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Sample records for plasma s1p levels

  1. Hepatic S1P deficiency lowers plasma cholesterol levels in apoB-containing lipoproteins when LDLR function is compromised.

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    Basu, Debapriya; Huq, Afroza; Iqbal, Jahangir; Hussain, M Mahmood; Jiang, Xian-Cheng; Jin, Weijun

    2015-01-01

    Site-1 protease (S1P) is the key enzyme required for activation of the sterol regulatory element binding proteins (SREBPs) that govern lipid synthesis. While S1P has been speculated to influence plasma apoB-containing lipoprotein (Blp) metabolism, there has been little investigative work. LDL receptor (LDLR) is the major receptor for clearing plasma LDL cholesterol (LDL-c). Proprotein convertase subtilisin kexin type 9 (PCSK9) modulates LDL-c through post-translational degradation of the LDLR. A hepatic-specific knockdown (KD) of S1P was achieved using floxed S1P mouse models (S1P(f/f) and LDLR(-/-)S1P(f/f)) and hepatic expression of Cre recombinase. Lipids were measured in total plasma and size fractionated plasma using colorimetric assays. Realtime polymerase chain reaction, western blotting and ELISA were used to determine hepatic expression of key genes/protein. Plasmid mediated overexpression and siRNA mediated knockdown of genes were performed in mouse primary hepatocytes to determine the mechanistic basis of PCSK9 gene regulation. A hepatic-specific KD of S1P resulted in a 45 % and 38 % reduction in plasma total cholesterol and triglyceride levels, respectively. Hepatic S1P KD had a minimal effect on plasma Blp cholesterol (Blp-c) in S1P(f/f) mice, despite significantly reducing VLDL secretion. Notably, hepatic S1P KD decreased the LDL receptor (LDLR) mRNA expression by 50 %. However, the reduction in LDLR protein levels was less than that of mRNA expression, especially under fed conditions. Further assessment of hepatic S1P deficiency revealed that it increased LDLR protein stability in vivo. Mechanistically, hepatic S1P KD was shown to decrease the liver and plasma levels of the protein proprotein convertase subtilisin/kexin type 9 (PCSK9), which degrades LDLR protein. This effect was more prominent in the fed condition and sufficient to account for the discordance in LDLR mRNA and protein levels. Furthermore, hepatic S1P was shown to regulate PCSK9

  2. Sphingosine-1-Phosphate (S1P) Lyase Inhibition Causes Increased Cardiac S1P Levels and Bradycardia in Rats.

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    Harris, Christopher M; Mittelstadt, Scott; Banfor, Patricia; Bousquet, Peter; Duignan, David B; Gintant, Gary; Hart, Michelle; Kim, Youngjae; Segreti, Jason

    2016-10-01

    Inhibition of the sphingosine-1-phosphate (S1P)-catabolizing enzyme S1P lyase (S1PL) elevates the native ligand of S1P receptors and provides an alternative mechanism for immune suppression to synthetic S1P receptor agonists. S1PL inhibition is reported to preferentially elevate S1P in lymphoid organs. Tissue selectivity could potentially differentiate S1PL inhibitors from S1P receptor agonists, the use of which also results in bradycardia, atrioventricular block, and hypertension. But it is unknown if S1PL inhibition would also modulate cardiac S1P levels or cardiovascular function. The S1PL inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile was used to determine the relationship in rats between drug concentration, S1P levels in select tissues, and circulating lymphocytes. Repeated oral doses of the S1PL inhibitor fully depleted circulating lymphocytes after 3 to 4 days of treatment in rats. Full lymphopenia corresponded to increased levels of S1P of 100- to 1000-fold in lymph nodes, 3-fold in blood (but with no change in plasma), and 9-fold in cardiac tissue. Repeated oral dosing of the S1PL inhibitor in telemeterized, conscious rats resulted in significant bradycardia within 48 hours of drug treatment, comparable in magnitude to the bradycardia induced by 3 mg/kg fingolimod. These results suggest that S1PL inhibition modulates cardiac function and does not provide immune suppression with an improved cardiovascular safety profile over fingolimod in rats. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  3. Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock.

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    Gazit, Salomé L; Mariko, Boubacar; Thérond, Patrice; Decouture, Benoit; Xiong, Yuquan; Couty, Ludovic; Bonnin, Philippe; Baudrie, Véronique; Le Gall, Sylvain M; Dizier, Blandine; Zoghdani, Nesrine; Ransinan, Jessica; Hamilton, Justin R; Gaussem, Pascale; Tharaux, Pierre-Louis; Chun, Jerold; Coughlin, Shaun R; Bachelot-Loza, Christilla; Hla, Timothy; Ho-Tin-Noé, Benoit; Camerer, Eric

    2016-09-30

    Sphingosine-1-phosphate (S1P) signaling is essential for vascular development and postnatal vascular homeostasis. The relative importance of S1P sources sustaining these processes remains unclear. To address the level of redundancy in bioactive S1P provision to the developing and mature vasculature. S1P production was selectively impaired in mouse platelets, erythrocytes, endothelium, or smooth muscle cells by targeted deletion of genes encoding sphingosine kinases -1 and -2. S1P deficiency impaired aggregation and spreading of washed platelets and profoundly reduced their capacity to promote endothelial barrier function ex vivo. However, and in contrast to recent reports, neither platelets nor any other source of S1P was essential for vascular development, vascular integrity, or hemostasis/thrombosis. Yet rapid and profound depletion of plasma S1P during systemic anaphylaxis rendered both platelet- and erythrocyte-derived S1P essential for survival, with a contribution from blood endothelium observed only in the absence of circulating sources. Recovery was sensitive to aspirin in mice with but not without platelet S1P, suggesting that platelet activation and stimulus-response coupling is needed. S1P deficiency aggravated vasoplegia in this model, arguing a vital role for S1P in maintaining vascular resistance during recovery from circulatory shock. Accordingly, the S1P2 receptor mediated most of the survival benefit of S1P, whereas the endothelial S1P1 receptor was dispensable for survival despite its importance for maintaining vascular integrity. Although source redundancy normally secures essential S1P signaling in developing and mature blood vessels, profound depletion of plasma S1P renders both erythrocyte and platelet S1P pools necessary for recovery and high basal plasma S1P levels protective during anaphylactic shock. © 2016 American Heart Association, Inc.

  4. [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

  5. Increased mRNA Levels of Sphingosine Kinases and S1P Lyase and Reduced Levels of S1P Were Observed in Hepatocellular Carcinoma in Association with Poorer Differentiation and Earlier Recurrence.

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    Uranbileg, Baasanjav; Ikeda, Hitoshi; Kurano, Makoto; Enooku, Kenichiro; Sato, Masaya; Saigusa, Daisuke; Aoki, Junken; Ishizawa, Takeaki; Hasegawa, Kiyoshi; Kokudo, Norihiro; Yatomi, Yutaka

    2016-01-01

    Although sphingosine 1-phosphate (S1P) has been reported to play an important role in cancer pathophysiology, little is known about S1P and hepatocellular carcinoma (HCC). To clarify the relationship between S1P and HCC, 77 patients with HCC who underwent surgical treatment were consecutively enrolled in this study. In addition, S1P and its metabolites were quantitated by LC-MS/MS. The mRNA levels of sphingosine kinases (SKs), which phosphorylate sphingosine to generate S1P, were increased in HCC tissues compared with adjacent non-HCC tissues. Higher mRNA levels of SKs in HCC were associated with poorer differentiation and microvascular invasion, whereas a higher level of SK2 mRNA was a risk factor for intra- and extra-hepatic recurrence. S1P levels, however, were unexpectedly reduced in HCC compared with non-HCC tissues, and increased mRNA levels of S1P lyase (SPL), which degrades S1P, were observed in HCC compared with non-HCC tissues. Higher SPL mRNA levels in HCC were associated with poorer differentiation. Finally, in HCC cell lines, inhibition of the expression of SKs or SPL by siRNA led to reduced proliferation, invasion and migration, whereas overexpression of SKs or SPL enhanced proliferation. In conclusion, increased SK and SPL mRNA expression along with reduced S1P levels were more commonly observed in HCC tissues compared with adjacent non-HCC tissues and were associated with poor differentiation and early recurrence. SPL as well as SKs may be therapeutic targets for HCC treatment.

  6. Accurate quantification of sphingosine-1-phosphate in normal and Fabry disease plasma, cells and tissues by LC-MS/MS with (13)C-encoded natural S1P as internal standard.

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    Mirzaian, Mina; Wisse, Patrick; Ferraz, Maria J; Marques, André R A; Gabriel, Tanit L; van Roomen, Cindy P A A; Ottenhoff, Roelof; van Eijk, Marco; Codée, Jeroen D C; van der Marel, Gijsbert A; Overkleeft, Herman S; Aerts, Johannes M

    2016-08-01

    We developed a mass spectrometric procedure to quantify sphingosine-1-phosphate (S1P) in biological materials. The use of newly synthesized (13)C5 C18-S1P and commercial C17-S1P as internal standards rendered very similar results with respect to linearity, limit of detection and limit of quantitation. Caution is warranted with determination of plasma S1P levels. Earlier it was reported that S1P is elevated in plasma of Fabry disease patients. We investigated this with the improved quantification. No clear conclusion could be drawn for patient plasma samples given the lack of uniformity of blood collection and plasma preparation. To still obtain insight, plasma and tissues were identically collected from α-galactosidase A deficient Fabry mice and matched control animals. No significant difference was observed in plasma S1P levels. A significant 2.3 fold increase was observed in kidney of Fabry mice, but not in liver and heart. Comparative analysis of S1P in cultured fibroblasts from normal subjects and classically affected Fabry disease males revealed no significant difference. In conclusion, accurate quantification of S1P in biological materials is feasible by mass spectrometry using the internal standards (13)C5 C18-S1P or C17-S1P. Significant local increases of S1P in the kidney might occur in Fabry disease as suggested by the mouse model. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. 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....

  8. 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.

  9. Sphingosine 1-Phosphate (S1P) Carrier-dependent Regulation of Endothelial Barrier

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    Wilkerson, Brent A.; Grass, G. Daniel; Wing, Shane B.; Argraves, W. Scott; Argraves, Kelley M.

    2012-01-01

    Sphingosine 1-phosphate (S1P) is a blood-borne lysosphingolipid that acts to promote endothelial cell (EC) barrier function. In plasma, S1P is associated with both high density lipoproteins (HDL) and albumin, but it is not known whether the carriers impart different effects on S1P signaling. Here we establish that HDL-S1P sustains EC barrier longer than albumin-S1P. We showed that the sustained barrier effects of HDL-S1P are dependent on signaling by the S1P receptor, S1P1, and involve persistent activation of Akt and endothelial NOS (eNOS), as well as activity of the downstream NO target, soluble guanylate cyclase (sGC). Total S1P1 protein levels were found to be higher in response to HDL-S1P treatment as compared with albumin-S1P, and this effect was not associated with increased S1P1 mRNA or dependent on de novo protein synthesis. Several pieces of evidence indicate that long term EC barrier enhancement activity of HDL-S1P is due to specific effects on S1P1 trafficking. First, the rate of S1P1 degradation, which is proteasome-mediated, was slower in HDL-S1P-treated cells as compared with cells treated with albumin-S1P. Second, the long term barrier-promoting effects of HDL-S1P were abrogated by treatment with the recycling blocker, monensin. Finally, cell surface levels of S1P1 and levels of S1P1 in caveolin-enriched microdomains were higher after treatment with HDL-S1P as compared with albumin-S1P. Together, the findings reveal S1P carrier-specific effects on S1P1 and point to HDL as the physiological mediator of sustained S1P1-PI3K-Akt-eNOS-sGC-dependent EC barrier function. PMID:23135269

  10. A Prokaryotic S1P Lyase Degrades Extracellular S1P In Vitro and In Vivo: Implication for Treating Hyperproliferative Disorders

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    Huwiler, Andrea; Bourquin, Florence; Kotelevets, Nataliya; Pastukhov, Oleksandr; Capitani, Guido; Grütter, Markus G.; Zangemeister-Wittke, Uwe

    2011-01-01

    Sphingosine-1-phosphate (S1P) regulates a broad spectrum of fundamental cellular processes like proliferation, death, migration and cytokine production. Therefore, elevated levels of S1P may be causal to various pathologic conditions including cancer, fibrosis, inflammation, autoimmune diseases and aberrant angiogenesis. Here we report that S1P lyase from the prokaryote Symbiobacterium thermophilum (StSPL) degrades extracellular S1P in vitro and in blood. Moreover, we investigated its effect on cellular responses typical of fibrosis, cancer and aberrant angiogenesis using renal mesangial cells, endothelial cells, breast (MCF-7) and colon (HCT 116) carcinoma cells as disease models. In all cell types, wild-type StSPL, but not an inactive mutant, disrupted MAPK phosphorylation stimulated by exogenous S1P. Functionally, disruption of S1P receptor signaling by S1P depletion inhibited proliferation and expression of connective tissue growth factor in mesangial cells, proliferation, migration and VEGF expression in carcinoma cells, and proliferation and migration of endothelial cells. Upon intravenous injection of StSPL in mice, plasma S1P levels rapidly declined by 70% within 1 h and then recovered to normal 6 h after injection. Using the chicken chorioallantoic membrane model we further demonstrate that also under in vivo conditions StSPL, but not the inactive mutant, inhibited tumor cell-induced angiogenesis as an S1P-dependent process. Our data demonstrate that recombinant StSPL is active under extracellular conditions and holds promise as a new enzyme therapeutic for diseases associated with increased levels of S1P and S1P receptor signaling. PMID:21829623

  11. 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.

  12. Accurate quantification of sphingosine-1-phosphate in normal and Fabry disease plasma, cells and tissues by LC-MS/MS with (13)C-encoded natural S1P as internal standard

    NARCIS (Netherlands)

    Mirzaian, Mina; Wisse, Patrick; Ferraz, Maria J.; Marques, André R. A.; Gabriel, Tanit L.; van Roomen, Cindy P. A. A.; Ottenhoff, Roelof; van Eijk, Marco; Codée, Jeroen D. C.; van der Marel, Gijsbert A.; Overkleeft, Herman S.; Aerts, Johannes M.

    2016-01-01

    We developed a mass spectrometric procedure to quantify sphingosine-1-phosphate (S1P) in biological materials. The use of newly synthesized (13)C5 C18-S1P and commercial C17-S1P as internal standards rendered very similar results with respect to linearity, limit of detection and limit of

  13. 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.

  14. 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

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. 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.

  18. 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.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  1. Decreased plasma levels of the endothelial protective sphingosine-1-phosphate are associated with dengue-induced plasma leakage

    NARCIS (Netherlands)

    Michels, M.; Japtok, L.; Alisjahbana, B.; Wisaksana, R.; Sumardi, U.; Puspita, M.; Kleuser, B.; Mast, Q. de; Ven, A.J.A.M. van der

    2015-01-01

    BACKGROUND: A transient endothelial hyperpermeability is a hallmark of severe dengue infections. Sphingosine-1-phosphate (S1P) maintains vascular integrity and protects against plasma leakage. We related plasma S1P levels to dengue-induced plasma leakage and studied mechanisms that may underlie the

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

    Science.gov (United States)

    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.

  3. A Shift in ApoM/S1P Between HDL-Particles in Women With Type 1 Diabetes Mellitus Is Associated With Impaired Anti-Inflammatory Effects of the ApoM/S1P Complex.

    Science.gov (United States)

    Frej, Cecilia; Mendez, Armando J; Ruiz, Mario; Castillo, Melanie; Hughes, Thomas A; Dahlbäck, Björn; Goldberg, Ronald B

    2017-06-01

    Type 1 diabetes mellitus (T1D) patients have an increased risk of cardiovascular disease despite high levels of high-density lipoproteins (HDL). Apolipoprotein M (apoM) and its ligand sphingosine 1-phospate (S1P) exert many of the anti-inflammatory effects of HDL. We investigated whether apoM and S1P are altered in T1D and whether apoM and S1P are important for HDL functionality in T1D. ApoM and S1P were quantified in plasma from 42 healthy controls and 89 T1D patients. HDL was isolated from plasma and separated into dense, medium-dense, and light HDL by ultracentrifugation. Primary human aortic endothelial cells were challenged with tumor necrosis factor-α in the presence or absence of isolated HDL. Proinflammatory adhesion molecules E-selectin and vascular cellular adhesion molecule-1 were quantified by flow cytometry. Activation of the S1P 1 - receptor was evaluated by analyzing downstream signaling targets and receptor internalization. There were no differences in plasma levels of apoM and S1P between controls and T1D patients, but the apoM/S1P complexes were shifted from dense to light HDL particles in T1D. ApoM/S1P in light HDL particles from women were less efficient in inhibiting expression of vascular cellular adhesion molecule-1 than apoM/S1P in denser particles. The light HDL particles were unable to activate Akt, whereas all HDL subfractions were equally efficient in activating Erk and receptor internalization. ApoM/S1P in light HDL particles were inefficient in inhibiting tumor necrosis factor-α-induced vascular cellular adhesion molecule-1 expression in contrast to apoM/S1P in denser HDL particles. T1D patients have a higher proportion of light particles and hence more dysfunctional HDL, which could contribute to the increased cardiovascular disease risk associated with T1D. © 2017 American Heart Association, Inc.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  6. 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.

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

    International Nuclear Information System (INIS)

    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.

  8. 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.

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

    Science.gov (United States)

    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.

  10. 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.

  11. Chemical and genetic tools to explore S1P biology.

    Science.gov (United States)

    Cahalan, Stuart M

    2014-01-01

    The zwitterionic lysophospholipid Sphingosine 1-Phosphate (S1P) is a pleiotropic mediator of physiology and pathology. The synthesis, transport, and degradation of S1P are tightly regulated to ensure that S1P is present in the proper concentrations in the proper location. The binding of S1P to five G protein-coupled S1P receptors regulates many physiological systems, particularly the immune and vascular systems. Our understanding of the functions of S1P has been aided by the tractability of the system to both chemical and genetic manipulation. Chemical modulators have been generated to affect most of the known components of S1P biology, including agonists of S1P receptors and inhibitors of enzymes regulating S1P production and degradation. Genetic knockouts and manipulations have been similarly engineered to disrupt the functions of individual S1P receptors or enzymes involved in S1P metabolism. This chapter will focus on the development and utilization of these chemical and genetic tools to explore the complex biology surrounding S1P and its receptors, with particular attention paid to the in vivo findings that these tools have allowed for.

  12. Shaping the landscape: Metabolic regulation of S1P gradients

    Science.gov (United States)

    Olivera, Ana; Allende, Maria Laura; Proia, Richard L.

    2012-01-01

    Sphingosine-1-phosphate (S1P) is a lipid that functions as a metabolic intermediate and a cellular signaling molecule. These roles are integrated when compartments with differing extracellular S1P concentrations are formed that serve to regulate functions within the immune and vascular systems, as well as during pathologic conditions. Gradients of S1P concentration are achieved by the organization of cells with specialized expression of S1P metabolic pathways within tissues. S1P concentration gradients underpin the ability of S1P signaling to regulate in vivo physiology. This review will discuss the mechanisms that are necessary for the formation and maintenance of S1P gradients, with the aim of understanding how a simple lipid controls complex physiology. PMID:22735358

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  18. S1P and the birth of platelets

    Science.gov (United States)

    Galvani, Sylvain; Rafii, Shahin; Nachman, Ralph

    2012-01-01

    Recent work has highlighted the multitude of biological functions of sphingosine 1-phosphate (S1P), which include roles in hematopoietic cell trafficking, organization of immune organs, vascular development, and neuroinflammation. Indeed, a functional antagonist of S1P1 receptor, FTY720/Gilenya, has entered the clinic as a novel therapeutic for multiple sclerosis. In this issue of the JEM, Zhang et al. highlight yet another function of this lipid mediator: thrombopoiesis. The S1P1 receptor is required for the growth of proplatelet strings in the bloodstream and the shedding of platelets into the circulation. Notably, the sharp gradient of S1P between blood and the interstitial fluids seems to be essential to ensure the production of platelets, and S1P appears to cooperate with the CXCL12–CXCR4 axis. Pharmacologic modulation of the S1P1 receptor altered circulating platelet numbers acutely, suggesting a potential therapeutic strategy for controlling thrombocytopenic states. However, the S1P4 receptor may also regulate thrombopoiesis during stress-induced accelerated platelet production. This work reveals a novel physiological action of the S1P/S1P1 duet that could potentially be harnessed for clinical translation. PMID:23166370

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  5. An engineered S1P chaperone attenuates hypertension and ischemic injury.

    Science.gov (United States)

    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.

  6. Exit Strategies: S1P Signaling and T Cell Migration.

    Science.gov (United States)

    Baeyens, Audrey; Fang, Victoria; Chen, Cynthia; Schwab, Susan R

    2015-12-01

    Whereas the role of sphingosine 1-phosphate receptor 1 (S1PR1) in T cell egress and the regulation of S1P gradients between lymphoid organs and circulatory fluids in homeostasis are increasingly well understood, much remains to be learned about S1P signaling and distribution during an immune response. Recent data suggest that the role of S1PR1 in directing cells from tissues into circulatory fluids is reprised again and again, particularly in guiding activated T cells from non-lymphoid tissues into lymphatics. Conversely, S1P receptor 2 (S1PR2), which antagonizes migration towards chemokines, confines cells within tissues. Here we review the current understanding of the roles of S1P signaling in activated T cell migration. In this context, we outline open questions, particularly regarding the shape of S1P gradients in different tissues in homeostasis and inflammation, and discuss recent strategies to measure S1P. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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.

  8. Expression of S1P metabolizing enzymes and receptors correlate with survival time and regulate cell migration in glioblastoma multiforme.

    Science.gov (United States)

    Bien-Möller, Sandra; Lange, Sandra; Holm, Tobias; Böhm, Andreas; Paland, Heiko; Küpper, Johannes; Herzog, Susann; Weitmann, Kerstin; Havemann, Christoph; Vogelgesang, Silke; Marx, Sascha; Hoffmann, Wolfgang; Schroeder, Henry W S; Rauch, Bernhard H

    2016-03-15

    A signaling molecule which is involved in proliferation and migration of malignant cells is the lipid mediator sphingosine-1-phosphate (S1P). There are hints for a potential role of S1P signaling in malignant brain tumors such as glioblastoma multiforme (GBM) which is characterized by a poor prognosis. Therefore, a comprehensive expression analysis of S1P receptors (S1P1-S1P5) and S1P metabolizing enzymes in human GBM (n = 117) compared to healthy brain (n = 10) was performed to evaluate their role for patient´s survival. Furthermore, influence of S1P receptor inhibition on proliferation and migration were studied in LN18 GBM cells. Compared to control brain, mRNA levels of S1P1, S1P2, S1P3 and S1P generating sphingosine kinase-1 were elevated in GBM. Kaplan-Meier analyses demonstrated an association between S1P1 and S1P2 with patient´s survival times. In vitro, an inhibitory effect of the SphK inhibitor SKI-II on viability of LN18 cells was shown. S1P itself had no effect on viability but stimulated LN18 migration which was blocked by inhibition of S1P1 and S1P2. The participation of S1P1 and S1P2 in LN18 migration was further supported by siRNA-mediated silencing of these receptors. Immunoblots and inhibition experiments suggest an involvement of the PI3-kinase/AKT1 pathway in the chemotactic effect of S1P in LN18 cells.In summary, our data argue for a role of S1P signaling in proliferation and migration of GBM cells. Individual components of the S1P pathway represent prognostic factors for patients with GBM. Perspectively, a selective modulation of S1P receptor subtypes could represent a therapeutic approach for GBM patients and requires further evaluation.

  9. 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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  13. Late-stage optimization of a tercyclic class of S1P3-sparing, S1P1 receptor agonists.

    Science.gov (United States)

    Horan, Joshua C; Kuzmich, Daniel; Liu, Pingrong; DiSalvo, Darren; Lord, John; Mao, Can; Hopkins, Tamara D; Yu, Hui; Harcken, Christian; Betageri, Raj; Hill-Drzewi, Melissa; Patenaude, Lori; Patel, Monica; Fletcher, Kimberly; Terenzzio, Donna; Linehan, Brian; Xia, Heather; Patel, Mita; Studwell, Debbie; Miller, Craig; Hickey, Eugene; Levin, Jeremy I; Smith, Dustin; Kemper, Raymond A; Modis, Louise K; Bannen, Lynne C; Chan, Diva S; Mac, Morrison B; Ng, Stephanie; Wang, Yong; Xu, Wei; Lemieux, René M

    2016-01-15

    Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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.

  15. S1P transporter SPNS2 regulates proper postnatal retinal morphogenesis.

    Science.gov (United States)

    Fang, Chao; Bian, Ganlan; Ren, Pan; Xiang, Jie; Song, Jun; Yu, Caiyong; Zhang, Qian; Liu, Ling; Chen, Kun; Liu, Fangfang; Zhang, Kun; Wu, Chunfeng; Sun, Ruixia; Hu, Dan; Ju, Gong; Wang, Jian

    2018-02-08

    Spinster homolog 2 (SPNS2) is the membrane transporter of sphingosine-1-phosphate (S1P), and it participates in several physiologic processes by activating different S1P receptors (S1PRs). However, its functions in the nervous system remain largely unclear. We explored the important role of SPNS2 in the process of retinal morphogenesis using a spns2-deficient rat model. In the absence of the functional SPNS2 transporter, we observed progressively aggravating laminar disorganization of the epithelium at the postnatal stage of retinal development. Disrupted cell polarity, delayed cell-cycle exit of retinal progenitor cells, and insufficient migration of newborn neurons were proposed in this study as potential mechanisms accounting for this structural disorder. In addition, we analyzed the expression profiles of spns2 and s1prs, and proposed that SPNS2 regulated retinal morphogenesis by establishing the S1P level in the eye and activating S1PR3 signaling. These data indicate that SPNS2 is indispensable for normal retinal morphogenesis and provide new insights on the role of S1P in the developing retina using an established in vivo model.-Fang, C., Bian, G., Ren, P., Xiang, J., Song, J., Yu, C., Zhang, Q., Liu, L., Chen, K., Liu, F., Zhang, K., Wu, C., Sun, R., Hu, D., Ju, G., Wang, J. S1P transporter SPNS2 regulates proper postnatal retinal morphogenesis.

  16. 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

  17. 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.

  18. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  20. The sphingosine 1-phosphate receptor S1P(2) triggers hepatic wound healing

    NARCIS (Netherlands)

    Serriere-Lanneau, Valerie; Teixeira-Clerc, Fatima; Li, Liying; Schippers, Marlies; de Wries, Willie; Julien, Boris; Tran-Van-Nhieu, Jeanne; Manin, Sylvie; Poelstra, Klaas; Chun, Jerold; Carpentier, Stephane; Levade, Thierry; Mallat, Ariane; Lotersztajn, Sophie

    Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid produced by sphingosine kinase (SphK1 and 2). We previously showed that S1P receptors (S1P(1), S1P(2), and S1P(3)) are expressed in hepatic myofibroblasts (hMF), a population of cells that triggers matrix remodeling during liver injury. Here

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  4. 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.

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

    Science.gov (United States)

    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.

  6. S1P Signalling Differentially Affects Migration of Peritoneal B Cell Populations In Vitro and Influences the Production of Intestinal IgA In Vivo

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    Annabel Kleinwort

    2018-01-01

    Full Text Available Introduction: Sphingosine-1-phosphate (S1P regulates the migration of follicular B cells (B2 cells and directs the positioning of Marginal zone B cells (MZ B cells within the spleen. The function of S1P signalling in the third B cell lineage, B1 B cells, mainly present in the pleural and peritoneal cavity, has not yet been determined. Methods: S1P receptor expression was analysed in peritoneal B cells by real-time polymerase chain reaction (qPCR. The chemotactic response to S1P was studied in vitro. The role of S1P signalling was further explored in a s1p4−/− mouse strain. Results: Peritoneal B cells expressed considerable amounts of the S1P receptors 1 and 4 (S1P1 and S1P4, respectively. S1P1 showed differential expression between the distinct peritoneal B cell lineages. While B2 cells showed no chemotactic response to S1P, B1 B cells showed a migration response to S1P. s1p4−/− mice displayed significant alterations in the composition of peritoneal B cell populations, as well as a significant reduction of mucosal immunoglobulin A (IgA in the gut. Discussion: S1P signalling influences peritoneal B1 B cell migration. S1P4 deficiency alters the composition of peritoneal B cell populations and reduces secretory IgA levels. These findings suggest that S1P signalling may be a target to modulate B cell function in inflammatory intestinal pathologies.

  7. 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.

  8. Berberine reduces fibronectin expression by suppressing the S1P-S1P2 receptor pathway in experimental diabetic nephropathy models.

    Directory of Open Access Journals (Sweden)

    Kaipeng Huang

    Full Text Available The accumulation of glomerular extracellular matrix (ECM is one of the critical pathological characteristics of diabetic renal fibrosis. Fibronectin (FN is an important constituent of ECM. Our previous studies indicate that the activation of the sphingosine kinase 1 (SphK1-sphingosine 1- phosphate (S1P signaling pathway plays a key regulatory role in FN production in glomerular mesangial cells (GMCs under diabetic condition. Among the five S1P receptors, the activation of S1P2 receptor is the most abundant. Berberine (BBR treatment also effectively inhibits SphK1 activity and S1P production in the kidneys of diabetic models, thus improving renal injury. Based on these data, we further explored whether BBR could prevent FN production in GMCs under diabetic condition via the S1P2 receptor. Here, we showed that BBR significantly down-regulated the expression of S1P2 receptor in diabetic rat kidneys and GMCs exposed to high glucose (HG and simultaneously inhibited S1P2 receptor-mediated FN overproduction. Further, BBR also obviously suppressed the activation of NF-κB induced by HG, which was accompanied by reduced S1P2 receptor and FN expression. Taken together, our findings suggest that BBR reduces FN expression by acting on the S1P2 receptor in the mesangium under diabetic condition. The role of BBR in S1P2 receptor expression regulation could closely associate with its inhibitory effect on NF-κB activation.

  9. S1P prophylaxis mitigates acute hypobaric hypoxia-induced molecular, biochemical, and metabolic disturbances: A preclinical report.

    Science.gov (United States)

    Chawla, Sonam; Rahar, Babita; Saxena, Shweta

    2016-05-01

    Sphingosine-1-phosphate (S1P) is emerging to have hypoxic preconditioning potential in various preclinical studies. The study aims to evaluate the preclinical preconditioning efficacy of exogenously administered S1P against acute hypobaric hypoxia (HH)-induced pathological disturbances. Male Sprague Dawley rats (200 ± 20 g) were preconditioned with 1, 10, and 100 μg/kg body weight (b.w.) S1P (i.v.) for three consecutive days. On the third day, S1P preconditioned animals, along with hypoxia control animals, were exposed to HH equivalent to 7,620 m (280 mm Hg) for 6 h. Postexposure status of cardiac energy production, circulatory vasoactive mediators, pulmonary and cerebral oxidative damage, and inflammation were assessed. HH exposure led to cardiac energy deficit indicated by low ATP levels and pronounced AMPK activation levels, raised circulatory levels of brain natriuretic peptide and endothelin-1 with respect to total nitrate (NOx), redox imbalance, inflammation, and alterations in NOx levels in the pulmonary and cerebral tissues. These pathological precursors have been routinely reported to be coincident with high-altitude diseases. Preconditioning with S1P, especially 1 µg/kg b.w. dose, was seen to reverse the manifestation of these pathological disturbances. The protective efficacy could be attributed, at least in part, to enhanced activity of cardioprotective protein kinase C and activation of small GTPase Rac1, which led to further induction of hypoxia-adaptive molecular mediators: hypoxia-inducible factor (HIF)-1α and Hsp70. This is a first such report, to the best of our knowledge, elucidating the mechanism of exogenous S1P-mediated HIF-1α/Hsp70 induction. Conclusively, systemic preconditioning with 1 μg/kg b.w. S1P in rats protects against acute HH-induced pathological disturbances. © 2016 IUBMB Life 68(5):365-375, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

  10. Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model.

    Directory of Open Access Journals (Sweden)

    Ken Murakami

    Full Text Available Sphingosine-1-phosphate (S1P is a bioactive sphingolipid metabolite involved in many critical cellular processes, including proliferation, migration, and angiogenesis, through interaction with a family of five G protein-coupled receptors (S1P1-5. Some reports have implicated S1P as an important inflammatory mediator of the pathogenesis of airway inflammation, but the role of S1P3 in the pathogenesis of lung diseases is not completely understood. We used S1P3-deficient (knockout (KO mice to clarify the role of S1P3 receptor signaling in the pathogenesis of pulmonary inflammation and fibrosis using a bleomycin-induced model of lung injury. On the seventh day after bleomycin administration, S1P3 KO mice exhibited significantly less body weight loss and pulmonary inflammation than wild-type (WT mice. On the 28th day, there was less pulmonary fibrosis in S1P3 KO mice than in WT mice. S1P3 KO mice demonstrated a 56% reduction in total cell count in bronchoalveolar lavage fluid (BALF collected on the seventh day compared with WT mice; however, the differential white blood cell profiles were similar. BALF analysis on the seventh day showed that connective tissue growth factor (CTGF levels were significantly decreased in S1P3 KO mice compared with WT mice, although no differences were observed in monocyte chemotactic protein-1 (MCP-1 or transforming growth factor β1 (TGF-β1 levels. Finally, S1P levels in BALF collected on the 7th day after treatment were not significantly different between WT and S1P3 KO mice. Our results indicate that S1P3 receptor signaling plays an important role in pulmonary inflammation and fibrosis and that this signaling occurs via CTGF expression. This suggests that this pathway might be a therapeutic target for pulmonary fibrosis.

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

    Science.gov (United States)

    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.

  12. High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation

    International Nuclear Information System (INIS)

    Akao, Yukihiro; Banno, Yoshiko; Nakagawa, Yoshihito; Hasegawa, Nobuko; Kim, Tack-Joong; Murate, Takashi; Igarashi, Yasuyuki; Nozawa, Yoshinori

    2006-01-01

    Although most of pharmacological therapies for cancer utilize the apoptotic machinery of the cells, the available anti-cancer drugs are limited due to the ability of prostate cancer cells to escape from the anti-cancer drug-induced apoptosis. A human prostate cancer cell line PC3 is resistant to camptothecin (CPT). To elucidate the mechanism of this resistance, we have examined the involvement of sphingosine kinase (SPHK) and sphingosine 1-phosphate (S1P) receptor in CPT-resistant PC3 and -sensitive LNCaP cells. PC3 cells exhibited higher activity accompanied with higher expression levels of protein and mRNA of SPHK1, and also elevated expression of S1P receptors, S1P 1 and S1P 3 , as compared with those of LNCaP cells. The knockdown of SPHK1 by small interfering RNA and inhibition of S1P receptor signaling by pertussis toxin in PC3 cells induced significant inhibition of cell growth, suggesting implication of SPHK1 and S1P receptors in cell proliferation in PC3 cells. Furthermore, the treatment of PC3 cells with CPT was found to induce up-regulation of the SPHK1/S1P signaling by induction of both SPHK1 enzyme and S1P 1 /S1P 3 receptors. These findings strongly suggest that high expression and up-regulation of SPHK1 and S1P receptors protect PC3 cells from the apoptosis induced by CPT

  13. S1P Signalling Differentially Affects Migration of Peritoneal B Cell Populations In Vitro and Influences the Production of Intestinal IgA In Vivo.

    Science.gov (United States)

    Kleinwort, Annabel; Lührs, Felix; Heidecke, Claus-Dieter; Lipp, Martin; Schulze, Tobias

    2018-01-29

    Introduction: Sphingosine-1-phosphate (S1P) regulates the migration of follicular B cells (B2 cells) and directs the positioning of Marginal zone B cells (MZ B cells) within the spleen. The function of S1P signalling in the third B cell lineage, B1 B cells, mainly present in the pleural and peritoneal cavity, has not yet been determined. Methods: S1P receptor expression was analysed in peritoneal B cells by real-time polymerase chain reaction (qPCR). The chemotactic response to S1P was studied in vitro. The role of S1P signalling was further explored in a s1p₄ -/- mouse strain. Results: Peritoneal B cells expressed considerable amounts of the S1P receptors 1 and 4 (S1P₁ and S1P₄, respectively). S1P₁ showed differential expression between the distinct peritoneal B cell lineages. While B2 cells showed no chemotactic response to S1P, B1 B cells showed a migration response to S1P. s1p₄ -/- mice displayed significant alterations in the composition of peritoneal B cell populations, as well as a significant reduction of mucosal immunoglobulin A (IgA) in the gut. Discussion: S1P signalling influences peritoneal B1 B cell migration. S1P₄ deficiency alters the composition of peritoneal B cell populations and reduces secretory IgA levels. These findings suggest that S1P signalling may be a target to modulate B cell function in inflammatory intestinal pathologies.

  14. Sphingosine 1-Phosphate (S1P) Receptors 1 and 2 Coordinately Induce Mesenchymal Cell Migration through S1P Activation of Complementary Kinase Pathways*

    Science.gov (United States)

    Quint, Patrick; Ruan, Ming; Pederson, Larry; Kassem, Moustapha; Westendorf, Jennifer J.; Khosla, Sundeep; Oursler, Merry Jo

    2013-01-01

    Normal bone turnover requires tight coupling of bone resorption and bone formation to preserve bone quantity and structure. With aging and during several pathological conditions, this coupling breaks down, leading to either net bone loss or excess bone formation. To preserve or restore normal bone metabolism, it is crucial to determine the mechanisms by which osteoclasts and osteoblast precursors interact and contribute to coupling. We showed that osteoclasts produce the chemokine sphingosine 1-phosphate (S1P), which stimulates osteoblast migration. Thus, osteoclast-derived S1P may recruit osteoblasts to sites of bone resorption as an initial step in replacing lost bone. In this study we investigated the mechanisms by which S1P stimulates mesenchymal (skeletal) cell chemotaxis. S1P treatment of mesenchymal (skeletal) cells activated RhoA GTPase, but this small G protein did not contribute to migration. Rather, two S1P receptors, S1PR1 and S1PR2, coordinately promoted migration through activation of the JAK/STAT3 and FAK/PI3K/AKT signaling pathways, respectively. These data demonstrate that the chemokine S1P couples bone formation to bone resorption through activation of kinase signaling pathways. PMID:23300082

  15. 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.

  16. ApoA-I induces S1P release from endothelial cells through ABCA1 and SR-BI in a positive feedback manner.

    Science.gov (United States)

    Liu, Xing; Ren, Kun; Suo, Rong; Xiong, Sheng-Lin; Zhang, Qing-Hai; Mo, Zhong-Cheng; Tang, Zhen-Li; Jiang, Yue; Peng, Xiao-Shan; Yi, Guang-Hui

    2016-12-01

    Sphingosine-1-phosphate (S1P), which has emerged as a pivotal signaling mediator that participates in the regulation of multiple cellular processes, is derived from various cells, including vascular endothelial cells. S1P accumulates in lipoproteins, especially HDL, and the majority of free plasma S1P is bound to HDL. We hypothesized that HDL-associated S1P is released through mechanisms associated with the HDL maturation process. ApoA-I, a major HDL apolipoprotein, is a critical factor for nascent HDL formation and lipid trafficking via ABCA1. Moreover, apoA-I is capable of promoting bidirectional lipid movement through SR-BI. In the present study, we confirmed that apoA-I can facilitate the production and release of S1P by HUVECs. Furthermore, we demonstrated that ERK1/2 and SphK activation induced by apoA-I is involved in the release of S1P from HUVECs. Inhibitor and siRNA experiments showed that ABCA1 and SR-BI are required for S1P release and ERK1/2 phosphorylation induced by apoA-I. However, the effects triggered by apoA-I were not suppressed by inhibiting ABCA1/JAK2 or the SR-BI/Src pathway. S1P released due to apoA-I activation can stimulate the (ERK1/2)/SphK1 pathway through S1PR (S1P receptor) 1/3. These results indicated that apoA-I not only promotes S1P release through ABCA1 and SR-BI but also indirectly activates the (ERK1/2)/SphK1 pathway by releasing S1P to trigger their receptors. In conclusion, we suggest that release of S1P induced by apoA-I from endothelial cells through ABCA1 and SR-BI is a self-positive-feedback process: apoA-I-(ABCA1 and SR-BI)-(S1P release)-S1PR-ERK1/2-SphK1-(S1P production)-(more S1P release induced by apoA-I).

  17. Pathophysiological Consequences of a Break in S1P1-Dependent Homeostasis of Vascular Permeability Revealed by S1P1 Competitive Antagonism.

    Science.gov (United States)

    Bigaud, Marc; Dincer, Zuhal; Bollbuck, Birgit; Dawson, Janet; Beckmann, Nicolau; Beerli, Christian; Fishli-Cavelti, Gina; Nahler, Michaela; Angst, Daniela; Janser, Philipp; Otto, Heike; Rosner, Elisabeth; Hersperger, Rene; Bruns, Christian; Quancard, Jean

    2016-01-01

    Homeostasis of vascular barriers depends upon sphingosine 1-phosphate (S1P) signaling via the S1P1 receptor. Accordingly, S1P1 competitive antagonism is known to reduce vascular barrier integrity with still unclear pathophysiological consequences. This was explored in the present study using NIBR-0213, a potent and selective S1P1 competitive antagonist. NIBR-0213 was tolerated at the efficacious oral dose of 30 mg/kg BID in the rat adjuvant-induced arthritis (AiA) model, with no sign of labored breathing. However, it induced dose-dependent acute vascular pulmonary leakage and pleural effusion that fully resolved within 3-4 days, as evidenced by MRI monitoring. At the supra-maximal oral dose of 300 mg/kg QD, NIBR-0213 impaired lung function (with increased breathing rate and reduced tidal volume) within the first 24 hrs. Two weeks of NIBR-0213 oral dosing at 30, 100 and 300 mg/kg QD induced moderate pulmonary changes, characterized by alveolar wall thickening, macrophage accumulation, fibrosis, micro-hemorrhage, edema and necrosis. In addition to this picture of chronic inflammation, perivascular edema and myofiber degeneration observed in the heart were also indicative of vascular leakage and its consequences. Overall, these observations suggest that, in the rat, the lung is the main target organ for the S1P1 competitive antagonism-induced acute vascular leakage, which appears first as transient and asymptomatic but could lead, upon chronic dosing, to lung remodeling with functional impairments. Hence, this not only raises the question of organ specificity in the homeostasis of vascular barriers, but also provides insight into the pre-clinical evaluation of a potential safety window for S1P1 competitive antagonists as drug candidates.

  18. Vitamin D attenuates sphingosine-1-phosphate (S1P)-mediated inhibition of extravillous trophoblast migration.

    Science.gov (United States)

    Westwood, Melissa; Al-Saghir, Khiria; Finn-Sell, Sarah; Tan, Cherlyn; Cowley, Elizabeth; Berneau, Stéphane; Adlam, Daman; Johnstone, Edward D

    2017-12-01

    Failure of trophoblast invasion and remodelling of maternal blood vessels leads to the pregnancy complication pre-eclampsia (PE). In other systems, the sphingolipid, sphingosine-1-phosphate (S1P), controls cell migration therefore this study determined its effect on extravillous trophoblast (EVT) function. A transwell migration system was used to assess the behaviour of three trophoblast cell lines, Swan-71, SGHPL-4, and JEG3, and primary human trophoblasts in the presence or absence of S1P, S1P pathway inhibitors and 1,25(OH) 2 D 3 . QPCR and immunolocalisation were used to demonstrate EVT S1P receptor expression. EVTs express S1P receptors 1, 2 and 3. S1P inhibited EVT migration. This effect was abolished in the presence of the specific S1PR2 inhibitor, JTE-013 (p S1P alone) whereas treatment with the S1R1/3 inhibitor, FTY720, had no effect. In other cell types S1PR2 is regulated by vitamin D; here we found that treatment with 1,25(OH) 2 D 3 for 48 or 72 h reduces S1PR2 (4-fold; S1P did not inhibit the migration of cells exposed to 1,25(OH) 2 D 3 (p S1P receptor isoforms, S1P predominantly signals through S1PR2/Gα 12/13 to activate Rho and thereby acts as potent inhibitor of EVT migration. Importantly, expression of S1PR2, and therefore S1P function, can be down-regulated by vitamin D. Our data suggest that vitamin D deficiency, which is known to be associated with PE, may contribute to the impaired trophoblast migration that underlies this condition. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells.

    Science.gov (United States)

    Mendoza, Alejandra; Fang, Victoria; Chen, Cynthia; Serasinghe, Madhavika; Verma, Akanksha; Muller, James; Chaluvadi, V Sai; Dustin, Michael L; Hla, Timothy; Elemento, Olivier; Chipuk, Jerry E; Schwab, Susan R

    2017-06-01

    Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide. Because the production of T cells declines with age, naive T cells must be long-lived. However, it remains unclear how naive T cells survive for years while constantly travelling. The chemoattractant sphingosine 1-phosphate (S1P) guides T cell circulation among secondary lymphoid organs, including spleen, lymph nodes and Peyer's patches, where T cells search for antigens. The concentration of S1P is higher in circulatory fluids than in lymphoid organs, and the S1P 1 receptor (S1P 1 R) directs the exit of T cells from the spleen into blood, and from lymph nodes and Peyer's patches into lymph. Here we show that S1P is essential not only for the circulation of naive T cells, but also for their survival. Using transgenic mouse models, we demonstrate that lymphatic endothelial cells support the survival of T cells by secreting S1P via the transporter SPNS2, that this S1P signals through S1P 1 R on T cells, and that the requirement for S1P 1 R is independent of the established role of the receptor in guiding exit from lymph nodes. S1P signalling maintains the mitochondrial content of naive T cells, providing cells with the energy to continue their constant migration. The S1P signalling pathway is being targeted therapeutically to inhibit autoreactive T cell trafficking, and these findings suggest that it may be possible simultaneously to target autoreactive or malignant cell survival.

  20. Curcumin ameliorates diabetic nephropathy by inhibiting the activation of the SphK1-S1P signaling pathway.

    Science.gov (United States)

    Huang, Juan; Huang, Kaipeng; Lan, Tian; Xie, Xi; Shen, Xiaoyan; Liu, Peiqing; Huang, Heqing

    2013-01-30

    Curcumin, a major polyphenol from the golden spice Curcuma longa commonly known as turmeric, has been recently discovered to have renoprotective effects on diabetic nephropathy (DN). However, the mechanisms underlying these effects remain unclear. We previously demonstrated that the sphingosine kinase 1-sphingosine 1-phosphate (SphK1-S1P) signaling pathway plays a pivotal role in the pathogenesis of DN. This study aims to investigate whether the renoprotective effects of curcumin on DN are associated with its inhibitory effects on the SphK1-S1P signaling pathway. Our results demonstrated that the expression and activity of SphK1 and the production of S1P were significantly down-regulated by curcumin in diabetic rat kidneys and glomerular mesangial cells (GMCs) exposed to high glucose (HG). Simultaneously, SphK1-S1P-mediated fibronectin (FN) and transforming growth factor-beta 1 (TGF-β1) overproduction were inhibited. In addition, curcumin dose dependently reduced SphK1 expression and activity in GMCs transfected with SphK(WT) and significantly suppressed the increase in SphK1-mediated FN levels. Furthermore, curcumin inhibited the DNA-binding activity of activator protein 1 (AP-1), and c-Jun small interference RNA (c-Jun-siRNA) reversed the HG-induced up-regulation of SphK1. These findings suggested that down-regulation of the SphK1-S1P pathway is probably a novel mechanism by which curcumin improves the progression of DN. Inhibiting AP-1 activation is one of the therapeutic targets of curcumin to modulate the SphK1-S1P signaling pathway, thereby preventing diabetic renal fibrosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  1. To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling.

    Science.gov (United States)

    Chew, Wee Siong; Wang, Wei; Herr, Deron R

    2016-11-01

    Sphingosine 1-phosphate (S1P) is an extracellular lipid signaling molecule that acts as a selective, high-affinity ligand for a family of five G protein-coupled receptors. This signaling system was first identified twenty years ago, and has since been shown to regulate a diverse range of physiological processes and disease states, such as cardiovascular development, immune function, hypoxic responses, and cancer. The therapeutic potential of targeting this system took center stage when it was demonstrated that the immune modulator, fingolimod (FTY720/Gilenya), exerts it lymphopenic effect by acting on S1P receptors, primarily on S1P receptor 1 (S1P 1 ). In 2010, fingolimod became the first oral medication approved for the treatment of multiple sclerosis (MS). Since then, second-generation S1P receptor modulators have been under development in an effort to provide improved safety and efficacy profiles for MS, and to broaden their use to other autoimmune indications. Beyond the development of S1P 1 -modulators, there has been considerable effort in targeting other components of the S1P signaling pathway for the treatment of other diseases, such as cardiovascular disease, sepsis, and cancer. This manuscript provides an overview of the clinical and preclinical development of drugs targeting S1P signaling. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  4. A role of the sphingosine-1-phosphate (S1P)-S1P receptor 2 pathway in epithelial defense against cancer (EDAC).

    Science.gov (United States)

    Yamamoto, Sayaka; Yako, Yuta; Fujioka, Yoichiro; Kajita, Mihoko; Kameyama, Takeshi; Kon, Shunsuke; Ishikawa, Susumu; Ohba, Yusuke; Ohno, Yusuke; Kihara, Akio; Fujita, Yasuyuki

    2016-02-01

    At the initial step of carcinogenesis, transformation occurs in single cells within epithelia, where the newly emerging transformed cells are surrounded by normal epithelial cells. A recent study revealed that normal epithelial cells have an ability to sense and actively eliminate the neighboring transformed cells, a process named epithelial defense against cancer (EDAC). However, the molecular mechanism of this tumor-suppressive activity is largely unknown. In this study, we investigated a role for the sphingosine-1-phosphate (S1P)-S1P receptor 2 (S1PR2) pathway in EDAC. First, we show that addition of the S1PR2 inhibitor significantly suppresses apical extrusion of RasV12-transformed cells that are surrounded by normal cells. In addition, knockdown of S1PR2 in normal cells induces the same effect, indicating that S1PR2 in the surrounding normal cells plays a positive role in the apical elimination of the transformed cells. Of importance, not endogenous S1P but exogenous S1P is involved in this process. By using FRET analyses, we demonstrate that S1PR2 mediates Rho activation in normal cells neighboring RasV12-transformed cells, thereby promoting accumulation of filamin, a crucial regulator of EDAC. Collectively these data indicate that S1P is a key extrinsic factor that affects the outcome of cell competition between normal and transformed epithelial cells. © 2016 Yamamoto, Yako, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  5. Regulation of S1P receptors and sphingosine kinases expression in acute pulmonary endothelial cell injury

    Directory of Open Access Journals (Sweden)

    Huiying Liu

    2016-12-01

    Full Text Available Background Acute lung injury and acute respiratory distress syndrome (ALI/ARDS is a severe clinical syndrome with mortality rate as high as 30–40%. There is no treatment yet to improve pulmonary endothelial barrier function in patients with severe pulmonary edema. Developing therapies to protect endothelial barrier integrity and stabilizing gas exchange is getting more and more attention. Sphingosine-1-phosphate (S1P is able to enhance the resistance of endothelial cell barrier. S1P at physiological concentrations plays an important role in maintaining endothelial barrier function. Proliferation, regeneration and anti-inflammatory activity that mesenchymal stem cells (MSCs exhibit make it possible to regulate the homeostatic control of S1P. Methods By building a pulmonary endothelial cell model of acute injury, we investigated the regulation of S1P receptors and sphingosine kinases expression by MSCs during the treatment of acute lung injury using RT-PCR, and investigated the HPAECs Micro-electronics impedance using Real Time Cellular Analysis. Results It was found that the down-regulation of TNF-α expression was more significant when MSC was used in combination with S1P. The combination effection mainly worked on S1PR2, S1PR3 and SphK2. The results show that when MSCs were used in combination with S1P, the selectivity of S1P receptors was increased and the homeostatic control of S1P concentration was improved through regulation of expression of S1P metabolic enzymes. Discussions The study found that, as a potential treatment, MSCs could work on multiple S1P related genes simultaneously. When it was used in combination with S1P, the expression regulation result of related genes was not simply the superposition of each other, but more significant outcome was obtained. This study establishes the experimental basis for further exploring the efficacy of improving endothelial barrier function in acute lung injury, using MSCs in combination with S1

  6. Regulation of S1P receptors and sphingosine kinases expression in acute pulmonary endothelial cell injury.

    Science.gov (United States)

    Liu, Huiying; Zhang, Zili; Li, Puyuan; Yuan, Xin; Zheng, Jing; Liu, Jinwen; Bai, Changqing; Niu, Wenkai

    2016-01-01

    Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) is a severe clinical syndrome with mortality rate as high as 30-40%. There is no treatment yet to improve pulmonary endothelial barrier function in patients with severe pulmonary edema. Developing therapies to protect endothelial barrier integrity and stabilizing gas exchange is getting more and more attention. Sphingosine-1-phosphate (S1P) is able to enhance the resistance of endothelial cell barrier. S1P at physiological concentrations plays an important role in maintaining endothelial barrier function. Proliferation, regeneration and anti-inflammatory activity that mesenchymal stem cells (MSCs) exhibit make it possible to regulate the homeostatic control of S1P. By building a pulmonary endothelial cell model of acute injury, we investigated the regulation of S1P receptors and sphingosine kinases expression by MSCs during the treatment of acute lung injury using RT-PCR, and investigated the HPAECs Micro-electronics impedance using Real Time Cellular Analysis. It was found that the down-regulation of TNF- α expression was more significant when MSC was used in combination with S1P. The combination effection mainly worked on S1PR2, S1PR3 and SphK2. The results show that when MSCs were used in combination with S1P, the selectivity of S1P receptors was increased and the homeostatic control of S1P concentration was improved through regulation of expression of S1P metabolic enzymes. The study found that, as a potential treatment, MSCs could work on multiple S1P related genes simultaneously. When it was used in combination with S1P, the expression regulation result of related genes was not simply the superposition of each other, but more significant outcome was obtained. This study establishes the experimental basis for further exploring the efficacy of improving endothelial barrier function in acute lung injury, using MSCs in combination with S1P and their possible synergistic mechanism.

  7. Modulation of sphingosine 1-phosphate (S1P) attenuates spatial learning and memory impairments in the valproic acid rat model of autism.

