist VPbib2319 decreased baseline and/or S1P-stimulated aldosterone release. Compared to saline-treated SD rats, plasma aldosterone increased by ~50 pg/mL after infusing S1P. Baseline levels of S1P and aldosterone were higher in obese than in lean SHRs. Adrenal S1PR expression did not differ between chow- or CD-fed rats that had the highest S1PR1 and lowest S1PR4 levels. S1P induced a short-lasting increase in plasma aldosterone in obese, but not in lean SHRs. However, 2-ANOVA did not demonstrate any difference between lean and obese rats. S1P-induced aldosterone release was also similar between obese and lean Zucker rats. We conclude that S1P is a local regulator of aldosterone production. S1PR1 agonism induces an increase in aldosterone secretion, while stimulating adrenal S1PR2 receptor suppresses aldosterone production. A significant role of S1P in influencing aldosterone secretion in states of obesity seems unlikely. © 2017 Society for Endocrinology.

Alterations in plasma soluble vascular endothelial growth factor receptor-1 (sFlt-1 concentrations during coronary artery bypass graft surgery: relationships with post-operative complications

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Orsel Isabelle

2008-04-01

Full Text Available Abstract Background Plasma concentrations of sFlt-1, the soluble form of the vascular endothelial growth factor receptor (VEGF, markedly increase during coronary artery bypass graft (CABG surgery with extracorporeal circulation (ECC. We investigated if plasma sFlt-1 values might be related to the occurrence of surgical complications after CABG. Methods Plasma samples were collected from the radial artery catheter before vascular cannulation and after opening the chest, at the end of ECC just before clamp release, after cross release, after weaning from ECC, at the 6th and 24th post-operative hour. Thirty one patients were investigated. The presence of cardiovascular, haematological and respiratory dysfunctions was prospectively assessed. Plasma sFlt-1 levels were measured with commercially ELISA kits. Results Among the 31 investigated patients, 15 had uneventful surgery. Patients with and without complications had similar pre-operative plasma sFlt-1 levels. Lowered plasma sFlt-1 levels were observed at the end of ECC in patients with haematological (p = 0.001, ANOVA or cardiovascular (p = 0.006 impairments, but not with respiratory ones (p = 0.053, as compared to patients with uneventful surgery. Conclusion These results identify an association between specific post-CABG complication and the lower release of sFlt-1 during ECC. sFlt-1-induced VEGF neutralisation might, thus, be beneficial to reduce the development of post-operative adverse effects after CABG.

Plasma sphingosine-1-phosphate is elevated in obesity.

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Greg M Kowalski

Full Text Available BACKGROUND: Dysfunctional lipid metabolism is a hallmark of obesity and insulin resistance and a risk factor for various cardiovascular and metabolic complications. In addition to the well known increase in plasma triglycerides and free fatty acids, recent work in humans and rodents has shown that obesity is associated with elevations in the bioactive class of sphingolipids known as ceramides. However, in obesity little is known about the plasma concentrations of sphinogsine-1-phosphate (S1P, the breakdown product of ceramide, which is an important signaling molecule in mammalian biology. Therefore, the purpose of this study was to examine the impact of obesity on circulating S1P concentration and its relationship with markers of glucose metabolism and insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: Plasma S1P levels were determined in high-fat diet (HFD-induced and genetically obese (ob/ob mice along with obese humans. Circulating S1P was elevated in both obese mouse models and in obese humans compared with lean healthy controls. Furthermore, in humans, plasma S1P positively correlated with total body fat percentage, body mass index (BMI, waist circumference, fasting insulin, HOMA-IR, HbA1c (%, total and LDL cholesterol. In addition, fasting increased plasma S1P levels in lean healthy mice. CONCLUSION: We show that elevations in plasma S1P are a feature of both human and rodent obesity and correlate with metabolic abnormalities such as adiposity and insulin resistance.

Plasma CXCL10, sCD163 and sCD14 Levels Have Distinct Associations with Antiretroviral Treatment and Cardiovascular Disease Risk Factors.

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Alison Castley

Full Text Available We investigate the associations of three established plasma biomarkers in the context of HIV and treatment-related variables including a comprehensive cardiovascular disease risk assessment, within a large ambulatory HIV cohort. Patients were recruited in 2010 to form the Royal Perth Hospital HIV/CVD risk cohort. Plasma sCD14, sCD163 and CXCL10 levels were measured in 475 consecutive patients with documented CVD risk (age, ethnicity, gender, smoking, blood pressure, BMI, fasting metabolic profile and HIV treatment history including immunological/virological outcomes. The biomarkers assessed showed distinct associations with virological response: CXCL10 strongly correlated with HIV-1 RNA (p0.2. Associations between higher sCD163 and protease inhibitor therapy (p = 0.05 and lower sCD14 with integrase inhibitor therapy (p = 0.02 were observed. Levels of sCD163 were also associated with CVD risk factors (age, ethnicity, HDL, BMI, with a favourable influence of Framingham score <10% (p = 0.04. Soluble CD14 levels were higher among smokers (p = 0.002, with no effect of other CVD risk factors, except age (p = 0.045. Our findings confirm CXCL10, sCD163 and sCD14 have distinct associations with different aspects of HIV infection and treatment. Levels of CXCL10 correlated with routinely monitored variables, sCD163 levels reflect a deeper level of virological suppression and influence of CVD risk factors, while sCD14 levels were not associated with routinely monitored variables, with evidence of specific effects of smoking and integrase inhibitor therapy warranting further investigation.

Plasma CXCL10, sCD163 and sCD14 Levels Have Distinct Associations with Antiretroviral Treatment and Cardiovascular Disease Risk Factors

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Castley, Alison; Williams, Leah; James, Ian; Guelfi, George; Berry, Cassandra; Nolan, David

2016-01-01

We investigate the associations of three established plasma biomarkers in the context of HIV and treatment-related variables including a comprehensive cardiovascular disease risk assessment, within a large ambulatory HIV cohort. Patients were recruited in 2010 to form the Royal Perth Hospital HIV/CVD risk cohort. Plasma sCD14, sCD163 and CXCL10 levels were measured in 475 consecutive patients with documented CVD risk (age, ethnicity, gender, smoking, blood pressure, BMI, fasting metabolic profile) and HIV treatment history including immunological/virological outcomes. The biomarkers assessed showed distinct associations with virological response: CXCL10 strongly correlated with HIV-1 RNA (p0.2). Associations between higher sCD163 and protease inhibitor therapy (p = 0.05) and lower sCD14 with integrase inhibitor therapy (p = 0.02) were observed. Levels of sCD163 were also associated with CVD risk factors (age, ethnicity, HDL, BMI), with a favourable influence of Framingham score <10% (p = 0.04). Soluble CD14 levels were higher among smokers (p = 0.002), with no effect of other CVD risk factors, except age (p = 0.045). Our findings confirm CXCL10, sCD163 and sCD14 have distinct associations with different aspects of HIV infection and treatment. Levels of CXCL10 correlated with routinely monitored variables, sCD163 levels reflect a deeper level of virological suppression and influence of CVD risk factors, while sCD14 levels were not associated with routinely monitored variables, with evidence of specific effects of smoking and integrase inhibitor therapy warranting further investigation. PMID:27355513

Seminal Plasma HIV-1 RNA Concentration Is Strongly Associated with Altered Levels of Seminal Plasma Interferon-γ, Interleukin-17, and Interleukin-5

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Hoffman, Jennifer C.; Anton, Peter A.; Baldwin, Gayle Cocita; Elliott, Julie; Anisman-Posner, Deborah; Tanner, Karen; Grogan, Tristan; Elashoff, David; Sugar, Catherine; Yang, Otto O.

2014-01-01

Abstract Seminal plasma HIV-1 RNA level is an important determinant of the risk of HIV-1 sexual transmission. We investigated potential associations between seminal plasma cytokine levels and viral concentration in the seminal plasma of HIV-1-infected men. This was a prospective, observational study of paired blood and semen samples from 18 HIV-1 chronically infected men off antiretroviral therapy. HIV-1 RNA levels and cytokine levels in seminal plasma and blood plasma were measured and analyzed using simple linear regressions to screen for associations between cytokines and seminal plasma HIV-1 levels. Forward stepwise regression was performed to construct the final multivariate model. The median HIV-1 RNA concentrations were 4.42 log10 copies/ml (IQR 2.98, 4.70) and 2.96 log10 copies/ml (IQR 2, 4.18) in blood and seminal plasma, respectively. In stepwise multivariate linear regression analysis, blood HIV-1 RNA level (pplasma HIV-1 RNA level. After controlling for blood HIV-1 RNA level, seminal plasma HIV-1 RNA level was positively associated with interferon (IFN)-γ (p=0.03) and interleukin (IL)-17 (p=0.03) and negatively associated with IL-5 (p=0.0007) in seminal plasma. In addition to blood HIV-1 RNA level, cytokine profiles in the male genital tract are associated with HIV-1 RNA levels in semen. The Th1 and Th17 cytokines IFN-γ and IL-17 are associated with increased seminal plasma HIV-1 RNA, while the Th2 cytokine IL-5 is associated with decreased seminal plasma HIV-1 RNA. These results support the importance of genital tract immunomodulation in HIV-1 transmission. PMID:25209674

[Role of serum S1P levels during asthma attack in the evaluation of asthma severity].

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Zhao, Yunwei; Xu, Yiqin; Li, Shuang; Wei, Yu; Wang, Chunling

2017-09-01

To observe the changes of serum sphingosine-1-phosphate (S1P) level in asthmatic patients with different severity of bronchial asthma, and to explore the evaluation value of S1P on the severity of asthma. A prospective observational study was conducted. Fifty-two patients with asthma admitted to Department of Respiratory Medicine of the First Affiliated Hospital of Jiamusi University from November 2015 to January 2017 were enrolled. According to the severity of the disease, the patients were divided into mild, moderate and severe groups. In the same period, 25 healthy subjects were served as healthy control group. All the subjects got the peripheral venous blood collection in the morning fasting, the level of serum S1P was determined by enzyme linked immunosorbent assay (ELISA), the peripheral blood eosinophil (EOS) was counted, and the pulmonary function test was performed. The correlation among the parameters was analyzed by Pearson correlation analysis. Receiver operating characteristic curve (ROC) was plotted, and the value of serum S1P on evaluating the severity of asthma was analyzed. Fifty-two asthma patients were enrolled, including 17 patients of the mild, 19 of the moderate, and 16 of the severe. Compared with the healthy control group, serum S1P level and peripheral blood EOS in different degree asthma groups were significantly increased, and forced expiratory volume in 1 second (FEV1) was decreased significantly; and with asthma exacerbations, serum S1P levels and peripheral blood EOS were gradually increased [mild, moderate and severe S1P (nmol/L) were 1 537.0±120.3, 1 980.7±149.5, 2 202.2±117.2 (F = 274.624, P = 0.001); EOS (×10 9 /L) were 0.13±0.06, 0.20±0.07, 0.37±0.14 , respectively (F = 44.093, P = 0.001)], and FEV1 was decreased gradually [mild, moderate and severe were 0.89±0.05, 0.63±0.06, 0.42±0.10, respectively (F = 159.756, P = 0.001)]. Correlation analysis showed that there were significant positive correlations between serum S1P

Levels of tissue inhibitor of metalloproteinases 1 in plasma and urine frompatients with bladder cancer

DEFF Research Database (Denmark)

Holten Andersen, MN; Brunner, N; Nielsen, HJ

2006-01-01

Aim: To assess the potential use of plasma and urine levels of tissue inhibitor of metalloproteinases 1 (TIMP-1) in urothelial cancer. Methods: TIMP-1 levels were determined in urine and plasma from healthy donors (n=26), patients with bacterial bladder infection (n=24), urothelial bladder adenoma...... (n=3) or adenocarcinoma (n=7). Results: Free and total TIMP-1 in plasma were weakly but significantly correlated with age; urinary TIMP-1 was not. A strong correlation between free and total TIMP-1 in plasma was observed, with an average ratio of 0.85. No correlation between total TIMP-1 in urine...... and plasma was found (p=0.55). No significant differences in free or total TIMP-1 in plasma were found between healthy individuals, patients with cystitis or bladder cancer (p=0.4). Urinary TIMP-1 levels were significantly increased in patients with cystitis (p=0.001). No apparent differences in TIMP-1...

Plasma levels of IGF-1 and IGFBP-3 in patients with brain tumor

International Nuclear Information System (INIS)

Zhang Bin; Wu Yiwei; Li Xiangdong

2004-01-01

Objective: To determinate the plasma levels of Insulin like growth factor-1 (IGF-1) and Insulin like Growth Factor Binding Protein-3 (IGFBP-3) in patients with glioma and meningioma. Methods: IGF-1 and IGFBP-3 Immunoradiometric assay on coated tubes kits (BIOCODE-HYCEL Belgium) were used to determinate the plasma levels of IGF-1 and IGFBP-3 in 41 cases of glioma (12 cases age 40), 14 cases of meningioma(age>40), and 22 cases of healthy subjects (10 cases age 40). All the diagnosis of patients was confirmed by pathology. Cap-Ria 16 Gamma Counter (CAPINTEC, INC U.S.A) was used to count the radioactivity. Results: Plasma levels of IGF-1 and IGFBP-3 in patients with glioma were 322.20±80.89 ng/mL, 1524.63±373.18 ng/mL (age 40), respectively. Plasma levels of IGF-1 and IGFBP-3 in patients with meningioma were 211.06±75.11 ng/mL, 1403.08±350.78 ng/mL (age >40); control groups were 272.46±49.67 ng/mL, 1453.38±378.73 ng/mL (age 40), respectively. Plasma levels of IGF-1 and IGFBP-3 in patients with glioma(age>40) were significantly higher than in controls (P 0.05). Conclusion: IGF-1 is a risk factor for glioma and play important role in the pathophysiological process of glioma. Endogenous regulation of the balance between IGF-1 and IGFBP-3 may be a model of regulation of cellular growth in tumor cells. (authors)

HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver.

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Ding, Bi-Sen; Liu, Catherine H; Sun, Yue; Chen, Yutian; Swendeman, Steven L; Jung, Bongnam; Chavez, Deebly; Cao, Zhongwei; Christoffersen, Christina; Nielsen, Lars Bo; Schwab, Susan R; Rafii, Shahin; Hla, Timothy

2016-12-22

Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P 1 ) by its natural ligand bound to HDL (HDL-S1P) induces liver regeneration and curtails fibrosis. In mice lacking HDL-S1P, liver regeneration after partial hepatectomy was impeded and associated with aberrant vascular remodeling, thrombosis and peri-sinusoidal fibrosis. Notably, this "maladaptive repair" phenotype was recapitulated in mice that lack S1P 1 in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P 1 enhanced regeneration of metabolically functional vasculature and alleviated fibrosis in mouse chronic injury and cholestasis models. This study shows that natural and pharmacological ligands modulate endothelial S1P 1 to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.

Ceramide synthase 2 facilitates S1P-dependent egress of thymocytes into the circulation in mice.

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Rieck, Michael; Kremser, Christiane; Jobin, Katarzyna; Mettke, Elisabeth; Kurts, Christian; Gräler, Markus; Willecke, Klaus; Kolanus, Waldemar

2017-04-01

Well-defined gradients of the lipid mediator sphingosine-1-phosphate (S1P) direct chemotactic egress of mature thymocytes from the thymus into the circulation. Although it is known that these gradients result from low S1P levels in the thymic parenchyma and high S1P concentrations at the exit sites and in the plasma, the biochemical mechanisms that regulate these differential S1P levels remain unclear. Several studies demonstrated that ceramide synthase 2 (Cers2) regulates the levels of the S1P precursor sphingosine. We, therefore, investigated whether Cers2 is involved in the regulation of S1P gradients and S1P-dependent egress into the circulation. By analyzing Cers2-deficient mice, we demonstrate that Cers2 limits the levels of S1P in thymus and blood to maintain functional S1P gradients that mediate thymocyte emigration into the circulation. This function is specific for Cers2, as we also show that Cers4 is not involved in the regulation of thymic egress. Our study identified Cers2 as an important regulator of S1P-dependent thymic egress, and thus contributes to the understanding of how S1P gradients are maintained in vivo. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Clinical significance of determination of plasma Leptin and serum Hcy, S100B and NSE levels in patients with alzheimer disease

International Nuclear Information System (INIS)

Dou Huanzhi; Lu Meng

2011-01-01

To explore the clinical significance of changes of plasma leptin and serun Hcy, S100B and NSE levels in patients with Alzheimer Disease (AD). The plasma leptin and serum NSE levels in 32 AD patients and 30 controls were determined by using RIA, and the serum Hcy and S100B levels were measured by using CLIA. The results showed that the plasma leptin and serun Hcy, S100B and NSE levels in AD patients were significantly higher than these in controls (P<0.01). The plasma leptin levels in AD patients was mutually positively correlated with serum Hcy, S100B and NSE levels (r=0.5982, 0.4762, 0.6014, P<0.01). The detection of plasma leptin and serum Hcy, S100B and NSE levels may be helpful for the prediction of treatment efficiency in patients with Alzheimer disease. (authors)

Association of Sphingosine-1-phosphate (S1P)/S1P Receptor-1 Pathway with Cell Proliferation and Survival in Canine Hemangiosarcoma.

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Rodriguez, A M; Graef, A J; LeVine, D N; Cohen, I R; Modiano, J F; Kim, J-H

2015-01-01

Sphingosine-1-phosphate (S1P) is a key biolipid signaling molecule that regulates cell growth and survival, but it has not been studied in tumors from dogs. S1P/S1P1 signaling will contribute to the progression of hemangiosarcoma (HSA). Thirteen spontaneous HSA tissues, 9 HSA cell lines, 8 nonmalignant tissues, including 6 splenic hematomas and 2 livers with vacuolar degeneration, and 1 endothelial cell line derived from a dog with splenic hematoma were used. This was a retrospective case series and in vitro study. Samples were obtained as part of medically necessary diagnostic procedures. Microarray, qRT-PCR, immunohistochemistry, and immunoblotting were performed to examine S1P1 expression. S1P concentrations were measured by high-performance liquid chromatography/mass spectrometry. S1P signaling was evaluated by intracellular Ca(2+) mobilization; proliferation and survival were evaluated using the MTS assay and Annexin V staining. Canine HSA cells expressed higher levels of S1P1 mRNA than nonmalignant endothelial cells. S1P1 protein was present in HSA tissues and cell lines. HSA cells appeared to produce low levels of S1P, but they selectively consumed S1P from the culture media. Exogenous S1P induced an increase in intracellular calcium as well as increased proliferation and viability of HSA cells. Prolonged treatment with FTY720, an inhibitor of S1P1 , decreased S1P1 protein expression and induced apoptosis of HSA cells. S1P/S1P1 signaling pathway functions to maintain HSA cell viability and proliferation. The data suggest that S1P1 or the S1P pathway in general could be targets for therapeutic intervention for dogs with HSA. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Intracellular S1P generation is essential for S1P-induced motility of human lung endothelial cells: role of sphingosine kinase 1 and S1P lyase.

Directory of Open Access Journals (Sweden)

Evgeny V Berdyshev

Full Text Available BACKGROUND: Earlier we have shown that extracellular sphingosine-1-phosphate (S1P induces migration of human pulmonary artery endothelial cells (HPAECs through the activation of S1P(1 receptor, PKCε, and PLD2-PKCζ-Rac1 signaling cascade. As endothelial cells generate intracellular S1P, here we have investigated the role of sphingosine kinases (SphKs and S1P lyase (S1PL, that regulate intracellular S1P accumulation, in HPAEC motility. METHODOLOGY/PRINCIPAL FINDINGS: Inhibition of SphK activity with a SphK inhibitor 2-(p-Hydroxyanilino-4-(p-Chlorophenyl Thiazole or down-regulation of Sphk1, but not SphK2, with siRNA decreased S1P(int, and attenuated S1P(ext or serum-induced motility of HPAECs. On the contrary, inhibition of S1PL with 4-deoxypyridoxine or knockdown of S1PL with siRNA increased S1P(int and potentiated motility of HPAECs to S1P(ext or serum. S1P(ext mediates cell motility through activation of Rac1 and IQGAP1 signal transduction in HPAECs. Silencing of SphK1 by siRNA attenuated Rac1 and IQGAP1 translocation to the cell periphery; however, knockdown of S1PL with siRNA or 4-deoxypyridoxine augmented activated Rac1 and stimulated Rac1 and IQGAP1 translocation to cell periphery. The increased cell motility mediated by down-regulation was S1PL was pertussis toxin sensitive suggesting "inside-out" signaling of intracellularly generated S1P. Although S1P did not accumulate significantly in media under basal or S1PL knockdown conditions, addition of sodium vanadate increased S1P levels in the medium and inside the cells most likely by blocking phosphatases including lipid phosphate phosphatases (LPPs. Furthermore, addition of anti-S1P mAb to the incubation medium blocked S1P(ext or 4-deoxypyridoxine-dependent endothelial cell motility. CONCLUSIONS/SIGNIFICANCE: These results suggest S1P(ext mediated endothelial cell motility is dependent on intracellular S1P production, which is regulated, in part, by SphK1 and S1PL.

Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration.

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Koch, Alexander; Jäger, Manuel; Völzke, Anja; Grammatikos, Georgios; Zu Heringdorf, Dagmar Meyer; Huwiler, Andrea; Pfeilschifter, Josef

2015-06-01

Sphingosine 1-phosphate (S1P) is generated by sphingosine kinase (SK)-1 and -2 and acts mainly as an extracellular ligand at five specific receptors, denoted S1P1-5. After activation, S1P receptors regulate important processes in the progression of renal diseases, such as mesangial cell migration and survival. Previously, we showed that dexamethasone enhances SK-1 activity and S1P formation, which protected mesangial cells from stress-induced apoptosis. Here we demonstrate that dexamethasone treatment lowered S1P1 mRNA and protein expression levels in rat mesangial cells. This effect was abolished in the presence of the glucocorticoid receptor antagonist RU-486. In addition, in vivo studies showed that dexamethasone downregulated S1P1 expression in glomeruli isolated from mice treated with dexamethasone (10 mg/kg body weight). Functionally, we identified S1P1 as a key player mediating S1P-induced mesangial cell migration. We show that dexamethasone treatment significantly lowered S1P-induced migration of mesangial cells, which was again reversed in the presence of RU-486. In summary, we suggest that dexamethasone inhibits S1P-induced mesangial cell migration via downregulation of S1P1. Overall, these results demonstrate that dexamethasone has functional important effects on sphingolipid metabolism and action in renal mesangial cells.

Reliable measurement of the Li-like 2248Ti 1s2s2p 4P5/2o level lifetime by beam-foil and beam-two-foil experiments

International Nuclear Information System (INIS)

Nandi, T.; Ahmad, Nissar; Wani, A. A.; Marketos, P.

2006-01-01

We have determined the lifetime of the Li-like 22 48 Ti 1s2s2p 4 P 5/2 o level (210.5±13.5 ps) using data from its x-ray decay channel through beam single- and two-foil experiments, coupled to a multicomponent iterative growth and decay analysis. Theoretical lifetime estimates for this zero-nuclear-spin ion lies within the uncertainty range of our experimental results, indicating that blending contributions to this level from the He-like 1s2p 3 P 2 o and 1s2s 3 S 1 levels are eliminated within the current approach. A previously reported discrepancy between experimental and theoretical 1s2s2p 4 P 5/2 o level lifetimes in 23 51 V may, as a result, be attributed to hyperfine quenching

Identification of the 1s2s2p 4P5/2-->1s22s 2S1/2 magnetic quadrupole inner-shell satellite line in the Ar16+ K-shell x-ray spectrum

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Beiersdorfer, P.; Bitter, M.; Hey, D.; Reed, K. J.

2002-09-01

We have identified the dipole-forbidden 1s2s2p 4P5/2-->1s22s 2S1/2 transition in lithiumlike Ar15+ in high-resolution K-shell x-ray emission spectra recorded at the Livermore EBIT-II electron-beam ion trap and the Princeton National Spherical Tokamak Experiment. Unlike other Ar15+ satellite lines, which can be excited by dielectronic recombination, the line is exclusively excited by electron-impact excitation. Its predicted radiative rate is comparable to that of the well-known 1s2p 3P1-->1s2 1S0 magnetic quadrupole transition in heliumlike Ar16+. As a result, it can also only be observed in low-density plasma. We present calculations of the electron-impact excitation cross sections of the innershell excited Ar15+ satellite lines, including the magnetic sublevels needed for calculating the linear line polarization. We compare these calculations to the relative magnitudes of the observed 1s2s2p-->1s22s transitions and find good agreement, confirming the identification of the lithiumlike 1s2s2p 4P5/2-->1s22s 2S1/2 magnetic quadrupole line.

Sphingosine-1-phosphate (S1P) displays sustained S1P1 receptor agonism and signaling through S1P lyase-dependent receptor recycling.

