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Sample records for acids decreases fibrinolysis

  1. Mechanism of action of omega-amino acids on plasminogen activation and fibrinolysis induced by staphylokinase.

    PubMed

    Levashov, M Yu; Aisina, R B; Gershkovich, K B; Varfolomeyev, S D

    2007-07-01

    Stimulation of Lys-plasminogen (Lys-Pg) and Glu-plasminogen (Glu-Pg) activation under the action of staphylokinase and Glu-Pg activation under the action of preformed plasmin-staphylokinase activator complex (Pm-STA) by low concentrations and inhibition by high concentrations of omega-amino acids (>90-140 mM) were found. Maximal stimulation of the activation was observed at concentrations of L-lysine, 6-aminohexanoic acid (6-AHA), and trans-(4-aminomethyl)cyclohexanecarboxylic acid 8.0, 2.0, and 0.8 mM, respectively. In contrast, the Lys-Pg activation rate by Pm-STA complex sharply decreased when concentrations of omega-amino acids exceeded the above-mentioned values. It was found that formation of Pm-STA complex from a mixture of equimolar concentrations of staphylokinase and Glu-Pg or Lys-Pg is stimulated by low concentrations (maximal at 10 mM) of 6-AHA. Negligible increase in the specific activities of plasmin and Pm-STA complex was detected at higher concentrations of 6-AHA (to maximal at 70 and 50 mM, respectively). Inhibitory effects of omega-amino acids on the rate of fibrinolysis induced by staphylokinase, Pm-STA complex, and plasmin were compared. It was found that inhibition of staphylokinase-induced fibrinolysis by omega-amino acids includes blocking of the reactions of Pm-STA complex formation, plasminogen activation by this complex, and lysis of fibrin by forming plasmin as a result of displacement of plasminogen and plasmin from the fibrin surface. Thus, the slow stage of Pm-STA complex formation plays an important role in the mechanism of action of omega-amino acids on Glu-Pg activation and fibrinolysis induced by staphylokinase. In addition to alpha-->beta change of Glu-Pg conformation, stimulation of Pm-STA complex formation leads to increase in Glu-Pg activation rate in the presence of low concentrations of omega-amino acids. Inhibition of Pm-STA complex formation on fibrin surface by omega-amino acids is responsible for appearance of long lag

  2. Systematic elucidation of effects of tranexamic acid on fibrinolysis and bleeding during and after cardiopulmonary bypass surgery.

    PubMed

    Kojima, T; Gando, S; Morimoto, Y; Mashio, H; Goda, Y; Kawahigashi, H; Kemmotsu, O

    2001-12-01

    The aim of this study was to systematically elucidate the effects of tranexamic acid on fibrinolysis and bleeding during and after cardiopulmonary bypass (CPB) surgery. Twenty-two patients undergoing CPB surgery were randomized to receive 100 mg/kg tranexamic acid or an equal volume of saline after anesthesia induction and prior to skin incision. Plasma levels of tissue plasminogen activator (t-PA) antigen and activity, crosslinked fibrin degradation products (D-dimer), alpha2-antiplasmin-plasmin complex, and plasminogen activator inhibitor-1 (PAI-1) antigen were measured. Blood samples were obtained after induction of anesthesia, before, during, and after CPB, at the end of surgery, and the next morning after surgery. Intraoperative and postoperative blood loss during 24 h after surgery was recorded. Patients' demographics were similar between the two groups. No patients suffered from thrombotic complications after surgery. In the tranexamic acid group, fibrinolytic activity and secondary fibrinolysis as measured by t-PA activity and D-dimer were markedly suppressed during CPB surgery (P=.042 and P=.015, respectively). Decreased fibrinolytic activity and fibrinolysis were accompanied by reduction of perioperative bleeding in the tranexamic acid group. We could also find a good positive correlation between the peak levels of t-PA activity and D-dimer (r(2)=.4203, P=.0011). No differences in the t-PA antigen, PAI-1 antigen release, and plasmin inhibition by alpha2-antiplasmin were apparent between the two groups. In a randomized, prospective trial of patients undergoing CPB surgery, we demonstrated that the synthetic antifibrinolytic drug tranexamic acid effectively suppresses fibrinolysis by inhibiting t-PA and plasmin activity with clear reduction of perioperative blood loss. While tranexamic acid had no effects on the other important fibrinolytic inhibitors like PAI-1 and alpha2-antiplasmin.

  3. Continuous or discontinuous tranexamic acid effectively inhibits fibrinolysis in children undergoing cardiac surgery with cardiopulmonary bypass.

    PubMed

    Couturier, Roland; Rubatti, Marina; Credico, Carmen; Louvain-Quintard, Virginie; Anerkian, Vregina; Doubine, Sylvie; Vasse, Marc; Grassin-Delyle, Stanislas

    2014-04-01

    Tranexamic acid is given continuously or discontinuously as an anti-fibrinolytic therapy during cardiac surgery, but the effects on fibrinolysis parameters remain poorly investigated. We sought to assess the effects of continuous and discontinuous tranexamic acid on fibrinolysis parameters in children undergoing cardiac surgery with cardiopulmonary bypass (CPB). Children requiring cardiac surgery or repeat surgery by sternotomy with CPB for congenital heart disease were randomized to receive either continuous or discontinuous tranexamic acid. Blood tranexamic acid, D-dimers, tissue plasminogen activator (tPA), tPA-plasminogen activator inhibitor 1 (tPA-PAI1) complexes, fibrinogen and fibrin monomers were measured and compared to values obtained from children who did not receive tranexamic acid. Tranexamic acid inhibited the CPB-induced increase in D-dimers, with a similar potency between continuous and discontinuous regimens. Time courses for tPA, fibrin monomers, and fibrinogen were also similar for both regimen, and there was a significant difference in tPA-PAI1 complex concentrations at the end of surgery, which may be related to a significantly higher tranexamic acid concentration. Continuous and discontinuous regimen are suitable for an effective inhibition of fibrinolysis in children undergoing cardiac surgery with CPB, but the continuous regimen was previously shown to be more effective to maintain stable tranexamic acid concentrations.

  4. An in vitro study of the effects of t-PA and tranexamic acid on whole blood coagulation and fibrinolysis.

    PubMed

    Godier, Anne; Parmar, Kiran; Manandhar, Karuna; Hunt, Beverley J

    2017-02-01

    Acute traumatic coagulopathy is characterised by fibrinolysis and low fibrinogen. It is unclear how much fibrinogenolysis contributes to reduce fibrinogen levels. The study aim was to: investigate in vitro the effects of tissue-plasminogen activator (t-PA) and tranexamic acid (TXA) on coagulation and fibrinolysis. Whole blood was spiked with varying t-PA concentrations. Clauss fibrinogen levels and thrombelastography (TEG, Haemonetics) were performed, including functional fibrinogen level (FLEV). TXA effects were assessed using four TXA concentrations. Recorded parameters from kaolin activated TEG included maximal amplitude (MA), clot strength (G), percentage lysis (LY). Plasmin-antiplasmin complex (PAP), endogenous thrombin potential (ETP), prothrombin fragment 1+2 (PF1+2), factor V and factor VIII levels were all measured. t-PA induced fibrinolysis: it increased PAP and LY, but decreased MA and G. t-PA induced fibrinogenolysis, with a concentration-dependant decrease in fibrinogen from 2.7 (2.6-3.1) to 0.8 (0.8-0.9) g/L with 60 nM t-PA. FLEV and fibrinogen levels were well correlated. High t-PA doses increased PF1+2, decreased ETP of 19% and FVIII of 63% but not FV. TXA had no effect on plasmin generation as evidenced by no change in PAP. It corrected LY, MA and G and partly protected fibrinogen against fibrinogenolysis: 0.03 mg/mL TXA reduced the fibrinogen fall induced by t-PA 20 nM from 43% to 14%. TXA halved the FVIII fall and increased ETP. t-PA induced plasminogen activation and fibrinogenolysis in a concentration-dependant manner. TXA did not affect plasmin activation but reduced fibrinogenolysis. These results suggest that TXA given early in bleeding patients may prevent fibrinogenolysis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  5. The effect of n-3 polyunsaturated fatty acids on lipids, platelet function, coagulation, fibrinolysis and monocyte chemotaxis in patients with hypertension.

    PubMed

    Schmidt, E B; Nielsen, L K; Pedersen, J O; Kornerup, H J; Dyerberg, J

    1990-07-01

    We have studied the effect of dietary supplementation with 4 g of n-3 polyunsaturated fatty acids (n-3 PUFA) daily for 6 wk on plasma lipids, haemostasis and monocyte chemotaxis in 10 patients with untreated hypertension. Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides did not change, but the ratio of total to HDL-cholesterol was significantly reduced after the fish oil supplement. Platelet function was unaltered by intake of n-3. Plasma fibrinogen and fibronectin decreased after supplementation with n-3 PUFA, while the effects on fibrinolysis were equivocal. Monocyte chemotaxis was reduced by the supplement. These data lend support to a role for an increased intake of n-3 PUFA in the management of patients with hypertension.

  6. Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): protocol and statistical analysis plan for a randomized controlled trial.

    PubMed

    Shakur, Haleema; Fawole, Bukola; Kuti, Modupe; Olayemi, Oladapo; Bello, Adenike; Ogunbode, Olayinka; Kotila, Taiwo; Aimakhu, Chris O; Huque, Sumaya; Gregg, Meghann; Roberts, Ian

    2016-12-16

    Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid has the potential to reduce bleeding and a large randomized controlled trial of its effect on maternal health outcomes in women with PPH (The WOMAN trial) is ongoing. We will examine the effect of tranexamic acid on fibrinolysis and coagulation in a subset of WOMAN trial participants. Methods. Adult women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion in the WOMAN trial. In a sub-group of trial participants, blood samples will be collected at baseline and 30 minutes after the first dose of tranexamic acid or matching placebo.  Our primary objective is to evaluate the effect of tranexamic acid on fibrinolysis. Fibrinolysis will be assessed by measuring D-dimers and by rotational thromboelastometry (ROTEM). Secondary outcomes are international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, haemoglobin and platelets. We aim to include about 180 women from the University College Hospital, Ibadan in Nigeria. Discussion:  This sub-study of WOMAN trial participants should provide information on the mechanism of action of tranexamic acid in women with postpartum haemorrhage. We present the trial protocol and statistical analysis plan. The trial protocol was registered prior to the start of patient recruitment. The statistical analysis plan was completed before un-blinding. Trial registration: The trial was registered: ClinicalTrials.gov, Identifier NCT00872469 https://clinicaltrials.gov/ct2/show/NCT00872469; ISRCTN registry, Identifier ISRCTN76912190 http://www.isrctn.com/ISRCTN76912190 (Registration date: 22/03/2012).

  7. Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): protocol and statistical analysis plan for a randomized controlled trial

    PubMed Central

    2016-01-01

    Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid has the potential to reduce bleeding and a large randomized controlled trial of its effect on maternal health outcomes in women with PPH (The WOMAN trial) is ongoing. We will examine the effect of tranexamic acid on fibrinolysis and coagulation in a subset of WOMAN trial participants. Methods. Adult women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion in the WOMAN trial. In a sub-group of trial participants, blood samples will be collected at baseline and 30 minutes after the first dose of tranexamic acid or matching placebo.  Our primary objective is to evaluate the effect of tranexamic acid on fibrinolysis. Fibrinolysis will be assessed by measuring D-dimers and by rotational thromboelastometry (ROTEM). Secondary outcomes are international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, haemoglobin and platelets. We aim to include about 180 women from the University College Hospital, Ibadan in Nigeria. Discussion:  This sub-study of WOMAN trial participants should provide information on the mechanism of action of tranexamic acid in women with postpartum haemorrhage. We present the trial protocol and statistical analysis plan. The trial protocol was registered prior to the start of patient recruitment. The statistical analysis plan was completed before un-blinding. Trial registration: The trial was registered: ClinicalTrials.gov, Identifier NCT00872469 https://clinicaltrials.gov/ct2/show/NCT00872469; ISRCTN registry, Identifier ISRCTN76912190 http://www.isrctn.com/ISRCTN76912190 (Registration date: 22/03/2012). PMID:28317031

  8. Tissue fibrinolysis in experimental gastric ulcer: a study in the rat.

    PubMed

    Stenberg, B; Risberg, B; Hedman, L; Peterson, H I

    1981-10-01

    Gastric mucosal lesions were induced in rats by pyloric ligature and intragastric instillation of hydrochloric acid. Within 4 h all rats developed focal mucosal lesions. Early regeneration was observed 72 h after release of the pyloric ligature and replacement of the hydrochloric acid by a phosphate buffer. A significantly increased gastric mucosal fibrinolytic activity was found 4 h after pylorus ligation. The submucosal vascular fibrinolysis remained unchanged. Following release of the pyloric ligature the increased mucosal fibrinolysis returned to normal values after 72 h. Intravenous administration of tranexamic acid significantly decreased the mucosal and vascular fibrinolytic activity without influencing the formation of induced gastric lesions. Increased mucosal fibrinolysis is probably not involved in the development of mucosal lesions.

  9. Influence of natural humic acids and synthetic phenolic polymers on fibrinolysis

    NASA Astrophysics Data System (ADS)

    Klöcking, Hans-Peter

    The influence of synthetic and natural phenolic polymers on the release of plasminogen activator was studied in an isolated, perfused, vascular preparation (pig ear). Of the tested synthetic phenolic polymers, the oxidation products of caffeic acid (KOP) and 3,4-dihydroxyphenylacetic acid (3,4-DHPOP), at a concentration of 50 µg/ml perfusate, were able to increase the plasminogen activator activity by 70%. The oxidation products of chlorogenic acid (CHOP), hydrocaffeic acid (HYKOP), pyrogallol (PYROP) and gallic acid (GALOP), at the same concentration, exerted no influence on the release of plasminogen activator. Of the naturally occurring humic acids, the influence of sodium humate was within the same order of magnitude as KOP and 3,4-DHPOP. Ammonium humate was able to increase the plasminogen activator release only at a concentration of 100 µg/ml perfusate. In rats, the t-PA activity increased after i.v. application of 10 mg/kg of KOP, Na-HS or NH4-HS.