    Science.gov (United States)

    Wu, Hongmei; Zhang, Quanzhi; Gao, Jingquan; Sun, Caihong; Wang, Jia; Xia, Wei; Cao, Yonggang; Hao, Yanqiu; Wu, Lijie

    2018-03-01

    Autism spectrum disorders (ASD) are a set of pervasive neurodevelopmental disorders that manifest in early childhood, and it is growing up to be a major cause of disability in children. However, the etiology and treatment of ASD are not well understood. In our previous study, we found that serum levels of sphingosine 1-phosphate (S1P) were increased significantly in children with autism, indicating that S1P levels may be involved in ASD. The objective of this study was to identify a link between increased levels of S1P and neurobehavioral changes in autism. We utilized a valproic acid (VPA) -induced rat model of autism to evaluate the levels of S1P and the expression of sphingosine kinase (SphK), a key enzyme for S1P production, in serum and hippocampal tissue. Furthermore, we assessed cognitive functional changes and histopathological and neurochemical alterations in VPA-exposed rats after SphK blockade to explore the possible link between increased levels of S1P and neurobehavioral changes in autism. We found that SphK2 and S1P are upregulated in hippocampal tissue from VPA-exposed rats, while pharmacological inhibition of SphK reduced S1P levels, attenuated spatial learning and memory impairments, increased the expression of phosphorylated CaMKII and CREB and autophagy-related proteins, inhibited cytochrome c release, decreased the expression of apoptosis related proteins, and protected against neuronal loss in the hippocampus. We have demonstrated that an increased level of SphK2/S1P is involved in the spatial learning and memory impairments of autism, and this signaling pathway represents a novel therapeutic target and direction for future studies.

  8. Role of Sphingosine Kinase 1 and S1P Transporter Spns2 in HGF-mediated Lamellipodia Formation in Lung Endothelium.

    Science.gov (United States)

    Fu, Panfeng; Ebenezer, David L; Berdyshev, Evgeny V; Bronova, Irina A; Shaaya, Mark; Harijith, Anantha; Natarajan, Viswanathan

    2016-12-30

    Hepatocyte growth factor (HGF) signaling via c-Met is known to promote endothelial cell motility and angiogenesis. We have previously reported that HGF stimulates lamellipodia formation and motility of human lung microvascular endothelial cells (HLMVECs) via PI3K/Akt signal transduction and reactive oxygen species generation. Here, we report a role for HGF-induced intracellular sphingosine-1-phosphate (S1P) generation catalyzed by sphingosine kinase 1 (SphK1), S1P transporter, spinster homolog 2 (Spns2), and S1P receptor, S1P 1 , in lamellipodia formation and perhaps motility of HLMVECs. HGF stimulated SphK1 phosphorylation and enhanced intracellular S1P levels in HLMVECs, which was blocked by inhibition of SphK1. HGF enhanced co-localization of SphK1/p-SphK1 with actin/cortactin in lamellipodia and down-regulation or inhibition of SphK1 attenuated HGF-induced lamellipodia formation in HLMVECs. In addition, down-regulation of Spns2 also suppressed HGF-induced lamellipodia formation, suggesting a key role for inside-out S1P signaling. The HGF-mediated phosphorylation of SphK1 and its localization in lamellipodia was dependent on c-Met and ERK1/2 signaling, but not the PI3K/Akt pathway; however, blocking PI3K/Akt signaling attenuated HGF-mediated phosphorylation of Spns2. Down-regulation of S1P 1 , but not S1P 2 or S1P 3 , with specific siRNA attenuated HGF-induced lamellipodia formation. Further, HGF enhanced association of Spns2 with S1P 1 that was blocked by inhibiting SphK1 activity with PF-543. Moreover, HGF-induced migration of HLMVECs was attenuated by down-regulation of Spns2 . Taken together, these results suggest that HGF/c-Met-mediated lamellipodia formation, and perhaps motility is dependent on intracellular generation of S1P via activation and localization of SphK1 to cell periphery and Spns2-mediated extracellular transportation of S1P and its inside-out signaling via S1P 1 . © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. SIRT1 mediates Sphk1/S1P-induced proliferation and migration of endothelial cells.

    Science.gov (United States)

    Gao, Zhan; Wang, Hua; Xiao, Feng-Jun; Shi, Xue-Feng; Zhang, Yi-Kun; Xu, Qin Qin; Zhang, Xiao-Yan; Ha, Xiao-Qin; Wang, Li-Sheng

    2016-05-01

    Angiogenesis is one of the most important components of embryonic organ formation and vessel growth after birth. Sphingosine kinase 1 (Sphk1) and S1P has been confirmed to participate in various cell signaling pathways and physiological processes including neovascularisation. However, the mechanisms that Sphk1/S1P regulates neovascularisation remain unclear. In this study, we elucidated that Sphk1/S1P upregulates sirtuin 1 (SIRT1), a NAD+ dependent deacetylases protease which exerts multiple cellular functions, to regulate the proliferation and migration of endothelial cells. By using CCK8 and Transwell assays, we demonstrated that Sphk1 and SIRT1 knockdown could significantly decrease proliferation and migration of HUVEC cells. Sphk1 inhibition results in SIRT1 downregulation which could be reversed by exogenous S1P in HUVEC cells. Treatment of HUVECs with S1P reverses the impaired proliferation and migration caused by SIRT1 knockdown. Furthermore, Sphk1 knockdown inhibits the phosphorylation of P38 MAPK, ERK and AKT. Treatment of HUVECs with PD98059, SB203580 and Wortmannin, which are the inhibitors of ERK, P38 MAPK and AKT respectively, resulted in decreased SIRT1 expression and reduced migration of HUVEC cells. Thus, we conclude that Sphk1/S1P induces SIRT1 upregulation through multiple pathways including P38 MAPK, ERK and AKT signals. This is the first report to disclose the existence and roles of Sphk1/S1P/SIRT1 axis in regulation of endothelial cell proliferation and migration, which may provide a theoretical basis for angiogenesis. Copyright © 2016. Published by Elsevier Ltd.

  10. ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex.

    Science.gov (United States)

    Park, Kyungho; Ikushiro, Hiroko; Seo, Ho Seong; Shin, Kyong-Oh; Kim, Young Il; Kim, Jong Youl; Lee, Yong-Moon; Yano, Takato; Holleran, Walter M; Elias, Peter; Uchida, Yoshikazu

    2016-03-08

    We recently identified a previously unidentified sphingosine-1-phosphate (S1P) signaling mechanism that stimulates production of a key innate immune element, cathelicidin antimicrobial peptide (CAMP), in mammalian cells exposed to external perturbations, such as UVB irradiation and other oxidative stressors that provoke subapoptotic levels of endoplasmic reticulum (ER) stress, independent of the well-known vitamin D receptor-dependent mechanism. ER stress increases cellular ceramide and one of its distal metabolites, S1P, which activates NF-κB followed by C/EBPα activation, leading to CAMP production, but in a S1P receptor-independent fashion. We now show that S1P activates NF-κB through formation of a previously unidentified signaling complex, consisting of S1P, TRAF2, and RIP1 that further associates with three stress-responsive proteins; i.e., heat shock proteins (GRP94 and HSP90α) and IRE1α. S1P specifically interacts with the N-terminal domain of heat shock proteins. Because this ER stress-initiated mechanism is operative in both epithelial cells and macrophages, it appears to be a universal, highly conserved response, broadly protective against diverse external perturbations that lead to increased ER stress. Finally, these studies further illuminate how ER stress and S1P orchestrate critical stress-specific signals that regulate production of one protective response by stimulating production of the key innate immune element, CAMP.

  11. The effect of the bioactive sphingolipids S1P and C1P on multipotent stromal cells--new opportunities in regenerative medicine.

    Science.gov (United States)

    Marycz, Krzysztof; Śmieszek, Agnieszka; Jeleń, Marta; Chrząstek, Klaudia; Grzesiak, Jakub; Meissner, Justyna

    2015-09-01

    Sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) belong to a family of bioactive sphingolipids that act as important extracellular signaling molecules and chemoattractants. This study investigated the influence of S1P and C1P on the morphology, proliferation activity and osteogenic properties of rat multipotent stromal cells derived from bone marrow (BMSCs) and subcutaneous adipose tissue (ASCs). We show that S1P and C1P can influence mesenchymal stem cells (MSCs), each in a different manner. S1P stimulation promoted the formation of cellular aggregates of BMSCs and ASCs, while C1P had an effect on the regular growth pattern and expanded intercellular connections, thereby increasing the proliferative activity. Although osteogenic differentiation of MSCs was enhanced by the addition of S1P, the effectiveness of osteoblast differentiation was more evident in BMSCs, particularly when biochemical and molecular marker levels were considered. The results of the functional osteogenic differentiation assay, which includes an evaluation of the efficiency of extracellular matrix mineralization (SEM-EDX), revealed the formation of numerous mineral aggregates in BMSC cultures stimulated with S1P. Our data demonstrated that in an appropriate combination, the bioactive sphingolipids S1P and C1P may find wide application in regenerative medicine, particularly in bone regeneration with the use of MSCs.

  12. S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling

    Science.gov (United States)

    Kumar, Ashok; Zamora-Pineda, Jesus; Degagné, Emilie

    2017-01-01

    Sphingosine-1-phosphate (S1P) is a potent lipid signaling molecule that regulates pleiotropic biological functions including cell migration, survival, angiogenesis, immune cell trafficking, inflammation, and carcinogenesis. It acts as a ligand for a family of cell surface receptors. S1P concentrations are high in blood and lymph but low in tissues, especially the thymus and lymphoid organs. S1P chemotactic gradients are essential for lymphocyte egress and other aspects of physiological cell trafficking. S1P is irreversibly degraded by S1P lyase (SPL). SPL regulates lymphocyte trafficking, inflammation and other physiological and pathological processes. For example, SPL located in thymic dendritic cells acts as a metabolic gatekeeper that controls the normal egress of mature T lymphocytes from the thymus into the circulation, whereas SPL deficiency in gut epithelial cells promotes colitis and colitis-associated carcinogenesis (CAC). Recently, we identified a complex syndrome comprised of nephrosis, adrenal insufficiency, and immunological defects caused by inherited mutations in human SGPL1, the gene encoding SPL. In the present article, we review current evidence supporting the role of SPL in thymic egress, inflammation, and cancer. Lastly, we summarize recent progress in understanding other SPL functions, its role in inherited disease, and SPL targeting for therapeutic purposes. PMID:29333002

  13. Targeting S1P in Inflammatory bowel disease: new avenues for modulating intestinal leukocyte migration.

    Science.gov (United States)

    Danese, Silvio; Furfaro, Federica; Vetrano, Stefania

    2017-07-28

    Sphingosine 1 phosphate (S1P) is a bioactive lipid mediator involved in the regulation of several cellular processes though the activation of a G protein-coupled receptor family known as the S1P receptors (S1PRs). Advances in the understanding of the biological activities mediated by S1PRs have sparked great interest in the S1P/S1PRs axes as new therapeutic targets for the modulation of several cellular processes. In particular, S1P/ S1PR1 axis has been identified as key regulator for the lymphocyte migration from lymph nodes. The blockade of this axis is emerging as a new therapeutic approach to control the aberrant leukocytes migration into the mucosa in inflammatory bowel disease (IBD). This review briefly summarizes the current evidence coming from clinical studies and discusses the future prospects of S1P inhibitors for treatment of inflammatory bowel disease. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  14. S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling

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    Ashok Kumar

    2017-01-01

    Full Text Available Sphingosine-1-phosphate (S1P is a potent lipid signaling molecule that regulates pleiotropic biological functions including cell migration, survival, angiogenesis, immune cell trafficking, inflammation, and carcinogenesis. It acts as a ligand for a family of cell surface receptors. S1P concentrations are high in blood and lymph but low in tissues, especially the thymus and lymphoid organs. S1P chemotactic gradients are essential for lymphocyte egress and other aspects of physiological cell trafficking. S1P is irreversibly degraded by S1P lyase (SPL. SPL regulates lymphocyte trafficking, inflammation and other physiological and pathological processes. For example, SPL located in thymic dendritic cells acts as a metabolic gatekeeper that controls the normal egress of mature T lymphocytes from the thymus into the circulation, whereas SPL deficiency in gut epithelial cells promotes colitis and colitis-associated carcinogenesis (CAC. Recently, we identified a complex syndrome comprised of nephrosis, adrenal insufficiency, and immunological defects caused by inherited mutations in human SGPL1, the gene encoding SPL. In the present article, we review current evidence supporting the role of SPL in thymic egress, inflammation, and cancer. Lastly, we summarize recent progress in understanding other SPL functions, its role in inherited disease, and SPL targeting for therapeutic purposes.

  15. S1P4 Regulates Passive Systemic Anaphylaxis in Mice but Is Dispensable for Canonical IgE-Mediated Responses in Mast Cells

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    Joseph M. Kulinski

    2018-04-01

    Full Text Available Mast cells are key players in the development of inflammatory allergic reactions. Cross-linking of the high-affinity receptor for IgE (FcεRI on mast cells leads to the generation and secretion of the sphingolipid mediator, sphingosine-1-phosphate (S1P which is able, in turn, to transactivate its receptors on mast cells. Previous reports have identified the expression of two of the five receptors for S1P on mast cells, S1P1 and S1P2, with functions in FcεRI-mediated chemotaxis and degranulation, respectively. Here, we show that cultured mouse mast cells also express abundant message for S1P4. Genetic deletion of S1pr4 did not affect the differentiation of bone marrow progenitors into mast cells or the proliferation of mast cells in culture. A comprehensive characterization of IgE-mediated responses in S1P4-deficient bone marrow-derived and peritoneal mouse mast cells indicated that this receptor is dispensable for mast cell degranulation, cytokine/chemokine production and FcεRI-mediated chemotaxis in vitro. However, interleukin-33 (IL-33-mediated enhancement of IgE-induced degranulation was reduced in S1P4-deficient peritoneal mast cells, revealing a potential negative regulatory role for S1P4 in an IL-33-rich environment. Surprisingly, genetic deletion of S1pr4 resulted in exacerbation of passive systemic anaphylaxis to IgE/anti-IgE in mice, a phenotype likely related to mast cell-extrinsic influences, such as the high circulating levels of IgE in these mice which increases FcεRI expression and consequently the extent of the response to FcεRI engagement. Thus, we provide evidence that S1P4 modulates anaphylaxis in an unexpected manner that does not involve regulation of mast cell responsiveness to IgE stimulation.

  16. 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.

  17. S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

    Science.gov (United States)

    Cantalupo, Anna

    2016-01-01

    Initially discovered as abundant components of eukaryotic cell membranes, sphingolipids are now recognized as important bioactive signaling molecules that modulate a variety of cellular functions, including those relevant to cancer and immunologic, inflammatory, and cardiovascular disorders. In this review, we discuss recent advances in our understanding of the role of sphingosine-1-phosphate (S1P) receptors in the regulation of vascular function, and focus on how de novo biosynthesized sphingolipids play a role in blood pressure homeostasis. The therapeutic potential of new drugs that target S1P signaling is also discussed. PMID:27317800

  18. Long noncoding RNA LISPR1 is required for S1P signaling and endothelial cell function.

    Science.gov (United States)

    Josipovic, Ivana; Pflüger, Beatrice; Fork, Christian; Vasconez, Andrea E; Oo, James A; Hitzel, Juliane; Seredinski, Sandra; Gamen, Elisabetta; Heringdorf, Dagmar Meyer Zu; Chen, Wei; Looso, Mario; Pullamsetti, Soni Savai; Brandes, Ralf P; Leisegang, Matthias S

    2018-03-01

    Sphingosine-1-Phosphate (S1P) is a potent signaling lipid. The effects of S1P are mediated by the five S1P receptors (S1PR). In the endothelium S1PR1 is the predominant receptor and thus S1PR1 abundance limits S1P signaling. Recently, lncRNAs were identified as a novel class of molecules regulating gene expression. Interestingly, the lncRNA NONHSAT004848 (LISPR1, Long intergenic noncoding RNA antisense to S1PR1), is closely positioned to the S1P1 receptors gene and in part shares its promoter region. We hypothesize that LISPR1 controls endothelial S1PR1 expression and thus S1P-induced signaling in endothelial cells. In vitro transcription and translation as well as coding potential assessment showed that LISPR1 is indeed noncoding. LISPR1 was localized in both cytoplasm and nucleus and harbored a PolyA tail at the 3'end. In human umbilical vein endothelial cells, as well as human lung tissue, qRT-PCR and RNA-Seq revealed high expression of LISPR1. S1PR1 and LISPR1 were downregulated in human pulmonary diseases such as COPD. LISPR1 but also S1PR1 were induced by inflammation, shear stress and statins. Knockdown of LISPR1 attenuated endothelial S1P-induced migration and spheroid outgrowth of endothelial cells. LISPR1 knockdown decreased S1PR1 expression, which was paralleled by an increase of the binding of the transcriptional repressor ZNF354C to the S1PR1 promoter and a reduction of the recruitment of RNA Polymerase II to the S1PR1 5'end. This resulted in attenuated S1PR1 expression and attenuated S1P downstream signaling. Collectively, the disease relevant lncRNA LISPR1 acts as a novel regulatory unit important for S1PR1 expression and endothelial cell function. Copyright © 2018 Elsevier Ltd. All rights reserved.

  19. Enhancement of S1P-induced contractile response in detrusor smooth muscle of rats having cystitis.

    Science.gov (United States)

    Anjum, Irfan; Denizalti, Merve; Kandilci, Hilmi Burak; Durlu-Kandilci, Nezahat Tugba; Sahin-Erdemli, Inci

    2017-11-05

    Interstitial cystitis is a chronic disease characterized by lower abdominal pain and some nonspecific symptoms including an increase in urinary frequency and urgency. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that controls smooth muscle tone via G-protein coupled receptors (S1P 1-3 receptors). S1P production is known to take place both in physiological states and some pathological situations, such as in overactive bladder syndrome. The intracellular mechanism of S1P-induced contractile response was investigated in β-escin permeabilized detrusor smooth muscle of rats having cyclophosphamide-induced cystitis. The bladder was isolated from rats and detrusor smooth muscle strips were permeabilized with β-escin. S1P (50µM)-induced contraction and calcium sensitization response were significantly increased in cystitis. S1P-induced augmented contractile response was inhibited by S1P 2 receptor antagonist JTE-013 and S1P 3 receptor antagonist suramin. S1P 2 receptor protein expressions were increased in cystitis, where no change was observed in S1P 3 expressions between control and cystitis groups. S1P-induced contraction was reduced by Rho kinase (ROCK) inhibitor Y-27632 and protein kinase C (PKC) inhibitor GF-109203X in both control and cystitis group. S1P-induced increased calcium sensitization response was decreased by ROCK inhibitor and PKC inhibitor in cystitis. Our findings provide the first evidence that interstitial cystitis triggers S1P-induced increase in intracellular calcium in permeabilized detrusor smooth muscle of female rats. Both S1P 2 and S1P 3 receptors are involved in S1P mediated enhanced contractile response. The augmentation in S1P-induced contraction in interstitial cystitis involves both PKC and ROCK pathways of calcium sensitization. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Sphingosine kinase 1 deficiency confers protection against hyperoxia-induced bronchopulmonary dysplasia in a murine model: role of S1P signaling and Nox proteins.

    Science.gov (United States)

    Harijith, Anantha; Pendyala, Srikanth; Reddy, Narsa M; Bai, Tao; Usatyuk, Peter V; Berdyshev, Evgeny; Gorshkova, Irina; Huang, Long Shuang; Mohan, Vijay; Garzon, Steve; Kanteti, Prasad; Reddy, Sekhar P; Raj, J Usha; Natarajan, Viswanathan

    2013-10-01

    Bronchopulmonary dysplasia of the premature newborn is characterized by lung injury, resulting in alveolar simplification and reduced pulmonary function. Exposure of neonatal mice to hyperoxia enhanced sphingosine-1-phosphate (S1P) levels in lung tissues; however, the role of increased S1P in the pathobiological characteristics of bronchopulmonary dysplasia has not been investigated. We hypothesized that an altered S1P signaling axis, in part, is responsible for neonatal lung injury leading to bronchopulmonary dysplasia. To validate this hypothesis, newborn wild-type, sphingosine kinase1(-/-) (Sphk1(-/-)), sphingosine kinase 2(-/-) (Sphk2(-/-)), and S1P lyase(+/-) (Sgpl1(+/-)) mice were exposed to hyperoxia (75%) from postnatal day 1 to 7. Sphk1(-/-), but not Sphk2(-/-) or Sgpl1(+/-), mice offered protection against hyperoxia-induced lung injury, with improved alveolarization and alveolar integrity compared with wild type. Furthermore, SphK1 deficiency attenuated hyperoxia-induced accumulation of IL-6 in bronchoalveolar lavage fluids and NADPH oxidase (NOX) 2 and NOX4 protein expression in lung tissue. In vitro experiments using human lung microvascular endothelial cells showed that exogenous S1P stimulated intracellular reactive oxygen species (ROS) generation, whereas SphK1 siRNA, or inhibitor against SphK1, attenuated hyperoxia-induced S1P generation. Knockdown of NOX2 and NOX4, using specific siRNA, reduced both basal and S1P-induced ROS formation. These results suggest an important role for SphK1-mediated S1P signaling-regulated ROS in the development of hyperoxia-induced lung injury in a murine neonatal model of bronchopulmonary dysplasia. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  1. Protective Effect of Protocatechuic Acid on TNBS-Induced Colitis in Mice Is Associated with Modulation of the SphK/S1P Signaling Pathway.

    Science.gov (United States)

    Crespo, Irene; San-Miguel, Beatriz; Mauriz, José Luis; Ortiz de Urbina, Juan José; Almar, Mar; Tuñón, María Jesús; González-Gallego, Javier

    2017-03-16

    (1) Background: The present study aimed to investigate whether beneficial effects of protocatechuic acid (PCA) are associated with inhibition of the SphK/S1P axis and related signaling pathways in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) model of inflammatory bowel disease; (2) Methods: Colitis was induced in male Balb/c mice by intracolonic administration of 2 mg of TNBS. PCA (30 or 60 mg/kg body wt) was given intraperitoneally daily for five days; (3) Results: Administration of PCA prevented the macroscopic and microscopic damage to the colonic mucosa, the decrease in body weight gain and the increase in myeloperoxidase activity induced by TNBS. PCA-treated mice exhibited a lower oxidized/reduced glutathione ratio, increased expression of antioxidant enzymes and Nrf2 and reduced expression of proinflammatory cytokines. Following TNBS treatment mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production and expression of S1P receptor 1 and S1P phosphatase 2 were significantly elevated. However, there was a decreased expression of S1P lyase. Furthermore, TNBS-treated mice exhibited increased phosphorylation of AKT and ERK, and a higher expression of pSTAT3 and the NF-κB p65 subunit. PCA administration significantly prevented those changes; (4) Conclusions: Data obtained suggest a contribution of the SphK/S1P system and related signaling pathways to the anti-inflammatory effect of PCA.

  2. Disrupted epithelial/macrophage crosstalk via Spinster homologue 2-mediated S1P signaling may drive defective macrophage phagocytic function in COPD.

    Science.gov (United States)

    Tran, Hai B; Jersmann, Hubertus; Truong, Tung Thanh; Hamon, Rhys; Roscioli, Eugene; Ween, Miranda; Pitman, Melissa R; Pitson, Stuart M; Hodge, Greg; Reynolds, Paul N; Hodge, Sandra

    2017-01-01

    We have previously established a link between impaired phagocytic capacity and deregulated S1P signaling in alveolar macrophages from COPD subjects. We hypothesize that this defect may include a disruption of epithelial-macrophage crosstalk via Spns2-mediated intercellular S1P signaling. Primary alveolar macrophages and bronchial epithelial cells from COPD subjects and controls, cell lines, and a mouse model of chronic cigarette smoke exposure were studied. Cells were exposed to 10% cigarette smoke extract, or vehicle control. Spns2 expression and subcellular localization was studied by immunofluorescence, confocal microscopy and RT-PCR. Phagocytosis was assessed by flow-cytometry. Levels of intra- and extracellular S1P were measured by S1P [3H]-labeling. Spns2 expression was significantly increased (pS1P in the airway and that there is a possible disruption of epithelial/macrophage cross talk via Spns2-mediated S1P signaling in COPD and in response to cigarette smoke exposure.

  3. Differential S1P Receptor Profiles on M1- and M2-Polarized Macrophages Affect Macrophage Cytokine Production and Migration.

    Science.gov (United States)

    Müller, Jan; von Bernstorff, Wolfram; Heidecke, Claus-Dieter; Schulze, Tobias

    2017-01-01

    Introduction . Macrophages are key players in complex biological processes. In response to environmental signals, macrophages undergo polarization towards a proinflammatory (M1) or anti-inflammatory (M2) phenotype. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid that acts via 5 G-protein coupled receptors (S1P 1-5 ) in order to influence a broad spectrum of biological processes. This study assesses S1P receptor expression on macrophages before and after M1 and M2 polarization and performs a comparative analysis of S1P signalling in the two activational states of macrophages. Methods . Bone marrow derived macrophages (BMDM) from C57 BL/6 mice were cultured under either M1- or M2-polarizing conditions. S1P-receptor expression was determined by quantitative RT-PCR. Influence of S1P on macrophage activation, migration, phagocytosis, and cytokine secretion was assessed in vitro. Results . All 5 S1P receptor subclasses were expressed in macrophages. Culture under both M1- and M2-polarizing conditions led to significant downregulation of S1P 1 . In contrast, M1-polarized macrophages significantly downregulated S1P 4 . The expression of the remaining three S1P receptors did not change. S1P increased expression of iNOS under M2-polarizing conditions. Furthermore, S1P induced chemotaxis in M1 macrophages and changed cytokine production in M2 macrophages. Phagocytosis was not affected by S1P-signalling. Discussion . The expression of different specific S1P receptor profiles may provide a possibility to selectively influence M1- or M2-polarized macrophages.

  4. Suppressive Effects of the Site 1 Protease (S1P Inhibitor, PF-429242, on Dengue Virus Propagation

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    Leo Uchida

    2016-02-01

    Full Text Available Dengue virus (DENV infection causes one of the most widespread mosquito-borne diseases in the world. Despite the great need, effective vaccines and practical antiviral therapies are still under development. Intracellular lipid levels are regulated by sterol regulatory elements-binding proteins (SREBPs, which are activated by serine protease, site 1 protease (S1P. Small compound PF-429242 is known as a S1P inhibitor and the antivirus effects have been reported in some viruses. In this study, we examined the anti-DENV effects of PF-429242 using all four serotypes of DENV by several primate-derived cell lines. Moreover, emergence of drug-resistant DENV mutants was assessed by sequential passages with the drug. DENV dependency on intracellular lipids during their infection was also evaluated by adding extracellular lipids. The addition of PF-429242 showed suppression of viral propagation in all DENV serotypes. We showed that drug-resistant DENV mutants are unlikely to emerge after five times sequential passages through treatment with PF-429242. Although the levels of intracellular cholesterol and lipid droplets were reduced by PF-429242, viral propagations were not recovered by addition of exogenous cholesterol or fatty acids, indicating that the reduction of LD and cholesterol caused by PF-429242 treatment is not related to its mechanism of action against DENV propagation. Our results suggest that PF-429242 is a promising candidate for an anti-DENV agent.

  5. Suppressive Effects of the Site 1 Protease (S1P) Inhibitor, PF-429242, on Dengue Virus Propagation.

    Science.gov (United States)

    Uchida, Leo; Urata, Shuzo; Ulanday, Gianne Eduard L; Takamatsu, Yuki; Yasuda, Jiro; Morita, Kouichi; Hayasaka, Daisuke

    2016-02-10

    Dengue virus (DENV) infection causes one of the most widespread mosquito-borne diseases in the world. Despite the great need, effective vaccines and practical antiviral therapies are still under development. Intracellular lipid levels are regulated by sterol regulatory elements-binding proteins (SREBPs), which are activated by serine protease, site 1 protease (S1P). Small compound PF-429242 is known as a S1P inhibitor and the antivirus effects have been reported in some viruses. In this study, we examined the anti-DENV effects of PF-429242 using all four serotypes of DENV by several primate-derived cell lines. Moreover, emergence of drug-resistant DENV mutants was assessed by sequential passages with the drug. DENV dependency on intracellular lipids during their infection was also evaluated by adding extracellular lipids. The addition of PF-429242 showed suppression of viral propagation in all DENV serotypes. We showed that drug-resistant DENV mutants are unlikely to emerge after five times sequential passages through treatment with PF-429242. Although the levels of intracellular cholesterol and lipid droplets were reduced by PF-429242, viral propagations were not recovered by addition of exogenous cholesterol or fatty acids, indicating that the reduction of LD and cholesterol caused by PF-429242 treatment is not related to its mechanism of action against DENV propagation. Our results suggest that PF-429242 is a promising candidate for an anti-DENV agent.

  6. MMP2 and MMP9 participate in S1P-induced invasion of follicular ML-1 thyroid cancer cells.

    Science.gov (United States)

    Kalhori, Veronica; Törnquist, Kid

    2015-03-15

    The bioactive lipid sphingosine-1-phosphate (S1P) has emerged as a potent inducer of cancer cell migration and invasion. Previously, we have shown that S1P induces invasion of ML-1 follicular thyroid cancer cells via S1P receptors 1 and 3 (S1P1,3). Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes used by cells for degradation of the extracellular matrix during invasion and migration. In the present study, we examined the role of MMP2 and MMP9 for S1P-induced invasion of ML-1 cells, and found that S1P regulates the secretion and activity of MMP2 and MMP9 via S1P1,3. Both pharmacological inhibitors and siRNA knockdown of MMP2 and MMP9 could attenuate S1P-induced invasion. Additionally, we show that calpains and Rac1 mediate S1P-induced secretion of MMP2 and MMP9. In conclusion, MMP2 and MMP9 participate in S1P-evoked follicular ML-1 thyroid cancer cell invasion. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Plasma homocysteine levels in multiple sclerosis

    NARCIS (Netherlands)

    Ramsaransing, G S M; Fokkema, M R; Teelken, A; Arutjunyan, A V; Koch, M; De Keyser, J

    Background: There is evidence that homocysteine contributes to various neurodegenerative disorders, and elevated plasma homocysteine levels have been observed in patients with multiple sclerosis (MS). Objective: To investigate if and why plasma homocysteine levels are increased in MS, and whether

  8. Sphingosine-1-Phosphate (S1P) Impacts Presynaptic Functions by Regulating Synapsin I Localization in the Presynaptic Compartment.

    Science.gov (United States)

    Riganti, Loredana; Antonucci, Flavia; Gabrielli, Martina; Prada, Ilaria; Giussani, Paola; Viani, Paola; Valtorta, Flavia; Menna, Elisabetta; Matteoli, Michela; Verderio, Claudia

    2016-04-20

    Growing evidence indicates that sphingosine-1-P (S1P) upregulates glutamate secretion in hippocampal neurons. However, the molecular mechanisms through which S1P enhances excitatory activity remain largely undefined. The aim of this study was to identify presynaptic targets of S1P action controlling exocytosis. Confocal analysis of rat hippocampal neurons showed that S1P applied at nanomolar concentration alters the distribution of Synapsin I (SynI), a presynaptic phosphoprotein that controls the availability of synaptic vesicles for exocytosis. S1P induced SynI relocation to extrasynaptic regions of mature neurons, as well as SynI dispersion from synaptic vesicle clusters present at axonal growth cones of developing neurons. S1P-induced SynI relocation occurred in a Ca(2+)-independent but ERK-dependent manner, likely through the activation of S1P3 receptors, as it was prevented by the S1P3 receptor selective antagonist CAY1044 and in neurons in which S1P3 receptor was silenced. Our recent evidence indicates that microvesicles (MVs) released by microglia enhance the metabolism of endogenous sphingolipids in neurons and stimulate excitatory transmission. We therefore investigated whether MVs affect SynI distribution and whether endogenous S1P could be involved in the process. Analysis of SynI immunoreactivity showed that exposure to microglial MVs induces SynI mobilization at presynaptic sites and growth cones, whereas the use of inhibitors of sphingolipid cascade identified S1P as the sphingolipid mediating SynI redistribution. Our data represent the first demonstration that S1P induces SynI mobilization from synapses, thereby indicating the phosphoprotein as a novel target through which S1P controls exocytosis. Growing evidence indicates that the bioactive lipid sphingosine and its metabolite sphingosine-1-P (S1P) stimulate excitatory transmission. While it has been recently clarified that sphingosine influences directly the exocytotic machinery by activating the

  9. Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer.

    Science.gov (United States)

    Bouquerel, P; Gstalder, C; Müller, D; Laurent, J; Brizuela, L; Sabbadini, R A; Malavaud, B; Pyronnet, S; Martineau, Y; Ader, I; Cuvillier, O

    2016-03-14

    The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway has been reported to modulate the expression of the canonical transcription factor hypoxia-inducible HIF-1α in multiple cell lineages. HIF-2α is also frequently overexpressed in solid tumors but its role has been mostly studied in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, where HIF-2α has been established as a driver of a more aggressive disease. In this study, the role of SphK1/S1P signaling with regard to HIF-2α was investigated in various cancer cell models including ccRCC cells. Under hypoxic conditions or in ccRCC lacking a functional von Hippel-Lindau (VHL) gene and expressing high levels of HIF-2α, SphK1 activity controls HIF-2α expression and transcriptional activity through a phospholipase D (PLD)-driven mechanism. SphK1 silencing promotes a VHL-independent HIF-2α loss of expression and activity and reduces cell proliferation in ccRCC. Importantly, downregulation of SphK1 is associated with impaired Akt and mTOR signaling in ccRCC. Taking advantage of a monoclonal antibody neutralizing extracellular S1P, we show that inhibition of S1P extracellular signaling blocks HIF-2α accumulation in ccRCC cell lines, an effect mimicked when the S1P transporter Spns2 or the S1P receptor 1 (S1P1) is silenced. Here, we report the first evidence that the SphK1/S1P signaling pathway regulates the transcription factor hypoxia-inducible HIF-2α in diverse cancer cell lineages notably ccRCC, where HIF-2α has been established as a driver of a more aggressive disease. These findings demonstrate that SphK1/S1P signaling may act as a canonical regulator of HIF-2α expression in ccRCC, giving support to its inhibition as a therapeutic strategy that could contribute to reduce HIF-2 activity in ccRCC.

  10. FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P(3) and phosphoinositide 3-kinase.

    Science.gov (United States)

    Imeri, Faik; Blanchard, Olivier; Jenni, Aurelio; Schwalm, Stephanie; Wünsche, Christin; Zivkovic, Aleksandra; Stark, Holger; Pfeilschifter, Josef; Huwiler, Andrea

    2015-12-01

    Sphingosine-1-phosphate (S1P) is a key lipid regulator of a variety of cellular responses including cell proliferation and survival, cell migration, and inflammatory reactions. Here, we investigated the effect of S1P receptor activation on immune cell adhesion to endothelial cells under inflammatory conditions. We show that S1P reduces both tumor necrosis factor (TNF)-α- and lipopolysaccharide (LPS)-stimulated adhesion of Jurkat and U937 cells to an endothelial monolayer. The reducing effect of S1P was reversed by the S1P1+3 antagonist VPC23019 but not by the S1P1 antagonist W146. Additionally, knockdown of S1P3, but not S1P1, by short hairpin RNA (shRNA) abolished the reducing effect of S1P, suggesting the involvement of S1P3. A suppression of immune cell adhesion was also seen with the immunomodulatory drug FTY720 and two novel butterfly derivatives ST-968 and ST-1071. On the molecular level, S1P and all FTY720 derivatives reduced the mRNA expression of LPS- and TNF-α-induced adhesion molecules including ICAM-1, VCAM-1, E-selectin, and CD44 which was reversed by the PI3K inhibitor LY294002, but not by the MEK inhibitor U0126.In summary, our data demonstrate a novel molecular mechanism by which S1P, FTY720, and two novel butterfly derivatives acted anti-inflammatory that is by suppressing gene transcription of various endothelial adhesion molecules and thereby preventing adhesion of immune cells to endothelial cells and subsequent extravasation.

  11. S1P-induced airway smooth muscle hyperresponsiveness and lung inflammation in vivo: molecular and cellular mechanisms.

    Science.gov (United States)

    Roviezzo, F; Sorrentino, R; Bertolino, A; De Gruttola, L; Terlizzi, M; Pinto, A; Napolitano, M; Castello, G; D'Agostino, B; Ianaro, A; Sorrentino, R; Cirino, G

    2015-04-01

    Sphingosine-1-phosphate (S1P) has been shown to be involved in the asthmatic disease as well in preclinical mouse experimental models of this disease. The aim of this study was to understand the mechanism(s) underlying S1P effects on the lung. BALB/c, mast cell-deficient and Nude mice were injected with S1P (s.c.) on days 0 and 7. Functional, molecular and cellular studies were performed. S1P administration to BALB/c mice increased airway smooth muscle reactivity, mucus production, PGD2 , IgE, IL-4 and IL-13 release. These features were associated to a higher recruitment of mast cells to the lung. Mast cell-deficient Kit (W) (-sh/) (W) (-sh) mice injected with S1P did not display airway smooth muscle hyper-reactivity. However, lung inflammation and IgE production were still present. Treatment in vivo with the anti-CD23 antibody B3B4, which blocks IgE production, inhibited both S1P-induced airway smooth muscle reactivity in vitro and lung inflammation. S1P administration to Nude mice did not elicit airway smooth muscle hyper-reactivity and lung inflammation. Naïve (untreated) mice subjected to the adoptive transfer of CD4+ T-cells harvested from S1P-treated mice presented all the features elicited by S1P in the lung. S1P triggers a cascade of events that sequentially involves T-cells, IgE and mast cells reproducing several asthma-like features. This model may represent a useful tool for defining the role of S1P in the mechanism of action of currently-used drugs as well as in the development of new therapeutic approaches for asthma-like diseases. © 2014 The British Pharmacological Society.

  12. Different response patterns of several ligands at the sphingosine-1-phosphate receptor subtype 3 (S1P(3))

    NARCIS (Netherlands)

    Jongsma, M.; van Unen, J.; van Loenen, P. B.; Michel, M. C.; Peters, S. L. M.; Alewijnse, A. E.

    2009-01-01

    Recently, some ligands targeting the sphingosine-1-phosphate receptor subtype 3 (S1P(3)) have become available. The characterization of these compounds was mainly based on one functional read-out system, although S1P(3) receptors are known to activate different signal transduction pathways.

  13. Sphingosine 1-phosphate (S1P) signalling: Role in bone biology and potential therapeutic target for bone repair.

    Science.gov (United States)

    Sartawi, Ziad; Schipani, Ernestina; Ryan, Katie B; Waeber, Christian

    2017-11-01

    The lipid mediator sphingosine 1-phosphate (S1P) affects cellular functions in most systems. Interest in its therapeutic potential has increased following the discovery of its G protein-coupled receptors and the recent availability of agents that can be safely administered in humans. Although the role of S1P in bone biology has been the focus of much less research than its role in the nervous, cardiovascular and immune systems, it is becoming clear that this lipid influences many of the functions, pathways and cell types that play a key role in bone maintenance and repair. Indeed, S1P is implicated in many osteogenesis-related processes including stem cell recruitment and subsequent differentiation, differentiation and survival of osteoblasts, and coupling of the latter cell type with osteoclasts. In addition, S1P's role in promoting angiogenesis is well-established. The pleiotropic effects of S1P on bone and blood vessels have significant potential therapeutic implications, as current therapeutic approaches for critical bone defects show significant limitations. Because of the complex effects of S1P on bone, the pharmacology of S1P-like agents and their physico-chemical properties, it is likely that therapeutic delivery of S1P agents will offer significant advantages compared to larger molecular weight factors. Hence, it is important to explore novel methods of utilizing S1P agents therapeutically, and improve our understanding of how S1P and its receptors modulate bone physiology and repair. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. The effect of S1P receptor signaling pathway on the survival and drug resistance in multiple myeloma cells.

    Science.gov (United States)

    Fu, Di; Li, Yingchun; Li, Jia; Shi, Xiaoyan; Yang, Ronghui; Zhong, Yuan; Wang, Huihan; Liao, Aijun

    2017-01-01

    Multiple myeloma (MM) remains incurable by conventional chemotherapy. Sphingosine-1-phosphate (S1P) receptor-mediated signaling has been recently demonstrated to have critical roles in cell survival and drug resistance in a number of hematological malignancies. To dissect the roles of S1P receptor pathway in MM, we systematically examined cell viability and protein expression associated with cell survival and drug resistance in MM cell lines upon treatment with either pathway activator (S1P) or inhibitor (FTY720). Our results reveal that FTY720 inhibits cell proliferation by downregulating expression of target genes, while S1P has an opposite effect. Knocking down of S1P receptor S1P5R results in a reduction of cell survival-related gene expression; however, it does not have impacts on expression of drug resistance genes. These results suggest that S1P signaling plays a role in cell proliferation and drug resistance in MM, and targeting this pathway will provide a new therapeutic direction for MM management.

  15. Population pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator.

    Science.gov (United States)

    Krause, Andreas; Brossard, Patrick; D'Ambrosio, Daniele; Dingemanse, Jasper

    2014-06-01

    Ponesimod (ACT-128800), a reversible, orally active, selective S1P1 receptor modulator, prevents the egress of lymphocytes from the lymph node into the systemic circulation. It is currently in clinical development for the treatment of relapsing multiple sclerosis. Modulation of circulating lymphocytes serves as biomarker of efficacy and safety, such that the quantitative characterization of the pharmacokinetic/pharmacodynamic (PK/PD) relationship guides the clinical development of the compound. The availability of a variety of doses, dosing regimens, and treatment durations permitted estimation of the pharmacokinetics characterized by an absorption lag time followed by a sequential zero/first-order absorption and two compartments with first-order elimination. The PD are modeled as an indirect-effect model with rates of appearance and disappearance of lymphocytes in blood with a circadian rhythm and a drug effect on the rate of appearance. The model suggests a circadian variation of 9% and a maximum inhibition of 86% of total lymphocyte count with high doses at steady state. It was instrumental for the selection of doses for subsequent studies that confirmed the effect plateau in total lymphocyte count at approximately 0.5 × 10(9) counts/L.

  16. Modeling clinical efficacy of the S1P receptor modulator ponesimod in psoriasis.

    Science.gov (United States)

    Krause, Andreas; D'Ambrosio, Daniele; Dingemanse, Jasper

    2018-02-01

    Ponesimod is currently the only S1P receptor modulator studied in psoriasis. In a dose-finding study, the active doses showed similar efficacy. Prediction of efficacy at lower doses to aid clinical phase 3 planning with respect to dose selection, duration of treatment, and patient inclusion criteria based on pharma-co-kinetic/pharmacodynamic (PK/PD) modeling and simulation. The dose-finding study treated 326 patients (67 on placebo, 126 on 20mg, and 133 on 40mg) over 16 weeks. PK/PD modeling of steady-state trough concentrations and longitudinal PASI scores was employed to characterize data and simulate scenarios. PASI score continually decreased with time on ponesimod treatment, reaching a plateau at 16 weeks. Absolute and relative (percent) PASI score change was larger in patients with higher PASI score at baseline. Doses below 10mg were predicted to show lower efficacy than doses of 10mg and higher. Concentration-response modeling was able to predict the efficacy of doses that were not studied. In psoriasis patients, a dose of 10mg (not administered in the study) was predicted to show efficacy similar to 20mg. Disease status (PASI score at baseline) as study inclusion criterion has pronounced influence on study outcome. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

  17. Sphingosine-1-phosphate (S1P) activates STAT3 to protect against de novo acute heart failure (AHF).

    Science.gov (United States)

    Deshpande, Gaurang P; Imamdin, Aqeela; Lecour, Sandrine; Opie, Lionel H

    2018-03-01

    Acute heart failure (AHF) is a burden disease, with high mortality and re-hospitalisations. Using an ex-vivo model of AHF, we have previously reported that sphingosine-1-phosphate (S1P) confers cardioprotection. However, the mechanisms remain to be elucidated. In the present study, we aimed to examine the role of the cardioprotective signal transducer and activator of transcription 3 (STAT3) in S1P mediated improved functional recovery in AHF. Isolated hearts from male Long-Evans rats were subjected to hypotensive AHF for 35 min followed by a recovery phase of 30 min (n ≥ 4/group). S1P (10 nM) was given during either the hypotensive or the recovery phase with/without an inhibitor of STAT3, AG490. Functional parameters were recorded throughout the experiment. Following an AHF insult, S1P, given during the recovery phase, improved the heart rate (HR) compared to the control (175.2 ± 30.7 vs. 71.6 ± 27.4 beats per minute (BPM); p S1P abolished the cardioprotective effect of S1P (42.3 ± 17.1 vs. 148.8 ± 26.4 BPM for S1P; p S1P protects in an ex-vivo rat heart model of AHF by activation of STAT3 and provide further evidence for the usage of S1P as a potential therapy in patients suffering from AHF. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells.

    Science.gov (United States)

    González-Fernández, Bárbara; Sánchez, Diana I; Crespo, Irene; San-Miguel, Beatriz; Álvarez, Marcelino; Tuñón, María J; González-Gallego, Javier

    2017-03-01

    The sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) system is involved in different pathological processes, including fibrogenesis. Melatonin abrogates activation of hepatic stellate cells (HSCs) and attenuates different profibrogenic pathways in animal models of fibrosis, but it is unknown if protection associates with its inhibitory effect on the SphK1/S1P axis. Mice in treatment groups received carbon tetrachloride (CCl 4 ) 5 μL g -1 body wt i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg kg -1  day -1 i.p, beginning 2 weeks after the start of CCl 4 administration. At both 4 and 6 weeks following CCl 4 treatment, liver mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production, and expression of S1P receptor (S1PR)1, S1PR3 and acid sphingomyelinase (ASMase) were significantly elevated. However, there was a decreased expression of S1PR2 and S1P lyase (S1PL). Melatonin attenuated liver fibrosis, as shown by a significant inhibition of the expression of α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β and collagen (Col) Ι. Furthermore, melatonin inhibited S1P production, lowered expression of SphK1, S1PR1, SP1R3, and ASMase, and increased expression of S1PL. Melatonin induced a reversal of activated human HSCs cell line LX2, as evidenced by a reduction in α-SMA, TGF-β, and Col I expression. Melatonin-treated cells also exhibited an inhibition of the SphK1/S1P axis. Antifibrogenic effect of SphK1 inhibition was confirmed by treatment of LX2 cells with PF543. Abrogation of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in liver fibrogenesis. © 2016 BioFactors, 43(2):272-282, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

  19. Transforming growth factor-β-sphingosine kinase 1/S1P signaling upregulates microRNA-21 to promote fibrosis in renal tubular epithelial cells.

    Science.gov (United States)

    Liu, Xiujuan; Hong, Quan; Wang, Zhen; Yu, Yanyan; Zou, Xin; Xu, Lihong

    2016-02-01

    Renal fibrosis is a progressive pathological change characterized by tubular cell apoptosis, tubulointerstitial fibroblast proliferation, and excessive deposition of extracellular matrix (ECM). miR-21 has been implicated in transforming growth factor-β (TGF-β)-stimulated tissue fibrosis. Recent studies showed that sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) are also critical for TGF-β-stimulated tissue fibrosis; however, it is not clear whether SphK/S1P interacts with miR-21 or not. In this study, we hypothesized that SphK/S1P signaling is linked to upregulation of miR-21 by TGF-β. To verify this hypothesis, we first determined that miR-21 was highly expressed in renal tubular epithelial cells (TECs) stimulated with TGF-β by using qRT-PCR and Northern blotting. Simultaneously, inhibition of miR-21, mediated by the corresponding antimir, markedly decreased the expression and deposition of type I collagen, fibronectin (Fn), cysteine-rich protein 61 (CCN1), α-smooth muscle actin, and fibroblast-specific protein1 in TGF-β-treated TECs. ELISA and qRT-PCR were used to measure the S1P and SphK1 levels in TECs. S1P production was induced by TGF-β through activation of SphK1. Furthermore, it was observed that TGF-β-stimulated upregulation of miR-21 was abolished by SphK1 siRNA and was restored by the addition of exogenous S1P. Blocking S1PR2 also inhibited upregulation of miR-21. Additionally, miR-21 overexpression attenuated the repression of TGF-β-stimulated ECM deposition and epithelial-mesenchymal transition by SphK1 and S1PR2 siRNA. In summary, our study demonstrates a link between SphK1/S1P and TGF-β-induced miR-21 in renal TECs and may represent a novel therapeutic target in renal fibrosis. © 2015 by the Society for Experimental Biology and Medicine.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  2. Role of JAK-STAT pathway in reducing cardiomyocytes hypoxia/reoxygenation injury induced by S1P postconditioning.

    Science.gov (United States)

    Wang, Yuqing; Wang, Dongfei; Zhang, Lizhi; Ye, Fangyu; Li, Mengmeng; Wen, Ke

    2016-08-05

    This experiment was designed to explore the protection of sphingosine1-phosphate (S1P) postconditioning on rat myocardial cells injured by hypoxia/reoxygenation acting via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signal pathway. The data showed that S1P could significantly increase cell viability, lower the rate of apoptosis, decrease the content of lactate dehydrogenase (LDH) and caspase3 activity in the culture medium, increase the activity of total superoxide dismutase (T-SOD) and manganese superoxide dismutase (Mn-SOD), reduce the loss of mitochondrial membrane potential and the fluorescence intensity of intracellular calcium, as well as increase the phosphorylation of JAK2 and STAT3 in comparison with the H/R group. When the JAK inhibitor AG490 or the STAT inhibitor stattic were added, the effects of S1P were inhibited. Our date shows that S1P protects H9c2 cells from hypoxia/reoxygenation injury and that the protection by S1P was inhibited by AG490 and stattic. Therefore S1P protects H9c2 cells against hypoxia/reoxygenation injury via the JAK-STAT pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Fluoride absorption: independence from plasma fluoride levels

    International Nuclear Information System (INIS)

    Whitford, G.M.; Williams, J.L.

    1986-01-01

    The concept that there are physiologic mechanisms to homeostatically regulate plasma fluoride concentrations has been supported by results in the literature suggesting an inverse relationship between plasma fluoride levels and the absorption of the ion from the gastrointestinal tract of the rat. The validity of the relationship was questioned because of possible problems in the experimental design. The present work used four different methods to evaluate the effect of plasma fluoride levels on the absorption of the ion in rats: (i) the percentage of the daily fluoride intake that was excreted in the urine; (ii) the concentration of fluoride in femur epiphyses; (iii) the net areas under the time-plasma fluoride concentration curves after intragastric fluoride doses; and (iv) the residual amounts or fluoride in the gastrointestinal tracts after the intragastric fluoride doses. None of these methods indicated that plasma fluoride levels influence the rate or the degree or fluoride absorption. It was concluded that, unless extremely high plasma fluoride levels are involved (pharmacologic or toxic doses), the absorption of the ion is independent of plasma levels. The results provide further evidence that plasma fluoride concentrations are not homeostatically regulated

  4. Oxidized LDL-induced angiogenesis involves sphingosine 1-phosphate: prevention by anti-S1P antibody.

    Science.gov (United States)

    Camaré, Caroline; Trayssac, Magali; Garmy-Susini, Barbara; Mucher, Elodie; Sabbadini, Roger; Salvayre, Robert; Negre-Salvayre, Anne

    2015-01-01

    Neovascularization occurring in atherosclerotic lesions may promote plaque expansion, intraplaque haemorrhage and rupture. Oxidized LDL (oxLDL) are atherogenic, but their angiogenic effect is controversial; both angiogenic and anti-angiogenic effects have been reported. The angiogenic mechanism of oxLDL is partly understood, but the role of the angiogenic sphingolipid, sphingosine 1-phosphate (S1P), in this process is not known. Thus, we investigated whether S1P is involved in the oxLDL-induced angiogenesis and whether an anti-S1P monoclonal antibody can prevent this effect. Angiogenesis was assessed by capillary tube formation by human microvascular endothelial cells (HMEC-1) cultured on Matrigel and in vivo by the Matrigel plug assay in C57BL/6 mice. Human oxLDL exhibited a biphasic angiogenic effect on HMEC-1; low concentrations were angiogenic, higher concentrations were cytotoxic. The angiogenic response to oxLDL was blocked by the sphingosine kinase (SPHK) inhibitor, dimethylsphingosine, by SPHK1-siRNA and by an anti-S1P monoclonal antibody. Moreover, inhibition of oxLDL uptake and subsequent redox signalling by anti-CD36 and anti-LOX-1 receptor antibodies and by N-acetylcysteine, respectively, blocked SPHK1 activation and tube formation. In vivo, in the Matrigel plug assay, low concentrations of human oxLDL or murine oxVLDL also triggered angiogenesis, which was prevented by i.p. injection of the anti-S1P antibody. These data highlight the role of S1P in angiogenesis induced by oxLDL both in HMEC-1 cultured on Matrigel and in vivo in the Matrigel plug model in mice, and demonstrate that the anti-S1P antibody effectively blocks the angiogenic effect of oxLDL. © 2014 The British Pharmacological Society.

  5. Sphingosine-1-Phosphate and the S1P3 Receptor Initiate Neuronal Retraction via RhoA/ROCK Associated with CRMP2 Phosphorylation

    Science.gov (United States)

    Quarta, Serena; Camprubí-Robles, Maria; Schweigreiter, Rüdiger; Matusica, Dusan; Haberberger, Rainer V.; Proia, Richard L.; Bandtlow, Christine E.; Ferrer-Montiel, Antonio; Kress, Michaela

    2017-01-01

    The bioactive lipid sphingosine-1-phosphate (S1P) is an important regulator in the nervous system. Here, we explored the role of S1P and its receptors in vitro and in preclinical models of peripheral nerve regeneration. Adult sensory neurons and motor neuron-like cells were exposed to S1P in an in vitro assay, and virtually all neurons responded with a rapid retraction of neurites and growth cone collapse which were associated with RhoA and ROCK activation. The S1P1 receptor agonist SEW2871 neither activated RhoA or neurite retraction, nor was S1P-induced neurite retraction mitigated in S1P1-deficient neurons. Depletion of S1P3 receptors however resulted in a dramatic inhibition of S1P-induced neurite retraction and was on the contrary associated with a significant elongation of neuronal processes in response to S1P. Opposing responses to S1P could be observed in the same neuron population, where S1P could activate S1P1 receptors to stimulate elongation or S1P3 receptors and retraction. S1P was, for the first time in sensory neurons, linked to the phosphorylation of collapsin response-mediated protein-2 (CRMP2), which was inhibited by ROCK inhibition. The improved sensory recovery after crush injury further supported the relevance of a critical role for S1P and receptors in fine-tuning axonal outgrowth in peripheral neurons. PMID:29066950

  6. Disrupted epithelial/macrophage crosstalk via Spinster homologue 2-mediated S1P signaling may drive defective macrophage phagocytic function in COPD.