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Gatfield, John; Monnier, Lucile; Studer, Rolf; Bolli, Martin H; Steiner, Beat; Nayler, Oliver

2014-07-01

The sphingosine-1-phosphate (S1P) type 1 receptor (S1P1R) is a novel therapeutic target in lymphocyte-mediated autoimmune diseases. S1P1 receptor desensitization caused by synthetic S1P1 receptor agonists prevents T-lymphocyte egress from secondary lymphoid organs into the circulation. The selective S1P1 receptor agonist ponesimod, which is in development for the treatment of autoimmune diseases, efficiently reduces peripheral lymphocyte counts and displays efficacy in animal models of autoimmune disease. Using ponesimod and the natural ligand S1P, we investigated the molecular mechanisms leading to different signaling, desensitization and trafficking behavior of S1P1 receptors. In recombinant S1P1 receptor-expressing cells, ponesimod and S1P triggered Gαi protein-mediated signaling and β-arrestin recruitment with comparable potency and efficiency, but only ponesimod efficiently induced intracellular receptor accumulation. In human umbilical vein endothelial cells (HUVEC), ponesimod and S1P triggered translocation of the endogenous S1P1 receptor to the Golgi compartment. However, only ponesimod treatment caused efficient surface receptor depletion, receptor accumulation in the Golgi and degradation. Impedance measurements in HUVEC showed that ponesimod induced only short-lived Gαi protein-mediated signaling followed by resistance to further stimulation, whereas S1P induced sustained Gαi protein-mediated signaling without desensitization. Inhibition of S1P lyase activity in HUVEC rendered S1P an efficient S1P1 receptor internalizing compound and abrogated S1P-mediated sustained signaling. This suggests that S1P lyase - by facilitating S1P1 receptor recycling - is essential for S1P-mediated sustained signaling, and that synthetic agonists are functional antagonists because they are not S1P lyase substrates. Copyright © 2014 Elsevier Inc. All rights reserved.

Intracellular S1P Generation Is Essential for S1P-Induced Motility of Human Lung Endothelial Cells: Role of Sphingosine Kinase 1 and S1P Lyase

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Berdyshev, Evgeny V.; Gorshkova, Irina; Usatyuk, Peter; Kalari, Satish; Zhao, Yutong; Pyne, Nigel J.; Pyne, Susan; Sabbadini, Roger A.; Garcia, Joe G. N.; Natarajan, Viswanathan

2011-01-01

Background Earlier we have shown that extracellular sphingosine-1-phosphate (S1P) induces migration of human pulmonary artery endothelial cells (HPAECs) through the activation of S1P1 receptor, PKCε, and PLD2-PKCζ-Rac1 signaling cascade. As endothelial cells generate intracellular S1P, here we have investigated the role of sphingosine kinases (SphKs) and S1P lyase (S1PL), that regulate intracellular S1P accumulation, in HPAEC motility. Methodology/Principal Findings Inhibition of SphK activity with a SphK inhibitor 2-(p-Hydroxyanilino)-4-(p-Chlorophenyl) Thiazole or down-regulation of Sphk1, but not SphK2, with siRNA decreased S1Pint, and attenuated S1Pext or serum-induced motility of HPAECs. On the contrary, inhibition of S1PL with 4-deoxypyridoxine or knockdown of S1PL with siRNA increased S1Pint and potentiated motility of HPAECs to S1Pext or serum. S1Pext mediates cell motility through activation of Rac1 and IQGAP1 signal transduction in HPAECs. Silencing of SphK1 by siRNA attenuated Rac1 and IQGAP1 translocation to the cell periphery; however, knockdown of S1PL with siRNA or 4-deoxypyridoxine augmented activated Rac1 and stimulated Rac1 and IQGAP1 translocation to cell periphery. The increased cell motility mediated by down-regulation was S1PL was pertussis toxin sensitive suggesting “inside-out” signaling of intracellularly generated S1P. Although S1P did not accumulate significantly in media under basal or S1PL knockdown conditions, addition of sodium vanadate increased S1P levels in the medium and inside the cells most likely by blocking phosphatases including lipid phosphate phosphatases (LPPs). Furthermore, addition of anti-S1P mAb to the incubation medium blocked S1Pext or 4-deoxypyridoxine-dependent endothelial cell motility. Conclusions/Significance These results suggest S1Pext mediated endothelial cell motility is dependent on intracellular S1P production, which is regulated, in part, by SphK1 and S1PL. PMID:21304987

The elusive 2s3s1S level in B II

International Nuclear Information System (INIS)

Martinson, I; Awaya, Y; Ekberg, J O; Kink, I; Mannervik, S; Ryabtsev, A N

2003-01-01

It has been known for nearly 30 years that the theoretical and experimental values for the energy of the 2s3s 1 S level in singly ionized boron, B II, differ strongly. Since there is much better agreement for other B II levels, it has been concluded that the experimental value for 2s3s 1 S must be revised. Despite a number of recordings over the years of sliding-spark, hollow cathode and beam-foil spectra, this level has not been located. We have now performed another beam-foil experiment, using higher resolution and sensitivity than in most previous studies. By combining these new data with previous results, we have identified transitions from the 2s4p, 2s5p and 2p3s 1 P levels to 2s3s 1 S, the excitation energy (137 622 ± 3 cm -1 ) of which is now well established and in excellent agreement with theoretical predictions

Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human.

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Sato, Masaya; Ikeda, Hitoshi; Uranbileg, Baasanjav; Kurano, Makoto; Saigusa, Daisuke; Aoki, Junken; Maki, Harufumi; Kudo, Hiroki; Hasegawa, Kiyoshi; Kokudo, Norihiro; Yatomi, Yutaka

2016-08-26

The role of sphingosine 1-phosphate (S1P) in liver fibrosis or inflammation was not fully examined in human. Controversy exists which S1P receptors, S1P1 and S1P3 vs S1P2, would be importantly involved in its mechanism. To clarify these matters, 80 patients who received liver resection for hepatocellular carcinoma and 9 patients for metastatic liver tumor were enrolled. S1P metabolism was analyzed in background, non-tumorous liver tissue. mRNA levels of sphingosine kinase 1 (SK1) but not SK2 were increased in livers with fibrosis stages 3-4 compared to those with 0-2 and to normal liver. However, S1P was not increased in advanced fibrotic liver, where mRNA levels of S1P transporter spinster homolog 2 (SPNS2) but not S1P-degrading enzymes were enhanced. Furthermore, mRNA levels of S1P2 but not S1P1 or S1P3 were increased in advanced fibrotic liver. These increased mRNA levels of SK1, SPNS2 and S1P2 in fibrotic liver were correlated with α-smooth muscle actin mRNA levels in liver, and with serum ALT levels. In conclusion, S1P may be actively generated, transported to outside the cells, and bind to its specific receptor in human liver to play a role in fibrosis or inflammation. Altered S1P metabolism in fibrotic liver may be their therapeutic target.

Blocking S1P interaction with S1P1 receptor by a novel competitive S1P1-selective antagonist inhibits angiogenesis

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Fujii, Yasuyuki; Ueda, Yasuji; Ohtake, Hidenori; Ono, Naoya; Takayama, Tetsuo; Nakazawa, Kiyoshi; Igarashi, Yasuyuki; Goitsuka, Ryo

2012-01-01

Highlights: ► The effect of a newly developed S1P 1 -selective antagonist on angiogenic responses. ► S1P 1 is a critical component of VEGF-related angiogenic responses. ► S1P 1 -selective antagonist showed in vitro activity to inhibit angiogenesis. ► S1P 1 -selective antagonist showed in vivo activity to inhibit angiogenesis. ► The efficacy of S1P 1 -selective antagonist for anti-cancer therapies. -- Abstract: Sphingosine 1-phosphate receptor type 1 (S1P 1 ) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P 1 and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P 1 -selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P 1 antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P 1 is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

Sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis is involved in liver fibrosis-associated angiogenesis.

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Yang, Le; Yue, Shi; Yang, Lin; Liu, Xin; Han, Zhen; Zhang, Yuanyuan; Li, Liying

2013-07-01

Sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) axis is involved in multiple biological processes, including liver fibrosis. Angiogenesis is an important pathophysiological process closely associated with liver fibrosis; however, the functional role of SphK/S1P/S1PR in this process remains incompletely defined. Bile duct ligation or carbon tetrachloride was used to induce liver fibrosis in mice. Human fibrotic samples were obtained from livers of patients undergoing liver transplantation. S1P levels in the liver were examined by HPLC. Expression of angiogenic markers, including angiopoietin 1, CD31, vascular cell adhesion molecule-1, and von Willebrand factor, was characterized by immunofluorescence, real-time RT-PCR, and Western blot in the fibrotic liver and primary mouse hepatic stellate cells (HSCs). SphK inhibitor (SKI) or S1PR antagonists were administered intraperitoneally in mice. S1P levels in the liver were closely correlated with mRNA expression of angiogenic markers. Ang1 is expressed in activated HSCs of the fibrotic liver and in primary HSCs. In HSCs, by using specific antagonists or siRNAs, we demonstrated S1P stimulation induced Ang1 expression via S1PR1 and S1PR3. In vivo, S1P reduction by SKI inhibited angiogenesis in fibrotic mice. Furthermore, S1PR1/3 antagonist significantly blocked upregulation of angiogenic markers in the injured liver, and attenuated the extent of liver fibrosis, while S1PR2 antagonist had no effect on angiogenesis, supporting the key role of S1PR1 and S1PR3 in angiogenesis underlying liver fibrosis process. SphK1/S1P/S1PR1/3 axis plays a crucial role in the angiogenic process required for fibrosis development, which may represent an effective therapeutic strategy for liver fibrosis. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Sphingosine kinase 1/sphingosine-1-phosphate (S1P)/S1P receptor axis is involved in ovarian cancer angiogenesis.

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Dai, Lan; Liu, Yixuan; Xie, Lei; Wu, Xia; Qiu, Lihua; Di, Wen

2017-09-26

Sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) signaling pathway has been implicated in a variety of pathological processes of ovarian cancer. However, the function of this axis in ovarian cancer angiogenesis remains incompletely defined. Here we provided the first evidence that SphK1/S1P/S1PR 1/3 pathway played key roles in ovarian cancer angiogenesis. The expression level of SphK1, but not SphK2, was closely correlated with the microvascular density (MVD) of ovarian cancer tissue. In vitro , the angiogenic potential and angiogenic factor secretion of ovarian cancer cells could be attenuated by SphK1, but not SphK2, blockage and were restored by the addition of S1P. Moreover, in these cells, we found S1P stimulation induced the angiogenic factor secretion via S1PR 1 and S1PR 3 , but not S1PR 2 . Furthermore, inhibition of S1PR 1/3 , but not S1PR 2 , attenuated the angiogenic potential and angiogenic factor secretion of the cells. in vivo , blockage of SphK or S1PR 1/3 could attenuate ovarian cancer angiogenesis and inhibit angiogenic factor expression in mouse models. Collectively, the current study showed a novel role of SphK1/S1P/S1PR 1/3 axis within the ovarian cancer, suggesting a new target to block ovarian cancer angiogenesis.

Quenching of 4He(21S,21P) and 3He(21S,21P) states by collisions with Ne(1S0) atoms

International Nuclear Information System (INIS)

Blagoev, K.B.; Dimova, E.; Petrov, G.M.

2004-01-01

The cross sections and rate constants for quenching 4 He(2 1 S), 4 He(2 1 P), 3 He(2 1 S) and 3 He(2 1 P) states by collisions with ground state Ne atoms are measured by a time-resolved method in a He-Ne electron beam excited plasma at low pressure. These rate constants at T g =600 K are: k 4 He(2 1 S) =(1.6±0.2)x10 -10 , k 4 He(2 1 P) =(3.4±2.5)x10 -10 , k 3 He(2 1 S) =(1.6±0.2)x10 -10 and k 3 He(2 1 P) =(5.7±1.2)x10 -10 cm 3 s -1 . The cross sections derived from the rate constant are σ 4 He(2 1 S) =(8.4±0.8)x10 -16 , σ 4 He(2 1 P) =(1.8±1.3)x10 -15 , σ 3 He(2 1 S) =(7.1±0.9)x10 -16 and σ 3 He(2 1 P) =(2.6±0.5)x10 -15 cm 2 , respectively. The diffusion coefficient of 3 He(2 1 S) in 3 He is estimated to be D 3 He(2 1 S)- 3 He =1.9D 4 He(2 1 S)- 4 He , based on comparison with 4 He. A time-dependent collisional radiative model for an e-beam sustained He-Ne plasma is developed and the predicted line intensity of NeI λ=6328 A line is compared with the experimental data. The influence of different processes involved in population and depopulation dynamics of He(2 1 S) state are evaluated

Long-term impact of radiation on plasma concentrations of cytokines (IL-1 and IL-6) and adhesion molecules (ICAM-1 and P-selectin) in Chernobyl clean-up workers from Latvia

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Kurjane, N.; Kirsfinks, M.; Hagina, E.; Socnevs, A.

2001-01-01

Study was undertaken to evaluate plasma concentrations of interleukin-1beta (IL-1), interleukin-6 (IL-6), and adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and P-selectin in persons who participated in the clean-up work of the Chernobyl NPP explosion aftereffects. 40 Chernobyl clean-up workers suffering from most common neurological diseases - polyneuropathy and encephalopathy, and 40 healthy blood donors were analyzed for plasma levels of IL-6, IL1-β, sICAM-1 and sP-selectin 13 years after the accident. The documented external radiation dosage to the investigated Chernobyl clean-up workers was exposed from 0,009 to 0,28 Gy. Significantly elevated plasma concentrations of IL-6 and P-selectin but not of IL-1β were found in Chernobyl clean-up labourers as compared to those in healthy blood donors. (p<0.01). There was no obvious association of cytokine and adhesion molecule levels with radiation doses, as individuals working in the Chernobyl area in 1986 at a time when the external radiation exposure was higher revealed similar plasma concentrations if compared to those of a later period of time (1987-1990). (authors)

[Role and related mechanism of S1P/S1P1 signal pathway during post conditioning of hypertrophic cardiomyocytes].

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Bao, X H; Li, H X; Tao, J; Li, X M; Yang, Y N; Ma, Y T; Chen, B D

2016-05-24

To study the role and mechanism of sphingosine-1-phosphate (S1P)/ sphingosine-1-phosphate receptor 1(S1P1) signal pathway during post conditioning of hypertrophic cardiomyocytes. Neonatal rat cardiomyocytes were isolated and cultured, then stimulated by norepinephrine (NE) to induce cardiomyocytes hypertrophy. Using tri-gas incubator to create hypoxia and reoxygenation enviroment to mimic ischemia-reperfusion and postconditioning. Hypertrophic cardiomyoctyes were divided into five groups according to the presence or absence of various drugs and postconditiong and relevant signal pathways changes were detected: (1) IPost group (hypoxia+ postconditioning); (2) IPost+ S1P group (cells were pretreated with S1P (1 μmol/L) for 2 h before IPost); (3) IPost+ W-146+ S1P group (cells in IPost+ W-146+ S1P group were pretreated with S1P1 inhibitor W-146 (0.4 μmol/L) for 20 min); (4) IPost+ PD98059+ S1P group (cells in IPost+ S1P group were pretreated with MAPK antagonist PD98059 (125 μmol/L) for 20 min); (5) IPost+ LY-294002+ S1P group (cells in IPost+ S1P group were pretreated with PI3K antagonist LY294002 (0.1 μmol/L) for 20 min). Apoptosis was detected by flow cytometry and protein expression of relevant signal pathways were detected by Western blot. (1)Apoptosis rate was significantly increased in hypoxia/reoxygenation (27.90±4.49)% group compared with normal control group (7.97±2.18)%, which could be significantly reduced in IPost group (15.90±1.77)% (all PS1P and IPost+ S1P+ LY-294002 groups than in IPost and IPost+ S1P+ W-146 and IPost+ S1P+ PD98059 group (all PS1P and IPost+ S1P+ LY-294002 group than in IPost and IPost+ S1P+ W-146 group and IPost+ S1P+ PD98059 group (all PS1P+ W-146 and IPost+ S1P+ PD98059 groups. p-ERK1/2 and p-Akt levels in IPost+ S1P+ W-146 group and IPost+ S1P+ PD98059 were similar as in IPost group. S1P can play protective role on NE induced cardiomyocytes hypertrophy during post conditioning through downregulating caspase-3 expression and

First evidence of SGPL1 expression in the cell membrane silencing the extracellular S1P siren in mammary epithelial cells.

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Engel, Nadja; Adamus, Anna; Frank, Marcus; Kraft, Karin; Kühn, Juliane; Müller, Petra; Nebe, Barbara; Kasten, Annika; Seitz, Guido

2018-01-01

The bioactive lipid sphingosine-1-phosphate (S1P) is a main regulator of cell survival, proliferation, motility, and platelet aggregation, and it is essential for angiogenesis and lymphocyte trafficking. In that S1P acts as a second messenger intra- and extracellularly, it might promote cancer progression. The main cause is found in the high S1P concentration in the blood, which encourage cancer cells to migrate through the endothelial barrier into the blood vessels. The irreversible degradation of S1P is solely caused by the sphingosine-1-phosphate lyase (SGPL1). SGPL1 overexpression reduces cancer cell migration and therefore silences the endogenous S1P siren, which promotes cancer cell attraction-the main reason for metastasis. Since our previous metabolomics studies revealed an increased SGPL1 activity in association with successful breast cancer cell treatment in vitro, we further investigated expression and localization of SGPL1. Expression analyses confirmed a very low SGPL1 expression in all breast cancer samples, regardless of their subtype. Additionally, we were able to prove a novel SGPL expression in the cytoplasm membrane of non-tumorigenic breast cells by fusing three independent methods. The general SGPL1 downregulation and the loss of the plasma membrane expression resulted in S1P dependent stimulation of migration in the breast cancer cell lines MCF-7 and BT-20. Not only S1P stimulated migration could be repressed by overexpressing the natural SGPL1 variant not but also more general migratory activity was significantly reduced. Here, for the first time, we report on the SGPL1 plasma membrane location in human, non-malignant breast epithelial cell lines silencing the extracellular S1P siren in vitro, and thereby regulating pivotal cellular functions. Loss of this plasma membrane distribution as well as low SGPL1 expression levels could be a potential prognostic marker and a viable target for therapy. Therefore, the precise role of SGPL1 for cancer

First evidence of SGPL1 expression in the cell membrane silencing the extracellular S1P siren in mammary epithelial cells.

Directory of Open Access Journals (Sweden)

Nadja Engel

Full Text Available The bioactive lipid sphingosine-1-phosphate (S1P is a main regulator of cell survival, proliferation, motility, and platelet aggregation, and it is essential for angiogenesis and lymphocyte trafficking. In that S1P acts as a second messenger intra- and extracellularly, it might promote cancer progression. The main cause is found in the high S1P concentration in the blood, which encourage cancer cells to migrate through the endothelial barrier into the blood vessels. The irreversible degradation of S1P is solely caused by the sphingosine-1-phosphate lyase (SGPL1. SGPL1 overexpression reduces cancer cell migration and therefore silences the endogenous S1P siren, which promotes cancer cell attraction-the main reason for metastasis. Since our previous metabolomics studies revealed an increased SGPL1 activity in association with successful breast cancer cell treatment in vitro, we further investigated expression and localization of SGPL1. Expression analyses confirmed a very low SGPL1 expression in all breast cancer samples, regardless of their subtype. Additionally, we were able to prove a novel SGPL expression in the cytoplasm membrane of non-tumorigenic breast cells by fusing three independent methods. The general SGPL1 downregulation and the loss of the plasma membrane expression resulted in S1P dependent stimulation of migration in the breast cancer cell lines MCF-7 and BT-20. Not only S1P stimulated migration could be repressed by overexpressing the natural SGPL1 variant not but also more general migratory activity was significantly reduced. Here, for the first time, we report on the SGPL1 plasma membrane location in human, non-malignant breast epithelial cell lines silencing the extracellular S1P siren in vitro, and thereby regulating pivotal cellular functions. Loss of this plasma membrane distribution as well as low SGPL1 expression levels could be a potential prognostic marker and a viable target for therapy. Therefore, the precise role of

Sphingosine 1-phosphate (S1P) suppresses the collagen-induced activation of human platelets via S1P4 receptor.

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Onuma, Takashi; Tanabe, Kumiko; Kito, Yuko; Tsujimoto, Masanori; Uematsu, Kodai; Enomoto, Yukiko; Matsushima-Nishiwaki, Rie; Doi, Tomoaki; Nagase, Kiyoshi; Akamatsu, Shigeru; Tokuda, Haruhiko; Ogura, Shinji; Iwama, Toru; Kozawa, Osamu; Iida, Hiroki

2017-08-01

Sphingosine 1-phosphate (S1P) is as an extracellular factor that acts as a potent lipid mediator by binding to specific receptors, S1P receptors (S1PRs). However, the precise role of S1P in human platelets that express S1PRs has not yet been fully clarified. We previously reported that heat shock protein 27 (HSP27) is released from human platelets accompanied by its phosphorylation stimulated by collagen. In the present study, we investigated the effect of S1P on the collagen-induced platelet activation. S1P pretreatment markedly attenuated the collagen-induced aggregation. Co-stimulation with S1P and collagen suppressed collagen-induced platelet activation, but the effect was weaker than that of S1P-pretreatment. The collagen-stimulated secretion of platelet-derived growth factor (PDGF)-AB and the soluble CD40 ligand (sCD40L) release were significantly reduced by S1P. In addition, S1P suppressed the collagen-induced release of HSP27 as well as the phosphorylation of HSP27. S1P significantly suppressed the collagen-induced phosphorylation of p38 mitogen-activated protein kinase. S1P increased the levels of GTP-bound Gαi and GTP-bound Gα13 coupled to S1PPR1 and/or S1PR4. CYM50260, a selective S1PR4 agonist, but not SEW2871, a selective S1PR1 agonist, suppressed the collagen-stimulated platelet aggregation, PDGF-AB secretion and sCD40L release. In addition, CYM50260 reduced the release of phosphorylated-HSP27 by collagen as well as the phosphorylation of HSP27. The selective S1PR4 antagonist CYM50358, which failed to affect collagen-induced HSP27 phosphorylation, reversed the S1P-induced attenuation of HSP27 phosphorylation by collagen. These results strongly suggest that S1P inhibits the collagen-induced human platelet activation through S1PR4 but not S1PR1. Copyright © 2017 Elsevier Ltd. All rights reserved.

ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs.

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Ren, Kun; Lu, Yan-Ju; Mo, Zhong-Cheng; -Liu, Xing; Tang, Zhen-Li; Jiang, Yue; Peng, Xiao-Shan; Li, Li; Zhang, Qing-Hai; Yi, Guang-Hui

2017-05-01

Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-κB (NF-κB) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway.

Impact of Delayed Whole Blood Processing Time on Plasma Levels of miR-1 and miR-423-5p up to 24 Hours.

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Borges, Danielle Pazzotti; Cunha-Neto, Edecio; Bocchi, Edimar A; Rigaud, Vagner Oliveira Carvalho

2018-03-21

Circulating cell-free miRNAs hold great promise as a new class of biomarkers due to their high stability in body fluids and association with disease stages. However, even using sensitive and specific methods, technical challenges are associated with miRNA analysis in body fluids. A major source of variation in plasma and serum is the potential cell-derived miRNA contamination from hemolysis. To evaluate the effect of the delayed whole blood processing time on the concentrations of miR-1 and -423-5p. Ten blood samples were incubated for 0, 3 and 24 hours at room temperature prior processing into plasma. For each time point, hemolysis was assessed in plasma by UV spectrophotometry at 414nm wavelength (λ414). Circulating levels of miR-1 and -423-5p were measured by RT-qPCR; miR-23a and -451 were also analyzed as controls. A significant hemolysis was observed only after 24h (λ414 0.3±0.02, plevels were observed up to 24h of storage at room temperature (Ct 31.5±0.5 to 31.8±0.6for miR-1, p=0.989; and 29.01±0.3 to 29.04±0.3, p=0.614 for -423-5p). No correlation was observed between hemolysis and levels of miR-1 and -423-5p. Our data indicate the storage of whole blood samples at room temperature for up to 24h prior their processing into plasma does not appear to have a significant impact on miR-1 and -423-5p concentrations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

PAI-1 4G/5G polymorphism and plasma levels association in patients with coronary artery disease.

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Lima, Luciana Moreira; Carvalho, Maria das Graças; Fonseca Neto, Cirilo Pereira; Garcia, José Carlos Faria; Sousa, Marinez Oliveira

2011-12-01

Type-1 plasminogen activator inhibitor (PAI-1) 4G/5G polymorphism may influence the PAI-1 expression. High plasma levels of PAI-1 are associated with coronary artery disease (CAD). This study investigated the influence of PAI-1 4G/5G polymorphism on plasma PAI-1 levels and its association with CAD assessed by coronary angiography. Blood sample of 35 individuals with angiographically normal coronary arteries, 31 individuals presenting mild/moderate atheromatosis, 57 individuals presenting severe atheromatosis and 38 healthy individuals (controls) were evaluated. In patients and controls, the PAI-1 4G/5G polymorphism was determined by PCR amplification using allele-specific primers. Plasma PAI-1 levels were quantified by ELISA assay (American Diagnostica). No difference was found between groups regarding age, gender and body mass index. Plasma PAI-1 levels and 4G/4G genotype frequency were significantly higher in the severe atheromatosis group compared to the other groups (p5G/5G genotype (r=0.02, p=0.4511). In addition, in a multiple logistic regression model, adjusted for all the other variables, PAI-1 was observed to be independently associated with CAD > 70% (p<0.001). The most important finding of this study was the association between 4G/4G genotype, high plasma PAI-1 levels and coronary stenosis higher than 70% in Brazilian individuals. Whether high plasma PAI-1 levels are a decisive factor for atherosclerosis worsening or it is a consequence remains to be established.

[Substance P and vasoactive intestinal peptide in patients with progressive scleroderma. Determination of plasma level before and after autogenic training].