  10. EFFECT OF ε-AMINOCAPROIC ACID ON FIBRINOLYSIS IN PLASMA OF ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

    PubMed

    Kaye, Sarrah; Abou-Madi, Noha; Fletcher, Daniel J

    2016-06-01

    ε-Aminocaproic acid (EACA) is a lysine analogue antifibrinolytic drug used to treat bleeding disorders in humans and domestic animals. Use in zoological medicine is rare and dose recommendations are anecdotal, but EACA may be a valuable therapeutic option for bleeding disorders in exotic species, including Asian elephants ( Elephas maximus ). This study used an in vitro model of hyperfibrinolysis and a thromboelastograph-based assay to estimate the therapeutic plasma concentration of EACA in Asian elephants (61.5 μg/ml, 95% CI = 34.6-88.5 μg/ml). Substantial but incomplete inhibition of lysis was seen at relatively low concentrations of EACA (40 μg/ml). Asian elephants appear sensitive to EACA-mediated inhibition of hyperfibrinolysis. Doses published for domestic animals, targeting higher plasma concentrations, may be inappropriate in this species.

  11. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial

    PubMed Central

    Jimenez, Juan J; Iribarren, Jose L; Lorente, Leonardo; Rodriguez, Jose M; Hernandez, Domingo; Nassar, Ibrahim; Perez, Rosalia; Brouard, Maitane; Milena, Antonio; Martinez, Rafael; Mora, Maria L

    2007-01-01

    Introduction Extracorporeal circulation induces hemostatic alterations that lead to inflammatory response (IR) and postoperative bleeding. Tranexamic acid (TA) reduces fibrinolysis and blood loss after cardiopulmonary bypass (CPB). However, its effects on IR and vasoplegic shock (VS) are not well known and elucidating these effects was the main objective of this study. Methods A case control study was carried out to determine factors associated with IR after CPB. Patients undergoing elective CPB surgery were randomly assigned to receive 2 g of TA or placebo (0.9% saline) before and after intervention. We performed an intention-to-treat analysis, comparing the incidence of IR and VS. We also analyzed several biological parameters related to inflammation, coagulation, and fibrinolysis systems. We used SPSS version 12.2 for statistical purposes. Results In the case control study, 165 patients were studied, 20.6% fulfilled IR criteria, and the use of TA proved to be an independent protective variable (odds ratio 0.38, 95% confidence interval 0.18 to 0.81; P < 0.01). The clinical trial was interrupted. Fifty patients were randomly assigned to receive TA (24) or placebo (26). Incidence of IR was 17% in the TA group versus 42% in the placebo group (P = 0.047). In the TA group, we observed a significant reduction in the incidence of VS (P = 0.003), the use of norepinephrine (P = 0.029), and time on mechanical ventilation (P = 0.018). These patients showed significantly lower D-dimer, plasminogen activator inhibitor 1, and creatine-kinase levels and a trend toward lower levels of soluble tumor necrosis factor receptor and interleukin-6 within the first 24 hours after CPB. Conclusion The use of TA attenuates the development of IR and VS after CPB. Trial registration number ISRCTN05718824. PMID:17988379

  12. Fibrinolysis in Trauma: "Myth," "Reality," or "Something in Between".

    PubMed

    Walsh, Mark; Shreve, Jacob; Thomas, Scott; Moore, Ernest; Moore, Hunter; Hake, Daniel; Pohlman, Tim; Davis, Patrick; Ploplis, Victoria; Piscoya, Andres; Wegner, Julie; Bryant, John; Crepinsek, Anton; Lantry, James; Sheppard, Forest; Castellino, Francis

    2017-03-01

    The emphasis on fibrinolysis as an important contributor to trauma-induced coagulopathy (TIC) has led to a debate regarding the relative clinical significance of fibrinolysis in the setting of trauma. The debate has centered on two camps. The one camp defines fibrinolysis in trauma by standard coagulation tests as well as fibrin split products, D-dimers, and plasmin/antiplasmin levels. This camp favors a more liberal use of tranexamic acid and attributes more significance to hyperfibrinolysis in TIC. The other camp favors a definition of fibrinolysis based on the viscoelastic tests (VET), rotational thromboelastometry (ROTEM), and thromboelastography (TEG). These whole blood assays define hyperfibrinolysis at a higher threshold than plasma-based tests. Therefore, this VET camp reserves antifibrinolytic treatment for patients who demonstrate severe coagulopathy associated with hyperfibrinolysis. This bimodal attribution of the clinical relevance of fibrinolysis in trauma suggests that there may be an underlying "Myth" of the concept of TIC that was historically defined by plasma-based tests and a future "Reality" of the concept of TIC that is grounded on an understanding of TIC based on a VET-defined "fibrinolytic spectrum" of TIC. This narrative review explores this "Myth" and "Reality" of fibrinolysis in TIC and proposes a direction that will allow a "Future" interpretation of TIC that incorporates both the past "Myth" and present "Reality" of fibrinolysis TIC. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  13. Pyrazinoic acid decreases peritoneal transfer rates.

    PubMed

    Grzegorzewska, A E; Czyzewska, K; Szary, B

    1995-01-01

    It was shown elsewhere that in a peritoneally dialyzed woman with pulmonary tuberculosis, oral treatment with rifampicin and pyrazinamide (11 and 25 mg/kg/day, respectively) caused a decrease in the peritoneal transport of sodium, potassium, urea, uric acid, protein, and ultrafiltration rate by 48% to 75% compared to the pretreatment values. Pyrazinoic acid (PA), a metabolite of pyrazinamide, may account for these changes, because rifampicin was also previously used in this patient without peritoneal function impairment. Thus in the present study the influence of PA on the human peritoneum is examined using the modified Ussing-type chamber. PA (1 mg/dL) was introduced into the medium on the interstitial side of the membrane. After the introduction of PA, uric acid transfer from the interstitial to the mesothelial side decreased by about 50%. There were no significant changes in the urea and albumin transfer rates. In conclusion, PA induces changes in uric acid transfer acting directly on mesothelial cells, whereas a decrease in the peritoneal transfer of other solutes may be caused by a decrease in convective transfer rates due to impaired ultrafiltration.

  14. Coagulation fibrinolysis in sickle-cell disease

    PubMed Central

    Gordon, P. A.; Breeze, G. R.; Mann, J. R.; Stuart, J.

    1974-01-01

    A study of fibrinolytic activity in sickle-cell patients during asymptomatic periods has shown a normal fibrinolytic response to exercise and local heat to the arm. During vasoocclusive crises there was no significant decrease in fibrinolytic activity. These results contrast with earlier reports of decreased fibrinolysis during crisis and a suggestion that fibrinolytic activators might be of value in preventing vasoocclusive episodes. Patients in painful crisis showed a significant rise in fibrinogen concentration and fall in platelet count. The former may contribute to localized vascular sludging by increasing whole-blood viscosity, while the latter probably results from local trapping of platelets in areas of sickling or from subsequent splenic sequestration of damaged platelets. There was no evidence of disseminated, as opposed to localized, intravascular coagulation during crisis. PMID:4412492

  15. Impaired activation of the fibrinolytic system in children with Henoch-Schönlein purpura: beneficial effect of hydrocortisone plus Sigma-aminocaproic acid therapy on disappearance rate of cutaneous vasculitis and fibrinolysis.

    PubMed

    Prandota, J; Pankow-Prandota, L; Kotecki, L

    2001-01-01

    Systemic vasculitis is a predominant clinical symptom in Henoch-Schönlein purpura (HSP), and some studies suggested that decreased blood fibrinolytic activity, as well as blood platelets, is of importance in the development of cutaneous vasculitis. Although patients with HSP have normal blood coagulation, little is known about the fibrinolytic system. On the other hand, it is known that the focus of Sigma-aminocaproic acid (EACA) activity in vivo is probably the blood platelet-vessel wall interaction or a vascular component alone. The aim of this study was, therefore, to investigate blood coagulation and fibrinolytic system as well as the effect of hydrocortisone (H) plus EACA therapy (Group I) on plasma antithrombin-III (AT-III), alpha1-proteinase inhibitor (alpha1-PI), alpha2-antiplasmin (alpha2-A), alpha2-macroglobulin (alpha2-M) activity, fibrinogen and plasminogen concentrations in plasma, euglobulin clot lysis time (ELT), and disappearance rate of cutaneous vasculitis in 14 children with HSP aged 7.6 +/- 3.1 (SD) years. Ten patients (8.6 +/- 2.5 years old) were treated with H alone (Group II), and 8 healthy, age-matched children served as controls. Plasma proteinase inhibitor activity was estimated with the kinetic method using Boehringer chromozyme tests before administration of H (9.2 +/- 3.3 mg/kg/d, i.v.) plus EACA (140 +/- 52 mg/kg/d, p.o.) for 5.93 +/- 2.05 days, and 24 hours after the last dose of EACA, as well as before and after treatment with H alone (8.25 +/- 1.74 mg/kg/24 h, i.v.) for 7.1 +/- 1.2 days. It was found that patients with HSP had the initial fibrinogen and plasminogen plasma concentrations significantly increased compared with the controls (Group I: 3.93 +/- 1.3 g/L and 124 +/- 38%; Group II: 4.24 +/- 0.89 g/L and 134 +/- 42% vs. 2.96 +/- 0.34 g/L, and 90 +/- 14%, respectively). Also, there was a marked decrease of the initial plasma alpha2-A activity in Group II compared with the controls (0.69 +/- 0.29 vs. 0.94 +/- 0.11 IU

  16. The euglobulin clot lysis time to assess the impact of nanoparticles on fibrinolysis

    NASA Astrophysics Data System (ADS)

    Minet, Valentine; Alpan, Lutfiye; Mullier, François; Toussaint, Olivier; Lucas, Stéphane; Dogné, Jean-Michel; Laloy, Julie

    2015-07-01

    Nanoparticles (NPs) are developed for many applications in various fields, including nanomedicine. The NPs used in nanomedicine may disturb homeostasis in blood. Secondary hemostasis (blood coagulation) and fibrinolysis are complex physiological processes regulated by activators and inhibitors. An imbalance of this system can either lead to the development of hemorrhages or thrombosis. No data are currently available on the impact of NPs on fibrinolysis. The objectives of this study are (1) to select a screening test to study ex vivo the impact of NPs on fibrinolysis and (2) to test NPs with different physicochemical properties. Euglobulin clot lysis time test was selected to screen the impact of some NPs on fibrinolysis using normal pooled plasma. A dose-dependent decrease in the lysis time was observed with silicon dioxide and silver NPs without disturbing the fibrin network. Carbon black, silicon carbide, and copper oxide did not affect the lysis time at the tested concentrations.

  17. The effect of fibrin structure on fibrinolysis.

    PubMed

    Gabriel, D A; Muga, K; Boothroyd, E M

    1992-12-05

    Fibrin structure contributes to the regulation of the fibrinolytic rate. As the fibrin fiber size is decreased, the fibrinolytic rate also decreases. Fibrin structure was altered by either changing the ratio of thrombin to fibrinogen, i.e. altering the assembly rate or by adding a fibrin assembly inhibitor, iopamidol. Changes in the fibrinolytic rate were followed by measuring the time dependence of the decrease in the fiber mass/length ratio during fibrinolysis. A measure of the overall fibrinolytic rate was determined from the decrease in the mass/length ratio versus time. An 8-fold reduction in the fibrinolytic rate was seen on decreasing the mass/length ratio from 2.7 x 10(12) daltons/cm to 0.5 x 10(12) daltons/cm. It is shown that thin fibrin fibers have a decreased rate of conversion of plasminogen to plasmin by tissue plasminogen activator and that thin fibrin fibers are lysed more slowly than thick fibrin fibers.

  18. A novel hemostasis assay for the simultaneous measurement of coagulation and fibrinolysis.

    PubMed

    van Geffen, Mark; Loof, Arnoud; Lap, Paul; Boezeman, Jan; Laros-van Gorkom, Britta A P; Brons, Paul; Verbruggen, Bert; van Kraaij, Marian; van Heerde, Waander L

    2011-11-01

    Thrombin and plasmin are the key enzymes involved in coagulation and fibrinolysis. A novel hemostasis assay (NHA) was developed to measure thrombin and plasmin generation in a single well by a fluorimeter. The NHA uses two fluorescent substrates with non-interfering fluorescent excitation and emission spectra. The assay was tested in vitro using modulators like heparin, hirudin, epsilon-aminocaproic acid, gly-pro-arg-pro peptide and reptilase and validated by measurement of prothrombin fragment 1+2 and plasmin-alpha2-antiplasmin levels. Intra- and inter-assay coefficients of variation were < 9% and 6-25%, respectively. Interplay between coagulation and fibrinolysis was demonstrated by the effect of tissue-type plasminogen activator on thrombin generation and by the different responses of activated protein C and thrombomodulin on fibrinolysis. The last responses showed the linkage between coagulation and fibrinolysis by thrombin activatable fibrinolysis inhibitor. In conclusion, this strategy allows detection of coagulation, fibrinolysis and their interplay in a single assay.

  19. Fibrinolysis and the control of blood coagulation

    PubMed Central

    Chapin, John C.; Hajjar, Katherine A.