    Directory of Open Access Journals (Sweden)

    Hai B Tran

    Full Text Available We have previously established a link between impaired phagocytic capacity and deregulated S1P signaling in alveolar macrophages from COPD subjects. We hypothesize that this defect may include a disruption of epithelial-macrophage crosstalk via Spns2-mediated intercellular S1P signaling.Primary alveolar macrophages and bronchial epithelial cells from COPD subjects and controls, cell lines, and a mouse model of chronic cigarette smoke exposure were studied. Cells were exposed to 10% cigarette smoke extract, or vehicle control. Spns2 expression and subcellular localization was studied by immunofluorescence, confocal microscopy and RT-PCR. Phagocytosis was assessed by flow-cytometry. Levels of intra- and extracellular S1P were measured by S1P [3H]-labeling.Spns2 expression was significantly increased (p<0.05 in alveolar macrophages from current-smokers/COPD patients (n = 5 compared to healthy nonsmokers (n = 8 and non-smoker lung transplant patients (n = 4. Consistent with this finding, cigarette smoke induced a significant increase in Spns2 expression in both human alveolar and THP-1 macrophages. In contrast, a remarkable Spns2 down-regulation was noted in response to cigarette smoke in 16HBE14o- cell line (p<0.001 in 3 experiments, primary nasal epithelial cells (p<0.01 in 2 experiments, and in smoke-exposed mice (p<0.001, n = 6 animals per group. Spns2 was localized to cilia in primary bronchial epithelial cells. In both macrophage and epithelial cell types, Spns2 was also found localized to cytoplasm and the nucleus, in line with a predicted bipartile Nuclear Localization Signal at the position aa282 of the human Spns2 sequence. In smoke-exposed mice, alveolar macrophage phagocytic function positively correlated with Spns2 protein expression in bronchial epithelial cells.Our data suggest that the epithelium may be the major source for extracellular S1P in the airway and that there is a possible disruption of epithelial/macrophage cross talk via

  7. Desensitization by progressive up-titration prevents first-dose effects on the heart: guinea pig study with ponesimod, a selective S1P1 receptor modulator.

    Directory of Open Access Journals (Sweden)

    Markus Rey

    Full Text Available Ponesimod, a selective S1P1 receptor modulator, reduces the blood lymphocyte count in all tested species by preventing egress of T and B cells from thymus and peripheral lymphoid organs. In addition, ponesimod transiently affects heart rate and atrioventricular (AV conduction in humans, effects not observed in mice, rats, and dogs with selective S1P1 receptor modulators, suggesting that the regulation of heart rate and rhythm is species dependent. In the present study, we used conscious guinea pigs implanted with a telemetry device to investigate the effects of single and multiple oral doses of ponesimod on ECG variables, heart rate, and blood pressure. Oral administration of ponesimod did not affect the sinus rate (P rate but dose-dependently induced AV block type I to III. A single oral dose of 0.1 mg/kg had no effect on ECG variables, while a dose of 3 mg/kg induced AV block type III in all treated guinea pigs. Repeated oral dosing of 1 or 3 mg/kg ponesimod resulted in rapid desensitization, so that the second dose had no or a clearly reduced effect on ECG variables as compared with the first dose. Resensitization of the S1P1 receptor in the heart was concentration dependent. After desensitization had been induced by the first dose of ponesimod, the cardiac system remained desensitized as long as the plasma concentration was ≥75 ng/ml. By using a progressive up-titration regimen, the first-dose effect of ponesimod on heart rate and AV conduction was significantly reduced due to desensitization of the S1P1 receptor. In summary, conscious guinea pigs implanted with a telemetry device represent a useful model to study first-dose effects of S1P1 receptor modulators on heart rate and rhythm. This knowledge was translated to a dosing regimen of ponesimod to be tested in humans to avoid or significantly reduce the first-dose effects.

  8. Mechanism of Folding and Activation of Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P).

    Science.gov (United States)

    da Palma, Joel Ramos; Cendron, Laura; Seidah, Nabil Georges; Pasquato, Antonella; Kunz, Stefan

    2016-01-29

    The proprotein convertase subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is implicated in lipid homeostasis, the unfolded protein response, and lysosome biogenesis. The protease is further hijacked by highly pathogenic emerging viruses for the processing of their envelope glycoproteins. Zymogen activation of SKI-1/S1P requires removal of an N-terminal prodomain, by a multistep process, generating the mature enzyme. Here, we uncover a modular structure of the human SKI-1/S1P prodomain and define its function in folding and activation. We provide evidence that the N-terminal AB fragment of the prodomain represents an autonomous structural and functional unit that is necessary and sufficient for folding and partial activation. In contrast, the C-terminal BC fragment lacks a defined structure but is crucial for autoprocessing and full catalytic activity. Phylogenetic analysis revealed that the sequence of the AB domain is highly conserved, whereas the BC fragment shows considerable variation and seems even absent in some species. Notably, SKI-1/S1P of arthropods, like the fruit fly Drosophila melanogaster, contains a shorter prodomain comprised of full-length AB and truncated BC regions. Swapping the prodomain fragments between fly and human resulted in a fully mature and active SKI-1/S1P chimera. Our study suggests that primordial SKI-1/S1P likely contained a simpler prodomain consisting of the highly conserved AB fragment that represents an independent folding unit. The BC region appears as a later evolutionary acquisition, possibly allowing more subtle fine-tuning of the maturation process. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Mechanism of Folding and Activation of Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P)*

    Science.gov (United States)

    da Palma, Joel Ramos; Cendron, Laura; Seidah, Nabil Georges; Pasquato, Antonella; Kunz, Stefan

    2016-01-01

    The proprotein convertase subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is implicated in lipid homeostasis, the unfolded protein response, and lysosome biogenesis. The protease is further hijacked by highly pathogenic emerging viruses for the processing of their envelope glycoproteins. Zymogen activation of SKI-1/S1P requires removal of an N-terminal prodomain, by a multistep process, generating the mature enzyme. Here, we uncover a modular structure of the human SKI-1/S1P prodomain and define its function in folding and activation. We provide evidence that the N-terminal AB fragment of the prodomain represents an autonomous structural and functional unit that is necessary and sufficient for folding and partial activation. In contrast, the C-terminal BC fragment lacks a defined structure but is crucial for autoprocessing and full catalytic activity. Phylogenetic analysis revealed that the sequence of the AB domain is highly conserved, whereas the BC fragment shows considerable variation and seems even absent in some species. Notably, SKI-1/S1P of arthropods, like the fruit fly Drosophila melanogaster, contains a shorter prodomain comprised of full-length AB and truncated BC regions. Swapping the prodomain fragments between fly and human resulted in a fully mature and active SKI-1/S1P chimera. Our study suggests that primordial SKI-1/S1P likely contained a simpler prodomain consisting of the highly conserved AB fragment that represents an independent folding unit. The BC region appears as a later evolutionary acquisition, possibly allowing more subtle fine-tuning of the maturation process. PMID:26645686

  10. Pharmacologic inhibition of S1P attenuates ATF6 expression, causes ER stress and contributes to apoptotic cell death.

    Science.gov (United States)

    Lebeau, Paul; Byun, Jae Hyun; Yousof, Tamana; Austin, Richard C

    2018-04-22

    Mammalian cells express unique transcription factors embedded in the endoplasmic reticulum (ER) membrane, such as the sterol regulatory element-binding proteins (SREBPs), that promote de novo lipogenesis. Upon their release from the ER, the SREBPs require proteolytic activation in the Golgi by site-1-protease (S1P). As such, inhibition of S1P, using compounds such as PF-429242 (PF), reduces cholesterol synthesis and may represent a new strategy for the management of dyslipidemia. In addition to the SREBPs, the unfolded protein response (UPR) transducer, known as the activating transcription factor 6 (ATF6), is another ER membrane-bound transcription factor that requires S1P-mediated activation. ATF6 regulates ER protein folding capacity by promoting the expression of ER chaperones such as the 78-kDa glucose-regulated protein (GRP78). ER-resident chaperones like GRP78 prevent and/or resolve ER polypeptide accumulation and subsequent ER stress-induced UPR activation by folding nascent polypeptides. Here we report that pharmacological inhibition of S1P reduced the expression of ATF6 and GRP78 and induced the activation of UPR transducers inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like ER kinase (PERK). As a consequence, S1P inhibition also increased the susceptibility of cells to ER stress-induced cell death. Our findings suggest that S1P plays a crucial role in the regulation of ER folding capacity and also identifies a compensatory cross-talk between UPR transducers in order to maintain adequate ER chaperone expression and activity. Copyright © 2018. Published by Elsevier Inc.

  11. Memo has a novel role in S1P signaling and is [corrected] crucial for vascular development.

    Science.gov (United States)

    Kondo, Shunya; Bottos, Alessia; Allegood, Jeremy C; Masson, Regis; Maurer, Francisca G; Genoud, Christel; Kaeser, Patrick; Huwiler, Andrea; Murakami, Masato; Spiegel, Sarah; Hynes, Nancy E

    2014-01-01

    Memo is a conserved protein that was identified as an essential mediator of tumor cell motility induced by receptor tyrosine kinase activation. Here we show that Memo null mouse embryonic fibroblasts (MEFs) are impaired in PDGF-induced migration and this is due to a defect in sphingosine-1-phosphate (S1P) signaling. S1P is a bioactive phospholipid produced in response to multiple stimuli, which regulates many cellular processes. S1P is secreted to the extracellular milieu where it exerts its function by binding a family of G-protein coupled receptors (S1PRs), causing their activation in an autocrine or paracrine manner. The process, termed cell-autonomous S1PR signaling, plays a role in survival and migration. Indeed, PDGF uses cell-autonomous S1PR signaling to promote cell migration; we show here that this S1P pathway requires Memo. Using vascular endothelial cells (HUVECs) with Memo knock-down we show that their survival in conditions of serum-starvation is impaired. Furthermore, Memo loss in HUVECs causes a reduction of junctional VE-cadherin and an increase in sprout formation. Each of these phenotypes is rescued by S1P or S1P agonist addition, showing that Memo also plays an important role in cell-autonomous S1PR signaling in endothelial cells. We also produced conventional and endothelial cell-specific conditional Memo knock-out mouse strains and show that Memo is essential for embryonic development. Starting at E13.5 embryos of both strains display bleeding and other vascular problems, some of the phenotypes that have been described in mouse strains lacking S1PRs. The essential role of Memo in embryonic vascular development may be due in part to alterations in S1P signaling. Taken together our results show that Memo has a novel role in the S1P pathway and that Memo is needed to promote cell-autonomous S1PR activation.

  12. Cross talk between MMP2-Spm-Cer-S1P and ERK1/2 in proliferation of pulmonary artery smooth muscle cells under angiotensin II stimulation.

    Science.gov (United States)

    Chowdhury, Animesh; Sarkar, Jaganmay; Pramanik, Pijush Kanti; Chakraborti, Tapati; Chakraborti, Sajal

    2016-08-01

    The aim of the present study is to establish the mechanism associated with the proliferation of PASMCs under ANG II stimulation. The results showed that treatment of PASMCs with ANG II induces an increase in cell proliferation and 100 nM was the optimum concentration for maximum increase in proliferation of the cells. Pretreatment of the cells with AT1, but not AT2, receptor antagonist inhibited ANG II induced cell proliferation. Pretreatment with pharmacological and genetic inhibitors of sphingomyelinase (SMase) and sphingosine kinase (SPHK) prevented ANG II-induced cell proliferation. ANG II has also been shown to induce SMase activity, SPHK phosphorylation and S1P production. In addition, ANG II caused an increase in proMMP-2 expression and activation, ERK1/2 phosphorylation and NADPH oxidase activation. Upon inhibition of MMP-2, SMase activity and S1P level were curbed leading to inhibition of cell proliferation. SPHK was phosphorylated by ERK1/2 during ET-1 stimulation of the cells. ANG II-induced ERK1/2 phosphorylation and proMMP-2 expression and activation in the cells were abrogated upon inhibition of NADPH oxidase activity. Overall, NADPH oxidase plays an important role in proMMP-2 expression and activation and that MMP-2 mediated SMC proliferation occurs through the involvement of Spm-Cer-S1P signaling axis under ANG II stimulation of PASMCs. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Plasma sphingosine-1-phosphate is elevated in obesity.

    Directory of Open Access Journals (Sweden)

    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.

  14. S1P receptor signalling and RGS proteins; expression and function in vascular smooth muscle cells and transfected CHO cells

    NARCIS (Netherlands)

    Hendriks-Balk, Mariëlle C.; van Loenen, Pieter B.; Hajji, Najat; Michel, Martin C.; Peters, Stephan L. M.; Alewijnse, Astrid E.

    2009-01-01

    Sphingosine-1-phosphate (S1P) signalling via G protein-coupled receptors is important for the regulation of cell function and differentiation. Specific Regulators of G protein Signalling (RGS) proteins modulate the function of these receptors in many cell types including vascular smooth muscle cells

  15. Altered levels of acetylcholinesterase in Alzheimer plasma.

    Directory of Open Access Journals (Sweden)

    María-Salud García-Ayllón

    Full Text Available BACKGROUND: Many studies have been conducted in an extensive effort to identify alterations in blood cholinesterase levels as a consequence of disease, including the analysis of acetylcholinesterase (AChE in plasma. Conventional assays using selective cholinesterase inhibitors have not been particularly successful as excess amounts of butyrylcholinesterase (BuChE pose a major problem. PRINCIPAL FINDINGS: Here we have estimated the levels of AChE activity in human plasma by first immunoprecipitating BuChE and measuring AChE activity in the immunodepleted plasma. Human plasma AChE activity levels were approximately 20 nmol/min/mL, about 160 times lower than BuChE. The majority of AChE species are the light G(1+G(2 forms and not G(4 tetramers. The levels and pattern of the molecular forms are similar to that observed in individuals with silent BuChE. We have also compared plasma AChE with the enzyme pattern obtained from human liver, red blood cells, cerebrospinal fluid (CSF and brain, by sedimentation analysis, Western blotting and lectin-binding analysis. Finally, a selective increase of AChE activity was detected in plasma from Alzheimer's disease (AD patients compared to age and gender-matched controls. This increase correlates with an increase in the G(1+G(2 forms, the subset of AChE species which are increased in Alzheimer's brain. Western blot analysis demonstrated that a 78 kDa immunoreactive AChE protein band was also increased in Alzheimer's plasma, attributed in part to AChE-T subunits common in brain and CSF. CONCLUSION: Plasma AChE might have potential as an indicator of disease progress and prognosis in AD and warrants further investigation.

  16. Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation.

    Science.gov (United States)

    Grenald, Shaness A; Doyle, Timothy M; Zhang, Hong; Slosky, Lauren M; Chen, Zhoumou; Largent-Milnes, Tally M; Spiegel, Sarah; Vanderah, Todd W; Salvemini, Daniela

    2017-09-01

    Metastatic bone pain is the single most common form of cancer pain and persists as a result of peripheral and central inflammatory, as well as neuropathic mechanisms. Here, we provide the first characterization of sphingolipid metabolism alterations in the spinal cord occurring during cancer-induced bone pain (CIBP). Following femoral arthrotomy and syngenic tumor implantation in mice, ceramides decreased with corresponding increases in sphingosine and the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P). Intriguingly, de novo sphingolipid biosynthesis was increased as shown by the elevations of dihydro-ceramides and dihydro-S1P. We next identified the S1P receptor subtype 1 (S1PR1) as a novel target for therapeutic intervention. Intrathecal or systemic administration of the competitive and functional S1PR1 antagonists, TASP0277308 and FTY720/Fingolimod, respectively, attenuated cancer-induced spontaneous flinching and guarding. Inhibiting CIBP by systemic delivery of FTY720 did not result in antinociceptive tolerance over 7 days. FTY720 administration enhanced IL-10 in the lumbar ipsilateral spinal cord of CIBP animals and intrathecal injection of an IL-10 neutralizing antibody mitigated the ability of systemic FTY720 to reverse CIBP. FTY720 treatment was not associated with alterations in bone metabolism in vivo. Studies here identify a novel mechanism to inhibit bone cancer pain by blocking the actions of the bioactive metabolites S1P and dihydro-S1P in lumbar spinal cord induced by bone cancer and support potential fast-track clinical application of the FDA-approved drug, FTY720, as a therapeutic avenue for CIBP.

  17. Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival.

    Science.gov (United States)

    Maiti, Aparna; Takabe, Kazuaki; Hait, Nitai C

    2017-04-01

    About 40,000 American women die from metastatic breast cancer each year despite advancements in treatment. Approximately, 15% of breast cancers are triple-negative for estrogen receptor, progesterone receptor, and HER2. Triple-negative cancer is characterized by more aggressive, harder to treat with conventional approaches and having a greater possibility of recurrence. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid signaling mediator has emerged as a key regulatory molecule in breast cancer progression. Therefore, we investigated whether cytosolic sphingosine kinase type 1 (SphK1) and nuclear sphingosine kinase type 2 (SphK2), the enzymes that make S1P are critical for growth and PI3K/AKT, ERK-MAP kinase mediated survival signaling of lung metastatic variant LM2-4 breast cancer cells, generated from the parental triple-negative MDA-MB-231 human breast cancer cell line. Similar with previous report, SphKs/S1P signaling is critical for the growth and survival of estrogen receptor positive MCF-7 human breast cancer cells, was used as our study control. MDA-MB-231 did not show a significant effect of SphKs/S1P signaling on AKT, ERK, and p38 pathways. In contrast, LM2-4 cells that gained lung metastatic phenotype from primary MDA-MB-231 cells show a significant effect of SphKs/S1P signaling requirement on cell growth, survival, and cell motility. PF-543, a selective potent inhibitor of SphK1, attenuated epidermal growth factor (EGF)-mediated cell growth and survival signaling through inhibition of AKT, ERK, and p38 MAP kinase pathways mainly in LM2-4 cells but not in parental MDA-MB-231 human breast cancer cells. Moreover, K-145, a selective inhibitor of SphK2, markedly attenuated EGF-mediated cell growth and survival of LM2-4 cells. We believe this study highlights the importance of SphKs/S1P signaling in metastatic triple-negative breast cancers and targeted therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Differential Effects of Long Term FTY720 Treatment on Endothelial versus Smooth Muscle Cell Signaling to S1P in Rat Mesenteric Arteries

    NARCIS (Netherlands)

    Shishavan, Mahdi Hamidi; Bidadkosh, Arash; Yazdani, Saleh; Lambooy, Sebastiaan; van den Born, Jacob; Buikema, Hendrik; Henning, Robert H.; Deelman, Leo E.

    2016-01-01

    The sphingosine-1-phosphate (S1P) analog FTY720 exerts pleiotropic effects on the cardiovascular system and causes down-regulation of S1P receptors. Myogenic constriction is an important mechanism regulating resistance vessel function and is known to be modulated by S1P. Here we investigated

  19. Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer

    Science.gov (United States)

    Ader, Isabelle; Golzio, Muriel; Andrieu, Guillaume; Zalvidea, Santiago; Richard, Sylvain; Sabbadini, Roger A.; Malavaud, Bernard; Cuvillier, Olivier

    2015-01-01

    Hypoxia promotes neovascularization, increased tumor growth, and therapeutic resistance. The transcription factor, hypoxia-inducible factor 1α (HIF-1α), has been reported as the master driver of adaptation to hypoxia. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α under hypoxia. Taking advantage of a monoclonal antibody neutralizing extracellular S1P (sphingomab), we report that inhibition of S1P extracellular signaling blocks HIF-1α accumulation and activity in several cancer cell models exposed to hypoxia. In an orthotopic xenograft model of prostate cancer, we show that sphingomab reduces hypoxia and modifies vessel architecture within 5 days of treatment, leading to increased intratumoral blood perfusion. Supporting the notion that a transient vascular normalization of tumor vessels is the mechanism by which sphingomab exerts its effects, we demonstrate that administration of the antibody for 5 days before chemotherapy is more effective at local tumor control and metastatic dissemination than any other treatment scheduling. These findings validate sphingomab as a potential new normalization agent that could contribute to successful sensitization of hypoxic tumors to chemotherapy. PMID:25915662

  20. Mesenchymal Stromal Cell Secreted Sphingosine 1-Phosphate (S1P) Exerts a Stimulatory Effect on Skeletal Myoblast Proliferation

    Science.gov (United States)

    Tani, Alessia; Anderloni, Giulia; Pierucci, Federica; Matteini, Francesca; Chellini, Flaminia; Zecchi Orlandini, Sandra; Meacci, Elisabetta

    2014-01-01

    Bone-marrow-derived mesenchymal stromal cells (MSCs) have the potential to significantly contribute to skeletal muscle healing through the secretion of paracrine factors that support proliferation and enhance participation of the endogenous muscle stem cells in the process of repair/regeneration. However, MSC-derived trophic molecules have been poorly characterized. The aim of this study was to investigate paracrine signaling effects of MSCs on skeletal myoblasts. It was found, using a biochemical and morphological approach that sphingosine 1-phosphate (S1P), a natural bioactive lipid exerting a broad range of muscle cell responses, is secreted by MSCs and represents an important factor by which these cells exert their stimulatory effects on C2C12 myoblast and satellite cell proliferation. Indeed, exposure to conditioned medium obtained from MSCs cultured in the presence of the selective sphingosine kinase inhibitor (iSK), blocked increased cell proliferation caused by the conditioned medium from untreated MSCs, and the addition of exogenous S1P in the conditioned medium from MSCs pre-treated with iSK further increased myoblast proliferation. Finally, we also demonstrated that the myoblast response to MSC-secreted vascular endothelial growth factor (VEGF) involves the release of S1P from C2C12 cells. Our data may have important implications in the optimization of cell-based strategies to promote skeletal muscle regeneration. PMID:25264785

  1. Modeling Tolerance Development for the Effect on Heart Rate of the Selective S1P1 Receptor Modulator Ponesimod.

    Science.gov (United States)

    Lott, Dominik; Lehr, Thorsten; Dingemanse, Jasper; Krause, Andreas

    2017-09-15

    Ponesimod is a selective sphingosine-1-phosphate-1 (S1P 1 ) receptor modulator currently under investigation for the treatment of multiple sclerosis. S1P receptor modulators reduce heart rate following treatment initiation. This effect disappears with repeated dosing, enabling development of innovative uptitration regimens to optimize patient safety. There are currently no published pharmacokinetic/pharmacodynamic models describing the heart rate reduction of S1P receptor modulators in humans. The model developed here provides quantification of this effect for ponesimod. A direct-effect I max model with estimated maximum reduction of 45%, tolerance development, and circadian variation best described this effect. The pooled data from nine clinical studies enabled characterization of interindividual variability. The model was used to simulate different treatment regimens to compare the effect of high initial doses vs. gradual uptitration with respect to the occurrence of bradycardia. The results indicate a better safety profile when using gradual uptitration. The model allows studying dosing regimens not clinically tested in silico. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  2. Impairment of memory and plasma flunitrazepam levels

    NARCIS (Netherlands)

    Bareggi, [No Value; Ferini-Strambi, L; Pirola, R; Smirne, S

    Flunitrazepam was administered to volunteers in three different oral doses. The effects on psychomotor sedation, attention, working memory and explicit memory were then assessed at various intervals after dosing and compared with levels of the drug in the plasma. Three groups of 12 healthy males

  3. Impairment of memory and plasma flunitrazepam levels

    NARCIS (Netherlands)

    Bareggi, [No Value; Ferini-Strambi, L; Pirola, R; Smirne, S

    1998-01-01

    Flunitrazepam was administered to volunteers in three different oral doses. The effects on psychomotor sedation, attention, working memory and explicit memory were then assessed at various intervals after dosing and compared with levels of the drug in the plasma. Three groups of 12 healthy males

  4. Multi-Accuracy-Level Burning Plasma Simulations

    International Nuclear Information System (INIS)

    Artaud, J. F.; Basiuk, V.; Garcia, J.; Giruzzi, G.; Huynh, P.; Huysmans, G.; Imbeaux, F.; Johner, J.; Scheider, M.

    2007-01-01

    The design of a reactor grade tokamak is based on a hierarchy of tools. We present here three codes that are presently used for the simulations of burning plasmas. At the first level there is a 0-dimensional code that allows to choose a reasonable range of global parameters; in our case the HELIOS code was used for this task. For the second level we have developed a mixed 0-D / 1-D code called METIS that allows to study the main properties of a burning plasma, including profiles and all heat and current sources, but always under the constraint of energy and other empirical scaling laws. METIS is a fast code that permits to perform a large number of runs (a run takes about one minute) and design the main features of a scenario, or validate the results of the 0-D code on a full time evolution. At the top level, we used the full 1D1/2 suite of codes CRONOS that gives access to a detailed study of the plasma profiles evolution. CRONOS can use a variety of modules for source terms and transport coefficients computation with different level of complexity and accuracy: from simple estimators to highly sophisticated physics calculations. Thus it is possible to vary the accuracy of burning plasma simulations, as a trade-off with computation time. A wide range of scenario studies can thus be made with CRONOS and then validated with post-processing tools like MHD stability analysis. We will present in this paper results of this multi-level analysis applied to the ITER hybrid scenario. This specific example will illustrate the importance of having several tools for the study of burning plasma scenarios, especially in a domain that present devices cannot access experimentally. (Author)

  5. Investigating the Et-1/SphK/S1P Pathway as a Novel Approach for the Prevention of Inflammation-Induced Preterm Birth.

    Science.gov (United States)

    Giusto, Kiersten; Ashby, Charles R

    2018-01-30

    Preterm birth (PTB), defined as birth before 37 completed weeks of gestation, occurs in up to 18 percent of births worldwide and accounts for the majority of perinatal morbidity and mortality. While the single most common cause of PTB has been identified as inflammation, safe and effective pharmacotherapy to prevent PTB has yet to be developed. Our group has used an in vivo model of inflammation driven PTB, biochemical methods, pharmacological approaches, a novel endothelin receptor antagonist that we synthesized and RNA knockdown to help establish the role of endothelin-1 (ET-1) in inflammation-associated PTB. Further, we have used our in vivo model to test whether sphingosine kinase, which acts downstream of ET-1, plays a role in PTB. We have shown that levels of endothelin converting enzyme-1 (ECE-1) and ET-1 are increased when PTB is induced in timed pregnant mice with lipopolysaccharide (LPS) and that blocking ET-1 action, pharmacologically or using ECE-1 RNA silencing, rescues LPS-induced mice from PTB. ET-1 activates the sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) pathway. S1P, in turn, is an important signaling molecule in the pro-inflammatory response. Interestingly, we have shown that SphK inhibition also prevents LPS-induced PTB in timed pregnant mice. Further, we showed that SphK inhibition suppresses the ECE-1/ET-1 axis, implicating positive feedback regulation of the SphK/S1P/ECE-1/ET-1 axis. The ET-1/SphK/SIP pathway is a potential pharmacotherapeutic target for the prevention of PTB. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Downregulation of the S1P Transporter Spinster Homology Protein 2 (Spns2 Exerts an Anti-Fibrotic and Anti-Inflammatory Effect in Human Renal Proximal Tubular Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Olivier Blanchard

    2018-05-01

    Full Text Available Sphingosine kinase (SK catalyses the formation of sphingosine 1-phosphate (S1P, which acts as a key regulator of inflammatory and fibrotic reactions, mainly via S1P receptor activation. Here, we show that in the human renal proximal tubular epithelial cell line HK2, the profibrotic mediator transforming growth factor β (TGFβ induces SK-1 mRNA and protein expression, and in parallel, it also upregulates the expression of the fibrotic markers connective tissue growth factor (CTGF and fibronectin. Stable downregulation of SK-1 by RNAi resulted in the increased expression of CTGF, suggesting a suppressive effect of SK-1-derived intracellular S1P in the fibrotic process, which is lost when SK-1 is downregulated. In a further approach, the S1P transporter Spns2, which is known to export S1P and thereby reduces intracellular S1P levels, was stably downregulated in HK2 cells by RNAi. This treatment decreased TGFβ-induced CTGF and fibronectin expression, and it abolished the strong induction of the monocyte chemotactic protein 1 (MCP-1 by the pro-inflammatory cytokines tumor necrosis factor (TNFα and interleukin (IL-1β. Moreover, it enhanced the expression of aquaporin 1, which is an important water channel that is expressed in the proximal tubules, and reverted aquaporin 1 downregulation induced by IL-1β/TNFα. On the other hand, overexpression of a Spns2-GFP construct increased S1P secretion and it resulted in enhanced TGFβ-induced CTGF expression. In summary, our data demonstrate that in human renal proximal tubular epithelial cells, SK-1 downregulation accelerates an inflammatory and fibrotic reaction, whereas Spns2 downregulation has an opposite effect. We conclude that Spns2 represents a promising new target for the treatment of tubulointerstitial inflammation and fibrosis.

  7. Differential Effects of Long Term FTY720 Treatment on Endothelial versus Smooth Muscle Cell Signaling to S1P in Rat Mesenteric Arteries.

    Science.gov (United States)

    Hamidi Shishavan, Mahdi; Bidadkosh, Arash; Yazdani, Saleh; Lambooy, Sebastiaan; van den Born, Jacob; Buikema, Hendrik; Henning, Robert H; Deelman, Leo E

    2016-01-01

    The sphingosine-1-phosphate (S1P) analog FTY720 exerts pleiotropic effects on the cardiovascular system and causes down-regulation of S1P receptors. Myogenic constriction is an important mechanism regulating resistance vessel function and is known to be modulated by S1P. Here we investigated myogenic constriction and vascular function of mesenteric arteries of rats chronically treated with FTY720. Wistar rats received FTY720 1mg/kg/daily for six weeks. At termination, blood pressure was recorded and small mesenteric arteries collected for vascular studies in a perfusion set up. Myogenic constriction to increased intraluminal pressure was low, but a sub-threshold dose of S1P profoundly augmented myogenic constriction in arteries of both controls and animals chronically treated with FTY720. Interestingly, endothelial denudation blocked the response to S1P in arteries of FTY720-treated animals, but not in control rats. In acute experiments, presence of FTY720 significantly augmented the contractile response to S1P, an effect that was partially abolished after the inhibition of cyclooxygenase (COX-)-derived prostaglandins. FTY720 down regulated S1P1 but not S1P2 in renal resistance arteries and in cultured human endothelial cells. This study therefore demonstrates the endothelium is able to compensate for the complete loss of responsiveness of the smooth muscle layer to S1P after long term FTY720 treatment through a mechanism that most likely involves enhanced production of contractile prostaglandins by the endothelium.

  8. A Novel Perspective on the ApoM-S1P Axis, Highlighting the Metabolism of ApoM and Its Role in Liver Fibrosis and Neuroinflammation

    DEFF Research Database (Denmark)

    Hajny, Stefan; Christoffersen, Christina

    2017-01-01

    signaling molecule S1P is associated with several physiological as well as pathological pathways whereas the role of apoM is less explored. Hepatic apoM acts as a chaperone to transport S1P through the circulation and kidney derived apoM seems to play a role in S1P recovery to prevent urinal loss. Finally......, polarized endothelial cells constituting the lining of the BBB express apoM and secrete the protein to the brain as well as to the blood compartment. The review will provide novel insights on apoM and S1P, and its role in hepatic fibrosis, neuroinflammation and BBB integrity....

  9. 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

  10. The relationship between the high-density lipoprotein (HDL)-associated sphingosine-1-phosphate (S1P) and coronary in-stent restenosis.

    Science.gov (United States)

    Jing, Xiao-Dong; Wei, Xiao-Ming; Deng, Song-Bai; Du, Jian-Lin; Liu, Ya-Jie; She, Qiang

    2015-06-15

    High-density lipoprotein (HDL)-associated sphingosine-1-phosphate (S1P) contributed to several beneficial effects in the cardiovascular system. We explored the relationship between the HDL-S1P concentrations and coronary in-stent restenosis (ISR). Fifty consecutive patients with ISR and 50 normal control subjects were included. The serum S1P, HDL-S1P and clinical data were collected to explore the relationships between these parameters and ISR. The patients with ISR had significantly lower concentrations of serum S1P (96.10 ± 26.33 vs. 113.40 ± 32.72; P = 0.004) and HDL-S1P (32.81 ± 10.02 vs. 42.72 ± 11.75; P S1P: Quartile 1 (18.63-28.51 ng/ml), Quartile 2 (28.62-37.28 ng/ml), Quartile 3 (37.35-45.27 ng/ml), and Quartile 4 (45.59-79.36 ng/ml). The rates of ISR were 84%, 48%, 40% and 28%, respectively. The patients in Quartile 1 exhibited significantly higher rates of ISR compared with the other groups (P = 0.001). A multivariate stepwise logistic regression analysis indicated that HDL-S1P (OR = 0.846, 95% CI = 0.767-0.932, P = 0.001) was an independent predictor of ISR. An ROC analysis indicated that HDL-S1P = 30.37 ng/ml and had a 90% sensitivity and a 52% specificity in predicting ISR. HDL-S1P is an independent predictor of ISR, and patients with higher concentrations of HDL-S1P have a low risk of ISR. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. High density lipoprotein (HDL)-associated sphingosine 1-phosphate (S1P) inhibits macrophage apoptosis by stimulating STAT3 activity and survivin expression.

    Science.gov (United States)

    Feuerborn, Renata; Becker, Susen; Potì, Francesco; Nagel, Petra; Brodde, Martin; Schmidt, Harmut; Christoffersen, Christina; Ceglarek, Uta; Burkhardt, Ralph; Nofer, Jerzy-Roch

    2017-02-01

    Macrophage apoptosis is critically involved in atherosclerosis. We here examined the effect of anti-atherogenic high density lipoprotein (HDL) and its component sphingosine-1-phosphate (S1P) on apoptosis in RAW264.7 murine macrophages. Mitochondrial or endoplasmic reticulum-dependent apoptosis was induced by exposure of macrophages to etoposide or thapsigargin/fukoidan, respectively. Cell death induced by these compounds was inhibited by S1P as inferred from reduced annexin V binding, TUNEL staining, and caspase 3, 9 and 12 activities. S1P induced expression of the inhibitor of apoptosis protein (IAP) family proteins cIAP1, cIAP2 and survivin, but only the inhibitor of survivin expression YM155 and not the cIAP1/2 blocker GDC0152 reversed the inhibitory effect of S1P on apoptosis. Moreover, S1P activated signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2 (JAK2) and the stimulatory effect of S1P on survivin expression and inhibitory effects on apoptosis were attenuated by STAT3 or JAK2 inhibitors, S3I-201 or AG490, respectively. The effects of S1P on STAT3 activation, survivin expression and macrophage apoptosis were emulated by HDL, HDL lipids, and apolipoprotein (apo) M-containing HDL, but not by apoA-I or HDL deprived of S1P or apoM. In addition, JTE013 and CAY10444, S1P receptor 2 and 3 antagonists, respectively, compromised the S1P and HDL capacities to stimulate STAT3 activation and survivin expression, and to inhibit apoptosis. HDL-associated S1P inhibits macrophage apoptosis by stimulating STAT3 activity and survivin expression. The suppression of macrophage apoptosis may represent a novel mechanism utilized by HDL to exert its anti-atherogenic effects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Plasma progesterone levels in progesterone treated cows

    International Nuclear Information System (INIS)

    Grosskopf, J.F.W.; Van Niekerk, C.H.; Morgenthal, J.C.

    1979-01-01

    A technique for the radioimmunoassay of progesterone in plasma is described. In one trial the oestrous cycles of four cycling cows and in another trial of one non-cycling cow and two cycling heifers were synchronized by the administration of progesterone. Each female received either 50 mg or 0,1 mg/kg of progesterone intramuscularly on alternate days in two courses of four and six injections respectively. Blood samples of the animals were collected either daily or two-daily before, over the entire period of treatment and for eight days after the last progesterone injection. The results of the progesterone assays are represented graphically for each individual cow or heifer. The plasma progesterone levels during treatment were maintained reasonably well at levels corresponding to those normally encountered during the luteal phase of the cycle. The progesterone levels, however, did not drop as rapidly as desired after the last injection but might have been influenced by a residual corpus luteum from a previous ovulation

  13. A Novel Perspective on the ApoM-S1P Axis, Highlighting the Metabolism of ApoM and Its Role in Liver Fibrosis and Neuroinflammation.

    Science.gov (United States)

    Hajny, Stefan; Christoffersen, Christina

    2017-07-27

    Hepatocytes, renal proximal tubule cells as well as the highly specialized endothelium of the blood brain barrier (BBB) express and secrete apolipoprotein M (apoM). ApoM is a typical lipocalin containing a hydrophobic binding pocket predominantly carrying Sphingosine-1-Phosphate (S1P). The small signaling molecule S1P is associated with several physiological as well as pathological pathways whereas the role of apoM is less explored. Hepatic apoM acts as a chaperone to transport S1P through the circulation and kidney derived apoM seems to play a role in S1P recovery to prevent urinal loss. Finally, polarized endothelial cells constituting the lining of the BBB express apoM and secrete the protein to the brain as well as to the blood compartment. The review will provide novel insights on apoM and S1P, and its role in hepatic fibrosis, neuroinflammation and BBB integrity.

  14. Role of Spm-Cer-S1P signalling pathway in MMP-2 mediated U46619-induced proliferation of pulmonary artery smooth muscle cells: protective role of epigallocatechin-3-gallate.

    Science.gov (United States)

    Chowdhury, Animesh; Sarkar, Jaganmay; Chakraborti, Tapati; Chakraborti, Sajal

    2015-10-01

    During remodelling of pulmonary artery, marked proliferation of pulmonary artery smooth muscle cells (PASMCs) occurs, which contributes to pulmonary hypertension. Thromboxane A2 (TxA2) has been shown to produce pulmonary hypertension. The present study investigates the inhibitory effect of epigallocatechin-3-gallate (EGCG) on the TxA2 mimetic, U46619-induced proliferation of PASMCs. U46619 at a concentration of 10 nM induces maximum proliferation of bovine PASMCs. Both pharmacological and genetic inhibitors of p(38)MAPK, NF-κB and MMP-2 significantly inhibit U46619-induced cell proliferation. EGCG markedly abrogate U46619-induced p(38)MAPK phosphorylation, NF-κB activation, proMMP-2 expression and activation, and also the cell proliferation. U46619 causes an increase in the activation of sphingomyelinase (SMase) and sphingosine kinase (SPHK) and also increase sphingosine 1 phosphate (S1P) level. U46619 also induces phosphorylation of ERK1/2, which phosphorylates SPHK leading to an increase in S1P level. Both pharmacological and genetic inhibitors of SMase and SPHK markedly inhibit U46619-induced cell proliferation. Additionally, pharmacological and genetic inhibitors of MMP-2 markedly abrogate U46619-induced SMase activity and S1P level. EGCG markedly inhibit U46619-induced SMase activity, ERK1/2 and SPHK phosphorylation and S1P level in the cells. Overall, Sphingomyeline-Ceramide-Sphingosine-1-phosphate (Spm-Cer-S1P) signalling axis plays an important role in MMP-2 mediated U46619-induced proliferation of PASMCs. Importantly, EGCG inhibits U46619 induced increase in MMP-2 activation by modulating p(38)MAPK-NFκB pathway and subsequently prevents the cell proliferation. Copyright © 2015 John Wiley & Sons, Ltd.

  15. Sphingosine-1-Phosphate (S1P) Is a Feasible Biomarker in Predicting the Efficacy of Polymyxin B-Immobilized Fiber Direct Hemoperfusion (PMX-DHP) in Patients with Septic Shock.

    Science.gov (United States)

    Inoue, Satoshi; Sakamoto, Yuichiro; Koami, Hiroyuki; Yamada C, Kosuke; Nagashima, Futoshi; Miike, Toru; Iwamura, Takashi; Obata, Toru

    2018-01-01

    The aim of this study was to identify a useful biomarker to predict the efficacy of polymyxin B-immobilized fiber direct hemoperfusion (PMX-DHP) in patients with septic shock. The 44 patients included in this study were divided into two groups. Group A had an increase in systolic blood pressure (SBP) over 30 mmHg after PMX-DHP treatment. Group B had an increase in SBP less than 30 mmHg after PMX-DHP treatment. We evaluated the clinical characteristics and demographics of both groups. We also assessed whether the cause of sepsis affected the efficacy of PMX-DHP and compared the prognosis of both groups. Finally, we investigated whether there were any significant differences in the levels of sepsis-related biomarkers, including sphingosine-1-phosphate (S1P), between both groups before PMX-DHP in an effort to identify a biomarker that could predict the efficacy of PMX-DHP. PMX-DHP significantly increased SBP regardless of the cause of sepsis. Although there was some tendency, PMX-DHP did not significantly improve the prognosis of effective cases in comparison with non-effective cases, probably because of the limited number of patients included. Among the sepsis-related biomarkers, only S1P values were significantly different between the two groups before PMX-DHP, and S1P levels were significantly increased after treatment in the effective cases. S1P levels prior to PMX-DHP can be used to predict its efficacy. In addition, continuous monitoring of S1P levels can indicate the effectiveness of PMX-DHP in patients with septic shock.

  16. Dairy products and plasma cholesterol levels

    Directory of Open Access Journals (Sweden)

    Lena Ohlsson

    2010-08-01

    Full Text Available Cholesterol synthesized in the body or ingested is an essential lipid component for human survival from our earliest life. Newborns ingest about 3–4 times the amount per body weight through mother's milk compared to the dietary intake of adults. A birth level of 1.7 mmol/L plasma total cholesterol will increase to 4–4.5 mmol/L during the nursing period and continue to increase from adulthood around 40% throughout life. Coronary artery disease and other metabolic disorders are strongly associated with low-density lipoprotein (LDL and high-density lipoprotein (HDL cholesterol as well as triacylglycerol concentration. Milk fat contains a broad range of fatty acids and some have a negative impact on the cholesterol rich lipoproteins. The saturated fatty acids (SFAs, such as palmitic acid (C16:0, myristic acid (C14:0, and lauric acid (C12:0, increase total plasma cholesterol, especially LDL, and constitute 11.3 g/L of bovine milk, which is 44.8% of total fatty acid in milk fat. Replacement of dairy SFA and trans-fatty acids with polyunsaturated fatty acids decreases plasma cholesterol, especially LDL cholesterol, and is associated with a reduced risk of cardiovascular disease. Available data shows different effects on lipoproteins for different dairy products and there is uncertainty as to the impact a reasonable intake amount of dairy items has on cardiovascular risk. The aim of this review is to elucidate the effect of milk components and dairy products on total cholesterol, LDL, HDL, and the LDL/HDL quotients. Based on eight recent randomized controlled trials of parallel or cross-over design and recent reviews it can be concluded that replacement of saturated fat mainly (but not exclusively derived from high-fat dairy products with low-fat dairy products lowers LDL/HDL cholesterol and total/HDL cholesterol ratios. Whey, dairy fractions enriched in polar lipids, and techniques such as fermentation, or fortification of cows feeding can be used

  17. Enhancement of Human Endothelial Cell Adhesion to Type I Collagen by Lysophosphatidic Acid (LPA and Sphingosine-1-Phosphate (S1P

    Directory of Open Access Journals (Sweden)

    Hsinyu Lee

    2004-06-01

    Full Text Available The diverse cellular effects of lysophosphatidic acid (LPA and sphingosine-1-phosphate (S1P are transduced by two structurally homologous subfamilies of G protein-coupled receptors, which are encoded by endothelial differentiation genes (Edg Rs. Human umbilical cord vein endothelial cells (HUVECs express Edg Rs for LPA (Edg2 and S1P (Edg1 and 3, which transduce signals for migration of HUVECs through micropore filters coated with type I collagen. Since activation of integrins is essential for optimal migration of endothelial cells, we now examine the capacity of LPA and S1P to augment integrin mediation of endothelial cell binding to type I collagen. Lysophospholipid enhancement of HUVEC adhesion to type I collagen is detectable within 20 minutes. Enhancement of adhesion by both LPA and S1P is significant at 50 nM and optimal at 5µM. Pertussis toxin (PTx, a specific inhibitor of Gi, and C3 exotoxin, a specific inhibitor of Rho, both suppress LPA and S1P enhancement of HUVEC adhesion. In contrast, PD98059, which blocks MAP kinase kinase (MEK, and wortmannin, which inhibits phosphatidylinositol 3-kinase (PI3K, had no effect on LPA- or S1P-enhancement of HUVEC adhesion. Neutralizing monoclonal antibodies specific for α2 and β1 integrin chains, concomitantly decrease LPA and S1P enhancement of HUVEC adhesion to type I collagen. LPA and S1P thus promote type I collagen-dependent adhesion and migration of HUVECs by recruiting α2 and β1 integrin through both Gi and Rho pathways. Integrin α2/β1 therefore appears to be critical on the effects of LPA and S1P on endothelial cell physiology.

  18. Plasma progesterone levels following breeding in goats

    International Nuclear Information System (INIS)

    Jain, G.C.; Arora, R.C.; Pahwa, G.S.; Batra, S.K.; Pandey, R.S.

    1980-01-01

    Progesterone concentration in the peripheral blood plasma of ten lactating goats of mixed breeds following breeding were determined by radioimmunoassay to diagnose early pregnancy. The mean concentration was very low (0.25 +- 0.15 ng/ml) on the day of oestrus and reached at peak level on day 13 (1.30 +- 0.07 ng/ml) and on day 19 (2.77 +- 1.18 ng/ml) in non-pregnant and pregnant goats, respectively. The level sharply declined on day 19 (0.40 +- 0.07 ng/ml) of oestrous cycle in non-pregnant goats. However, the level remained below 1.5 ng/ml on day 9, 13, 15 and 17 and 3 ng/ml on day 9, 13, 15, 17, 19, 21 and 23 in nonpregnant and pregnant goats, respectively. The progesterone concentration continued to increase to 2.94 +- 0.70, 4.42 +- 0.92 and 6.2 +- 0.61 ng/ml on day 45, 60 and 75 of gestation, respectively. (auth.)

  19. The activation of RhoC in vascular endothelial cells is required for the S1P receptor type 2-induced inhibition of angiogenesis.

    Science.gov (United States)

    Del Galdo, Sabrina; Vettel, Christiane; Heringdorf, Dagmar Meyer Zu; Wieland, Thomas

    2013-12-01

    Sphingosine-1-phosphate (S1P) is a multifunctional phospholipid inducing a variety of cellular responses in endothelial cells (EC). S1P responses are mediated by five G protein coupled receptors of which three types (S1P1R-S1P3R) have been described to be of importance in vascular endothelial cells (EC). Whereas the S1P1R regulates endothelial barrier function by coupling to Gαi and the monomeric GTPase Rac1, the signaling pathways involved in the S1P-induced regulation of angiogenesis are ill defined. We therefore studied the sprouting of human umbilical vein EC (HUVEC) in vitro and analyzed the activation of the RhoGTPases RhoA and RhoC. Physiological relevant concentrations of S1P (100-300nM) induce a moderate activation of RhoA and RhoC. Inhibition or siRNA-mediated depletion of the S1P2R preferentially decreased the activation of RhoC. Both manipulations caused an increase of sprouting in a spheroid based in vitro sprouting assay. Interestingly, a similar increase in sprouting was detected after effective siRNA-mediated knockdown of RhoC. In contrast, the depletion of RhoA had no influence on sprouting. Furthermore, suppression of the activity of G proteins of the Gα12/13 subfamily by adenoviral overexpression of the regulator of G protein signaling domain of LSC as well as siRNA-mediated knockdown of the Rho specific guanine nucleotide exchange factor leukemia associated RhoGEF (LARG) inhibited the S1P-induced activation of RhoC and concomitantly increased sprouting of HUVEC with similar efficacy. We conclude that the angiogenic sprouting of EC is suppressed via the S1P2R subtype. Thus, the increase in basal sprouting can be attributed to blocking of the inhibitory action of autocrine S1P stimulating the S1P2R. This inhibitory pathway involves the activation of RhoC via Gα12/13 and LARG, while the simultaneously occurring activation of RhoA is apparently dispensable here. © 2013.

  20. Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects.

    Science.gov (United States)

    Scherz, Michael W; Brossard, Patrick; D'Ambrosio, Daniele; Ipek, Murat; Dingemanse, Jasper

    2015-06-01

    Ponesimod is a selective S1P1 receptor modulator, and induces dose-dependent reduction of circulating lymphocytes upon oral dosing. Previous studies showed that single doses up to 75 mg or multiple doses up to 40 mg once daily are well tolerated, and heart rate (HR) reduction and atrio-ventricular conduction delays upon treatment initiation are reduced by gradual up-titration to the maintenance dose. This single-center, open-label, randomized, multiple-dose, 3-treatment, 3-way crossover study compared the tolerability, safety, pharmacokinetics, cardiodynamics, and effects on lymphocytes of 3 different up-titration regimens of ponesimod in healthy male and female subjects. Up-titration regimens comprised escalating periods of b.i.d. dosing (2.5 or 5 mg) and q.d. dosing (10 or 20 mg or both). After the third up-titration period a variable-duration washout period of 1-3 days was followed by re-challenge with a single 20-mg dose of ponesimod. Adverse events were transient and mild to moderate in intensity, not different between regimens. HR decrease after the first dose was greater than after all subsequent doses, including up-titration doses. Little or no HR change was observed with morning doses of b.i.d. regimens, suggesting that 2.5 and 5 mg b.i.d. are sufficient to sustain cardiac desensitization for the 12-hours dosing interval. © 2015, The American College of Clinical Pharmacology.

  1. Activation of RhoA, but Not Rac1, Mediates Early Stages of S1P-Induced Endothelial Barrier Enhancement.

    Science.gov (United States)

    Zhang, Xun E; Adderley, Shaquria P; Breslin, Jerome W

    2016-01-01

    Compromised endothelial barrier function is a hallmark of inflammation. Rho family GTPases are critical in regulating endothelial barrier function, yet their precise roles, particularly in sphingosine-1-phosphate (S1P)-induced endothelial barrier enhancement, remain elusive. Confluent cultures of human umbilical vein endothelial cells (HUVEC) or human dermal microvascular endothelial cells (HDMEC) were used to model the endothelial barrier. Barrier function was assessed by determining the transendothelial electrical resistance (TER) using an electrical cell-substrate impedance sensor (ECIS). The roles of Rac1 and RhoA were tested in S1P-induced barrier enhancement. The results show that pharmacologic inhibition of Rac1 with Z62954982 failed to block S1P-induced barrier enhancement. Likewise, expression of a dominant negative form of Rac1, or knockdown of native Rac1 with siRNA, failed to block S1P-induced elevations in TER. In contrast, blockade of RhoA with the combination of the inhibitors Rhosin and Y16 significantly reduced S1P-induced increases in TER. Assessment of RhoA activation in real time using a fluorescence resonance energy transfer (FRET) biosensor showed that S1P increased RhoA activation primarily at the edges of cells, near junctions. This was complemented by myosin light chain-2 phosphorylation at cell edges, and increased F-actin and vinculin near intercellular junctions, which could all be blocked with pharmacologic inhibition of RhoA. The results suggest that S1P causes activation of RhoA at the cell periphery, stimulating local activation of the actin cytoskeleton and focal adhesions, and resulting in endothelial barrier enhancement. S1P-induced Rac1 activation, however, does not appear to have a significant role in this process.

  2. Targeting the SphK1/S1P/S1PR1 Axis That Links Obesity, Chronic Inflammation, and Breast Cancer Metastasis.

    Science.gov (United States)

    Nagahashi, Masayuki; Yamada, Akimitsu; Katsuta, Eriko; Aoyagi, Tomoyoshi; Huang, Wei-Ching; Terracina, Krista P; Hait, Nitai C; Allegood, Jeremy C; Tsuchida, Junko; Yuza, Kizuki; Nakajima, Masato; Abe, Manabu; Sakimura, Kenji; Milstien, Sheldon; Wakai, Toshifumi; Spiegel, Sarah; Takabe, Kazuaki

    2018-04-01

    Although obesity with associated inflammation is now recognized as a risk factor for breast cancer and distant metastases, the functional basis for these connections remain poorly understood. Here, we show that in breast cancer patients and in animal breast cancer models, obesity is a sufficient cause for increased expression of the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), which mediates cancer pathogenesis. A high-fat diet was sufficient to upregulate expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, along with its receptor S1PR1 in syngeneic and spontaneous breast tumors. Targeting the SphK1/S1P/S1PR1 axis with FTY720/fingolimod attenuated key proinflammatory cytokines, macrophage infiltration, and tumor progression induced by obesity. S1P produced in the lung premetastatic niche by tumor-induced SphK1 increased macrophage recruitment into the lung and induced IL6 and signaling pathways important for lung metastatic colonization. Conversely, FTY720 suppressed IL6, macrophage infiltration, and S1P-mediated signaling pathways in the lung induced by a high-fat diet, and it dramatically reduced formation of metastatic foci. In tumor-bearing mice, FTY720 similarly reduced obesity-related inflammation, S1P signaling, and pulmonary metastasis, thereby prolonging survival. Taken together, our results establish a critical role for circulating S1P produced by tumors and the SphK1/S1P/S1PR1 axis in obesity-related inflammation, formation of lung metastatic niches, and breast cancer metastasis, with potential implications for prevention and treatment. Significance: These findings offer a preclinical proof of concept that signaling by a sphingolipid may be an effective target to prevent obesity-related breast cancer metastasis. Cancer Res; 78(7); 1713-25. ©2018 AACR . ©2018 American Association for Cancer Research.

  3. Activation of RhoA, but Not Rac1, Mediates Early Stages of S1P-Induced Endothelial Barrier Enhancement.

    Directory of Open Access Journals (Sweden)

    Xun E Zhang

    Full Text Available Compromised endothelial barrier function is a hallmark of inflammation. Rho family GTPases are critical in regulating endothelial barrier function, yet their precise roles, particularly in sphingosine-1-phosphate (S1P-induced endothelial barrier enhancement, remain elusive. Confluent cultures of human umbilical vein endothelial cells (HUVEC or human dermal microvascular endothelial cells (HDMEC were used to model the endothelial barrier. Barrier function was assessed by determining the transendothelial electrical resistance (TER using an electrical cell-substrate impedance sensor (ECIS. The roles of Rac1 and RhoA were tested in S1P-induced barrier enhancement. The results show that pharmacologic inhibition of Rac1 with Z62954982 failed to block S1P-induced barrier enhancement. Likewise, expression of a dominant negative form of Rac1, or knockdown of native Rac1 with siRNA, failed to block S1P-induced elevations in TER. In contrast, blockade of RhoA with the combination of the inhibitors Rhosin and Y16 significantly reduced S1P-induced increases in TER. Assessment of RhoA activation in real time using a fluorescence resonance energy transfer (FRET biosensor showed that S1P increased RhoA activation primarily at the edges of cells, near junctions. This was complemented by myosin light chain-2 phosphorylation at cell edges, and increased F-actin and vinculin near intercellular junctions, which could all be blocked with pharmacologic inhibition of RhoA. The results suggest that S1P causes activation of RhoA at the cell periphery, stimulating local activation of the actin cytoskeleton and focal adhesions, and resulting in endothelial barrier enhancement. S1P-induced Rac1 activation, however, does not appear to have a significant role in this process.