Science.gov (United States)

Haustein, U F; Weber, B; Seikowski, K

1995-02-01

In 12 patients suffering from systemic sclerosis (SSc) the influence of autogenic training on the plasma level of the neuropeptides substance P and vasoactive intestinal peptide (VIP) was studied. Compared with healthy controls the SSc patients exhibited significantly elevated levels of substance P (mean +/- SD: 7.1 +/- 3.2 pmol/l vs 1.6 +/- 1.6 pmol/l). Apart from variations the VIP plasma concentration did not significantly differ from that in healthy controls (mean +/- SD 10.7 +/- 7.1 pmol/l versus 12.0 +/- 5.3 pmol/l). Autogenic training did not bring about any significant changes in the plasma levels of neuropeptides.

Blocking S1P interaction with S1P{sub 1} receptor by a novel competitive S1P{sub 1}-selective antagonist inhibits angiogenesis

Energy Technology Data Exchange (ETDEWEB)

Fujii, Yasuyuki, E-mail: y.fujii@po.rd.taisho.co.jp [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Ueda, Yasuji; Ohtake, Hidenori; Ono, Naoya; Takayama, Tetsuo; Nakazawa, Kiyoshi [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Igarashi, Yasuyuki [Laboratory of Biomembrane and Biofunctional Chemistry, Hokkaido University, Sapporo, Hokkaido 060-0812 (Japan); Goitsuka, Ryo [Division of Development and Aging, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022 (Japan)

2012-03-23

Highlights: Black-Right-Pointing-Pointer The effect of a newly developed S1P{sub 1}-selective antagonist on angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1} is a critical component of VEGF-related angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vitro activity to inhibit angiogenesis. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vivo activity to inhibit angiogenesis. Black-Right-Pointing-Pointer The efficacy of S1P{sub 1}-selective antagonist for anti-cancer therapies. -- Abstract: Sphingosine 1-phosphate receptor type 1 (S1P{sub 1}) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P{sub 1} and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P{sub 1}-selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P{sub 1} antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P{sub 1} is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

Ti 2p and O 1s core levels and chemical bonding in titanium-bearing oxides

International Nuclear Information System (INIS)

Atuchin, Victor V.; Kesler, Valery G.; Pervukhina, Natalia V.; Zhang, Zhaoming

2006-01-01

A set of available experimental data on the binding energies of Ti 2p 3/2 and O 1s core levels in titanium-bearing oxides has been presented by using the binding energy difference (O 1s-Ti 2p 3/2 ) as a robust parameter to characterize these compounds. An empirical relationship between the (O 1s-Ti 2p 3/2 ) values measured with XPS and the mean chemical bond length L(Ti-O) in these crystals has been discussed for Ti 4+ -compounds

Ti 2p and O 1s core levels and chemical bonding in titanium-bearing oxides

Energy Technology Data Exchange (ETDEWEB)

Atuchin, Victor V. [Laboratory of Optical Materials and Structures, Institute of Semiconductor Physics, SB RAS, Novosibirsk 630090 (Russian Federation)]. E-mail: atuchin@thermo.isp.nsc.ru; Kesler, Valery G. [Technical Centre, Institute of Semiconductor Physics, SB RAS, Novosibirsk 630090 (Russian Federation); Pervukhina, Natalia V. [Laboratory of Crystal Chemistry, Institute of Inorganic Chemistry, SB RAS, Novosibirsk 630090 (Russian Federation); Zhang, Zhaoming [Australian Nuclear Science and Technology Organisation, PMB 1, Menai, NSW 2234 (Australia)

2006-06-15

A set of available experimental data on the binding energies of Ti 2p{sub 3/2} and O 1s core levels in titanium-bearing oxides has been presented by using the binding energy difference (O 1s-Ti 2p{sub 3/2}) as a robust parameter to characterize these compounds. An empirical relationship between the (O 1s-Ti 2p{sub 3/2}) values measured with XPS and the mean chemical bond length L(Ti-O) in these crystals has been discussed for Ti{sup 4+}-compounds.

Plasma Endothelin-1 Levels in Preterm Neonatal Infants with Acute Respiratory Failure

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D. V. Dmitriyev

2008-01-01

Full Text Available Increased pulmonary vascular resistance in preterm infants is associated with acute respiratory failure (ARF and at the same time endothelin-1 (E-1 plays an important role in neonatal pulmonary vascular responsiveness. Methods. Endothelin-1 levels were measured in two blood samples in 12 preterm infants with ARF and in 12 controls (at 32.2±1.3 and 29.8±1.2 weeks of gestation, respectively by enzyme immunoassay. For this, the first and second blood samples were taken at 18 to 40 hours after birth. Results. The plasma level of E-1 in the first sample did not differ between the neonates of both groups. In the second sample, significantly higher E-1 concentrations were observed in the newborns with ARF than in the controls. In the first sample, E-1 concentration were higher than in the second one in both groups (p<0.001. There was a significant positive correlation between the second E-1 sample and the SNAPPE 2 scale rating (r=0.38; p=0.02. The plasma level of E-1 in the first sample did not differ in both groups (11.9 and 12.2 pg/ml, respectively. Conclusion. Neonates with and without ARF had the similar plasma E-1 levels in the first sample, by taking into account the fact that the E-1 levels were higher in ARF than in the controls at 18 to 40 hour after birth. Increased vascular resistance in ARF may be associated with the high level of E-1. Key words: endothe-lin-1, acute respiratory failure.

Theobroma cacao increases cells viability and reduces IL-6 and sVCAM-1 level in endothelial cells induced by plasma from preeclamptic patients.

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Rahayu, Budi; Baktiyani, Siti Candra Windu; Nurdiana, Nurdiana

2016-01-01

This study aims to investigate whether an ethanolic extract of Theobroma cacao bean is able to increase cell viability and decrease IL-6 and sVCAM-1 in endothelial cells induced by plasma from preeclamptic patients. Endothelial cells were obtained from human umbilical vascular endothelial cells. At confluency, endothelial cells were divided into six groups, which included control (untreated), endothelial cells exposed to plasma from normal pregnancy, endothelial cells exposed to 2% plasma from preeclamptic patients (PP), endothelial cells exposed to PP in the presence of ethanolic extract of T. cacao (PP+TC) at the following three doses: 25, 50, and 100 ppm. The analysis was performed in silico using the Hex 8.0, LigPlus and LigandScout 3.1 software. Analysis on IL-6 and sVCAM-1 levels were done by enzyme linked immunosorbent assay (ELISA). We found that seven of them could bind to the protein NFκB (catechin, leucoanthocyanidin, niacin, phenylethylamine, theobromine, theophylline, and thiamin). This increase in IL-6 was significantly (Pcacao extract. Plasma from PP significantly increased sVCAM-1 levels compared to untreated cells. This increase in sVCAM-1 was significantly attenuated by all doses of the extract. In conclusion, T. cacao extract prohibits the increase in IL-6 and sVCAM-1 in endothelial cells induced by plasma from preeclamptic patients. Therefore this may provide a herbal therapy for attenuating the endothelial dysfunction found in preeclampsia. Copyright © 2016 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.

Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer.

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Mahon, K L; Qu, W; Devaney, J; Paul, C; Castillo, L; Wykes, R J; Chatfield, M D; Boyer, M J; Stockler, M R; Marx, G; Gurney, H; Mallesara, G; Molloy, P L; Horvath, L G; Clark, S J

2014-10-28

Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.

PAI-1 mRNA expression and plasma level in rheumatoid arthritis: relationship with 4G/5G PAI-1 polymorphism.

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Muñoz-Valle, José Francisco; Ruiz-Quezada, Sandra Luz; Oregón-Romero, Edith; Navarro-Hernández, Rosa Elena; Castañeda-Saucedo, Eduardo; De la Cruz-Mosso, Ulises; Illades-Aguiar, Berenice; Leyva-Vázquez, Marco Antonio; Castro-Alarcón, Natividad; Parra-Rojas, Isela

2012-12-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane, cartilage and bone. PAI-1 is a key regulator of the fibrinolytic system through which plasminogen is converted to plasmin. The plasmin activates the matrix metalloproteinase system, which is closely related with the joint damage and bone destruction in RA. The aim of this study was to investigate the relationship between 4G/5G PAI-1 polymorphism with mRNA expression and PAI-1 plasma protein levels in RA patients. 113 RA patients and 123 healthy subjects (HS) were included in the study. The 4G/5G PAI-1 polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism method; the PAI-1 mRNA expression was determined by real-time PCR; and the soluble PAI-1 (sPAI-1) levels were quantified using an ELISA kit. No significant differences in the genotype and allele frequencies of 4G/5G PAI-1 polymorphism were found between RA patients and HS. However, the 5G/5G genotype was the most frequent in both studied groups: RA (42%) and HS (44%). PAI-1 mRNA expression was slightly increased (0.67 fold) in RA patients with respect to HS (P = 0.0001). In addition, in RA patients, the 4G/4G genotype carriers showed increased PAI-1 mRNA expression (3.82 fold) versus 4G/5G and 5G/5G genotypes (P = 0.0001), whereas the sPAI-1 plasma levels did not show significant differences. Our results indicate that the 4G/5G PAI-1 polymorphism is not a marker of susceptibility in the Western Mexico. However, the 4G/4G genotype is associated with high PAI-1 mRNA expression but not with the sPAI-1 levels in RA patients.

The Effect of Naloxone on Plasma ET-1 and CGRP Levels in Patients with Traumatic Brain Injury

International Nuclear Information System (INIS)

Zhang Chunyin; Guang Ming; Cai Liang; Chen Boxun; Gan Xilun

2009-01-01

To investigate the effect of naloxone on the changes of plasma ET-1 and CGRP levels in patients with traumatic brain injury, ninety patients with traumatic brain injury were randomly divided into naloxone treated group and conventionally treated group (both n=45). The plasma levels of ET-1 and CGRP in both groups before and after treatment and in 30 healthy controls were measured by RIA. The results showed that the plasma levels of ET-1 were significantly increased in the patient before treatment and decreased markedly after treatment in both groups. The magnitude of decrease of the plasma ET-1 levels in the naloxone treated group was significantly higher than that in the conventionally treated group (P<0.01). The plasma levels of CGRP were significantly decreased in the patients before treatment and increased markedly after treatment in both groups. The magnitude of increase of the plasma CGRP levels in the naloxone treated group was significantly higher than that in the conventionally treated group (P<0.01). The plasma ET-1 levels in patients with traumatic brain injury was remarkably increased and markedly decreased after treatment with naloxone. The plasma CGRP levels in patients with traumatic brain injury was remarkably decreased and markedly increased after treatment with naloxone. Naloxone has a favorable effect on patient with traumatic brain injury, it may protect the neural cells and improve their living quality. (authors)

PPARγ agonists upregulate sphingosine 1-phosphate (S1P) receptor 1 expression, which in turn reduces S1P-induced [Ca(2+)]i increases in renal mesangial cells.

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Koch, Alexander; Völzke, Anja; Puff, Bianca; Blankenbach, Kira; Meyer Zu Heringdorf, Dagmar; Huwiler, Andrea; Pfeilschifter, Josef

2013-11-01

We previously identified peroxisome proliferator-activated receptor gamma (PPARγ) agonists (thiazolidinediones, TZDs) as modulators of the sphingolipid metabolism in renal mesangial cells. TZDs upregulated sphingosine kinase 1 (SK-1) and increased the formation of intracellular sphingosine 1-phosphate (S1P), which in turn reduced the expression of pro-fibrotic connective tissue growth factor. Since S1P also acts as extracellular ligand at specific S1P receptors (S1PR, S1P1-5), we investigated here the effect of TZDs on S1PR expression in mesangial cells and evaluated the functional consequences by measuring S1P-induced increases in intracellular free Ca(2+) concentration ([Ca(2+)]i). Treatment with two different TZDs, troglitazone and rosiglitazone, enhanced S1P1 mRNA and protein expression in rat mesangial cells, whereas S1P2-5 expression levels were not altered. Upregulation of S1P1 mRNA upon TZD treatment was also detected in human mesangial cells and mouse glomeruli. PPARγ antagonism and promoter studies revealed that the TZD-dependent S1P1 mRNA induction involved a functional PPAR response element in the S1P1 promoter. Pharmacological approaches disclosed that S1P-induced [Ca(2+)]i increases in rat mesangial cells were predominantly mediated by S1P2 and S1P3. Interestingly, the transcriptional upregulation of S1P1 by TZDs resulted in a reduction of S1P-induced [Ca(2+)]i increases, which was reversed by the S1P1/3 antagonist VPC-23019, the protein kinase C (PKC) inhibitor PKC-412, and by S1P1 siRNA. These data suggest that PPARγ-dependent upregulation of S1P1 leads to an inhibition of S1P-induced Ca(2+) signaling in a PKC-dependent manner. Overall, these results reveal that TZDs not only modulate intracellular S1P levels but also regulate S1PR signaling by increasing S1P1 expression in mesangial cells. © 2013.

Radioimmunoassay of Human Thyrotropin - Part 1. Plasma TSH levels in various thyroid functions

International Nuclear Information System (INIS)

Koh, Chang Soon; Lee, Hong Kyu; Ro, Heung Kyu; Lee, Mun Ho

1972-01-01

The radioimmunoassay of human thyrotropin was performed in various thyroid states, utilizing the anti-h-T.S.H. antibody and purified human thyrotropin supplied from National Institute of Arthritis and Metabolic Diseases, Bethesda, Ma., U.S.A., and human thyrotropin standard-A obtained from National Institute for Biologic Standards, Mill Hill, London, England. 131 I labelled h-TSH was prepared after the Chloramine-T method of Greenwood et al. This double antibody system had a assay sensitivity of about l. 0 μU/ml of plasma HTS-A and could detect the plasma h-TSH level in the euthyroid patients. Plasma h-TSH level of the normal 26 Korean was l.1±0. 83 μU/ml, and that of the 8 hypothyroidisms were 8.3 to 67.5 μU/ml. In hyperthyroidisms, no cases showed the plasma h-TSH levels over l. 0 μU/ ml. Between the hypothyroidism and euthyroidism, no overlap is noticed on plasma h-TSH levels. A case of transient hypothyroid state identified by determination of plasma h-TSH level is presented. These results revealed that the radioimmunoassay of h-TSH in plasma could be a sensitive method to diagnose the hypothyroidism, if not caused by a pituitary disease.

Ionization Spectroscopic Measurement of nP Rydberg Levels of 87Rb Cold Atoms

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Li, Yufan; Zaheeruddin, Syed; Zhao, Dongmei; Ma, Xinwen; Yang, Jie

2018-05-01

We created an ultracold plasma via the spontaneous ionization of cold dense Rydberg atoms of 87Rb in a magneto-optical trap (MOT), and measured the nS1/2 (n = 50-80), nP1/2 (n = 16-23), nP3/2 (n = 16-98), and nD5/2 (n = 49-96) Rydberg levels by detecting the electrons in the ultracold plasma. By fitting the energy levels of Rydberg states, the first ionization potential of 33690.950(11) cm-1 and the quantum defects of S, P, and D orbitals were obtained. The absolute transition energies of nS1/2 (n = 66-80), nP1/2 (n = 16-23), nP3/2 (n = 16-98), and nD5/2 (n = 58-96) states of 87Rb, as well as the quantum defects for p1/2 and p3/2 series, are given for the first time.

Plasma Monocyte Chemoattractant Protein-1 Level as a Predictor of the Severity of Community-Acquired Pneumonia

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Kok-Khun Yong

2016-01-01

Full Text Available Monocyte chemoattractant protein (MCP-1 increases in the serum of immunocompetent patients with community-acquired pneumonia (CAP. However, the correlation between the circulating level of MCP-1 and severity of CAP remains unclear. This study investigated differential changes in the plasma MCP-1 levels of patients with CAP before and after an antibiotic treatment and further analyzes the association between the CAP severity and MCP-1 levels. We measured the plasma MCP-1 levels of 137 patients with CAP and 74 healthy controls by using a commercial enzyme-linked immunosorbent assay. Upon initial hospitalization, Acute Physiology and Chronic Health Evaluation II (APACHE II; confusion, urea level, respiratory rate, blood pressure, and age of >64 years (CURB-65; and pneumonia severity index (PSI scores were determined for assessing the CAP severity in these patients. The antibiotic treatment reduced the number of white blood cells (WBCs and neutrophils as well as the level of C-reactive protein (CRP and MCP-1. The plasma MCP-1 level, but not the CRP level or WBC count, correlated with the CAP severity according to the PSI (r = 0.509, p < 0.001, CURB-65 (r = 0.468, p < 0.001, and APACHE II (r = 0.360, p < 0.001 scores. We concluded that MCP-1 levels act in the development of CAP and are involved in the severity of CAP.

Plasma plasminogen activator inhibitor-1 levels and nonalcoholic fatty liver in individuals with features of metabolic syndrome.

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de Larrañaga, Gabriela; Wingeyer, Silvia Perés; Graffigna, Mabel; Belli, Susana; Bendezú, Karla; Alvarez, Silvia; Levalle, Oscar; Fainboim, Hugo

2008-07-01

Fatty liver represents the liver component of metabolic syndrome and may be involved in plasminogen activator inhibitor-1 (PAI-1) synthesis. We studied plasma PAI-1 levels and relationships with risk factors for metabolic syndrome, including fatty liver, in 170 patients. Liver ultrasound scan was performed on all patients, and a liver biopsy was performed on those patients with chronically elevated transaminase levels. Plasma PAI-1 levels correlated significantly (P < .05) with body mass index, degree of steatosis, insulin resistance, insulin level, waist circumference, triglycerides, and high-density lipoprotein (HDL) -cholesterol. However, only body mass index (beta = .455) and HDL-cholesterol (beta = .293) remained predictors of PAI-1 levels. Liver biopsy revealed a significant correlation (P < .05) between insulin resistance (r = 0.381) or insulin level (r = 0.519) and liver fibrosis. In patients presenting features of metabolic syndrome, plasma PAI-1 levels were mainly conditioned by the whole-body fat content.

Quasimolecular emission near the Xe(5p 56s 1,3 P 1 - 5p 6 1 S 0) and Kr (4p 55s 1,3 P 1 - 4p 6 1 S 0) resonance lines induced by collisions with He atoms

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Alekseeva, O. S.; Devdariani, A. Z.; Grigorian, G. M.; Lednev, M. G.; Zagrebin, A. L.

2017-02-01

This study is devoted to the theoretical investigation of the quasimolecular emission of Xe*-He and Kr*-He collision pairs near the Xe (5p 56s 1,3 P 1 - 5p 6 1 S 0) and Kr (4p 55s 1,3 P 1 - 4p 6 1 S 0) resonance atomic lines. The potential curves of the quasimolecules Xe(5p 56s) + He and Kr(4p 55s) + He have been obtained with the use of the effective Hamiltonian and pseudopotential methods. Based on these potential curves the processes of quasimolecular emission of Xe*+He and Kr*+He mixtures have been considered and the spectral distributions I(ħΔω) of photons emitted have been obtained in the framework of quasistatic approximation.

Phospholipid transfer protein deficiency decreases the content of S1P in HDL via the loss of its transfer capability.

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Yu, Yang; Guo, Shoudong; Feng, Yumei; Feng, Lei; Cui, Yingjie; Song, Guohua; Luo, Tian; Zhang, Ke; Wang, Yiwei; Jiang, Xian-Cheng; Qin, Shucun

2014-02-01

Sphingosine-1-phosphate (S1P) is an amphiphilic signaling molecule, which is enriched in functional high density lipoprotein (HDL) and shows arterial protection. The distribution of S1P is changed with increased plasma phospholipid transfer protein (PLTP) activity and impaired HDL function in patients with coronary heart diseases. Therefore, we hypothesized that PLTP might transfer S1P among cells or lipoproteins. We found that plasma S1P contents were decreased by 60.1 % in PLTP knockout mice (PLTP-/-, N = 5) compared with their wild type littermates (WT, N = 5) (151.70 ± 38.59 vs. 379.32 ± 59.90 nmol/l, PS1P content in HDL fraction (HDL-S1P) from PLTP-/- was decreased by 64.7 % compared with WT (49.36 ± 1.49 vs. 139.76 ± 2.94 nmol/l, PS1P transfer assay indicated that PLTP could facilitate S1P transport from erythrocytes to HDL at 37 °C in D-Hanks buffer. Plasma content of apolipoprotein M, a specific adaptor of S1P, was not changed in PLTP-/- compared with WT. Therefore, we concluded that PLTP was a key factor to maintain plasma HDL-S1P, and PLTP deficiency could decrease the S1P content in plasma lipoproteins, which involves its capability of transferring S1P from erythrocyte to HDL.

Risk of classical Kaposi sarcoma by plasma levels of Epstein-Barr virus antibodies, sCD26, sCD23 and sCD30

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Viviano Enza

2010-10-01

Full Text Available Abstract Background To clarify the immunological alterations leading to classical Kaposi sarcoma (cKS among people infected with KS-associated herpesvirus (KSHV. Methods In a population-based study of 119 cKS cases, 105 KSHV-seropositive controls, and 155 KSHV-seronegative controls, we quantified plasma soluble cluster of differentiation (sCD levels and antibodies against Epstein-Barr virus nuclear antigen-1 (anti-EBNA-1 and viral capsid antigen (anti-VCA. Differences between groups in prevalence of low-tertile anti-EBNA-1 and high-tertile anti-VCA were compared by logistic regression. Continuous levels between groups and by presence of cKS co-factors among controls were compared by linear regression and Mann-Whitney-Wilcoxon methods. Results Comparisons of cKS cases to seropositive controls and of seropositive to seronegative controls revealed no significant differences. However, controls with known cKS cofactors (male sex, nonsmoking, diabetes and cortisone use had significantly lower levels of anti-EBNA (P = 0.0001 - 0.07 and anti-VCA (P = 0.0001 - 0.03. Levels of sCD26 were significantly lower for male and non-smoking controls (Padj ≤ 0.03, and they were marginally lower with older age and cortisone use (Padj ≤ 0.09. Conclusions Anti-EBV and sCD26 levels were associated with cofactors for cKS, but they did not differ between cKS cases and matched controls. Novel approaches and broader panels of assays are needed to investigate immunological contributions to cKS.

Role of sphingosine 1-phosphate (S1P and effects of fingolimod, an S1P receptor 1 functional antagonist in lymphocyte circulation and autoimmune diseases

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Kenji Chiba

2014-11-01

Full Text Available Sphingosine 1-phosphate (S1P, a multi-functional phospholipid mediator, is generated from sphingosine by sphingosine kinases and binds to five known G protein-coupled S1P receptors (S1P1, S1P2, S1P3, S1P4, and S1P5. It is widely accepted that S1P receptor 1 (S1P1 plays an essential role in lymphocyte egress from the secondary lymphoid organs (SLO and thymus, because lymphocyte egress from these organs to periphery is at extremely low levels in mice lacking lymphocytic S1P1. Fingolimod hydrochloride (FTY720 is a first-in-class, orally active S1P1 functional antagonist which was discovered by chemical modification of a natural product, myriocin. Since FTY720 has a structure closely related to sphingosine, the phosphorylated FTY720 (FTY720-P is converted by sphingosine kinases and binds 4 types of S1P receptors. FTY720-P strongly induces down-regulation of S1P1 by internalization and degradation of this receptor and acts as a functional antagonist at S1P1. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from the SLO and thymus to reduce circulating lymphocytes including autoreactive Th17 cells, and is highly effective in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS. In relapsing remitting MS patients, oral FTY720 shows a superior efficacy when compared to intramuscular interferon-β-1a. Based on these data, it is presumed that modulation of the S1P-S1P1 axis provides an effective therapy for autoimmune diseases including MS.

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.

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Nyberg, M; Mortensen, S P; Hellsten, Y

2013-03-01

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 and age on endothelin-1 levels in plasma and skeletal muscle and endothelin receptors in skeletal muscle in human subjects. In study 1, normotensive (46 ± 1 years, n = 11) and hypertensive (47 ± 1 years, n = 10) subjects were studied before and after 8 weeks of aerobic exercise training. In study 2, young (23 ± 1 years, n = 8), older lifelong sedentary (66 ± 2 years, n = 8) and older lifelong endurance-trained (62 ± 2 years, n = 8) subjects were studied in a cross-sectional design. Skeletal muscle and plasma endothelin-1 levels were increased with age and plasma endothelin-1 levels were higher in hypertensive than normotensive individuals. Eight weeks of exercise training normalized plasma endothelin-1 levels in the hypertensive subjects and increased the protein expression of the ET(A) receptor in skeletal muscle of normotensive subjects. Similarly, individuals that had performed lifelong physical activity had similar plasma and muscle endothelin-1 levels as the young controls and had higher ET(A) receptor levels. 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. © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society.

Determination of Sphingosine-1-Phosphate in Human Plasma Using Liquid Chromatography Coupled with Q-Tof Mass Spectrometry

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Egom, Emmanuel E.; Fitzgerald, Ross; Canning, Rebecca; Pharithi, Rebabonye B.; Murphy, Colin; Maher, Vincent

2017-01-01

Evidence suggests that high-density lipoprotein (HDL) components distinct from cholesterol, such as sphingosine-1-phosphate (S1P), may account for the anti-atherothrombotic effects attributed to this lipoprotein. The current method for the determination of plasma levels of S1P as well as levels associated with HDL particles is still cumbersome an assay method to be worldwide practical. Recently, a simplified protocol based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the sensitive and specific quantification of plasma levels of S1P with good accuracy has been reported. This work utilized a triple quadrupole (QqQ)-based LC-MS/MS system. Here we adapt that method for the determination of plasma levels of S1P using a quadrupole time of flight (Q-Tof) based LC-MS system. Calibration curves were linear in the range of 0.05 to 2 µM. The lower limit of quantification (LOQ) was 0.05 µM. The concentration of S1P in human plasma was determined to be 1 ± 0.09 µM (n = 6). The average accuracy over the stated range of the method was found to be 100 ± 5.9% with precision at the LOQ better than 10% when predicting the calibration standards. The concentration of plasma S1P in the prepared samples was stable for 24 h at room temperature. We have demonstrated the quantification of plasma S1P using Q-Tof based LC-MS with very good sensitivity, accuracy, and precision that can used for future studies in this field. PMID:28820460

Reduced levels of S-nitrosothiols in plasma of patients with systemic sclerosis and Raynaud's phenomenon.