    2014-01-01

    Fibrin plays an essential role in hemostasis as both the primary product of the coagulation cascade and the ultimate substrate for fibrinolysis. Fibrinolysis efficiency is greatly influenced by clot structure, fibrinogen isoforms and polymorphisms, the rate of thrombin generation, the reactivity of thrombus-associated cells such as platelets, and the overall biochemical environment. Regulation of the fibrinolytic system, like that of the coagulation cascade, is accomplished by a wide array of cofactors, receptors, and inhibitors. Fibrinolytic activity can be generated either on the surface of a fibrin-containing thrombus, or on cells that express profibrinolytic receptors. In a widening spectrum of clinical disorders, acquired and congenital defects in fibrinolysis contribute to disease morbidity, and new assays of global fibrinolysis now have potential predictive value in multiple clinical settings. Here, we summarize the basic elements of the fibrinolytic system, points of interaction with the coagulation pathway, and some recent clinical advances. PMID:25294122

  20. Fibrinolysis and the control of blood coagulation.

    PubMed

    Chapin, John C; Hajjar, Katherine A

    2015-01-01

    Fibrin plays an essential role in hemostasis as both the primary product of the coagulation cascade and the ultimate substrate for fibrinolysis. Fibrinolysis efficiency is greatly influenced by clot structure, fibrinogen isoforms and polymorphisms, the rate of thrombin generation, the reactivity of thrombus-associated cells such as platelets, and the overall biochemical environment. Regulation of the fibrinolytic system, like that of the coagulation cascade, is accomplished by a wide array of cofactors, receptors, and inhibitors. Fibrinolytic activity can be generated either on the surface of a fibrin-containing thrombus, or on cells that express profibrinolytic receptors. In a widening spectrum of clinical disorders, acquired and congenital defects in fibrinolysis contribute to disease morbidity, and new assays of global fibrinolysis now have potential predictive value in multiple clinical settings. Here, we summarize the basic elements of the fibrinolytic system, points of interaction with the coagulation pathway, and some recent clinical advances.

  1. The effects of 2-chloroprocaine on coagulation and fibrinolysis in the parturient: an in vitro study.

    PubMed

    Kodali, Bhavani Shankar; Sa Rego, Monica; Kaynar, A Murat; Urman, Richard D

    2014-12-01

    Amide local anesthetics are known to inhibit coagulation. 2-chloroprocaine is the only ester agent used in obstetric anesthesia. It is used during obstetric emergencies, and also to supplement inadequate epidural block produced by amide local anesthetics. There is no study to date that has evaluated the effect of ester local anesthetics on blood coagulation and fibrinolysis in the parturient. In this study, we obtained blood samples from healthy, term-parturients and mixed them with varying amounts of 2-chloroprocaine for final concentrations ranging from 0.26 to 7.8 mM. Thromboelastograph(®) was used to study the coagulation profile of these samples. Chloroprocaine impaired coagulation in a dose dependent manner, with increased R and K, and decreased MA and α. The difference, when compared to saline controls, reached statistical significance at a dose of 7.8 mM. An additional significant finding was that 2-chloroprocaine also enhanced fibrinolysis. Amide local anesthetics are known to impair coagulation, but 2-chloroprocaine produced significant fibrinolysis in addition to decreasing coagulation. This is the first study to date to demonstrate fibrinolytic properties of an ester local anesthetic. Further study evaluations are required to determine the cause of the variation in fibrinolysis. There is also a need to address the mechanism of increased fibrinolysis observed with 2-chroloprocaine.

  2. ASCORBIC ACID IS DECREASED IN INDUCED SPUTUM OF MILD ASTHMATICS

    EPA Science Inventory

    Asthma is primarily an airways inflammatory disease, and the bronchial airways have been shown to be particularly susceptible to oxidant-induced tissue damage. The antioxidant ascorbic acid (AA) plays an essential role in defending against oxidant attack in the airways. Decreased...

  3. ASCORBIC ACID IS DECREASED IN INDUCED SPUTUM OF MILD ASTHMATICS

    EPA Science Inventory

    Asthma is primarily an airways inflammatory disease, and the bronchial airways have been shown to be particularly susceptible to oxidant-induced tissue damage. The antioxidant ascorbic acid (AA) plays an essential role in defending against oxidant attack in the airways. Decreased...

  4. ASCORBID ACID IS DECREASED IN INDUCED SPUTUM OF MILD ASTHMATICS

    EPA Science Inventory

    ABSTRACT
    Evidence suggests that the antioxidant ascorbic acid (AA), plays an essential role in defending against oxidant attack in the airways. Decreased levels of AA have been reported in asthmatics but not at the site directly proximal to asthma pathology, i.e. the bronchial...

  5. Coagulation and fibrinolysis in injured patients

    PubMed Central

    Innes, D.; Sevitt, S.

    1964-01-01

    Serial changes in coagulation and fibrinolysis studied among 42 patients admitted to hospital with a wide variety of injuries are reported. The first hours after trauma are dominated by an acceleration of fibrinolysis (clot lysis) and clotting time which are often followed by an abrupt rebound to prolonged fibrinolysis and normal clotting. Evidence is presented that acceleration of fibrinolysis is due to flooding of the circulation by plasminogen activator and that prolongation is probably due to an inhibitor. A prolonged prothrombin time, increased prothrombin consumption index, an acceleration of the heparin-retarded clotting time, and a fall in the platelet count are also frequent during the first hours after injury. There is evidence also of an early deficiency in factor V and the onset of a fall in factor VII and prothrombin. The following days are characterized by continued prolongation of fibrinolysis, a lengthening of clotting time, and an increased prothrombin consumption index suggestive of a defect in thrombo-plastin generation. Subsequent periods of prolonged fibrinolysis may develop. Prothrombin time often continues prolonged for one to three weeks and may vary phasically; plasma prothrombin and factor VII are reduced but there is now little change in factor V. The platelet count continues to fall for one to three days, then a thrombocytosis develops, often with abnormally high platelet levels, a week or so later. Plasma fibrinogen rises within 24 hours to reach a plateau maximum a few days later and levels remain high for prolonged periods in the severely injured. Various changes are related to or influenced by the severity of trauma. Mechanisms are discussed, including thrombosis in vivo, and reference is made to homeostatic significance and its possible breakdown. PMID:14103515

  6. Can Delignification Decrease Cellulose Digestibility in Acid Pretreated Corn Stover?

    SciTech Connect

    Ishizawa, C. I.; Jeoh, T.; Adney, W. S.; Himmel, M. E.; Johnson, D. K.; Davis, M. F.

    2009-01-01

    It has previously been shown that the improved digestibility of dilute acid pretreated corn stover is at least partially due to the removal of xylan and the consequent increase in accessibility of the cellulose to cellobiohydrolase enzymes. We now report on the impact that lignin removal has on the accessibility and digestibility of dilute acid pretreated corn stover. Samples of corn stover were subjected to dilute sulfuric acid pretreatment with and without simultaneous (partial) lignin removal. In addition, some samples were completely delignified after the pretreatment step using acidified sodium chlorite. The accessibility and digestibility of the samples were tested using a fluorescence-labeled cellobiohydrolase (Trichoderma reesei Cel7A) purified from a commercial cellulase preparation. Partial delignification of corn stover during dilute acid pretreatment was shown to improve cellulose digestibility by T. reesei Cel7A; however, decreasing the lignin content below 5% (g g{sup -1}) by treatment with acidified sodium chlorite resulted in a dramatic reduction in cellulose digestibility. Importantly, this effect was found to be enhanced in samples with lower xylan contents suggesting that the near complete removal of xylan and lignin may cause aggregation of the cellulose microfibrils resulting in decreased cellulase accessibility.

  7. Effect of remote ischaemic conditioning on coagulation and fibrinolysis.

    PubMed

    Kristiansen, Jacobina; Grove, Erik L; Rise, Nina; Neergaard-Petersen, Søs; Würtz, Morten; Kristensen, Steen Dalby; Hvas, Anne-Mette

    2016-05-01

    Remote ischaemic conditioning (RIC) reduces infarct size and may improve prognosis in patients with acute myocardial infarction. To explore the potential mechanisms, we investigated the effects of RIC on coagulation and fibrinolysis. Interventional crossover study including 30 healthy drug-naïve males. Participants were exposed to a sham intervention (visit 1) and to RIC (visit 2 and 3) induced by intermittent arm ischaemia through four cycles of 5-min inflation of a blood pressure cuff followed by 5-min deflation. Prior to visit 3, all participants received aspirin 75mg daily for seven days. Blood samples were obtained at baseline as well as 5 and 45min after intervention. Whole blood coagulation was assessed by thromboelastometry (ROTEM®) and thrombin generation. Fibrinolysis was evaluated by clot turbidity-lysis, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1). No differences were found in clot initiation, clot propagation or clot strength evaluated by ROTEM® (all p-values≥0.98). During aspirin treatment, clot initiation and clot propagation decreased after RIC evaluated by ROTEM® EXTEM® clotting time (p=0.04) and ROTEM® EXTEM® maximum velocity (p=0.03). After sham and RIC, thrombin generation declined as evaluated by reduced endogenous thrombin potential (RIC: p=0.001) and peak (RIC: p=0.01). After RIC during aspirin treatment, changes in thrombin generation were inconsistent; increased peak (p=0.04) and time to peak (p<0.001) and a decrease in lag-time (p<0.001). Clot lysis time was prolonged both after sham and after RIC (p<0.001). After RIC, PAI-1 levels declined (p=0.03), but t-PA levels also declined after all interventions (p-values≤0.04). RIC did not have substantial effects on coagulation or fibrinolysis compared to sham. Overall, aspirin did not influence the results. Copyright © 2016. Published by Elsevier Ltd.

  8. Enhanced Fibrinolysis with Magnetically Powered Colloidal Microwheels.

    PubMed

    Tasci, Tonguc O; Disharoon, Dante; Schoeman, Rogier M; Rana, Kuldeepsinh; Herson, Paco S; Marr, David W M; Neeves, Keith B

    2017-09-01

    Thrombi that occlude blood vessels can be resolved with fibrinolytic agents that degrade fibrin, the polymer that forms between and around platelets to provide mechanical stability. Fibrinolysis rates however are often constrained by transport-limited delivery to and penetration of fibrinolytics into the thrombus. Here, these limitations are overcome with colloidal microwheel (µwheel) assemblies functionalized with the fibrinolytic tissue-type plasminogen activator (tPA) that assemble, rotate, translate, and eventually disassemble via applied magnetic fields. These microwheels lead to rapid fibrinolysis by delivering a high local concentration of tPA to induce surface lysis and, by taking advantage of corkscrew motion, mechanically penetrating into fibrin gels and platelet-rich thrombi to initiate bulk degradation. Fibrinolysis of plasma-derived fibrin gels by tPA-microwheels is fivefold faster than with 1 µg mL(-1) tPA. µWheels following corkscrew trajectories can also penetrate through 100 µm sized platelet-rich thrombi formed in a microfluidic model of hemostasis in ≈5 min. This unique combination of surface and bulk dissolution mechanisms with mechanical action yields a targeted fibrinolysis strategy that could be significantly faster than approaches relying on diffusion alone, making it well-suited for occlusions in small or penetrating vessels not accessible to catheter-based removal. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Poly-L-histidine downregulates fibrinolysis.

    PubMed

    Chu, Arthur J; Mathews, Suresh T

    2003-10-01

    The elevated level of histidine-rich glycoprotein was considered a risk factor of inherited thrombophilia. However, the mode of action remains largely unclear. In the current study, we employ poly-l-histidine (PLH) mimicking the histidine-rich region and determine whether PLH modulates urokinase (uPA)-dependent fibrinolysis. In an in vitro model, turbidity appearance and clearance monitored fibrin polymer formation and lysis, respectively. Fibrin polymer formed upon fibrinogen incubation with thrombin. In the presence of uPA or plasmin, fibrin polymer lysis took place in a dose-dependent manner as a function of time. We demonstrated that PLH significantly downregulated uPA-dependent fibrinolysis. PLH had no effect on plasminogen activation, as evidenced by no inhibitions on either uPA amidolytic activity or plasmin formation derived from its zymogen. Nor did PLH show any inhibition on plasmin amidolytic activity. PLH caused a profound delay of plasmin-dependent fibrinolysis upon pre-incubation of either plasmin or fibrinogen with PLH. The observations taken together suggest that the complex [plasmin-PLH-fibrin] formation significantly delayed plasmin-dependent fibrinolysis.

  10. Decreased plasma arachidonic acid binding capacity in neonates.

    PubMed

    Sadowitz, P D; Walenga, R W; Clark, D; Stuart, M J

    1987-01-01

    Arachidonic acid (AA) metabolites have been implicated in neonatal pathologic states such as respiratory distress syndrome (RDS). Since free (nonprotein bound) AA is the substrate for synthesis of these compounds, a decreased capacity to bind AA in neonatal plasma could contribute to these disorders. AA binding was assayed by equilibrium dialysis in plasma samples from healthy adults and various infant groups. Plasma from these infant groups bound significantly less AA than adult plasma. Premature infants with RDS and premature infants receiving intralipid had the lowest capacity to bind AA. The increased availability of free AA may be important in neonatal pathophysiologic states involving arachidonate metabolites.

  11. Chlorogenic acid decreases retinal vascular hyperpermeability in diabetic rat model.

    PubMed

    Shin, Joo Young; Sohn, Joonhong; Park, Kyu Hyung

    2013-04-01

    To evaluate the effect of chlorogenic acid (CGA), a polyphenol abundant in coffee, on retinal vascular leakage in the rat model of diabetic retinopathy, Sprague-Dawley rats were divided into four groups: controls, streptozotocin-induced diabetic rats, and diabetic rats treated with 10 and 20 mg/kg chlorogenic acid intraperitoneally daily for 14 days, respectively. Blood-retinal barrier (BRB) breakdown was evaluated using FITC-dextran. Vascular endothelial growth factor (VEGF) distribution and expression level was evaluated with immunohistochemistry and Western blot analysis. Expression of tight junction proteins, occludin and claudin-5, and zonula occludens protein, ZO-1 was also evaluated with immunohistochemistry and Western blot analysis. BRB breakdown and increased vascular leakage was found in diabetic rats, with increased VEGF expression and down-regulation of occludin, claudin-5, and ZO-1. CGA treatment effectively preserved the expression of occludin, and decreased VEGF levels, leading to less BRB breakdown and less vascular leakage. CGA may have a preventive role in BRB breakdown in diabetic retinopathy by preserving tight junction protein levels and low VEGF levels.