  4. Coronin 1B regulates S1P-induced human lung endothelial cell chemotaxis: role of PLD2, protein kinase C and Rac1 signal transduction.

    Directory of Open Access Journals (Sweden)

    Peter V Usatyuk

    Full Text Available Coronins are a highly conserved family of actin binding proteins that regulate actin-dependent processes such as cell motility and endocytosis. We found that treatment of human pulmonary artery endothelial cells (HPAECs with the bioactive lipid, sphingosine-1-phosphate (S1P rapidly stimulates coronin 1B translocation to lamellipodia at the cell leading edge, which is required for S1P-induced chemotaxis. Further, S1P-induced chemotaxis of HPAECs was attenuated by pretreatment with small interfering RNA (siRNA targeting coronin 1B (∼36%, PLD2 (∼45% or Rac1 (∼50% compared to scrambled siRNA controls. Down regulation PLD2 expression by siRNA also attenuated S1P-induced coronin 1B translocation to the leading edge of the cell periphery while PLD1 silencing had no effect. Also, S1P-induced coronin 1B redistribution to cell periphery and chemotaxis was attenuated by inhibition of Rac1 and over-expression of dominant negative PKC δ, ε and ζ isoforms in HPAECs. These results demonstrate that S1P activation of PLD2, PKC and Rac1 is part of the signaling cascade that regulates coronin 1B translocation to the cell periphery and the ensuing cell chemotaxis.

  5. Sphingosine 1 Phosphate at the Blood Brain Barrier: Can the Modulation of S1P Receptor 1 Influence the Response of Endothelial Cells and Astrocytes to Inflammatory Stimuli?

    Directory of Open Access Journals (Sweden)

    Simona F Spampinato

    Full Text Available The ability of the Blood Brain Barrier (BBB to maintain proper barrier functions, keeping an optimal environment for central nervous system (CNS activity and regulating leukocytes' access, can be affected in CNS diseases. Endothelial cells and astrocytes are the principal BBB cellular constituents and their interaction is essential to maintain its function. Both endothelial cells and astrocytes express the receptors for the bioactive sphingolipid S1P. Fingolimod, an immune modulatory drug whose structure is similar to S1P, has been approved for treatment in multiple sclerosis (MS: fingolimod reduces the rate of MS relapses by preventing leukocyte egress from the lymph nodes. Here, we examined the ability of S1P and fingolimod to act on the BBB, using an in vitro co-culture model that allowed us to investigate the effects of S1P on endothelial cells, astrocytes, and interactions between the two. Acting selectively on endothelial cells, S1P receptor signaling reduced cell death induced by inflammatory cytokines. When acting on astrocytes, fingolimod treatment induced the release of a factor, granulocyte macrophage colony-stimulating factor (GM-CSF that reduced the effects of cytokines on endothelium. In an in vitro BBB model incorporating shear stress, S1P receptor modulation reduced leukocyte migration across the endothelial barrier, indicating a novel mechanism that might contribute to fingolimod efficacy in MS treatment.

  6. Escitalopram plasma levels and antidepressant response.

    Science.gov (United States)

    Florio, Vincenzo; Porcelli, Stefano; Saria, Alois; Serretti, Alessandro; Conca, Andreas

    2017-09-01

    Major Depression Disorder (MDD) has a highly variable treatment response due to the large inter-individual variation in the pharmacokinetics and pharmacodynamics of drug treatments. In detail the correlation between plasma level and efficacy has been much debated. Among first-line drugs for MDD, one of the most used is escitalopram. In the present study we investigated the association between serum concentration of escitalopram (SCE) and antidepressant response (AR). 70 MDD patients treated with escitalopram monotherapy were recruited and followed for three months. Hamilton Depression Rating Scale - 21 (HAMD-21) was administrated at baseline, month 1, and month 3 to assess AR. SCE was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCE and AR. We found an association between SCE and AR both at month 1 (pescitalopram the association between SCE and AR likely follows a nearly-asymptotic function, with poor AR at sub-therapeutic SCE and stable AR response at therapeutic SCE. Thus, when a patient reaches the therapeutic SCE range, further increase of escitalopram dosage seems to be useless, although further studies are needed to confirm our findings. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

  7. PLASMA PROGESTERONE LEVELS TN LACTATING EWES AFTER ...

    African Journals Online (AJOL)

    Oestrus, ovulation and perrpheral plasma progesterone concentrations were recorded in ... progestagen and PMS were srmilar to those reported for spontaneous oesttous cycles in ..... involved could perhaps cast some light on the problem.

  8. The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells.

    Science.gov (United States)

    Rahman, Md Mostafizur; Prünte, Laura; Lebender, Leonard F; Patel, Brijeshkumar S; Gelissen, Ingrid; Hansbro, Philip M; Morris, Jonathan C; Clark, Andrew R; Verrills, Nicole M; Ammit, Alaina J

    2016-11-16

    Protein phosphatase 2A (PP2A) activity can be enhanced pharmacologically by PP2A-activating drugs (PADs). The sphingosine analog FTY720 is the best known PAD and we have shown that FTY720 represses production of pro-inflammatory cytokines responsible for respiratory disease pathogenesis. Whether its phosphorylated form, FTY720-P, also enhances PP2A activity independently of the sphingosine 1-phosphate (S1P) pathway was unknown. Herein, we show that FTY720-P enhances TNF-induced PP2A phosphatase activity and significantly represses TNF-induced interleukin 6 (IL-6) and IL-8 mRNA expression and protein secretion from A549 lung epithelial cells. Comparing FTY720 and FTY720-P with S1P, we show that unlike S1P, the sphingosine analogs do not induce cytokine production on their own. In fact, FTY720 and FTY720-P significantly repress S1P-induced IL-6 and IL-8 production. We then examined their impact on expression of cyclooxygenase 2 (COX-2) and resultant prostaglandin E 2 (PGE 2) production. S1P did not increase production of this pro-inflammatory enzyme because COX-2 mRNA gene expression is NF-κB-dependent, and unlike TNF, S1P did not activate NF-κB. However, TNF-induced COX-2 mRNA expression and PGE 2 secretion is repressed by FTY720 and FTY720-P. Hence, FTY720-P enhances PP2A activity and that PADs can repress production of pro-inflammatory cytokines and enzymes in A549 lung epithelial cells in a manner devoid of S1P agonism.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Plasma levels of acylated ghrelin in patients with functional dyspepsia

    Science.gov (United States)

    Kim, Yeon Soo; Lee, Joon Seong; Lee, Tae Hee; Cho, Joo Young; Kim, Jin Oh; Kim, Wan Jung; Kim, Hyun Gun; Jeon, Seong Ran; Jeong, Hoe Su

    2012-01-01

    AIM: To investigate the relationship between plasma acylated ghrelin levels and the pathophysiology of functional dyspepsia. METHODS: Twenty-two female patients with functional dyspepsia and twelve healthy volunteers were recruited for the study. The functional dyspepsia patients were each diagnosed based on the Rome III criteria. Eligible patients completed a questionnaire concerning the severity of 10 symptoms. Plasma acylated ghrelin levels before and after a meal were determined in the study participants using a commercial human acylated enzyme immunoassay kit; electrogastrograms were performed for 50 min before and after a standardized 10-min meal containing 265 kcal. RESULTS: There were no significant differences in plasma acylated ghrelin levels between healthy volunteers and patients with functional dyspepsia. However, in patients with functional dyspepsia, there was a negative correlation between fasting plasma acylated ghrelin levels and the sum score of epigastric pain (r = -0.427, P = 0.047) and a positive correlation between the postprandial/fasting plasma acylated ghrelin ratio and the sum score of early satiety (r = 0.428, P =0.047). Additionally, there was a negative correlation between fasting acylated ghrelin plasma levels and fasting normogastria (%) (r = -0.522, P = 0.013). Interestingly, two functional dyspepsia patients showed paradoxically elevated plasma acylated ghrelin levels after the meal. CONCLUSION: Abnormal plasma acylated ghrelin levels before or after a meal may be related to several of the dyspeptic symptoms seen in patients with functional dyspepsia. PMID:22611317

  11. The cholesterol, fatty acid and triglyceride synthesis pathways regulated by site 1 protease (S1P) are required for efficient replication of severe fever with thrombocytopenia syndrome virus.

    Science.gov (United States)

    Urata, Shuzo; Uno, Yukiko; Kurosaki, Yohei; Yasuda, Jiro

    2018-06-12

    Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus (SFTSV), which has a high mortality rate. Currently, no licensed vaccines or therapeutic agents have been approved for use against SFTSV infection. Here, we report that the cholesterol, fatty acid, and triglyceride synthesis pathways regulated by S1P is involved in SFTSV replication, using CHO-K1 cell line (SRD-12B) that is deficient in site 1 protease (S1P) enzymatic activity, PF-429242, a small compound targeting S1P enzymatic activity, and Fenofibrate and Lovastatin, which inhibit triglyceride and cholesterol synthesis, respectively. These results enhance our understanding of the SFTSV replication mechanism and may contribute to the development of novel therapies for SFTSV infection. Copyright © 2018. Published by Elsevier Inc.

  12. Differential Recognition of Old World and New World Arenavirus Envelope Glycoproteins by Subtilisin Kexin Isozyme 1 (SKI-1)/Site 1 Protease (S1P)

    Science.gov (United States)

    Burri, Dominique J.; Ramos da Palma, Joel; Seidah, Nabil G.; Zanotti, Giuseppe; Cendron, Laura

    2013-01-01

    The arenaviruses are an important family of emerging viruses that includes several causative agents of severe hemorrhagic fevers in humans that represent serious public health problems. A crucial step of the arenavirus life cycle is maturation of the envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P). Comparison of the currently known sequences of arenavirus GPCs revealed the presence of a highly conserved aromatic residue at position P7 relative to the SKI-1/S1P cleavage side in Old World and clade C New World arenaviruses but not in New World viruses of clades A and B or cellular substrates of SKI-1/S1P. Using a combination of molecular modeling and structure-function analysis, we found that residueY285 of SKI-1/S1P, distal from the catalytic triad, is implicated in the molecular recognition of the aromatic “signature residue” at P7 in the GPC of Old World Lassa virus. Using a quantitative biochemical approach, we show that Y285 of SKI-1/S1P is crucial for the efficient processing of peptides derived from Old World and clade C New World arenavirus GPCs but not of those from clade A and B New World arenavirus GPCs. The data suggest that during coevolution with their mammalian hosts, GPCs of Old World and clade C New World viruses expanded the molecular contacts with SKI-1/S1P beyond the classical four-amino-acid recognition sequences and currently occupy an extended binding pocket. PMID:23536681

  13. Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation†

    Science.gov (United States)

    Selvam, Shanmugam P.; De Palma, Ryan M.; Oaks, Joshua J.; Oleinik, Natalia; Peterson, Yuri K.; Stahelin, Robert V.; Skordalakes, Emmanuel; Ponnusamy, Suriyan; Garrett-Mayer, Elizabeth; Smith, Charles D.; Ogretmen, Besim

    2015-01-01

    During DNA replication, the enzyme telomerase maintains the ends of chromosomes, called telomeres. Shortened telomeres trigger cell senescence, and cancer cells often have increased telomerase activity to promote their ability to proliferate indefinitely. The catalytic subunit, human telomerase reverse transcriptase (hTERT), is stabilized by phosphorylation. Here, we found that the lysophospholipid sphingosine 1-phosphate (S1P), generated by sphingosine kinase 2 (SK2), bound hTERT at the nuclear periphery in human and mouse fibroblasts. Docking predictions and mutational analyses revealed that binding occurred between a hydroxyl group (C′3-OH) in S1P and Asp684 in hTERT. Inhibiting or depleting SK2 or mutating the S1P binding site decreased the stability of hTERT in cultured cells and promoted senescence and loss of telomere integrity. S1P binding inhibited the interaction of hTERT with MKRN1, an E3 ubiquitin ligase that tags hTERT for degradation. Murine Lewis lung carcinoma (LLC) cells formed smaller tumors in mice lacking SK2 than in wild-type mice, and knocking down SK2 in LLC cells before implantation into mice suppressed their growth. Pharmacologically inhibiting SK2 decreased the growth of subcutaneous A549 lung cancer cell-derived xenografts in mice, and expression of wild-type hTERT, but not an S1P-binding mutant, restored tumor growth. Thus, our data suggest that S1P binding to hTERT allosterically mimicks phosphorylation, promoting telomerase stability and hence telomere maintenance, cell proliferation, and tumor growth PMID:26082434

  14. Human subtilase SKI-1/S1P is a master regulator of the HCV Lifecycle and a potential host cell target for developing indirect-acting antiviral agents.

    Directory of Open Access Journals (Sweden)

    Andrea D Olmstead

    2012-01-01

    Full Text Available HCV infection is a major risk factor for liver cancer and liver transplantation worldwide. Overstimulation of host lipid metabolism in the liver by HCV-encoded proteins during viral infection creates a favorable environment for virus propagation and pathogenesis. In this study, we hypothesize that targeting cellular enzymes acting as master regulators of lipid homeostasis could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with human Flaviviridae viruses such as hepatitis C virus (HCV, whose assembly and pathogenesis depend on interaction with lipid droplets (LDs. One such master regulator of cholesterol metabolic pathways is the host subtilisin/kexin-isozyme-1 (SKI-1--or site-1 protease (S1P. SKI-1/S1P plays a critical role in the proteolytic activation of sterol regulatory element binding proteins (SREBPs, which control expression of the key enzymes of cholesterol and fatty-acid biosynthesis. Here we report the development of a SKI-1/S1P-specific protein-based inhibitor and its application to blocking the SREBP signaling cascade. We demonstrate that SKI-1/S1P inhibition effectively blocks HCV from establishing infection in hepatoma cells. The inhibitory mechanism is associated with a dramatic reduction in the abundance of neutral lipids, LDs, and the LD marker: adipose differentiation-related protein (ADRP/perilipin 2. Reduction of LD formation inhibits virus assembly from infected cells. Importantly, we confirm that SKI-1/S1P is a key host factor for HCV infection by using a specific active, site-directed, small-molecule inhibitor of SKI-1/S1P: PF-429242. Our studies identify SKI-1/S1P as both a novel regulator of the HCV lifecycle and as a potential host-directed therapeutic target against HCV infection and liver steatosis. With identification of an increasing number of human viruses that use host LDs for infection, our results suggest that SKI-1/S1P inhibitors may allow

  15. Low plasma progranulin levels in children with autism

    Directory of Open Access Journals (Sweden)

    Mostafa Gehan A

    2011-09-01

    Full Text Available Abstract Background Autoimmunity to brain may play a pathogenic role in autism. In autoimmune disorders, the formation of antigen-antibody complexes triggers an inflammatory response by inducing the infiltration of neutrophils. Local administration of recombinant progranulin, which is an anti-inflammatory neurotrophic factor, potently inhibit neutrophilic inflammation in vivo, demonstrating that progranulin represents a crucial inflammation-suppressing mediator. We are the first to measure plasma progranulin levels in autism. Methods Plasma levels of progranulin were measured, by ELISA, in 40 autistic patients, aged between 3 and 12 years, and 40 healthy-matched children. Results Autistic children had significantly lower plasma progranulin levels, P = 0.001. Reduced plasma progranulin levels were found in 65% (26/40 of autistic children. On the other hand, there was a non significant difference between plasma progranulin levels of children with mild to moderate autism and patients with severe autism, P = 0.11. Conclusions Plasma progranulin levels were reduced in a subgroup of patients with autism. Progranulin insufficiency in some patients with autism may result in many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation that may have a role in autism. However, these data should be treated with caution until further investigations are performed, with a larger subject population, to determine whether the decrease of plasma progranulin levels is a mere consequence of autism or has a pathogenic role in the disease. The role of progranulin therapy should also be studied in autism.

  16. Low plasma progranulin levels in children with autism.

    Science.gov (United States)

    Al-Ayadhi, Laila Y; Mostafa, Gehan A

    2011-09-05

    Autoimmunity to brain may play a pathogenic role in autism. In autoimmune disorders, the formation of antigen-antibody complexes triggers an inflammatory response by inducing the infiltration of neutrophils. Local administration of recombinant progranulin, which is an anti-inflammatory neurotrophic factor, potently inhibit neutrophilic inflammation in vivo, demonstrating that progranulin represents a crucial inflammation-suppressing mediator. We are the first to measure plasma progranulin levels in autism. Plasma levels of progranulin were measured, by ELISA, in 40 autistic patients, aged between 3 and 12 years, and 40 healthy-matched children. Autistic children had significantly lower plasma progranulin levels, P = 0.001. Reduced plasma progranulin levels were found in 65% (26/40) of autistic children.On the other hand, there was a non significant difference between plasma progranulin levels of children with mild to moderate autism and patients with severe autism, P = 0.11. Plasma progranulin levels were reduced in a subgroup of patients with autism. Progranulin insufficiency in some patients with autism may result in many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation that may have a role in autism. However, these data should be treated with caution until further investigations are performed, with a larger subject population, to determine whether the decrease of plasma progranulin levels is a mere consequence of autism or has a pathogenic role in the disease. The role of progranulin therapy should also be studied in autism.

  17. Plasma Total Homocysteine (tHcy) Levels in Healthy Nigerian ...

    African Journals Online (AJOL)

    Establishment and stratification of reference values for a laboratory area of practice enhances the test result interpretation and sensitivity. Plasma total homocysteine (tHcy) is a metabolite of methionine which is dependent on vitamin B6, B12 and folate as co-factors. Plasma level (Hyperhomocysteinemia) is influenced by ...

  18. Effect of experimental quinine administration on plasma levels of ...

    African Journals Online (AJOL)

    Six hours after the last dose administration, blood samples were withdrawn for the determination of plasma levels of hemoglobin and methemoglobin. Plasma hemoglobin concentration increased from 11.55 +0.32 g/100ml to a critical value of 14.30 g/100ml from the control to 0.08 g/kg dose administration. A further increase ...

  19. Involvement of Gβγ subunits of Gi protein coupled with S1P receptor on multivesicular endosomes in F-actin formation and cargo sorting into exosomes.

    Science.gov (United States)

    Kajimoto, Taketoshi; Mohamed, Nesma Nabil Ibrahim; Badawy, Shaymaa Mohamed Mohamed; Matovelo, Shubi Ambwene; Hirase, Mitsuhiro; Nakamura, Shunsuke; Yoshida, Daisuke; Okada, Taro; Ijuin, Takeshi; Nakamura, Shun-Ichi

    2018-01-05

    Exosomes play a critical role in cell-to-cell communication by delivering cargo molecules to recipient cells. However, the mechanism underlying the generation of the exosomal multivesicular endosome (MVE) is one of the mysteries in the field of endosome research. Although sphingolipid metabolites such as ceramide and sphingosine 1-phosphate (S1P) are known to play important roles in MVE formation and maturation, the detailed molecular mechanisms are still unclear. Here, we show that Rho family GTPases, including Cdc42 and Rac1, are constitutively activated on exosomal MVEs and are regulated by S1P signaling as measured by fluorescence resonance energy transfer (FRET)-based conformational changes. Moreover, we detected S1P signaling-induced filamentous actin (F-actin) formation. A selective inhibitor of Gβγ subunits, M119, strongly inhibited both F-actin formation on MVEs and cargo sorting into exosomal intralumenal vesicles of MVEs, both of which were fully rescued by the simultaneous expression of constitutively active Cdc42 and Rac1. Our results shed light on the mechanism underlying exosomal MVE maturation and inform the understanding of the physiological relevance of continuous activation of the S1P receptor and subsequent downstream G protein signaling to Gβγ subunits/Rho family GTPases-regulated F-actin formation on MVEs for cargo sorting into exosomal intralumenal vesicles. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. High density lipoprotein (HDL)-associated sphingosine 1-phosphate (S1P) inhibits macrophage apoptosis by stimulating STAT3 activity and survivin expression

    DEFF Research Database (Denmark)

    Feuerborn, Renata; Becker, Susen; Potì, Francesco

    2017-01-01

    BACKGROUND AND AIMS: Macrophage apoptosis is critically involved in atherosclerosis. We here examined the effect of anti-atherogenic high density lipoprotein (HDL) and its component sphingosine-1-phosphate (S1P) on apoptosis in RAW264.7 murine macrophages. METHODS: Mitochondrial or endoplasmic re...

  1. 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.

  2. Plasma Triglyceride and Cholesterol Levels in Normotensive and ...

    African Journals Online (AJOL)

    Plasma Triglyceride and Cholesterol Levels in Normotensive and Hypertensive Pregnant and Parturient Nigerian Women. Kashope D. Thomas, Oyebola G. Adeosun, Norah O. Akinola, Uche Onwudiegwu, Alexander T. Owolabi ...

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

    Directory of Open Access Journals (Sweden)

    Alejandra Mendoza

    2012-11-01

    Full Text Available Plasma sphingosine-1-phosphate (S1P regulates vascular permeability, and plasma and lymph S1P guide lymphocyte egress from lymphoid organs. S1P is made intracellularly, and little is known about how S1P is delivered into circulatory fluids. Here, we find that mice without the major facilitator superfamily transporter Spns2 have a profound reduction in lymph S1P, but only a minor decrease in plasma S1P. Spns2-deficient mice have a redistribution of lymphocytes from the spleen to lymph nodes and a loss of circulating lymphocytes, consistent with normal egress from the spleen directed by plasma S1P and blocked egress from lymph nodes directed by lymph S1P. Spns2 is needed in endothelial cells to supply lymph S1P and support lymphocyte circulation. As a differential requirement for lymph and blood S1P, Spns2 may be an attractive target for immune suppressive drugs.

  4. Increased Plasma Levels of Heme Oxygenase-1 in Human Brucellosis.

    Science.gov (United States)

    Chen, Zhe; Zhang, Yu-Xue; Fu, Dong-Wei; Gao, Qing-Feng; Ge, Feng-Xia; Liu, Wei-Hua

    2016-08-01

    Brucellosis is associated with inflammation and the oxidative stress response. Heme oxygenase-1 (HO-1) is a cytoprotective stress-responsive enzyme that has anti-inflammatory and anti-oxidant effects. Nevertheless, the role of HO-1 in human brucellosis has not yet been studied. The aim of this study was to examine the plasma levels of HO-1 in patients with brucellosis and to evaluate the ability of plasma HO-1 levels as an auxiliary diagnosis, a severity predictor, and a monitor for brucellosis treatments. A total of 75 patients with brucellosis were divided into the acute, subacute, chronic active, and chronic stable groups. An additional 20 volunteers were included as the healthy control group. The plasma HO-1 levels and other laboratory parameters were measured in all groups. Furthermore, the plasma levels of HO-1 in the acute group were compared before and after treatment. The plasma HO-1 levels were considerably increased in the acute (4.97 ± 3.55), subacute (4.98 ± 3.23), and chronic active groups (4.43 ± 3.00) with brucellosis compared to the healthy control group (1.03 ± 0.63) (p brucellosis (r = 0.707, p brucellosis status and may be used as a supplementary plasma marker for diagnosing brucellosis and monitoring its treatment.

  5. Enhanced nuclear level decay in hot dense plasmas

    International Nuclear Information System (INIS)

    Gosselin, G.; Morel, P.

    2004-01-01

    A model of nuclear level decay in a plasma environment is described. Nuclear excitation and decay by photon processes, nuclear excitation by electron capture, and decay by internal conversion are taken into account. The electrons in the plasma are described by a relativistic average atom model for the bound electrons and by a relativistic Thomas-Fermi-Dirac model for the free electrons. Nuclear decay of isomeric level may be enhanced through an intermediate level lying above the isomer. An enhanced nuclear decay rate may occur for temperatures far below the excitation energy of the transition to the intermediate level. In most cases, the enhancement factor may reach several decades

  6. Plasma diamine oxidase levels in pregnancy complicated by threatened abortion.

    Science.gov (United States)

    Legge, M; Duff, G B

    1981-02-01

    Plasma diamine oxidase levels were assayed in 66 patients who presented with pregnancy complicated by threatened abortion. Levels within the normal range were associated with continuing pregnancies, whereas levels below the normal range were associated with subsequent abortion. Among those patients in whom gestation was greater than eight weeks, 66.6% of diamine oxidase levels correctly predicted the pregnancy outcome. Assay of the diamine oxidase levels at eight weeks of gestation or less gave little useful information.

  7. Plasma diamine oxidase levels in pregnancy complicated by threatened abortion.

    OpenAIRE

    Legge, M; Duff, G B

    1981-01-01

    Plasma diamine oxidase levels were assayed in 66 patients who presented with pregnancy complicated by threatened abortion. Levels within the normal range were associated with continuing pregnancies, whereas levels below the normal range were associated with subsequent abortion. Among those patients in whom gestation was greater than eight weeks, 66.6% of diamine oxidase levels correctly predicted the pregnancy outcome. Assay of the diamine oxidase levels at eight weeks of gestation or less ga...

  8. Concentrations in plasma clozapine levels in schizophrenic and schizoaffective patients.

    Science.gov (United States)

    Iglesias García, Celso; Iglesias Alonso, Ana; Bobes, Julio

    There is great variability in plasma levels of clozapine. The objective of this study is to know the characteristics of patients treated with clozapine and the relationship between them and the variability of plasma levels. Descriptive, cross-sectional study of all patients currently treated with clozapine in a Psychiatric Service with a diagnosis of schizophrenic psychosis or schizoaffective disorder. The present study assessed physical situation, psychopathology and functionality of the patients and explored the associations and correlations between clinical variables and plasma levels. We studied 39 patients, predominantly men, with negative and depressive symptoms and cardiovascular risk factors (metabolic syndrome and smoking). Significant variability in dose and even greater in clozapine levels were observed. The levels of clozapine at equal doses/kg of body weight were higher in non-smokers, they had positive correlation with BMI and negative correlation with systolic BP, disruptive behaviors and number of cigarettes consumed. Plasma level monitoring clozapine is an important tool to avoid clozapine plasma levels monitoring and minimize undesirable clinical situations (metabolic syndrome, sedation, negative symptoms and functional impairment). It is also important to control the effects of a smoking habit for optimum drug bioavailability. Copyright © 2017 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.

  9. Plasma kisspeptin levels in male cases with hypogonadism.

    Science.gov (United States)

    Kotani, Masato; Katagiri, Fumihiko; Hirai, Tsuyoshi; Kagawa, Jiro

    2014-01-01

    The hypothalamic hormone kisspeptin (metastin) regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is detected in peripheral blood, although GnRH is not. In this study, we measured plasma kisspeptin levels in four male cases with hypogonadism and seven normal male controls using enzyme immunoassay (EIA) to elucidate the clinical implications of kisspeptin levels in male hypogonadism. The results showed a variety of plasma kisspeptin levels: 6.0 fmol/mL in a male with isolated hypogonadotropic hypogonadism (IHH), 43.2 fmol/mL in a male with Kallmann's syndrome, 40.7 fmol/mL in a male with azoospermia, 323.2 fmol/mL in a male with hypergonadotropic hypogonadism, and 12.3 ± 2.5 fmol/mL (mean ± SD) in seven normal controls. Except for the case with IHH, the plasma kisspetin levels were elevated in the three cases with Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism. The reason why the three cases had high values was their lesions were downstream of the kisspeptin neuron in the hypothalamic-pituitary-gonadal axis, suggesting that elevated kisspeptin levels were implicated in hypothalamic kisspeptin secretion under decreased negative feedback of gonadal steroids. The result that the plasma kisspeptin levels were decreased by gonadotropin therapy in the case with Kallmann's syndrome supported this hypothesis. In conclusion, to measure plasma kisspeptin levels could be useful for better understanding of male hypogonadism.

  10. Measurement of plasma 11-deoxycorticosterone levels by radioimmunoassay in man

    International Nuclear Information System (INIS)

    Fukuchi, Soitsu; Nakajima, Katsuo; Takenouchi, Takahiko; Nishisato, Koji

    1974-01-01

    A radioimmunoassay procedure has been developed to measure 11-deoxycorticosterone (DOC) in human peripheral plasma. DOC-oxime was coupled with porcine gamma globulin and antibodies produced in rabbits. One to 3 ml of plasma, with 1, 2 3 H-DOC added for recovery, was extracted with dichloromethane and purification achieved by a silica gel column and by one paper chromatograph. After overnight incubation of the antibody-steroid mixture at 4 0 C, bound and free fractions were separated using ammonium sulfate. The mean recovery of 3 H-DOC, after extraction and chromatography, was 84.6 +- 7.4%. The method showed adequate specificity, precision and accuracy. Normal plasma DOC levels were found to be 4.4 +- 2.5 ng/100 ml (n=8). Plasma DOC levels were almost normal (0.3 - 26.8 ng/100 ml) in fifteen patients with benign essential hypertension. The mean level of 8.1 +- 8.2 ng/100 ml obtained in hypertensive patients with suppressed plasma renin activity, was not significantly different from normal. Plasma DOC showed a high level, 3.0 - 30.5 (11.4 +- 7.5) ng/100 ml, in 9 patients with primary aldosteronism. Four out of 8 patients with Cushing's syndrome were found to have elevated plasma DOC levels. Higher levels of 21.2 +- 15.8 ng/100 ml were found in 5 patients with adrenal hyperplasia than those of 12.3 +- 8.0 ng/100 ml in 3 with adrenal adenoma. Plasma DOC levels were high, 113 - 176 ng/100 ml, in 2 patients with 17α-hydroxylase deficiency. ACTH administered to 5 subjects produced a mean increase in plasma DOC from 4.8 to 25.8 ng/100 ml. Angiotensin II infused at a rate of 10 ng/kg/min for 30 min into 4 subjects did not increase mean plasma DOC. Similarly, dietary sodium restriction or postural change did not increase plasma DOC. (auth.)

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

    Science.gov (United States)

    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

  12. Association of plasma manganese levels with chronic renal failure.

    Science.gov (United States)

    Sánchez-González, Cristina; López-Chaves, Carlos; Gómez-Aracena, Jorge; Galindo, Pilar; Aranda, Pilar; Llopis, Juan

    2015-01-01

    Manganese (Mn) is an essential trace element involved in the formation of bone and in amino acid, lipid and carbohydrate metabolism. Mn excess may be neurotoxic to humans, affecting specific areas of the central nervous system. However, relatively little is known about its physiological and/or toxicological effects, and very few data are available concerning the role of Mn in chronic renal failure (CRF). This paper describes a 12-month study of the evolution of plasma Mn levels in predialysis patients with CRF and the relationship with energy and macronutrient intake. The participants in this trial were 64 patients with CRF in predialysis and 62 healthy controls. Plasma levels of creatinine, urea, uric acid, total protein and Mn were measured. The glomerular filtration rate (GFR) was calculated using the Cockcroft-Gault index. The CRF patients had higher plasma levels of creatinine, urea, uric acid and Mn and a lower GFR than the controls. Plasma Mn was positively correlated with creatinine, plasma urea and plasma uric acid and was negatively correlated with the GFR and the intake of energy and macronutrients. In conclusion, CRF in predialysis patients is associated with increases in circulating levels of Mn. Copyright © 2015 Elsevier GmbH. All rights reserved.

  13. Modeling the Effect of the Selective S1P1 Receptor Modulator Ponesimod on Subsets of Blood Lymphocytes.

    Science.gov (United States)

    Lott, Dominik; Krause, Andreas; Seemayer, Christian A; Strasser, Daniel S; Dingemanse, Jasper; Lehr, Thorsten

    2017-03-01

    This analysis aimed at describing the effect of the selective sphingosine-1-phosphate receptor 1 modulator ponesimod on lymphocyte subsets in peripheral blood. As the involvement of different lymphocyte subsets varies among different autoimmune diseases, characterizing the effect of ponesimod on these may be beneficial in better understanding treatment effects. Three phase 1 clinical studies in healthy human subjects were pooled. Non-linear mixed-effects modeling techniques were used to study the effect of ponesimod on lymphocyte subsets such as B cells, T helper cells, T cytotoxic cells, and natural killer cells in a qualitative and quantitative manner. Indirect-response I max models including circadian variation best described the effect of ponesimod on lymphocyte subsets. B cells and T helper cells were shown to be more affected compared to T cytotoxic cells with respect to the maximum possible reduction (100% for B and T helper cells, 95% for T cytotoxic cells) and the concentration required to reach half the maximum effect. Inter-individual variability was found to be larger for T cytotoxic compared to T helper, and B cells. These first models for ponesimod on the level of lymphocyte subsets offer a valuable tool for the analysis and interpretation of results from ponesimod trials in autoimmune diseases.

  14. The role of sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) in the trafficking of normal and malignant cells

    Science.gov (United States)

    Ratajczak, Mariusz Z.; Suszynska, Malwina; Borkowska, Sylwia; Ratajczak, Janina; Schneider, Gabriela

    2014-01-01

    Introduction A common feature of many types of cells is their responsiveness to chemotactic gradients of factors for which they express the corresponding receptors. The most studied chemoattractants so far are peptide-based growth factors and a family of cytokines endowed with strong chemotactic properties, called chemokines. However, additional evidence has accumulated that, in addition to these peptide-based chemoattractants, an important role in cell migration is played by bioactive lipids. Areas covered Solid evidence has accumulated that two bioactive phosphorylated sphingolipids that are derivatives of sphingolipid metabolism, namely sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), are potent chemoattractants for a variety of cells. In this review, we will discuss the effect of these two phosphorylated sphingolipids on the trafficking of normal and malignant cells, and, in particular, we will focus on their role in trafficking of normal hematopoietic stem/progenitor cells. Unlike other mediators, S1P under steady state conditions maintain a steep gradient between interstitial fluid and peripheral blood and lymph across the endothelial barrier, which is important in the egress of cells from bone marrow. Both S1P and C1P may be upregulated in damaged tissues, which may result in reversal of this gradient. Expert opinion S1P and C1P are important regulators of the trafficking of normal and malignant cells, and modification of their biological effects will have important applications in optimizing stem cell mobilization and homing, tissue organ/regeneration, and preventing cancer metastasis. PMID:24188167

  15. Increased plasma agmatine levels in patients with schizophrenia.

    Science.gov (United States)

    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.

  16. The promotion of mandibular defect healing by the targeting of S1P receptors and the recruitment of alternatively activated macrophages.

    Science.gov (United States)

    Das, Anusuya; Segar, Claire E; Hughley, Brian B; Bowers, Daniel T; Botchwey, Edward A

    2013-12-01

    Endogenous signals originating at the site of injury are involved in the paracrine recruitment, proliferation, and differentiation of circulating progenitor and diverse inflammatory cell types. Here, we investigate a strategy to exploit endogenous cell recruitment mechanisms to regenerate injured bone by local targeting and activation of sphingosine-1-phosphate (S1P) receptors. A mandibular defect model was selected for evaluating regeneration of bone following trauma or congenital disease. The particular challenges of mandibular reconstruction are inherent in the complex anatomy and function of the bone given that the area is highly vascularized and in close proximity to muscle. Nanofibers composed of poly(DL-lactide-co-glycolide) (PLAGA) and polycaprolactone (PCL) were used to delivery FTY720, a targeted agonist of S1P receptors 1 and 3. In vitro culture of bone progenitor cells on drug-loaded constructs significantly enhanced SDF1α mediated chemotaxis of bone marrow mononuclear cells. In vivo results show that local delivery of FTY720 from composite nanofibers enhanced blood vessel ingrowth and increased recruitment of M2 alternatively activated macrophages, leading to significant osseous tissue ingrowth into critical sized defects after 12 weeks of treatment. These results demonstrate that local activation of S1P receptors is a regenerative cue resulting in recruitment of wound healing or anti-inflammatory macrophages and bone healing. Use of such small molecule therapy can provide an alternative to biological factors for the clinical treatment of critical size craniofacial defects. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Plasma oxalic acid and calcium levels in oxalate poisoning

    Science.gov (United States)

    Zarembski, P. M.; Hodgkinson, A.

    1967-01-01

    Observations are reported on five cases of suicide or attempted suicide by poisoning with oxalic acid or ethylene glycol. Elevated oxalic acid levels were observed in the plasma, stomach contents, and a number of tissues. Raised oxalic acid levels in plasma were associated with reduced total and ultrafilterable calcium levels. It is suggested that the reduction in plasma total calcium level is due mainly to the deposition of calcium oxalate in the soft tissues, but inhibition of the parathyroid glands may be a contributory factor. Microscopic examination of various tissues indicated that oxalic acid is deposited in the tissues in two forms: (1) crystalline calcium oxalate dihydrate in the kidney and (2) a non-crystalline complex of calcium oxalate and lipid in liver and other tissues. PMID:5602563

  18. Plasma lactoferrin levels in pregnancy and cystic fibrosis

    International Nuclear Information System (INIS)

    Sykes, J.A.C.; Thomas, M.J.; Goldie, D.J.; Turner, G.M.

    1982-01-01

    Plasma lactoferrin levels have been determined by radioimmunoassay for the different weeks of normal pregnancy, in normal healthy adults and in children with and without cystic fibrosis. The lactoferrin levels were higher in pregnancy than in both male and female normal adults and showed a slight progressive increase up to week 29 and thereafter remained high. Five out of seven children with cystic fibrosis had markedly raised plasma lactoferrin levels from six to 16 times higher than the mean of a control group of children. (Auth.)

  19. Study of plasma adrenomedullin level in normal pregnancy and preclampsia.

    Science.gov (United States)

    Senna, Azza Abo; Zedan, Magda; el-Salam, Gamal E Abd; el-Mashad, Ashraf I

    2008-02-06

    The aim of this study was to evaluate whether maternal circulating adrenomedullin (AM) values in patients with preeclampsia are different from those in normotensive pregnant women at different gestational ages. In a prospective clinical study, 90 women aged 17 to 40 years old, were divided into 4 main groups: group I (45 women): Normotensive pregnant women at first trimester (15 women), second trimester (15 women), and third trimester (15 women) of pregnancies. Group II (15 women): Pregnant women with preeclampsia at 25 to 38 weeks of gestation. Group III (15 women): Normotensive healthy nonpregnant women. Group IV (15 women): Hypertensive nonpregnant women. The plasma AM concentration was measured in all women by using enzyme immunoassay kits. Plasma AM levels in pregnant women with normal blood pressure at different gestational ages (first, second, and third trimesters) were statistically significantly higher than those detected in nonpregnant normotensive women and significantly increased with increasing gestational age (P < .001). Moreover, there was significant positive correlation between plasma AM levels and increasing gestational age (r = 0.915, P < .001). Preeclamptic patients had the highest mean plasma AM levels compared with all other groups, which is statistically significant (P < .001) and there was a significant positive correlation between plasma AM levels and systolic blood pressure, diastolic blood pressure, severity of preeclampsia, and proteinuria in pregnant patients with preeclampsia. Maternal plasma AM concentration increases throughout pregnancy and increases as gestational age progresses. AM production starts very early in gestation, suggesting that it may have an important role in human reproduction, from implantation to delivery. Maternal plasma AM level in preeclampsia appears to be higher than that in normal pregnancy.

  20. Pavlovian autoshaping procedures increase plasma corticosterone levels in rats.

    Science.gov (United States)

    Tomie, Arthur; Silberman, Yuval; Williams, Kayon; Pohorecky, Larissa A

    2002-06-01

    Pavlovian autoshaping conditioned responses (CRs) are complex sequences of conditioned stimulus (CS)-directed skeletal-motor responses that are elicited by CS objects predictive of food unconditioned stimulus (US). Autoshaping CRs are observed under conditions known to be conducive to elevations in plasma corticosterone levels, as, for example, in response to the eating of food as well as in response to signals predictive of food. Two experiments investigated the relationships between Pavlovian autoshaping procedures, the performance of Pavlovian autoshaping CRs, and plasma corticosterone levels in male Long-Evans rats. In Experiment 1, rats in the CS-US paired group (n=30) were given 20 daily sessions of Pavlovian autoshaping training wherein the insertion of a retractable lever CS was followed by the response-independent presentation of the food US. Tail blood samples obtained after the 20th autoshaping session revealed higher plasma corticosterone levels in the CS-US paired group than in the CS-US random control group (n=10). In Experiment 2, rats (n=35) were assessed for basal plasma corticosterone levels 2 weeks prior to autoshaping training. Plasma samples obtained immediately following the first autoshaping session, and prior to the acquisition of lever-press autoshaping CR performance, revealed higher plasma corticosterone levels in the CS-US paired group (n=24) relative to basal levels. This effect was not observed in the CS-US random control group (n=11). Data suggest that corticosterone release is a physiological endocrine Pavlovian CR induced by lever CS-food US pairings during Pavlovian autoshaping procedures, rather than a by-product of autoshaping CR performance. Implications of the link between autoshaping procedures and corticosterone release are discussed.

  1. Effects of Rakkyofructan on Postprandial Glucose Level in Plasma

    OpenAIRE

    谷, 政八; 池田, 涼子; 谷, 洋子; 小林, 恭一; Tani, Masahachi; Ikeda, Ryouko; Tani, Hiroko; Kobayashi, Kyoichi

    2010-01-01

    The effect of Rakkyofructan on the glucose level in plasma after intake of high carbohydrate diet was investigated.The six healthy female volunteers consumed 50 g of carbohydrate meal (the glucose, the cooked white rice, the bread, or the cooked sweet potato) with or without Rakkyofructan.Blood specimen was collected of before and 30, 45, 60, 90, 120 and 150 min after intake, and the glucose level in plasma was measured.The peak value (Cmax) and the area under curve (AUC) of blood glucose lev...

  2. Alteration of plasma prednisolone levels by indomethacin and naproxen.

    OpenAIRE

    Rae, S A; Williams, I A; English, J; Baylis, E M

    1982-01-01

    Eleven patients with stable rheumatoid disease (RD) who were receiving regular corticosteroid therapy (CS) were investigated to discover the effect on plasma prednisolone levels of additional therapy with the non-steroidal anti-inflammatory (NSAI) drugs, indomethacin and naproxen. There was a highly significant (P less than 0.001) increase in free prednisolone levels after concurrent therapy with either indomethacin or naproxen for 2 weeks. Total prednisolone levels were unchanged. These resu...

  3. S1P1 receptor modulation preserves vascular function in mesenteric and coronary arteries after CPB in the rat independent of depletion of lymphocytes.

    Directory of Open Access Journals (Sweden)

    Iryna V Samarska

    Full Text Available BACKGROUND: Cardiopulmonary bypass (CPB may induce systemic inflammation and vascular dysfunction. Sphingosine 1-phosphate (S1P modulates various vascular and immune responses. Here we explored whether agonists of the S1P receptors, FTY720 and SEW2871 improve vascular reactivity after CPB in the rat. METHODS: Experiments were done in male Wistar rats (total n = 127. Anesthesia was induced by isoflurane (2.5-3% and maintained by fentanyl and midazolam during CPB. After catheterization of the left femoral artery, carotid artery and the right atrium, normothermic extracorporeal circulation was instituted for 60 minutes. In the first part of the study animals were euthanized after either 1 hour, 1 day, 2 or 5 days of the recovery period. In second part of the study animals were euthanized after 1 day of postoperative period. We evaluated the contractile response to phenylephrine (mesenteric arteries or to serotonin (coronary artery and vasodilatory response to acethylcholine (both arteries. RESULTS: Contractile responses to phenylephrine were reduced at 1 day recovery after CPB and Sham as compared to healthy control animals (Emax, mN: 7.9 ± 1.9, 6.5 ± 1.5, and 11.3 ± 1.3, respectively. Mainly FTY720, but not SEW2871, caused lymphopenia in both Sham and CPB groups. In coronary and mesenteric arteries, both FTY720 and SEW2871 normalized serotonin and phenylephrine-mediated vascular reactivity after CPB (p<0.05 and FTY720 increased relaxation to acetylcholine as compared with untreated rats that underwent CPB. CONCLUSION: Pretreatment with FTY720 or SEW2871 preserves vascular function in mesenteric and coronary artery after CPB. Therefore, pharmacological activation of S1P1 receptors may provide a promising therapeutic intervention to prevent CPB-related vascular dysfunction in patients.

  4. Association of plasma protein C levels and coronary artery disease ...

    African Journals Online (AJOL)

    Several studies have shown the risk factor causes of coronary heart disease. In this study we tested the hypothesis that plasma protein C level might be used as a biomarker for coronary heart disease and myocardial infarction. The study included 60 men that were classified into 3 groups according to clinical examination; ...

  5. Relationship between soil contents and plasma levels of selenium ...

    African Journals Online (AJOL)

    The soil contents of trace elements selenium, chromium and manganese were measured to determine their impact on the plasma levels of 160 healthy adult Nigerians in five different experimental locations in Cross River and Akwa Ibom States, South - South Nigeria. The mean (±SD) soil selenium, chromium and ...

  6. Plasma TGF beta level in rats after hemithoracic irradiation

    NARCIS (Netherlands)

    Vujaskovic, Z; Down, JD; vanWaarde, MAWH; vanAssen, AJ; Szabo, BG; Konings, AWT

    Changes in TGF-beta plasma levels were observed 18 weeks after hemithoracic irradiation in rats. This coincides with an increase in the breathing frequency, being most pronounced between 22 and 28 weeks after irradiation. The correlation suggests a potential role of the circulating TGF-beta in the

  7. Seasonal changes in plasma testosterone levels in the male South ...

    African Journals Online (AJOL)

    1991-02-18

    Feb 18, 1991 ... It is also known that melatonin, B-endorphin and prolactin are important in the timing of reactivation of reproduction in the European hedgehog (Fowler 1988b). Although the present study, based upon total circulating testosterone levels illustrates a clear seasonal cycle in plasma testosterone in A. fronlalis,.

  8. Plasma klotho levels decrease in both anorexia nervosa and obesity.

    Science.gov (United States)

    Amitani, Marie; Asakawa, Akihiro; Amitani, Haruka; Kaimoto, Kaori; Sameshima, Nanami; Koyama, Ken Ichiro; Haruta, Izumi; Tsai, Minglun; Nakahara, Toshihiro; Ushikai, Miharu; Cheng, Kai-Chun; Hamada, Satoshi; Inui, Akio

    2013-09-01

    The aim of this study was to examine the associations of klotho with body mass index (BMI) in patients with restricting-type anorexia nervosa (r-AN) and obesity. We examined plasma klotho as well as adiponectin and its isoform levels in comparison in 11 obese patients, 12 r-AN patients, and 11 control participants. Plasma klotho levels were markedly lower in the obesity and r-AN groups than in the control group. Moreover, plasma klotho levels increased significantly after the recovery of BMI in r-AN patients. Total and high-molecular-weight adiponectin levels were significantly decreased only in obesity. There was no relationship between klotho and total adiponectin levels or klotho and respective adiponectin isoform levels in the entire study population. These results suggest that klotho may reflect normal nutritional state, and that the decrease of klotho in r-AN and obesity may underlie the deteriorating processes of these disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Plasma levels of progesterone in cycling and pregnant ewes

    International Nuclear Information System (INIS)

    Reddy, K.P.; Rao, P.N.; Reddy, B.B.; Murthy, A.S.N.

    1989-01-01

    The plasma progesterone profile of six cycling and three pregnant Nellore ewes was estimated by radioimmunoassay. The progesterone level of cycling ewes started rising from undetectable level on the day of oestrus to a mean peak value of 0.41 ± 0.09ng/ml during post oestrus day 10 to 14 and then declined to undetectable levels 1 to 2 days before subsequent oestrus. But the progesterone levels of pregnant ewes exhibited further raise from the post oestrus day 14 to the day 40. However, no correlation between oestrous cycle length and the total progesterone produced during the oestrous cycle was observed. (author). 9 refs., 2 figs

  10. High levels of circulating triiodothyronine induce plasma cell differentiation.

    Science.gov (United States)

    Bloise, Flavia Fonseca; Oliveira, Felipe Leite de; Nobrega, Alberto Félix; Vasconcellos, Rita; Cordeiro, Aline; Paiva, Luciana Souza de; Taub, Dennis D; Borojevic, Radovan; Pazos-Moura, Carmen Cabanelas; Mello-Coelho, Valéria de

    2014-03-01

    The effects of hyperthyroidism on B-cell physiology are still poorly known. In this study, we evaluated the influence of high-circulating levels of 3,5,3'-triiodothyronine (T3) on bone marrow, blood, and spleen B-cell subsets, more specifically on B-cell differentiation into plasma cells, in C57BL/6 mice receiving daily injections of T3 for 14 days. As analyzed by flow cytometry, T3-treated mice exhibited increased frequencies of pre-B and immature B-cells and decreased percentages of mature B-cells in the bone marrow, accompanied by an increased frequency of blood B-cells, splenic newly formed B-cells, and total CD19(+)B-cells. T3 administration also promoted an increase in the size and cellularity of the spleen as well as in the white pulp areas of the organ, as evidenced by histological analyses. In addition, a decreased frequency of splenic B220(+) cells correlating with an increased percentage of CD138(+) plasma cells was observed in the spleen and bone marrow of T3-treated mice. Using enzyme-linked immunospot assay, an increased number of splenic immunoglobulin-secreting B-cells from T3-treated mice was detected ex vivo. Similar results were observed in mice immunized with hen egg lysozyme and aluminum adjuvant alone or together with treatment with T3. In conclusion, we provide evidence that high-circulating levels of T3 stimulate plasma cytogenesis favoring an increase in plasma cells in the bone marrow, a long-lived plasma cell survival niche. These findings indicate that a stimulatory effect on plasma cell differentiation could occur in untreated patients with Graves' disease.

  11. Plasma neuropeptide Y levels differ in distinct diabetic conditions.

    Science.gov (United States)

    Ilhan, Aysegül; Rasul, Sazan; Dimitrov, Alexander; Handisurya, Ammon; Gartner, Wolfgang; Baumgartner-Parzer, Sabina; Wagner, Ludwig; Kautzky-Willer, Alexandra; Base, Wolfgang

    2010-12-01

    Neuropeptide Y (NPY) is an important hormone in appetite regulation. Although the contribution of NPY to metabolic disease has been previously demonstrated, there are only a few reports addressing NPY plasma levels under distinct diabetic conditions. In this study we evaluated NPY plasma levels in diabetes mellitus type 2 (DM2) patients with (n=34) and without (n=34) diabetic polyneuropathy (PNP) and compared these with age and gender matched healthy controls (n=34). We also analyzed NPY plasma levels in gestational diabetes mellitus (GDM) patients with age and pregnancy-week matched controls with normal glucose tolerance (NGT). NPY concentration was determined using a commercially available radioimmunoassay kit. In addition, metabolic parameters of DM2 and GDM patients were recorded. One-way ANOVA tests with appropriate post hoc corrections showed elevated levels of NPY in DM2 patients with and without PNP when compared with those of healthy controls (122.32±40.86 and 117.33±29.92 vs. 84.65±52.17 pmol/L; pwomen with NGT (74.87±14.36 vs. 84.82±51.13 pmol/L, respectively). Notably, the NPY concentration correlated positively with insulin levels in DM2 patients (R=0.35, pDM2 pathology. Copyright © 2010 Elsevier Ltd. All rights reserved.

  12. Low and intermediate level radioactive waste processing in plasma reactor

    International Nuclear Information System (INIS)

    Sauchyn, V.; Khvedchyn, I.; Van Oost, G.

    2013-01-01

    Methods of low and intermediate level radioactive waste processing comprise: cementation, bituminization, curing in polymer matrices, combustion and pyrolysis. All these methods are limited in their application in the field of chemical, morphological, and aggregate composition of material to be processed. The thermal plasma method is one of the universal methods of RAW processing. The use of electric-arc plasma with mean temperatures 2000 - 8000 K can effectively carry out the destruction of organic compounds into atoms and ions with very high speeds and high degree of conversion. Destruction of complex substances without oxygen leads to a decrease of the volume of exhaust gases and dimension of gas cleaning system. This paper presents the plasma reactor for thermal processing of low and intermediate level radioactive waste of mixed morphology. The equipment realizes plasma-pyrolytic conversion of wastes and results in a conditioned product in a single stage. As a result, the volume of conditioned waste is significantly reduced (more than 10 times). Waste is converted into an environmentally friendly form that suits long-term storage. The leaching rate of macro-components from the vitrified compound is less than 1.10 -7 g/(cm 2 .day). (authors)

  13. Alteration of plasma prednisolone levels by indomethacin and naproxen.

    Science.gov (United States)

    Rae, S A; Williams, I A; English, J; Baylis, E M

    1982-01-01

    Eleven patients with stable rheumatoid disease (RD) who were receiving regular corticosteroid therapy (CS) were investigated to discover the effect on plasma prednisolone levels of additional therapy with the non-steroidal anti-inflammatory (NSAI) drugs, indomethacin and naproxen. There was a highly significant (P less than 0.001) increase in free prednisolone levels after concurrent therapy with either indomethacin or naproxen for 2 weeks. Total prednisolone levels were unchanged. These results could provide an explanation for clinical reports that these two NSAI drugs possess a steroid-sparing effect. PMID:7126420

  14. Radio frequency plasma nitriding of aluminium at higher power levels

    International Nuclear Information System (INIS)

    Gredelj, Sabina; Kumar, Sunil; Gerson, Andrea R.; Cavallaro, Giuseppe P.