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Kundu, Devi; Abraham, David; Black, Carol M; Denton, Christopher P; Bruckdorfer, K Richard

2014-12-01

S-Nitrosothiols (RSNOs) are bioactive forms of nitric oxide which are involved in cell signalling and redox regulation of vascular function. Circulating S-nitrosothiols are predominantly in the form of S-nitrosoalbumin. In this study plasma concentrations of S-nitrosothiols were measured in patients with systemic sclerosis (SSc) where NO metabolism is known to be abnormal. Venous blood was collected from 16 patients with Raynaud's phenomenon (RP), 45 with systemic sclerosis (SSc) (34 patients had limited SSc (IcSSc) and 11 diffuse cutaneous disease (dcSSc)). Twenty six healthy subjects were used as controls. Plasma S-nitrosothiol concentrations were measured by chemiluminescence. The measurements were related to the extent of biological age, capillary/skin scores and disease duration. Plasma RSNO levels in patients with Raynaud's phenomenon (RP) and in those with SSc was significantly lower compared to the concentrations in control subjects. In SSc, plasma S-nitrosothiols were often below the level of detection (1nM). Low S-nitrosothiol concentrations were observed in the blood of patients with SSc and patients with RP indicating a profound disturbance of nitric oxide metabolism. Copyright © 2014 Elsevier Inc. All rights reserved.

An engineered S1P chaperone attenuates hypertension and ischemic injury.

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Swendeman, Steven L; Xiong, Yuquan; Cantalupo, Anna; Yuan, Hui; Burg, Nathalie; Hisano, Yu; Cartier, Andreane; Liu, Catherine H; Engelbrecht, Eric; Blaho, Victoria; Zhang, Yi; Yanagida, Keisuke; Galvani, Sylvain; Obinata, Hideru; Salmon, Jane E; Sanchez, Teresa; Di Lorenzo, Annarita; Hla, Timothy

2017-08-15

Endothelial dysfunction, a hallmark of vascular disease, is restored by plasma high-density lipoprotein (HDL). However, a generalized increase in HDL abundance is not beneficial, suggesting that specific HDL species mediate protective effects. Apolipoprotein M-containing HDL (ApoM + HDL), which carries the bioactive lipid sphingosine 1-phosphate (S1P), promotes endothelial function by activating G protein-coupled S1P receptors. Moreover, HDL-bound S1P is limiting in several inflammatory, metabolic, and vascular diseases. We report the development of a soluble carrier for S1P, ApoM-Fc, which activated S1P receptors in a sustained manner and promoted endothelial function. In contrast, ApoM-Fc did not modulate circulating lymphocyte numbers, suggesting that it specifically activated endothelial S1P receptors. ApoM-Fc administration reduced blood pressure in hypertensive mice, attenuated myocardial damage after ischemia/reperfusion injury, and reduced brain infarct volume in the middle cerebral artery occlusion model of stroke. Our proof-of-concept study suggests that selective and sustained targeting of endothelial S1P receptors by ApoM-Fc could be a viable therapeutic strategy in vascular diseases. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

The study of 3s3p4 configuration in the P-Sequence, Co X III - Ni X IV, by laser-produced plasmas

International Nuclear Information System (INIS)

Borges, F.O.; Cavalcanti, G.H.; Farias, E.E.; Trigueiros, A.G.

2007-01-01

Wavelengths from radiation of plasmas produced by a Nd:YAG/glass laser focused on target of Co and Ni have been recorded photographically in the region 240-600 A with a 3m normal incidence spectrograph. For this sequence (Co X III and Ni X IV) we have identified 13 new lines belonging to the array 3s 2 3p 3 -3s3p 4 and derived 7 new levels for the 3s3p 4 configuration. The classification was established by comparison of the relative intensities for the lines along the isoelectronic sequence, extrapolation, and Hartree-Fock calculation. (author)

Sphingosine 1-phosphate (S1P) induces COX-2 expression and PGE2 formation via S1P receptor 2 in renal mesangial cells.

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Völzke, Anja; Koch, Alexander; Meyer Zu Heringdorf, Dagmar; Huwiler, Andrea; Pfeilschifter, Josef

2014-01-01

Understanding the mechanisms of sphingosine 1-phosphate (S1P)-induced cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) formation in renal mesangial cells may provide potential therapeutic targets to treat inflammatory glomerular diseases. Thus, we evaluated the S1P-dependent signaling mechanisms which are responsible for enhanced COX-2 expression and PGE2 formation in rat mesangial cells under basal conditions. Furthermore, we investigated whether these mechanisms are operative in the presence of angiotensin II (Ang II) and of the pro-inflammatory cytokine interleukin-1β (IL-1β). Treatment of rat and human mesangial cells with S1P led to concentration-dependent enhanced expression of COX-2. Pharmacological and molecular biology approaches revealed that the S1P-dependent increase of COX-2 mRNA and protein expression was mediated via activation of S1P receptor 2 (S1P2). Further, inhibition of Gi and p42/p44 MAPK signaling, both downstream of S1P2, abolished the S1P-induced COX-2 expression. In addition, S1P/S1P2-dependent upregulation of COX-2 led to significantly elevated PGE2 levels, which were further potentiated in the presence of Ang II and IL-1β. A functional consequence downstream of S1P/S1P2 signaling is mesangial cell migration that is stimulated by S1P. Interestingly, inhibition of COX-2 by celecoxib and SC-236 completely abolished the migratory response. Overall, our results demonstrate that extracellular S1P induces COX-2 expression via activation of S1P2 and subsequent Gi and p42/p44 MAPK-dependent signaling in renal mesangial cells leading to enhanced PGE2 formation and cell migration that essentially requires COX-2. Thus, targeting S1P/S1P2 signaling pathways might be a novel strategy to treat renal inflammatory diseases. © 2013.

Significance of changes of levels of plasma proBNP1-76 in patients with chronic pulmonary heart disease

International Nuclear Information System (INIS)

Li Guizhong; Xu Hua; Cao Jun; Jiang Wei; Pang Yongzheng; Tang Chaoshu

2003-01-01

Objective: To investigate the significance of the changes levels of plasma proBNP 1-76 in patients with COPD and chronic pulmonary heart disease. Methods: Plasma proBNP 1-76 levels were determined with radioimmunoassay in patients with CHPD (n=23), COPD (n=24) and 32 controls. Results: The concentrations of plasma proBNP 1-76 in patients with chronic obstructive pulmonary disease were significantly increased (vs controls, p 1-76 (r=0.541, p 1-76 , right inferior pulmonary artery diameter, right ventricle out flow tract diameter and right ventricle anterior wall thickness in patients with chronic pulmonary heart disease were increased significantly (vs COPD patients and controls, p 1-76 (r=0.477, p 1-76 is an early marker of right ventricular hypertrophy and right ventricular dysfunction, measurement of which is useful in the management of patients with chronic pulmonary heart disease in daily practice

Higher plasma soluble Receptor for Advanced Glycation End Products (sRAGE) levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes

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Nin, Johanna W M; Jorsal, Anders; Ferreira, Isabel

2010-01-01

To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunct......To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal...

Hyperoxia-induced p47phox activation and ROS generation is mediated through S1P transporter Spns2, and S1P/S1P1&2 signaling axis in lung endothelium.

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Harijith, Anantha; Pendyala, Srikanth; Ebenezer, David L; Ha, Alison W; Fu, Panfeng; Wang, Yue-Ting; Ma, Ke; Toth, Peter T; Berdyshev, Evgeny V; Kanteti, Prasad; Natarajan, Viswanathan

2016-08-01

Hyperoxia-induced lung injury adversely affects ICU patients and neonates on ventilator assisted breathing. The underlying culprit appears to be reactive oxygen species (ROS)-induced lung damage. The major contributor of hyperoxia-induced ROS is activation of the multiprotein enzyme complex NADPH oxidase. Sphingosine-1-phosphate (S1P) signaling is known to be involved in hyperoxia-mediated ROS generation; however, the mechanism(s) of S1P-induced NADPH oxidase activation is unclear. Here, we investigated various steps in the S1P signaling pathway mediating ROS production in response to hyperoxia in lung endothelium. Of the two closely related sphingosine kinases (SphKs)1 and 2, which synthesize S1P from sphingosine, only Sphk1(-/-) mice conferred protection against hyperoxia-induced lung injury. S1P is metabolized predominantly by S1P lyase and partial deletion of Sgpl1 (Sgpl1(+/-)) in mice accentuated lung injury. Hyperoxia stimulated S1P accumulation in human lung microvascular endothelial cells (HLMVECs), and downregulation of S1P transporter spinster homolog 2 (Spns2) or S1P receptors S1P1&2, but not S1P3, using specific siRNA attenuated hyperoxia-induced p47(phox) translocation to cell periphery and ROS generation in HLMVECs. These results suggest a role for Spns2 and S1P1&2 in hyperoxia-mediated ROS generation. In addition, p47(phox) (phox:phagocyte oxidase) activation and ROS generation was also reduced by PF543, a specific SphK1 inhibitor in HLMVECs. Our data indicate a novel role for Spns2 and S1P1&2 in the activation of p47(phox) and production of ROS involved in hyperoxia-mediated lung injury in neonatal and adult mice. Copyright © 2016 the American Physiological Society.

Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase.

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Ebenezer, David L; Fu, Panfeng; Suryadevara, Vidyani; Zhao, Yutong; Natarajan, Viswanathan

2017-01-01

Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes. Here, we present data on the role of S1P lyase mediated S1P signaling in regulating LPS-induced inflammation in lung endothelium. Blocking S1P lyase expression or activity attenuated LPS-induced histone acetylation and secretion of pro-inflammatory cytokines. Degradation of S1P by S1P lyase generates Δ2-hexadecenal and ethanolamine phosphate and the long-chain fatty aldehyde produced in the cytoplasmic compartment of the endothelial cell seems to modulate histone acetylation pattern, which is different from the nuclear SphK2/S1P signaling and inhibition of HDAC1/2. These in vitro studies suggest that S1P derived long-chain fatty aldehyde may be an epigenetic regulator of pro-inflammatory genes in sepsis-induced lung inflammation. Trapping fatty aldehydes and other short chain aldehydes such as 4-hydroxynonenal derived from S1P degradation and lipid peroxidation, respectively by cell permeable agents such as phloretin or other aldehyde trapping agents may be useful in treating sepsis-induced lung inflammation via modulation of histone acetylation. . Copyright © 2016 Elsevier Ltd. All rights reserved.

Extracellular matrix protein fibulin-1 plasma levels are associated with increased cardiovascular risk in chronic kidney disease

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Scholze, Alexandra

INTRODUCTION AND AIMS: Fibulin-1 is one of the few extracellular matrix proteins present in blood in high concentrations. We aimed to define the relationship between plasma fibulin-1 levels and risk markers of cardiovascular disease in patients with chronic kidney disease. METHODS: Plasma fibulin-1...... hemodynamic and arterial stiffness indices. RESULTS: We observed a positive correlation of fibulin-1 levels with age (r=0.38; p=0.033), glycated hemoglobin (r=0.80; p=0.003), creatinine (r=0.35; p=0.045), and fibrinogen (r=0.39; p=0.027). Glomerular filtration rate and fibulin-1 were inversely correlated (r......=-0.57; p=0.022). There was a positive correlation between fibulin-1 and central pulse pressure (r=0.44; p=0.011) and central augmentation pressure (r=0.55; p=0.001). In a multivariable regression model, diabetes, creatinine, fibrinogen and central augmentation pressure were independent predictors...

Clinical significance of determination of plasma CF6, 6-Keto-PGF1α and RLX levels in patients with preeclampsia

International Nuclear Information System (INIS)

Xu Fei; Chen Daozhen; Wang Junfeng; Yang Min; Pan Donghui

2010-01-01

Objective: To study the relationship between development of the disease and changes of plasma mitochondrial coupling factor 6 (CF6), prostacyclin (6-Keto-PGF 1α ) and relaxin (RLX) levels in patients with preeclampsia. Methods: Serum CF6, 6-Keto-PGF 1α (as the stable metabolite of 6-Keto-PGF 1α ) and relaxin levels were determined with RIA in (1) 22 pregnant women with mild pre-eclampsia (2) 20 pregnant women with severe pre-eclampsia and (3) 40 normal pregnant women (as controls). Results: The plasma levels of CF6 were significantly higher in patients with mild as well as severe preeclampsia than those in the controls (P 1α were only insignificantly decreased in patients with mild preeclampsia than those in the controls (P > 0.05). In severe preeclampsia group, plasma levels of 6-Keto-PGF 1α were significantly decreased than those in the controls (P 1α and RLX (r =-0.058, r =-0.601, all P 1α and RLX levels in patients with preeclampsia were helpful for assessment of progress of disease and outcome prediction. (authors)

High plasma levels of soluble intercellular adhesion molecule (ICAM)-1 are associated with cerebral malaria.

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Adukpo, Selorme; Kusi, Kwadwo A; Ofori, Michael F; Tetteh, John K A; Amoako-Sakyi, Daniel; Goka, Bamenla Q; Adjei, George O; Edoh, Dominic A; Akanmori, Bartholomew D; Gyan, Ben A; Dodoo, Daniel

2013-01-01

Cerebral malaria (CM) is responsible for most of the malaria-related deaths in children in sub-Saharan Africa. Although, not well understood, the pathogenesis of CM involves parasite and host factors which contribute to parasite sequestration through cytoadherence to the vascular endothelium. Cytoadherence to brain microvasculature is believed to involve host endothelial receptor, CD54 or intercellular adhesion molecule (ICAM)-1, while other receptors such as CD36 are generally involved in cytoadherence of parasites in other organs. We therefore investigated the contributions of host ICAM-1 expression and levels of antibodies against ICAM-1 binding variant surface antigen (VSA) on parasites to the development of CM. Paediatric malaria patients, 0.5 to 13 years were recruited and grouped into CM and uncomplicated malaria (UM) patients, based on well defined criteria. Standardized ELISA protocol was used to measure soluble ICAM-1 (sICAM-1) levels from acute plasma samples. Levels of IgG to CD36- or ICAM-1-binding VSA were measured by flow cytometry during acute and convalescent states. Wilcoxon sign rank-test analysis to compare groups revealed association between sICAM-1 levels and CM (p0.05). Median levels of antibodies to CD36-binding VSAs were also comparable between acute and convalescent samples within any patient group. Median levels of antibodies to ICAM-1-binding VSAs were however significantly lower at admission time than during recovery in both groups. High levels of sICAM-1 were associated with CM, and the sICAM-1 levels may reflect expression levels of the membrane bound form. Anti-VSA antibody levels to ICAM-binding parasites was more strongly associated with both UM and CM than antibodies to CD36 binding parasites. Thus, increasing host sICAM-1 levels were associated with CM whilst antibodies to parasite expressing non-ICAM-1-binding VSAs were not.

Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway: Therapeutic Targets in Autoimmunity and Inflammation.

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Tsai, Hsing-Chuan; Han, May H

2016-07-01

Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are ubiquitously expressed. S1P-S1PR signaling has been well characterized in immune trafficking and activation in innate and adaptive immune systems. However, the full extent of its involvement in the pathogenesis of autoimmune diseases is not well understood. FTY720 (fingolimod), a non-selective S1PR modulator, significantly decreased annualized relapse rates in relapsing-remitting multiple sclerosis (MS). FTY720, which primarily targets S1P receptor 1 as a functional antagonist, arrests lymphocyte egress from secondary lymphoid tissues and reduces neuroinflammation in the central nervous system (CNS). Recent studies suggest that FTY720 also decreases astrogliosis and promotes oligodendrocyte differentiation within the CNS and may have therapeutic benefit to prevent brain atrophy. Since S1P signaling is involved in multiple immune functions, therapies targeting S1P axis may be applicable to treat autoimmune diseases other than MS. Currently, over a dozen selective S1PR and S1P pathway modulators with potentially superior therapeutic efficacy and better side-effect profiles are in the pipeline of drug development. Furthermore, newly characterized molecules such as apolipoprotein M (ApoM) (S1P chaperon) and SPNS2 (S1P transporter) are also potential targets for treatment of autoimmune diseases. Finally, the application of therapies targeting S1P and S1P signaling pathways may be expanded to treat several other immune-mediated disorders (such as post-infectious diseases, post-stroke and post-stroke dementia) and inflammatory conditions beyond their application in primary autoimmune diseases.

HDL-S1P: cardiovascular functions, disease-associated alterations, and therapeutic applications.

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Levkau, Bodo

2015-01-01

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid contained in High-density lipoproteins (HDL) and has drawn considerable attention in the lipoprotein field as numerous studies have demonstrated its contribution to several functions inherent to HDL. Some of them are partly and some entirely due to the S1P contained in HDL (HDL-S1P). Despite the presence of over 1000 different lipids in HDL, S1P stands out as it possesses its own cell surface receptors through which it exercises key physiological functions. Most of the S1P in human plasma is associated with HDL, and the amount of HDL-S1P influences the quality and quantity of HDL-dependent functions. The main binding partner of S1P in HDL is apolipoprotein M but others may also exist particularly under conditions of acute S1P elevations. HDL not only exercise functions through their S1P content but have also an impact on genuine S1P signaling by influencing S1P bioactivity and receptor presentation. HDL-S1P content is altered in human diseases such as atherosclerosis, coronary artery disease, myocardial infarction, renal insufficiency and diabetes mellitus. Low HDL-S1P has also been linked to impaired HDL functions associated with these disorders. Although the pathophysiological and molecular reasons for such disease-associated shifts in HDL-S1P are little understood, there have been successful approaches to circumvent their adverse implications by pharmacologically increasing HDL-S1P as means to improve HDL function. This mini-review will cover the current understanding of the contribution of HDL-S1P to physiological HDL function, its alteration in disease and ways for its restoration to correct HDL dysfunction.

Increasing plasma fibrinogen, but unchanged levels of intraplatelet cyclic nucleotides, plasma endothelin-1, factor VII, and neopterin during cholesterol lowering with fluvastatin.

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Gottsäter, A; Anwaar, I; Lind, P; Mattiasson, I; Lindgärde, F

1999-04-01

Lipid-lowering statin treatment reduces cardiovascular morbidity and mortality and improves endothelial function in patients with hypercholesterolemia. The aim of the present study was to evaluate plasma levels of fibrinogen, factor VII, and the macrophage-derived inflammatory mediator neopterin during lipid lowering. In addition, the endothelial production of platelet antiaggregatory and vasodilatory factors such as nitric oxide and prostacyclin, and vasoconstrictive factors such as endothelin-1, was assessed. Plasma fibrinogen, factor VII, endothelin-1, and the neopterin and intraplatelet nitric oxide and prostacyclin mediators cyclic 3'-5'guanosine monophosphate (cGMP) and cyclic 3'-5'adenosine monophosphate (cAMP) were measured before and 6 months after the institution of treatment with fluvastatin in 17 patients (eight men and nine women, median age 60 years) with vascular disease and previously untreated hypercholesterolemia. After 6 months, a decrease of 1.62 mmol/l [1.26-2.18 (19%); P factor VII [from 1.14 IE/ml (0.58-1.38) to 1.22 IE/ml (0.96-1.46); NS], or plasma neopterin [from 8.6 nmol/l (7.1-11.5) to 8.7 nmol/l (7.9-11.3); NS]. In conclusion, during cholesterol-lowering treatment with fluvastatin, plasma levels of fibrinogen increased whereas intraplatelet cyclic nucleotide levels and plasma endothelin-1, factor VII and neopterin levels were unchanged.

Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P2 on cell migration and invasiveness

International Nuclear Information System (INIS)

Young, Nicholas; Van Brocklyn, James R.

2007-01-01

Sphingosine-1-phosphate (S1P) is a bioactive lipid that signals through a family of five G-protein-coupled receptors, termed S1P 1-5 . S1P stimulates growth and invasiveness of glioma cells, and high expression levels of the enzyme that forms S1P, sphingosine kinase-1, correlate with short survival of glioma patients. In this study we examined the mechanism of S1P stimulation of glioma cell proliferation and invasion by either overexpressing or knocking down, by RNA interference, S1P receptor expression in glioma cell lines. S1P 1 , S1P 2 and S1P 3 all contribute positively to S1P-stimulated glioma cell proliferation, with S1P 1 being the major contributor. Stimulation of glioma cell proliferation by these receptors correlated with activation of ERK MAP kinase. S1P 5 blocks glioma cell proliferation, and inhibits ERK activation. S1P 1 and S1P 3 enhance glioma cell migration and invasion. S1P 2 inhibits migration through Rho activation, Rho kinase signaling and stress fiber formation, but unexpectedly, enhances glioma cell invasiveness by stimulating cell adhesion. S1P 2 also potently enhances expression of the matricellular protein CCN1/Cyr61, which has been implicated in tumor cell adhesion, and invasion as well as tumor angiogenesis. A neutralizing antibody to CCN1 blocked S1P 2 -stimulated glioma invasion. Thus, while S1P 2 decreases glioma cell motility, it may enhance invasion through induction of proteins that modulate glioma cell interaction with the extracellular matrix

Studies on the relationship between plasma CRP and TNF-α, IL-1β levels in aged patients with acute coronary syndrome

International Nuclear Information System (INIS)

Luo Nanping; Wang Xiangang; Hu Chengjin; Wang Ruishan

2002-01-01

Objective: To investigate the relationship between plasma TNF-α, IL-1β and CRP levels in aged patients with coronary heart disease and to define the inflammation marker which might recognize and predict acute coronary syndrome. Methods: Radioimmunoassay was used to detect plasma levels of TNF-α, IL-1β and CRP. Results: Plasma levels of TNF-α and IL-β in patients with acute coronary syndrome (ACS) were significantly higher than those in controls (p<0.05; p<0.01) and stable coronary heart disease (SCHD) (p<0.05; p<0.01). Plasma CRP levels in patients with ACS (7.99 +- 11.9 ml/L) were also significantly higher than those in controls (0.99 +- 1.5 mg/L; p<0.01) and patients with SCHD (2.71 +- 5.45 mg/L; p<0.05). There was positive correlation between CRP level and TNF-α (r=0.0545; p<0.01) as well as IL-β (r=0.31, p<0.05). Conclusion: The abnormal expression of cytokines in aged patients with coronary heart disease was correlative to inflammation marker CRP, which suggested that the abnormal expression to the occurrence of acute coronary syndrome and might serve as a marker of unstable atherosclerosis plaque

Combined plasma gas-phase synthesis and colloidal processing of InP/ZnS core/shell nanocrystals

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Gresback, Ryan; Hue, Ryan; Gladfelter, Wayne L.; Kortshagen, Uwe R.

2011-12-01

Indium phosphide nanocrystals (InP NCs) with diameters ranging from 2 to 5 nm were synthesized with a scalable, flow-through, nonthermal plasma process at a rate ranging from 10 to 40 mg/h. The NC size is controlled through the plasma operating parameters, with the residence time of the gas in the plasma region strongly influencing the NC size. The NC size distribution is narrow with the standard deviation being less than 20% of the mean NC size. Zinc sulfide (ZnS) shells were grown around the plasma-synthesized InP NCs in a liquid phase reaction. Photoluminescence with quantum yields as high as 15% were observed for the InP/ZnS core-shell NCs.

An Investigation on the He−(1s2s2 2S Resonance in Debye Plasmas

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Arijit Ghoshal

2017-01-01

Full Text Available The effect of Debye plasma on the 1 s 2 s 2 2 S resonance states in the scattering of electron from helium atom has been investigated within the framework of the stabilization method. The interactions among the charged particles in Debye plasma have been modelled by Debye–Huckel potential. The 1 s 2 s excited state of the helium atom has been treated as consisting of a H e + ionic core plus an electron moving around. The interaction between the core and the electron has then been modelled by a model potential. It has been found that the background plasma environment significantly affects the resonance states. To the best of our knowledge, such an investigation of 1 s 2 s 2 2 S resonance states of the electron–helium system embedded in Debye plasma environment is the first reported in the literature.

Changes in plasma TIMP-1 levels after resection for primary colorectal cancer

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Frederiksen, C.; Lomholt, A.F.; Davis, G.J.

2009-01-01

BACKGROUND: Increased plasma levels of tissue inhibitor of metalloproteinases (TIMP-1) are associated with poor outcome in colorectal cancer (CRC), however postoperative changes in plasma TIMP-1 levels after resections for CRC have not been thoroughly evaluated. MATERIALS AND METHODS: Plasma samp...

S1P, dihydro-S1P and C24:1-ceramide levels in the HDL-containing fraction of serum inversely correlate with occurrence of ischemic heart disease

DEFF Research Database (Denmark)

Argraves, Kelley M; Sethi, Amar A; Gazzolo, Patrick J

2011-01-01

The lysosphingolipid sphingosine 1-phosphate (S1P) is carried in the blood in association with lipoproteins, predominantly high density lipoproteins (HDL). Emerging evidence suggests that many of the effects of HDL on cardiovascular function may be attributable to its S1P cargo....