  12. Prothrombotic state and impaired fibrinolysis in bullous pemphigoid, the most frequent autoimmune blistering disease

    PubMed Central

    Marzano, A V; Tedeschi, A; Polloni, I; Crosti, C; Cugno, M

    2013-01-01

    Bullous pemphigoid (BP) is a potentially life-threatening autoimmune blistering disease that is burdened with an increased risk of cardiovascular events. In BP, there is an interplay between inflammation and coagulation both locally, which contributes to skin damage, and systemically, which leads to a prothrombotic state. Fibrinolysis is an important defence mechanism against thrombosis, but has only been studied locally in BP and no systemic data are available. The aim of this observational study was to evaluate systemic fibrinolysis and coagulation activation in patients with BP. We measured parameters of fibrinolysis and coagulation by immunoenzymatic methods in plasma from 20 patients with BP in an active phase and during remission after corticosteroid treatment. The controls were 20 age- and sex-matched healthy subjects. Plasma levels of plasminogen activator inhibitor type 1 (PAI-1) antigen, PAI-1 activity and tissue plasminogen activator (t-PA) antigen were significantly higher in the BP patients with active disease than in healthy controls (P = 0·0001 for all), as were the plasma levels of the fibrin fragment d-dimer and prothrombin fragment F1+2 (P = 0·0001 for both). During remission after treatment, levels of PAI-1 antigen and PAI-1 activity decreased significantly (P = 0·008 and P = 0·006, respectively), and there was also a significant decrease in plasma levels of d-dimer (P = 0·0001) and F1+2 (P = 0·0001). Fibrinolysis is inhibited in patients with active BP, due mainly to an increase in plasma levels of PAI-1. Corticosteroids not only induce the regression of BP lesions, but also reduce the inhibition of fibrinolysis, which may contribute to decreasing thrombotic risk. PMID:23199326

  13. Effects of heparin therapy on fibrinolysis in patients with pulmonary embolism.

    PubMed

    Minnema, M C; ten Cate, H; van Beek, E J; van den Ende, A; Hack, C E; Brandjes, D P

    1997-06-01

    Previous investigations suggested that heparin administration to humans enhances the tissue type plasminogen activator (tPA) levels in blood, but it remains uncertain whether this effect induces fibrinolysis. We studied the effect of therapeutic levels of heparinization on plasma markers for fibrinolysis in patients suspected of pulmonary embolism (PE). Blood samples were taken from 49 consecutive patients; 28 had confirmed PE, 21 had PE excluded. On admission, the plasma levels of plasmin-alpha 2antiplasmin complexes and D-dimer were significantly higher in the patient group with PE compared to those in whom PE was excluded. After heparinization the tPA levels increased in both groups, showing that this effect was not dependent on the initial level of activity of fibrinolysis. In spite of this increment in tPA levels, the concentrations of plasmin-alpha 2antiplasmin complexes and D-dimer decreased. In conclusion, although heparinization in patients with or without pulmonary embolism does lead to elevated tPA:Ag levels, this is not accompanied by enhanced fibrinolysis.

  14. Venous ulceration, fibrinogen and fibrinolysis.

    PubMed Central

    Leach, R. D.

    1984-01-01

    The effect of long and short-term venous hypertension upon lymph fibrinogen concentrations was studied in an attempt to explain the peri-capillary deposition of fibrin reported in patients with post-phlebitic syndromes. The clearance of radioactive fibrinogen/thrombin clots from the subcutaneous tissues of rats and human volunteers was also studied. Both long- and short-term venous hypertension were found to increase fibrinogen transport across the interstitial space by more than 600%. Not only was there evidence of fibrinolytic activity in the lymph but after long-term venous hypertension alpha 2 antiplasmin activity was also detectable. Skin biopsies from the venous hypertensive ankles showed deposition of interstitial fibrin. The clearance of radioactive fibrinogen/thrombin clots from the subcutaneous tissues of the rat was found to be delayed if the rats were given epsilon amino caproic acid but it could not be increased with stanozolol. In human subjects it was found that patients with lipodermatosclerosis had delayed clot clearance and retarded blood fibrinolytic activity when compared with normal volunteers and patients with uncomplicated varicose veins. The principle cause why tall men are more subject to ulcers than short men, Dr Young conceived to be then length of the column of blood in their veins; which by its pressure, renders the legs less able to recover when hurt by any violence. Images Fig. 1 Fig. 2 Fig. 5 PMID:6742738

  15. Phytic acid plus calcium, but not phytic acid alone, decreases fluoride bioavailability in the rat

    SciTech Connect

    Cerklewski, F.L. )

    1991-03-15

    Results of in vitro studies have suggested that fluoride becomes insoluble when some soy-based infant formulas are diluted with fluoridated water because of the presence of phytate, added calcium or a combination of these factors. The present study was designed to test this hypothesis in vivo. Male albino rats were fed a purified diet containing phytic acid, calcium and fluoride for 4 weeks in a factorial design of treatments. Phytic acid was added to the diet by chemically reacting a phytic acid concentrate with casein prior to diet preparation to mimic a soy-protein. Food intake, weight gain and femur P were unaffected by dietary treatments. Both phytic acid and supplemental calcium alone had little or no effect upon fluoride uptake into either bone or teeth. The combination of phytic acid plus supplemental calcium, however, significantly increased % of fluoride intake found in the feces which was reflected in a significant decrease in fluoride concentration of femur, 2nd molar teeth and vertebrate bone. These results provide evidence that insoluble complex formation produced by a calcium and phytate interaction can explain reduced fluoride solubility in some soy-based infant formulas as well as decreased fluoride absorbability in vivo.

  16. Blood markers of fibrinolysis and endothelial activation in canine babesiosis.

    PubMed

    Kuleš, Josipa; Gotić, Jelena; Mrljak, Vladimir; Barić Rafaj, Renata

    2017-03-31

    Canine babesiosis is a tick-borne disease caused by hemoprotozoan parasites of the genus Babesia. The disease can be clinically classified into uncomplicated and complicated forms. The aim of this study was to assess the level of endothelial activation and alterations in the fibrinolytic pathway during canine babesiosis. Blood samples were collected on the day of admission and on the 6th day after treatment with imidocarb propionate, from 30 dogs of various breeds and of both sexes with naturally occurring babesiosis caused by B. canis. In this prospective study, plasminogen activity was assessed using a chromogenic assay, and concentrations of high mobility group box-1 protein (HMGB-1), intercellular adhesive molecule-1 (ICAM-1), vascular adhesive molecule-1 (VCAM-1), soluble urokinase receptor of plasminogen activator (suPAR), thrombin activatable fibrinolysis inhibitor (TAFI), soluble thrombomodulin (TM) and plasminogen activator inhibitor-1 (PAI-1) were determined using a canine specific ELISA. Concentrations of TM, HMGB-1, VCAM-1 and suPAR were increased in dogs with babesiosis at admission compared to healthy dogs. After treatment, concentrations of TM were lower in infected dogs compared to healthy dogs. Dogs with babesiosis also had increased concentrations of TM, ICAM-1 and HMGB-1 and decreased plasminogen and PAI-1 at presentation compared to day 6 after treatment. Dogs with complicated babesiosis had higher concentrations of TM, HMGB1 and TAFI at admission compared to the 6th day. Biomarkers of endothelial activation and fibrinolysis were altered in dogs with babesiosis. Further studies into their usefulness as biomarkers of disease severity or prognosis is warranted.

  17. Assessment of Fibrinolysis in Sepsis Patients with Urokinase Modified Thromboelastography

    PubMed Central

    Panigada, Mauro; Zacchetti, Lucia; L’Acqua, Camilla; Cressoni, Massimo; Anzoletti, Massimo Boscolo; Bader, Rossella; Protti, Alessandro; Consonni, Dario; D’Angelo, Armando; Gattinoni, Luciano

    2015-01-01

    Introduction Impairment of fibrinolysis during sepsis is associated with worse outcome. Early identification of this condition could be of interest. The aim of this study was to evaluate whether a modified point-of-care viscoelastic hemostatic assay can detect sepsis-induced impairment of fibrinolysis and to correlate impaired fibrinolysis with morbidity and mortality. Methods This single center observational prospective pilot study was performed in an adult Intensive Care Unit (ICU) of a tertiary academic hospital. Forty consecutive patients admitted to the ICU with severe sepsis or septic shock were included. Forty healthy individuals served as controls. We modified conventional kaolin activated thromboelastography (TEG) adding urokinase to improve assessment of fibrinolysis in real time (UK-TEG). TEG, UK-TEG, plasminogen activator inhibitor (PAI)-1, thrombin-activatable fibrinolysis inhibitor (TAFI), d-dimer, DIC scores and morbidity (rated with the SOFA score) were measured upon ICU admission. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) of mortality at ICU discharge. Results UK-TEG revealed a greater impairment of fibrinolysis in sepsis patients compared to healthy individuals confirmed by PAI-1. TAFI was not different between sepsis patients and healthy individuals. 18/40 sepsis patients had fibrinolysis impaired according to UK-TEG and showed higher SOFA score (8 (6–13) vs 5 (4–7), p = 0.03), higher mortality (39% vs 5%, p = 0.01) and greater markers of cellular damage (lactate levels, LDH and bilirubin). Mortality at ICU discharge was predicted by the degree of fibrinolysis impairment measured by UK-TEG Ly30 (%) parameter (OR 0.95, 95% CI 0.93–0.98, p = 0.003). Conclusions Sepsis-induced impairment of fibrinolysis detected at UK-TEG was associated with increased markers of cellular damage, morbidity and mortality. PMID:26308340

  18. Decreased consumption of branched chain amino acids improves metabolic health

    PubMed Central

    Arriola Apelo, Sebastian I.; Neuman, Joshua C.; Kasza, Ildiko; Schmidt, Brian A.; Cava, Edda; Spelta, Francesco; Tosti, Valeria; Syed, Faizan A.; Baar, Emma L.; Veronese, Nicola; Cottrell, Sara E.; Fenske, Rachel J.; Bertozzi, Beatrice; Brar, Harpreet K.; Pietka, Terri; Bullock, Arnold D.; Figenshau, Robert S.; Andriole, Gerald L.; Merrins, Matthew J.; Alexander, Caroline M.; Kimple, Michelle E.; Lamming, Dudley W.

    2016-01-01

    Protein restricted, high carbohydrate diets improve metabolic health in rodents, yet the precise dietary components that are responsible for these effects have not been identified. Further, the applicability of these studies to humans is unclear. Here, we demonstrate in a randomized controlled trial that a moderately protein restricted (PR) diet also improves markers of metabolic health in humans. Intriguingly, we find that feeding mice a diet specifically reduced in branched chain amino acids (BCAAs) is sufficient to improve glucose tolerance and body composition equivalently to a PR diet, via metabolically distinct pathways. Our results highlight a critical role for dietary quality at the level of amino acids in the maintenance of metabolic health, and suggest that diets specifically reduced in BCAAs, or pharmacological interventions in this pathway, may offer a translatable way to achieve many of the metabolic benefits of a PR diet. PMID:27346343

  19. Study of Proteins and Fibrinolysis in Patients with Glomerulonephritis

    PubMed Central

    Wardle, E. N.; Menon, I. S.; Rastogi, S. P.

    1970-01-01

    Plasma and urine fibrinolysis were studied in 36 patients with glomerulonephritis and proteinuria. In 40% of these plasma fibrinolytic activator activity was moderately reduced and fibrinolytic inhibitors were increased. Globulins with antiplasmin effect were raised, particularly in the earlier months. Both the serum cholesterol and the plasma fibrinogen were related to the level of serum albumin, and those patients with high fibrinogen levels were also those with poor plasma fibrinolytic activator and those showing a steady deterioration. Urinary fibrinolysis was greatly reduced in most patients and bore no relation to plasma fibrinolysis levels. Hence urokinase is not derived from circulating plasminogen activator. PMID:4246192

  20. Effect of coffee extracts on plasma fibrinolysis and platelet aggregation.

    PubMed

    Naito, Sawa; Yatagai, Chieko; Maruyama, Masugi; Sumi, Hiroyuki

    2011-04-01

    We have previously reported on study results showing that certain types of coffee have the activity to enhance fibrinolysis. This report covers the activity of 10 types of hot water extracts of coffee on human tissue-type plasminogen activator producing cells. Particularly strong activity (29-35 times the control amount) was observed for Blue Mountain, Yunnan and Kilimanjaro beans. It was found that the hot water extracts have anti-thrombin activity, and that coffee components have anti-platelet aggregation activity, although weak. It was revealed that there is no activity affecting tissue-type plasminogen activator producing cells in the coffee components chlorogenic acid, caffeine, quinic acid, trigonelline hydrochloride, 5-(hydroxymethyl)-2-furfuryl and caffeic acid. It was also revealed that there is activity in fractions with a molecular weight of 10,000 or less. This could also be inferred from the fact that oral administration of such fractions of coffee to human subjects resulted in a shortening of their plasma ELT (p<0.05).

  1. Reduced platelet-mediated and enhanced leukocyte-mediated fibrinolysis in experimentally induced diabetes in rats

    SciTech Connect

    Winocour, P.D.; Colwell, J.A.

    1985-05-01

    Studies of fibrinolytic activity in diabetes mellitus have produced conflicting results. This may be a result of methodologic insensitivity or of variable contributions of the different blood components to whole blood fibrinolysis. To explore these two possibilities, the authors used a sensitive solid-phase radiometric assay to examine the fibrinolytic activity of whole blood, platelet-rich plasma, leukocytes, and platelet- and leukocyte-poor plasma prepared from control rats and rats with streptozocin-induced diabetes at various times after induction of diabetes. Fibrinolytic activity of whole blood from diabetic rats after 7 days was significantly reduced, and remained reduced after longer durations of diabetes up to 28 days. Platelet-rich plasma from diabetic rats had decreased fibrinolytic activity, which followed the same time course of changes as in whole blood. The platelet contribution to whole blood fibrinolysis was further reduced in vivo after 14 days of diabetes by a reduced whole blood platelet count. In contrast, fibrinolytic activity of leukocytes from diabetic rats became enhanced after 7 days of diabetes. After 49 days of diabetes, the whole blood leukocyte count was reduced, and in vivo would offset the enhanced activity. Plasma fibrinolytic activity was small compared with that of whole blood and was unaltered in diabetic rats. The authors conclude that altered platelet function contributes to decreased fibrinolytic activity of whole blood in diabetic rats, and that this may be partially offset by enhanced leukocyte-mediated fibrinolysis.