    2006-01-01

    Nitriding of aluminium 2011 using a radio frequency plasma at higher power levels (500 and 700 W) and lower substrate temperature (500 deg. C) resulted in higher AlN/Al 2 O 3 ratios than obtained at 100 W and 575 deg. C. AlN/Al 2 O 3 ratios derived from X-ray photoelectron spectroscopic analysis (and corroborated by heavy ion elastic recoil time of flight spectrometry) for treatments preformed at 100 (575 deg. C), 500 (500 deg. C) and 700 W (500 deg. C) were 1.0, 1.5 and 3.3, respectively. Scanning electron microscopy revealed that plasma nitrided surfaces obtained at higher power levels exhibited much finer nodular morphology than obtained at 100 W

  15. Haloperidol plasma levels in relation to antimanic effect

    DEFF Research Database (Denmark)

    Gjerris, Annette; Bech, P.; Christensen, Christian Broen

    2016-01-01

    n the treatment of mania, lithium (Li) has been found in several controlled studies as clearly superior to placebo, but haloperidol, when compared to Li, seems to be faster acting, at least with regard to motor activity (Shopsin et al., 1975). Hence, haloperidol has increasingly been recommended...... as the antimanic drug of choice (Shaw, 1979). However, the recommended dose of haloperidol for mania varies extremely, from 4 mg to 100 mg daily (Hollister, 1978). The haloperidol dose required obviously depends on the severity of the manic state, but might also depend on the metabolism of the drug, which varies...... in different patients (Forsman, 1977). To our knowledge the relationship between plasma levels of haloperidol and antimanic effect has not been evaluated. In the present study we have measured plasma levels of haloperidol in manic patients treated with a fixed haloperidol dose and examined the relationship...

  16. Modulation of Human Plasma Fibronectin Levels Following Exercise,

    Science.gov (United States)

    1988-01-01

    forms of this large molecular weight (440 kilodaltons) glycoprotein,(17. While the tissue type is cell-associated and important to cell adhesion and...increased under conditions of pathology, such as in obesity (6). cancer (3). proteinuria (4). diabetic retinopathy (5). and preeclampsia (27). in the absence...Res. 1977: 22:709-716. 27. Stubbs. T.M.. Lazarchick. J.. and Horger. E.O. Plasma fibronectin levels in preeclampsia : A possible biochemical marker

  17. Relationship between Plasma Leptin Level and Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Anoop Shankar

    2012-01-01

    Full Text Available Background. Leptin is an adipose tissue-derived hormone shown to be related to several metabolic, inflammatory, and hemostatic factors related to chronic kidney disease. Recent animal studies have reported that infusion of recombinant leptin into normal rats for 3 weeks fosters the development of glomerulosclerosis. However, few studies have examined the association between leptin and CKD in humans. Therefore, we examined the association between plasma leptin levels and CKD in a representative sample of US adults. Methods. We examined the third National Health and Nutrition Examination Survey participants >20 years of age (n=5820, 53.6% women. Plasma leptin levels were categorized into quartiles (≤4.3 Fg/L, 4.4–8.7 Fg/L, 8.8–16.9 Fg/L, >16.9 Fg/L. CKD was defined as a glomerular filtration rate of <60 mL/min/1.73 m2 estimated from serum creatinine. Results. Higher plasma leptin levels were associated with CKD after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, body mass index (BMI, diabetes, hypertension, and serum cholesterol. Compared to quartile 1 of leptin (referent, the odds ratio (95% confidence interval of CKD associated with quartile 4 was 3.31 (1.41 to 7.78; P-trend = 0.0135. Subgroup analyses examining the relation between leptin and CKD by gender, BMI categories, diabetes, and hypertension status also showed a consistent positive association. Conclusion. Higher plasma leptin levels are associated with CKD in a representative sample of US adults.

  18. Plasma total antioxidant capacity is associated with dietary intake and plasma level of antioxidants in postmenopausal women.

    Science.gov (United States)

    Wang, Ying; Yang, Meng; Lee, Sang-Gil; Davis, Catherine G; Kenny, Anne; Koo, Sung I; Chun, Ock K

    2012-12-01

    Increased plasma total antioxidant capacity (TAC) has been associated with a high consumption of fruits and vegetables. However, limited information is available on whether plasma TAC reflects the dietary intake of antioxidants and the levels of individual antioxidants in plasma. By using three different assays, the study aimed to determine if plasma TAC can effectively predict dietary intake of antioxidants and plasma antioxidant status. Forty overweight and apparently healthy postmenopausal women were recruited. Seven-day food records and 12-h fasting blood samples were collected for dietary and plasma antioxidant assessments. Plasma TAC was determined by vitamin C equivalent antioxidant capacity (VCEAC), ferric-reducing ability of plasma (FRAP) and oxygen radical absorbance capacity (ORAC) assays. TAC values determined by VCEAC were highly correlated with FRAP (r=0.79, Pantioxidants and represents more closely the plasma antioxidant levels than ORAC and FRAP. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Tocopherols and tocotrienols plasma levels are associated with cognitive impairment.

    Science.gov (United States)

    Mangialasche, Francesca; Xu, Weili; Kivipelto, Miia; Costanzi, Emanuela; Ercolani, Sara; Pigliautile, Martina; Cecchetti, Roberta; Baglioni, Mauro; Simmons, Andrew; Soininen, Hilkka; Tsolaki, Magda; Kloszewska, Iwona; Vellas, Bruno; Lovestone, Simon; Mecocci, Patrizia

    2012-10-01

    Vitamin E includes 8 natural compounds (4 tocopherols, 4 tocotrienols) with potential neuroprotective activity. α-Tocopherol has mainly been investigated in relation to cognitive impairment. We examined the relation of all plasma vitamin E forms and markers of vitamin E damage (α-tocopherylquinone, 5-nitro-γ-tocopherol) to mild cognitive impairment (MCI) and Alzheimer's disease (AD). Within the AddNeuroMed-Project, plasma tocopherols, tocotrienols, α-tocopherylquinone, and 5-nitro-γ-tocopherol were assessed in 168 AD cases, 166 MCI, and 187 cognitively normal (CN) people. Compared with cognitively normal subjects, AD and MCI had lower levels of total tocopherols, total tocotrienols, and total vitamin E. In multivariable-polytomous-logistic regression analysis, both MCI and AD cases had 85% lower odds to be in the highest tertile of total tocopherols and total vitamin E, and they were, respectively, 92% and 94% less likely to be in the highest tertile of total tocotrienols than the lowest tertile. Further, both disorders were associated with increased vitamin E damage. Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Ghrelin plasma levels in patients with idiopathic short stature.

    Science.gov (United States)

    Iñiguez, Germán; Román, Rossana; Youlton, Ronald; Cassorla, Fernando; Mericq, Verónica

    2011-02-01

    Novel molecular insights have suggested that ghrelin may be involved in the pathogenesis of some forms of short stature. Recently, growth hormone secretagogue receptor (GHSR) mutations that segregate with short stature have been reported. To study plasma ghrelin levels in prepubertal patients with idiopathic short stature (ISS). Fasting total plasma ghrelin levels (radioimmunoassay) in 41 prepubertal patients with ISS (18 females, age 7.9 ± 0.5 years) compared with 42 age- and sex-matched controls (27 females, age 8.0 ± 0.3 years) with normal height. In a subset of 28 patients, the ghrelin receptor was sequenced. ISS patients exhibited a higher level of ghrelin (1,458 ± 137 vs. 935 ± 55 pg/ml, p ghrelin levels greater than +2 SDS compared to controls. These patients did not differ in height, BMI or IGF-I SDS compared to ISS patients with ghrelin levels within the normal range. Molecular analysis of GHSR did not show any mutations, but showed some polymorphisms. These results suggest that in ISS patients, short stature does not appear to be frequently caused by abnormalities in ghrelin signaling. Copyright © 2010 S. Karger AG, Basel.

  1. Association between plasma kisspeptin levels and adolescent gynecomastia.

    Science.gov (United States)

    Aluclu, Mustafa Arif; Sen, Selcuk; Cevik, Muazez

    2016-01-01

    Gynecomastia is defined as benign proliferation of male breast glandular tissue. To date, the pathophysiology of adolescent gynecomastia (AG) remains unclear. Kisspeptin is a polypeptide that plays an important role in the regulation of the hypothalamic-pituitary-gonadal hormonal axis. In this study, we investigated whether there is a relationship between kisspeptin and AG. This study included 40 males between 9 and 18 years of age diagnosed with gynecomastia. The control group consisted of 30 young healthy males in the same age range. The participants were evaluated with respect to anthropometric measurements (age, height, body weight, body mass index, breast and pubic stages and testicular volume). The levels of kisspeptin, follicle-stimulating hormone, luteinizing hormone, estradiol (E2), testosterone (T), and ratio of E2 to T were measured in both groups. The mean age was 13.8 years. There were no differences between the groups in terms of anthropometric parameters, plasma gonadotropin levels, estrogen levels, and E2/T (P > 0.05). Plasma kisspeptin (0.77 and 0.54 ng/mL, P < 0.05) and T (253.9 ng/dL and 117.9 ng/dL) levels were significantly higher in the AG group than in the control group (P < 0.001). Kisspeptin levels are an important factor in AG.

  2. Association between plasma kisspeptin levels and adolescent gynecomastia

    Directory of Open Access Journals (Sweden)

    Mustafa Arif Aluclu

    2016-01-01

    Full Text Available Background: Gynecomastia is defined as benign proliferation of male breast glandular tissue. To date, the pathophysiology of adolescent gynecomastia (AG remains unclear. Kisspeptin is a polypeptide that plays an important role in the regulation of the hypothalamic-pituitary-gonadal hormonal axis. In this study, we investigated whether there is a relationship between kisspeptin and AG. Materials and Methods: This study included 40 males between 9 and 18 years of age diagnosed with gynecomastia. The control group consisted of 30 young healthy males in the same age range. The participants were evaluated with respect to anthropometric measurements (age, height, body weight, body mass index, breast and pubic stages and testicular volume. The levels of kisspeptin, follicle-stimulating hormone, luteinizing hormone, estradiol (E2, testosterone (T, and ratio of E2 to T were measured in both groups. Results: The mean age was 13.8 years. There were no differences between the groups in terms of anthropometric parameters, plasma gonadotropin levels, estrogen levels, and E2/T (P > 0.05. Plasma kisspeptin (0.77 and 0.54 ng/mL, P < 0.05 and T (253.9 ng/dL and 117.9 ng/dL levels were significantly higher in the AG group than in the control group (P < 0.001. Conclusion: Kisspeptin levels are an important factor in AG.

  3. Plasma debrisoquin levels in the assessment of reduction of plasma homovanillic acid. The debrisoquin method.

    Science.gov (United States)

    Riddle, M A; Jatlow, P I; Anderson, G M; Cho, S C; Hardin, M T; Cohen, D J; Leckman, J F

    1989-06-01

    Plasma concentrations of unconjugated homovanillic acid (pHVA) reflect both central nervous system (CNS) and peripheral dopamine metabolism. Debrisoquin sulfate (DBQ) blocks peripheral, but not CNS, production of HVA from dopamine. Administration of DBQ has been used to decrease the proportion of peripherally produced HVA in pHVA measurements, making such measurements more reflective of CNS turnover of dopamine. We studied the relationships between DBQ dose, plasma DBQ (pDBQ) levels, and changes in pHVA in a group of 21 subjects (9 normal controls and 12 with Tourette's syndrome). DBQ dose was moderately correlated with pDBQ levels (r = 0.63, p = 0.002). Subjects (n = 8) with mean pDBQ levels above 60 ng/ml had a 48% to 66% decrease in mean pHVA levels; this may reflect nearly complete inhibition of peripheral HVA production. Subjects (n = 13) with mean pDBQ levels below 55 ng/ml had decreases in pHVA levels from 10% to 58%. No debrisoquin was detected in cerebrospinal fluid samples. These data suggest that pDBQ levels above 60 ng/ml are sufficient to assure substantial inhibition of peripheral HVA production and that monitoring pDBQ levels may be useful when employing this method for studying CNS metabolism.

  4. Analysis of Plasma Homocysteine Levels in Patients with Unstable Angina

    Directory of Open Access Journals (Sweden)

    José Roberto Tavares

    2002-08-01

    Full Text Available OBJECTIVE - To determine the prevalence of hyperhomocystinemia in patients with acute ischemic syndrome of the unstable angina type. METHODS - We prospectively studied 46 patients (24 females with unstable angina and 46 control patients (19 males, paired by sex and age, blinded to the laboratory data. Details of diets, smoking habits, medication used, body mass index, and the presence of hypertension and diabetes were recorded, as were plasma lipid and glucose levels, C-reactive protein, and lipoperoxidation in all participants. Patients with renal disease were excluded. Plasma homocysteine was estimated using high-pressure liquid chromatography. RESULTS - Plasma homocysteine levels were significantly higher in the group of patients with unstable angina (12.7±6.7 µmol/L than in the control group (8.7±4.4 µmol/L (p<0.05. Among males, homocystinemia was higher in the group with unstable angina than in the control group, but this difference was not statistically significant (14.1±5.9 µmol/L versus 11.9±4.2 µmol/L. Among females, however, a statistically significant difference was observed between the 2 groups: 11.0±7.4 µmol/L versus 6.4±2.9 µmol/L (p<0.05 in the unstable angina and control groups, respectively. Approximately 24% of the patients had unstable angina at homocysteine levels above 15 µmol/L. CONCLUSION - High homocysteine levels seem to be a relevant prevalent factor in the population with unstable angina, particularly among females.

  5. The association between estimated average glucose levels and fasting plasma glucose levels

    Directory of Open Access Journals (Sweden)

    Giray Bozkaya

    2010-01-01

    Full Text Available OBJECTIVE: The level of hemoglobin A1c (HbA1c, also known as glycated hemoglobin, determines how well a patient's blood glucose level has been controlled over the previous 8-12 weeks. HbA1c levels help patients and doctors understand whether a particular diabetes treatment is working and whether adjustments need to be made to the treatment. Because the HbA1c level is a marker of blood glucose for the previous 120 days, average blood glucose levels can be estimated using HbA1c levels. Our aim in the present study was to investigate the relationship between estimated average glucose levels, as calculated by HbA1c levels, and fasting plasma glucose levels. METHODS: The fasting plasma glucose levels of 3891 diabetic patient samples (1497 male, 2394 female were obtained from the laboratory information system used for HbA1c testing by the Department of Internal Medicine at the Izmir Bozyaka Training and Research Hospital in Turkey. These samples were selected from patient samples that had hemoglobin levels between 12 and 16 g/dL. The estimated glucose levels were calculated using the following formula: 28.7 x HbA1c - 46.7. Glucose and HbA1c levels were determined using hexokinase and high performance liquid chromatography (HPLC methods, respectively. RESULTS: A strong positive correlation between fasting plasma glucose levels and estimated average blood glucose levels (r=0.757, p<0.05 was observed. The difference was statistically significant. CONCLUSION: Reporting the estimated average glucose level together with the HbA1c level is believed to assist patients and doctors determine the effectiveness of blood glucose control measures.

  6. Atomic properties in hot plasmas from levels to superconfigurations

    CERN Document Server

    Bauche, Jacques; Peyrusse, Olivier

    2015-01-01

    This book is devoted to the calculation of hot-plasma properties which generally requires a huge number of atomic data. It is the first book that combines information on the details of the basic atomic physics and its application to atomic spectroscopy with the use of the relevant statistical approaches. Information like energy levels, radiative rates, collisional and radiative cross-sections, etc., must be included in equilibrium or non-equilibrium models in order to describe both the atomic-population kinetics and the radiative properties. From the very large number of levels and transitions involved in complex ions, some statistical (global) properties emerge. The book presents a coherent set of concepts and compact formulas suitable for tractable and accurate calculations. The topics addressed are: radiative emission and absorption, and a dozen of other collisional and radiative processes; transition arrays between level ensembles (configurations, superconfigurations); effective temperatures of configurat...

  7. Heterogeneity in plasma homovanillic Acid levels in schizophreniform disorder.

    Science.gov (United States)

    Pradhan, N; Harihar, C; Das, P; Andrade, C

    1992-04-01

    Plasma homovanillic acid (pHVA) levels were estimated in 20 cases of schizophreniform disorder, 14 cases of schizophrenia 'on medication' and 17 cases of schizophrenia 'off medication'. A bimodal distribution of pHVA was seen in schizophreniform disorder subjects, suggesting heterogenous groups in terms of dopaminergic function. No significant difference in the pHVA values was seen in the 3 groups, nor was there a relationship between the severity of the illness and the pHVA values; these results suggest plasticity of the dopaminergic system to neuroleptics.

  8. HETEROGENEITY IN PLASMA HOMOVANILLIC ACID LEVELS IN SCHIZOPHRENIFORM DISORDER

    OpenAIRE

    Pradhan, N.; Harihar, C.; Das, P.; Andrade, C.

    1992-01-01

    Plasma homovanillic acid (pHVA) levels were estimated in 20 cases of schizophreniform disorder, 14 cases of schizophrenia ‘on medication’ and 17 cases of schizophrenia ‘off medication’. A bimodal distribution of pHVA was seen in schizophreniform disorder subjects, suggesting heterogenous groups in terms of dopaminergic function. No significant difference in the pHVA values was seen in the 3 groups, nor was there a relationship between the severity of the illness and the pHVA values; these res...

  9. Delivery of S1P receptor-targeted drugs via biodegradable polymer scaffolds enhances bone regeneration in a critical size cranial defect.

    Science.gov (United States)

    Das, Anusuya; Tanner, Shaun; Barker, Daniel A; Green, David; Botchwey, Edward A

    2014-04-01

    Biodegradable polymer scaffolds can be used to deliver soluble factors to enhance osseous remodeling in bone defects. To this end, we designed a poly(lactic-co-glycolic acid) (PLAGA) microsphere scaffold to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors. The microsphere scaffolds were created from fast degrading 50:50 PLAGA and/or from slow-degrading 85:15 PLAGA. Temporal and spatial regulation of bone remodeling depended on the use of appropriate scaffolds for drug delivery. The release profiles from the scaffolds were used to design an optimal delivery system to treat critical size cranial defects in a rodent model. The ability of local FTY720 delivery to maximize bone regeneration was evaluated with micro-computed tomography (microCT) and histology. Following 4 weeks of defect healing, FTY720 delivery from 85:15 PLAGA scaffolds resulted in a significant increase in bone volumes in the defect region compared to the controls. A 85:15 microsphere scaffolds maintain their structural integrity over a longer period of time, and cause an initial burst release of FTY720 due to surface localization of the drug. This encourages cellular in-growth and an increase in new bone formation. Copyright © 2013 Wiley Periodicals, Inc.

  10. Delivery of S1P Receptor-Targeted Drugs via Biodegradable Polymer Scaffolds Enhances Bone Regeneration in a Critical Size Cranial Defect*

    Science.gov (United States)

    Das, Anusuya; Tanner, Shaun; Barker, Daniel A.; Green, David; Botchwey, Edward A.

    2014-01-01

    Biodegradable polymer scaffolds can be used to deliver soluble factors to enhance osseous remodeling in bone defects. To this end, we designed a poly(lactic-co-glycolic acid) (PLAGA) microsphere scaffold to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors. The microsphere scaffolds were created from fast degrading 50:50 PLAGA and/or from slow-degrading 85:15 PLAGA. Temporal and spatial regulation of bone remodeling depended on the use of appropriate scaffolds for drug delivery. The release profiles from the scaffolds were used to design an optimal delivery system to treat critical size cranial defects in a rodent model. The ability of local FTY720 delivery to maximize bone regeneration was evaluated with microcomputed tomography (microCT) and histology. Following 4 weeks of defect healing, FTY720 delivery from 85:15 PLAGA scaffolds resulted in a significant increase in bone volumes in the defect region compared to the controls. 85:15 microsphere scaffolds maintain their structural integrity over a longer period of time, and cause an initial burst release of FTY720 due to surface localization of the drug. This encourages cellular in-growth and an increase in new bone formation. PMID:23640833

  11. Caloric Restriction and Exercise Increase Plasma ANGPTL4 Levels in Humans via Elevated Free Fatty Acids

    NARCIS (Netherlands)

    Kersten, A.H.; Lichtenstein, L.L.; Steenbergen, E.; Mudde, C.M.; Hendriks, H.F.J.; Hesselink, M.K.; Schrauwen, P.; Müller, M.R.

    2009-01-01

    Objective - Plasma lipoprotein levels are determined by the balance between lipoprotein production and clearance. Recently, angiopoietin-like protein 4 (ANGPTL4) was uncovered as a novel endocrine factor that potently raises plasma triglyceride levels by inhibiting triglyceride clearance. However,

  12. Caloric restriction and exercise increase plasma ANGPTL4 levels in humans via elevated free fatty acids.

    NARCIS (Netherlands)

    Kersten, S.; Lichtenstein, L.; Steenbergen, E.; Mudde, K.; Hendriks, H.F.; Hesselink, M.K.; Schrauwen, P.; Muller, M

    2009-01-01

    OBJECTIVE: Plasma lipoprotein levels are determined by the balance between lipoprotein production and clearance. Recently, angiopoietin-like protein 4 (ANGPTL4) was uncovered as a novel endocrine factor that potently raises plasma triglyceride levels by inhibiting triglyceride clearance. However,

  13. Caloric restriction and exercise increase plasma ANGPTL4 levels in humans via elevated free fatty acids

    NARCIS (Netherlands)

    Kersten, S.; Lichtenstein, L.; Steenbergen, E.; Mudde, K.; Hendriks, H.F.J.; Hesselink, M.K.; Schrauwen, P.; Müller, M.

    2009-01-01

    OBJECTIVE-: Plasma lipoprotein levels are determined by the balance between lipoprotein production and clearance. Recently, angiopoietin-like protein 4 (ANGPTL4) was uncovered as a novel endocrine factor that potently raises plasma triglyceride levels by inhibiting triglyceride clearance. However,

  14. Plasma testosterone levels in Alzheimer and Parkinson diseases.

    Science.gov (United States)

    Okun, M S; DeLong, M R; Hanfelt, J; Gearing, M; Levey, A

    2004-02-10

    Testosterone deficiency, a treatable condition commonly seen in aging men, has been linked to Parkinson disease (PD) and Alzheimer disease (AD). In normal subjects, low testosterone levels are associated with cognitive and neuropsychiatric symptoms, yet the relationship between testosterone levels and cognitive function in PD and AD remains unclear. To examine the relationship of testosterone levels to age and cognitive function in PD and AD. Plasma testosterone levels were determined in men enrolled in a clinical registry of subjects with PD and AD, and neuropsychological testing was performed on subjects who consented. Testosterone levels in men with PD were compared with those in men with AD. In both groups, the relationship between testosterone levels and neuropsychological test scores was analyzed, adjusting for age and education. Linear regression analysis revealed that testosterone levels decreased with age in male PD patients (p frontal lobe dysfunction in normal aged men, together with these results, suggest that the hormonal deficiency may act as a "second hit" to impair cognitive function in neurodegenerative disease.

  15. [Levels of plasma cholinesterase in Colombian working-class populations].

    Science.gov (United States)

    Carmona-Fonseca, Jaime

    2003-12-01

    Levels of plasma cholinesterase in Colombian working-class populations Reference values for plasma cholinesterase (EC 3.1.1.8) are not available for Colombian populations. A representative sample of a working-class population was used to establish these values to provide reference data for use by the social security system. Two working-class populations were sampled from the Aburrá Valley (Aburrá) and eastern Antioquia (Oriente). Cholinesterase activity was measured in 827 workers, with ages spanning 18-49 years, 415 from Aburrá and 412 people from Oriente. Three methods were used to measure cholinesterase: Michel, EQM and Monotest The average values by Michel and EQM were not statistically different between regions (Michel: Aburrá, 1.11, and East, 1.13 deltas pH/hora; EQM: Aburrá, 2.55, and Oriente, 2.48 U/ml). By the Monotest, the enzyme average was statistically higher in Aburra than in Oriente (5,743 and 5,459 U/L respectively; p = 0 .012). By region and technique, men had significantly higher enzymatic levels than women. Within both regions and sexes, no statistically significant difference among the three aged groups was noted. Our obtained Colombian values differed significantly from foreign reference values: Michel and Monotest levels were higher and EQM levels were lower. For making clinical and epidemiologic decisions in Colombia related to these data, the values obtained for the Colombian populations are preferred over values derived from external sources.

  16. Effects of exercise on plasma adiponectin levels in athletes

    Directory of Open Access Journals (Sweden)

    Popović Mirjana

    2016-01-01

    Full Text Available Adipose tissue is an endocrine organ which releases biologically active adipokines. Adiponectin, an adipocyte-derived protein structurally similar to complement 1q, plays a significant role in metabolic disorders, due to its insulin sensitizing, anti-inflammatory and anti-atherogenic properties. AdipoR1 and AdipoR2, mediate the metabolic actions of adiponectin by activating adenosine monophosphate-activated protein kinase (AMPK and peroxisome proliferator-activated receptors- alpha (PPAR-α which leads to an increase in fatty acid combustion and energy consumption, fatty acid oxidation and glucose uptake in myocytes and reduces gluconeogenesis and thus leads to increased insulin sensitivity. Plasma adiponectin level is affected by multiple factors: gender (females have higher plasma adiponectin levels, obesity-linked diseases (metabolic syndrome, diabetes mellitus type 2 and atherosclerosis are associated with lower adiponectin levels, lifestyle -including exercise. Yet, to date, little is known about the response of adiponectin concentrations to exercise and, in particular, the response of this hormone to training in population of athletes. The aim of this review is to overview the published evidence for the effects of exercise on adiponectin levels in athletes. Adiponectin concentration presents a delayed increase (30 min after short-term intense performance, by athletes, both male and female. It seems that adiponectin concentrations do not change in response to long-term exercise. No significant difference was found in total adiponectin and/or high-molecular weight (HMW oligomers in long-term effects of high physical training in athletes. Adiponectin can serve to monitor training loads and the establishment of individual limit values of training loads. Further studies are needed to clarify possible mechanisms by which adiponectin might influence energy homeostasis during heavy training in elite athletes.

  17. Plasma Glucose Level Is Predictive of Serum Ammonia Level After Retrograde Occlusion of Portosystemic Shunts.

    Science.gov (United States)

    Ishikawa, Tsuyoshi; Aibe, Yuki; Matsuda, Takashi; Iwamoto, Takuya; Takami, Taro; Sakaida, Isao

    2017-09-01

    The purpose of this study was to evaluate predictors of reduction in ammonia levels by occlusion of portosystemic shunts (PSS) in patients with cirrhosis. Forty-eight patients with cirrhosis (21 women, 27 men; mean age, 67.8 years) with PSS underwent balloon-occluded retrograde transvenous obliteration (BRTO) at one institution between February 2008 and June 2014. The causes of cirrhosis were hepatitis B in one case, hepatitis C in 20 cases, alcohol in 15 cases, nonalcoholic steatohepatitis in eight cases, and other conditions in four cases. The Child-Pugh classes were A in 24 cases, B in 23 cases, and C in one case. The indication for BRTO was gastric varices in 40 cases and hepatic encephalopathy in eight cases. Testing was conducted before and 1 month after the procedure. Statistical analyses were performed to identify predictors of a clinically significant decline in ammonia levels after BRTO. Occlusion of PSS resulted in a clinically significant decrease in ammonia levels accompanied by increased portal venous flow and improved Child-Pugh score. Univariate analyses showed that a reduction in ammonia levels due to BRTO was significantly related to lower plasma glucose levels, higher RBC counts, and higher hemoglobin concentration before the treatment. Furthermore, multivariate logistic regression identified preoperative plasma glucose level as the strongest independent predictor of a significant ammonia reduction in response to BRTO. In addition, although BRTO resulted in significantly declined ammonia levels in patients with normal glucose tolerance before the procedure, ammonia levels were not significantly decreased after shunt occlusion in patients with diabetes mellitus or impaired glucose tolerance before BRTO, according to 75-g oral glucose tolerance test results. Preoperative plasma glucose level is a useful predictor of clinically significant ammonia reduction resulting from occlusion of PSS in patients with cirrhosis. Even if PSS are present, control

  18. PLASMA CYTOKINES LEVELS IN PATIENTS UNDERGOING LONG-TERM HAEMODIALYSIS

    Directory of Open Access Journals (Sweden)

    D. S. Polyakov

    2011-01-01

    Full Text Available Аbstract.  Patients  with  end-stage  renal  disease  need  their  kidney  functions  to  be  replaced.  Chronic haemodialysis represents a most common method of such substitution treatment. This procedure results in successful survival of such patients for years. Chronic haemodialysis is accompanied by a complication which is known as β2-microglobulin amyloidosis. In this case, amyloid substance consisting of β2-microglobulin (β2-MG accumulates in bones, ligaments and joints. Biological causes of β2-MG amyloidosis are still not established. To elucidate the role of inflammation in the pathogenesis of β2-MG amyloidosis, the levels of  IL-2,  IL-4,  IL-6,  IL-8,  IL-10,  GM-CSF,  IFNγ, TNFα were quantified in plasma of patients undergoing  long-term haemodialysis. Mean amounts of all the mentioned cytokines in haemodialysis patients proved to be significantly higher than in control group consisting of healthy subjects. When comparing a group receiving standard  dialysis  procedure  versus  a  subgroup  receiving  haemodiafiltration,  a  single  reliable  difference  was revealed for GM-CSF levels (p < 0.04, without any differences shown for other cytokines. With increasing terms of chronic haemodialysis, the levels of IL-2, IL-4, IL-6, IL-8, GM-CSF, IFNγ, TNFα were increased, or, at least, they did not decrease. After three years of dialysis, IL-10 concentrations were statistically indistinguishable from normal levels. In patients undergoing haemodiafiltration, plasma levels of IL-2, IL-4, IL-8, GM-CSF, IFNγ, TNFα did not drop with increasing terms of dialysis. The levels of IL-6 and IL-10 decreased after three years of dialysis, to near-normal levels.In general, these results suggest that IL-10 and IL-6 may be regarded as candidates for further studies as potential markers of β2-microglobulin amyloidosis. (Med. Immunol., 2011, vol. 13, N 2-3, pp 211-218

  19. Multi-level molecular modelling for plasma medicine

    International Nuclear Information System (INIS)

    Bogaerts, Annemie; Khosravian, Narjes; Van der Paal, Jonas; Verlackt, Christof C W; Yusupov, Maksudbek; Kamaraj, Balu; Neyts, Erik C

    2016-01-01

    Modelling at the molecular or atomic scale can be very useful for obtaining a better insight in plasma medicine. This paper gives an overview of different atomic/molecular scale modelling approaches that can be used to study the direct interaction of plasma species with biomolecules or the consequences of these interactions for the biomolecules on a somewhat longer time-scale. These approaches include density functional theory (DFT), density functional based tight binding (DFTB), classical reactive and non-reactive molecular dynamics (MD) and united-atom or coarse-grained MD, as well as hybrid quantum mechanics/molecular mechanics (QM/MM) methods. Specific examples will be given for three important types of biomolecules, present in human cells, i.e. proteins, DNA and phospholipids found in the cell membrane. The results show that each of these modelling approaches has its specific strengths and limitations, and is particularly useful for certain applications. A multi-level approach is therefore most suitable for obtaining a global picture of the plasma–biomolecule interactions. (paper)

  20. Antibacterial plasma at safe levels for skin cells

    NARCIS (Netherlands)

    Boekema, B.K.H.L.; Hofmann, S.; van Ham, B.T.J.; Bruggeman, P.J.; Middelkoop, E.

    2013-01-01

    Plasmas produce various reactive species, which are known to be very effective in killing bacteria. Plasma conditions, at which efficient bacterial inactivation is observed, are often not compatible with leaving human cells unharmed. The purpose of this study was to determine plasma settings for

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

    DEFF Research Database (Denmark)

    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...

  2. Both hypothyroidism and hyperthyroidism increase plasma irisin levels in rats.

    Science.gov (United States)

    Atici, Emine; Mogulkoc, Rasim; Baltaci, Abdulkerim Kasim; Menevse, Esma

    2017-11-28

    Background A recently discovered hormone, irisin is accepted to be significantly involved in the regulation of body weight. Thyroid functions may be, directly or indirectly, associated with irisin. Aim The aim of the present study is to determine the effect of experimental thyroid dysfunction on irisin levels in rats. Methods The study registered 40 adult male Sprague-Dawley rats, which were allocated to groups as follows: 1. Control; 2. Hypothyroidism induced by injection of 10 mg/kg/day intraperitoneal propylthiouracil (PTU) for 3 weeks; 3. Hypothyroidism (PTU 2 weeks) + L-thyroxin (1.5 mg/kg/day for 1 week); 4. Hyperthyroidism induced in rats by 3-week thyroxin (0.3 mg/kg/day); 5. Hyperthyroidism + PTU. At the end of the study, blood samples were collected to quantify free triiodothyronine (FT3), free triiodothyronine (FT4) and irisin levels. Results FT3 and FT4 levels were reduced in hypothyroidism and were significantly elevated in hyperthyroidism (p hyperthyroidism groups (p hyperthyroidism, and that when hypothyroidism is corrected by thyroxin administration and hyperthyroidism by PTU injection, plasma irisin values go back to normal.

  3. Plasma levels of 8-methoxypsoralen following PUVA-bath photochemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Kobyletzki, G. von; Hoffmann, K.; Kerscher, M.; Altmeyer, P. [Ruhr-Univ., Dept. of Dermatology, Bochum (Germany)

    1998-08-01

    Administration of 8-methoxypsoralen (8-MOP) in a dilute bath water solution is an effective therapeutic alternative to oral PUVA therapy, avoiding systemic side effects, offering better bioavailability of the psoralen and requiring much smaller amounts of UVA for induction of therapeutic effects. To obtain exact data about the percutaneous absorption of 8-MOP during a psoralen bath, the plasma levels of the drug were determined in 26 patients with different skin diseases by a reverse high-performance liquid chromatographic method. Fifteen patients receiving oral PUVA therapy (0.8 mg 8-MOP/kg body weight) served as a positive control group. Bath solutions were prepared by diluting 15 ml of 0.5% stock solution of 8-MOP in 150 l of bath water (0.5 mg/l, 37 deg. C). Blood samples were drawn from patients 5, 30, 60, 120 and 180 min after the bath. In the oral PUVA group, blood samples were obtained 1 1/2 h after administration of the drug. In 23 og 26 patients, 8-MOP levels were undetectable in every blood sample. After 30 min, two patients showed detectable levels of 8-MOP (5 ng/ml, 7 ng/ml), while 60 min after the PUVA bath 8-MOP was detectable in only one volunteer (5 ng/ml). In patients receiving oral 8-MOP therapy, serum levels varied between 45 and 360 ng/ml 1 1/2 h after drug administration. Our data confirm extremely low 8-MOP levels resulting from 8-MOP bath water treatments and provide confirmation of the absence of systemic side effects in patients who are undergoing PUVA-bath therapy. (au) 15 refs.

  4. Plasma levels of 8-methoxypsoralen following PUVA-bath photochemotherapy

    International Nuclear Information System (INIS)

    Kobyletzki, G. von; Hoffmann, K.; Kerscher, M.; Altmeyer, P.

    1998-01-01

    Administration of 8-methoxypsoralen (8-MOP) in a dilute bath water solution is an effective therapeutic alternative to oral PUVA therapy, avoiding systemic side effects, offering better bioavailability of the psoralen and requiring much smaller amounts of UVA for induction of therapeutic effects. To obtain exact data about the percutaneous absorption of 8-MOP during a psoralen bath, the plasma levels of the drug were determined in 26 patients with different skin diseases by a reverse high-performance liquid chromatographic method. Fifteen patients receiving oral PUVA therapy (0.8 mg 8-MOP/kg body weight) served as a positive control group. Bath solutions were prepared by diluting 15 ml of 0.5% stock solution of 8-MOP in 150 l of bath water (0.5 mg/l, 37 deg. C). Blood samples were drawn from patients 5, 30, 60, 120 and 180 min after the bath. In the oral PUVA group, blood samples were obtained 1 1/2 h after administration of the drug. In 23 og 26 patients, 8-MOP levels were undetectable in every blood sample. After 30 min, two patients showed detectable levels of 8-MOP (5 ng/ml, 7 ng/ml), while 60 min after the PUVA bath 8-MOP was detectable in only one volunteer (5 ng/ml). In patients receiving oral 8-MOP therapy, serum levels varied between 45 and 360 ng/ml 1 1/2 h after drug administration. Our data confirm extremely low 8-MOP levels resulting from 8-MOP bath water treatments and provide confirmation of the absence of systemic side effects in patients who are undergoing PUVA-bath therapy. (au)

  5. Association of plasma fatty acid composition with plasma irisin levels in normal weight and overweight/obese children.

    Science.gov (United States)

    Viitasalo, A; Ågren, J; Venäläinen, T; Pihlajamäki, J; Jääskeläinen, J; Korkmaz, A; Atalay, M; Lakka, T A

    2016-08-01

    Irisin has been suggested to protect against overweight. There are no previous data on the association of plasma fatty acid (FA) composition with plasma irisin. We studied the association of FA composition with plasma irisin in normal weight and overweight/obese children. This cross-sectional study included pre-pubertal children (388 normal weight children and 55 overweight/obese children); 6-9 years of age, taking part in the Physical Activity and Nutrition in Children Study. After an overnight fast, we measured plasma FA composition by gas chromatography and plasma irisin levels by enzyme-linked immunosorbent assay. Higher proportion of total monounsaturated fatty acids in plasma cholesteryl esters (CEs) (β = 0.139, P = 0.003) and phospholipids (PLs) (β = 0.147, P = 0.002) and lower proportion of total polyunsaturated fatty acids in plasma CE (β = -0.130, P = 0.006) and PL (β = -0.165, P overweight/obese children compared to normal weight children. Higher proportion of γ-linolenic acid (β = 0.324, P = 0.017) and lower proportion of linoleic acid (β = -0.397, P = 0.005) in plasma CE were related to higher plasma irisin level among overweight/obese children, indicating the direct association of estimated D6D activity in plasma CE (β = 0.343, P = 0.011) with plasma irisin. Furthermore, higher proportion of oleic acid in plasma CE (β = 0.345, P = 0.012) and PL (β = 0.292, P = 0.033) and higher proportion of adrenic acid (β = 0.366, P = 0.008) and docosapentaenoic acid (β = 0.351, P = 0.010) in plasma PL were associated with higher plasma irisin level among overweight/obese children. Metabolically unfavourable plasma FA profile was associated with higher plasma irisin level especially in overweight/obese children, suggesting that excess body fat might modulate these relationships. © 2015 World Obesity.

  6. Nonlinear associations between plasma cholesterol levels and neuropsychological function.

    Science.gov (United States)

    Wendell, Carrington R; Zonderman, Alan B; Katzel, Leslie I; Rosenberger, William F; Plamadeala, Victoria V; Hosey, Megan M; Waldstein, Shari R

    2016-11-01

    Although both high and low levels of total and low-density lipoprotein (LDL) cholesterol have been associated with poor neuropsychological function, little research has examined nonlinear effects. We examined quadratic relations of cholesterol to performance on a comprehensive neuropsychological battery. Participants were 190 older adults (53% men, ages 54-83) free of major medical, neurologic, and psychiatric disease. Measures of fasting plasma total and high-density lipoprotein (HDL) cholesterol were assayed, and LDL cholesterol was calculated. Participants completed neuropsychological measures of attention, executive function, memory, visuospatial judgment, and manual speed and dexterity. Multiple regression analyses examined cholesterol levels as quadratic predictors of each measure of cognitive performance, with age (dichotomized as Reproduction II ( b = -.0020, p = .026) and log of the Trail Making Test, Part B (b = .0001, p = .044). Quadratic associations between HDL cholesterol and cognitive performance were nonsignificant. Results indicate differential associations between cholesterol and neuropsychological function across different ages and domains of function. High and low total and LDL cholesterol may confer both risk and benefit for suboptimal cognitive function at different ages. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  7. Effect of carvedilol treatment on plasma neuropeptides levels in patients with essential hypertension

    International Nuclear Information System (INIS)

    Li Qian; Cheng Guanghua; Yang Jian

    2008-01-01

    Objective: To study the changes of plasma neuropeptide Y(NPY) and neurotension (NT) levels in patients with essential hypertension after treatment with carvedilol. Methods: Blood pressure and plasma NPY and NT concentrations (with RIA) were measured in 56 patients with essential hypertension both before and after carvedilol therapy (5-10 mg bid) for 3 months as well as 30 controls. Results: Before treatment plasma NPY levels were significantly higher in hypertensive patients than those in controls (P<0.01), but plasma NT levels were significantly lower (P also <0.01). After carvedilol treatment, blood pressure and plasma NPY levels were reduced significantly and plasma NT levels were increased significantly. Conclusion: Treatment with carvedilol results in the correction of plasma concentrations of NPY and NT in patients with essential hypertension, the effect may be related to blood pressure decrease. (authors)

  8. Clinical significance of measurement of plasma homocysteine (Hcy) levels in patients with hepatic cirrhosis

    International Nuclear Information System (INIS)

    Wu Jiaming

    2006-01-01

    Objective: To investigate the correlationship between the plasma homocysteine (Hcy) levels and development of hepatic cirrhosis as well as the diagnostic value of plasma Hcy determination. Method: Plasma Hcy levels were measured with ELISA in: (1) 64 patients with post-hepatitis cirrhosis (2) 42 patients with various types of hepatitis but no cirrhosis and (3) 60 controls. Results: The plasma levels of Hcy in patients with cirrhosis were significantly higher than those in the other two groups (P<0.01). The plasma Hcy levels in cirrhotic patients were well correlated with the levels of other hepatic fibrosis markers such as hyaluronic acid and laminin (r=0.87 and r=0.88 respectively, P<0.01), but were not correlated with cholesterol, triglyceride and HDL levels. Conclusion: Plasma Hcy levels was markedly elevated in cirrhotic patients and might be taken as a diagnostic marker. (authors)

  9. S1P/S1PR3 signaling mediated proliferation of pericytes via Ras/pERK pathway and CAY10444 had beneficial effects on spinal cord injury.

    Science.gov (United States)

    Tang, Hai-Bin; Jiang, Xiao-Jian; Wang, Chen; Liu, Shi-Chang

    2018-04-15

    Pericytes have long been regarded merely to maintain structural and functional integrity of blood-brain barrier (BBB). Nevertheless, it has also been identified as a component of scar-forming stromal cells after spinal cord injury (SCI). In process of enlargement of spinal cavity after SCI, the number of pericytes increased and outnumbered astrocytes. However, the mechanism of proliferation of pericytes remains unclear. Sphingosine-1-phosphate (S1P) has been reported to play important roles in the formation of glia scar, but previous studies had paid more attention to the astrocytes. The present study aimed to observe the effects of S1P and S1P receptors (S1PRs) on proliferation of pericytes and investigate the underlying mechanism. By double immunostaining, we found that the number of PDGFRβ-positive pericytes was gradually increased and sealed the cavity, which surrounded by reactive astrocytes. Moreover, the subtype of S1PR3 was found to be induced by SCI and mainly expressed on pericytes. Further, by use of CAY10444, an inhibitor of S1PR3, we showed that S1P/S1PR3 mediated the proliferation of pericytes through Ras/pERK pathway. Moreover, CAY10444 was found to have the effects of enhancing neuronal survival, alleviating glial scar formation, and improving locomotion recovery after SCI. The results suggested that S1P/S1PR3 might be a promising target for clinical therapy for SCI. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Decrease in plasma high-density lipoprotein cholesterol levels at puberty in boys with delayed adolescence: correlation with plasma testosterone levels

    International Nuclear Information System (INIS)

    Kirkland, R.T.; Keenan, B.S.; Probstfield, J.L.; Patsch, W.; Lin, T.L.; Clayton, G.W.; Insull, W. Jr.

    1987-01-01

    A three-phase study tested the hypothesis that the decrease in the high-density lipoprotein cholesterol (HDL-C) level observed in boys at puberty is related to an increase in the plasma testosterone concentration. In phase I, 57 boys aged 10 to 17 years were categorized into four pubertal stages based on clinical parameters and plasma testosterone levels. These four groups showed increasing plasma testosterone values and decreasing HDL-C levels. In phase II, 14 boys with delayed adolescence were treated with testosterone enanthate. Plasma testosterone levels during therapy were in the adult male range. Levels of HDL-C decreased by a mean of 7.4 mg/dL (0.20 mmol/L) and 13.7 mg/dL (0.35 mmol/L), respectively, after the first two doses. In phase III, 13 boys with delayed adolescence demonstrated increasing plasma testosterone levels and decreasing HDL-C levels during spontaneous puberty. Levels of HDL-C and apolipoprotein A-1 were correlated during induced and spontaneous puberty. Testosterone should be considered a significant determinant of plasma HDL-C levels during pubertal development

  11. Plasma Etching of Tapered Features in Silicon for MEMS and Wafer Level Packaging Applications

    International Nuclear Information System (INIS)

    Ngo, H-D; Hiess, Andre; Seidemann, Volker; Studzinski, Daniel; Lange, Martin; Leib, Juergen; Shariff, Dzafir; Ashraf, Huma; Steel, Mike; Atabo, Lilian; Reast, Jon

    2006-01-01

    This paper is a brief report of plasma etching as applied to pattern transfer in silicon. It will focus more on concept overview and strategies for etching of tapered features of interest for MEMS and Wafer Level Packaging (WLP). The basis of plasma etching, the dry etching technique, is explained and plasma configurations are described elsewhere. An important feature of plasma etching is the possibility to achieve etch anisotropy. The plasma etch process is extremely sensitive to many variables such as mask material, mask openings and more important the plasma parameters

  12. Plasma levels of immunosuppressive mediators during cardiopulmonary bypass

    Directory of Open Access Journals (Sweden)

    E. Borrelli

    1996-01-01

    Full Text Available The aim of this study was to evaluate plasma levels of two mediators with immunosuppressive properties, complement fraction C3a (C3a and transforming growth factor-β1 (TGF-β1, during extracorporeal circulation. The proliferation index after phytohaemagglutinin (PHA stimulation of isolated peripheral blood mononuclear cells was also investigated. Sixteen patients undergoing hypothermic (n = 8, group 1 and normothermic (n = 8, group 2 cardiopulmormry bypass (CPB were enrolled in this study. As a control, we evaluated four patients undergoing thoracovascular operations without CPB. Blood samples were collected before CPB but after anaesthesia, every 30 min during CPB, at the end of CPB and 10 min after protamine administration. Both C3a and TGF-β1 increased significantly during CPB and after protamine administration in the hypothermic as well as the normothermic group. In the latter case the increase of C3a and TGF-β1, although more prominent, was not significantl higher than in the former group. Conversely, the proliferation, index of peripheral mononuclear cells had already decreased 30 min after CPB was started and remained depressed throughout the CPB time. These results suggest a possible role of C3a and TGF-β1 in the immunological changes occurring during extracorporeal circulation.

  13. Differences in Plasma Cytokine Levels between Elite Kayakers and Nonathletes

    Directory of Open Access Journals (Sweden)

    G. F. Borges

    2013-01-01

    Full Text Available Regular moderate exercise has been shown to have anti-inflammatory effects that help prevent several chronic diseases. However, the effects of chronic training an elite athletes have not been the focus of much research. This study aimed to determine whether there were differences in cytokine levels (IL-1β, IL-1ra, IL-6, IL-10, IL-18, IFN-γ, and TNF-α in circulating peripheral blood (PB between elite kayakers and nonathletes. Subjects were 13 elite male kayakers, aged 20.0±3 years, with average body mass of 75.0±7.9 kg and 177.3±7.1 cm height and with a VO2max of 58.3±7.8 mL·kg−1·min−1. The nonathletes were 7 men, aged 18.2±1.1 years, body mass of 81.3±13.8 kg, and 171.9±4.5 cm height. Blood samples were collected after six weeks of offtraining and before the start of a new training season. PB leukocyte populations were determined by flow cytometry. Cytokine levels were quantified by ELISA. When nonathletes were compared with the kayakers, the latter exhibited lower plasma concentrations of IL-1β, IL-18, and IFN-γ as well as a lower concentration of IL-1ra. Positive correlations between IL-18 and B cells in the athletes were also found. These results seem to reinforce the anti-inflammatory role of regular training.

  14. Differences in plasma cytokine levels between elite kayakers and nonathletes.

    Science.gov (United States)

    Borges, G F; Rama, L; Pedreiro, S; Alves, F; Santos, A; Massart, A; Paiva, A; Teixeira, A M

    2013-01-01

    Regular moderate exercise has been shown to have anti-inflammatory effects that help prevent several chronic diseases. However, the effects of chronic training an elite athletes have not been the focus of much research. This study aimed to determine whether there were differences in cytokine levels (IL-1 β , IL-1ra, IL-6, IL-10, IL-18, IFN- γ , and TNF- α ) in circulating peripheral blood (PB) between elite kayakers and nonathletes. Subjects were 13 elite male kayakers, aged 20.0 ± 3 years, with average body mass of 75.0 ± 7.9 kg and 177.3 ± 7.1 cm height and with a VO2max of 58.3 ± 7.8 mL·kg(-1)·min(-1). The nonathletes were 7 men, aged 18.2 ± 1.1 years, body mass of 81.3 ± 13.8 kg, and 171.9 ± 4.5 cm height. Blood samples were collected after six weeks of offtraining and before the start of a new training season. PB leukocyte populations were determined by flow cytometry. Cytokine levels were quantified by ELISA. When nonathletes were compared with the kayakers, the latter exhibited lower plasma concentrations of IL-1 β , IL-18, and IFN- γ as well as a lower concentration of IL-1ra. Positive correlations between IL-18 and B cells in the athletes were also found. These results seem to reinforce the anti-inflammatory role of regular training.

  15. Plasma Lactate Dehydrogenase Levels Predict Mortality in Acute Aortic Syndromes

    Science.gov (United States)

    Morello, Fulvio; Ravetti, Anna; Nazerian, Peiman; Liedl, Giovanni; Veglio, Maria Grazia; Battista, Stefania; Vanni, Simone; Pivetta, Emanuele; Montrucchio, Giuseppe; Mengozzi, Giulio; Rinaldi, Mauro; Moiraghi, Corrado; Lupia, Enrico

    2016-01-01

    Abstract In acute aortic syndromes (AAS), organ malperfusion represents a key event impacting both on diagnosis and outcome. Increased levels of plasma lactate dehydrogenase (LDH), a biomarker of malperfusion, have been reported in AAS, but the performance of LDH for the diagnosis of AAS and the relation of LDH with outcome in AAS have not been evaluated so far. This was a bi-centric prospective diagnostic accuracy study and a cohort outcome study. From 2008 to 2014, patients from 2 Emergency Departments suspected of having AAS underwent LDH assay at presentation. A final diagnosis was obtained by aortic imaging. Patients diagnosed with AAS were followed-up for in-hospital mortality. One thousand five hundred seventy-eight consecutive patients were clinically eligible, and 999 patients were included in the study. The final diagnosis was AAS in 201 (20.1%) patients. Median LDH was 424 U/L (interquartile range [IQR] 367–557) in patients with AAS and 383 U/L (IQR 331–460) in patients with alternative diagnoses (P < 0.001). Using a cutoff of 450 U/L, the sensitivity of LDH for AAS was 44% (95% confidence interval [CI] 37–51) and the specificity was 73% (95% CI 69–76). Overall in-hospital mortality for AAS was 23.8%. Mortality was 32.6% in patients with LDH ≥ 450 U/L and 16.8% in patients with LDH < 450 U/L (P = 0.006). Following stratification according to LDH quartiles, in-hospital mortality was 12% in the first (lowest) quartile, 18.4% in the second quartile, 23.5% in the third quartile, and 38% in the fourth (highest) quartile (P = 0.01). LDH ≥ 450 U/L was further identified as an independent predictor of death in AAS both in univariate and in stepwise logistic regression analyses (odds ratio 2.28, 95% CI 1.11–4.66; P = 0.025), in addition to well-established risk markers such as advanced age and hypotension. Subgroup analysis showed excess mortality in association with LDH ≥ 450 U/L in elderly, hemodynamically stable

  16. Plasma levels and symptom complaints in patients maintained on daily dosage of methadone hydrochloride.

    Science.gov (United States)

    Horns, W H; Rado, M; Goldstein, A

    1975-06-01

    Plasma methadone levels, symptom complaints, and urine tests for illicit opiate use were followed weekly in 17 patients on a methadone maintenance program. There were very large differences between patients in the plasma level established at a given dosage, implying large differences in the rate of methadone metabolism. Despite virtually constant daily dosage, the plasma methadone levels fluctuated greatly from week to week and from day to day in individual patients. With rate exceptions there was no relationship between plasma methadone level and symptom complaints or between weekly chamges in plasma methadone level and changes in symptom complaints. Except possible to identify the ocassional patient with unusually low plasam methadone levels, the determination of methadone levels is not likely to be or practical value in methadone programs.

  17. Clinical significance of changes of plasma ET and NPY levels after treatment in patients with AMI

    International Nuclear Information System (INIS)

    Zhou Jinbao

    2005-01-01

    Objective: To investigate the changes of plasma ET and NPY levels in patients with AMI. Methods: Plasma ET and NPY levels were dynamically determined in 36 patients with AMI right after establishment of diagnosis and 8h, 24h, 4ph, 72h, 7d, 14d later. Levels in 35 healthy individuals were taken as control. Results: Before treatment was initiated, the levels of Et and Np in patients with AMI were significantly higher than those in controls (P <0.01). After one week of treatment, the levels dropped toward normal. Conclusion: Dynamic measurement of plasma ET and NPY levels in patients with AMI is of clinical importance. (authors)

  18. 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.

    Science.gov (United States)

    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.

  19. Dynamic changes of plasma acylcarnitine levels induced by fasting and sunflower oil challenge test in children

    NARCIS (Netherlands)

    Costa, C. C.; de Almeida, I. T.; Jakobs, C.; Poll-The, B. T.; Duran, M.

    1999-01-01

    The dynamic changes of plasma acylcarnitine levels in 1- to 7-y-old children during fasting and after the ingestion of sunflower oil were studied. Glucose, 3-hydroxybutyrate, acetoacetate, FFA, and individual plasma acylcarnitine levels were monitored in both conditions. Fasting experiments lasted

  20. Plasma cortisol and metabolite level profiles in two isogenic strains of common carp during confinement

    NARCIS (Netherlands)

    Ruane, N.M.; Huisman, E.A.; Komen, J.

    2001-01-01

    A rapid increase in common carp Cyprinus carpio plasma cortisol levels was noted, in two experiments, after 30 mins of a 3 h net confinement, which was sustained while the fish were held in the nets. After release from the nets, cortisol levels returned to control values in 1 h. Plasma glucose and

  1. Modulation of plasma fibrinogen levels by ciprofibrate and gemfibrozil in primary hyperlipidaemia

    NARCIS (Netherlands)

    de Maat, M. P.; Knipscheer, H. C.; Kastelein, J. J.; Kluft, C.

    1997-01-01

    An elevated plasma fibrinogen level is increasingly accepted as an independent risk indicator of cardiovascular disease. This has enhanced the interest in identifying agents that can normalize elevated plasma fibrinogen levels. One group of agents with this capacity are the fibric acid derivatives,

  2. 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...