Sphingosine-1-Phosphate (S1P)-Related Response of Human Conjunctival Fibroblasts After Filtration Surgery for Glaucoma.

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Aoyama-Araki, Yuka; Honjo, Megumi; Uchida, Takatoshi; Yamagishi, Reiko; Kano, Kuniyuki; Aoki, Junken; Aihara, Makoto

2017-04-01

To investigate levels of sphingosine-1-phosphate (S1P) in aqueous fluid samples taken before and after filtration surgery and S1P-induced human conjunctival fibroblast (HCF) responses. Levels of S1P and its related sphingophospholipids in aqueous fluid obtained immediately before and after filtration surgery were determined by liquid chromatography-tandem mass spectrometry. HCFs were used for all in vitro experiments. The expression of five S1P receptor subtypes in HCFs was examined by quantitative real-time PCR. The effect of S1P and receptor-specific antagonists on HCF viability and cell migration was assessed by WST-1 assay and scratch migration assay, respectively. Differentiation to myofibroblasts and extracellular matrix production was evaluated by examining changes in F-actin, α-smooth muscle actin (αSMA), and collagen expression with immunocytochemistry, Western blotting, and collagen accumulation assay, respectively. No significant S1P levels in the aqueous fluid samples were detectable immediately before surgery, but postoperative levels of several lysophospholipids, including S1P, dehydro-S1P, and sphingosine, were significantly increased to bioactive concentrations in aqueous fluid in the blebs (P S1P receptor subtypes was detected in HCFs. Although S1P levels did not influence HCF proliferation, S1P enhanced cell migration, which could be inhibited by the S1P2 antagonist JTE 013. F-actin, αSMA, and collagen expression was significantly increased by S1P stimulation and was reduced by JTE 013. Bioactive S1P concentrations were present in the aqueous fluid at the end of filtration surgery. S1P activated HCFs via S1P2 receptors. These results revealed the potential of S1P2 antagonists in preventing scarring after glaucoma filtration surgery.

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

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......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...... and age on endothelin-1 levels in plasma and skeletal muscle and endothelin receptors in skeletal muscle in human subjects. METHODS: In study 1, normotensive (46 ± 1 years, n = 11) and hypertensive (47 ± 1 years, n = 10) subjects were studied before and after 8 weeks of aerobic exercise training. In study...

Clinical significance of measurement of changes of plasma ET-1 and serum TGF-β1, urinary microalbuminuria (MAU) levels in patients with type II diabetes

International Nuclear Information System (INIS)

Feng Liming; Xu Shan

2010-01-01

Objective: To study the clinical significance of changes of plasma ET-1 and serum TGF-β 1 , urinary microalbuminuria levels in patients with type II diabetes. Methods: Plasma ET-1 (with RIA) serum TGF-β 1 (with ELISA)microalbuminuria (with immune method) levels were determination in 40 cases of DM2 without nephropathy, 32 cases of DM2 with nephropathy and 35 controls. Results: The plasma ET-1, serum TGF-β 1 , microalbuminuria levels in diabetic patients with nephropathy were significantly higher than those in controls(P 0.05). Conclusion: Plasma ET-1 and serum TGF-β 1 , microalbuminuria levels increased gradually as the diabetic nephropathy got more severe. They could be used as sensitive markers for early diagnosis of development of diabetic nephropathy. (authors)

Increased plasma agmatine levels in patients with schizophrenia.

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Uzbay, Tayfun; Goktalay, Gokhan; Kayir, Hakan; Eker, Salih S; Sarandol, Asli; Oral, Sema; Buyukuysal, Levent; Ulusoy, Gokhan; Kirli, Selcuk

2013-08-01

Agmatine is an endogenous substance, synthesized from l-arginine, and it is proposed to be a new neurotransmitter. Preclinical studies indicated that agmatine may have an important role in the pathophysiology of schizophrenia. This study was organized to investigate plasma agmatine in patients with schizophrenia and in healthy controls. Eighteen patients with schizophrenia and 19 healthy individuals constituted the subjects. Agmatine levels in the plasma were measured using the HPLC method. The S100B protein level, which is a peripheral biomarker for brain damage, was also measured using the ELISA method. While plasma levels of agmatine in patients with schizophrenia were significantly increased (p agmatine levels as a clinical diagnostic test would significantly differentiate between patients with schizophrenia and those in the control group (predictive value: 0.969; p  0.05). A multiple regression analysis revealed that the age of the patient and the severity of the illness, as indicated by the PANSS score, significantly contributed the plasma agmatine levels in patients with schizophrenia. These results support the hypothesis that an excess agmatine release is important in the development of schizophrenia. The findings also imply that the plasma agmatine level may be a potential biomarker of schizophrenia. Copyright © 2013 Elsevier Ltd. All rights reserved.

Comparison of p53 levels in lymphocytes and in blood plasma of nuclear power plant workers

International Nuclear Information System (INIS)

Roessner, Pavel; Chvatalova, Irena; Schmuczerova, Jana; Milcova, Alena; Roessner, Pavel; Sram, Radim J.

2004-01-01

p53 levels were assessed in lymphocytes and in blood plasma of workers from two Czech nuclear power plants (NPP): 114 subjects working in Temelin and 108 subjects working in Dukovany. Ionizing radiation (IR) exposure data were available for 64 and 59 subjects working in the monitored zones from the NPP in Temelin and Dukovany, respectively. The short-term doses of IR for these subjects were 0.01 and 0.12 mSv, and the long-term doses were 0.46 and 5.68 mSv, in the Temelin and Dukovany NPP, respectively. As a control group, 46 subjects living in Ceske Budejovice, a city nearby the Temelin NPP, were analyzed. The concentration of p53 in lymphocytes was significantly higher in workers from the monitored zone in the Dukovany NPP (median value 6.4 pg/μg protein, P < 0.001) than in workers from the Temelin NPP (3.2 pg/μg) as well as in the control group (3.5 pg/μg). In contrast, plasma levels of p53 were comparable in the control group (median value 116 pg/ml plasma) and workers from the monitored zone of Dukovany NPP (102 pg/ml), but lower in workers from Temelin NPP (5 pg/ml). Other factors affecting p53 levels were studied. Smoking resulted in increased p53 lymphocyte levels. The effect of polymorphisms in metabolic and DNA repair genes on p53 levels was analyzed. The correlation was found between p53 levels in lymphocytes and p53 codon 72 polymorphism in subjects working in NPPs, but not in the control group. The results of measurement p53 levels in lymphocytes suggest that this biomarker could reflect the short-term as well as long-term effects of low doses IR. Its impact on human health should be further explored

Regulation of human cerebro-microvascular endothelial baso-lateral adhesion and barrier function by S1P through dual involvement of S1P1 and S1P2 receptors.

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Wiltshire, Rachael; Nelson, Vicky; Kho, Dan Ting; Angel, Catherine E; O'Carroll, Simon J; Graham, E Scott

2016-01-27

Herein we show that S1P rapidly and acutely reduces the focal adhesion strength and barrier tightness of brain endothelial cells. xCELLigence biosensor technology was used to measure focal adhesion, which was reduced by S1P acutely and this response was mediated through both S1P1 and S1P2 receptors. S1P increased secretion of several pro-inflammatory mediators from brain endothelial cells. However, the magnitude of this response was small in comparison to that mediated by TNFα or IL-1β. Furthermore, S1P did not significantly increase cell-surface expression of any key cell adhesion molecules involved in leukocyte recruitment, included ICAM-1 and VCAM-1. Finally, we reveal that S1P acutely and dynamically regulates microvascular endothelial barrier tightness in a manner consistent with regulated rapid opening followed by closing and strengthening of the barrier. We hypothesise that the role of the S1P receptors in this process is not to cause barrier dysfunction, but is related to controlled opening of the endothelial junctions. This was revealed using real-time measurement of barrier integrity using ECIS ZΘ TEER technology and endothelial viability using xCELLigence technology. Finally, we show that these responses do not occur simply though the pharmacology of a single S1P receptor but involves coordinated action of S1P1 and S1P2 receptors.

Plasma levels of sphingosine-1-phosphate and apolipoprotein M in patients with monogenic disorders of HDL metabolism

NARCIS (Netherlands)

Karuna, Ratna; Park, Rebekka; Othman, Alaa; Holleboom, Adriaan G.; Motazacker, Mohammad Mahdi; Sutter, Iryna; Kuivenhoven, Jan Albert; Rohrer, Lucia; Matile, Hugues; Hornemann, Thorsten; Stoffel, Markus; Rentsch, Katharina M.; von Eckardstein, Arnold

2011-01-01

Apolipoprotein M (apoM) has been identified as a specific sphingosine-1-phosphate (S1P) binding protein of HDL. To investigate the in vivo effects of disturbed apoM or HDL metabolism we quantified S1P and apoM in plasmas of wild-type, apoM-knock-out, and apoM transgenic mice as well as 50 patients

High plasma levels of soluble intercellular adhesion molecule (ICAM-1 are associated with cerebral malaria.

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Selorme Adukpo

Full Text Available BACKGROUND: Cerebral malaria (CM is responsible for most of the malaria-related deaths in children in sub-Saharan Africa. Although, not well understood, the pathogenesis of CM involves parasite and host factors which contribute to parasite sequestration through cytoadherence to the vascular endothelium. Cytoadherence to brain microvasculature is believed to involve host endothelial receptor, CD54 or intercellular adhesion molecule (ICAM-1, while other receptors such as CD36 are generally involved in cytoadherence of parasites in other organs. We therefore investigated the contributions of host ICAM-1 expression and levels of antibodies against ICAM-1 binding variant surface antigen (VSA on parasites to the development of CM. METHODOLOGY/PRINCIPAL FINDINGS: Paediatric malaria patients, 0.5 to 13 years were recruited and grouped into CM and uncomplicated malaria (UM patients, based on well defined criteria. Standardized ELISA protocol was used to measure soluble ICAM-1 (sICAM-1 levels from acute plasma samples. Levels of IgG to CD36- or ICAM-1-binding VSA were measured by flow cytometry during acute and convalescent states. Wilcoxon sign rank-test analysis to compare groups revealed association between sICAM-1 levels and CM (p0.05. Median levels of antibodies to CD36-binding VSAs were also comparable between acute and convalescent samples within any patient group. Median levels of antibodies to ICAM-1-binding VSAs were however significantly lower at admission time than during recovery in both groups. CONCLUSIONS/SIGNIFICANCE: High levels of sICAM-1 were associated with CM, and the sICAM-1 levels may reflect expression levels of the membrane bound form. Anti-VSA antibody levels to ICAM-binding parasites was more strongly associated with both UM and CM than antibodies to CD36 binding parasites. Thus, increasing host sICAM-1 levels were associated with CM whilst antibodies to parasite expressing non-ICAM-1-binding VSAs were not.

Higher plasma level of STIM1, OPG are correlated with stent restenosis after PCI.

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Li, Haibin; Jiang, Zhian; Liu, Xiangdong; Yang, Zhihui

2015-01-01

Percutaneous Coronary Intervention (PCI) is one of the most effective treatments for Coronary Heart Disease (CHD), but the high rate of In Stent Restenosis (ISR) has plagued clinicians after PCI. We aim to investigate the correlation of plasma Stromal Interaction Molecular 1 (STIM1) and Osteoprotegerin (OPG) level with stent restenosis after PCI. A total of 100 consecutive patients with Coronary Heart Disease (CHD) received PCI procedure were recruited. Coronary angiography was performed 8 months after their PCI. Then patients were divided into 2 groups: observation group was composed by patients who existing postoperative stenosis after intervention; Control group was composed by patients with no postoperative stenosis. The plasma levels of STIM, OPG in all patients were tested before and after intervention. Pearson correlation and multiple linear regression analysis were performed to analysis the correlation between STIM, OPG level and postoperative stenosis. 35 cases were divided into observation group and other 65 were divided into control group. The plasma levels of STIM, OPG have no statistical difference before their PCI procedure, but we observed higher level of High-sensitivity C-reactive protein (Hs-CRP) existed in observation group. We observed higher level of plasma STIM, OPG in observation group when compared with control group after PCI procedure (P PCI, which could provide useful information for the restenosis control after PCI.

Oncogenic S1P signalling in EBV-associated nasopharyngeal carcinoma activates AKT and promotes cell migration through S1P receptor 3.

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Lee, Hui Min; Lo, Kwok-Wai; Wei, Wenbin; Tsao, Sai Wah; Chung, Grace Tin Yun; Ibrahim, Maha Hafez; Dawson, Christopher W; Murray, Paul G; Paterson, Ian C; Yap, Lee Fah

2017-05-01

Undifferentiated nasopharyngeal carcinoma (NPC) is a cancer with high metastatic potential that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the functional contribution of sphingosine-1-phosphate (S1P) signalling to the pathogenesis of NPC. We show that EBV infection or ectopic expression of the EBV-encoded latent genes (EBNA1, LMP1, and LMP2A) can up-regulate sphingosine kinase 1 (SPHK1), the key enzyme that produces S1P, in NPC cell lines. Exogenous addition of S1P promotes the migration of NPC cells through the activation of AKT; shRNA knockdown of SPHK1 resulted in a reduction in the levels of activated AKT and inhibition of cell migration. We also show that S1P receptor 3 (S1PR3) mRNA is overexpressed in EBV-positive NPC patient-derived xenografts and a subset of primary NPC tissues, and that knockdown of S1PR3 suppressed the activation of AKT and the S1P-induced migration of NPC cells. Taken together, our data point to a central role for EBV in mediating the oncogenic effects of S1P in NPC and identify S1P signalling as a potential therapeutic target in this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer.

Science.gov (United States)

Zhang, Liang; Wang, Xiaoen; Bullock, Andrea J; Callea, Marcella; Shah, Harleen; Song, Jiaxi; Moreno, Kelli; Visentin, Barbara; Deutschman, Douglas; Alsop, David C; Atkins, Michael B; Mier, James W; Signoretti, Sabina; Bhasin, Manoj; Sabbadini, Roger A; Bhatt, Rupal S

2015-04-15

VEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic renal cell carcinoma (RCC). However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for patients with TKI-naïve or -resistant RCC. In this study, we performed transcriptome analysis of VEGFR TKI-resistant tumors in a murine model and discovered that the SPHK-S1P pathway is upregulated at the time of resistance. We tested sphingosine-1-phosphate (S1P) pathway inhibition using an anti-S1P mAb (sphingomab), in two mouse xenograft models of RCC, and assessed tumor SPHK expression and S1P plasma levels in patients with metastatic RCC. Resistant tumors expressed several hypoxia-regulated genes. The SPHK1 pathway was among the most highly upregulated pathways that accompanied resistance to VEGFR TKI therapy. SPHK1 was expressed in human RCC, and the product of SPHK1 activity, S1P, was elevated in patients with metastatic RCC, suggesting that human RCC behavior could, in part, be due to overproduction of S1P. Sphingomab neutralization of extracellular S1P slowed tumor growth in both mouse models. Mice bearing tumors that had developed resistance to sunitinib treatment also exhibited tumor growth suppression with sphingomab. Sphingomab treatment led to a reduction in tumor blood flow as measured by MRI. Our findings suggest that S1P inhibition may be a novel therapeutic strategy in patients with treatment-naïve RCC and also in the setting of resistance to VEGFR TKI therapy. ©2015 American Association for Cancer Research.

Hemoglobin A1c, fasting plasma glucose, and 2-hour plasma glucose distributions in U.S. population subgroups: NHANES 2005-2010.

Science.gov (United States)

Menke, Andy; Rust, Keith F; Savage, Peter J; Cowie, Catherine C

2014-02-01

Although mean concentrations of hemoglobin A1c (A1C), fasting plasma glucose, and 2-hour plasma glucose differ by demographics, it is unclear what other characteristics of the distributions may differ, such as the amount of asymmetry of the distribution (skewness) and shift left or right compared with another distribution (shift). Using kernel density estimation, we created smoothed plots of the distributions of fasting plasma glucose (N = 7250), 2-hour plasma glucose (N = 5851), and A1C (N = 16,209) by age, race-ethnicity, and sex in the 2005-2010 National Health and Nutrition Examination Survey, a nationally representative sample of U.S. adults including people with and without diabetes. We tested differences in distributions using cumulative logistic regression. The distributions were generally unimodal and right-skewed. All distributions were shifted higher and more right-skewed for older age groups (P Mexican-Americans (P = .01), whereas the distribution of A1C was shifted higher for non-Hispanic blacks (P rights reserved.

Measurement of the relative yields of ψ (2 S ) to ψ (1 S ) mesons produced at forward and backward rapidity in p +p , p +Al , p +Au , and 3He+Au collisions at √{sNN}=200 GeV

Science.gov (United States)

Adare, A.; Aidala, C.; Ajitanand, N. N.; Akiba, Y.; Alfred, M.; Andrieux, V.; Aoki, K.; Apadula, N.; Asano, H.; Ayuso, C.; Azmoun, B.; Babintsev, V.; Bai, M.; Bandara, N. S.; Bannier, B.; Barish, K. N.; Bathe, S.; Bazilevsky, A.; Beaumier, M.; Beckman, S.; Belmont, R.; Berdnikov, A.; Berdnikov, Y.; Blau, D. S.; Boer, M.; Bok, J. S.; Bownes, E. K.; Boyle, K.; Brooks, M. L.; Bryslawskyj, J.; Bumazhnov, V.; Butler, C.; Campbell, S.; Canoa Roman, V.; Cervantes, R.; Chen, C.-H.; Chi, C. Y.; Chiu, M.; Choi, I. J.; Choi, J. B.; Chujo, T.; Citron, Z.; Connors, M.; Cronin, N.; Csanád, M.; Csörgő, T.; Danley, T. W.; Datta, A.; Daugherity, M. S.; David, G.; Deblasio, K.; Dehmelt, K.; Denisov, A.; Deshpande, A.; Desmond, E. J.; Dion, A.; Diss, P. B.; Dixit, D.; Do, J. H.; Drees, A.; Drees, K. A.; Dumancic, M.; Durham, J. M.; Durum, A.; Dusing, J. P.; Elder, T.; Enokizono, A.; En'yo, H.; Esumi, S.; Fadem, B.; Fan, W.; Feege, N.; Fields, D. E.; Finger, M.; Finger, M.; Fokin, S. L.; Frantz, J. E.; Franz, A.; Frawley, A. D.; Fukuda, Y.; Gal, C.; Gallus, P.; Garg, P.; Ge, H.; Giordano, F.; Glenn, A.; Goto, Y.; Grau, N.; Greene, S. V.; Grosse Perdekamp, M.; Gunji, T.; Guragain, H.; Hachiya, T.; Haggerty, J. S.; Hahn, K. I.; Hamagaki, H.; Hamilton, H. F.; Han, S. Y.; Hanks, J.; Hasegawa, S.; Haseler, T. O. S.; Hashimoto, K.; He, X.; Hemmick, T. K.; Hill, J. C.; Hill, K.; Hollis, R. S.; Homma, K.; Hong, B.; Hoshino, T.; Hotvedt, N.; Huang, J.; Huang, S.; Imai, K.; Imrek, J.; Inaba, M.; Iordanova, A.; Isenhower, D.; Ito, Y.; Ivanishchev, D.; Jacak, B. V.; Jezghani, M.; Ji, Z.; Jia, J.; Jiang, X.; Johnson, B. M.; Jorjadze, V.; Jouan, D.; Jumper, D. S.; Kanda, S.; Kang, J. H.; Kapukchyan, D.; Karthas, S.; Kawall, D.; Kazantsev, A. V.; Key, J. A.; Khachatryan, V.; Khanzadeev, A.; Kim, C.; Kim, D. J.; Kim, E.-J.; Kim, G. W.; Kim, M.; Kimball, M. L.; Kimelman, B.; Kincses, D.; Kistenev, E.; Kitamura, R.; Klatsky, J.; Kleinjan, D.; Kline, P.; Koblesky, T.; Komkov, B.; Kotler, J. R.; Kotov, D.; Kudo, S.; Kurita, K.; Kurosawa, M.; Kwon, Y.; Lacey, R.; Lajoie, J. G.; Lallow, E. O.; Lebedev, A.; Lee, S.; Lee, S. H.; Leitch, M. J.; Leung, Y. H.; Lewis, N. A.; Li, X.; Li, X.; Lim, S. H.; Liu, L. D.; Liu, M. X.; Loggins, V.-R.; Loggins, V.-R.; Lovasz, K.; Lynch, D.; Majoros, T.; Makdisi, Y. I.; Makek, M.; Malaev, M.; Manion, A.; Manko, V. I.; Mannel, E.; Masuda, H.; McCumber, M.; McGaughey, P. L.; McGlinchey, D.; McKinney, C.; Meles, A.; Mendez, A. R.; Mendoza, M.; Mignerey, A. C.; Mihalik, D. E.; Milov, A.; Mishra, D. K.; Mitchell, J. T.; Mitsuka, G.; Miyasaka, S.; Mizuno, S.; Mohanty, A. K.; Montuenga, P.; Moon, T.; Morrison, D. P.; Morrow, S. I. M.; Moukhanova, T. V.; Murakami, T.; Murata, J.; Mwai, A.; Nagai, K.; Nagashima, K.; Nagashima, T.; Nagle, J. L.; Nagy, M. I.; Nakagawa, I.; Nakagomi, H.; Nakano, K.; Nattrass, C.; Netrakanti, P. K.; Niida, T.; Nishimura, S.; Nouicer, R.; Novák, T.; Novitzky, N.; Novotny, R.; Nyanin, A. S.; O'Brien, E.; Ogilvie, C. A.; Orjuela Koop, J. D.; Osborn, J. D.; Oskarsson, A.; Ottino, G. J.; Ozawa, K.; Pak, R.; Pantuev, V.; Papavassiliou, V.; Park, J. S.; Park, S.; Pate, S. F.; Patel, M.; Peng, J.-C.; Peng, W.; Perepelitsa, D. V.; Perera, G. D. N.; Peressounko, D. Yu.; Perezlara, C. E.; Perry, J.; Petti, R.; Phipps, M.; Pinkenburg, C.; Pinson, R.; Pisani, R. P.; Press, C. J.; Pun, A.; Purschke, M. L.; Rak, J.; Ramson, B. J.; Ravinovich, I.; Read, K. F.; Reynolds, D.; Riabov, V.; Riabov, Y.; Richford, D.; Rinn, T.; Rolnick, S. D.; Rosati, M.; Rowan, Z.; Rubin, J. G.; Runchey, J.; Safonov, A. S.; Sahlmueller, B.; Saito, N.; Sakaguchi, T.; Sako, H.; Samsonov, V.; Sarsour, M.; Sato, K.; Sato, S.; Schaefer, B.; Schmoll, B. K.; Sedgwick, K.; Seidl, R.; Sen, A.; Seto, R.; Sett, P.; Sexton, A.; Sharma, D.; Shein, I.; Shibata, T.-A.; Shigaki, K.; Shimomura, M.; Shioya, T.; Shukla, P.; Sickles, A.; Silva, C. L.; Silva, J. A.; Silvermyr, D.; Singh, B. K.; Singh, C. P.; Singh, V.; Slunečka, M.; Smith, K. L.; Snowball, M.; Soltz, R. A.; Sondheim, W. E.; Sorensen, S. P.; Sourikova, I. V.; Stankus, P. W.; Stepanov, M.; Stien, H.; Stoll, S. P.; Sugitate, T.; Sukhanov, A.; Sumita, T.; Sun, J.; Syed, S.; Sziklai, J.; Takeda, A.; Taketani, A.; Tanida, K.; Tannenbaum, M. J.; Tarafdar, S.; Taranenko, A.; Tarnai, G.; Tieulent, R.; Timilsina, A.; Todoroki, T.; Tomášek, M.; Towell, C. L.; Towell, R.; Towell, R. S.; Tserruya, I.; Ueda, Y.; Ujvari, B.; van Hecke, H. W.; Vazquez-Carson, S.; Velkovska, J.; Virius, M.; Vrba, V.; Vukman, N.; Wang, X. R.; Wang, Z.; Watanabe, Y.; Watanabe, Y. S.; Wei, F.; White, A. S.; Wong, C. P.; Woody, C. L.; Wysocki, M.; Xia, B.; Xu, C.; Xu, Q.; Xue, L.; Yalcin, S.; Yamaguchi, Y. L.; Yamamoto, H.; Yanovich, A.; Yin, P.; Yoo, J. H.; Yoon, I.; Yu, H.; Yushmanov, I. E.; Zajc, W. A.; Zelenski, A.; Zharko, S.; Zhou, S.; Zou, L.; Phenix Collaboration

2017-03-01

The PHENIX Collaboration has measured the ratio of the yields of ψ (2 S ) to ψ (1 S ) mesons produced in p +p , p +Al , p +Au , and 3He+Au collisions at √{s NN}=200 GeV over the forward and backward rapidity intervals 1.2 <|y |<2.2 . We find that the ratio in p +p collisions is consistent with measurements at other collision energies. In collisions with nuclei, we find that in the forward (p -going or 3He-going) direction, the relative yield of ψ (2 S ) mesons to ψ (1 S ) mesons is consistent with the value measured in p +p collisions. However, in the backward (nucleus-going) direction, the ψ (2 S ) meson is preferentially suppressed by a factor of ˜2 . This suppression is attributed in some models to the breakup of the weakly bound ψ (2 S ) meson through final-state interactions with comoving particles, which have a higher density in the nucleus-going direction. These breakup effects may compete with color screening in a deconfined quark-gluon plasma to produce sequential suppression of excited quarkonia states.