  2. Effect of endovascular and open abdominal aortic aneurysm repair on thrombin generation and fibrinolysis.

    PubMed

    Abdelhamid, Mohamed F; Davies, Robert S M; Vohra, Rajiv K; Adam, Donald J; Bradbury, Andrew W

    2013-01-01

    Abdominal aortic aneurysm (AAA) is associated with a prothrombotic diathesis that may increase the risk of cardiovascular events. This diathesis is exacerbated in the short term by open aneurysm repair (OAR) and endovascular aneurysm repair (EVAR). However, the effect of EVAR and OAR on coagulation and fibrinolysis in the medium and long term is poorly understood. The purpose of this study was to investigate the medium-term effects of EVAR and OAR on thrombin generation, neutralization, and fibrinolysis. Prothrombin fragment (PF)1+2, thrombin antithrombin (TAT) complex, plasminogen activator inhibitor (PAI) activity, and tissue-plasminogen activator (t-PA) antigen were measured in eight age-matched controls (AMCs), 29 patients with AAA immediately before (preoperatively) and 12 months after EVAR (post-EVAR), and in 11 patients at a mean of 16 months after OAR (post-OAR). Preoperatively, PF1+2 levels were significantly higher in patients with AAAs than in AMC. PF1+2 levels post-EVAR and post-OAR were significantly lower than preoperative values and similar to AMC. There was no significant difference in TAT, PAI, or t-PA between AMC, AAA preoperatively, and post-EVAR. Post-OAR, PAI activity was significantly higher than in preoperative patients. AAA is associated with increased thrombin generation without upregulation of fibrinolysis. The prothrombotic, hypofibrinolytic diathesis observed in patients with AAA returns toward normal in the medium term after EVAR and OAR, although there is a trend toward decreased fibrinolysis post-OAR. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  3. Massive Bleeding as the First Clinical Manifestation of Metastatic Prostate Cancer due to Disseminated Intravascular Coagulation with Enhanced Fibrinolysis

    PubMed Central

    Lopes, João Madeira; Victorino, Rui M. M.; Meneses Santos, João

    2016-01-01

    Disseminated intravascular coagulation (DIC) is the most frequent coagulation disorder associated with metastatic prostate adenocarcinoma. However, DIC with enhanced fibrinolysis as an initial presentation of prostate cancer is extremely rare. The appropriate treatment to control bleeding in these situations is challenging, controversial, and based on isolated case reports in the literature. A 66-year-old male presented at the emergency department with acute severe spontaneous ecchymoses localized to the limbs, laterocervical hematoma, and hemothorax. Prostate specific antigen level was 385 μg/L, bone scintigraphy revealed multiple bone metastases, and prostate biopsy confirmed adenocarcinoma (Gleason 9; 4 + 5). Laboratory investigation showed a pattern of enhanced fibrinolysis rather than the more common intravascular coagulation mechanism. Epsilon aminocaproic acid in monotherapy was initiated with a clear and rapid control of bleeding manifestations. This rare case of massive bleeding due to DIC with enhanced fibrinolysis as the first manifestation of prostate cancer suggests that in selected cases where the acute bleeding dyscrasia is clearly associated with a dominant fibrinolysis mechanism it is possible to use an approach of monotherapy with antifibrinolytics. PMID:27803823

  4. Elastase mediated fibrinolysis in acute promyelocytic leukemia.

    PubMed

    Oudijk, E J; Nieuwenhuis, H K; Bos, R; Fijnheer, R

    2000-06-01

    The bleeding syndrome of acute promyelocytic leukemia (APL) is complex and consists of disseminated intravascular coagulation (DIC) and hyperfibrinolysis. Elastase, derived from malignant promyelocytes, is believed to mediate the fibrinogeno- and fibrinolysis by aspecific proteolysis. In this study we measured the role of elastase in fifteen patients with APL by using an assay for elastase degraded fibrin(ogen) and the results were compared with those obtained in patients with sepsis induced DIC. High levels of elastase were observed in sepsis and APL. The levels of fibrinogen and fibrin degradation products were significantly higher in APL patients compared to patients with sepsis induced DIC. Nevertheless, the level of elastase degraded fibrin(ogen) was higher in the sepsis group (635.3 ng/ml, compared to 144.3 ng/ml in APL; p <0.0001). So, the enormous increase in fibrin and fibrinogen degradation products in APL cannot be explained by elastase activity. This study suggests a minor role for elastase mediated proteolysis in the hemorrhagic diathesis in APL patients.

  5. Thrombin-activatable fibrinolysis inhibitor in hypothyroidism and hyperthyroxinaemia.

    PubMed

    Verkleij, Chantal J N; Stuijver, Danka J F; van Zaane, Bregje; Squizzato, Alessandro; Brandjes, Dees P M; Büller, Harry R; Meijers, Joost C M; Gerdes, Victor E A

    2013-02-01

    Endocrine disorders affect both the coagulation and fibrinolytic systems, and have been associated with the development of cardiovascular diseases. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a link between coagulation and the fibrinolytic system. The aim of this study was to determine the effect of thyroid hormone excess and deficiency on TAFI levels and function. The effect of hyperthyroxinemia on TAFI was studied in healthy volunteers who were randomised to receive levothyroxine or no medication for 14 days in a crossover design. The effect of hypothyroidism on TAFI was studied in a multicentre observational cohort study. Blood was drawn before treatment of patients with newly diagnosed hypothyroidism and when euthyroidism was achieved. Plasma clot-lysis times, activated TAFI (TAFIa)-dependent prolongation of clot-lysis and TAFI levels were measured. Thyroid hormone excess resulted in a hypofibrinolytic condition and in an enhanced TAFIa-dependent prolongation of clot lysis. A trend towards decreased plasma TAFI levels was observed in healthy volunteers who used levothyroxine. Hypothyroidism resulted in hyperfibrinolysis and a reduced TAFIa-dependent prolongation of clot lysis. In conclusion, alterations of TAFIa-dependent prolongation of clot lysis in patients with thyroid disorders may cause an impaired haemostatic balance. The disturbed haemostatic balance in patients with hyperthyroidism might make them prone to thrombosis, while the risk for bleeding may increase in patients with hypothyroidism.

  6. Trending Fibrinolytic Dysregulation: Fibrinolysis Shutdown in the Days After Injury Is Associated With Poor Outcome in Severely Injured Children.

    PubMed

    Leeper, Christine M; Neal, Matthew D; McKenna, Christine J; Gaines, Barbara A

    2017-09-01

    To trend fibrinolysis after injury and determine the influence of traumatic brain injury (TBI) and massive transfusion on fibrinolysis status. Admission fibrinolytic derangement is common in injured children and adults, and is associated with poor outcome. No studies examine fibrinolysis days after injury. Prospective study of severely injured children at a level 1 pediatric trauma center. Rapid thromboelastography was obtained on admission and daily for up to 7 days. Standard definitions of hyperfibrinolysis (HF; LY30 ≥3), fibrinolysis shutdown (SD; LY30 ≤0.8), and normal (LY30 = 0.9-2.9) were applied. Antifibrinolytic use was documented. Outcomes were death, disability, and thromboembolic complications. Wilcoxon rank-sum and Fisher exact tests were performed. Exploratory subgroups included massively transfused and severe TBI patients. In all, 83 patients were analyzed with median (interquartile ranges) age 8 (4-12) and Injury Severity Score 22 (13-34), 73.5% blunt mechanism, 47% severe TBI, 20.5% massively transfused. Outcomes were 14.5% mortality, 43.7% disability, and 9.8% deep vein thrombosis. Remaining in or trending to SD was associated with death (P = 0.007), disability (P = 0.012), and deep vein thrombosis (P = 0.048). Median LY30 was lower on post-trauma day (PTD)1 to PTD4 in patients with poor compared with good outcome; median LY30 was lower on PTD1 to PTD3 in TBI patients compared with non-TBI patients. HF without associated shutdown was not related to poor outcome, but extreme HF (LY30 >30%, n = 3) was lethal. Also, 50% of massively transfused patients in hemorrhagic shock demonstrated SD physiology on admission. All with HF (fc31.2%) corrected after hemostatic resuscitation without tranexamic acid. Fibrinolysis shutdown is common postinjury and predicts poor outcomes. Severe TBI is associated with sustained shutdown. Empiric antifibrinolytics for children should be questioned; thromboelastography-directed selective use should be considered for

  7. Optimal dose of oral omeprazole for maximal 24 hour decrease of intragastric acidity.

    PubMed Central

    Sharma, B K; Walt, R P; Pounder, R E; Gomes, M D; Wood, E C; Logan, L H

    1984-01-01

    In a series of 59 experiments in nine duodenal ulcer patients, 24 hour intragastric acidity was measured before, during, and after treatment with daily oral omeprazole. Omeprazole 10, 20, and 30 mg/day for one week caused a 37, 90, and 97% decrease of 24 hour intragastric acidity, respectively. No further decrease of acidity was observed when the dose of omeprazole was doubled to 60 mg/day, or after a second week of treatment with 30 mg/day. One week after stopping treatment with omeprazole (14 doses) there was a significant 26% decrease of 24 hour intragastric acidity, with full recovery seven weeks later. Fasting plasma gastrin concentration was significantly raised during treatment with all doses of omeprazole. Omeprazole 30 mg/day is the optimal dose for a maximal decrease of 24 hour intragastric acidity in duodenal ulcer patients. PMID:6469081

  8. Duodenal ulcerogens cysteamine and propionitrile decrease duodenal neutralization of acid in the rat

    SciTech Connect

    Adler, R.S.; Gallagher, G.T.; Szabo, S.

    1983-08-01

    Neutralization of acid was evaluated in rat proximal duodenal segments isolated from biliary and pancreatic secretions. Duodenal ulcerogenic doses of cysteamine produced a significant decrease in acid disposal 0.5-2 hr after treatment. Oral or subcutaneous administration of the duodenal ulcerogen was effective. The potent ulcerogen cysteamine produced a more pronounced decrease than propionitrile (a weak duodenal ulcerogen). The failure of ethanolamine, a nonulcerogenic structural analog of cysteamine to significantly alter acid disposal suggests that the effect is not due to the toxic properties of the duodenal ulcerogen. The results reinforce the concept that the duodenum is able to dispose of significant quantities of acid. The decrease in acid-handling may contribute to duodenal susceptibility to acid after treatment with ulcerogens and possibly reflects pathophysiologic changes early in duodenal ulceration.

  9. Molecular mechanisms of the effect of ultrasound on the fibrinolysis of clots

    PubMed Central

    Chernysh, Irina N.; Everbach, E. Carr; Purohit, Prashant K.; Weisel, John W.

    2016-01-01

    Summary Background Ultrasound accelerates tissue-type plasminogen activator (t-PA)-induced fibrinolysis of clots in vitro and in vivo. Objective To identify mechanisms for the enhancement of t-PA-induced fibrinolysis of clots. Methods Turbidity is an accurate and convenient method, not previously used, to follow the effects of ultrasound. Deconvolution microscopy was used to determine changes in structure, while fluorescence recovery after photobleaching was used to characterize the kinetics of binding/unbinding and transport. Results The ultrasound pulse repetition frequency affected clot lysis times, but there were no thermal effects. Ultrasound in the absence of t-PA produced a slight but consistent decrease in turbidity, suggesting a decrease in fibrin diameter due solely to the action of the ultrasound, likely caused by an increase in protofibril tension because of vibration from ultrasound. Changes in fibrin network structure during lysis with ultrasound were visualized in real time by deconvolution microscopy, revealing that the network becomes unstable when 30–40% of the protein in the network was digested, whereas without ultrasound, the fibrin network was digested gradually and retained structural integrity. Fluorescence recovery after photobleaching during lysis revealed that the off-rate of oligomers from digesting fibers was not much affected but the number of binding/unbinding sites was increased. Conclusions Ultrasound causes a decrease in the diameter of the fibers due to tension as a result of vibration, leading to increased binding sites for plasmin(ogen)/t-PA. The positive feedback of this structural change together with increased mixing/transport of t-PA/plasmin(ogen) is likely to account for the observed enhancement of fibrinolysis by ultrasound. PMID:25619618

  10. Influence of resuscitation fluids, fresh frozen plasma and antifibrinolytics on fibrinolysis in a thrombelastography-based, in-vitro, whole-blood model.

    PubMed

    Kostousov, Vadim; Wang, Yao-Wei W; Cotton, Bryan A; Wade, Charles E; Holcomb, John B; Matijevic, Nena

    2013-07-01

    Hyperfibrinolysis has been identified as a mechanism of trauma coagulopathy associated with poor outcome. The aim of the study was to create a trauma coagulopathy model (TCM) with a hyperfibrinolysis thrombelastography (TEG) pattern similar to injured patients and test the effects of different resuscitation fluids and antifibrinolytics on fibrinolysis. TCM was established from whole blood by either 15% dilution with isotonic saline, lactated Ringer's, Plasma-Lyte, 5% albumin, Voluven, Hextend, 6% dextran in isotonic saline or 30% dilution with lactated Ringer's plus Voluven and supplementation with tissue factor and tissue plasminogen activator (tPA). These combinations resulted in a TCM that could then be 'treated' with tranexamic acid (TXA) or 6-aminocaproic acid (ACA). Clot formation was evaluated by TEG. Whole-blood dilution by 15% with crystalloids and albumin in the presence of tissue factor plus tPA resulted in an abnormal TEG pattern and increased fibrinolysis, as did dilution with synthetic colloids. TXA 1 μg/ml or ACA 10 μg/ml were sufficient to suppress fibrinolysis when TCM was diluted 15% with lactated Ringer's, but 3 μg/ml of TXA or 30 μg/ml of ACA were needed for fibrinolysis inhibition induced by simultaneous euvolemic dilution with lactated Ringer's plus Voluven by 30%. A total of 15% dilution of whole blood in the presence of tissue factor plus tPA results in a hyperfibrinolysis TEG pattern similar to that observed in severely injured patients. Synthetic colloids worsen TEG variables with a further increase of fibrinolysis. Low concentrations of TXA or ACA reversed hyperfibrinolysis, but the efficient concentrations were dependent on the degree of fibrinolysis and whole-blood dilution.