  3. The antimicrobial propeptide hCAP-18 plasma levels in neutropenia of various aetiologies

    DEFF Research Database (Denmark)

    Ye, Ying; Carlsson, Göran; Karlsson-Sjöberg, Jenny M T

    2015-01-01

    The underlying cause of neutropenia may be difficult to determine due to similar clinical presentation in many neutropenic conditions. The neutrophil protein hCAP-18 (pro-LL-37) is a major component of neutrophil secondary granules and in this prospective study we assessed the use of hCAP-18 levels...... in blood plasma for differential diagnosis of neutropenic patients (n = 133) of various aetiologies. Plasma levels of hCAP-18 were determined using immunoblot and ELISA. Patients with severe congenital neutropenia (n = 23) presented with the lowest levels of plasma hCAP-18 and differential diagnostic...... diagnostic value in differential diagnosis of chronic neutropenia. Neutropenic patients with Shwachman-Diamond syndrome, Barth syndrome, Cohen syndrome, acute myeloid leukaemia and specific granule deficiency presented with reduced plasma hCAP-18 levels as well. The blood plasma level of hCAP-18 was thus low...

  4. Study of plasma amino acid levels in children with autism: An Egyptian sample

    Directory of Open Access Journals (Sweden)

    Farida M. ElBaz

    2014-04-01

    Conclusions: Autistic children had lower levels of some plasma amino acids except for glycine and glutamic acids and phosphoserine were increased with normal serum levels of urea, ammonia, total proteins, albumin and globulins (alpha 1, alpha 2, beta and gamma.

  5. Changes in Plasma Copeptin Levels during Hemodialysis : Are the Physiological Stimuli Active in Hemodialysis Patients?

    NARCIS (Netherlands)

    Ettema, Esmee M.; Kuipers, Johanna; Assa, Solmaz; Bakker, Stephan J. L.; Groen, Henk; Westerhuis, Ralf; Gaillard, Carlo A. J. M.; Gansevoort, Ron T.; Franssen, Casper F. M.

    2015-01-01

    Objectives Plasma levels of copeptin, a surrogate marker for the vasoconstrictor hormone arginine vasopressin (AVP), are increased in hemodialysis patients. Presently, it is unknown what drives copeptin levels in hemodialysis patients. We investigated whether the established physiological stimuli

  6. Plasma serotonin level is a predictor for recurrence and poor prognosis in colorectal cancer patients.

    Science.gov (United States)

    Xia, Yan; Wang, Dawei; Zhang, Nan; Wang, Zhihao; Pang, Li

    2018-02-01

    To investigate the prognostic value of plasma serotonin levels in colorectal cancer (CRC). Preoperative plasma serotonin levels of 150 healthy control (HC) cases, 150 benign colorectal polyp (BCP) cases, and 176 CRC cases were determined using radioimmunoassay assay. Serotonin levels were compared between HC, BCP, and CRC cases, and those in CRC patients were related to 5-year outcome. Plasma serotonin levels were markedly higher in CRC patients than in either HCs or BCP cases. An elevated serotonin level was significantly associated with advanced tumor node metastasis. Receiver operating characteristic curve analysis showed that the level of serotonin had a high predictive value for disease recurrence and mortality. Multivariate analysis revealed that high serotonin level was significantly associated with poor recurrence-free survival and overall survival. Our results suggest that a high peri-operative plasma serotonin level is useful as a prognostic biomarker for CRC recurrence and poor survival. © 2017 Wiley Periodicals, Inc.

  7. HLA-G levels in serum and plasma

    Czech Academy of Sciences Publication Activity Database

    Rudstein-Svetlicky, N.; Loewenthal, R.; Hořejší, Václav; Gazit, E.

    2007-01-01

    Roč. 69, č. 1 (2007), s. 140-142 ISSN 0001-2815 Institutional research plan: CEZ:AV0Z50520514 Keywords : HLA-G * serum * plasma Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.245, year: 2007

  8. Plasma cholesterol and related lipid levels of seemingly healthy ...

    African Journals Online (AJOL)

    The purpose of this study was achieved through analysis of fasting plasma samples for the following: Total cholesterol (TC), Triacylglycerols (TG), High density lipoprotein cholesterol (HDL), Low density lipoprotein cholesterol (LDL), and molar ratios of LDL/HDL, TC/ HDL, and TC/TG. Methods: One hundred and seventy four ...

  9. Plasma Ascorbic Acid and Non-Enzymatic Antioxidants Level in ...

    African Journals Online (AJOL)

    Free radicals have been implicated in the pathology of several diseases including cataract. Ascorbic acid functions as the major chain breaking antioxidant vitamin in the aqueous phase. Bilirubin, albumin and uric acid are regarded as natural antioxidants. There are conflicting reports on plasma concentrations of these ...

  10. Exercise increases sphingoid base-1-phosphate levels in human blood and skeletal muscle in a time- and intensity-dependent manner

    DEFF Research Database (Denmark)

    Baranowski, Marcin; Błachnio-Zabielska, Agnieszka U; Charmas, Małgorzata

    2015-01-01

    PURPOSE: Sphingosine-1-phosphate (S1P) regulates cardiovascular function and plays an important role in muscle biology. We have previously reported that cycling exercise increased plasma S1P. Here, we investigated the effect of exercise duration and intensity on plasma and skeletal muscle S1P lev...

  11. 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...

  12. Plasma oxalate levels in prevalent hemodialysis patients and potential implications for ascorbic acid supplementation.

    Science.gov (United States)

    Liu, Yuguan; Weisberg, Lawrence S; Langman, Craig B; Logan, Amanda; Hunter, Krystal; Prasad, Deepali; Avila, Jose; Venkatchalam, Thaliga; Berns, Jeffrey S; Handelman, Garry J; Sirover, William D

    2016-10-01

    Ascorbic acid (AA) supplementation may increase hemoglobin levels and decrease erythropoiesis-stimulating agent dose requirement in patients with end stage renal disease (ESRD). While plasma AA levels >100μM may be supratherapeutic, levels of at least 30μM may be needed to improve wound healing and levels may need to reach 70μM to optimize erythropoiesis. Of concern, oxalate (Ox), an AA metabolite, can accumulate in ESRD. Historically, if plasma Ox levels remain ≥30μM, oxalosis was of concern. Contemporary hemodialysis (HD) efficiencies may decrease the risk of oxalosis by maintaining pre-HD Ox levels HD patients. A prospective, observational study of 197 HD patients with pre-HD AA levels and pre-HD and post-HD Ox levels. Mean plasma Ox levels decreased 71% during the intradialytic period (22.3±11.1μM to 6.4±3.2μM, PHD plasma AA levels ≤100μM were not associated with a pre-HD plasma Ox level≥30μM, even if ferritin levels were increased. Pre-HD plasma Ox levels ≥20 or ≥30μM were not associated with lower cumulative 4-year survival. Pre-HD plasma AA levels up to 100μM in HD patients do not appear to be associated with an increased risk of developing secondary oxalosis, as the corresponding pre-HD plasma Ox level appears to be maintained at tolerable levels. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  13. The observation on plasma endothelin levels in patients with graves' disease

    International Nuclear Information System (INIS)

    Hao Xiaojun; Liu Changshan; Yang Lianrong; Zhang Qiliang; Wang Honggang; Liu Xudong

    2002-01-01

    Observing the plasma endothelin levels in patients with Graves' disease to probe its clinical significance, plasma endothelin levels were measured in 55 cases of Graves' disease before and after treatment respectively, and these were compared with that of 23 health subjects. Results: plasma endothelin levels in patients with Graves' disease significantly increase, compared with heath subjects (150.4 +- 29.31 ng/L vs 42.80 +- 7.58 ng/L, P < 0.01); post-treatment endothelin levels apparently decrease (97.61 +- 15.99 ng/L vs 150.4 +- 29.31 ng/L, P < 0.01). Plasma endothelin levels in patients with Graves' disease significantly increase, and after treatment the endothelin levels decrease following decreasing of thyroid hormone level and high hemodynamics

  14. Krill protein hydrolysate reduces plasma triacylglycerol level with concurrent increase in plasma bile acid level and hepatic fatty acid catabolism in high-fat fed mice

    Directory of Open Access Journals (Sweden)

    Marie S. Ramsvik

    2013-11-01

    Full Text Available Background: Krill powder, consisting of both lipids and proteins, has been reported to modulate hepatic lipid catabolism in animals. Fish protein hydrolysate diets have also been reported to affect lipid metabolism and to elevate bile acid (BA level in plasma. BA interacts with a number of nuclear receptors and thus affects a variety of signaling pathways, including very low density lipoprotein (VLDL secretion. The aim of the present study was to investigate whether a krill protein hydrolysate (KPH could affect lipid and BA metabolism in mice. Method: C57BL/6 mice were fed a high-fat (21%, w/w diet containing 20% crude protein (w/w as casein (control group or KPH for 6 weeks. Lipids and fatty acid composition were measured from plasma, enzyme activity and gene expression were analyzed from liver samples, and BA was measured from plasma. Results: The effect of dietary treatment with KPH resulted in reduced levels of plasma triacylglycerols (TAG and non-esterified fatty acids (NEFAs. The KPH treated mice had also a marked increased plasma BA concentration. The increased plasma BA level was associated with induction of genes related to membrane canalicular exporter proteins (Abcc2, Abcb4 and to BA exporters to blood (Abcc3 and Abcc4. Of note, we observed a 2-fold increased nuclear farnesoid X receptor (Fxr mRNA levels in the liver of mice fed KPH. We also observed increased activity of the nuclear peroxiosme proliferator-activated receptor alpha (PPARα target gene carnitine plamitoyltransferase 2 (CPT-2. Conclusion: The KPH diet showed to influence lipid and BA metabolism in high-fat fed mice. Moreover, increased mitochondrial fatty acid oxidation and elevation of BA concentration may regulate the plasma level of TAGs and NEFAs.

  15. Multi-Level iterative methods in computational plasma physics

    International Nuclear Information System (INIS)

    Knoll, D.A.; Barnes, D.C.; Brackbill, J.U.; Chacon, L.; Lapenta, G.

    1999-01-01

    Plasma physics phenomena occur on a wide range of spatial scales and on a wide range of time scales. When attempting to model plasma physics problems numerically the authors are inevitably faced with the need for both fine spatial resolution (fine grids) and implicit time integration methods. Fine grids can tax the efficiency of iterative methods and large time steps can challenge the robustness of iterative methods. To meet these challenges they are developing a hybrid approach where multigrid methods are used as preconditioners to Krylov subspace based iterative methods such as conjugate gradients or GMRES. For nonlinear problems they apply multigrid preconditioning to a matrix-few Newton-GMRES method. Results are presented for application of these multilevel iterative methods to the field solves in implicit moment method PIC, multidimensional nonlinear Fokker-Planck problems, and their initial efforts in particle MHD

  16. Clinical significance of the changes of plasma cortisol levels in patients with acute cerebral hemorrhage

    International Nuclear Information System (INIS)

    Wu Zhiqiang

    2005-01-01

    Objective: To explore the changes of plasma cortisol levels in patients with acute cerebral hemorrhage. Methods: Plasma cortisol levels were measured with RIA at 24:00 and 8:00 right after admission in 68 patients with acute cerebral hemorrhage and the tests were repeated in 61 patients one week later 40 controls entered this study. Results: The plasma cortisol levels were significantly higher in the patients than the corresponding readings in controls (P<0.001) with obliteration of the normal diurnal rhythm of secretion. The increase of the cortisol levels was positively correlated with the severity of the disease. As the condition of the patients improved, the cortisol levels dropped gradually. Conclusion: The plasma cortisol levels in patients with acute cerebral hemorrhage were closely related to the severity of the disease and were of prognostic value. (authors)

  17. Immunoglobulin G levels during collection of large volume plasma for fractionation.

    Science.gov (United States)

    Burkhardt, Thomas; Rothe, Remo; Moog, Rainer

    2017-06-01

    There is a need of comprehensive work dealing with the quality of plasma for fractionation with respect to the IgG content as today most plasma derivates are used to treat patients with immunodeficiencies and autoimmune disorders. Therefore, a prospective study was carried out to analyse IgG levels before plasmapheresis and every 200ml collected plasma. Fifty-four experienced plasmapheresis donors were recruited for subsequent 850ml plasmapheresis using the Aurora Plasmapheresis System. Donorś peripheral blood counts were analysed before and after plasmapheresis using an electronic counter. Total protein, IgG and citrate were measured turbidometrically before, during and after apheresis as well as in the plasma product. Furthermore, platelets, red and white blood cells were analysed as parameters of product quality. An average of 2751±247ml blood was processed in 47±6min. The collected plasma volume was 850±1mL and citrate consumption was 177±15mL. A continuous drop of donors' IgG level was observed during plasmapheresis. The drop was 13% of the IgG baseline value at 800mL collected plasma. Total protein, IgG and cell counts of the plasma product met current guidelines of plasma for fractionation. Donors' IgG levels during apheresis showed a steady decrease without compromising the quality of plasma product. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Effect of deafferentation of the rat tongue on plasma corticosterone, aldosterone, angiotensin and ACTH levels

    International Nuclear Information System (INIS)

    Polyntsev, Yu.V.; Serova, O.N.

    1987-01-01

    The effect of deafferentation of the tongue on the plasma level of hormones involved in regulation of the sodium ion level -- aldosterone, corticosterone, ACTH, and angiotensin -- was studied. Plasma hormone levels were determined by radioimmunoassay. The results indicate the important role of orosensory and taste perception in the processes of regulation of the sodium balance in the body. The experiments in this study were conducted on rats

  20. Parvovirus B19 infection modulates the levels of cytokines in the plasma of rheumatoid arthritis patients.

    Science.gov (United States)

    Naciute, Milda; Mieliauskaite, Diana; Rugiene, Rita; Maciunaite, Gabriele; Mauricas, Mykolas; Murovska, Modra; Girkontaite, Irute

    2017-08-01

    Parvovirus B19 (B19V) infection is associated with various autoimmune diseases. We investigated the levels of pro-inflammatory (IFNᵧ, TNFα, IL-2, IL-12) and anti-inflammatory (IL-4, IL-10) cytokines in the plasma of B19V DNA positive (B19 + ) and negative (B19 - ) rheumatoid arthritis (RA) patients in comparison with the control group (healthy persons). Blood samples were collected from 118 patients with RA and 49 healthy voluntaries. B19V sequence was determined in whole blood and cell-free plasma DNA by nested PCR. The levels of cytokines in the plasma and cell culture medium from Concanavalin A (ConA) or B19V VP1 protein stimulated PBMC were determined by ELISA. The levels of IL-4, IL-10, IL-12, IL-2 and TNFα were higher in plasma of RA patients in comparison with control persons. B19 + controls and RA patients had lower levels of IFNᵧ in comparison with B19 - controls and RA patients. Within RA patients the plasma levels of IFNᵧ were lower in patients with low RA disease activity or remission. Plasma level of IL-4 was increased and IL-10 level was decreased in B19 + RA patients in comparison with B19 - RA patients and did not differ between B19 + and B19 - controls. B19V infection did not affect plasma levels of IL-12, IL-2, and TNFα. ConA and B19 VP1 protein stimulated PBMC from RA patients produced less IFNᵧ than stimulated PBMC from the healthy controls. B19V infection could differently modulate the amount of cytokines in the plasma of healthy persons and RA patients. Decreased production of IFNᵧ and raised level of plasma IL-4 in RA patients could lower antiviral clearance. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Level lifetimes of Au52+ in Au plasma

    International Nuclear Information System (INIS)

    Liu Bo; Zhu Zhiyan; Jiang Gang; Zhu Zhenghe

    2003-01-01

    Based on the extended relativistic multiconfiguration Dirac-Fock theory, the level lifetimes, level widths and wavelengths of Au 52+ have been calculated using the General-purpose Relativistic Atomic Structure Program. The wavelengths obtained are in good agreement with the experimental data available. The relationship between the level lifetimes and the level widths satisfies the Heisenberg uncertainty principle

  2. A Taiwanese food frequency questionnaire correlates with plasma docosahexaenoic acid but not with plasma eicosapentaenoic acid levels: questionnaires and plasma biomarkers.

    Science.gov (United States)

    Chien, Kuo-Liong; Lee, Meei-Shyuan; Tsai, Yi-Tsen; Chen, Pey-Rong; Lin, Hung-Ju; Hsu, Hsiu-Ching; Lee, Yuan-The; Chen, Ming-Fong

    2013-02-16

    Little evidence is available for the validity of dietary fish and polyunsaturated fatty acid intake derived from interviewer-administered questionnaires and plasma docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentration. We estimated the correlation of DHA and EPA intake from both questionnaires and biochemical measurements. Ethnic Chinese adults with a mean (± SD) age of 59.8 (±12.8) years (n = 297) (47% women) who completed a 38-item semi-quantitative food-frequency questionnaire and provided a plasma sample were enrolled. Plasma fatty acids were analyzed by capillary gas chromatography. The Spearmen rank correlation coefficients between the intake of various types of fish and marine n-3 fatty acids as well as plasma DHA were significant, ranging from 0.20 to 0.33 (P food frequency questionnaire, were correlated with the percentages of these fatty acids in plasma, and in particular with plasma DHA. Plasma DHA levels were correlated to dietary intake of long-chain n-3 fatty acids.

  3. Increased osteopontin plasma levels in multiple sclerosis patients correlate with bone-specific markers

    NARCIS (Netherlands)

    Vogt, M.H.J.; ten Kate, J.; Drent, R.J.M.; Polman, C.H.; Hupperts, R.

    2010-01-01

    The pro-inflammatory cytokine osteopontin has been found to be highly expressed in multiple sclerosis lesions and plasma levels are increased during relapses in relapse-onset multiple sclerosis patients. The objective was to determine the relationship between osteopontin plasma and cerebrospinal

  4. Contrast media effect on interleukin-2 levels in human plasma in vitro

    International Nuclear Information System (INIS)

    Napolov, Yu.K.; Borsukova, N.M.; Shimanovskij, N.L.

    1992-01-01

    As shown in the study of bilignost, iodamide and triombrast action on interleukin-2 (IL-2) level in human plasma in vitro, these contrast media (2.5x10 -2 -2.5x10 -4 M) elevate IL-2 content in blood plasma of sensitive to contrast media subjects in dose-dependent manner

  5. 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.

  6. Plasma visfatin level in lean women with PCOS: relation to proinflammatory markers and insulin resistance.

    Science.gov (United States)

    Gen, Ramazan; Akbay, Esen; Muslu, Necati; Sezer, Kerem; Cayan, Filiz

    2009-04-01

    The present study was undertaken to investigate the association between plasma visfatin concentrations and inflammatory markers such as interleukin-6 (IL-6) and high-sensitive C-reactive protein (hsCRP) in company with several metabolic parameters in lean women with polycystic ovary syndrome (PCOS). The study group consisted of 21 lean women with PCOS (BMI 20.74 +/- 1.74 kg/m(2)) and 15 healthy, normally menstruating women (BMI 20.85 +/- 2.08 kg/m(2) control group). PCOS was defined according to the Rotterdam criteria. Visfatin, IL-6, hsCRP, hyperandrogenism markers and metabolic markers were examined in all PCOS and control women. Plasma visfatin level in the PCOS group was higher than that in the control group. Plasma hsCRP and IL-6 levels in PCOS group were similar with the control group. Plasma visfatin levels were positively associated with total cholesterol, high density lipoprotein, hirsutism score, total testosterone and FAI. Plasma visfatin level was negatively associated with SHBG. However, there were no correlation between plasma visfatin level and IL-6 and hsCRP. In multivariate regression analyses, only FAI and high density lipoprotein-cholesterol (HDL-C) showed a significant association with serum visfatin. Our data indicates that plasma visfatin levels are associated with HDL-C and markers of hyperandrogenism, but it is not associated with proinflammatory markers and insulin resistance in lean women with PCOS.

  7. Relationship between respiratory failure and plasma noradrenaline levels in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Yamashita, A; Koike, Y; Takahashi, A; Hirayama, M; Murakami, N; Sobue, G

    1997-08-01

    We evaluated plasma noradrenaline (NA) levels at test and during head-up tilt test in 20 patients with sporadic amyotrophic lateral sclerosis (ALS). Their fasting plasma NA levels ranged from 195 to 4227 pg/ml. The average plasma NA level was 483 pg/ml in five ambulatory patients, 341 in two wheelchair-bound patients, 1264 in 11 bedridden patients, and 208 in two respirator-dependent patients whose disability grading was the worst among the four groups. Arterial carbon dioxide (PCO2) was evaluated as a measure of respiratory function. The coefficient of correlation between PCO2 and plasma NA was r = 0.654 (p respiratory failure or lower motor neuron dysfunction may relate to the elevation of plasma NA levels. In the two bedridden patients, plasma NA levels and heart rate at rest increased significantly as the disease progressed. Cardiovascular responses to head-up tilting were normal. These data suggest that the elevation of plasma NA levels may be related to progression of respiratory failure and lower motor neuron dysfunction. In conclusion, sympathetic hyperactivity in ALS is considered to be not primary, but secondary to somatic motor disabilities and respiratory failure.

  8. Measurement of plasma neuropeptide Y levels with RIA in diabetic patients

    International Nuclear Information System (INIS)

    Cheng Guanghua; Zhang Xinlu; Yang Jun

    2002-01-01

    Objective: To investigate the clinical significance of the levels of plasma neuropeptide Y(NPY) in NIDDM patients with the occurrence of vascular complications. Methods: The plasma NPY levels were measured in 67 cases with DM (Group A: no Vascular complication, n = 38, Group B: with renal and retinal Vascular Changes, n = 29) and 37 normal subjects by radioimmunoassay. Results: NPY levels were higher in diabetic patients than those in normal subjects (p < 0.001). Also the plasma NPY levels were higher (p < 0.001) in diabetic patients with angiopathy (29 cases) than in those without it (38 cases). Conclusion: These data suggested that the changes of plasma NPY levels might be closely related to the occurrence and development of complications in DM patients

  9. Clinical significance of changes of plasma CGRP and VIP levels in infants with bronchiolitis

    International Nuclear Information System (INIS)

    Yang Chun; Gu Ling; Zhang Yanjun; Xin Haiyan

    2005-01-01

    Objective: To explore the clinical significance of changes of calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) levels in infants (2-24months) with bronchiolitis. Methods: Plasma levels of CGRP and VIP were determined with RIA in 31 infants with bronchiolitis both during acute infection and convalescence as well as in 35 controls. Results: Plasma CGRP levels in patients during acute infection were significantly higher than those in patients during convalescence and in controls (P<0.05). Levels of CGRP dropped during convalescence, but still remained significantly higher than those in controls (P<0.05). The reverse was true for the plasma VIP levels. The plasma VIP levels in patients during acute infection were significantly lower than those in patients during convalescence and in controls (P<0.05). During convalescence, the plasma VIP levels rose but remained significantly lower than those in controls (P<0.05). Conclusion: There were dynamic changes of plasma CGRP and VIP levels in the course of infant bronchiolitis and the two peptides played opposite roles. (authors)

  10. 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.

  11. 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

  12. Plasma cytokine levels and risks of abdominal aortic aneurysms

    DEFF Research Database (Denmark)

    Liao, Mengyang; Liu, Cong-Lin; Lv, Bing-Jie

    2015-01-01

    BACKGROUND: Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell accumulation in AAA lesions that produce inflammatory cytokines and advance its pathogenesis. Peripheral cytokines may predict the degree or risk of AAA. METHODS AND RESULTS: ELISA determined plasma interleukin-6 (IL6......), IL10, IL17A, IFN-γ, and C-reactive protein (CRP) from 476 AAA patients and 200 controls. AAA patients had lower IL6, IFN-γ, IL10, IL17A, and higher CRP than controls. IL10 correlated positively with IFN-γ, IL17A, or IL6, but not CRP in control or AAA populations. IL10 associated negatively...... with systolic blood pressure, whereas CRP associated positively with diastolic blood pressure and body mass index. CRP was an independent AAA risk factor and correlated positively with aortic diameters before and after adjustments for other risk factors. IFN-γ, IL17A, and CRP correlated positively with cross...

  13. Effects of acute doses of prosocial drugs methamphetamine and alcohol on plasma oxytocin levels.

    Science.gov (United States)

    Bershad, Anya K; Kirkpatrick, Matthew G; Seiden, Jacob A; de Wit, Harriet

    2015-06-01

    Many drugs, including alcohol and stimulants, demonstrably increase sociability and verbal interaction and are recreationally consumed in social settings. One drug, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), seems to produce its prosocial effects by increasing plasma oxytocin levels, and the oxytocin system has been implicated in responses to several other drugs of abuse. Here, we sought to investigate the effects of 2 other "social" drugs on plasma oxytocin levels--methamphetamine and alcohol. Based on their shared capacity to enhance sociability, we hypothesized that both methamphetamine and alcohol would increase plasma oxytocin levels. In study 1, 11 healthy adult volunteers attended 3 sessions during which they received methamphetamine (10 mg or 20 mg) or placebo under double-blind conditions. Subjective drug effects, cardiovascular effects, and plasma oxytocin levels were measured at regular intervals throughout the sessions. In study 2, 8 healthy adult volunteers attended a single session during which they received 1 beverage containing placebo, and then a beverage containing alcohol (0.8 g/kg). Subjective effects, breath alcohol levels, and plasma oxytocin levels were measured at regular intervals. Both methamphetamine and alcohol produced their expected physiological and subjective effects, but neither of these drugs increased plasma oxytocin levels. The neurobiological mechanisms mediating the prosocial effects of drugs such as alcohol and methamphetamine remain to be identified.

  14. Plasma homocysteine level in cardiac syndrome X and its relation with duke treadmill score

    International Nuclear Information System (INIS)

    Timurkaynak, T.; Balcioglu, S.; Arslan, U.; Kocaman, Sinan A.; Cengel, A.

    2008-01-01

    Objective was to investigate the plasma homocysteine level and relationship between plasma homocysteine level and duke treadmill score (DTS) in cardiac syndrome X (CSX) patients. Seventy-nine patients (36 male, 43 female, mean age: 50+-8.8 years) admitted to Gazi University Hospital, Ankara, Turkey with typical effort angina, positive stress test and angiographically normal coronary arteries between January and September 2006 were included in this prospective and controlled study. Thirty asymptomatic patients (11 male, 19 female, mean age: 47.6+-8.3 years) with two cardiovascular risk factors were chosen as a control group. Plasma homocysteine level was measured in both groups and DTS was calculated in the CSX group. Plasma homocysteine was measured with AxSYM homocysteine immunoassay method in both groups. Plasma homocysteine level was higher in the CSx group compared to the control group 16.5+-4.9 umol/L, n=79, versus 12.4+-4.1 umol/L, n=30, p<0.001). The DTS was -2.7+-5.3 in the CSX group. There was a negative correlation between the DTS and homocysteine levels in the CSX group. (r=-0.506, p<0.001). Plasma homocysteine level, which is known to cause endothelial dysfunction and microvascular ischemia were higher in CSX patients. Also, this increase in homocysteine level correlated with the DTS, which represents the magnitude of ischemia. (author)

  15. The clinical application of determination of plasma NPY levels for diagnosis and treatment of cardiovascular diseases

    International Nuclear Information System (INIS)

    Zheng Qing; Bao Yimin; Yang Yongqing

    2010-01-01

    Objective: To study the clinical usefulness of determination of plasma NPY levels for diagnosis and treatment of cardiovascular disease. Methods: Plasma levels of NPY were determined with RIA in 180 patients with heart failure from CHD, 89 patients with AMI, 58 patients with essential hypertension, 109 patients with PIH and 47 controls. Results: The plasma levels of NPY in 180 patients with heart failure were 206.37±40.1 pg/ml (I grade, P<0.05), 218.62±64.83 pg/ml (II grade, P<0.05), 269.16±56.57 pg/ml (III grade, P<0.01) and 314.82±56.73 pg/ml (IV grade, P<0.001), respectively. The plasma levels were 345.12±68.71 pg/ml and 191.46±38.92 pg/ml in patients with AMI and hypertension as a whole, respectively. All these levels were significantly higher than those in controls (P<0.05∼0.001). Among the patients, the plasma NPY levels increased along with advance of the disease process. Conclusion: Plasma NPY level was a useful marker for diagnosis and treatment of cardiovascular diseases. (authors)

  16. Polybrominated diphenyl ethers--plasma levels and thyroid status of workers at an electronic recycling facility.

    Science.gov (United States)

    Julander, A; Karlsson, M; Hagström, K; Ohlson, C G; Engwall, M; Bryngelsson, I-L; Westberg, H; van Bavel, B

    2005-08-01

    Personnel working with electronic dismantling are exposed to polybrominated diphenyl ethers (PBDEs), which in animal studies have been shown to alter thyroid homeostasis. The aim of this longitudinal study was to measure plasma level of PBDEs in workers at an electronic recycling facility and to relate these to the workers' thyroid status. PBDEs and three thyroid hormones: triiodothyronine (T(3)), thyroxin (T(4)) and thyroid stimulating hormone (TSH) were repeatedly analysed in plasma from 11 workers during a period of 1.5 years. Plasma levels of PBDEs at start of employment were plasma levels of PBDEs fluctuated during the study period. Due to small changes in thyroid hormone levels it was concluded that no relevant changes were present in relation to PBDE exposure within the workers participating in this study.

  17. Gold in semen: Level in seminal plasma and spermatozoa of normal ...

    African Journals Online (AJOL)

    K.P. Skandhan

    2016-07-01

    Jul 1, 2016 ... Gold level in sediment (spermatozoa) of normal was almost same as observed in its seminal plasma ... showed, gold was not detected in semen by Direct Couple ... Diffraction Analysis, revealed presence of gold throughout.

  18. Betaine supplementation lowers plasma homocysteine levels in healthy men and women

    NARCIS (Netherlands)

    Steenge, G.R.S.; Verhoef, P.; Katan, M.B.

    2003-01-01

    Elevated levels of plasma total homocysteine are associated with a higher risk of cardiovascular disease. Betaine and 5-methyltetrahydrofolate can remethylate homocysteine into methionine via independent reactions. We determined the effect of daily betaine supplementation, compared with both folic

  19. Plasma levels of gastrointestinal regulatory peptides in patients receiving maintenance hemodialysis

    International Nuclear Information System (INIS)

    Hegbrant, J.; Thysell, H.; Ekmann, R.

    1991-01-01

    The fasting plasma levels of nine gastrointestinal regulatory peptides were measured by radioimmunoassay in 13 stable patients with chronic renal failure, receiving hemodialysis treatment regularly and compared with those of ten healthy controls. The plasma concentrations of gastrin-releasing peptide, motilin, neurotensin, pancreatic polypeptide, peptide YY, somatostatin, substance P, and vasoactive intestinal peptide were increased. The plasma level of gastrin was not statistically different from that of the control (p=0.077). It is concluded that patients with chronic renal failure, receiving hemodialysis treatment regularly, have increased concentrations of eight of nine measured gastrointestinal regulatory peptides. The elevated levels of gastrointestinal peptides in patients with chronic renal failure may contribute to uremic gastrointestinal symptoms and dysfunctions. It is necessary to make a renal function evaluation before interpreting measured plasma levels of gastrointestinal regulatory peptides. 62 refs., 2 tabs

  20. Observation on the changes of plasma neuroendocrine hormones levels in patients with congestive heart failure (CHF)

    International Nuclear Information System (INIS)

    Rui Shibao; Xia Chaohoung; Cheng Guanghua

    2009-01-01

    Objective: To study the changes of plasma levels of endothelin (ET), calcitonin gene related peptide (CGRP), neuropeptide Y (NPY) and adrenomedullin (ADM) both before and after treatment in patients with CHF. Methods: Plasma levels of ET, CGRP, NPY and ADM were determined with RIA both before and after treatment in 79 patients with CHF and once in 31 controls. The 79 patients were of two groups: Group A cardiac function Grade III or better, n=45, Group B, cardiac function Grade IV, n=34 with 3 deaths. Results: Before treatment, the plasma levels of ET and CGRP were significantly higher in both groups of patients than those in controls, with higher values in more severe cases. After treatment,the levels dropped markedly but remained significantly higher than those in controls. Most remarkably was that in the three deaths: the CGRP levels before treatment, though higher than those in the controls, were significantly lower than the mean value in Group B patients as a whole, and dropped furthur to below those in controls as the patients deteriorated. With NPY and ADM, before treatment the plasma levels in both groups of patients were also significantly higher than those in controls. The levels also dropped markedly after treatment, but still remained significantly higher than those in controls. Again, in the 3 deaths, the plasma levels of ADM were significantly lower than the mean value of Group B patients and were not much different from those in controls (P>0.05) and dropped furthur to even below the levels of controls as the patients deteriorated. Conclusion: Changes of plasma levels of ET and NPY might reflect the severity of the disease process of CHF while changes of plasma CGRP and ADM levels might even be of prognostic value. (authors)

  1. Plasma NOV/CCN3 Levels Are Closely Associated with Obesity in Patients with Metabolic Disorders

    Science.gov (United States)

    Pakradouni, Jihane; Le Goff, Wilfried; Calmel, Claire; Antoine, Bénédicte; Villard, Elise; Frisdal, Eric; Abifadel, Marianne; Tordjman, Joan; Poitou, Christine; Bonnefont-Rousselot, Dominique; Bittar, Randa; Bruckert, Eric; Clément, Karine; Fève, Bruno; Martinerie, Cécile; Guérin, Maryse

    2013-01-01

    Objective Evidence points to a founder of the multifunctional CCN family, NOV/CCN3, as a circulating molecule involved in cardiac development, vascular homeostasis and inflammation. No data are available on the relationship between plasma NOV/CCN3 levels and cardiovascular risk factors in humans. This study investigated the possible relationship between plasma NOV levels and cardiovascular risk factors in humans. Methods NOV levels were measured in the plasma from 594 adults with a hyperlipidemia history and/or with lipid-lowering therapy and/or a body mass index (BMI) >30 kg/m2. Correlations were measured between NOV plasma levels and various parameters, including BMI, fat mass, and plasma triglycerides, cholesterol, glucose, and C-reactive protein. NOV expression was also evaluated in adipose tissue from obese patients and rodents and in primary cultures of adipocytes and macrophages. Results After full multivariate adjustment, we detected a strong positive correlation between plasma NOV and BMI (r = 0.36 p<0.0001) and fat mass (r = 0.33 p<0.0005). According to quintiles, this relationship appeared to be linear. NOV levels were also positively correlated with C-reactive protein but not with total cholesterol, LDL-C or blood glucose. In patients with drastic weight loss induced by Roux-en-Y bariatric surgery, circulating NOV levels decreased by 28% (p<0.02) and 48% (p<0.0001) after 3 and 6 months, respectively, following surgery. In adipose tissue from obese patients, and in human primary cultures NOV protein was detected in adipocytes and macrophages. In mice fed a high fat diet NOV plasma levels and its expression in adipose tissue were also significantly increased compared to controls fed a standard diet. Conclusion Our results strongly suggest that in obese humans and mice plasma NOV levels positively correlated with NOV expression in adipose tissue, and support a possible contribution of NOV to obesity-related inflammation. PMID:23785511

  2. Impact of elective resection on plasma TIMP-1 levels in patients with colon cancer

    DEFF Research Database (Denmark)

    Hammer, J. H.; Basse, L.; Svedsen, M. N.

    2006-01-01

    OBJECTIVE: Pre- and post-operative plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) levels have a prognostic impact on patients with colorectal cancer. However, the surgical trauma may play an essential role in regulation of plasma TIMP-1 levels, which in turn may influence subsequent TIMP......-1 measurements. PATIENTS AND METHODS: Consecutively, 48 patients with colon cancer (CC) and 12 patients with nonmalignant colonic disease were randomised to undergo elective laparoscopically assisted or open resection followed by fast track recovery. Plasma samples were collected just before and 1...

  3. Impact of elective resection on plasma TIMP-1 levels in patients with colon cancer

    DEFF Research Database (Denmark)

    Hammer, J. H.; Basse, L.; Svedsen, M. N.

    2006-01-01

    -1 measurements. PATIENTS AND METHODS: Consecutively, 48 patients with colon cancer (CC) and 12 patients with nonmalignant colonic disease were randomised to undergo elective laparoscopically assisted or open resection followed by fast track recovery. Plasma samples were collected just before and 1......OBJECTIVE: Pre- and post-operative plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) levels have a prognostic impact on patients with colorectal cancer. However, the surgical trauma may play an essential role in regulation of plasma TIMP-1 levels, which in turn may influence subsequent TIMP...

  4. Plasma. beta. -endorphin and stress hormone levels during adaptation and stress

    Energy Technology Data Exchange (ETDEWEB)

    Lishmanov, Yu.B.; Trifonova, Zh.V.; Tsibin, A.N.; Maslova, L.V.; Dement' eva, L.A.

    1987-09-01

    This paper describes a comparative study of ..beta..-endorphin and stress hormone levels in the blood plasma of rats during stress and adaptation. Immunoreactive ..beta..-endorphin in the blood plasma was assayed by means of a kit after preliminary isolation of the ..beta..-endorphin fraction by affinity chromatography on sepharose; ACTH was assayed with a kit and cortisol, insulin, thyroxine and tri-iodothyronine by means of kits from Izotop. Determination of plasma levels of ..beta..-endorphin and other opioids could evidently be an important method of assessing the state of resistance of the organism to stress.

  5. Plasma arc and cold crucible furnace vitrification for medium level waste: a review

    International Nuclear Information System (INIS)

    Poitou, S.; Fiquet, O.; Bourdeloie, C.; Gramondi, P.; Rebollo, F.; Girold, C.; Charvillat, J.P.; Boen, R.; Jouan, A.; Ladirat, C.; Nabot, J.P.; Ochem, D.; Baronnet, J.M.

    2001-01-01

    Initially developed for high-level waste reprocessing, several vitrification processes have been under study since the 80's at the French Atomic Energy Commission (CEA) for other waste categories. According to the French law concerning waste management research passed on December 30, 1991, vitrification may be applied to mixed medium-level waste. A review of processes developed at CEA is presented: cold crucible furnace heated by induced current, refractory furnace heated by nitrogen transferred arc plasma torch, and coupling of cold crucible furnace with oxygen transferred plasma arc twin torch. Furthermore, gas post-combustion has been studied with an oxygen non-transferred plasma torch. (authors)

  6. Factors Associated With Plasma IL-6 Levels During HIV Infection

    DEFF Research Database (Denmark)

    Borges, Álvaro H; O'Connor, Jemma L; Phillips, Andrew N

    2015-01-01

    (Strategies for Management of Anti-Retroviral Therapy) trial, CD4/CD8 ratio, smoking, comorbid conditions, serum lipids, renal function (estimated glomerular filtration rate [eGFR]), and educational level were assessed. RESULTS: Demographics associated with higher IL-6 levels were older age and lower...

  7. Decreased plasma chemerin levels in women with gestational diabetes mellitus

    DEFF Research Database (Denmark)

    Hare, K J; Bonde, L; Svare, J A

    2014-01-01

    circulating chemerin levels, which may act to reduce pregnancy-induced insulin resistance and prevent glucose intolerance. Women with gestational diabetes, however, have severely reduced chemerin levels that remain low after delivery, which may contribute to the insulin resistance, glucose intolerance......AIMS: To evaluate fasting and post-prandial serum chemerin levels in pregnant women with and without gestational diabetes, and again following delivery when normal glucose homeostasis is re-established. METHODS: Chemerin levels were measured in serum from nine women with gestational diabetes......, and from eight age- and BMI-matched pregnant women with normal glucose tolerance during two meal tests: in the third trimester and 3-4 months post partum. All women with gestational diabetes re-established normal glucose tolerance after delivery. RESULTS: Meal intake did not affect serum chemerin levels...

  8. Plasma taurine levels are not affected by vigabatrin in pediatric patients.

    Science.gov (United States)

    Spelbrink, Emily M; Mabud, Tarub S; Reimer, Richard; Porter, Brenda E

    2016-08-01

    Vigabatrin is a highly effective antiseizure medication, but its use is limited due to concerns about retinal toxicity. One proposed mechanism for this toxicity is vigabatrin-mediated reduction of taurine. Herein we assess plasma taurine levels in a retrospective cohort of children with epilepsy, including a subset receiving vigabatrin. All children who underwent a plasma amino acid analysis as part of their clinical evaluation between 2006 and 2015 at Stanford Children's Health were included in the analysis. There were no significant differences in plasma taurine levels between children taking vigabatrin (n = 16), children taking other anti-seizure medications, and children not taking any anti-seizure medication (n = 556) (analysis of variance [ANOVA] p = 0.841). There were, however, age-dependent decreases in plasma taurine levels. Multiple linear regression revealed no significant association between vigabatrin use and plasma taurine level (p = 0.87) when controlling for age. These results suggest that children taking vigabatrin maintain normal plasma taurine levels, although they leave unanswered whether taurine supplementation is necessary or sufficient to prevent vigabatrin-associated visual field loss. They also indicate that age should be taken into consideration when evaluating taurine levels in young children. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  9. Clinical significance of detection of plasma β-amyloid protein (β-AP) levels in patients with senile dementia

    International Nuclear Information System (INIS)

    Yu Binwei; Xu Shangao; Lu Zhifeng; Wang Weihua; Mao Xiaohua; Zhou Chaohua

    2007-01-01

    Objective: To explore the value of determination of plasma β-AP levels in the diagnosis and monitoring of Alzheimer's disease (AD). Methods: Plasma β-AP levels were weasured with RIA in 43 patients with AD and 58 controls, as well as in 8 AD patients after a course of cerebrolysin treatment. Results: The plasma β-AP levels in the AD patients were significance higher those in controls (P<0.01). The plasma β-AP levels were especially higher in the severe eases, however, the plasma β-AP levels in some late AD patients dropped again, even lower than those in the controls. The plasma β-AP levels in the 8 AD patients decreased significantly after treatment with cerebrolysin. Conclusion: The plasma β-AP is a biochemical maker of AD. Dynamic examnation of plasma β-AP levels is valuable in assessing the progression and prognosis of the disease. (authors)

  10. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients.

    Science.gov (United States)

    Logozzi, Mariantonia; De Milito, Angelo; Lugini, Luana; Borghi, Martina; Calabrò, Luana; Spada, Massimo; Perdicchio, Maurizio; Marino, Maria Lucia; Federici, Cristina; Iessi, Elisabetta; Brambilla, Daria; Venturi, Giulietta; Lozupone, Francesco; Santinami, Mario; Huber, Veronica; Maio, Michele; Rivoltini, Licia; Fais, Stefano

    2009-01-01

    Metastatic melanoma is an untreatable cancer lacking reliable and non-invasive markers of disease progression. Exosomes are small vesicles secreted by normal as well as tumor cells. Human tumor-derived exosomes are involved in malignant progression and we evaluated the presence of exosomes in plasma of melanoma patients as a potential tool for cancer screening and follow-up. We designed an in-house sandwich ELISA (Exotest) to capture and quantify exosomes in plasma based on expression of housekeeping proteins (CD63 and Rab-5b) and a tumor-associated marker (caveolin-1). Western blot and flow cytometry analysis of exosomes were used to confirm the Exotest-based findings. The Exotest allowed sensitive detection and quantification of exosomes purified from human tumor cell culture supernatants and plasma from SCID mice engrafted with human melanoma. Plasma levels of exosomes in melanoma-engrafted SCID mice correlated to tumor size. We evaluated the levels of plasma exosomes expressing CD63 and caveolin-1 in melanoma patients (n = 90) and healthy donors (n = 58). Consistently, plasma exosomes expressing CD63 (504+/-315) or caveolin-1 (619+/-310) were significantly increased in melanoma patients as compared to healthy donors (223+/-125 and 228+/-102, respectively). While the Exotest for CD63+ plasma exosomes had limited sensitivity (43%) the Exotest for detection of caveolin-1+ plasma exosomes showed a higher sensitivity (68%). Moreover, caveolin-1+ plasma exosomes were significantly increased with respect to CD63+ exosomes in the patients group. We describe a new non-invasive assay allowing detection and quantification of human exosomes in plasma of melanoma patients. Our results suggest that the Exotest for detection of plasma exosomes carrying tumor-associated antigens may represent a novel tool for clinical management of cancer patients.

  11. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients.

    Directory of Open Access Journals (Sweden)

    Mariantonia Logozzi

    Full Text Available BACKGROUND: Metastatic melanoma is an untreatable cancer lacking reliable and non-invasive markers of disease progression. Exosomes are small vesicles secreted by normal as well as tumor cells. Human tumor-derived exosomes are involved in malignant progression and we evaluated the presence of exosomes in plasma of melanoma patients as a potential tool for cancer screening and follow-up. METHODOLOGY/PRINCIPAL FINDINGS: We designed an in-house sandwich ELISA (Exotest to capture and quantify exosomes in plasma based on expression of housekeeping proteins (CD63 and Rab-5b and a tumor-associated marker (caveolin-1. Western blot and flow cytometry analysis of exosomes were used to confirm the Exotest-based findings. The Exotest allowed sensitive detection and quantification of exosomes purified from human tumor cell culture supernatants and plasma from SCID mice engrafted with human melanoma. Plasma levels of exosomes in melanoma-engrafted SCID mice correlated to tumor size. We evaluated the levels of plasma exosomes expressing CD63 and caveolin-1 in melanoma patients (n = 90 and healthy donors (n = 58. Consistently, plasma exosomes expressing CD63 (504+/-315 or caveolin-1 (619+/-310 were significantly increased in melanoma patients as compared to healthy donors (223+/-125 and 228+/-102, respectively. While the Exotest for CD63+ plasma exosomes had limited sensitivity (43% the Exotest for detection of caveolin-1+ plasma exosomes showed a higher sensitivity (68%. Moreover, caveolin-1+ plasma exosomes were significantly increased with respect to CD63+ exosomes in the patients group. CONCLUSIONS/SIGNIFICANCE: We describe a new non-invasive assay allowing detection and quantification of human exosomes in plasma of melanoma patients. Our results suggest that the Exotest for detection of plasma exosomes carrying tumor-associated antigens may represent a novel tool for clinical management of cancer patients.

  12. Plasma, salivary and urinary cortisol levels following physiological and stress doses of hydrocortisone in normal volunteers.

    Science.gov (United States)

    Jung, Caroline; Greco, Santo; Nguyen, Hanh H T; Ho, Jui T; Lewis, John G; Torpy, David J; Inder, Warrick J

    2014-11-26

    Glucocorticoid replacement is essential in patients with primary and secondary adrenal insufficiency, but many patients remain on higher than recommended dose regimens. There is no uniformly accepted method to monitor the dose in individual patients. We have compared cortisol concentrations in plasma, saliva and urine achieved following "physiological" and "stress" doses of hydrocortisone as potential methods for monitoring glucocorticoid replacement. Cortisol profiles were measured in plasma, saliva and urine following "physiological" (20 mg oral) or "stress" (50 mg intravenous) doses of hydrocortisone in dexamethasone-suppressed healthy subjects (8 in each group), compared to endogenous cortisol levels (12 subjects). Total plasma cortisol was measured half-hourly, and salivary cortisol and urinary cortisol:creatinine ratio were measured hourly from time 0 (between 0830 and 0900) to 5 h. Endogenous plasma corticosteroid-binding globulin (CBG) levels were measured at time 0 and 5 h, and hourly from time 0 to 5 h following administration of oral or intravenous hydrocortisone. Plasma free cortisol was calculated using Coolens' equation. Plasma, salivary and urine cortisol at 2 h after oral hydrocortisone gave a good indication of peak cortisol concentrations, which were uniformly supraphysiological. Intravenous hydrocortisone administration achieved very high 30 minute cortisol concentrations. Total plasma cortisol correlated significantly with both saliva and urine cortisol after oral and intravenous hydrocortisone (P cortisol and urinary cortisol:creatinine ratio may provide useful alternatives to plasma cortisol measurements to monitor replacement doses in hypoadrenal patients.

  13. The changes of plasma adrenomedullin level in Han and tibetan health adult men in plateau area

    International Nuclear Information System (INIS)

    Chen Shaolin

    2011-01-01

    To investigate the changes and clinical significance of plasma adrenomedullin in Han and Tibetan health adult men at the state of chronic hypoxia. The Han health adult who migrated and lived above sea level 4200 meter for 1∼3 years and the native Tibetan were involved in this study. The plasma adrenomedullin levels in both Han and Tibetan health adult men were measured by RIA. The results showed that the plasma adrenomedullin levels of native Tibetan were significantly higher than that of migrated Han worker (P<0.05). The plasma adrenomedullin might play a regulatory role on the physiological function in the health adult men who live in high altitude hypoxic state. (authors)

  14. Variability of fasting and post-menthionine plasma homocysteine levels in normo- and hyperhomocysteinaemic individuals

    NARCIS (Netherlands)

    van den Berg, M.; de Jong, S.C.; Devilli, W.; Rauwerda, J.A.; Jakobs, C.A.J.M.; Pals, G.; Boers, G.H.J.; Stehouwer, C.D.A.

    1999-01-01

    To assess the variability of plasma homocysteine levels, fasting and post-methionine homocysteine levels were measured twice, at baseline and after follow-up of 1-4 months, in 16 individuals with normal and 26 with elevated homocysteine levels after methionine loading. The intra-individual

  15. Plasma glutamine levels before cardiac surgery are related to post-surgery infections; an observational study

    Directory of Open Access Journals (Sweden)

    Hanneke Buter

    2016-11-01

    Full Text Available Abstract Background A low plasma glutamine level was found in 34% of patients after elective cardiothoracic surgery. This could be a result of the inflammation caused by surgical stress or the use of extracorporeal circulation (ECC. But it is also possible that plasma glutamine levels were already lowered before surgery and reflect an impaired metabolic state and a higher likelihood to develop complications. In the present study plasma glutamine levels were measured before and after cardiac surgery and we questioned whether there is a relation between plasma glutamine levels and duration of ECC and the occurrence of postoperative infections. Methods We performed a single-centre prospective, observational study in a closed-format, 20-bed, mixed ICU in a tertiary teaching hospital. We included consecutive patients after elective cardiac surgery with use of extracorporeal circulation. Blood samples were collected on the day prior to surgery and at admission on the ICU. The study was approved by the local Medical Ethics Committee (Regional Review Committee Patient-related Research, Medical Centre Leeuwarden, nWMO 115, April 28th 2015. Results Ninety patients were included. Pre-operative plasma glutamine level was 0.42 ± 0.10 mmol/l and post-operative 0.38 ± 0.09 mmol/l (p < 0.001. There was no relation between duration of extracorporeal circulation or aortic occlusion time and changes in plasma glutamine levels. A logistic regression analysis showed a significant correlation between the presence of a positive culture during the post-operative course and pre-operative plasma glutamine levels (p = 0.04. Conclusion Plasma glutamine levels are significantly lower just after cardiac surgery compared to pre-operative levels. We did not find a relation between the decrease in plasma glutamine levels and the duration of extracorporeal circulation or aortic clamp time. There was a correlation between pre-operative plasma glutamine levels

  16. Plasma arc melting treatment of low level radioactive waste with centrifugal hearth

    International Nuclear Information System (INIS)

    Tsuji, Yukito

    1997-01-01

    Plasma Arc Melting technology may possible be able to treat various kinds of waste streams through volume reduction and stabilization into a disposal waste form. The ability of other melting technologies to convert inorganic material in a single step, however, varies according to the characteristics of the materials. Plasma technology also can treat organic waste by selecting the oxidation atmosphere. The Japan Atomic Power Company (JAPC) has decided to construct a low level radioactive waste treatment facility using the Plasma Arc Centrifugal Treatment (PACT) process with an 8 ft rotating hearth and 1.2 MW transferred torch developed by Retech (Ukiah, CA. USA) in the Tsuruga power station. In Japan, the plasma technology has been developed for incineration ash treatment, but the JAPC plant will be the first treatment system using plasma technology for solid waste with various characteristics and shapes. (author)

  17. The influence of exothermic reactions on the nonequilibrium level of discharge plasma

    International Nuclear Information System (INIS)

    Chernyak, V.Ya.; Iukhymenko, V.V.; Prysiazhnevych, I.V.; Martysh, Eu.V.

    2013-01-01

    The comparative analysis of plasma parameters of transverse arc and discharge in the gas channel with liquid wall was made for different working gas and liquids (for air, distilled water and for its mixtures with ethanol). Electronic excitation temperatures Te of atoms, vibrational Tv and rotational Tr temperatures of molecules in the generated plasma were determined by optical emission spectroscopy. It was shown that both discharges generate nonequilibrium plasma in the case of working gas air and working liquid-distilled water. Adding a fuel (ethanol) into the plasma system with O 2 leads to the increasing of rotational and vibrational temperatures of molecules, which became equal to each other within the errors. This may indicate that the exothermic reactions reduce the level of nonthermality of the generated plasma as a result of additional energy supply for heavy components in the process of complete combustion of hydrocarbons.

  18. Normal fasting plasma glucose levels and type 2 diabetes in young men.

    Science.gov (United States)

    Tirosh, Amir; Shai, Iris; Tekes-Manova, Dorit; Israeli, Eran; Pereg, David; Shochat, Tzippora; Kochba, Ilan; Rudich, Assaf

    2005-10-06

    The normal fasting plasma glucose level was recently defined as less than 100 mg per deciliter (5.55 mmol per liter). Whether higher fasting plasma glucose levels within this range independently predict type 2 diabetes in young adults is unclear. We obtained blood measurements, data from physical examinations, and medical and lifestyle information from men in the Israel Defense Forces who were 26 to 45 years of age. A total of 208 incident cases of type 2 diabetes occurred during 74,309 person-years of follow-up (from 1992 through 2004) among 13,163 subjects who had baseline fasting plasma glucose levels of less than 100 mg per deciliter. A multivariate model, adjusted for age, family history of diabetes, body-mass index, physical-activity level, smoking status, and serum triglyceride levels, revealed a progressively increased risk of type 2 diabetes in men with fasting plasma glucose levels of 87 mg per deciliter (4.83 mmol per liter) or more, as compared with those whose levels were in the bottom quintile (less than 81 mg per deciliter [4.5 mmol per liter], P for trend <0.001). In multivariate models, men with serum triglyceride levels of 150 mg per deciliter (1.69 mmol per liter) or more, combined with fasting plasma glucose levels of 91 to 99 mg per deciliter (5.05 to 5.50 mmol per liter), had a hazard ratio of 8.23 (95 percent confidence interval, 3.6 to 19.0) for diabetes, as compared with men with a combined triglyceride level of less than 150 mg per deciliter and fasting glucose levels of less than 86 mg per deciliter (4.77 mmol per liter). The joint effect of a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more and a fasting plasma glucose level of 91 to 99 mg per deciliter resulted in a hazard ratio of 8.29 (95 percent confidence interval, 3.8 to 17.8), as compared with a body-mass index of less than 25 and a fasting plasma glucose level of less than 86 mg per deciliter. Higher fasting plasma glucose

  19. Arterial and venous plasma levels of bupivacaine following peripheral nerve blocks.

    Science.gov (United States)

    Moore, D C; Mather, L E; Bridenbaugh, L D; Balfour, R I; Lysons, D F; Horton, W G

    1976-01-01

    Mean arterial plasma (MAP) and peripheral mean venous plasma (MVP) levels of bupivacaine were ascertained in 3 groups of 10 patients each for: (1) intercostal nerve block, 400 mg; (2) block of the sciatic, femoral, and lateral femoral cutaneous nerves, with or without block of the obturator nerve, 400 mg; and (3) supraclavicular brachial plexus block, 300 mg. MAP levels were consistently higher than simultaneously sampled MVP levels, the highest levels occurring from bilateral intercostal nerve block. No evidence of systemic toxicity was observed. The results suggest that bupivacaine has a much wider margin of safety in humans than is now stated.