Sphingosine-1-phosphate promotes extravillous trophoblast cell invasion by activating MEK/ERK/MMP-2 signaling pathways via S1P/S1PR1 axis activation.

Science.gov (United States)

Yang, Weiwei; Li, Qinghua; Pan, Zhifang

2014-01-01

Successful placentation depends on the proper invasion of extravillous trophoblast (EVT) cells into maternal tissues. Previous reports demonstrated that S1P receptors are expressed in the EVT cells and S1P could regulate migration and function of trophoblast cells via S1P receptors. However, little is known about roles of S1P in the invasion of EVT cells. Our study was performed to investigate S1P effect on the invasion of EVT cells. We used the extravillous trophoblast cell line HTR8/SVneo cells to evaluate the effect. In vitro invasion assay was employed to determine the invasion of HTR8/SVneo cells induced by S1P. MMP-2 enzyme activity and relative level in the supernatants of HTR8/SVneo was assessed by gelatin zymography and western blot. Based on the above, siRNA and specific inhibitors were used for the intervention and study of potential signal pathways, and Real-time qPCR and western blot were used to test the mRNA and protein level of potential signal targets. We found that S1P could promote HTR8/SVneo cell invasion and upregulates activity and level of MMP-2. The promotion requires activation of MEK-ERK and is dependent on the axis of S1P/S1PR1. Our investigation of S1P may provide new insights into the molecular mechanisms of EVT invasion.

Plasma soluble cluster of differentiation 147 levels are increased in breast cancer patients and associated with lymph node metastasis and chemoresistance.

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Kuang, Y H; Liu, Y J; Tang, L L; Wang, S M; Yan, G J; Liao, L Q

2018-05-25

Cluster of differentiation 147 (CD147) contributes to breast cancer invasion, metastasis, and multidrug resistance. Recent studies have shown that peripheral soluble CD147 (sCD147) is increased in hepatocellular tumour and multiple myeloma patients and correlated with disease severity. The primary aim of our study was to assess the level, as well as the biological and clinical significance of sCD147 in breast cancer. We tested plasma sCD147 levels in 308 breast cancer patients by enzyme-linked immunosorbent assay between February 2014 and February 2017. A subset of 165 cases of benign breast diseases was included as a control group at the same period. We analysed the clinical significance of plasma sCD147 with relevance to clinicopathological factors of breast cancer patients. Plasma sCD147 levels were significantly higher in patients with primary breast cancer than those with benign breast diseases (P=0.001), in patients with locally advanced breast cancer (T3-T4 tumour) than those in early breast cancer (T1-T2 tumour; P=0.001), in patients with lymph node metastasis than in those without (P<0.001), and in patients with high recurrence risk than those with medium recurrence risk (P<0.001). Plasma sCD147 levels were also significantly higher in the chemotherapy-resistant group than in the chemotherapy-sensitive group (P=0.040). Plasma sCD147 was an independent predictor for lymph node metastasis in breast cancer patients (P=0.001). This is the first study to demonstrate that plasma sCD147 levels are elevated in breast cancer patients. Soluble CD147 is also associated with tumour size, lymph node metastasis, high recurrent risk, and chemoresistance. Our findings support that plasma sCD147 is an independent predictive factor for lymph node metastasis.

Albumin modulates S1P delivery from red blood cells in perfused microvessels: mechanism of the protein effect.

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Adamson, R H; Clark, J F; Radeva, M; Kheirolomoom, A; Ferrara, K W; Curry, F E

2014-04-01

Removal of plasma proteins from perfusates increases vascular permeability. The common interpretation of the action of albumin is that it forms part of the permeability barrier by electrostatic binding to the endothelial glycocalyx. We tested the alternate hypothesis that removal of perfusate albumin in rat venular microvessels decreased the availability of sphingosine-1-phosphate (S1P), which is normally carried in plasma bound to albumin and lipoproteins and is required to maintain stable baseline endothelial barriers (Am J Physiol Heart Circ Physiol 303: H825-H834, 2012). Red blood cells (RBCs) are a primary source of S1P in the normal circulation. We compared apparent albumin permeability coefficients [solute permeability (Ps)] measured using perfusates containing albumin (10 mg/ml, control) and conditioned by 20-min exposure to rat RBCs with Ps when test perfusates were in RBC-conditioned protein-free Ringer solution. The control perfusate S1P concentration (439 ± 46 nM) was near the normal plasma value at 37 °C and established a stable baseline Ps (0.9 ± 0.4 × 10(-6) cm/s). Ringer solution perfusate contained 52 ± 8 nM S1P and increased Ps more than 10-fold (16.1 ± 3.9 × 10(-6) cm/s). Consistent with albumin-dependent transport of S1P from RBCs, S1P concentrations in RBC-conditioned solutions decreased as albumin concentration, hematocrit, and temperature decreased. Protein-free Ringer solution perfusates that used liposomes instead of RBCs as flow markers failed to maintain normal permeability, reproducing the "albumin effect" in these mammalian microvessels. We conclude that the albumin effect depends on the action of albumin to facilitate the release and transport of S1P from RBCs that normally provide a significant amount of S1P to the endothelium.

Cascade generation in Al laser induced plasma

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Nagli, Lev; Gaft, Michael; Raichlin, Yosef; Gornushkin, Igor

2018-05-01

We found cascade IR generation in Al laser induced plasma. This generation includes doublet transitions 3s 25s 2S1/2 → 3s24p 2P1/2,3/2 → 3s24s 2S1/2; corresponding to strong lines at 2110 and 2117 nm, and much weaker lines at 1312-1315 nm. The 3s25s2S 1/2 starting IR generation level is directly pumped from the 3s23p 2P3/2 ground level. The starting level for UV generation at 396.2 nm (transitions 3s24s 2S1/2 → 4p 2P3/2) is populated due to the fast collisional processes in the plasma plume. These differences led to different time and special dependences on the lasing in the IR and UV spectral range within the aluminum laser induced plasma.

Decline of plasma 5alpha-dihydrotestosterone (DHT) levels upon testosterone administration to elderly men with subnormal plasma testosterone and high DHT levels.

Science.gov (United States)

Gooren, L J; Saad, F; Haide, A; Yassin, A

2008-10-01

The study was performed to measure the impact of testosterone (T) administration on circulating levels of 5alpha-dihydrotestosterone (DHT). Group 1 (32 men; mean age 61 years; mean T 6.9 +/- 1.9 nmol l(-1)) were treated for 15 months with long-acting T undecanoate. Group 2 (23 men, mean age 60 years, mean T 7.6 +/- 2.0 nmol l(-1)) were treated for 9 months with T gel. Plasma T and DHT were measured before and after 9 months T administration. In the men treated with T undecanoate plasma T and DHT were also measured after 12 and 15 months. Before T administration, plasma DHT ranged from 0.39 to 1.76 nmol l(-1) (0.30-1.90 nmol l(-1)). Mean DHT declined upon T administration from 0.95 +/- 0.50 to 0.55 +/- 0.30 nmol l(-1) (P DHT > 0.60 nmol l(-1) had fallen from 1.29 +/- 0.50 to 0.70 +/- 0.60 nmol l(-1) (P DHT levels declined upon T administration when they were in the higher range of normal (>0.6 nmol l(-1)), with a profound shift of DHT/T ratios presumed to be an indicator of a reduced 5alpha-reductase activity. Below plasma DHT levels of 0.6 nmol l(-1), responses of plasma DHT to T administration varied.

S-Nitrosation destabilizes glutathione transferase P1-1.

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Balchin, David; Stoychev, Stoyan H; Dirr, Heini W

2013-12-23

Protein S-nitrosation is a post-translational modification that regulates the function of more than 500 human proteins. Despite its apparent physiological significance, S-nitrosation is poorly understood at a molecular level. Here, we investigated the effect of S-nitrosation on the activity, structure, stability, and dynamics of human glutathione transferase P1-1 (GSTP1-1), an important detoxification enzyme ubiquitous in aerobes. S-Nitrosation at Cys47 and Cys101 reduces the activity of the enzyme by 94%. Circular dichroism spectroscopy, acrylamide quenching, and amide hydrogen-deuterium exchange mass spectrometry experiments indicate that the loss of activity is caused by the introduction of local disorder at the active site of GSTP1-1. Furthermore, the modification destabilizes domain 1 of GSTP1-1 against denaturation, smoothing the unfolding energy landscape of the protein and introducing a refolding defect. In contrast, S-nitrosation at Cys101 alone introduces a refolding defect in domain 1 but compensates by stabilizing the domain kinetically. These data elucidate the physical basis for the regulation of GSTP1-1 by S-nitrosation and provide general insight into the consequences of S-nitrosation on protein stability and dynamics.

Absolute transition probabilities of 5s-5p transitions of Kr I from interferometric measurements in LTE-plasmas

International Nuclear Information System (INIS)

Kaschek, K.; Ernst, G.K.; Boetticher, W.

1984-01-01

Absolute transition probabilities of nine 5s-5p transitions of Kr I have been evaluated by using the hook method. The plasma was produced in a shock tube. The population density of the 5s-levels was calculated, under the assumption of LTE, from the electron density and the ground state number measured by means of a dual wavelength interferometer. An evaluation is given which proves the validity of the LTE assumption. (orig.)

Plasma Antimicrobial Peptide LL-37 Level Is Inversely Associated with HDL Cholesterol Level in Patients with Type 2 Diabetes Mellitus

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Shu Meguro

2014-01-01

Full Text Available Introduction. Relation between atherosclerosis and innate immunity has attracted attention. As the antimicrobial peptide, LL-37, could have an important role in atherosclerosis, we supposed that there could be a meaningful association of plasma LL-37 level with risk factors for cardiovascular disease in subjects with type 2 diabetes mellitus. Materials and Methods. We evaluated plasma LL-37 level and other clinical markers in Japanese subjects with type 2 diabetes mellitus (n=133, 115 men and 18 women; age 64.7±11.5 years; HbA1c 8.1±1.6%. Plasma level of LL-37 was measured by ELISA. Results. Mean plasma LL-37 level was 71.2±22.3 ng/mL. Plasma LL-37 level showed significant correlations with HDL cholesterol (r=−0.450, P<0.01, triglyceride (r=0.445, P<0.01, and high sensitive C-reactive protein (r=0.316, P<0.01 but no significant correlation with age, body mass index, HbA1c, estimated glomerular filtration rate, 25-hydroxyvitamin D, or vitamin D binding protein. Multiple linear regression analysis showed significant correlations of plasma LL-37 level with HDL cholesterol (β=−0.411, P<0.01 and high sensitive C-reactive protein (β=0.193, P<0.05. Conclusion. Plasma LL-37 level was positively correlated with inflammatory markers and negatively correlated with HDL cholesterol in patients with type 2 diabetes mellitus.

Decreased insulin clearance in individuals with elevated 1-h post-load plasma glucose levels.

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Maria Adelaide Marini

Full Text Available Reduced insulin clearance has been shown to predict the development of type 2 diabetes. Recently, it has been suggested that plasma glucose concentrations ≥ 8.6 mmol/l (155 mg/dl at 1 h during an oral glucose tolerance test (OGTT can identify individuals at high risk for type 2 diabetes among those who have normal glucose tolerance (NGT 1 h-high. The aim of this study was to examine whether NGT 1 h-high have a decrease in insulin clearance, as compared with NGT individuals with 1-h post-load glucose <8.6 mmol/l (l (155 mg/dl, NGT 1 h-low. To this end, 438 non-diabetic White individuals were subjected to OGTT and euglycemic-hyperinsulinemic clamp to evaluate insulin clearance and insulin sensitivity. As compared with NGT 1 h-low individuals, NGT 1 h-high had significantly higher 1-h and 2-h post-load plasma glucose and 2-h insulin levels as well as higher fasting glucose and insulin levels. NGT 1 h-high exhibited also a significant decrease in both insulin sensitivity (P<0.0001 and insulin clearance (P = 0.006 after adjusting for age, gender, adiposity measures, and insulin sensitivity. The differences in insulin clearance remained significant after adjustment for fasting glucose (P = 0.02 in addition to gender, age, and BMI. In univariate analyses adjusted for gender and age, insulin clearance was inversely correlated with body weight, body mass index, waist, fat mass, 1-h and 2-h post-load glucose levels, fasting, 1-h and 2-h post-load insulin levels, and insulin-stimulated glucose disposal. In conclusion, our data show that NGT 1 h-high have a reduction in insulin clearance as compared with NGT 1 h-low individuals; this suggests that impaired insulin clearance may contribute to sustained fasting and post-meal hyperinsulinemia.

Sphingosine 1-phosphate (S1P) signaling in glioblastoma multiforme-A systematic review.

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Mahajan-Thakur, Shailaja; Bien-Möller, Sandra; Marx, Sascha; Schroeder, Henry; Rauch, Bernhard H

2017-11-17

The multifunctional sphingosine-1-phosphate (S1P) is a lipid signaling molecule and central regulator in the development of several cancer types. In recent years, intriguing information has become available regarding the role of S1P in the progression of Glioblastoma multiforme (GBM), the most aggressive and common brain tumor in adults. S1P modulates numerous cellular processes in GBM, such as oncogenesis, proliferation and survival, invasion, migration, metastasis and stem cell behavior. These processes are regulated via a family of five G-protein-coupled S1P receptors (S1PR1-5) and may involve mainly unknown intracellular targets. Distinct expression patterns and multiple intracellular signaling pathways of each S1PR subtype enable S1P to exert its pleiotropic cellular actions. Several studies have demonstrated alterations in S1P levels, the involvement of S1PRs and S1P metabolizing enzymes in GBM pathophysiology. While the tumorigenic actions of S1P involve the activation of several kinases and transcription factors, the specific G-protein (Gi, Gq, and G12/13)-coupled signaling pathways and downstream mediated effects in GBM remain to be elucidated in detail. This review summarizes the recent findings concerning the role of S1P and its receptors in GBM. We further highlight the current insights into the signaling pathways considered fundamental for regulating the cellular processes in GMB and ultimately patient prognosis.

Relationship of serum S1P and HC-II levels with vasoactive substances and cytokines in patients with cerebral vascular restenosis after stent implantation

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Yong Liu

2017-04-01

Full Text Available Objective: To study the relationship of serum sphingosine 1-phosphate (S1P and heparin cofactor II (HCII levels with vasoactive substances and cytokines in patients with cerebral vascular restenosis after stent implantation. Methods: 52 patients who received cerebrovascular stent implantation and developed restenosis in our hospital between May 2012 and December 2015 were collected as observation group, and 40 healthy patients with cerebrovascular stent implantation who had re-examination in our hospital during the same period were selected as control group. ELISA method was used to detect serum S1P and HC-II levels as well as vasoactive substance and inflammatory factor contents. Spearman correlation analysis was used to evaluate the relationship of serum S1P and HC-II levels with vasoactive substances and inflammatory factors. Results: Serum S1P and HC-II levels of observation group were lower than those of control group (P<0.05; serum vasoactive substances endothelin (ET, angiotensin II (AngII and thromboxane B2 (TXB2 contents of observation group were higher than those of control group while nitric oxide (NO content was lower than that of control group (P<0.05; serum inflammatory factors hypersensitive C-reactive protein (hs-CRP, interleukin-1 (IL-1, IL-6, IL-8 and IL-11 contents of observation group were higher than those of control group (P<0.05. Serum S1P and HC-II levels in patients with cerebral vascular restenosis after stent implantation were directly correlated with vasoactive substance and inflammatory factor contents. Conclusion: Serum S1P and HC-II levels decrease in patients with cerebral vascular restenosis after stent implantation, and it is an important cause of cerebral vascular dysfunction and systemic inflammatory response.

Measurements of the ground-state ionization energy and wavelengths for the 1snp 1P1*-1s21S0 (n=4-9) lines of Mg XI and F VIII

International Nuclear Information System (INIS)

Pal'chikov, V.G.; Ya Faenov, A.; Yu Skobelev, I.

2002-01-01

The wavelengths of the 1snp 1 P 1 0 -1s 2 1 S 0 transitions in the He-like Mg XI (n = 4-9) and F VIII (n=4-8) have been measured in laser-produced plasmas. The accuracy of the present measurements (0.4-1.6 mA) is a large improvement over previous results. The Rydberg series is used to determine the ground-state ionization energy of F VIII and Mg XI: E i on (F VIII) 953.96±0.11 eV, E i on (Mg XI)=1761.88±0.15 eV. These experimental results are compared with theoretical data calculated by the 1/Z-expansion method and the HFR and MCDF approaches. Fairly good agreement between theory and experiment is observed with a precision up to 5x10 -5 . Radiative corrections to the 1s 2 1 S 0 state are analysed and compared with experiments. It is found that QED corrections to the ground-state ionization energy are significant at the present level of experimental accuracy. (author)

Study on the effect of edaravone on changes of plasma ET-1 and CGRP levels in patients with traumatic intracerebral hemorrhage

International Nuclear Information System (INIS)

Zhang Chunyin; Cai Liang; Guo Jia; Guan Ming; Gan Xilun

2009-01-01

Objective: To investigate the effect of edaravone treatment on plasma ET-1 and CGRP levels changes in patients with traumatic intracerebral hemorrhage. Methods: Plasma ET-1 and CGRP levels were measured with RIA in 40 patients with traumatic intracerebral hemorrhage both before and after treatment with 60mg of edaravone i. v. q. d. for 5 days, 40 patients both before and after treatment with conventional treatment only (without edaravone) and 30 controls (once only). Results: The plasma ET-1 levels were significantly increased in all the patients at admission than those in controls. After treatment, the levels in all the patients dropped significantly, but the levels were significantly lower in edaravone-treated patients than those in non-edaravone-treated patients (P<0.01). The reverse was true for plasma CGRP levels. Conclusion: Edaravone treatment could correct the abnormal plasma ET-1 and CGRP levels in patients with traumatic intracerebral hemorrhage and might be beneficial to recovery. (authors)

Study on the effect of edaravone on changes of plasma ET-1 and CGRP levels in patients with traumatic intracerebral hemorrhage

Energy Technology Data Exchange (ETDEWEB)

Chunyin, Zhang; Liang, Cai; Jia, Guo; Ming, Guan; Xilun, Gan [Department of Nuclear Medicine, The Affiliated Hospital, Luzhou Medical College, Luzhou (China)

2009-04-15

Objective: To investigate the effect of edaravone treatment on plasma ET-1 and CGRP levels changes in patients with traumatic intracerebral hemorrhage. Methods: Plasma ET-1 and CGRP levels were measured with RIA in 40 patients with traumatic intracerebral hemorrhage both before and after treatment with 60mg of edaravone i. v. q. d. for 5 days, 40 patients both before and after treatment with conventional treatment only (without edaravone) and 30 controls (once only). Results: The plasma ET-1 levels were significantly increased in all the patients at admission than those in controls. After treatment, the levels in all the patients dropped significantly, but the levels were significantly lower in edaravone-treated patients than those in non-edaravone-treated patients (P<0.01). The reverse was true for plasma CGRP levels. Conclusion: Edaravone treatment could correct the abnormal plasma ET-1 and CGRP levels in patients with traumatic intracerebral hemorrhage and might be beneficial to recovery. (authors)

Niacin treatment increases plasma homocyst(e)ine levels.

Science.gov (United States)

Garg, R; Malinow, M; Pettinger, M; Upson, B; Hunninghake, D

1999-12-01

Studies have reported high levels of plasma homocyst(e)ine as an independent risk factor for arterial occlusive disease. The Cholesterol Lowering Atherosclerosis Study reported an increase in plasma homocyst(e)ine levels in patients receiving both colestipol and niacin compared with placebo. Thus the objective of this study was to examine the effect of niacin treatment on plasma homocyst(e)ine levels. The Arterial Disease Multiple Intervention Trial, a multicenter randomized, placebo-controlled trial, examined the effect of niacin compared with placebo on homocyst(e)ine in a subset of 52 participants with peripheral arterial disease. During the screening phase, titration of niacin dose from 100 mg to 1000 mg daily resulted in a 17% increase in mean plasma homocyst(e)ine level from 13.1 +/- 4.4 micromol/L to 15.3 +/- 5.6 micromol/L (P ine levels in the niacin group and a 7% decrease in the placebo group (P =.0001). This difference remained statistically significant at the end of follow-up at 48 weeks. Niacin substantially increased plasma homocyst(e)ine levels, which could potentially reduce the expected benefits of niacin associated with lipoprotein modification. However, plasma homocyst(e)ine levels can be decreased by folic acid supplementation. Thus further studies are needed to determine whether B vitamin supplementation to patients undergoing long-term niacin treatment would be beneficial.

S1P lyase in thymic perivascular spaces promotes egress of mature thymocytes via up-regulation of S1P receptor 1.

Science.gov (United States)

Maeda, Yasuhiro; Yagi, Hideki; Takemoto, Kana; Utsumi, Hiroyuki; Fukunari, Atsushi; Sugahara, Kunio; Masuko, Takashi; Chiba, Kenji

2014-05-01

Sphingosine 1-phosphate (S1P) and S1P receptor 1 (S1P1) play an important role in the egress of mature CD4 or CD8 single-positive (SP) thymocytes from the thymus. Fingolimod hydrochloride (FTY720), an S1P1 functional antagonist, induced significant accumulation of CD62L(high)CD69(low) mature SP thymocytes in the thymic medulla. Immunohistochemical staining using anti-S1P1 antibody revealed that S1P1 is predominantly expressed on thymocytes in the thymic medulla and is strongly down-regulated even at 3h after FTY720 administration. 2-Acetyl-4-tetrahydroxybutylimidazole (THI), an S1P lyase inhibitor, also induced accumulation of mature SP thymocytes in the thymic medulla with an enlargement of the perivascular spaces (PVS). At 6h after THI administration, S1P1-expressing thymocytes reduced partially as if to form clusters and hardly existed in the proximity of CD31-expressing blood vessels in the thymic medulla, suggesting S1P lyase expression in the cells constructing thymic medullary PVS. To determine the cells expressing S1P lyase in the thymus, we newly established a mAb (YK19-2) specific for mouse S1P lyase. Immunohistochemical staining with YK19-2 revealed that S1P lyase is predominantly expressed in non-lymphoid thymic stromal cells in the thymic medulla. In the thymic medullary PVS, S1P lyase was expressed in ER-TR7-positive cells (reticular fibroblasts and pericytes) and CD31-positive vascular endothelial cells. Our findings suggest that S1P lyase expressed in the thymic medullary PVS keeps the tissue S1P concentration low around the vessels and promotes thymic egress via up-regulation of S1P1.

Sphingosine-1-Phosphate Induces Dose-Dependent Chemotaxis or Fugetaxis of T-ALL Blasts through S1P1 Activation

Science.gov (United States)

Messias, Carolina V.; Santana-Van-Vliet, Eliane; Lemos, Julia P.; Moreira, Otacilio C.; Cotta-de-Almeida, Vinicius; Savino, Wilson; Mendes-da-Cruz, Daniella Arêas

2016-01-01

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in several physiological processes including cell migration and differentiation. S1P signaling is mediated through five G protein-coupled receptors (S1P1-S1P5). S1P1 is crucial to the exit of T-lymphocytes from the thymus and peripheral lymphoid organs through a gradient of S1P. We have previously observed that T-ALL and T-LBL blasts express S1P1. Herein we analyzed the role of S1P receptors in the migratory pattern of human T-cell neoplastic blasts. S1P-triggered cell migration was directly related to S1P1 expression. T-ALL blasts expressing low levels of S1P1 mRNA (HPB-ALL) did not migrate toward S1P, whereas those expressing higher levels of S1P1 (MOLT-4, JURKAT and CEM) did migrate. The S1P ligand induced T-ALL cells chemotaxis in concentrations up to 500 nM and induced fugetaxis in higher concentrations (1000–10000 nM) through interactions with S1P1. When S1P1 was specifically blocked by the W146 compound, S1P-induced migration at lower concentrations was reduced, whereas higher concentrations induced cell migration. Furthermore, we observed that S1P/S1P1 interactions induced ERK and AKT phosphorylation, and modulation of Rac1 activity. Responding T-ALL blasts also expressed S1P3 mRNA but blockage of this receptor did not modify migratory responses. Our results indicate that S1P is involved in the migration of T-ALL/LBL blasts, which is dependent on S1P1 expression. Moreover, S1P concentrations in the given microenvironment might induce dose-dependent chemotaxis or fugetaxis of T-ALL blasts. PMID:26824863

Sphingosine-1-Phosphate Induces Dose-Dependent Chemotaxis or Fugetaxis of T-ALL Blasts through S1P1 Activation.

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Carolina V Messias

Full Text Available Sphingosine-1-phosphate (S1P is a bioactive sphingolipid involved in several physiological processes including cell migration and differentiation. S1P signaling is mediated through five G protein-coupled receptors (S1P1-S1P5. S1P1 is crucial to the exit of T-lymphocytes from the thymus and peripheral lymphoid organs through a gradient of S1P. We have previously observed that T-ALL and T-LBL blasts express S1P1. Herein we analyzed the role of S1P receptors in the migratory pattern of human T-cell neoplastic blasts. S1P-triggered cell migration was directly related to S1P1 expression. T-ALL blasts expressing low levels of S1P1 mRNA (HPB-ALL did not migrate toward S1P, whereas those expressing higher levels of S1P1 (MOLT-4, JURKAT and CEM did migrate. The S1P ligand induced T-ALL cells chemotaxis in concentrations up to 500 nM and induced fugetaxis in higher concentrations (1000-10000 nM through interactions with S1P1. When S1P1 was specifically blocked by the W146 compound, S1P-induced migration at lower concentrations was reduced, whereas higher concentrations induced cell migration. Furthermore, we observed that S1P/S1P1 interactions induced ERK and AKT phosphorylation, and modulation of Rac1 activity. Responding T-ALL blasts also expressed S1P3 mRNA but blockage of this receptor did not modify migratory responses. Our results indicate that S1P is involved in the migration of T-ALL/LBL blasts, which is dependent on S1P1 expression. Moreover, S1P concentrations in the given microenvironment might induce dose-dependent chemotaxis or fugetaxis of T-ALL blasts.