  11. Can activation of coagulation and impairment of fibrinolysis in patients with anxiety and depression be reversed after improvement of psychiatric symptoms? Results of a pilot study.

    PubMed

    Geiser, Franziska; Gessler, Katharina; Conrad, Rupert; Imbierowicz, Katrin; Albus, Christian; Harbrecht, Ursula

    2012-08-01

    Anxiety and depression are associated with an activation of coagulation and impairment of fibrinolysis. This study addresses the question whether these findings are reversed after psychotherapy and improvement of psychiatric symptoms. Three factors of coagulation and fibrinolysis as well as level of anxiety and depression were reassessed in 12 patients 1 to 3 years after intensive inpatient psychotherapy. The patients showed a substantial improvement of their severe anxiety disorder and comorbid depressive disorder. Simultaneously, we found a significant decrease in factor VII and plasminogen activator inhibitor. We conclude that reduction of severe anxiety and depression may be associated with a reversal of the procoagulant effect (activation of coagulation and impairment of fibrinolysis) of these psychological states. Because of the small sample size of this pilot study, further research is needed.

  12. Pyrazinoic acid decreases the proton motive force, respiratory ATP synthesis activity, and cellular ATP levels.

    PubMed

    Lu, Ping; Haagsma, Anna C; Pham, Hoang; Maaskant, Janneke J; Mol, Selena; Lill, Holger; Bald, Dirk

    2011-11-01

    Pyrazinoic acid, the active form of the first-line antituberculosis drug pyrazinamide, decreased the proton motive force and respiratory ATP synthesis rates in subcellular mycobacterial membrane assays. Pyrazinoic acid also significantly lowered cellular ATP levels in Mycobacterium bovis BCG. These results indicate that the predominant mechanism of killing by this drug may operate by depletion of cellular ATP reserves.

  13. Platelets Contain Tissue Factor Pathway Inhibitor-2 Derived from Megakaryocytes and Inhibits Fibrinolysis*

    PubMed Central

    Vadivel, Kanagasabai; Ponnuraj, Sathya-Moorthy; Kumar, Yogesh; Zaiss, Anne K.; Bunce, Matthew W.; Camire, Rodney M.; Wu, Ling; Evseenko, Denis; Herschman, Harvey R.; Bajaj, Madhu S.; Bajaj, S. Paul

    2014-01-01

    Tissue factor pathway inhibitor-2 (TFPI-2) is a homologue of TFPI-1 and contains three Kunitz-type domains and a basic C terminus region. The N-terminal domain of TFPI-2 is the only inhibitory domain, and it inhibits plasma kallikrein, factor XIa, and plasmin. However, plasma TFPI-2 levels are negligible (≤20 pm) in the context of influencing clotting or fibrinolysis. Here, we report that platelets contain significant amounts of TFPI-2 derived from megakaryocytes. We employed RT-PCR, Western blotting, immunohistochemistry, and confocal microscopy to determine that platelets, MEG-01 megakaryoblastic cells, and bone marrow megakaryocytes contain TFPI-2. ELISA data reveal that TFPI-2 binds factor V (FV) and partially B-domain-deleted FV (FV-1033) with Kd ∼9 nm and binds FVa with Kd ∼100 nm. Steady state analysis of surface plasmon resonance data reveal that TFPI-2 and TFPI-1 bind FV-1033 with Kd ∼36–48 nm and bind FVa with Kd ∼252–456 nm. Further, TFPI-1 (but not TFPI-1161) competes with TFPI-2 in binding to FV. These data indicate that the C-terminal basic region of TFPI-2 is similar to that of TFPI-1 and plays a role in binding to the FV B-domain acidic region. Using pull-down assays and Western blots, we show that TFPI-2 is associated with platelet FV/FVa. TFPI-2 (∼7 nm) in plasma of women at the onset of labor is also, in part, associated with FV. Importantly, TFPI-2 in platelets and in plasma of pregnant women inhibits FXIa and tissue-type plasminogen activator-induced clot fibrinolysis. In conclusion, TFPI-2 in platelets from normal or pregnant subjects and in plasma from pregnant women binds FV/Va and regulates intrinsic coagulation and fibrinolysis. PMID:25262870

  14. Response of DOC in acid-sensitive Maine lakes to decreasing sulfur deposition (1993 - 2009)

    EPA Science Inventory

    In response to the Clean Air Act Amendments of 1990, sulfur deposition has decreased across the northeastern United States. As a result, sulfate concentrations in lakes and streams have also decreased and many surface waters have become less acidic. Over the same time period, th...

  15. Response of DOC in acid-sensitive Maine lakes to decreasing sulfur deposition (1993 - 2009)

    EPA Science Inventory

    In response to the Clean Air Act Amendments of 1990, sulfur deposition has decreased across the northeastern United States. As a result, sulfate concentrations in lakes and streams have also decreased and many surface waters have become less acidic. Over the same time period, th...

  16. Micronized benzoic acid decreases the concentration necessary to preserve acidic beverages against Alicyclobacillus.

    PubMed

    Kawase, K Y F; Luchese, R H; Coelho, G L

    2013-08-01

    The aim of this study was a challenge testing the effect of lower concentrations of micronized benzoic acid against two strains of Alicyclobacillus. The effect of micronized benzoic acid was compared with the usual levels of untreated commercial sodium benzoate and benzoic acid, at the challenge temperature of 45°C. The size of the benzoic acid particles was determined by scanning electron microscopy. The diameter of the micronized particles was around 10 μm with a maximum length of 200 μm, while the untreated preservative structures were irregular with lengths up to 500 μm. A continuous bactericidal effect against two Alicyclobacillus strains, throughout the 28-day period, was observed with 50 mg l(-1) of micronized benzoic acid, but when the untreated preservative was used, the same lethal effect was not achieved even after doubling its concentration. The antimicrobial activity of benzoic acid was improved by micronization. The process proved to be an effective alternative to reduce the benzoic acid concentration necessary to ensure stability of an orange juice matrix. The results proved that the micronization process represents an alternative to reduce the required food preservative concentration; this method increased the stability of the compound, which maintains its bioavailability. © 2013 The Society for Applied Microbiology.

  17. Coated fatty acids alter virulence properties of Salmonella Typhimurium and decrease intestinal colonization of pigs.

    PubMed

    Boyen, F; Haesebrouck, F; Vanparys, A; Volf, J; Mahu, M; Van Immerseel, F; Rychlik, I; Dewulf, J; Ducatelle, R; Pasmans, F

    2008-12-10

    Salmonella Typhimurium infections in pigs are a major source of human foodborne salmonellosis. To reduce the number of infected pigs, acidification of feed or drinking water is a common practice. The aim of the present study was to determine whether some frequently used short- (SCFA) and medium-chain fatty acids (MCFA) are able to alter virulence gene expression and to decrease Salmonella Typhimurium colonization and shedding in pigs using well established and controlled in vitro and in vivo assays. Minimal inhibitory concentrations (MIC) of 4 SCFA (formic acid, acetic acid, propionic acid and butyric acid) and 2 MCFA (caproic and caprylic acid) were determined using 54 porcine Salmonella Typhimurium field strains. MIC values increased at increasing pH-values and were two to eight times lower for MCFA than for SCFA. Expression of virulence gene fimA was significantly lower when bacteria were grown in LB-broth supplemented with sub-MIC concentrations of caproic or caprylic acid (2 mM). Expression of hilA and invasion in porcine intestinal epithelial cells was significantly lower when bacteria were grown in LB-broth containing sub-MIC concentrations of butyric acid or propionic acid (10 mM) and caproic or caprylic acid (2 mM). When given as feed supplement to pigs experimentally infected with Salmonella Typhimurium, coated butyric acid decreased the levels of faecal shedding and intestinal colonization, but had no influence on the colonization of tonsils, spleen and liver. Uncoated fatty acids, however, did not influence fecal shedding, intestinal or tonsillar colonization in pigs. In conclusion, supplementing feed with certain coated fatty acids, such as butyric acid, may help to reduce the Salmonella load in pigs.

  18. Fibrinolysis inhibitors adversely affect remodeling of tissues sealed with fibrin glue.

    PubMed

    Krishnan, Lissy K; Vijayan Lal, Arthur; Uma Shankar, P R; Mohanty, Mira

    2003-01-01

    Experiments have been carried out to determine if aprotinin and epsilon -amino caproic acid increases the quality of Fibrin glue. A rat model was used for tissues such as liver and skin while rabbits were used for application of glue in dura mater. Apposition of all the tissues, glued with fibrin was found to be good and remnants of the polymerized fibrin were seen even on the seventh day of application, though inhibitors were not incorporated with the glue. In skin, excessive amounts of fibrin remained as a result of addition of aprotinin and epsilon -amino caproic acid, as compared to the glue applied without any inhibitor. After dural sealing, the wound repair and new bone formation at craniotomy site progressed well in the fibrin glue applied area as compared to the commercially available glue that contained aprotinin. The adhesive strength of the glue without or with fibrinolysis inhibitors was found to be similar, after 1h grafts on rat back. The observations from this study suggests that the use of aprotinin with fibrin glue may not be required because, even liver tissue that is known to have high fibrinolytic activity was sealed and repaired well in the absence of plasminogen inhibitors. On the other hand, it was found that if inhibitors were added, nondegraded matrix remained in the tissue even after 15 days and affected migration of repair cells. Thus, the inhibition of fibrinolysis after fibrin glue application is found detrimental to wound healing.

  19. A Simple Way to Visualize Fibrinolysis in the Classroom

    ERIC Educational Resources Information Center

    Nurachman, Zeily; Hermawan, Jatnika; Rachmayanti, Yanti; Baradja, Lubna

    2003-01-01

    Laboratory demonstration, as well as biochemistry lecture, has been used to complement explanation of biochemical processes. The laboratory demonstration is very useful in teaching biochemistry to students who lack background in biology. The experimental model of fibrinolysis described here presents a complex biological reaction in simplified…

  20. Model of trauma-induced coagulopathy including hemodilution, fibrinolysis, acidosis, and hypothermia: Impact on blood coagulation and platelet function.

    PubMed

    Shenkman, Boris; Budnik, Ivan; Einav, Yulia; Hauschner, Hagit; Andrejchin, Mykhaylo; Martinowitz, Uriel

    2017-02-01

    Trauma-induced coagulopathy (TIC) is commonly seen among patients with severe injury. The dynamic process of TIC is characterized by variability of the features of the disease. A model of TIC was created. Hemodilution was produced by mixing the blood with 40% Tris/saline solution, fibrinolysis by treating the blood with 160 ng/mL tPA, acidosis by adding 1.2 mg/mL lactic acid achieving pH 7.0 to 7.1, and hypothermia by running the assay at 31°C. Intact blood tested at 37°C served as control. Clot formation was evaluated using rotation thromboelastometry. Platelet adhesion and aggregation were assayed at a shear rate of 1800 s using Impact-R device. Clotting time was not affected by any of the TIC constituents used. Clotting initiation was reduced by hemodilution and further reduced by additive hypothermia. The propagation phase of blood clotting was reduced by hemodilution, further reduced by additive hypothermia, and maximally reduced if additionally combined with fibrinolysis. No effect of fibrinolysis on clot propagation was observed at 37°C. Maximum clot firmness was reduced by hemodilution, further reduced by additive fibrinolysis, and maximally reduced if additionally combined with hypothermia. No effect of hypothermia on clot strength was observed in the absence of fibrinolysis. Platelet adhesion (percentage of surface coverage) and aggregation (aggregate size) under flow condition were reduced by hemodilution and further reduced by additive acidosis. Introduction of tPA to diluted blood had no effect on platelet function. The study revealed a differential effect of TIC constituents-hemodilution, hypothermia, fibrinolysis, and acidosis-on clot formation and platelet function. The effect of one factor may influence that of another factor. These data may be helpful to better understand the pathogenesis of TIC and to elaborate an individually tailored treatment strategy. A new model of TIC is created. Contribution of various constituents to pathogenesis of

  1. Linoleic acid decreases leptin and adiponectin secretion from primary rat adipocytes in the presence of insulin.

    PubMed

    Pérez-Matute, P; Martínez, J A; Marti, A; Moreno-Aliaga, M J

    2007-10-01

    Obesity rates have dramatically increased over the last few decades and, at the same time, major changes in the type of fatty acid intake have occurred. Linoleic acid, an n-6 polyunsaturated fatty acid, is an essential fatty acid occurring in high amounts in several western diets. A potential role of this fatty acid on obesity has been suggested. Controversial effects of linoleic acid on insulin sensitivity have also been reported. Thus, the aim of this study was to examine the direct effects of linoleic acid on leptin and adiponectin production, two adipokines known to influence weight gain and insulin sensitivity. Because insulin-stimulated glucose metabolism is an important regulator of leptin production, the effects of linoleic acid on adipocyte metabolism were also examined. For this purpose, isolated rat adipocytes were incubated with linoleic acid (1-200 microM) in the absence or presence of insulin. Linoleic acid (1-200 microM) significantly decreased insulin-stimulated leptin secretion and expression (P < 0.05), however, no changes in basal leptin production were observed. Linoleic acid also induced a significant decrease (approximately 20%) in adiponectin secretion (P < 0.05), but only in the presence of insulin and at the highest concentration tested (200 microM). This fatty acid did not modify either glucose uptake or lactate production and the percentage of glucose metabolized to lactate was not changed either. Together, these results suggest that linoleic acid seems to interfere with other insulin signalling pathway different from those controlling glucose uptake and metabolism, but involved in the regulation of leptin and adiponectin production.

  2. Palmitic acid but not palmitoleic acid induces insulin resistance in a human endothelial cell line by decreasing SERCA pump expression.