  20. Plasma leptin levels in healthy children and adolescents

    DEFF Research Database (Denmark)

    Blum, W F; Englaro, P; Hanitsch, S

    1997-01-01

    children. With this assay, leptin proved to be a comparatively stable protein under common conditions of blood sampling and storage. Leptin levels increased in girls with age (r = 0.47, P stage showed a steady...... increase in girls between 2.51 micrograms/L (median) at Tanner stage 1 to 6.24 micrograms/L at Tanner stage 5. In boys, leptin levels were highest at Tanner stage 2 (2.19 micrograms/L) and declined thereafter to 0.71 microgram/L at Tanner stage 5. A strong exponential relationship was observed for leptin...... levels with body mass index (BMI) and percentage body fat as determined by bioelectric impedance measurements in a subgroup of subjects. This relationship was similar between boys and girls at Tanner stages 1 and 2. In boys, there was a significant decline of leptin at a given BMI with further...

  1. Relationship between Plasma Triglyceride Level and Severity of Hypertriglyceridemic Pancreatitis.

    Directory of Open Access Journals (Sweden)

    Sheng-Huei Wang

    Full Text Available Hypertriglyceridemia is the third most common cause of acute pancreatitis, but whether the level of triglyceride (TG is related to severity of pancreatitis is unclear.To evaluate the effect of TG level on the severity of hypertriglyceridemic pancreatitis (HTGP.Retrospective cohort study.We reviewed the records of 144 patients with HTGP from 1999 to 2013 at Tri-Service General Hospital. Patients with possible etiology of pancreatitis, such as gallstones, those consuming alcohol or drugs, or those with infections were excluded. The classification of severity of pancreatitis was based on the revised Atlanta classification. We allocated the patients into high-TG and low-TG groups based on the optimal cut-off value (2648 mg/dL, which was derived from the receiver operating characteristic (ROC curve between TG level and severity of HTGP. We then compared the clinical characteristics, pancreatitis severity, and mortality rates of the groups.There were 66 patients in the low-TG group and 78 patients in the high-TG group. There was no significant difference in the age, sex ratio, body mass index, and comorbidity between the 2 groups. The high-TG group had significantly higher levels of glucose (P = 0.022, total cholesterol (P = 0.002, and blood urea nitrogen (P = 0.037, and lower levels of sodium (P = 0.003 and bicarbonate (P = 0.002 than the low-TG group. The incidences of local complication (P = 0.002 and severe and moderate form of pancreatitis (P = 0.004 were significantly higher in the high-TG group than in the low-TG group. The mortality rate was higher in the high-TG group than in the low-TG group (P = 0.07.Higher TG level in patients with HTGP may be associated with adverse prognosis, but randomized and prospective studies are needed in the future verify this relationship.

  2. Relationship between Plasma Triglyceride Level and Severity of Hypertriglyceridemic Pancreatitis.

    Science.gov (United States)

    Wang, Sheng-Huei; Chou, Yu-Ching; Shangkuan, Wei-Chuan; Wei, Kuang-Yu; Pan, Yu-Han; Lin, Hung-Che

    2016-01-01

    Hypertriglyceridemia is the third most common cause of acute pancreatitis, but whether the level of triglyceride (TG) is related to severity of pancreatitis is unclear. To evaluate the effect of TG level on the severity of hypertriglyceridemic pancreatitis (HTGP). Retrospective cohort study. We reviewed the records of 144 patients with HTGP from 1999 to 2013 at Tri-Service General Hospital. Patients with possible etiology of pancreatitis, such as gallstones, those consuming alcohol or drugs, or those with infections were excluded. The classification of severity of pancreatitis was based on the revised Atlanta classification. We allocated the patients into high-TG and low-TG groups based on the optimal cut-off value (2648 mg/dL), which was derived from the receiver operating characteristic (ROC) curve between TG level and severity of HTGP. We then compared the clinical characteristics, pancreatitis severity, and mortality rates of the groups. There were 66 patients in the low-TG group and 78 patients in the high-TG group. There was no significant difference in the age, sex ratio, body mass index, and comorbidity between the 2 groups. The high-TG group had significantly higher levels of glucose (P = 0.022), total cholesterol (P = 0.002), and blood urea nitrogen (P = 0.037), and lower levels of sodium (P = 0.003) and bicarbonate (P = 0.002) than the low-TG group. The incidences of local complication (P = 0.002) and severe and moderate form of pancreatitis (P = 0.004) were significantly higher in the high-TG group than in the low-TG group. The mortality rate was higher in the high-TG group than in the low-TG group (P = 0.07). Higher TG level in patients with HTGP may be associated with adverse prognosis, but randomized and prospective studies are needed in the future verify this relationship.

  3. Levels of plasma selenium and urinary total arsenic interact to affect the risk for prostate cancer.

    Science.gov (United States)

    Hsueh, Yu-Mei; Su, Chien-Tien; Shiue, Horng-Sheng; Chen, Wei-Jen; Pu, Yeong-Shiau; Lin, Ying-Chin; Tsai, Cheng-Shiuan; Huang, Chao-Yuan

    2017-09-01

    This study investigated whether plasma selenium levels modified the risk for prostate cancer (PC) related to arsenic exposure. We conducted a case-control study that included 318 PC patients and 318 age-matched, healthy control subjects. Urinary arsenic profiles were examined using HPLC-HG-AAS and plasma selenium levels were measured by ICP-MS. We found that plasma selenium levels displayed a significant dose-dependent inverse association with PC. The odds ratio (OR) and 95% confidence interval (CI) for PC was 0.07 (0.04-0.13) among participants with a plasma selenium level >28.06 μg/dL vs. ≤19.13 μg/dL. A multivariate analysis showed that participants with a urinary total arsenic concentration >29.28 μg/L had a significantly higher OR (1.75, 1.06-2.89) for PC than participants with ≤29.89 μg/L. The combined presence of a low plasma selenium level and a high urinary total arsenic concentration exponentially increased the OR for PC, and additively interacted with PSA at levels ≥20 ng/mL. This is the first epidemiological study to examine the combined effects of plasma selenium and urinary total arsenic levels on the OR for PC. Our data suggest a low plasma selenium level coupled with a high urinary total arsenic concentration creates a significant risk for aggressive PC. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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.

  5. DNA damage and plasma homocysteine levels are associated with ...

    African Journals Online (AJOL)

    This study describes the association between levels of DNA damage and homocysteine (Hcy) in persistent diarrheic (PD) patients and correlates them with serum biochemical metabolites and mineral components. PD patients (n = 36) age 4 - 6 years from Faisalabad hospitals were examined for anthropometric factors, ...

  6. Lamivudine plasma levels in chronic hepatitis B patients

    NARCIS (Netherlands)

    L.M.M. Wolters (Leonieke); C.J. Geerlings; L.J. van Dijk (Laurens); H.G.M. Niesters (Bert); A.G. Vulto (Arnold); R.A. de Man (Robert)

    2003-01-01

    textabstractLamivudine has recently been registered for the treatment of chronic hepatitis B patients. The main therapeutic outcome in the studies on which the registration was based was a drop of HBV DNA below 10(7) genome equivalents/ml, the level of detection of the insensitive

  7. Effect of the stage of lactation in humans on carotenoid levels in milk, blood plasma and plasma lipoprotein fractions.

    Science.gov (United States)

    Schweigert, Florian J; Bathe, Katharina; Chen, Frank; Büscher, Ulrich; Dudenhausen, Joachim W

    2004-02-01

    In mammals the composition of milk changes during early lactation, with a rapid decline of fat-soluble vitamins and a continuous increase in total lipids. The mechanisms underlying this phenomenon are not well understood, but might involve selective mechanisms related to mammary uptake or secretion into the milk. Since carotenoids are specifically distributed among the lipoprotein fractions in plasma, the simultaneous determination of carotenoids in plasma, lipoprotein fractions and milk might offer an opportunity to gain insight into this phenomenon. In 21 healthy mothers carotenoids in plasma and lipoprotein fractions were investigated at day 2 and 19 and milk on day 4 and 19 after delivery. Plasma levels of alpha-tocopherol and cholesterol as well as lutein, zeaxanthin and cryptoxanthin were significantly lower later in lactation (day 19) than shortly after birth (P milk, triacylglycerol increased (P milk it was similar to the pattern found in the high density lipoprotein fraction. Based on these observations a selective mechanism might be responsible for the transfer of these components in milk involving different lipoprotein fractions at specific times of lactation.

  8. Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers

    Directory of Open Access Journals (Sweden)

    Lieke H.H. Meeter

    2016-07-01

    Full Text Available Background: Pathogenic mutations in the granulin gene (GRN are causative in 5-10% of patients with frontotemporal dementia (FTD, mostly leading to reduced progranulin protein (PGRN levels. Upcoming therapeutic trials focus on enhancing PGRN levels. Methods: Fluctuations in plasma PGRN (n = 41 and its relationship with cerebrospinal fluid (CSF, n = 32 and specific single nucleotide polymorphisms were investigated in pre- and symptomatic GRN mutation carriers and controls. Results: Plasma PGRN levels were lower in carriers than in controls and showed a mean coefficient of variation of 5.3% in carriers over 1 week. Although plasma PGRN correlated with CSF PGRN in carriers (r = 0.54, p = 0.02, plasma only explained 29% of the variability in CSF PGRN. rs5848, rs646776 and rs1990622 genotypes only partly explained the variability of PGRN levels between subjects. Conclusions: Plasma PGRN is relatively stable over 1 week and therefore seems suitable for treatment monitoring of PGRN-enhancing agents. Since plasma PGRN only moderately correlated with CSF PGRN, CSF sampling will additionally be needed in therapeutic trials.

  9. Clinical significance of determination of plasma ET and serum NSE, NPY levels in patients with Alzheimer diseases (AD)

    International Nuclear Information System (INIS)

    Song Hua

    2009-01-01

    Objective: To explore the clinical significance of changes of plasma ET and serum NSE, NPY levels in patients with Alzheimer diseases. Methods: Plasma ET and serum NSE, NPY levels were determined with RIA in 31 patients with Alzheimer diseases and 30 controls. Results: The plasma ET and serum NSE, NPY levels in the patients were significantly higher than those in controls (P<0.01). Plasma ET and serum NSE, NPY levels were mutually positively correlated (r=0.4895, 0.6014, P<0.01). Conclusion: Detection of plasma ET and serum NSE, NPY levels was helpful for the prediction of treatment effieacy in patients with Alzheimer diseases. (authors)

  10. Scalable synthesis and isolation of the four stereoisomers of methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate, useful intermediates for the synthesis of S1P1 receptor agonists.

    Science.gov (United States)

    Wallace, Grier A; Gordon, Thomas D; Hayes, Martin E; Konopacki, Donald B; Fix-Stenzel, Shannon R; Zhang, Xiaolei; Grongsaard, Pintipa; Cusack, Kevin P; Schaffter, Lisa M; Henry, Rodger F; Stoffel, Robert H

    2009-07-03

    The individual isomers of methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate are useful intermediates for the synthesis of S1P1 receptor agonists. Herein we describe a scalable synthesis and isolation of each of the four stereoisomers of this compound in gram quantities with >98% ee and de. The utility of this approach is demonstrated by the synthesis of ((1R,3R)-1-amino-3-(4-octylphenyl)cyclopentyl)methanol in 7 steps, 11% overall yield, and >98% ee and de.

  11. Plasma levels of cortisol and opioid peptide beta-endorphin during spontaneous vaginal delivery

    Directory of Open Access Journals (Sweden)

    Arsenijević Ljubica

    2006-01-01

    Full Text Available INTRODUCTION Labor pain is very frequent in clinical practice, but the underlying mechanisms as well as numerous neuroendocrine responses activated by such pain have not been fully explained yet. OBJECTIVE The objective of the study was to determine the influence of labor pain on plasma levels of cortisol and opioid peptide ß-endorphin. METHOD Cortisol and ß-endorphin levels were measured in blood plasma of: health, non-pregnant women (group 1, n=8, health pregnant women (group 2, n=8 and in parturitions, through fourth ages (group 3, n=8, Plasma level of cortisol was measured by radioimmunoassay, and ß-endorphin by enzyme immunoassay. Data were expressed as mean ± standard error of mean and were analyzed by Student's t test and Mann Whitney test. RESULTS Plasma level of cortisol in group 2 was significantly increased compared to the group 1. During labor progression, plasma level of cortisol was rising till the third labor age. Plasma level of cortisol in fourth labor age was not significantly different from the ag.e one and group 1. Plasma level of ß-endorphin was (n.g/L: in group 1:64±20, group 2:70±22, group 3:the first labor age: 75±15, the second labor age: 193±54, the third labor age: 346+97 and the fourth labor age: 114±31. CONCLUSION These results indicate that both ß-endorphin and cortisol are involved in regulation and modulation of labor pain and stress.

  12. Plasma levels of secretin in man and dogs: validation of a secretin radioimmunoassay

    International Nuclear Information System (INIS)

    Rayford, P.L.; Curtis, P.J.; Fender, H.R.; Thompson, J.C.

    1976-01-01

    We have developed and validated a secretin radioimmunoassay that is sufficiently sensitive to measure circulating levels of secretion in the plasma of man and dogs. At a final dilution of 1 : 50,000, the antibody bound 30 percent to 40 percent of radioiodinated ( 125 I) 6-tyrosyl synthetic secretin. Pure natural porcine secretin was used as a reference standard and a linear dose-response curve was generated with 10 to 1,000 pg. of the polypeptide. Little or no cross-reactivity was found when graded doses of other gastrointestinal polypeptides were assayed in the radioimmunoassay and immunoreactive secretin (IRS) in volumes of serum up to 300 μl could be measured accurately. Mean basal levels of IRS in the peripheral plasma of 22 normal human subjects was 216 +- 11.8 pg. per milliliter, in the peripheral plasma of dogs was 154 +- 6.1 pg. per milliliter, and in the portal plasma of dogs was 283 +- 22.2 pg. per milliliter. Basal IRS levels in portal plasma were significantly higher than in peripheral plasma (p < 0.05). In studies on the release of secretin in three normal human subjects, the mean basal level of secretin in peripheral plasma was 124 +- 8 pg. per milliliter. This level was increased to 137 +- 6, 137 +- 7, 149 +- 9, and 169 +- 10 pg. per milliliter during duodenal acidification with 0.15, 0.30, 0.77, and 1.25 mEq. 0.1N HCl per minute. The secretin response was related to the amount of acid used to irrigate the duodenum. In six dogs mean basal levels of secretin in the portal vein were 438 +- 102 pg. per milliliter. Secretin levels were significantly elevated above basal (p < 0.05) at 5, 10, 15, 20, 25, and 30 minutes during irrigation of the duodenum with 0.1N HCl and remained elevated for 5 and 10 minutes after duodenal acidification

  13. Resistin polymorphims, plasma resistin levels and obesity in Tunisian volunteers.

    Science.gov (United States)

    Zayani, Nesrine; Hamdouni, Haithem; Boumaiza, Imen; Achour, Ons; Neffati, Fadoua; Omezzine, Asma; Najjar, Mohamed Fadhel; Bouslama, Ali

    2018-02-01

    Adipose tissue is an important endocrine organ that secretes a number of adipokines, like Resistin (RETN); it's an adipocytes-secreted cytokine and has been proposed as a link between obesity and diabetes. Many resistin gene polymorphisms were described and their implication in obesity was controversial. This study was to investigate the prevalence of single nucleotide polymorphisms (SNPs) in RETN gene 420C/G; 44G/A; 62G/A; 394C/G and 299 G/A and their association with Resistin level and obesity in Tunisian volunteers. We recruited 169 nonobese (mean age=42.16-14.26 years; mean body mass index [BMI]=24.51-3.69 kg/m 2 ) and 160 obese (mean age=47.86-11.17 years; mean BMI=36-4.78 kg/m 2 ). Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. Anthropometric parameters, lipid levels, Glycemia and insulinemia were measured, BMI was calculated and insulinresistance was evaluated with the homeostasis model assessment insulin resistance (HOMA-IR) and resistin level was measured by ELISA. Statistical analyses were performed by SPSS19.0. After adjustment for confounding parameters; the Odds Ratio (OR) of obesity associated with mutated genotypes at 420C/G compared with normal genotype was as: OR=2.17; 95% CI [1.28-3.68], P=.004. The serum Resistin levels present no significant association with all RETN polymorphisms and it was significantly associated with BMI (P=.047). In our haplotype analysis, one haplotype seems to be protective and one other seems to be the highest risk to obesity. The 420 C/G Polymorphism were associated with obesity and Leptin concentration in our population. © 2017 Wiley Periodicals, Inc.

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    The regulation of fibroblast growth factor 23 (FGF23) synthesis and secretion is still incompletely understood. FGF23 is an important regulator of renal phosphate excretion and has regulatory effects on the calciotropic hormones calcitriol and parathyroid hormone (PTH). Calcium (Ca) and phosphate...... FGF23 levels and whether a close relationship, similar that known for Ca and PTH, exists between Ca and FGF23. Thus, the aim of the present study was to examine whether acute hypercalcemia and hypocalcemia regulate FGF23 levels in the rat. Acute hypercalcemia was induced by an intravenous Ca infusion...... and hypocalcemia by infusion of ethylene glycol tetraacetic acid (EGTA) in normal and acutely parathyroidectomized rats. Intact plasma FGF23 and intact plasma PTH and plasma Ca(2+) and phosphate were measured. Acute hypercalcemia and hypocalcemia resulted as expected in adequate PTH secretory responses. Plasma FGF...

  15. Post-cardiac arrest level of free-plasma DNA and DNA-histone complexes

    DEFF Research Database (Denmark)

    Jeppesen, A N; Hvas, A-M; Grejs, A M

    2017-01-01

    Background Plasma DNA-histone complexes and total free-plasma DNA have the potential to quantify the ischaemia-reperfusion damages occurring after cardiac arrest. Furthermore, DNA-histone complexes may have the potential of being a target for future treatment. The aim was to examine if plasma DNA-histone...... after 22, 46 and 70 h. Samples for DNA-histone complexes were quantified by Cell Death Detection ELISAplus. The total free-plasma DNA analyses were quantified with qPCR by analysing the Beta-2 microglobulin gene. The control group comprised 40 healthy individuals. Results We found no difference...... in the level of DNA-histone complexes between the 22-h sample and healthy individuals (P = 0.10). In the 46-h sample, there was an increased level of DNA-histone complexes in non-survivors compared with survivors 30 days after the cardiac arrest (P

  16. Increased plasma levels of microparticles expressing CD39 and CD133 in acute liver injury

    DEFF Research Database (Denmark)

    Schmelzle, Moritz; Splith, Katrin; Wiuff Andersen, Lars

    2013-01-01

    BACKGROUND: We have previously demonstrated that CD133 and CD39 are expressed by hematopoietic stem cells (HSC), which are mobilized after liver injury and target sites of injury, limit vascular inflammation, and boost hepatic regeneration. Plasma microparticles (MP) expressing CD39 can block...... sacrificed and plasma MP were isolated by ultracentrifugation. HSC and CD133 MP levels were analyzed by fluorescence-activated cell sorting. Patients were enrolled with acute (n=5) and acute on chronic (n=5) liver injury with matched controls (n=7). Blood was collected at admission and plasma CD133 and CD39...... MP subsets were analyzed by fluorescence-activated cell sorting. RESULTS: HSC and CD133 MP levels were significantly increased only in the plasma of wild-type mice with acetaminophen hepatotoxicity (P

  17. Study on plasma homocysteine (HCY) levels in patients with cerebral infarction and cerebral hemorrhage

    International Nuclear Information System (INIS)

    Zhou Guozhong

    2005-01-01

    Objective: To investigate the relationship between the plasma levels of HCY, folate and vitamin B 12 and the development of cerebrovascular accidents (infarction and hemorrhage). Methods: Plasma HCY concentrations (with fluorescence polarization immunoassay FPIA) and folate, VitB 12 contents (with immunofluorescence technique) were measured in 150 patients with cerebral infarction, 171 patients with cerebral hemorrhage (all patients confirmed with CT/MRI) and 96 controls. Results: Plasma HCY concentrations were significantly higher (P 12 contents were significantly lower (P 12 concentrations were critically involved in the development and pathogenesis of cerebrovascular accidents. (authors)

  18. Changes in Plasma Copeptin Levels during Hemodialysis: Are the Physiological Stimuli Active in Hemodialysis Patients?

    Directory of Open Access Journals (Sweden)

    Esmée M Ettema

    Full Text Available Plasma levels of copeptin, a surrogate marker for the vasoconstrictor hormone arginine vasopressin (AVP, are increased in hemodialysis patients. Presently, it is unknown what drives copeptin levels in hemodialysis patients. We investigated whether the established physiological stimuli for copeptin release, i.e. plasma osmolality, blood volume and mean arterial pressure (MAP, are operational in hemodialysis patients.One hundred and eight prevalent, stable hemodialysis patients on a thrice-weekly dialysis schedule were studied during hemodialysis with constant ultrafiltration rate and dialysate conductivity in this observational study. Plasma levels of copeptin, sodium, MAP, and blood volume were measured before, during and after hemodialysis. Multivariate analysis was used to determine the association between copeptin (dependent variable and the physiological stimuli plasma sodium, MAP, excess weight as well as NT-pro-BNP immediately prior to dialysis and between copeptin and changes of plasma sodium, MAP and blood volume with correction for age, sex and diabetes during dialysis treatment.Patients were 63 ± 15.6 years old and 65% were male. Median dialysis vintage was 1.6 years (IQR 0.7-4.0. Twenty-three percent of the patients had diabetes and 82% had hypertension. Median predialysis copeptin levels were 141.5 pmol/L (IQR 91.0-244.8 pmol/L. Neither predialysis plasma sodium levels, nor NT-proBNP levels, nor MAP were associated with predialysis copeptin levels. During hemodialysis, copeptin levels rose significantly (p<0.01 to 163.0 pmol/L (96.0-296.0 pmol/L. Decreases in blood volume and MAP were associated with increases in copeptin levels during dialysis, whereas there was no significant association between the change in plasma sodium levels and the change in copeptin levels.Plasma copeptin levels are elevated predialysis and increase further during hemodialysis. Volume stimuli, i.e. decreases in MAP and blood volume, rather than osmotic

  19. Higher Plasma Myostatin Levels in Cor Pulmonale Secondary to Chronic Obstructive Pulmonary Disease.

    Directory of Open Access Journals (Sweden)

    Chun-Rong Ju

    Full Text Available To analyze plasma myostatin levels and investigate their relationship with right ventricular (RV function in patients with cor pulmonale secondary to chronic obstructive pulmonary disease (COPD.The study recruited 81 patients with advanced COPD and 40 age-matched controls. The patients were divided into two groups: those with cor pulmonale and those without. Echocardiography was used to evaluate RV function and morphology, and the value of tricuspid annular plane systolic excursion (TAPSE less than 16 mm was considered RV dysfunction. Plasma myostatin levels were analyzed by enzyme-linked immunosorbent assay, and B-type natriuretic peptide (BNP levels were analyzed as a comparison of myostatin.The data detected cor pulmonale in 39/81 patients, with the mean value of TAPSE of 14.3 mm. Plasma myostatin levels (ng/mL were significantly higher in patients with cor pulmonale (16.68 ± 2.95 than in those without (13.56 ± 3.09, and much higher than in controls (8.79±2.79, with each p<0.01. Significant differences were also found in plasma BNP levels among the three groups (p<0.05. Multivariate regression analysis suggested that myostatin levels were significantly correlated with the values of TAPSE and RV myocardium performance index among the COPD patients, and that BNP levels were significantly correlated only with systolic pulmonary arterial pressure, with each p<0.05.Plasma myostatin levels are increased in COPD patients who have cor pulmonale. Stronger correlations of plasma myostatin levels with echocardiographic indexes of the right heart suggest that myostatin might be superior to BNP in the early diagnosis of cor pulmonale in COPD.

  20. Administration of Bioflavonoides Improves Plasma Levels of Adipocyte Hormones

    Directory of Open Access Journals (Sweden)

    Boncheva M.

    2014-12-01

    Full Text Available Since time immemorial the fruits of aronia melanocarpa (rich of bioflavonoides have been known for their medicinal properties. Present-day research of the pharmacological effects of aronia melanocarpa juice and fruits intake indicates that their high contents of anthocyanins is closely related to the health enhancing properties of this plant. This is a key fact which can be used in the prevention of most commonly spread, socially significant diseases, reducing for instance the total risk of cardio-vascular diseases. The great molecular variety anthocyanins possess and the role they play in cell metabolism, are still being investigated. This gives grounds to study the effects of Aronia melanocarpa on human cells, tissues, and organs. The aim of this study is to trace the effect of 150-200 ml aronia melanokarpa juice daily oral intake on the adipocyte hormones leptin (Lp, resistine (Rs and adiponectin (Adn blood levels in 10 patients with high body mass index (BMI, kg/m2 and high waist circumference. We used ELISA methods for hormonal analyses. During the study-period of two months patients did not change anything in their lifestyle. In the study group, the levels of Rs, Lp and Adn changed significantly compared to their baseline levels (averages, ng/mL - 6.93 ± 0.137, 18.40 ±1.021 and 7.98 ± 0.077 vs. 5.06 ± 0.011, 15.23 ± 0.906 and 10.45 ± 0.103 at the end of the second month, respectively. Compared with the control group of 6 people, matched for BMI, not receiving aronia melanocarpa juice, these values were markedly different. Patients taking aronia melanokarpa juice report improvement in various conditions that have caused them discomfort before the research started: pain in the muscles and joints faded away and were replaced by a new feeling of strength, headache attacks disappeared, improvement in memory and sleep were reported, regular defecation, no signs of gastric discomfort, better vision, a quicker auditory reaction, motivation

  1. Association between cholesterol plasma levels and craving among heroin users.

    Science.gov (United States)

    Lin, Shih-Hsien; Yang, Yen Kuang; Lee, Sheng-Yu; Hsieh, Pei Chun; Chen, Po See; Lu, Ru-Band; Chen, Kao Chin

    2012-12-01

    Lipids may play some roles in the central nervous system functions that are associated with drug addiction. To date, cholesterol is known to influence relapse of cocaine use. However, the relationship between cholesterol and heroin craving is unclear. This study examined the concurrent association between cholesterol and craving. The serum lipid levels of 70 heroin users who were undergoing or had undergone a methadone maintenance therapy were measured. Their craving and demographic data were assessed. Total cholesterol and low-density lipoprotein cholesterol are negatively associated with craving before (r = -0.33, P cognitive aspect of craving and may be a potential marker to predict risk of drug relapse.

  2. Fructose levels are markedly elevated in cerebrospinal fluid compared to plasma in pregnant women.

    Directory of Open Access Journals (Sweden)

    Janice J Hwang

    Full Text Available Fructose, unlike glucose, promotes feeding behavior in rodents and its ingestion exerts differential effects in the human brain. However, plasma fructose is typically 1/1000 th of glucose levels and it is unclear to what extent fructose crosses the blood-brain barrier. We investigated whether local endogenous central nervous system (CNS fructose production from glucose via the polyol pathway (glucose → sorbitol → fructose contributes to brain exposure to fructose.In this observational study, fasting glucose, sorbitol and fructose concentrations were measured using gas-chromatography-liquid mass spectroscopy in cerebrospinal fluid (CSF, maternal plasma, and venous cord blood collected from 25 pregnant women (6 lean, 10 overweight/obese, and 9 T2DM/gestational DM undergoing spinal anesthesia and elective cesarean section.As expected, CSF glucose was ~ 60% of plasma glucose levels. In contrast, fructose was nearly 20-fold higher in CSF than in plasma (p < 0.001, and CSF sorbitol was ~ 9-times higher than plasma levels (p < 0.001. Moreover, CSF fructose correlated positively with CSF glucose (ρ 0.45, p = 0.02 and sorbitol levels (ρ 0.75, p < 0.001. Cord blood sorbitol was also ~ 7-fold higher than maternal plasma sorbitol levels (p = 0.001. There were no differences in plasma, CSF, and cord blood glucose, fructose, or sorbitol levels between groups.These data raise the possibility that fructose may be produced endogenously in the human brain and that the effects of fructose in the human brain and placenta may extend beyond its dietary consumption.

  3. Fructose levels are markedly elevated in cerebrospinal fluid compared to plasma in pregnant women.

    Science.gov (United States)

    Hwang, Janice J; Johnson, Andrea; Cline, Gary; Belfort-DeAguiar, Renata; Snegovskikh, Denis; Khokhar, Babar; Han, Christina S; Sherwin, Robert S

    2015-01-01

    Fructose, unlike glucose, promotes feeding behavior in rodents and its ingestion exerts differential effects in the human brain. However, plasma fructose is typically 1/1000 th of glucose levels and it is unclear to what extent fructose crosses the blood-brain barrier. We investigated whether local endogenous central nervous system (CNS) fructose production from glucose via the polyol pathway (glucose → sorbitol → fructose) contributes to brain exposure to fructose. In this observational study, fasting glucose, sorbitol and fructose concentrations were measured using gas-chromatography-liquid mass spectroscopy in cerebrospinal fluid (CSF), maternal plasma, and venous cord blood collected from 25 pregnant women (6 lean, 10 overweight/obese, and 9 T2DM/gestational DM) undergoing spinal anesthesia and elective cesarean section. As expected, CSF glucose was ~ 60% of plasma glucose levels. In contrast, fructose was nearly 20-fold higher in CSF than in plasma (p < 0.001), and CSF sorbitol was ~ 9-times higher than plasma levels (p < 0.001). Moreover, CSF fructose correlated positively with CSF glucose (ρ 0.45, p = 0.02) and sorbitol levels (ρ 0.75, p < 0.001). Cord blood sorbitol was also ~ 7-fold higher than maternal plasma sorbitol levels (p = 0.001). There were no differences in plasma, CSF, and cord blood glucose, fructose, or sorbitol levels between groups. These data raise the possibility that fructose may be produced endogenously in the human brain and that the effects of fructose in the human brain and placenta may extend beyond its dietary consumption.

  4. Plasma ghrelin levels during exercise - effects of intensity and duration.

    Science.gov (United States)

    Erdmann, Johannes; Tahbaz, Rana; Lippl, Florian; Wagenpfeil, Stefan; Schusdziarra, Volker

    2007-10-04

    Ghrelin, a recently discovered hormone of gastric origin has been shown to stimulate appetite and food intake. In man it is considered to play a role in energy homeostasis and regulation of somatropic function. As exercise affects hunger/satiety sensations and food intake, at least under some experimental conditions, we investigated the effect of exercise intensity and duration on ghrelin release and subsequent ad libitum food intake in normal weight subjects. Bicycle exercise on an ergometer for 30 min at 50 W which was below the aerob-anaerobic threshold led to an increase of ghrelin which remained unchanged during the higher intensity at 100 W. Respective hunger/satiety ratings and subsequent food intake and postprandial ghrelin suppression were identical and not different from controls. In a second group 7 subjects cycled at 50 W for 30, 60 and 120 min, respectively. Ghrelin concentrations rose significantly by 50-70 pg/ml above baseline for the respective period of exercise. While postexercise premeal ghrelin levels were not significantly different subsequent food intake after 120 min of cycling was significantly greater compared to control, 30 min and 60 min exercise, respectively. The present data suggest that low rather than high-intensity exercise stimulates ghrelin levels independent of exercise duration. Stimulation of food intake during prolonged exercise is most likely not due to changes of ghrelin.

  5. Relevance of plasma malondialdehyde level and severity of portal hypertension in cirrhotic patients.

    Science.gov (United States)

    Wang, Sheng-Lan; Zhu, Xin-Yan; Zhang, Dong-Wei; Zhang, Zhao-Jie; Gao, Heng-Jun; Yang, Chang-Qing

    2015-01-01

    Portal hypertension is one of the death reasons for the liver cirrhosis patients. The oxidative stress is related to the occurrence and development of portal hypertension in cirrhosis. Malondialdehyde (MDA), one of the lipid peroxides, increases substantially in cirrhotic patients. To evaluate the relevance between the MDA level and portal hypertension in cirrhotic patients. 60 liver cirrhotic patients and 30 healthy controls were enrolled. The plasma MDA level and general blood tests including ALT, AST, ALB, total bilirubin, and platelet were measured. All people enrolled accepted endoscopic examination and B-Ultrasound check to evaluate the severity of portal hypertension. The MDA plasma level of cirrhotic patients was significantly higher than the controls (Pportal hypertension (Pportal vein (r=0.652, Pportal hypertension. Plasma MDA level may correlate with the severity of portal hypertension in cirrhotic patients.

  6. L-carnitine plasma levels in dogs and cats. A diagnostic parameter?

    International Nuclear Information System (INIS)

    Fischer, J.

    1993-04-01

    The relation between levels of carnitine in plasma and lesions of organs should be demonstrated. 52 dogs and 58 cats examined in veterinary clinics for several reasons and routinely screened for blood chemistry also were analysed for free plasma carnitine by a radiocarbon method. Increased carnitine levels were observed in both species in case of heart, liver and kidney disorders. Additionally the influence of food intake on carnitine levels in dogs was studied. Postprandial changes were insignificant. Because of lack of information about carnitine levels in cats and changes with age plasma carnitine was determined in cats and kittens. The range of normal values was 8.2 to 24.2 μmol/l without any significance of age

  7. Plasma beta-endorphin levels in obese and non-obese patients with polycystic ovary disease.

    Science.gov (United States)

    Martínez-Guisasola, J; Guerrero, M; Alonso, F; Díaz, F; Cordero, J; Ferrer, J

    2001-02-01

    The aim of this study was to determine the influence of body weight on circulating plasma levels of beta-endorphin and insulin in women with polycystic ovary disease (PCOD), as well as the correlation between the plasma levels of beta-endorphin and insulin. One-hundred and sixty-seven consecutive subjects with PCOD were recruited, 117 of whom had normal weight (body mass index (BMI) 25). A venous blood sample was taken and plasma concentrations of beta-endorphin, insulin, gonadotropins, prolactin, progesterone, 17 beta-estradiol, estrone, androgens, dehydroepiandrosterone sulfate and sex hormone-binding globulin (SHBG) were measured. Mean beta-endorphin and insulin plasma levels were significantly higher (p PCOD women than in non-obese ones. Correlation analysis showed a positive association between insulin and beta-endorphin, beta-endorphin and BMI (and weight), insulin and BMI (and weight), and a negative correlation was found between insulin and SHBG. A weak association was found between beta-endorphin and luteinizing hormone (LH) in peripheral plasma. Stratified and linear regression analysis showed that plasma beta-endorphin concentrations correlate more with BMI than with insulinemia.

  8. VEGF-121 plasma level as biomarker for response to anti-angiogenetic therapy in recurrent glioblastoma.

    Science.gov (United States)

    Martini, Maurizio; de Pascalis, Ivana; D'Alessandris, Quintino Giorgio; Fiorentino, Vincenzo; Pierconti, Francesco; Marei, Hany El-Sayed; Ricci-Vitiani, Lucia; Pallini, Roberto; Larocca, Luigi Maria

    2018-05-10

    Vascular endothelial growth factor (VEGF) isoforms, particularly the diffusible VEGF-121, could play a major role in the response of recurrent glioblastoma (GB) to anti-angiogenetic treatment with bevacizumab. We hypothesized that circulating VEGF-121 may reduce the amount of bevacizumab available to target the heavier isoforms of VEGF, which are the most clinically relevant. We assessed the plasma level of VEGF-121 in a brain xenograft model, in human healthy controls, and in patients suffering from recurrent GB before and after bevacizumab treatment. Data were matched with patients' clinical outcome. In athymic rats with U87MG brain xenografts, the level of plasma VEGF-121 relates with tumor volume and it significantly decreases after iv infusion of bevacizumab. Patients with recurrent GB show higher plasma VEGF-121 than healthy controls (p = 0.0002) and treatment with bevacizumab remarkably reduced the expression of VEGF-121 in plasma of these patients (p = 0.0002). Higher plasma level of VEGF-121 was significantly associated to worse PFS and OS (p = 0.0295 and p = 0.0246, respectively). Quantitative analysis of VEGF-121 isoform in the plasma of patients with recurrent GB could be a promising predictor of response to anti-angiogenetic treatment.

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

    Science.gov (United States)

    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

  10. PLASMA OXYTOCIN LEVELS PREDICT SOCIAL CUE RECOGNITION IN INDIVIDUALS WITH SCHIZOPHRENIA

    OpenAIRE

    Strauss, Gregory P.; Keller, William R.; Koenig, James I.; Gold, James M.; Frost, Katherine H.; Buchanan, Robert W.

    2015-01-01

    Lower endogenous levels of the neuropeptide oxytocin may be an important biological predictor of social cognition impairments in schizophrenia (SZ). Prior studies have demonstrated that lower-level social cognitive processes (e.g., facial affect perception) are significantly associated with reduced plasma oxytocin levels in SZ; however, it is unclear whether higher-level social cognition, which requires inferential processes and knowledge not directly presented in the stimulus, is associated ...

  11. Arterial and venous plasma levels of bupivacaine following epidural and intercostal nerve blocks.

    Science.gov (United States)

    Moore, D C; Mather, L E; Bridenbaugh, P O; Bridenbaugh, L D; Balfour, R I; Lysons, D F; Horton, W G

    1976-07-01

    Arterial and peripheral venous plasma levels of bupivacaine were determined in 30 patients following epidural anesthesia using 150 and 225 mg, as well as following intercostal nerve block with 400 mg. Arterial levels were consistently higher than levels in simultaneously sampled venous blood, and the highest levels occurred with bilateral intercostal nerve block. No evidence of systemic toxicity was observed. The results suggest that bupivacaine may have a wider margin of safety in man than is now stated.

  12. Clinical Significance of Plasma CEA Levels in the Patients with Cervical Carcinoma during Follow-Up

    Energy Technology Data Exchange (ETDEWEB)

    Bang, Sung Beom; Kim, Joo Young; Choi, Myung Sun; Rha, Joong Yeol; Lee, Min Jae [Korea University College of Medicine, Seoul (Korea, Republic of)

    1991-12-15

    Carcinoembryonic antigen (CEA) has been studied in the field of gynecologic malignancy to determine whether it can be used as a tumor marker for early detection of recurrence or evaluation of therapeutic results. From January 1985 through December 1989, a total of 239 cervical cancer patients were entered for an analysis of plasma CEA level in the group with cervical cancer compared to the control group consisting of 65 normal healthy women and 18 women with benign gynecologic disease. Plasma CEA levels appear to be directly related with the tumor extension and as stages advance, the incidence of patients with abnormal plasma CEA levels is increased. Also, there seems to be a little higher incidence of abnormal CEA levels in patients with adenocarcinomas or adenosquamous carcinoma but not statistically significant because of small number of patients. When the patients developed recurrence, plasma CEA levels are markedly elevated in the majority, particularly in patients with hepatic metastases. In conclusion, serial plasma CEA checks could be used to detect recurrence during follow-up after treatment of cervical cancer.

  13. Reduced plasma taurine level in Parkinson's disease: association with motor severity and levodopa treatment.

    Science.gov (United States)

    Zhang, Li; Yuan, Yongsheng; Tong, Qing; Jiang, Siming; Xu, Qinrong; Ding, Jian; Zhang, Lian; Zhang, Rui; Zhang, Kezhong

    2016-01-01

    This study aimed to evaluate the level of taurine in plasma, and its association with the severity of motor and non-motor symptoms (NMS) and chronic levodopa treatment in Parkinson's disease (PD). Plasma taurine level was measured in treated PD (tPD), untreated PD (ntPD) and control groups. Motor symptoms and NMS were assessed using the Unified Parkinson's Disease Rating Scale, the short form of the McGill Pain Questionnaire, the Hamilton Depression Scale, the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms and the Pittsburgh Sleep Quality Index. Longtime exposure to levodopa was indicated by its approximate cumulative dosage. The plasma taurine levels of PD patients were decreased when compared with controls and negatively associated with motor severity but not NMS. Moreover, tPD patients exhibited lower levels of plasma taurine than ntPD patients. Interestingly, plasma taurine levels negatively correlated with cumulative levodopa dosage in tPD. After controlling for potential confounders, the association between taurine and levodopa remained significant. Our study supports that taurine may play important roles in the pathophysiology of PD and the disturbances caused by chronic levodopa administration.

  14. Elevated plasma procalcitonin level predicts poor prognosis of ST elevation myocardial infarction in Asian elderly.

    Science.gov (United States)

    Dai, Junru; Xia, Bangbo; Wu, Xiaomiao

    Previous studies have focused on relationship between plasma procalcitonin level and myocardial infarction risk, but this relationship in Asian elderly has not been investigated. The aim of this study was to reveal the association of peripheral procalcitonin concentration (both immediate and average levels) with myocardial infarction prognosis in Asian elderly. A total of 400 ST-elevation myocardial infarction patients, 400 unstable angina patients and 400 controls were included. Plasma levels of high-sensitivity C-reactive protein and procalcitonin were measured using commercially available kits. Each myocardial infarction patient received a standard therapy and a 12-month follow-up unless major adverse cardiac events occurred. On admission, plasma procalcitonin level was higher in myocardial infarction patients than in unstable angina patients and controls (p < .001). In the follow-up period, 142 myocardial infarction patients suffered from major adverse cardiac events, and other 258 myocardial infarction patients did not. Higher admission, peak and average plasma levels of procalcitonin in the first week after chest pain onset were associated with elevated risk of major adverse cardiac events (HR: 1.46, 95%CI: 1.18-1.99; HR: 2.57, 95%CI: 1.99-3.52; HR: 2.36, 95%CI: 1.81-3.00). Plasma procalcitonin level had a positive linear correlation with plasma level of high-sensitivity C-reactive protein on admission (r = 0.650, p < .001). In conclusion, peripheral concentration of procalcitonin (both immediate and average levels) might be an independent predictor for prognosis in myocardial infarction patients. Prognostic significance of procalcitonin might be implicated in inflammation.

  15. Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers

    NARCIS (Netherlands)

    L.H.H. Meeter (Lieke H.H.); Patzke, H. (Holger); Loewen, G. (Gordon); E.G.P. Dopper (Elise); Y. Pijnenburg (Yolande); A.S. Thornton (Andrew); J.C. van Swieten (John)

    2016-01-01

    textabstractBackground: Pathogenic mutations in the granulin gene (GRN) are causative in 5-10% of patients with frontotemporal dementia (FTD), mostly leading to reduced progranulin protein (PGRN) levels. Upcoming therapeutic trials focus on enhancing PGRN levels. Methods: Fluctuations in plasma PGRN

  16. Effect of anticonvulsants on plasma testosterone and sex hormone binding globulin levels.

    Science.gov (United States)

    Barragry, J M; Makin, H L; Trafford, D J; Scott, D F

    1978-01-01

    Plasma sex hormone binding globulin (SHBG) and testosterone levels were measured in 29 patients with epilepsy (16 men and 13 women), most of them on chronic therapy with anticonvulsant drugs. Sex hormone binding globulin concentrations were increased in both sexes and testosterone levels in male patients. It is postulated that anticonvulsants may induce hepatic synthesis of SHBG. PMID:569688

  17. Higher Plasma Myostatin Levels in Cor Pulmonale Secondary to Chronic Obstructive Pulmonary Disease.

    Science.gov (United States)

    Ju, Chun-Rong; Chen, Miao; Zhang, Jian-Heng; Lin, Zhi-Ya; Chen, Rong-Chang

    2016-01-01

    To analyze plasma myostatin levels and investigate their relationship with right ventricular (RV) function in patients with cor pulmonale secondary to chronic obstructive pulmonary disease (COPD). The study recruited 81 patients with advanced COPD and 40 age-matched controls. The patients were divided into two groups: those with cor pulmonale and those without. Echocardiography was used to evaluate RV function and morphology, and the value of tricuspid annular plane systolic excursion (TAPSE) less than 16 mm was considered RV dysfunction. Plasma myostatin levels were analyzed by enzyme-linked immunosorbent assay, and B-type natriuretic peptide (BNP) levels were analyzed as a comparison of myostatin. The data detected cor pulmonale in 39/81 patients, with the mean value of TAPSE of 14.3 mm. Plasma myostatin levels (ng/mL) were significantly higher in patients with cor pulmonale (16.68 ± 2.95) than in those without (13.56 ± 3.09), and much higher than in controls (8.79±2.79), with each pmyostatin levels were significantly correlated with the values of TAPSE and RV myocardium performance index among the COPD patients, and that BNP levels were significantly correlated only with systolic pulmonary arterial pressure, with each pmyostatin levels are increased in COPD patients who have cor pulmonale. Stronger correlations of plasma myostatin levels with echocardiographic indexes of the right heart suggest that myostatin might be superior to BNP in the early diagnosis of cor pulmonale in COPD.

  18. Plasma tumor necrosis factor-a (TNF-a) levels in Gaucher disease

    NARCIS (Netherlands)

    Michelakakis, H.; Spanou, C.; Kondyli, A.; Dimitriou, E.; van Weely, S.; Hollak, C. E.; van Oers, M. H.; Aerts, J. M.

    1996-01-01

    Tumor necrosis factor-a (TNF-a) levels were measured in the plasma of patients with different types of Gaucher disease (GD) and patients with other lysosomal storage diseases. The highest TNF-a levels were observed in the most severe neuronopathic type of GD, exceeding those found in healthy

  19. Influence of Erythropoietin Dose and Albumin Level on the Plasma Brain Natriuretic Peptide in Hemodialysis Patients

    Directory of Open Access Journals (Sweden)

    Alsuwaida Abdulkareem

    2006-01-01

    Full Text Available Brain natriuretic peptide (BNP levels increase in patients with congestive heart failure. Theoretically, BNP levels can be helpful in the determination of the "dry weight" of hemodialysis patients. To evaluate the effect of hemodialysis on the plasma concentration of BNP and to determine the factors that affect BNP levels during hemodialysis in patients with chronic renal failure, we studied five stable patients with chronic renal failure. A total of 15 blood samples were obtained for BNP levels at 24, 48 and 72 hours after the last hemodialysis session. The plasma BNP levels did not change significantly either with ultrafiltration volume or with time since last dialysis. However, the BNP levels correlated positively with the erythropoietin (EPO dose (r=0.98, P< 0.001 and negatively with the serum albumin levels (r = 0.94, P=0.02. Univariate analysis showed that the EPO dose (P=0.001 and the albumin level (P=0.02 were significant predictors of BNP level. Adjusted multivariate analysis showed significant interaction between the EPO dose and the albumin level (P=0.01, P=0.03 respectively. In conclusion: the plasma BNP levels were not significantly influenced by ultrafiltration volume or time since last dialysis. However, the BNP levels may be a useful prognostic parameter for assessing the risk of cardiovascular morbidity and mortality in hemodialysis patients.

  20. Changes of plasma neuropeptide Y levels in patients with ischemic heart disease

    International Nuclear Information System (INIS)

    Cheng Guanghua; Zhang Xinlu; Yang Jun

    2001-01-01

    Objective: To study the pathophysiological significance of neuropeptide Y(NPY) in ischemic heart disease (IHD). Methods: The plasma NPY levels were measured by radioimmunoassay in 35 patients with angina pectoris (Group A), 31 patients with acute myocardial infarctions (AMI) without heart failure (Group B), 29 patients of AMI with left heart failure (Group C) and 27 normal subjects. Results: The plasma NPY levels were higher in all these patients on admission than those in controls with the highest values in the most severe patients. The NPY levels in group A decreased to normal levels on day 1. In group B a significant increase in the levels of NPY was observed on day 1. Their NPY levels decreased significantly on days 4 and 7, but never to normal levels until day 28. Considerable increase in the levels of NPY were observed in group C on days 1 and 4. The levels of NPY were extremely high in six AMI patients with acute left heart failure before death. The NPY levels began to decrease on day 7 but never to their levels on admission until day 28; at that time the NPY levels were still higher than those in controls. Conclusion: These information indicated that plasma NPY might be useful for monitoring and predicting prognosis in patients with ischemic heart disease

  1. Decreased plasma prorenin levels in primary aldosteronism: potential diagnostic implications.

    Science.gov (United States)

    Berge, Constance; Courand, Pierre-Yves; Harbaoui, Brahim; Paget, Vinciane; Khettab, Fouad; Bricca, Giampiero; Fauvel, Jean-Pierre; Lantelme, Pierre

    2015-01-01

    Primary aldosteronism could exert a negative feedback on prorenin secretion, of possibly different magnitude, whether it is related to an aldosterone-producing adenoma (APA) or an idiopathic hyperaldosteronism (IHA). The objectives of this study were to evaluate the level of prorenin in three subgroups: APA, IHA, and essential hypertension; and the performance of the aldosterone-to-prorenin ratio (APR) for the diagnosis of an APA. Seven hundred and forty-six hypertensive patients with a standardized work-up, including a prorenin measurement, were considered. Ninety-six patients without neutral treatment and 38 patients with other forms of secondary hypertension were excluded. APA and IHA were categorized according to computed tomography scan, adrenal venous sampling, pathological analysis and improvement of hypertension after surgery. Thirty-five patients had a diagnosis of APA, 57 of IHA and 504 of essential hypertension. Prorenin was lower in APA and IHA than in essential hypertension (32.9, 40.4 and 50.3  pg/ml, respectively; P < 0.001). APR was higher in patients with APA and IHA than in those with essential hypertension (24.0, 11.8, and 4.0  pmol/l per pg/ml, respectively; P < 0.001). The APR was more discriminant than the aldosterone-to-renin ratio to identify APA compared to IHA (area under the receiver operating curve at 0.750 and 0.639, respectively; P = 0.04). The optimal cut-off values were 22  pmol/l per pg/ml for APR (sensitivity 57.0%, specificity 93.0%) and 440  pmol/l per pg/ml for aldosterone-to-renin ratio (sensitivity 54.3%, specificity 82.5%). Primary aldosteronism and particularly its most caricatural form, that is APA, seems associated with a lower level of prorenin than essential hypertension. The APR could be included in the diagnostic strategy of APA.

  2. Hormonal Influence on Coenzyme Q10 Levels in Blood Plasma

    Directory of Open Access Journals (Sweden)

    Alfredo Pontecorvi

    2011-12-01

    Full Text Available Coenzyme Q10 (CoQ10, also known as ubiquinone for its presence in all body cells, is an essential part of the cell energy-producing system. However, it is also a powerful lipophilic antioxidant protecting lipoproteins and cell membranes. Due to these two actions, CoQ10 is commonly used in clinical practice in chronic heart failure, male infertility, and neurodegenerative disease. However, it is also taken as an anti-aging substance by healthy people aiming for long-term neuroprotection and by sportsmen to improve endurance. Many hormones are known to be involved in body energy regulation, in terms of production, consumption and dissipation, and their influence on CoQ10 body content or blood values may represent an important pathophysiological mechanism. We summarize the main findings of the literature about the link between hormonal systems and circulating CoQ10 levels. In particular the role of thyroid hormones, directly involved in the regulation of energy homeostasis, is discussed. There is also a link with gonadal and adrenal hormones, partially due to the common biosynthetic pathway with CoQ10, but also to the increased oxidative stress found in hypogonadism and hypoadrenalism.

  3. 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)

  4. Plasma adiponectin levels correlate positively with an increasing number of components of frailty in male elders.

    Directory of Open Access Journals (Sweden)

    Jaw-Shiun Tsai

    Full Text Available OBJECTIVE: Frailty is an important geriatric syndrome. Adiponectin is an important adipokine that regulates energy homeostasis. The aim of this study is to investigate the relationship between plasma adiponectin levels and frailty in elders. METHODS: The demographic data, body weight, metabolic and inflammatory parameters, including plasma glucose, total cholesterol, triglyceride, tumor necrosis factor alpha (TNF-α, c-reactive protein (CRP and adiponectin levels, were assessed. The frailty score was assessed using the Fried Frailty Index (FFI. RESULTS: The mean (SD age of the 168 participants [83 (49.4% men and 85 (50.6% women] was 76.86 (6.10 years. Judged by the FFI score, 42 (25% elders were robust, 92 (54.7% were pre-frail, and 34 (20.3% were frail. The mean body mass index was 25.19 (3.42 kg/m(2. The log-transformed mean (SD plasma adiponectin (µg/mL level was 1.00 (0.26. The log-transformed mean plasma adiponectin (µg/mL levels were 0.93 (0.23 in the robust elders, 1.00 (0.27 in the pre-frail elders, and 1.10 (0.22 in the frail elders, and the differences between these values were statistically significant (p  = 0.012. Further analysis showed that plasma adiponectin levels rose progressively with an increasing number of components of frailty in all participants as a whole (p for trend  = 0.024 and males (p for trend  = 0.037, but not in females (p for trend  = 0.223. CONCLUSION: Plasma adiponectin levels correlate positively with an increasing number of components of frailty in male elders. The difference between the sexes suggests that certain sex-specific mechanisms may exist to affect the association between adiponectin levels and frailty.

  5. Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Lian-Hua Cui

    2016-06-01

    Full Text Available Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B12 in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients’ clinical characteristics including tumor-node-metastasis (TNM stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B12 levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR (95% confidence intervals (CI of HCC from the highest to lowest quartile of folate were 0.30 (0.15–0.60, 0.33 (0.17–0.65, and 0.19 (0.09–0.38. Compared to the subjects in the lowest quartile of plasma vitamin B12, only the subjects in the highest quartile of vitamin B12 exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02–3.98. HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B12 levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels, whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B12 than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B12 levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results.