Plasma sCD14 as a biomarker to predict pulmonary exacerbations in cystic fibrosis.

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Bradley S Quon

Full Text Available BACKGROUND: One in four cystic fibrosis (CF patients diagnosed with a pulmonary exacerbation will not recover their baseline lung function despite standard treatment. This highlights the importance of preventing such events. Clinical decision-making can be improved through a simple blood test that predicts individuals at elevated short-term risk of an exacerbation. METHODS: We obtained plasma samples from 30 stable CF patients from the St. Paul's Hospital Adult CF Clinic (Vancouver, Canada. For 15 patients, an additional plasma sample was obtained during an exacerbation. Soluble CD14 (sCD14 and C-reactive protein (CRP were quantified using ELISA kits. Myeloperoxidase (MPO, interleukin(IL-6, IL-1β, monocyte chemoattractant protein-1 (MCP-1, vascular endothelial growth factor (VEGF, and granulocyte colony-stimulating factor (G-CSF were quantified using Luminex™ immunoassays. Stable state biomarker levels were examined in their ability to predict individuals that would experience a pulmonary exacerbation requiring intravenous (IV antibiotics within 4 months. Paired stable and exacerbation plasma biomarker levels were also compared. RESULTS: sCD14 levels were significantly higher in patients that experienced a pulmonary exacerbation requiring IV antibiotics within 4 months (p = 0.001. sCD14 cut-off value of 1450 ng/mL was associated with an area under the curve of 0.91 (95% CI 0.83-0.99 for predicting an exacerbation within 4 months of a stable visit, with a sensitivity of 100% and specificity of 82%. Plasma sCD14 levels were significantly higher during exacerbations than during periods of clinical stability (p = 0.03. CONCLUSIONS: Plasma sCD14 is a promising biomarker for identifying CF patients who will exacerbate within 4 months of a stable visit but requires further study in larger, independent cohorts.

Sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling regulates receptor activator of NF-κB ligand (RANKL) expression in rheumatoid arthritis

International Nuclear Information System (INIS)

Takeshita, Harunori; Kitano, Masayasu; Iwasaki, Tsuyoshi; Kitano, Sachie; Tsunemi, Sachi; Sato, Chieri; Sekiguchi, Masahiro; Azuma, Naoto; Miyazawa, Keiji; Hla, Timothy; Sano, Hajime

2012-01-01

Highlights: ► MH7A cells and CD4 + T cells expressed S1P1 and RANKL. ► S1P increased RANKL expression in MH7A cells and CD4 + T cells. ► The effect of S1P in MH7A cells was inhibited by specific Gi/Go inhibitors. -- Abstract: Sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1P1) signaling plays an important role in synovial cell proliferation and inflammatory gene expression by rheumatoid arthritis (RA) synoviocytes. The purpose of this study is to clarify the role of S1P/S1P1 signaling in the expression of receptor activator of NF-κB ligand (RANKL) in RA synoviocytes and CD4 + T cells. We demonstrated MH7A cells, a human RA synovial cell line, and CD4 + T cells expressed S1P1 and RANKL. Surprisingly, S1P increased RANKL expression in MH7A cells and CD4 + T cells in a dose-dependent manner. Moreover, S1P enhanced RANKL expression induced by stimulation with TNF-α in MH7A cells and CD4 + T cells. These effects of S1P in MH7A cells were inhibited by pretreatment with PTX, a specific Gi/Go inhibitor. These findings suggest that S1P/S1P1 signaling may play an important role in RANKL expression by MH7A cells and CD4 + T cells. S1P/S1P1 signaling of RA synoviocytes is closely connected with synovial hyperplasia, inflammation, and RANKL-induced osteoclastogenesis in RA. Thus, regulation of S1P/S1P1 signaling may become a novel therapeutic target for RA.

Sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling regulates receptor activator of NF-{kappa}B ligand (RANKL) expression in rheumatoid arthritis

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Takeshita, Harunori [Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Kitano, Masayasu, E-mail: mkitano6@hyo-med.ac.jp [Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Iwasaki, Tsuyoshi [Department of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima Kobe, Hyogo 650-8530 (Japan); Kitano, Sachie; Tsunemi, Sachi; Sato, Chieri; Sekiguchi, Masahiro; Azuma, Naoto [Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Miyazawa, Keiji [Discovery Research III, Research and Development, Kissei Pharmaceutical Company, 4365-1 Hodakakashiwara, Azumino, Nagano 399-8304 (Japan); Hla, Timothy [Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 1300 York Avenue, Box 69, NY 10065 (United States); Sano, Hajime [Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan)

2012-03-09

Highlights: Black-Right-Pointing-Pointer MH7A cells and CD4{sup +} T cells expressed S1P1 and RANKL. Black-Right-Pointing-Pointer S1P increased RANKL expression in MH7A cells and CD4{sup +} T cells. Black-Right-Pointing-Pointer The effect of S1P in MH7A cells was inhibited by specific Gi/Go inhibitors. -- Abstract: Sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1P1) signaling plays an important role in synovial cell proliferation and inflammatory gene expression by rheumatoid arthritis (RA) synoviocytes. The purpose of this study is to clarify the role of S1P/S1P1 signaling in the expression of receptor activator of NF-{kappa}B ligand (RANKL) in RA synoviocytes and CD4{sup +} T cells. We demonstrated MH7A cells, a human RA synovial cell line, and CD4{sup +} T cells expressed S1P1 and RANKL. Surprisingly, S1P increased RANKL expression in MH7A cells and CD4{sup +} T cells in a dose-dependent manner. Moreover, S1P enhanced RANKL expression induced by stimulation with TNF-{alpha} in MH7A cells and CD4{sup +} T cells. These effects of S1P in MH7A cells were inhibited by pretreatment with PTX, a specific Gi/Go inhibitor. These findings suggest that S1P/S1P1 signaling may play an important role in RANKL expression by MH7A cells and CD4{sup +} T cells. S1P/S1P1 signaling of RA synoviocytes is closely connected with synovial hyperplasia, inflammation, and RANKL-induced osteoclastogenesis in RA. Thus, regulation of S1P/S1P1 signaling may become a novel therapeutic target for RA.

High Plasma TIMP-1 and Serum CEA Levels during Combination Chemotherapy for Metastatic Colorectal Cancer Are Significantly Associated with Poor Outcome

DEFF Research Database (Denmark)

Aldulaymi, Bahir; Byström, Per; Berglund, Ake

2010-01-01

. The first response evaluation was performed after 8 weeks of chemotherapy. Results: Median plasma TIMP-1 and serum CEA levels did not change significantly during 6 weeks of treatment. High plasma TIMP-1 and high serum CEA levels before treatment and at weeks 2, 4 and 6 were related to poor objective...... associated with poor overall survival; p

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

DEFF Research Database (Denmark)

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

1995-01-01

before and immediately (5-30 s) after 80 min infusion of NTG (glyceryl trinitrate) or saline in 12 healthy subjects. On two different days separated by at least 1 week, NTG in four different doses, 0.015, 0.25, 1.0, and 2.0 micrograms. kg-1. min-1, or placebo (isotonic saline) was infused successively...... for 20 min each dose. During the infusion blood pressure and heart rate were measured. NTG infusion significantly decreased systolic blood pressure from 112.4 to 103.4 mmHg and pulse pressure from 39.3 to 29.5 mmHg. Heart rate increased from 62.7 to 73.1 beats. min-1. No changes in endothelin-1 plasma...... levels were induced by NTG infusion (2.4 pg.ml-1 before NTG vs. 2.7 pg.ml-1 after NTG) and placebo infusion also did not affect plasma endothelin-1. It is concluded that venous plasma levels of endothelin-1 are not altered immediately after NTG infusion....

BAYESZ, S-Wave, P-Wave Resonance Level Spacing and Strength Functions

International Nuclear Information System (INIS)

Moore, M.S.

1982-01-01

A - Description of problem or function: BAYESZ calculates average s- and p-wave level spacings, strength functions, and average radiation widths of a mixed sequence of s- and p-wave resonances whose parameters are supplied as input. The code is based on two physical assumptions: 1) The neutron reduced width distribution for each open channel is a chi-squared distribution with one degree of freedom, i.e. Porter-Thomas. 2) The spacing distribution follows the Gaussian Orthogonal Ensemble. This property is used, however, only to fix the s- to p-wave level density ratio as proportional to (2J+1) with a spin cut-off correction. B - Method of solution: The method used is an extension of that described by Moore et al. in reference (1), and is based on the method of moments of a truncated Porter-Thomas distribution. C - Restrictions on the complexity of the problem: Parameters for a maximum of 500 individual resonances can be specified. This restriction can be relaxed by increasing array dimensions

Evaluation of plasma H2S levels and H2S synthesis in streptozotocin induced Type-2 diabetes-an experimental study based on Swietenia macrophylla seeds

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Moumita Dutta

2014-05-01

Conclusions: Although considering a small sample size, it can conclude that the fasting blood glucose levels are inversely related to plasma H2S levels as well as H2S synthesis activity in plasma and the extract of S. macrophylla is associated with increased plasma H2S levels with effective lowering of blood glucose in streptozotocin induced diabetic rats.

Sphingosine-1-phosphate (S1P) enhances glomerular endothelial cells activation mediated by anti-myeloperoxidase antibody-positive IgG.

Science.gov (United States)

Sun, Xiao-Jing; Chen, Min; Zhao, Ming-Hui

2018-03-01

Cumulating evidences suggested an important role of sphingosine-1-phosphate (S1P) and its receptors in regulating endothelial barrier integrity. Our previous study revealed that the circulating S1P levels and renal expression of S1PRs correlated with disease activity and renal damage in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study investigated the role of S1P and its receptors in myeloperoxidase (MPO)-ANCA-positive IgG-mediated glomerular endothelial cell (GEnC) activation. The effect of S1P on morphological alteration of GEnCs in the presence of MPO-ANCA-positive IgG was observed. Permeability assay was performed to determine endothelial monolayer activation in quantity. Both membrane-bound and soluble ICAM-1 and VCAM-1 levels were measured. Furthermore, antagonists and/or agonists of various S1PRs were employed to determine the role of different S1PRs. S1P enhanced MPO-ANCA-positive IgG-induced disruption of tight junction and disorganization of cytoskeleton in GEnCs. S1P induced further increase in monolayer permeability of GEnC monolayers in the presence of MPO-ANCA-positive IgG. S1P enhanced MPO-ANCA-positive IgG-induced membrane-bound and soluble ICAM-1/VCAM-1 up-regulation of GEnCs. Soluble ICAM-1 levels in the supernatants of GEnCs stimulated by S1P and MPO-ANCA-positive IgG increased upon pre-incubation of S1PR1 antagonist, while pre-incubation of GEnCs with the S1PR1 agonist down-regulated sICAM-1 level. Blocking S1PR2-4 reduced sICAM-1 levels in the supernatants of GEnCs stimulated by S1P and MPO-ANCA-positive IgG. Pre-incubation with S1PR5 agonist could increase sICAM-1 level in the supernatants of GEnC stimulated by S1P and MPO-ANCA-positive IgG. S1P can enhance MPO-ANCA-positive IgG-mediated GEnC activation through S1PR2-5. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Elevated plasma endothelin-1 and pulmonary arterial pressure in children exposed to air pollution.

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Calderón-Garcidueñas, Lilian; Vincent, Renaud; Mora-Tiscareño, Antonieta; Franco-Lira, Maricela; Henríquez-Roldán, Carlos; Barragán-Mejía, Gerardo; Garrido-García, Luis; Camacho-Reyes, Laura; Valencia-Salazar, Gildardo; Paredes, Rogelio; Romero, Lina; Osnaya, Hector; Villarreal-Calderón, Rafael; Torres-Jardón, Ricardo; Hazucha, Milan J; Reed, William

2007-08-01

Controlled exposures of animals and humans to particulate matter (PM) or ozone air pollution cause an increase in plasma levels of endothelin-1, a potent vasoconstrictor that regulates pulmonary arterial pressure. The primary objective of this field study was to determine whether Mexico City children, who are chronically exposed to levels of PM and O(3) that exceed the United States air quality standards, have elevated plasma endothelin-1 levels and pulmonary arterial pressures. We conducted a study of 81 children, 7.9 +/- 1.3 years of age, lifelong residents of either northeast (n = 19) or southwest (n = 40) Mexico City or Polotitlán (n = 22), a control city with PM and O(3) levels below the U.S. air quality standards. Clinical histories, physical examinations, and complete blood counts were done. Plasma endothelin-1 concentrations were determined by immunoassay, and pulmonary arterial pressures were measured by Doppler echocardiography. Mexico City children had higher plasma endothelin-1 concentrations compared with controls (p < 0.001). Mean pulmonary arterial pressure was elevated in children from both northeast (p < 0.001) and southwest (p < 0.05) Mexico City compared with controls. Endothelin-1 levels in Mexico City children were positively correlated with daily outdoor hours (p = 0.012), and 7-day cumulative levels of PM air pollution < 2.5 mum in aerodynamic diameter (PM(2.5)) before endothelin-1 measurement (p = 0.03). Chronic exposure of children to PM(2.5) is associated with increased levels of circulating endothelin-1 and elevated mean pulmonary arterial pressure.

Elevated Plasma Endothelin-1 and Pulmonary Arterial Pressure in Children Exposed to Air Pollution

Science.gov (United States)

Calderón-Garcidueñas, Lilian; Vincent, Renaud; Mora-Tiscareño, Antonieta; Franco-Lira, Maricela; Henríquez-Roldán, Carlos; Barragán-Mejía, Gerardo; Garrido-García, Luis; Camacho-Reyes, Laura; Valencia-Salazar, Gildardo; Paredes, Rogelio; Romero, Lina; Osnaya, Hector; Villarreal-Calderón, Rafael; Torres-Jardón, Ricardo; Hazucha, Milan J.; Reed, William

2007-01-01

Background Controlled exposures of animals and humans to particulate matter (PM) or ozone air pollution cause an increase in plasma levels of endothelin-1, a potent vasoconstrictor that regulates pulmonary arterial pressure. Objectives The primary objective of this field study was to determine whether Mexico City children, who are chronically exposed to levels of PM and O3 that exceed the United States air quality standards, have elevated plasma endothelin-1 levels and pulmonary arterial pressures. Methods We conducted a study of 81 children, 7.9 ± 1.3 years of age, lifelong residents of either northeast (n = 19) or southwest (n = 40) Mexico City or Polotitlán (n = 22), a control city with PM and O3 levels below the U.S. air quality standards. Clinical histories, physical examinations, and complete blood counts were done. Plasma endothelin-1 concentrations were determined by immunoassay, and pulmonary arterial pressures were measured by Doppler echocardiography. Results Mexico City children had higher plasma endothelin-1 concentrations compared with controls (p < 0.001). Mean pulmonary arterial pressure was elevated in children from both northeast (p < 0.001) and southwest (p < 0.05) Mexico City compared with controls. Endothelin-1 levels in Mexico City children were positively correlated with daily outdoor hours (p = 0.012), and 7-day cumulative levels of PM air pollution < 2.5 μm in aerodynamic diameter (PM2.5) before endothelin-1 measurement (p = 0.03). Conclusions Chronic exposure of children to PM2.5 is associated with increased levels of circulating endothelin-1 and elevated mean pulmonary arterial pressure. PMID:17687455

Relationship Between Plasma Homocystein Levels and Polyneuropaty in Patients Using Levodopa For Idiopathic Parkinson’s Disease

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Mithat Bedir

2012-06-01

Full Text Available Objective: Recent studies showed high plasma homocysteine levels in patients treated with Levodopa for Parkinson’s disease (PD. Homocysteine, due to its exotoxic effect, might be the cause of polyneuropathy seen in PD. In this study, our aim was to show the correlation between high concentration of plasma homocysteine levels and polyneuropathy associated with PD.. Material and Methods: Forty-one patients with PD receiving levodopa treatment (patient group and 30 healthy subjects (control group were included in this study. We compared the two groups in terms of electrophysiological findings. Twelve patients had high plasma homocysteine levels and 29 of them had low plasma homocysteine levels. Results: Six of the 41 patients had sensorial polyneuropathy and decreased compound muscle action potantiel amplitude compared to controls. Two patients had high plasma homocysteine levels, two patients had nearly high plasma homocysteine levels, two patients had low plasma homocysteine levels who had sensorial polyneuropathy. Conclusion: Although in our study, we did not show any correlation between polyneuropathy and high plasma homocysteine levels, further studies including homogeneous groups of younger patients with PD are needed. (The Me di cal Bul - le tin of Ha se ki 2012; 50: 53-8

Exogenous S1P Exposure Potentiates Ischemic Stroke Damage That Is Reduced Possibly by Inhibiting S1P Receptor Signaling.

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Moon, Eunjung; Han, Jeong Eun; Jeon, Sejin; Ryu, Jong Hoon; Choi, Ji Woong; Chun, Jerold

2015-01-01

Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-α. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain.

Exogenous S1P Exposure Potentiates Ischemic Stroke Damage That Is Reduced Possibly by Inhibiting S1P Receptor Signaling

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Eunjung Moon

2015-01-01

Full Text Available Initial and recurrent stroke produces central nervous system (CNS damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-α. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain.

Selective coupling of the S1P3 receptor subtype to S1P-mediated RhoA activation and cardioprotection.

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Yung, Bryan S; Brand, Cameron S; Xiang, Sunny Y; Gray, Charles B B; Means, Christopher K; Rosen, Hugh; Chun, Jerold; Purcell, Nicole H; Brown, Joan Heller; Miyamoto, Shigeki

2017-02-01

Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is generated and released at sites of tissue injury in the heart and can act on S1P 1 , S1P 2 , and S1P 3 receptor subtypes to affect cardiovascular responses. We established that S1P causes little phosphoinositide hydrolysis and does not induce hypertrophy indicating that it does not cause receptor coupling to G q . We previously demonstrated that S1P confers cardioprotection against ischemia/reperfusion by activating RhoA and its downstream effector PKD. The S1P receptor subtypes and G proteins that regulate RhoA activation and downstream responses in the heart have not been determined. Using siRNA or pertussis toxin to inhibit different G proteins in NRVMs we established that S1P regulates RhoA activation through Gα 13 but not Gα 12 , Gα q , or Gα i . Knockdown of the three major S1P receptors using siRNA demonstrated a requirement for S1P 3 in RhoA activation and subsequent phosphorylation of PKD, and this was confirmed in studies using isolated hearts from S1P 3 knockout (KO) mice. S1P treatment reduced infarct size induced by ischemia/reperfusion in Langendorff perfused wild-type (WT) hearts and this protection was abolished in the S1P 3 KO mouse heart. CYM-51736, an S1P 3 -specific agonist, also decreased infarct size after ischemia/reperfusion to a degree similar to that achieved by S1P. The finding that S1P 3 receptor- and Gα 13 -mediated RhoA activation is responsible for protection against ischemia/reperfusion suggests that selective targeting of S1P 3 receptors could provide therapeutic benefits in ischemic heart disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

The use of radiation trapping in the measurement of the electron excitation cross section for the production of the 1s4 (3P1) level of Ne

International Nuclear Information System (INIS)

Miers, R.E.; Gastineau, J.E.; Phillps, M.H.; Anderson, L.W.; Lin, C.C.

1981-01-01

The authors report the use of laser induced fluorescence for the first measurement of the electron excitation cross section for the production of the 1s 4 ( 3 P 1 ) level of Ne. Radiation trapping is used to lengthen the effective lifetime of the 1s 4 level allowing for the electron excitation cross section of the 1s 4 level to be measured in a manner similar to the measurement of electron excitation cross sections of the metastable 1s 3 and 1s 5 levels. (Auth.)

Fine structure of the 1s5f and 1s5g levels of He I

International Nuclear Information System (INIS)

Kriescher, Y.; Hilt, O.; Oppen, G. v.

1994-01-01

The fine structure of the 1s 5f and 1s 5g levels of He I was measured using microwave spectroscopy. The helium atoms were excited by ion impact, and the eleven allowed 1s 5f 2S+1 F J -1s 5g 2S'+1 G J , transitions near ν∼15 GHz were induced and detected by measuring the 1s 4d-1s 2p or 1s 3d-1s 2p spectral-line intensities of the impact radiation as a function of the microwave frequency. The measured transition frequencies are in accord with theoretical values and, except for one transition frequency, with earlier experimental data. The existing discrepancy between these earlier data and theory could be solved. (orig.)

Magnetic flux conversion and relaxation toward a minimum-energy state in S-1 spheromak plasmas

International Nuclear Information System (INIS)

Janos, A.

1985-09-01

S-1 Spheromak currents and magnetic fluxes have been measured with Rogowski coils and flux loops external to the plasma. Toroidal plasma currents up to 350 kA and spheromak configuration lifetimes over 1.0 msec have been achieved at moderate power levels. The plasma formation in the S-1 Spheromak device is based on an inductive transfer of poloidal and toroidal magnetic flux from a toroidal ''flux core'' to the plasma. Formation is programmed to guide the configuration into a force-free, minimum-energy Taylor state. Properly detailed programming of the formation process is found not to be essential since plasmas adjust themselves during formation to a final equilibrium near the Taylor state. After formation, if the plasma evolves away from the stable state, then distinct relaxation oscillation events occur which restore the configuration to that stable state. The relaxation process involves reconnection of magnetic field lines, and conversion of poloidal to toroidal magnetic flux (and vice versa) has been observed and documented. The scaling of toroidal plasma current and toroidal magnetic flux in the plasma with externally applied currents is consistent with the establishment of a Taylor state after formation. In addition, the magnetic helicity is proportional to that injected from the flux core, independent of how that helicity is generated

Improved wavelengths for the 1s2s3S1-1s2p3P0,2 transitions in helium-like Si12+

International Nuclear Information System (INIS)

Armour, I.A.; Myers, E.G.; Silver, J.D.; Traebert, E.; Oxford Univ.

1979-01-01

The wavelengths of the 1s2s 3 S 1 -1s2p 3 P 0 , 2 transitions in He-like Si 12+ have been remaesured to be 87.86 +- 0.01 nm and 81.48 +- 0.01 nm. The use of Rydberg lines for the calibration of fast beam spectra is discussed. (orig.)

Aberrant expression of the S1P regulating enzymes, SPHK1 and SGPL1, contributes to a migratory phenotype in OSCC mediated through S1PR2.

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Patmanathan, Sathya Narayanan; Johnson, Steven P; Lai, Sook Ling; Panja Bernam, Suthashini; Lopes, Victor; Wei, Wenbin; Ibrahim, Maha Hafez; Torta, Federico; Narayanaswamy, Pradeep; Wenk, Markus R; Herr, Deron R; Murray, Paul G; Yap, Lee Fah; Paterson, Ian C

2016-05-10

Oral squamous cell carcinoma (OSCC) is a lethal disease with a 5-year mortality rate of around 50%. Molecular targeted therapies are not in routine use and novel therapeutic targets are required. Our previous microarray data indicated sphingosine 1-phosphate (S1P) metabolism and signalling was deregulated in OSCC. In this study, we have investigated the contribution of S1P signalling to the pathogenesis of OSCC. We show that the expression of the two major enzymes that regulate S1P levels were altered in OSCC: SPHK1 was significantly upregulated in OSCC tissues compared to normal oral mucosa and low levels of SGPL1 mRNA correlated with a worse overall survival. In in vitro studies, S1P enhanced the migration/invasion of OSCC cells and attenuated cisplatin-induced death. We also demonstrate that S1P receptor expression is deregulated in primary OSCCs and that S1PR2 is over-expressed in a subset of tumours, which in part mediates S1P-induced migration of OSCC cells. Lastly, we demonstrate that FTY720 induced significantly more apoptosis in OSCC cells compared to non-malignant cells and that FTY720 acted synergistically with cisplatin to induce cell death. Taken together, our data show that S1P signalling promotes tumour aggressiveness in OSCC and identify S1P signalling as a potential therapeutic target.

The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P₁ and hypertension (S1P₃ in rat.

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Ryan M Fryer

Full Text Available Sphingosine-1-phospate (S1P and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P(X receptor agonist produces modest hypertension in patients (2-3 mmHg in 1-yr trial as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension, and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P₁,₅ agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min elicited acute bradycardia in anesthetized rats demonstrating an S1P₁ mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls, BAF312 (0.3, 3.0, 30.0 mg/kg/d had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P₃ receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P₁ receptors mediate bradycardia while hypertension is mediated by S1P₃ receptor activation.

Interaction of integrin β4 with S1P receptors in S1P- and HGF-induced endothelial barrier enhancement.