    PubMed

    Gustavo Vazquez-Jimenez, J; Chavez-Reyes, Jesus; Romero-Garcia, Tatiana; Zarain-Herzberg, Angel; Valdes-Flores, Jesus; Manuel Galindo-Rosales, J; Rueda, Angelica; Guerrero-Hernandez, Agustin; Olivares-Reyes, J Alberto

    2016-01-01

    Palmitic acid is a negative regulator of insulin activity. At the molecular level, palmitic acid reduces insulin stimulated Akt Ser473 phosphorylation. Interestingly, we have found that incubation with palmitic acid of human umbilical vein endothelial cells induced a biphasic effect, an initial transient elevation followed by a sustained reduction of SERCA pump protein levels. However, palmitic acid produced a sustained inhibition of SERCA pump ATPase activity. Insulin resistance state appeared before there was a significant reduction of SERCA2 expression. The mechanism by which palmitic acid impairs insulin signaling may involve endoplasmic reticulum stress, because this fatty acid induced activation of both PERK, an ER stress marker, and JNK, a kinase associated with insulin resistance. None of these effects were observed by incubating HUVEC-CS cells with palmitoleic acid. Importantly, SERCA2 overexpression decreased the palmitic acid-induced insulin resistance state. All these results suggest that SERCA pump might be the target of palmitic acid to induce the insulin resistance state in a human vascular endothelial cell line. Importantly, these data suggest that HUVEC-CS cells respond to palmitic acid-exposure with a compensatory overexpression of SERCA pump within the first hour, which eventually fades out and insulin resistance prevails.

  3. Decreased sugar concentration in vegetable and fruit juices by growth of functional lactic acid bacteria.

    PubMed

    Ishii, Masaki; Matsumoto, Yasuhiko; Nishida, Satoshi; Sekimizu, Kazuhisa

    2017-03-22

    Leuconostoc carnosum #7-2, L. gelidum #4-2, and L. mesenteroides 8/11-3, which were isolated from fermented plant foods, are lactic acid bacteria. We previously reported that these bacteria are functional lactic acid bacteria whose innate immunity-stimulating activities are high based on a silkworm muscle contraction assay. The concentrations of these three lactic acid bacteria increased to more than 1 × 10(6) colony forming units (cfu)/mL in various vegetable and fruit juices when the pH values were appropriately adjusted. As the bacteria grew in the vegetable and fruit juices, the pH decreased and the concentrations of total sugars and glucose also decreased. These findings suggest that these functional lactic acid bacteria can be used to produce vegetable and fruit juices with reduced sugar levels, which is expected to be beneficial for human health.

  4. Low brain ascorbic acid increases susceptibility to seizures in mouse models of decreased brain ascorbic acid transport and Alzheimer's disease.

    PubMed

    Warner, Timothy A; Kang, Jing-Qiong; Kennard, John A; Harrison, Fiona E

    2015-02-01

    Seizures are a known co-occurring symptom of Alzheimer's disease, and they can accelerate cognitive and neuropathological dysfunction. Sub-optimal vitamin C (ascorbic acid) deficiency, that is low levels that do not lead the sufferer to present with clinical signs of scurvy (e.g. lethargy, hemorrhage, hyperkeratosis), are easily obtainable with insufficient dietary intake, and may contribute to the oxidative stress environment of both Alzheimer's disease and epilepsy. The purpose of this study was to test whether mice that have diminished brain ascorbic acid in addition to carrying human Alzheimer's disease mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes, had altered electrical activity in the brain (electroencephalography; EEG), and were more susceptible to pharmacologically induced seizures. Brain ascorbic acid was decreased in APP/PSEN1 mice by crossing them with sodium vitamin C transporter 2 (SVCT2) heterozygous knockout mice. These mice have an approximately 30% decrease in brain ascorbic acid due to lower levels of SVCT2 that supplies the brain with ASC. SVCT2+/-APP/PSEN1 mice had decreased ascorbic acid and increased oxidative stress in brain, increased mortality, faster seizure onset latency following treatment with kainic acid (10 mg/kg i.p.), and more ictal events following pentylenetetrazol (50 mg/kg i.p.) treatment. Furthermore, we report the entirely novel phenomenon that ascorbic acid deficiency alone increased the severity of kainic acid- and pentylenetetrazol-induced seizures. These data suggest that avoiding ascorbic acid deficiency may be particularly important in populations at increased risk for epilepsy and seizures, such as Alzheimer's disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Omega-9 Oleic Acid Induces Fatty Acid Oxidation and Decreases Organ Dysfunction and Mortality in Experimental Sepsis.

    PubMed

    Gonçalves-de-Albuquerque, Cassiano Felippe; Medeiros-de-Moraes, Isabel Matos; Oliveira, Flora Magno de Jesus; Burth, Patrícia; Bozza, Patrícia Torres; Castro Faria, Mauro Velho; Silva, Adriana Ribeiro; Castro-Faria-Neto, Hugo Caire de

    2016-01-01

    Sepsis is characterized by inflammatory and metabolic alterations, which lead to massive cytokine production, oxidative stress and organ dysfunction. In severe systemic inflammatory response syndrome, plasma non-esterified fatty acids (NEFA) are increased. Several NEFA are deleterious to cells, activate Toll-like receptors and inhibit Na+/K+-ATPase, causing lung injury. A Mediterranean diet rich in olive oil is beneficial. The main component of olive oil is omega-9 oleic acid (OA), a monounsaturated fatty acid (MUFA). We analyzed the effect of OA supplementation on sepsis. OA ameliorated clinical symptoms, increased the survival rate, prevented liver and kidney injury and decreased NEFA plasma levels in mice subjected to cecal ligation and puncture (CLP). OA did not alter food intake and weight gain but diminished reactive oxygen species (ROS) production and NEFA plasma levels. Carnitine palmitoyltransferase IA (CPT1A) mRNA levels were increased, while uncoupling protein 2 (UCP2) liver expression was enhanced in mice treated with OA. OA also inhibited the decrease in 5' AMP-activated protein kinase (AMPK) expression and increased the enzyme expression in the liver of OA-treated mice compared to septic animals. We showed that OA pretreatment decreased NEFA concentration and increased CPT1A and UCP2 and AMPK levels, decreasing ROS production. We suggest that OA has a beneficial role in sepsis by decreasing metabolic dysfunction, supporting the benefits of diets high in monounsaturated fatty acids (MUFA).

  6. Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2–dependent fibrinolysis

    PubMed Central

    Jacovina, Andrew T.; Deora, Arunkumar B.; Ling, Qi; Broekman, M. Johan; Almeida, Dena; Greenberg, Caroline B.; Marcus, Aaron J.; Smith, Jonathan D.; Hajjar, Katherine A.

    2009-01-01

    When plasma levels of homocysteine (HC), a thiol amino acid formed upon methionine demethylation, exceed 12 μM, individuals are at increased risk of developing large vessel atherothrombosis and small vessel dysfunction. The annexin A2 complex (termed “A2”) is the cell surface coreceptor for plasminogen and TPA and accelerates the catalytic activation of plasmin, the major fibrinolytic agent in mammals. We previously showed that HC prevents A2-mediated, TPA-dependent activation of plasminogen in vitro by disulfide derivatization of the “tail” domain of A2. We also demonstrated that fibrinolysis and angiogenesis are severely impaired in A2-deficient mice. We now report here that, although hyperhomocysteinemic mice had a normal coagulation profile and normal platelet function, fibrin accumulated in their tissues due to reduced perivascular fibrinolytic activity and angiogenesis was impaired. A2 isolated from hyperhomocysteinemic mice failed to fully support TPA-dependent plasmin activation. However, infusion of hyperhomocysteinemic mice with fresh recombinant A2, which localized to neoangiogenic endothelial cells, resulted in normalization of angiogenesis and disappearance of peri- and intravascular fibrin. We therefore conclude that hyperhomocysteinemia impairs postnatal angiogenesis by derivatizing A2, preventing perivascular fibrinolysis, and inhibiting directed endothelial cell migration. These findings provide a mechanistic explanation for microvascular dysfunction and macrovascular occlusion in individuals with hyperhomocysteinemia. PMID:19841537

  7. Efficacy of fibrinolysis in the emergency department for acute myocardial infarction.

    PubMed

    Lane, G; Cuddihy, J; Wright, P; Doherty, D; McShane, A

    2005-01-01

    Patients with an acute myocardial infarction require a rapid response to their symptoms and the earlier fibrinolysis is given (where indicated), the better the outcome. The aim of this study is to compare 'door to needle times' for fibrinolysis in Acute Myocardial Infarction (AMI) in three phases of one year each, at Letterkenny General Hospital. In the PREINTERVENTION year all fibrinolysis was performed in the Coronary Care Unit (CCU). In the INTERVENTION year Emergency Department (ED) fast track fibrinolysis was introduced and in the POST INTERVENTION year most fibrinolysis was performed on fast track in the ED. The time saved by the introduction of ED fibrinolysis was significant, 41 minutes on average per patient. Elderly, female patients were more likely to bypass ED fast track fibrinolysis and to be brought to CCU for fibrinolysis, with attendant delays. This has educational implications in relation to the variation in clinical presentation of AMI with age and sex. The ED fast track fibrinolysis system is recommended as an effective, safe, achievable and worthwhile intervention towards improving 'door to needle times' for fibrinolysis in AMI.

  8. Fish protein decreases serum cholesterol in rats by inhibition of cholesterol and bile acid absorption.

    PubMed

    Hosomi, Ryota; Fukunaga, Kenji; Arai, Hirofumi; Kanda, Seiji; Nishiyama, Toshimasa; Yoshida, Munehiro

    2011-05-01

    Fish protein has been shown to decrease serum cholesterol content by inhibiting absorption of cholesterol and bile acid in laboratory animals, though the mechanism underlying this effect is not yet fully understood. The purpose of this study was to elucidate the mechanism underlying the inhibition of cholesterol and bile acid absorption following fish protein intake. Male Wistar rats were divided into 2 dietary groups of 7 rats each, 1 group receiving a diet consisting of 20% casein and the other receiving a diet consisting of 10% casein and 10% fish protein. Both experimental diets also contained 0.5% cholesterol and 0.1% sodium cholate. After the rats had been on their respective diets for 4 wk, their serum and liver cholesterol contents and fecal cholesterol, bile acid, and nitrogen excretion contents were measured. Fish protein consumption decreased serum and liver cholesterol content and increased fecal cholesterol and bile acid excretion and simultaneously increased fecal nitrogen excretion. In addition, fish protein hydrolyzate prepared by in vitro digestion had lower micellar solubility of cholesterol and higher binding capacity for bile acids compared with casein hydrolyzate. These results suggest that the hypocholesterolemic effect of fish protein is mediated by increased fecal cholesterol and bile acid excretion, which is due to the digestion products of fish protein having reduced micellar solubility of cholesterol and increased bile acid binding capacity.

  9. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    SciTech Connect

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  10. Increased Rat Placental Fatty Acid, but Decreased Amino Acid and Glucose Transporters Potentially Modify Intrauterine Programming.

    PubMed

    Nüsken, Eva; Gellhaus, Alexandra; Kühnel, Elisabeth; Swoboda, Isabelle; Wohlfarth, Maria; Vohlen, Christina; Schneider, Holm; Dötsch, Jörg; Nüsken, Kai-Dietrich

    2016-07-01

    Regulation of placental nutrient transport significantly affects fetal development and may modify intrauterine growth restriction (IUGR) and fetal programming. We hypothesized that placental nutrient transporters are differentially affected both by utero-placental insufficiency and prenatal surgical stress. Pregnant rats underwent bilateral uterine artery and vein ligation (LIG), sham operation (SOP) or no operation (controls, C) on gestational day E19. Placentas were obtained by caesarean section 4 h (LIG, n=20 placentas; SOP, n=24; C, n=12), 24 h (LIG, n=28; SOP, n=20; C, n=12) and 72 h (LIG, n=20; SOP, n=20; C, n=24) after surgery. Gene and protein expression of placental nutrient transporters for fatty acids (h-FABP, CD36), amino acids (SNAT1, SNAT2) and glucose (GLUT-1, Connexin 26) were examined by qRT-PCR, western blot and immunohistochemistry. Interestingly, the mean protein expression of h-FABP was doubled in placentas of LIG and SOP animals 4, 24 (SOP significant) and 72 h (SOP significant) after surgery. CD36 protein was significantly increased in LIG after 72 h. SNAT1 and SNAT2 protein and gene expressions were significantly reduced in LIG and SOP after 24 h. Further significantly reduced proteins were GLUT-1 in LIG (4 h, 72 h) and SOP (24 h), and Connexin 26 in LIG (72 h). In conclusion, placental nutrient transporters are differentially affected both by reduced blood flow and stress, probably modifying the already disturbed intrauterine milieu and contributing to IUGR and fetal programming. Increased fatty acid transport capacity may affect energy metabolism and could be a compensatory reaction with positive effects on brain development. J. Cell. Biochem. 117: 1594-1603, 2016. © 2015 Wiley Periodicals, Inc.

  11. Blood pressure lowering, fibrinolysis enhancing and antioxidant activities of cardamom (Elettaria cardamomum).

    PubMed

    Verma, S K; Jain, Vartika; Katewa, S S

    2009-12-01

    Elettaria cardamomum (L.) Maton. (Small cardamom) fruit powder was evaluated for its antihypertensive potential and its effect on some of the cardiovascular risk factors in individuals with stage 1 hypertension. Twenty, newly diagnosed individuals with primary hypertension of stage 1 were administered 3 g of cardamom powder in two divided doses for 12 weeks. Blood pressure was recorded initially and at 4 weeks interval for 3 months. Blood samples were also collected initially and at 4 weeks interval for estimation of lipid profile, fibrinogen and fibrinolysis. Total antioxidant status, however, was assessed initially and at the end of the study. Administration of 3 g cardamom powder significantly (p<0.001) decreased systolic, diastolic and mean blood pressure and significantly (p<0.05) increased fibrinolytic activity at the end of 12th week. Total antioxidant status was also significantly (p<0.05) increased by 90% at the end of 3 months. However, fibrinogen and lipid levels were not significantly altered. All study subjects experienced a feeling of well being without any side-effects. Thus, the present study demonstrates that small cardamom effectively reduces blood pressure, enhances fibrinolysis and improves antioxidant status, without significantly altering blood lipids and fibrinogen levels in stage 1 hypertensive individuals.

  12. [Decrease in toxicity and therapeutic effect of zoledronic acid in combination therapy with different antioxidant extracts].