  6. Partitioning the variability of fasting plasma glucose levels in pedigrees. Genetic and environmental factors.

    Science.gov (United States)

    Boehnke, M; Moll, P P; Kottke, B A; Weidman, W H

    1987-04-01

    Fasting plasma glucose measurements made in 1972-1977 on normoglycemic individuals in three-generation Caucasian pedigrees from Rochester, Minnesota were analyzed. The authors determined the contributions of polygenic loci and environmental factors to fasting plasma glucose variability in these pedigrees. To that end, fasting plasma glucose measurements were normalized by an inverse normal scores transformation and then regressed separately for males and females on measured concomitants including age, body mass index (weight/height2), season of measurement, sex hormone use, and diuretic use. The authors found that 27.7% of the variability in normalized fasting plasma glucose in these pedigrees is explained by these measured concomitants. Subsequent variance components analysis suggested that unmeasured polygenic loci and unmeasured shared environmental factors together account for at least an additional 36.7% of the variability in normalized fasting plasma glucose, with genes alone accounting for at least 27.3%. These results are consistent with the known familiality of diabetes, for which fasting plasma glucose level is an important predictor. Further, these familial factors provide an explanation for at least half the variability in normalized fasting plasma glucose which remains after regression on known concomitants.

  7. The association between estimated average glucose levels and fasting plasma glucose levels in a rural tertiary care centre

    Directory of Open Access Journals (Sweden)

    Raja Reddy P

    2013-01-01

    Full Text Available The level of hemoglobin A1c (HbA1c, also known as glycated hemoglobin, determines how well a patient’s blood glucose level has been controlled over the previous 8-12 weeks. HbA1c levels help patients and doctors understand whether a particular diabetes treatment is working and whether adjustments need to be made to the treatment. Because the HbA1c level is a marker of blood glucose for the previous 60- 90 days, average blood glucose levels can be estimated using HbA1c levels. Aim in the present study was to investigate the relationship between estimated average glucose levels, as calculated by HbA1c levels, and fasting plasma glucose levels. Methods: Type 2 diabetes patients attending medicine outpatient department of RL Jalappa hospital, Kolar between March 2010 and July 2012 were taken. The estimated glucose levels (mg/dl were calculated using the following formula: 28.7 x HbA1c-46.7. Glucose levels were determined using the hexokinase method. HbA1c levels were determined using an HPLC method. Correlation and independent t- test was the test of significance for quantitative data. Results: A strong positive correlation between fasting plasma glucose level and estimated average blood glucose levels (r=0.54, p=0.0001 was observed. The difference was statistically significant. Conclusion: Reporting the estimated average glucose level together with the HbA1c level is believed to assist patients and doctors determine the effectiveness of blood glucose control measures.

  8. Myoglobin plasma level related to muscle mass and fiber composition: a clinical marker of muscle wasting?

    Science.gov (United States)

    Weber, Marc-André; Kinscherf, Ralf; Krakowski-Roosen, Holger; Aulmann, Michael; Renk, Hanna; Künkele, Annette; Edler, Lutz; Kauczor, Hans-Ulrich; Hildebrandt, Wulf

    2007-08-01

    Progressive muscle wasting is a central feature of cancer-related cachexia and has been recognized as a determinant of poor prognosis and quality of life. However, until now, no easily assessable clinical marker exists that allows to predict or to track muscle wasting. The present study evaluated the potential of myoglobin (MG) plasma levels to indicate wasting of large locomotor muscles and, moreover, to reflect the loss of MG-rich fiber types, which are most relevant for daily performance. In 17 cancer-cachectic patients (weight loss 22%) and 27 age- and gender-matched healthy controls, we determined plasma levels of MG and creatine kinase (CK), maximal quadriceps muscle cross-sectional area (CSA) by magnetic resonance imaging, muscle morphology and fiber composition in biopsies from the vastus lateralis muscle, body cell mass (BCM) by impedance technique as well as maximal oxygen uptake (VO(2)max). In cachectic patients, plasma MG, muscle CSA, BCM, and VO(2)max were 30-35% below control levels. MG showed a significant positive correlation to total muscle CSA (r = 0.65, p max as an important functional readout. CK plasma levels appear to be less reliable because prolonged increases are observed in even subclinical myopathies or after exercise. Notably, cancer-related muscle wasting was not associated with increases in plasma MG or CK in this study.

  9. [Is plasma selenium correlated to transthyretin levels in critically ill patients?

    Science.gov (United States)

    Freitas, Renata G B O N; Nogueira, Roberto Jose Negrão; Cozzolino, Silvia Maria Franciscato; Vasques, Ana Carolina Junqueira; Ferreira, Matthew Thomas; Hessel, Gabriel

    2017-06-05

    Selenium is an essential trace element, but critically ill patients using total parenteral nutrition (PN) do not receive selenium because this mineral is not commonly offered. Threfore, the eval uation of plasma selenium levels is very important for treating or preventing this deficiency. Recent studies have shown that transthyretin may reflect the selenium intake and could be considered a biomarker. However, this issue is still little explored in the literature. This study aims to investigate the correlation of transthyretin with the plasma selenium of critically ill patients receiving PN. This was a prospective cohort study with 44 patients using PN without selenium. Blood samples were carried out in 3 stages: initial, 7th and 14th day of PN. In order to evaluate the clinical condition and the inflammatory process, albumin, C-reactive protein (CRP), transthyretin, creatinine and HDL cholesterol levels were observed. To assess the selenium status, plasma selenium and glutathione peroxidase (GPx) in whole blood were measured. Descriptive analyses were performed and the ANOVA, Mann-Whitney and Spearman's coefficient tests were conducted; we assumed a significance level of 5%. A positive correlation of selenium with the GPx levels (r = 0.46; p = 0.03) was identified. During two weeks, there was a positive correlation of transthyretin with plasma selenium (r = 0.71; p = 0.05) regardless of the CRP values. Transthyretin may have reflected plasma selenium, mainly because the correlation was verified after the acute phase.

  10. Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke.

    Science.gov (United States)

    Yoo, J H; Lee, S C

    2001-10-01

    Cerebrovascular risk factors, including hypertension, smoking, diabetes mellitus, aging, dyslipidemia, and hyperhomocyst(e)inemia are linked to endothelial dysfunction. Endothelial-derived nitric oxide (NO) has inhibitory effects on key processes in atherothrombosis. Although asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is associated with atherosclerotic disease, there has been no report on association of ADMA with ischemic stroke. Here we investigated the relation of plasma ADMA, stroke, and homocyst(e)inemia in the elderly. Plasma ADMA and homocyst(e)ine concentration was determined using high-performance liquid chromatography and fluorescence detection. Patients with ischemic stroke had significantly higher concentrations of plasma ADMA than controls (1.85+/-1.32 vs. 0.93+/-0.32 micromol/l, P=0.0001). After adjustment for risk factors, elevated ADMA levels, above 90th percentile of normal controls (> or =1.43 micromol/l) was associated with stroke (OR=6.05, 95% CI; 2.77-13.3, P=0.02). ADMA plasma levels were positively correlated to homocyst(e)ine levels (r=0.43, P=0.01). Multiple logistic regression analysis revealed that hyperhomocyst(e)inemia (plasma homocyst(e)ine concentration > or =15.0 micromol/l) was a significant predictor of elevated ADMA level. Altogether, findings indicate that elevated ADMA concentrations are at increased risk for ischemic stroke in the elderly, and may account for increased risk of stroke in patients with hyperhomocyst(e)inemia.

  11. Pre-storage centrifugation conditions have significant impact on measured microRNA levels in biobanked EDTA plasma samples

    DEFF Research Database (Denmark)

    Binderup, Helle Glud; Houlind, Kim; Madsen, Jonna Skov

    2016-01-01

    in platelets this may partly be explained by residual platelets in the plasma samples used. When collecting fresh plasma samples, it is possible to produce cell-free/platelet-poor plasma by centrifugation. In this study, we systematically investigated whether biobanked EDTA plasma samples could be processed...... to be suitable for miRNA analysis. Materials and methods: Blood samples were collected from ten healthy volunteers and centrifuged to produce platelet-poor-plasma (PPP) and standard biobank plasma. After one week at -80 °C the biobanked EDTA plasma was re-centrifuged by different steps to remove residual...... platelets. Using RT-qPCR the levels of 14 miRNAs in the different plasma preparations were compared to that of PPP. Results: We were able to remove residual platelets from biobanked EDTA plasma by re-centrifugation of the thawed samples. Nevertheless, for most of the investigated miRNAs, the miRNA level...

  12. Soluble CD206 plasma levels in rheumatoid arthritis reflect decrease in disease activity

    DEFF Research Database (Denmark)

    Heftdal, Line Dam; Stengaard-Pedersen, Kristian; Ørnbjerg, Lykke Midtbøll

    2017-01-01

    internalization and degradation. The soluble form has been suggested as a biomarker of M2A-macrophage activation. The aim of this study was to investigate sCD206 plasma levels in early RA patients initiating anti-TNFα treatment. Plasma levels of sCD206 were measured by ELISA in samples from 155 early RA patients...... from baseline after 6 months. In the ADA group, however, levels remained lower than baseline throughout the treatment period. In conclusion, initially, plasma sCD206 in early RA patients decreased in accordance with disease activity and initiation of DMARD treatment. Treatment with anti-TNFα preserved......Rheumatoid arthritis (RA) is characterized by chronic joint inflammation and infiltration by activated macrophages. TNFα is a central mediator in this process. The mannose receptor, CD206, is a scavenger receptor expressed by M2A-macrophages and dendritic cells. It is involved in collagen...

  13. Clinical significance of determination of changes of serum TSGF and plasma VEGF levels after treatment in patients with endometriosis

    International Nuclear Information System (INIS)

    Shi Shaohong; Tian Xiaoping

    2006-01-01

    Objective: To investigate the changes of serum TSGF and plasma VEGF levels after treatment in patients with endometriosis. Methods: Serum TSGF levels were determined with ELISA mad plasma VEGF levels with biochemistry in 31 patients with endometriosis both before and after treatment as well as in 30 controls. Results: Before treatment the serum TSGF and plasma VEGF levels in patients were significantly higher than those in the controls (P 0.05). Conclusion: Development of endometriosis were closely related to the plasma levels of VEGF and serum TSGF levels. (authors)

  14. Plasma selenium levels in healthy blood bank donors in the central-eastern part of Belgium.

    Science.gov (United States)

    Van Cauwenbergh, Rudy; Robberecht, Harry; Van Vlaslaer, Veerle; De Smet, Annie; Emonds, Marie-Paule; Hermans, Nina

    2007-01-01

    Graphite furnace atomic absorption spectrometry, with Zeeman background correction and after improved matrix modification, was used to measure the plasma selenium content of healthy blood bank donors in the central part of Belgium. The mean plasma selenium concentration of 80 men and 80 women was 79.7+/-4.4ng/mL with a range of 55.0-117.4ng/mL. There was no gender difference observed. Plasma selenium level was significantly highest for the adult group, aged 45-64 years, compared to the others, except the young adults (18-24 years). The mean plasma selenium concentration measured corresponded well with literature data for Belgium. The obtained values were found to be in the medium range, compared with recent literature values for the European countries.

  15. Interleukin-7 Plasma Levels in Human Differentiate Anorexia Nervosa, Constitutional Thinness and Healthy Obesity.

    Science.gov (United States)

    Germain, Natacha; Viltart, Odile; Loyens, Anne; Bruchet, Céline; Nadin, Katia; Wolowczuk, Isabelle; Estour, Bruno; Galusca, Bogdan

    2016-01-01

    Interleukin-7 (IL-7) is a cytokine involved in energy homeostasis as demonstrated in rodents. Anorexia nervosa is characterized by restrained eating behavior despite adaptive orexigenic regulation profile including high ghrelin plasma levels. Constitutional thinness is a physiological condition of resistance to weight gain with physiological anorexigenic profile including high Peptide YY plasma level. Healthy obesity can be considered as a physiological state of resistance to weight loss with opposite appetite regulating profile to constitutional thinness including low Peptide YY plasma level. No studies in IL-7 are yet available in those populations. Therefore we evaluated circadian plasma levels of IL-7 in anorexia nervosa compared to constitutional thinness, healthy obese and control females. 10 restrictive-type anorexia nervosa women, 5 bingeing/purging anorexia nervosa woman, 5 recovered restrictive anorexia nervosa women, 4 bulimic females, 10 constitutional thinness women, 7 healthy obese females, and 10 normal weight women controls were enrolled in this cross-sectional study, performed in endocrinology unit and academic laboratory. Twelve-point circadian profiles of plasma IL-7 levels were measured in each subject. 24h mean IL-7 plasma levels (pg/ml, mean±SEM) were decreased in restrictive-type anorexia nervosa (123.4±14.4, panorexia nervosa (24.2±5.6, panorexia nervosa (64.2±16.1, p = 0.01) and healthy obese patients (51±3.2, panorexia nervosa, confirming its difference with constitutional thinness. Healthy obesity, with low IL-7, is once again in mirror image of constitutional thinness with normal high IL-7.

  16. YKL-40 tissue expression and plasma levels in patients with ovarian cancer

    International Nuclear Information System (INIS)

    Høgdall, Estrid VS; Christensen, Lise H; Ringsholt, Merete; Høgdall, Claus K; Christensen, Ib Jarle; Johansen, Julia S; Kjaer, Susanne K; Blaakaer, Jan; Ostenfeld-Møller, Lene; Price, Paul A

    2009-01-01

    YKL-40 (chitinase-3-like-1) is a member of 'mammalian chitinase-like proteins'. The protein is expressed in many types of cancer cells and the highest plasma YKL-40 levels have been found in patients with metastatic disease, short recurrence/progression-free intervals, and short overall survival. The aim of the study was to determine the expression of YKL-40 in tumor tissue and plasma in patients with borderline ovarian tumor or epithelial ovarian cancer (OC), and investigate prognostic value of this marker. YKL-40 protein expression was determined by immunohistochemistry in tissue arrays from 181 borderline tumors and 473 OC. Plasma YKL-40 was determined by ELISA in preoperative samples from 19 patients with borderline tumor and 76 OC patients. YKL-40 protein expression was found in cancer cells, tumor associated macrophages, neutrophils and mast cells. The tumor cell expression was higher in OC than in borderline tumors (p = 0.001), and associated with FIGO stage (p < 0.0001) and histological subtype (p = 0.0009). Positive YKL-40 expression (≥ 5% staining) was not associated with reduced survival. Plasma YKL-40 was also higher in patients with OC than in patients with borderline tumors (p < 0.0001), and it was positively correlated to serum CA-125 (p < 0.0001) and FIGO stage (p = 0.0001). Univariate Cox analysis of plasma YKL-40 showed association with overall survival (p < 0.0001). Multivariate Cox analysis, including plasma YKL-40, serum CA125, FIGO stage, age and radicality after primary surgery as variables, showed that elevated plasma YKL-40 was associated with a shorter survival (HR = 2.13, 95% CI: 1.40–3.25, p = 0.0004). YKL-40 in OC tissue and plasma are related to stage and histology, but only plasma YKL-40 is a prognostic biomarker in patients with OC

  17. Experimental relationships between levels of corticosterone in plasma and feathers in a free-living bird.

    Science.gov (United States)

    Fairhurst, Graham D; Marchant, Tracy A; Soos, Catherine; Machin, Karen L; Clark, Robert G

    2013-11-01

    Integrated measures of corticosterone (CORT), such as from feathers (CORTf), have intuitive appeal because they incorporate both the duration and amplitude of glucocorticoid secretion. An association between CORTf and plasma CORT has never been shown in wild birds, and it is unclear as to when and whether these measures should be correlated, given that they are fundamentally different yet related measures of physiology. We hypothesized that CORTf should correlate with instantaneous measurements of plasma CORT when the latter reflect sustained changes in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. To test this, we experimentally manipulated levels of plasma CORT in wild nestling tree swallows (Tachycineta bicolor) using 5 day time-release CORT pellets, and measured plasma CORT and growth parameters before, during and at the end of hormone manipulation (days 7, 9 and 11 post-hatch, respectively). CORTf and plasma CORT were significantly positively related only when the latter was at its highest and most variable among individuals (day 9). A similar relationship was expected at day 11, but plasma CORT had returned to near-original levels. Nestlings with higher CORTf were smaller, lighter and less likely to fledge, but we did not detect seasonal effects on CORTf. Our results clearly demonstrate that CORTf from free-living birds can reflect plasma CORT, but correlations may not always be expected, especially if elevations in plasma CORT are relatively modest and of short duration. Our work suggests that CORTf is best used to study the activity of the HPA axis over relatively long time frames and can be used effectively to advance avian ecology.

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

    Science.gov (United States)

    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.

  19. Determination of the changes of the plasma catecholamine level by radioenzymatic method following noise-exposition

    International Nuclear Information System (INIS)

    Pinter, Cs.; Vincze, I.

    1982-01-01

    A new method was applied for the determination of plasma catecholamine levels: all the catecholamines were methylated in the presence of S-adenosyl-1-methyl 3 H-methyonine and the radioactivity of the components - separated with thin-layer chromatography - was measured by liquid scintillation. It is concluded that noise exposition for one hour per day significantly increases the plasma concentration of noradrenaline and dopamine whereas the adrenaline-level shows biphasic change: after a short increase it decreases. (L.E.)

  20. SEMINAL PLASMA LEVELS OF LEAD AND MERCURY IN INFERTILE MALES IN BENIN CITY, NIGERIA

    Directory of Open Access Journals (Sweden)

    Emokpae MA

    2016-01-01

    Full Text Available Background/objectives: Studies on environmental exposure to toxic metals and their effects on male reproductive function are scare in our setting. This study evaluates the levels of lead and mercury in seminal plasma of infertile males who are non-occupationally exposed in Benin City, Nigeria and to determine the relationship between seminal quality and these toxic metals. Materials and Methods: A total of 80 subjects participated in this study which includes 60 infertile males on routine visit to the infertility clinics in Benin City and 20 fertile males as controls. The concentration of lead in seminal plasma was assayed by atomic absorption spectrophotometer while the concentration of mercury was measured using inductively coupled plasma Mass spectrometry. Semen analyses were performed using standard techniques as recommended by World Health Organization. Results: Mean seminal plasma lead and mercury levels were significantly higher (p<0.001 in infertile males compared with controls. Mercury and lead correlated negatively (p<0.001 with sperm count, progressive motility, total motility and morphology but not with semen volume. There was no significant correlation between toxic metals and sperm indices in fertile males (controls. Conclusion: The levels of the studied toxic metals were higher in seminal plasma of infertile males and appear to have adverse effect on seminal indices in non -occupationally exposed males.

  1. Plasma levels of selenium-containing proteins in Inuit adults from Nunavik.

    Science.gov (United States)

    Achouba, Adel; Dumas, Pierre; Ouellet, Nathalie; Lemire, Mélanie; Ayotte, Pierre

    2016-11-01

    Selenium (Se) is highly abundant in marine foods traditionally consumed by Inuit of Nunavik (Northern Quebec, Canada) and accordingly, their Se intake is among the highest in the world. However, little is known regarding the biological implications of this high Se status in this Arctic indigenous population. We used a method combining affinity chromatography and inductively coupled plasma-mass spectrometry with quantification by post-column isotope dilution to determine total Se levels and concentrations of Se-containing proteins in archived plasma samples of Inuit adults who participated to the 2004 Nunavik Inuit Health Survey (N = 852). Amounts of mercury (Hg) associated with Se-containing proteins were also quantified. Results show that glutathione peroxidase 3 (GPx3), selenoprotein P (SelP) and selenoalbumin (SeAlb) represented respectively 25%, 52% and 23% of total plasma Se concentrations. In addition, small amounts of Hg co-eluted with each Se-containing protein and up to 50% of plasma Hg was associated to SelP. Total plasma Se concentrations (median = 139 μg L− 1; interquartile range (IQR) = 22.7 μg L− 1) were markedly lower and less variable than whole blood Se concentration (median = 261 μg L− 1, IQR = 166 μg L− 1). A non linear relation was observed between whole blood Se and plasma Se levels, with plasma Se concentrations leveling off at approximately 200 μg L− 1, whereas 16% and 3% of individuals exhibited whole blood concentrations higher than 500 μg L− 1 and 1000 μg L− 1, respectively. In contrast, a linear relationship was previously reported in communities consuming Brazil nuts which are rich Se, mainly present as selenomethionine. This suggests that a different selenocompound, possibly selenoneine, is present in the Arctic marine food chain and accumulates in the blood cellular fraction of Inuit.

  2. Plasma Orexin-A Levels in COPD Patients with Hypercapnic Respiratory Failure

    Directory of Open Access Journals (Sweden)

    Lin-Yun Zhu

    2011-01-01

    Full Text Available Orexins have previously been shown to promote wakefulness, regulate lipid metabolism and participate in energy homeostasis. The aim of the study was to determine the relationship between plasma orexin-A and body composition in COPD in-patients with hypercapnic respiratory failure. 40 patients with hypercapnic respiratory failure and 22 healthy individuals were enrolled prospectively in this study. Plasma orexin-A levels, BMI, SaO2, PaCO2 and PaO2 were noted for all the patients. Plasma orexin-A levels were higher in the underweight (UW group, normal weight (NW group and overweight (OW group of COPD patients as compared with UW, NW and OW group of the control group (P<.05. Plasma orexin-A in COPD patients were higher in the OW group than in the NW group and the UW group. Plasma orexin-A levels showed significant correlation with body mass index (BMI, independent of PaO2 (r=0.576; P<.05 and %fat (r=0.367; P<.05; a negative correlation was noted between plasma orexin-A levels and PaO2 (r=−0.738; P<.05 and SaO2 (r=−0.616; P<.05. Our results suggest that orexin-A levels are high in COPD patients with hypercapnic respiratory failure, and vary according to BMI and body composition. Orexin-A may be associated with the severity of hypoxemia in COPD patients with hypercapnic respiratory failure.

  3. Study on the rhythmic variation of plasma cortisol levels in patients with essential hypertension (EH) and coronary heart disease (CHD)

    International Nuclear Information System (INIS)

    Zhu Mei; Wu Guo; Li Ying

    2007-01-01

    Objective: To study the rhythmic fluctuation of plasma cortisol levels in patients with EH and CHD. Methods: Plasma cortisol levels were determined with RIA at 8Am, 4Pm and midnight in 61 patients with EH, 46 patients with CHD and 36 controls. Results: The normal rhythmic fluctuation pattern of plasma cortisol levels was retained in the EH and CHD patients. However, the levels were all significantly higher in the patients than those in the controls, especially in the midnight specimens. Conclusion: Marked elevated plasma cortisol levels were observed in patients with EH and CHD, with the normal rhythmic fluctuation pattern retained. (authors)

  4. 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)

  5. Association Between Seminal Plasma Copper and Magnesium Levels with Oxidative Stress in Iraqi Infertile Men

    Directory of Open Access Journals (Sweden)

    Omar F. Abdul-Rasheed

    2010-06-01

    Full Text Available Objectives: To study the association between copper, magnesium and malondialdehyde levels in seminal plasma of oligozoospermic, azoospermic in relation to normozoospermic men.Methods: The present study was conducted at the Chemistry and Biochemistry department, College of Medicine, Al-Nahrain University, Baghdad-Iraq during September 2007 to February 2008 after obtaining approval from the research and ethics committee and obtaining written consent, 78 infertile men (age range 33.01±4.20 years were recruited at the institute of embryo research and infertility treatment, Al-Kadhimiya teaching hospital, Iraq and were categorized according to their seminal fluid parameters to oligozoospermia (n=43 and azoospermia (n=35. 41 fertile men (age range 30.29±2.30 years were selected as controls. Seminal plasma copper and magnesium were measured by atomic absorption spectrophotometry. Malondialdehyde was measured calorimetrically using thiobarbituric acid assay which detects thiobarbituric acid reactive substances. Results: Seminal plasma copper level was decreased significantly (p=0.000 in the azoospermic group compared to the control group. Whereas, the level decreased non-significantly in the oligozoospermic group. Seminal plasma magnesium levels were decreased significantly (p=0.000 in all the infertility groups studied. On the other hand, malondialdehyde levels which is an end product of lipid peroxidation were significantly elevated (p=0.000 in all the infertility groups studied.Conclusion: Copper and magnesium work in different ways in order to maintain normal environment for spermatozoa for normal fertilization to occur.

  6. Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

    Energy Technology Data Exchange (ETDEWEB)

    Adams, M.L.; Morris, D.L.; Dewey, W.L.

    1986-03-05

    ..beta..-endorphin, (met)enkephalin, and (leu)enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO/sub 4/ or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. ..beta..-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; (met)enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; (leu)-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs.

  7. Assessments of plasma ghrelin levels in the early stages of parkinson's disease.

    Science.gov (United States)

    Song, Ning; Wang, Weiwei; Jia, Fengjv; Du, Xixun; Xie, Anmu; He, Qing; Shen, Xiaoli; Zhang, Jing; Rogers, Jack T; Xie, Junxia; Jiang, Hong

    2017-10-01

    Gastrointestinal symptoms are early events in Parkinson's disease (PD). The gastrointestinal hormone ghrelin was neuroprotective in the nigrostriatal dopamine system. The objective of this study was to assess ghrelin levels in the early stages of PD. Plasma was collected in the fasting state in 291 PD patients in stages 1-3 and 303 age- and sex-matched healthy controls. Additional samples were taken in the glucose response test to assess nutrition-related ghrelin levels in 20 PD patients and 20 healthy controls. The enzyme-linked immunosorbent assay was used to measure total and active plasma ghrelin levels. We reported that total and active plasma ghrelin levels were decreased in PD, although there was no difference across progressive PD stages. Postprandial ghrelin suppression and preprandial peak responses were both attenuated in PD. Plasma ghrelin levels were decreased in PD; however, this event might be irrelevant to PD progression. Ghrelin responses to meals were also impaired in PD. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  8. Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

    International Nuclear Information System (INIS)

    Adams, M.L.; Morris, D.L.; Dewey, W.L.

    1986-01-01

    β-endorphin, [met]enkephalin, and [leu]enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO 4 or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. β-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; [met]enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; [leu]-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs

  9. Plasma apelin levels in obstructive sleep apnea and the effect of continuous positive airway pressure therapy.

    Science.gov (United States)

    Henley, David E; Buchanan, Fiona; Gibson, Rosemary; Douthwaite, Jennie A; Wood, Susan A; Woltersdorf, Wolfram W; Catterall, James R; Lightman, Stafford L

    2009-10-01

    Apelin is a peptide hormone with cardiovascular and glucose homeostasis properties, and obstructive sleep apnea (OSA) is complicated by cardiovascular and metabolic comorbidities. Plasma apelin has not been previously assessed in OSA. We investigated the response of plasma apelin to a 2-h 75 g oral glucose tolerance test (OGTT) and the effect of 3 months compliant continuous positive airway pressure (CPAP) therapy in 15 obese males with newly diagnosed OSA. Plasma apelin and serum cortisol were recorded 10 minutely, while serum insulin and glucose were measured 30 minutely. Ten subjects had plasma apelin measured at intervals across a 24-h period to investigate for circadian variation in apelin levels, and this was repeated following 3 months compliant CPAP therapy. Fasting (0.342+/-0.038 vs 0.288+/-0.024 ng/ml, P=0.04), 30 min (0.399+/-0.035 vs 0.312+/-0.036 ng/ml, P=0.007) and 120 min (0.402+/-0.030 vs 0.259+/-0.024 ng/ml, P<0.001) apelin levels were reduced following CPAP. The area under curve for apelin OGTT response was lower post-CPAP (44.1+/-3.3 vs 35.8+/-2.3 ng/ml per min, P<0.001). Mean OGTT apelin levels showed a significant treatment effect (P=0.006) and a time effect (P<0.001), and the effect of time was different pre- versus post-CPAP (P=0.005). No significant variability in apelin levels existed across the 24-h period at diagnosis. Lower levels were evident overnight following treatment (P=0.004). Improvements in insulin and glucose parameters and reduced cortisol levels were found post-CPAP. In summary, untreated OSA was associated with elevated plasma apelin levels, altered apelin secretory dynamics in response to oral glucose and lack of an apparent circadian variability, which was restored following CPAP.

  10. Better prognosis in overweight/obese coronary heart disease patients with high plasma levels of leptin.

    Science.gov (United States)

    Simiti, Luminita Animarie Vida; Todor, Irina; Stoia, Mirela Anca; Goidescu, Cerasela Mihaela; Anton, Florin Petru; Farcas, Anca Daniela

    2016-01-01

    The involvement of leptin in atherosclerosis is very complex, including inflammation, the oxidative stress and thrombosis. Leptin has atherogenic and also antiatherogenic actions. In obesity elevated leptin levels are not sufficient to prevent disturbances of energy balance, suggesting that obese people are leptin resistant. The aim of the study was to investigate the relationship between baseline plasma levels of leptin and the incidence of new ischemic events in patients with CHD. Plasma levels of leptin in fifty nine consecutive patients (29 men and 30 women) with CHD hospitalized in the County Emergency Clinical Hospital of Cluj-Napoca were measured using commercially available ELISA at admission. Patients with active infectious disease, neoplasia, acute coronary syndrome, stroke, hepatic or renal failure and severe heart failure were excluded The relationship between leptin levels and incident cardiovascular events (angina, nonfatal myocardial infarction or heart failure) over two years follow-up was studied using MEDCALC version 9.6. 73.6% patients with CHD were overweight or suffered of obesity. There were no significant differences between women and men regarding the plasma levels of leptin, the body mass index (BMI), the number of rehospitalizations, rehospitalizations/patient, diabetes mellitus, hypertension or dyslipidemia. Only in women plasma levels of leptin are correlated with BMI. As compared with men with overweight and obesity (BMI≥25kg/m(2)), plasma levels of leptin were significantly higher in women with overweight and obesity (3905.97±463.91 pg/ml vs 1835.17±533.9 pg/ml) (p2000 pg/ml and BMI >28kg/m(2) had a better prognosis, suggesting a protective role of leptin in overweight/mild obesity.

  11. Effects of dietary coconut oil, butter and safflower oil on plasma lipids, lipoproteins and lathosterol levels.

    Science.gov (United States)

    Cox, C; Sutherland, W; Mann, J; de Jong, S; Chisholm, A; Skeaff, M

    1998-09-01

    The aim of this present study was to determine plasma levels of lathosterol, lipids, lipoproteins and apolipoproteins during diets rich in butter, coconut fat and safflower oil. The study consisted of sequential six week periods of diets rich in butter, coconut fat then safflower oil and measurements were made at baseline and at week 4 in each diet period. Forty-one healthy Pacific island polynesians living in New Zealand participated in the trial. Subjects were supplied with some foods rich in the test fats and were given detailed dietary advice which was reinforced regularly. Plasma lathosterol concentration (P safflower oil diets compared with butter diets. Plasma total cholesterol, HDL cholesterol and apoA-levels were also significantly (Psafflower oil compared with diets rich in butter and might be associated with lower production rates of apoB-containing lipoproteins.

  12. Elevated Plasma YKL-40 Levels and Ischemic Stroke in the General Population

    DEFF Research Database (Denmark)

    Kjaergaard, A.D.; Bojesen, S.E.; Johansen, J.S.

    2010-01-01

    inside the vessel wall. Methods: We measured plasma YKL-40 in 8,899 21- to 93-year-old participants of the Copenhagen City Heart Study 1991-1994 examination, and followed them for up to 18 years. Endpoints were ischemic stroke, ischemic cerebrovascular disease, myocardial infarction, and ischemic heart......% confidence interval, 11%-30%) for ischemic stroke, 16% (8%-24%) for ischemic cerebrovascular disease, 3% (-5%-11%) for myocardial infarction, and 7% (1%-12%) for ischemic heart disease. Interpretation: In the general population, elevated plasma YKL-40 levels are associated with increased risk of ischemic...... stroke and ischemic cerebrovascular disease, independent of plasma CRP levels. ANN NEUROL 2010;68:672-680...

  13. Elevated Plasma Vitamin B12 Levels as a Marker for Cancer

    DEFF Research Database (Denmark)

    Arendt, Johan Frederik Berg; Pedersen, Lars; Nexo, Ebba

    2013-01-01

    ) with 95% confidence intervals (CIs), stratified by plasma Cbl levels. All statistical tests were two-sided. RESULTS: We identified 333 667 persons without prevalent cancer and not receiving Cbl treatment. Six percent had Cbl levels greater than the upper reference limit (≥601 pmol/L). Cancer risk......BACKGROUND: A substantial proportion of patients referred for plasma vitamin B12 (cobalamin [Cbl]) measurement present with high Cbl levels, which have been reported in patients with different cancer types. However, the cancer risk among patients with newly diagnosed high Cbl levels has not been...... adequately examined. METHODS: We conducted this cohort study using population-based Danish medical registries. Patients referred for Cbl measurement with levels greater than the lower reference limit (≥200 pmol/L) were identified from the population of Northern Denmark during the period of 1998 to 2009 using...

  14. 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...

  15. Effect of sinus rhythm restoration on plasma brain natriuretic peptide (BNP) levels in patients with atrial fibrillation

    International Nuclear Information System (INIS)

    An Liping; Jin Zhexiu; Zhang Chengqiu

    2005-01-01

    Objective: To study the changes of plasma brain natriuretic peptide (BNP) levels before and after sinus rhythm restoration in patients with paroxysmal or persistent atrial fibrillation (AF) but normal left ventricle function and to explore the role of BNP in AF. Methods: Plasma BNP levels were measured with RIA in 68 patients and 34 controls. Results: Twenty four hours after successful cardioversion, plasma BNP levels decreased significantly in all the patients. The 30 patients with paroxysmal atrial fibrillation were all restored to sinus rhythm and levels of plasma BNP dropped from 96±42pg/ml to 28 ±21pg/ml. Of the 38 patients with persistent atrial fibrillation, 28 of them were restored to sinus rhythm, in whom levels of plasma BNP dropped from 73±38pg/ml to 38±25pg/ml. Conclusion: The presence of AF should be taken into consideration when interpreting plasma BNP levels in patients with heart disease. (authors)

  16. Investigation on the correlationship between plasma homocysteine and blood glucose, insulin levels in patients with type 2 diabetes mellitus

    International Nuclear Information System (INIS)

    Ma Zhongwei

    2005-01-01

    Objective: To explore the correlationship between plasma homocysteine and blood glucose, insulin levels in patients with type 2 diabetes mellitus. Methods: Plasma homocysteine (with ELISA), blood glucose (with hexokinase method) and insulin (with RIA) levels were measured in 66 patients with type 2 diabetes mellitus as well as in 35 controls. Results: Plasma homocysteine levels in the diabetic patients (n=66) were significantly higher than those in controls (P<0.01), especially in those patients complicated with nephropathy (n=32). The homocysteine levels were positively correlated with those of blood glucose and insulin (r=0.3515, r=0.3486, both P<0.01). Conclusion: Plasma homocysteine is an independent risk factor for vascular diseases. The levels of plasma cysteine are significantly increased in patients with type 2 diabetes mellitus, especially in those complicated with nephropathy. Therefore, monitoring of plasma homocysteine level changes is clinically useful. (authors)

  17. Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers.

    Science.gov (United States)

    Hanon, Olivier; Vidal, Jean-Sébastien; Lehmann, Sylvain; Bombois, Stéphanie; Allinquant, Bernadette; Tréluyer, Jean-Marc; Gelé, Patrick; Delmaire, Christine; Blanc, Fredéric; Mangin, Jean-François; Buée, Luc; Touchon, Jacques; Hugon, Jacques; Vellas, Bruno; Galbrun, Evelyne; Benetos, Athanase; Berrut, Gilles; Paillaud, Elèna; Wallon, David; Castelnovo, Giovanni; Volpe-Gillot, Lisette; Paccalin, Marc; Robert, Philippe-Henri; Godefroy, Olivier; Dantoine, Thierry; Camus, Vincent; Belmin, Joël; Vandel, Pierre; Novella, Jean-Luc; Duron, Emmanuelle; Rigaud, Anne-Sophie; Schraen-Maschke, Suzanna; Gabelle, Audrey

    2018-02-17

    Diagnostic relevance of plasma amyloid β (Aβ) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aβ 42 and Aβ 40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers. One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoïd pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included. Plasma Aβ 1-42 and Aβ 1-40 were lower in AD (36.9 [11.7] and 263 [80] pg/mL) than in amnestic MCI (38.2 [11.9] and 269 [68] pg/mL) than in nonamnestic MCI (39.7 [10.5] and 272 [52] pg/mL), respectively (P = .01 for overall difference between groups for Aβ 1-42 and P = .04 for Aβ 1-40 ). Globally, plasma Aβ 1-42 correlated with age, Mini-Mental State Examination, and APOE ε4 allele. Plasma Aβ 1-42 correlated with all CSF biomarkers in MCI but only with CSF Aβ 42 in AD. Plasma Aβ was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Correlation of reversely increased level of plasma glucose during pregnancy to the pregnancy outcome

    Directory of Open Access Journals (Sweden)

    Xiao-ya SHEN

    2017-02-01

    Full Text Available Objective To explore the correlation of the reversely increased results of 75g oral glucose tolerance test (OGTT during pregnancy to the pregnancy outcome, so as to provide a reliable theoretical basis of the early intervention for the pregnant women with high plasma glucose. Methods The clinical data of 461 cases were retrospectively analyzed. Patients were chosen from the pregnant women undergoing routine antenatal examination in our hospital during 2014. According to the results of 75g OGTT, 226 patients were analyzed as the observation group, in whom the level of postprandial 2-hour plasma glucose was higher than that of postprandial 1-hour plasma glucose. Meanwhile 235 pregnant women with or without gestational diabetes mellitus (GDM were randomly selected as the control group. Results The levels of fasting plasma glucose and 1-hour postprandial plasma glucose were lower, but those of 2-hour postprandial plasma glucose was higher in observation group than in control group (P0.05 in the incidences of polyhydramnios, oligohydramnios, fetal growth restriction (FGR, premature labor (PTL, pregnancy induced hypertension (PIH, complicated with premature rupture of membrane (PROM, intrauterine fetal death (IUFD and non scar uterus cesarean section rate (CSR. Compared with the observation group, the rates of neonatal dysplasia and neonatal asphyxia and the newborn transfer rate were lower in the control group, of which the newborn transfer rate was statistically different (P<0.01. Conclusions There might be a delayed plasma glucose metabolism in the patients with reversely increased result of 75g OGTT during pregnancy, which may affect the long-term prognosis of the newborn. Therefore, more attention should be paid to such patients with reversely increased result of 75g OGTT. DOI: 10.11855/j.issn.0577-7402.2017.01.09

  19. Serum Creatinine Versus Plasma Methotrexate Levels to Predict Toxicities in Children Receiving High-dose Methotrexate.

    Science.gov (United States)

    Tiwari, Priya; Thomas, M K; Pathania, Subha; Dhawan, Deepa; Gupta, Y K; Vishnubhatla, Sreenivas; Bakhshi, Sameer

    2015-01-01

    Facilities for measuring methotrexate (MTX) levels are not available everywhere, potentially limiting administration of high-dose methotrexate (HDMTX). We hypothesized that serum creatinine alteration after HDMTX administration predicts MTX clearance. Overall, 122 cycles in 50 patients of non-Hodgkin lymphoma or acute lymphoblastic leukemia aged ≤18 years receiving HDMTX were enrolled prospectively. Plasma MTX levels were measured at 12, 24, 36, 48, 60, and 72 hours; serum creatinine was measured at baseline, 24, 48, and 72 hours. Correlation of plasma MTX levels with creatinine levels and changes in creatinine from baseline (Δ creatinine) were evaluated. Plasma MTX levels at 72 hours showed positive correlation with serum creatinine at 48 hours (P = .011) and 72 hours (P = .013) as also Δ creatinine at 48 hours (P = .042) and 72 hours (P = .045). However, cut-off value of either creatinine or Δ creatinine could not be established to reliably predict delayed MTX clearance. Greater than 50% Δ creatinine at 48 and 72 hours significantly predicted grade 3/4 leucopenia (P = .036 and P = .001, respectively) and thrombocytopenia (P = .012 and P = .009, respectively) but not mucositis (P = .827 and P = .910, respectively). Delayed MTX elimination did not predict any grade 3/4 toxicity. In spite of demonstration of significant correlation between serum creatinine and Δ creatinine with plasma MTX levels at 72 hours, cut-off value of either variable to predict MTX delay could not be established. Thus, either of these cannot be used as a surrogate for plasma MTX estimation. Interestingly, Δ creatinine effectively predicted hematological toxicities, which were not predicted by delayed MTX clearance.

  20. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans

    Directory of Open Access Journals (Sweden)

    Mbikay Majambu

    2008-06-01

    Full Text Available Abstract Background Proprotein convertase subtilisin kexin-like 9 (PCSK9 is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC by negatively regulating low density lipoprotein receptor (LDLR levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men. Results Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013. Atorvastatin administration (HMGCoA reductase inhibitor significantly increased plasma PCSK9 (7.40%, p = 0.033 and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012. Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6× vs 1.5×, respectively at 10 μM, while fenofibrate did not induce changes in either. Conclusion These results suggest that in vivo (1 statins directly increase PCSK9 expression while (2 fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3 that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy

  1. Effects of Red Palm Oil on Serum Lipids and Plasma Carotenoids Level in Chinese Male Adults

    Institute of Scientific and Technical Information of China (English)

    JIAN ZHANG; CHUN-RONG WANG; AN-NA XUE; KE-YOU GE

    2003-01-01

    Objective Effects of red palm oil on major plasma carotenoids, tocopherol, retinol and serumlipids were evaluated when used in Chinese diet. Methods Red palm oil group (RPO) composed of 20 male subjects(aged 18-32) and soybean oil group (SBO) composed of 22 male subjects (aged18-32). Dietary fat provided about 28% of total calories, and the test oil accounted for about 60% of total dietary fat. In the 3 weeks of pretest period, diets were prepared with soybean oil, and then in the next 6 weeks subjects in each group consumed the diet prepared by test oil. Results Plasmaα-carotene, β-carotene and lycopene concentration of RPO group significantly increased at the time of interim (21 days) and of the end (42 days) (P<0.05), and α-tocopherol concentration significantly increased at the time of the end (42 days) in this study. Though Chinese plasma retinol level was relatively low when compared with that of Westerners, red palm oil diet showed no significant effect on adult Chinese plasma retinol level. Serum concentration of total cholesterol, triglyceride, high density lipoprotein cholesterol, apolipoprotein AI and apolipoprotein B of all subjects showed no significant changes in RPO group during the study. Conclusions The data in our study suggest that red palm oil is a good source of carotenoids and vitamin E when used in Chinese diet preparation, and it can significantly increase plasma concentration of α-carotene, β-carotene, lycopene andα-tocopherol.

  2. Adopting plasma pyrolysis for management of low-level solid radioactive waste in India

    International Nuclear Information System (INIS)

    Gupta, R.K.; Singh, A.K.; Yeotikar, R.G.; Patil, S.P.; Jha, Jyoti; Mishra, S.K.; Gandhi, K.G.; Misra, S.D.

    2010-01-01

    Since Plasma Pyrolysis of Low-Level Solid Radioactive Waste has the potential of reducing waste volumes by a factor of up to 1000:1, the new technology is seen as a sound engineering and economic option for managing voluminous low-active wastes. Development and adoption of such technique, to replace existing methods of Low-Level Solid Radioactive Waste management, is borne out of a compelling need to conserve disposal space. While Plasma-based systems are already in use for disposal of medical, toxic and other industrial wastes, the level of maturity is yet to be attained in their radioactive applications. A Prototype Plasma Pyrolysis Unit is being set up in India which, after extensive trials, will function as a full-scale plant for the volume reduction of Low-Level Solid Radioactive Wastes. This paper deals with the transition philosophy from the current techniques to the Plasma-based process. The design and engineering of the proposed facility and various system components is also briefly touched upon. (author)

  3. Study of plasma amino acid levels in children with autism: An ...

    African Journals Online (AJOL)

    Background: The aetiology of autism is unclear and autistic symptoms had been attributed to an abnormal functional imbalance in neurotransmitter amines such as dopamine, noradrenaline and serotonin. Objective: To study plasma essential and non-essential amino acid levels, protein electrophoresis, serum ammonia, ...

  4. Elevated levels of IL-18 in plasma and skeletal muscle in chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Petersen, A M W; Penkowa, M; Iversen, M

    2007-01-01

    COPD [12 women, 66 +/- 9.4 years of age and forced expiratory volume in 1 second (FEV(1)) of 32% +/- 12 % of predicted value] and 20 healthy age-, gender-, and body mass index (BMI)-matched controls (10 nonsymptomatic smokers and 10 nonsmokers) were included in the study. Plasma levels of IL-18 were...

  5. Effects of varying levels of n-6:n-3 fatty acid ratio on plasma fatty acid ...

    African Journals Online (AJOL)

    This study investigated the effects of varying dietary levels of n-6:n-3 fatty acid ratio on plasma fatty acid composition and prostanoid synthesis in pregnant rats. Four groups consisting of seven rats per group of non pregnant rats were fed diets with either a very low n-6:n-3 ratio of 50% soybean oil (SBO): 50% cod liver oil ...

  6. Changes in plasma (hydrocortisone) levels after whole-body irradiation with ultraviolet rays of defined wavelengths

    International Nuclear Information System (INIS)

    Bartelt, R.N.

    1983-01-01

    One hour after whole-body irradiation with a radiation source having its maximum of emission in the UVB range, at a radiation dose of 0.44 J/cm 2 , a significant fall in the mean values of the blood plasma hydrocortisone level (p [de

  7. Plasma levels of cathepsins L, K, and V and risks of abdominal aortic aneurysms

    DEFF Research Database (Denmark)

    Lv, Bing-Jie; Lindholt, Jes S; Wang, Jing

    2013-01-01

    Cathepsin L (CatL), cathepsin K (CatK), and cathepsin V (CatV) are potent elastases implicated in human arterial wall remodeling. Whether plasma levels of these cathepsins are altered in patients with abdominal aortic aneurysms (AAAs) remains unknown....

  8. Plasma levels of antioxidants are not associated with Alzheimer's disease or cognitive decline.

    NARCIS (Netherlands)

    Engelhart, M.J.; Ruitenberg, A.; Meijer, J.T.; Kiliaan, A.J.; Swieten, J. van; Hofman, A.; Witteman, J.C.; Breteler, M.M.B.

    2005-01-01

    Antioxidants prevent oxidative stress that possibly causes neuronal loss in Alzheimer's disease (AD). We examined whether high plasma levels of the antioxidant vitamins A and E were associated with lower prevalence of AD or cognitive decline (CD). We performed a cross-sectional study within the

  9. Plasma coenzyme Q10 levels in type 2 diabetic patients with retinopathy

    Science.gov (United States)

    Ates, Orhan; Bilen, Habip; Keles, Sadullah; Alp, H. Hakan; Keleş, Mevlüt Sait; Yıldırım, Kenan; Öndaş, Osman; Pınar, L. Can; Civelekler, Mustafa; Baykal, Orhan

    2013-01-01

    AIM To determine the relationship between proliferative diabetic retinopathy (PDRP) and plasma coenzyme Q10(CoQ10) concentration. METHODS Patients with type 2 diabetes and PDRP were determined to be the case group (n=50). The control group was consist of healthy individuals (n=50). Plasma CoQ10 and malondialdehyde (MDA) levels were measured in both groups. RESULTS Ubiquinone-10 (Coenzyme Q10) levels in PDRP and control subjects are 3.81±1.19µmol/L and 1.91±0.62µmol/L, respectively. Plasma MDA levels in PDRP and control subjects were 8.16±2µmol/L and 3.44±2.08µmol/L, respectively. Ratio of Ubiquinol-10/ubiquinone-10 in PDRP and control subjects were 0.26±0.16 and 1.41±0.68, respectively. CONCLUSION The ratio of ubiquinol-10/ubiquinone-10 is found lower in patients with PDRP. High levels of plasma ubiquinol-10/ubiquinone-10 ratio indicate the protective effect on diabetic retinopathy. PMID:24195048

  10. Plasma coenzyme Q10 levels in type 2 diabetic patients with retinopathy

    Directory of Open Access Journals (Sweden)

    Orhan Ates

    2013-10-01

    Full Text Available AIM: To determine the relationship between proliferative diabetic retinopathy (PDRP and plasma coenzyme Q10(CoQ10 concentration.METHODS: Patients with type 2 diabetes and PDRP were determined to be the case group (n=50. The control group was consist of healthy individuals (n=50. Plasma CoQ10 and malondialdehyde (MDA levels were measured in both groups.RESULTS: Ubiquinone-10 (Coenzyme Q10 levels in PDRP and control subjects are 3.81±1.19µmol/L and 1.91±0.62µmol/L, respectively. Plasma MDA levels in PDRP and control subjects were 8.16±2µmol/L and 3.44±2.08µmol/L, respectively. Ratio of Ubiquinol-10/ubiquinone-10 in PDRP and control subjects were 0.26±0.16 and 1.41±0.68, respectively.CONCLUSION:The ratio of ubiquinol-10/ubiquinone-10 is found lower in patients with PDRP. High levels of plasma ubiquinol-10/ubiquinone-10 ratio indicate the protective effect on diabetic retinopathy.

  11. Ghrelin plasma levels, gastric ghrelin cell density and bone mineral density in women with rheumatoid arthritis.

    Science.gov (United States)

    Maksud, F A N; Kakehasi, A M; Guimarães, M F B R; Machado, C J; Barbosa, A J A

    2017-05-18

    Generalized bone loss can be considered an extra-articular manifestation of rheumatoid arthritis (RA) that may lead to the occurrence of fractures, resulting in decreased quality of life and increased healthcare costs. The peptide ghrelin has demonstrated to positively affect osteoblasts in vitro and has anti-inflammatory actions, but the studies that correlate ghrelin plasma levels and RA have contradictory results. We aimed to evaluate the correlation between total ghrelin plasma levels, density of ghrelin-immunoreactive cells in the gastric mucosa, and bone mineral density (BMD) in twenty adult women with established RA with 6 months or more of symptoms (mean age of 52.70±11.40 years). Patients with RA presented higher ghrelin-immunoreactive cells density in gastric mucosa (P=0.008) compared with healthy females. There was a positive relationship between femoral neck BMD and gastric ghrelin cell density (P=0.007). However, these same patients presented a negative correlation between plasma ghrelin levels and total femoral BMD (P=0.03). The present results indicate that ghrelin may be involved in bone metabolism of patients with RA. However, the higher density of ghrelin-producing cells in the gastric mucosa of these patients does not seem to induce a corresponding elevation in the plasma levels of this peptide.

  12. Ghrelin plasma levels, gastric ghrelin cell density and bone mineral density in women with rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    F.A.N. Maksud

    Full Text Available Generalized bone loss can be considered an extra-articular manifestation of rheumatoid arthritis (RA that may lead to the occurrence of fractures, resulting in decreased quality of life and increased healthcare costs. The peptide ghrelin has demonstrated to positively affect osteoblasts in vitro and has anti-inflammatory actions, but the studies that correlate ghrelin plasma levels and RA have contradictory results. We aimed to evaluate the correlation between total ghrelin plasma levels, density of ghrelin-immunoreactive cells in the gastric mucosa, and bone mineral density (BMD in twenty adult women with established RA with 6 months or more of symptoms (mean age of 52.70±11.40 years. Patients with RA presented higher ghrelin-immunoreactive cells density in gastric mucosa (P=0.008 compared with healthy females. There was a positive relationship between femoral neck BMD and gastric ghrelin cell density (P=0.007. However, these same patients presented a negative correlation between plasma ghrelin levels and total femoral BMD (P=0.03. The present results indicate that ghrelin may be involved in bone metabolism of patients with RA. However, the higher density of ghrelin-producing cells in the gastric mucosa of these patients does not seem to induce a corresponding elevation in the plasma levels of this peptide.

  13. Comparison of plasma endothelin levels between osteoporotic, osteopenic and normal subjects

    Directory of Open Access Journals (Sweden)

    Biçimoğlu Ali

    2005-09-01

    Full Text Available Abstract Background It has been demonstrated that endothelins (ET have significant roles in bone remodeling, metabolism and physiopathology of several bone diseases. We aimed to investigate if there was any difference between the plasma ET levels of osteoporotic patients and normals. Methods 86 patients (70 women and 16 men with a mean age of 62.6 (ranges: 51–90 years were included in this study. Patients were divided into groups of osteoporosis, osteopenia and normal regarding reported T scores of DEXA evaluation according to the suggestions of World Health Organization. According to these criteria 19, 43 and 24 were normal, osteopenic and osteoporotic respectively. Then total plasma level of ET was measured in all patients with monoclonal antibody based sandwich immunoassay (EIA method. One-way analysis of variance test was used to compare endothelin values between normals, osteopenics and osteoporotics. Results Endothelin total plasma level in patients was a mean of 98.36 ± 63.96, 100.92 ± 47.2 and 99.56 ± 56.6 pg/ml in osteoporotic, osteopenic and normal groups respectively. The difference between groups was not significant (p > 0.05. Conclusion No significant differences in plasma ET levels among three groups of study participants could be detected in this study.

  14. Plasma levels of trefoil factors are increased in patients with advanced prostate cancer

    DEFF Research Database (Denmark)

    Vestergaard, E.M.; Borregaard, Michael Krabbe; Poulsen, Steen Seier

    2006-01-01

    Through cDNA array analyses and immunohistochemistry on tissue microarrays, trefoil factor 3 (TFF3) was recently shown to be overexpressed in prostate cancer. The purpose of this study was to test the feasibility of using the levels of trefoil factors as a plasma marker for prostate cancer....

  15. Development of psychopathology in deployed armed forces in relation to plasma GABA levels

    NARCIS (Netherlands)

    Schür, Remmelt R; Boks, Marco P; Geuze, Elbert; Prinsen, Hubertus C M T; Verhoeven-Duif, Nanda M; Joëls, Marian; Kahn, René S; Vermetten, Eric; Vinkers, Christiaan H

    2016-01-01

    The GABA system is pivotal for an adequate response to a stressful environment but has remained largely unexplored in this context. The present study investigated the relationship of prospectively measured plasma GABA levels with psychopathology symptoms in military deployed to Afghanistan at risk

  16. Effect of Physical and Flexibility Exercise on Plasma Levels of Some ...

    African Journals Online (AJOL)

    Purpose: To evaluate the effect of physical and flexibility exercise on plasma levels of some liver enzymes and biomolecules of young Nigerian adults. Methods: Participants were subjected to a 2-h daily continuous physical and flexibility exercise for 6