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Ni, Xiuqin; Epshtein, Yulia; Chen, Weiguo; Zhou, Tingting; Xie, Lishi; Garcia, Joe G N; Jacobson, Jeffrey R

2014-06-01

We previously reported sphingosine 1-phosphate (S1P) and hepatocyte growth factor (HGF) augment endothelial cell (EC) barrier function and attenuate murine acute lung inury (ALI). While the mechanisms underlying these effects are not fully understood, S1P and HGF both transactivate the S1P receptor, S1PR1 and integrin β4 (ITGB4) at membrane caveolin-enriched microdomains (CEMs). In the current study, we investigated the roles of S1PR2 and S1PR3 in S1P/HGF-mediated EC signaling and their associations with ITGB4. Our studies confirmed ITGB4 and S1PR2/3 are recruited to CEMs in human lung EC in response to either S1P (1 µM, 5 min) or HGF (25 ng/ml, 5 min). Co-immunoprecipitation experiments identified an S1P/HGF-mediated interaction of ITGB4 with both S1PR2 and S1PR3. We then employed an in situ proximity ligation assay (PLA) to confirm a direct ITGB4-S1PR3 association induced by S1P/HGF although a direct association was not detectable between S1PR2 and ITGB4. S1PR1 knockdown (siRNA), however, abrogated S1P/HGF-induced ITGB4-S1PR2 associations while there was no effect on ITGB4-S1PR3 associations. Moreover, PLA confirmed a direct association between S1PR1 and S1PR2 induced by S1P and HGF. Finally, silencing of S1PR2 significantly attenuated S1P/HGF-induced EC barrier enhancement as measured by transendothelial resistance while silencing of S1PR3 significantly augmented S1P/HGF-induced barrier enhancement. These results confirm an important role for S1PR2 and S1PR3 in S1P/HGF-mediated EC barrier responses that are associated with their complex formation with ITGB4. Our findings elucidate novel mechanisms of EC barrier regulation that may ultimately lead to new therapeutic targets for disorders characterized by increased vascular permeability including ALI. © 2013 Wiley Periodicals, Inc.

Very low levels of 6-keto-prostaglandin F 1/sub α/ in human plasma

International Nuclear Information System (INIS)

Siess, W.; Dray, F.

1982-01-01

Two stable derivatives of PGI 2 , its nonenzymatic hydrolysis product (6-keto-PGF 1 /sub α/) and an enzymatic metabolite (6, 15-diketo-PGF 1 /sub α/) were determined in human plasma and urine. These compounds were measured by RIA after separation on rp-HPLC. Previous purification of the samples on rp=HPLC markedly enhanced the specificity of the RIA determinations of those compounds in plasma and urine. The PGI 2 derivative 6-keto-PGF 1 /sub α/ was detected in both plasma (4.7 +/- 3.2 pg/ml, mean +/- S.D., n = 34) and urine (166 +/- 61 pg/ml, n = 9). No gender differences of the plasma or urinary levels of 6-keto-PGF 1 /sub α/ were found. The PGI 2 metabolite 6, 15-diketo-PGF 1 /sub α/ was not measurable in plasma or urine ( 2 in man. When [ 3 H]PGI 2 was added to citrated blood immediately after venipuncture, it was recovered entirely as [ 3 H]6-keto-PGF 1 /sub α/ after rp-HPLC. Therefore any circulating PGI 2 would be measured as 6-keto-PGF 1 /sub α/ by our method. The results obtained suggest that PGI 2 could be present in human venous blood under physiological conditions, but only in very low concentrations

Plasma Biomarkers Differentiate Parkinson’s Disease From Atypical Parkinsonism Syndromes

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Chin-Hsien Lin

2018-04-01

Full Text Available Objective: Parkinson’s disease (PD has significant clinical overlaps with atypical parkinsonism syndromes (APS, which have a poorer treatment response and a more aggressive course than PD. We aimed to identify plasma biomarkers to differentiate PD from APS.Methods: Plasma samples (n = 204 were obtained from healthy controls and from patients with PD, dementia with Lewy bodies (DLB, multiple system atrophy, progressive supranuclear palsy (PSP, corticobasal degeneration (CBD, or frontotemporal dementia (FTD with parkinsonism (FTD-P or without parkinsonism. We measured plasma levels of α-synuclein, total tau, p-Tau181, and amyloid beta 42 (Aβ42 by immunomagnetic reduction-based immunoassay.Results: Plasma α-synuclein level was significantly increased in patients with PD and APS when compared with controls and FTD without parkinsonism (p < 0.01. Total tau and p-Tau181 were significantly increased in all disease groups compared to controls, especially in patients with FTD (p < 0.01. A multivariate and receiver operating characteristic curve analysis revealed that a cut-off value for Aβ42 multiplied by p-Tau181 for discriminating patients with FTD from patients with PD and APS was 92.66 (pg/ml2, with an area under the curve (AUC of 0.932. An α-synuclein cut-off of 0.1977 pg/ml could separate FTD-P from FTD without parkinsonism (AUC 0.947. In patients with predominant parkinsonism, an α-synuclein cut-off of 1.388 pg/ml differentiated patients with PD from those with APS (AUC 0.87.Conclusion: Our results suggest that integrated plasma biomarkers improve the differential diagnosis of PD from APS (PSP, CBD, DLB, and FTD-P.

Plasma levels of the MMP-9:TIMP-1 complex as prognostic biomarker in breast cancer: a retrospective study

International Nuclear Information System (INIS)

Thorsen, Stine B; Møller, Susanne; Brünner, Nils; Schrohl, Anne-Sofie; Stenvang, Jan; Christensen, Sarah LT; Würtz, Sidse Ø; Lundberg, Martin; Nielsen, Birgitte S; Vinther, Lena; Knowles, Mick; Gee, Nick; Fredriksson, Simon

2013-01-01

Worldwide more than one million women are annually diagnosed with breast cancer. A considerable fraction of these women receive systemic adjuvant therapy; however, some are cured by primary surgery and radiotherapy alone. Prognostic biomarkers guide stratification of patients into different risk groups and hence improve management of breast cancer patients. Plasma levels of Matrix Metalloproteinase-9 (MMP-9) and its natural inhibitor Tissue inhibitor of metalloproteinase-1 (TIMP-1) have previously been associated with poor patient outcome and resistance to certain forms of chemotherapy. To pursue additional prognostic information from MMP-9 and TIMP-1, the level of the MMP-9 and TIMP-1 complex (MMP-9:TIMP-1) was investigated in plasma from breast cancer patients. Detection of protein:protein complexes in plasma was performed using a commercially available ELISA kit and, for the first time, the highly sensitive in-solution proximity ligation assay (PLA). We screened plasma from 465 patients with primary breast cancer for prognostic value of the MMP-9:TIMP-1 complex. Both assays were validated and applied for quantification of MMP-9:TIMP-1 concentration. In this retrospective study, we analyzed the association between the concentration of the MMP-9:TIMP-1 complex and clinicopathological data and disease free survival (DFS) in univariate and multivariate survival analyses. Following successful validation both assays were applied for MMP-9:TIMP-1 measurements. Of the clinicopathological parameters, only menopausal status demonstrated significant association with the MMP-9:TIMP-1 complex; P = 0.03 and P = 0.028 for the ELISA and PLA measurements, respectively. We found no correlation between the MMP-9:TIMP-1 protein complex and DFS neither in univariate nor in multivariate survival analyses. Despite earlier reports linking MMP-9 and TIMP-1 with prognosis in breast cancer patients, we here demonstrate that plasma levels of the MMP-9:TIMP-1 protein complex hold no

Smad3 deficiency leads to mandibular condyle degradation via the sphingosine 1-phosphate (S1P)/S1P3 signaling axis.

Science.gov (United States)

Mori, Hiroki; Izawa, Takashi; Tanaka, Eiji

2015-10-01

Temporomandibular joint osteoarthritis is a degenerative disease that is characterized by permanent cartilage destruction. Transforming growth factor (TGF)-β is one of the most abundant cytokines in the bone matrix and is shown to regulate the migration of osteoprogenitor cells. It is hypothesized that TGF-β/Smad3 signaling affects cartilage homeostasis by influencing sphingosine 1-phosphate (S1P)/S1P receptor signaling and chondrocyte migration. We therefore investigated the molecular mechanisms by which crosstalk may occur between TGF-β/Smad3 and S1P/S1P receptor signaling to maintain condylar cartilage and to prevent temporomandibular joint osteoarthritis. Abnormalities in the condylar subchondral bone, including dynamic changes in bone mineral density and microstructure, were observed in Smad3(-/-) mice by microcomputed tomography. Cell-free regions and proteoglycan loss characterized the cartilage degradation present, and increased numbers of apoptotic chondrocytes and matrix metalloproteinase 13(+) chondrocytes were also detected. Furthermore, expression of S1P receptor 3 (S1P3), but not S1P1 or S1P2, was significantly down-regulated in the condylar cartilage of Smad3(-/-) mice. By using RNA interference technology and pharmacologic tools, S1P was found to transactivate Smad3 in an S1P3/TGF-β type II receptor-dependent manner, and S1P3 was found to be required for TGF-β-induced migration of chondrocyte cells and downstream signal transduction via Rac1, RhoA, and Cdc42. Taken together, these results indicate that the Smad3/S1P3 signaling pathway plays an important role in the pathogenesis of temporomandibular joint osteoarthritis. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Effects of in vivo irradiation on plasma levels of carotenoids and vitamin A

International Nuclear Information System (INIS)

White, W.S.; Roe, D.A.

1986-01-01

The aims of this investigation were to determine whether ultraviolet irradiation induces alterations in plasma carotenoid and vitamin A levels in human subjects. Twelve Caucasian women participated in an 8-week crossover trial. UV exposures were given to the anterior and posterior sides of the body on 11 days of a 2-week period. Mean cumulative UVA (320-400 nm) doses of 17.9 +/- 2.6 J/cm 2 and 24.1 +/- 1.5 J/cm 2 were delivered to the anterior and posterior sides, respectively. UVB (280-320 nm) doses were equivalent to 10% of the UVA doses given. Intake of carotenoids and preformed vitamin A was held constant. Plasma samples were collected weekly for spectrophotometric analysis of total carotenoids and vitamin A. A significant reduction (p < 0.003) in plasma carotenoid levels was observed following repeated irradiation. Although a significant treatment response could not be demonstrated for plasma vitamin A (p=0.11), a significant test for carryover (p < 0.02) suggested a delayed or continuing increase in plasma levels following irradiation. It is concluded that UV irradiation can reduce plasma carotenoid levels in vivo and may also affect plasma vitamin A levels in an adaptive response

Higher plasma soluble Receptor for Advanced Glycation End Products (sRAGE) levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study

DEFF Research Database (Denmark)

Nin, Johanna W M; Jorsal, Anders; Merces Ferreira, Isabel Maria

2010-01-01

To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunct......To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal...

Plasma uric acid levels correlate with inflammation and disease severity in Malian children with Plasmodium falciparum malaria.

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Tatiana M Lopera-Mesa

Full Text Available Plasmodium falciparum elicits host inflammatory responses that cause the symptoms and severe manifestations of malaria. One proposed mechanism involves formation of immunostimulatory uric acid (UA precipitates, which are released from sequestered schizonts into microvessels. Another involves hypoxanthine and xanthine, which accumulate in parasitized red blood cells (RBCs and may be converted by plasma xanthine oxidase to UA at schizont rupture. These two forms of 'parasite-derived' UA stimulate immune cells to produce inflammatory cytokines in vitro.We measured plasma levels of soluble UA and inflammatory cytokines and chemokines (IL-6, IL-10, sTNFRII, MCP-1, IL-8, TNFα, IP-10, IFNγ, GM-CSF, IL-1β in 470 Malian children presenting with uncomplicated malaria (UM, non-cerebral severe malaria (NCSM or cerebral malaria (CM. UA levels were elevated in children with NCSM (median 5.74 mg/dl, 1.21-fold increase, 95% CI 1.09-1.35, n = 23, p = 0.0007 and CM (median 5.69 mg/dl, 1.19-fold increase, 95% CI 0.97-1.41, n = 9, p = 0.0890 compared to those with UM (median 4.60 mg/dl, n = 438. In children with UM, parasite density and plasma creatinine levels correlated with UA levels. These UA levels correlated with the levels of seven cytokines [IL-6 (r = 0.259, p<0.00001, IL-10 (r = 0.242, p<0.00001, sTNFRII (r = 0.221, p<0.00001, MCP-1 (r = 0.220, p<0.00001, IL-8 (r = 0.147, p = 0.002, TNFα (r = 0.132, p = 0.006 and IP-10 (r = 0.120, p = 0.012]. In 39 children, UA levels were 1.49-fold (95% CI 1.34-1.65; p<0.0001 higher during their malaria episode [geometric mean titer (GMT 4.67 mg/dl] than when they were previously healthy and aparasitemic (GMT 3.14 mg/dl.Elevated UA levels may contribute to the pathogenesis of P. falciparum malaria by activating immune cells to produce inflammatory cytokines. While this study cannot identify the cause of elevated UA levels, their association with parasite density and creatinine levels suggest that parasite-derived UA

Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis

DEFF Research Database (Denmark)

Kragstrup, Tue Wenzel; Jalilian, Babak; Hvid, Malene

2014-01-01

of arthritis patients to have anti-inflammatory functions. Here, we study the mechanisms for these alterations and their association with SpA disease activity. METHODS: Plasma levels of sCD18 in a study population with 84 SpA patients and matched healthy controls were analyzed with a time resolved......A patients compared with healthy volunteers (P levels in the HLA-B27-positive subgroup (P levels exhibited an inverse correlation with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (P level of morning...... immunoflourometric assay (TRIFMA). Binding of sCD18 to endothelial cells and fibroblast-like synovial cells (FLS) was studied with confocal microscopy. Shedding of CD18 from peripheral blood mononuclear cells (PBMC) was studied with flow cytometry and TRIFMA. RESULTS: Plasma levels of sCD18 were decreased in Sp...

Measurement of operative plasma endotoxin levels in jaundiced and non-jaundiced patients.

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Pain, J A; Bailey, M E

1987-01-01

A study of portal plasma endotoxin levels was performed using a chromogenic limulus amoebocyte lysate (LAL) assay. The assay proved sensitive and reproducible. In only 1 of 25 healthy subjects was the systemic plasma endotoxin level above 100 pg/ml (equivalent Escherichia coli 0111B4). In 30 non-jaundiced patients undergoing surgery the mean (+SEM) portal plasma endotoxin level (60 + 9 pg/ml) was significantly higher (p less than 0.05) than the mean level in the systemic blood (46 + 6 pg/ml), supporting the concept of endotoxin absorption from the intestine into the portal blood. In 20 patients with obstructive jaundice undergoing surgery 42% of portal, 45% of inferior mesenteric and 35% of systemic venous plasma endotoxin levels were above 100 pg/ml. There were significantly higher levels in the portal (p less than 0.05) and inferior mesenteric (p less than 0.05) compared with the systemic blood. Neither the presence of malignancy nor the duration of surgery appeared to influence endotoxin absorption. The significance of raised plasma endotoxin levels in obstructive jaundice is discussed.

Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface.

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Bretillon, L; Lütjohann, D; Ståhle, L; Widhe, T; Bindl, L; Eggertsen, G; Diczfalusy, U; Björkhem, I

2000-05-01

We have previously presented evidence that most of the 24S-hydroxycholesterol present in the circulation originates from the brain and that most of the elimination of this oxysterol occurs in the liver. Plasma 24S-hydroxycholesterol levels decline by a factor of about 5 during the first decades of life. The concentration of the enzyme cholesterol 24S-hydroxylase in the brain is, however, about constant from the first year of life, and reduced enzyme levels thus cannot explain the decreasing plasma levels during infancy. In the present work we tested the hypothesis that the plasma levels of 24S-hydroxycholesterol may reflect the size of the brain relative to the capacity of the liver to eliminate the substance. It is shown here that the age-dependent changes in absolute as well as cholesterol-related plasma level of 24S-hydroxycholesterol closely follow the changes in the ratio between estimated brain weight and estimated liver volume. The size of the brain is increased only about 50% whereas the size of the liver is increased by about 6-fold after the age of 1 year. Liver volume is known to be highly correlated to body surface, and in accordance with this the absolute as well as the cholesterol-related plasma level of 24S-hydroxycholesterol was found to be highly inversely correlated to body surface in 77 healthy subjects of varying ages (r(2) = 0.74). Two chondrodystrophic dwarves with normal size of the brain but with markedly reduced body area had increased levels of 24S-hydroxycholesterol when related to age but normal levels when related to body surface. It is concluded that the balance between cerebral production and hepatic metabolism is a critical determinant for plasma levels of 24S-hydroxycholesterol at different ages and that endocrinological factors are less important. The results are discussed in relation to the possibility to use 24S-hydroxycholesterol in the circulation as a marker for cholesterol homeostasis in the brain.

Electron excitation cross sections of the 2p53s levels of neon

International Nuclear Information System (INIS)

Phillips, M.H.

1982-01-01

The electron excitation cross sections of the four 2p 5 3s levels of neon are measured by means of a new technique using laser induced fluorescenc. The values of both the apparent and direct excitatiuon cross sections are given as a function of incident electron energy (0-100eV for 1s 3 and 1s 5 metastable levels and 0-300 eV for the 1s 2 and 1s 4 resonance levels). The metastable levels are triplet states and their cross sections are sharply peaked. At the peak, 30 eV, the measured values of the cross sections are 0.59 x 10 -18 cm 2 for the 1s 3 level and 3.2 x 10 -18 cm 2 for the 1s 5 level. The 1s 2 and 1s 4 levels are mixtures of singlet and triplet states, and the cross sections are broad and peak at 60 eV. The apparent cross sections at 60 eV are 13.5 x 10 -18 cm 2 for the 1s 2 level and 2.9 x 10 -18 cm 2 for the 1s 4 level. Measurement of the atomic number density of each of the 1s levels is performed using the pulsed laser induced fluorescence. The measured values of the number density and the excitation cross section are used to obtain the lifetime of each level. The measured value of the reciprocal of the 1s 3 and 1s 5 lifetime is 1 x 10 5 s -1 . The 1s 2 and 1s 4 levels are radiation trapped, and the reciprocals of their lifetimes are 4 x 10 5 s -1 and 3 x 10 5 s -1 respectively. The electron excitation cross sections of the magnetic sublevels of each 1s level are obtained by measuring the polarization of the laser induced fluorescence as a function of laser polarization. The excitation cross sections of each of the magnetic sublevels within a particular 1s level are equal within experimental uncertainty

Correlation of plasma endothelin-1 levels with pulmonary hypertension after inhaled nitric oxide therapy

International Nuclear Information System (INIS)

Razzaq, Z.; Naqvi, S.; Aslam, M.

2009-01-01

Variable response to inhaled nitric oxide (iNO) therapy in patients with mitral stenosis (MS) having pulmonary hypertension (PH) has been documented in early studies. The objectives of this study were to measure plasma Endothelin-1 (ET-1) levels in those patients and to correlate them with pulmonary vascular indices after iNO therapy. It was Quesi-experimental study. Methods: Thirty patients with mitral or mixed mitral and aortic valve disease with severe pulmonary hypertension and enrolled for valve replacement surgery were included. Before the replacement, baseline pulmonary vascular indices and cardiac output were recorded. After the surgery, 10 - 20 was in administered for 1 hour and all the parameters were again recorded. Patients were grouped into responders and non responders on the basis of % reduction in Pulmonary Vascular Resistance (PVR) after iNO therapy. Plasma ET-1 levels were measured in both groups by ELISA before and after the iNO therapy. Paired sample t-test was used to compare mean values for significance. The correlations between variables were then calculated by using Pearson's coefficient. Results: The plasma ET-1 levels were very high in all patients. They reduced in responders after iNO therapy; non-responders paradoxically showed significant increase in the levels of ET-1 after iNO therapy. Moreover, a positive correlation was observed in plasma ET-1 levels and post operative levels of PVR. Conclusion: The correlation of changes in PVR and plasma ET-1 levels in responders suggests that high plasma ET-1 is a key mediator of poor response in PH secondary to MS, after iNO therapy. (author)

Sphingosine-1-Phosphate (S1P) Signaling in Neural Progenitors.

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Callihan, Phillip; Alqinyah, Mohammed; Hooks, Shelley B

2018-01-01

Sphingosine-1-phosphate (S1P) and its receptors are important in nervous system development. Reliable in vitro human model systems are needed to further define specific roles for S1P signaling in neural development. We have described S1P-regulated signaling, survival, and differentiation in a human embryonic stem cell-derived neuroepithelial progenitor cell line (hNP1) that expresses functional S1P receptors. These cells can be further differentiated to a neuronal cell type and therefore represent a good model system to study the role of S1P signaling in human neural development. The following sections describe in detail the culture and differentiation of hNP1 cells and two assays to measure S1P signaling in these cells.

Energy-Crossing and Its Effect on Lifetime of the 4s24p 2P3/2 Level for Highly Charged Ga-Like Ions

International Nuclear Information System (INIS)

Fan Jian-Zhong; Zhang Deng-Hong; Chang Zhi-Wei; Shi Ying-Long; Dong Chen-Zhong

2012-01-01

The multi-configuration Dirac—Fock method is employed to calculate the energy levels and transition probabilities for the electric dipole allowed (E1) and forbidden (M1, E2) lines for the 4s 2 4p, 4s4p 2 and 4s 2 4d configurations of highly charged Ga-like ions from Z = 68–95. The lifetimes of the 4s 2 4p 2 P 3/2 level of the ground configuration are also derived. Based on our calculations, it is found that the energy level of the 4s 2 4p 2 P 3/2 is higher than that of the 4s4p 2 4 P 1/2 for the high-Z Ga-like ions with Z ≥ 74, so as to generate an energy crossing at Z = 74. The effect of the energy crossing is important to the calculation of the 4s 2 4p 2 P 3/2 level lifetime for Ga-like ions with Z ≥ 74. (atomic and molecular physics)

Clinical value of plasma endothelin levels in children with cardiovascular diseases

International Nuclear Information System (INIS)

Chen Nianfa; Duan Yongqiang

2009-01-01

To explore the clinical value of plasma endothelin (ET-1) levels in children with cardiovascular diseases, 77 children with heart failure, obesity, hyperlipemia, fatty liver and hypertension were divided into 5 experimental groups and 21 health children with same age and gender as control group. The plasma levels of ET-1 in these children were tested by RIA. The results showed that plasma levels of ET-1 in 5 experimental groups were 112.8 ± 34.1ng/L, 57.8 ± 19.1ng/L,64.5 ± 25.3ng/L, 74.9 ± 28.4ng/L and 60.7 ± 21.6ng/L, respectively. The ET-1 levels in 5 groups were significantly higher than that in control group (P<0.01). The results indicate the higher plasma ET-1 levels in children are related with cardiovascular diseases, and it is useful in the diagnosis of children cardiovascular diseases. (authors)

A systematic review and meta-analysis of plasma amyloid 1-42 and tau as biomarkers for Alzheimer’s disease

Directory of Open Access Journals (Sweden)

Keerthanaa Balasubramanian Shanthi

2015-08-01

Full Text Available Objective: Amyloid 1-42 (Aβ42 and tau in cerebrospinal fluid are currently used as markers for diagnosis of Alzheimer’s disease. Conflicting reports exist regarding their plasma levels in Alzheimer’s disease patients. A meta-analysis was performed to statistically validate the use of plasma Aβ42 and tau as biomarkers for Alzheimer’s disease. Methods: Different databases were searched using the search key: (amyloid OR amyloid1-42 OR Aβ42 AND (tau OR total tau AND plasma AND (alzheimer’s OR alzheimer’s disease, and for databases not accepting boolean search, records were retrieved using the search key: plasma + amyloid + tau + alzheimer’s. A total of 1880 articles for Aβ42 and 1508 articles for tau were shortlisted. The abstracts were screened, and 69 articles reporting plasma Aβ42 levels and 6 articles reporting plasma tau were identified. After exclusion, 25 studies reporting plasma Aβ42 and 6 studies reporting total tau were analysed in Review Manager version 5.2 using weighted mean difference method, and the bias between studies was assessed using the funnel plot. Results: Plasma Aβ42 and tau did not vary significantly between Alzheimer’s disease patients and controls. The funnel plot showed that there was no bias between studies for Aβ42, while possible bias existed for tau due to availability of limited studies. Conclusion: This analysis pinpoints that plasma Aβ42 and tau could not serve as reliable markers independently for diagnosis of Alzheimer’s disease and a cohort study with age, sex and apolipoprotein E correction is warranted for their possible use as Alzheimer’s disease markers.

Correlation of plasma B-type natriuretic peptide levels with metabolic risk markers.

Science.gov (United States)

Ahued-Ortega, José Armando; León-García, Plácido Enrique; Hernández-Pérez, Elizabeth

2018-04-17

Natriuretic peptide type B (BNP) is a marker of myocardium injury. This peptide has been associated with metabolic risk markers, although controversy exists in this regard. The aim of the present study was to determine the correlation of plasma BNP levels with metabolic risk parameters. A retrospective, observational study that included 152 patients, who were classified according to their clinical diagnosis as patients with metabolic syndrome. Plasma BNP levels and clinical metabolic parameters were assessed by using Spearmańs rank correlation coefficient. A significant inverse association with weight (r=-.408; p<.0001) and BMI (r=-.443; p<.001) was obtained. While a positive significant association with systolic pressure (r=.324; p<.001) was observed. A significant decrease was found in BNP levels and components of metabolic syndrome. (p<.05). Based on the results from this study, we can conclude that BNP determination could be an adequate metabolic marker. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

The Transporter Spns2 Is Required for Secretion of Lymph but Not Plasma Sphingosine-1-Phosphate