    PubMed

    Lopez-Morata, José Antonio; Olivares, Amparo; Alcaraz, Miguel

    Zoledronic acid is used in the treatment of cancer-related diseases, although its use has been associated with avascular osteonecrosis. To determine the possible protective effect of a range of antioxidant substances against the inhibition of human prostate epithelial cell growth (PNT2) and transgenic adenocarcinoma mouse prostate tumour cells (TRAMP-C1), in treatments combining zoledronic acid and ionising radiation (IR). Cell survival is studied via cell viability assays (MTT) for 2 cell lines in isolated and combined treatments with zoledronic acid and/or IR, as well as the effect of adding 3 antioxidant substances. Zoledronic acid displays a significant cytotoxic effect over PNT2 and TRAMP-C1 cells (P<.001). The administration of antioxidants together with the zoledronic acid shows a protective effect for normal prostate cells, yet not so for prostate tumour cells. However, the administration of rosmarinic acid and apigenin in treatments combined with zoledronic acid provides a protective effect from the harmful effects of applying ionizing radiation, not only for normal PNT2 cells, but also for tumour cells. The use of antioxidant substances decreases the cytotoxic effect of zoledronic acid over non-tumour cells, and as such could be used in benign diseases. Furthermore, in the combined treatment using ionising radiation, these antioxidants also produced a protective effect in tumour cells, thus reducing the therapeutic effect sought by combining the treatment with radiation. Copyright © 2016 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

  13. Fibrin breakdown products and fibrinolysis in renal disease

    PubMed Central

    Wardle, E. N.; Taylor, G.

    1968-01-01

    In chronic renal failure and after acute renal failure, fibrinogen levels are raised and there is diminished fibrinolysis as the result of renal damage. A similar situation is found in nephrosis, possibly due to fibrinolytic inhibitors. Increased levels of cryofibrinogen were found in one quarter of cases of acute nephritis, nephrosis, and acute and chronic renal failure. In addition, after acute renal failure low platelet counts, prolonged thrombin times, and high levels of fibrin degradation products, yet with diminished fibrinolysis, indicate that intravascular coagulation has occurred. A positive result for fibrin degradation products was found in 17 of 20 cases of acute renal failure but in none of 10 cases of chronic uraemia. Intravascular coagulation is a process in which fibrin is deposited in the glomerular filters and may account for anuria, and, in the renal vasculature, where it may cause ischaemic tubular necrosis. Images PMID:5697045

  14. Nanocellulose coated with various free fatty acids can adsorb fumonisin B1, and decrease its toxicity.

    PubMed

    Zadeh, Mohammad Hossein Balal; Shahdadi, Hossein

    2015-10-01

    The aim of this study was to evaluate the adsorption and biological properties of nanocellulose coated with free fatty acids (NCCFFAs). At first, nanocellulose was synthesized by acid hydrolysis, and then separately coated with different free fatty acids (FFAs), including lauric acid, alpha linoleic acid, oleic acid, and palmitic acid. Next, the serial concentrations of NCCFFAs (1, 10, 100, and 1000 μg/mL) was separately added to fumonisin B1 (FB1) at 1000 μg/mL, and separately incubated at 37 °C for 1, 2, and 3h. Then, the percentage of adsorption was calculated. In the next experiment, the viability of mouse liver cells was measured when they exposed to serial concentrations of NCCFFAs, FFAs, and FB1. This study showed that the increase of incubation time and concentration of NCCFFAs led to increase of FB1 adsorption. Although FFAs and NCCFFAs had no remarkable toxicity, the high toxicity was observed for FB1. Importantly, the toxicity of FB1 was highly decreased, when incubated together with FFAs or NCCFFAs. These novel adsorbents, NCCFFAs, can be used together with different foodstuffs to remove FB1. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Response of DOC in Acid-Sensitive Maine Lakes to Decreasing Sulfur Deposition (1993 - 2009)

    NASA Astrophysics Data System (ADS)

    Oelsner, G. P.; Sanclements, M.; McKnight, D. M.; Stoddard, J. L.

    2010-12-01

    In response to the Clean Air Act Amendments of 1990, sulfur deposition has decreased across the northeastern United States. As a result, sulfate concentrations in lakes and streams have also decreased and many surface waters have become less acidic. Over the same time period, there has been a concurrent increase in dissolved organic carbon (DOC) concentrations in many lakes and streams which has been difficult to interpret. To assess the biogeochemical processes driving increasing DOC concentrations we analyzed archived samples from 9 acid-sensitive lakes in Maine collected between 1993 and 2009 using UV-Vis and fluorescence spectroscopy. The fluorescence index (FI) was calculated for all samples. The FI represents the ratio of the emission intensity at 450 nm to 550 nm at an excitation wavelength of 370 nm and provides information regarding the source of dissolved organic matter (DOM). This index has a value of approximately 1.9 for microbially derived fluvic acids and a value of approximately 1.4 for terrestrially (higher-plant) derived fluvic acids. All four lakes with increasing DOC trends had concomitant decreases in the FI index. Two of five lakes with no significant DOC trend also demonstrated no trend in FI values over time, while three lakes revealed a decrease in FI values. To confirm that the FI measured in whole water was primarily reflective of fulvic acids (FA), XAD-resin was used to isolate FA from a subset of samples. Analysis of the FA indicates that the FI values for the humic substances are slightly higher, yet well correlated with whole water samples. This suggests that despite prolonged storage in plastic, the FI trends are meaningful. The FI trends suggest a terrestrial source for the increasing DOC and may be driven by increased DOM production from soils experiencing decreased acid loading. Decreases in sulfate deposition can increase soil pH and soil organic matter solubility, as well as decrease the ionic strength of the soil solution, and

  16. Trans-10, cis-12 conjugated linoleic acid decreases de novo lipid synthesis in human adipocytes.

    PubMed

    Obsen, Thomas; Faergeman, Nils J; Chung, Soonkyu; Martinez, Kristina; Gobern, Semone; Loreau, Olivier; Wabitsch, Martin; Mandrup, Susanne; McIntosh, Michael

    2012-06-01

    Conjugated linoleic acid (CLA) reduces adiposity in vivo. However, mechanisms mediating these changes are unclear. Therefore, we treated cultures of human adipocytes with trans-10, cis-12 (10,12) CLA, cis-9, trans-11 (9,11) CLA or other trans fatty acids (FA), and measured indices of lipid metabolism. The lipid-lowering effects of 10,12 CLA were unique, as other trans FA did not reduce TG content to the same extent. Using low levels of [(14)C]-CLA isomers, it was shown that both isomers were readily incorporated into acylglycerols and phospholipids, albeit at lower levels than [(14)C]-oleic or [(14)C]-linoleic acids. When using [(14)C]-acetic acid and [(14)C]-pyruvic acid as substrates, 30 μM 10,12 CLA, but not 9,11 CLA, decreased de novo synthesis of triglyceride, free FA, diacylglycerol, cholesterol esters, cardiolipin, phospholipids and ceramides within 3-24 h. Treatment with 30 μM 10,12 CLA, but not 9,11 CLA, decreased total cellular lipids within 3 days and the ratio of monounsaturated FA (MUFA) to saturated FA, and increased C18:0 acyl-CoA levels within 24 h. Consistent with these data, stearoyl-CoA desaturase (SCD)-1 mRNA and protein levels were down-regulated by 10,12 CLA within 7-12 h, respectively. The mRNA levels of liver X receptor (LXR)α and sterol regulatory element binding protein (SREBP)-1c, transcription factors that regulate SCD-1, were decreased by 10,12 CLA within 5 h. These data suggest that the isomer-specific decrease in de novo lipid synthesis by 10,12 CLA is due, in part, to the rapid repression of lipogenic transcription factors that regulate MUFA synthesis, suggesting an anti-obesity mechanism unique to this trans FA. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Homocysteine mediated decrease in bone blood flow and remodeling: Role of Folic Acid

    PubMed Central

    Tyagi, Neetu; Kandel, Madhavi; Munjal, Charu; Vacek, Jonathan C.; Qipshidze, Natia; SB, Pushpakumar; Metreveli, Naria; Tyagi, Suresh C.

    2013-01-01

    Deficiencies in folate lead to increased serum concentrations of homocysteine (Hcy), which is known as hyperhomocysteinemia (HHcy), is associated with bone disorders. Although, homocysteine (Hcy) accumulates collagen in bone and contribute to decrease in bone strength. The mechanism of Hcy induced bone loss and remodeling is unclear. Therefore, the present study was aimed to determine the role of folic acid in genetically HHcy associated decrease in bone blood flow and remodeling. Wildtype (WT) and cystathionine-β-synthase heterozygous (CBS+/−) mice were used in this study and supplemented with or without folic acid (FA 300 mg/kg, Hcy reducing agent) in drinking water for 6 weeks. The tibial bone blood flow was measured by laser Doppler and ultrasonic flow probe method. The tibial bone density was assessed by dual energy X-ray absorptiometry. The bone homogenates were analyzed for oxidative stress,NOX-4 as oxidative marker and thioredoxin-1 (Trx-1) as anti-oxidant marker, bone remodeling (MMP-9) and bio-availability of nitric oxide (eNOS/iNOS/NO) by Western blot method. The results suggested that there was decrease in tibial blood flow in CBS+/− mice. The bone density was also reduced in CBS+/− mice. There was an increase in NOX-4, iNOS, MMP -9 protein as well as MMP-9 activity in CBS+/− mice and decrease in Trx-1, eNOS protein levels, in part by decreasing NO bio-availability in CBS+/− mice. Interestingly, these effects were ameliorated by folic acid and suggested that folic acid supplementation may have therapeutic potential against genetically HHcy induced bone loss. PMID:21469179

  18. Fibrinolysis status in the Budd-Chiari syndrome in China.

    PubMed

    Ke, Zhang; Hao, Xu; Ning, Wei; Zu, Mao-heng; Fun, Yu-fei

    2015-10-01

    Pathogenesis and clinical characteristics of the Budd-Chiari syndrome (BCS) in Asia are somewhat different from the ones observed in Western countries. Obstruction of the inferior vena cava (IVC) or of the hepatic veins is caused to a greater extent by membranous webs than by thrombosis. Impaired fibrinolysis has been found in European patients with BCS, but its status in Chinese patients with this condition is still unknown. To explore the characteristics of fibrinolysis in BCS patients in this country, we measured the euglobulin lysis time (ELT) for overall fibrinolysis and the plasma levels of five fibrinolytic components in 65 Chinese patients with BCS and 43 healthy controls. In patients, ELTs were slightly shorter than in controls (mean, 293 vs. 357 min, P < 0.02), tissue type plasminogen activator levels were higher than in controls (mean, 239 vs. 185 pg/ml, P < 0.01), and plasminogen activator inhibitor 1 levels were lower than in controls (mean, 1.43 vs. 1.73 ng/ml, P < 0.001). To explore BCS in more detail, we subgrouped the cases according to age, type of venous occlusion, Child-Pugh score, and thrombosis. As a result of this analysis, we found that young patients (age <30 years) had a longer ELT (mean, 440 min) than the older patient groups (30 ≤ age ≤ 44, 45 ≤ age ≤ 54, age>54 years; mean ELT = 242, 198, and 289 min, respectively, all P < 0.05). The independent hepatic vein occlusion subgroup showed a longer ELT (mean, 367 min) than the combined hepatic vein and IVC or the independent IVC occlusion subgroup (mean ELT = 233 and 260 min, both P < 0.05). ELT did not show significant differences between Child-Pugh class A and B subgroups (mean, 267 vs. 333 min, P > 0.05). ELT in the subgroup without thrombosis was shorter than in controls (mean, 288 vs. 358 min, P < 0.05), and in the subgroup with thrombosis, it was also slightly shorter than in controls, without reaching statistical significance (mean, 306 vs. 358 min, P > 0.05). By and large

  19. Plasma prolactin and homovanillic acid as markers for psychopathology and abnormal movements after neuroleptic dose decrease.

    PubMed

    Newcomer, J W; Riney, S J; Vinogradov, S; Csernansky, J G

    1992-01-01

    Plasma prolactin concentration (pPRL), plasma homovanillic acid concentration (pHVA), and symptomatology were measured in 24 male subjects with schizophrenia during maintenance haloperidol treatment. Fourteen subjects subsequently underwent 50 percent dose decreases under placebo-controlled, double-blind conditions. At baseline, a significant inverse correlation was found between pPRL and both tardive dyskinesia (TD) and "thinking disorder"; pPRL was directly correlated with negative symptoms. No such relationship was found with pHVA. In the patients who underwent a dose decrease, no relationship was found between baseline pPRL or pHVA and any clinical variable after the decrease. These data do not support the use of baseline pPRL or pHVA as markers of central dopamine function subsequent to a neuroleptic dose decrease.

  20. Autistic Children Exhibit Decreased Levels of Essential Fatty Acids in Red Blood Cells

    PubMed Central

    Brigandi, Sarah A.; Shao, Hong; Qian, Steven Y.; Shen, Yiping; Wu, Bai-Lin; Kang, Jing X.

    2015-01-01

    Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are essential nutrients for brain development and function. However, whether or not the levels of these fatty acids are altered in individuals with autism remains debatable. In this study, we compared the fatty acid contents between 121 autistic patients and 110 non-autistic, non-developmentally delayed controls, aged 3–17. Analysis of the fatty acid composition of red blood cell (RBC) membrane phospholipids showed that the percentage of total PUFA was lower in autistic patients than in controls; levels of n-6 arachidonic acid (AA) and n-3 docosahexaenoic acid (DHA) were particularly decreased (p < 0.001). In addition, plasma levels of the pro-inflammatory AA metabolite prostaglandin E2 (PGE2) were higher in a subset of the autistic participants (n = 20) compared to controls. Our study demonstrates an alteration in the PUFA profile and increased production of a PUFA-derived metabolite in autistic patients, supporting the hypothesis that abnormal lipid metabolism is implicated in autism. PMID:25946342

  1. Lithium Decreases Glial Fibrillary Acidic Protein in a Mouse Model of Alexander Disease.

    PubMed

    LaPash Daniels, Christine M; Paffenroth, Elizabeth; Austin, Elizabeth V; Glebov, Konstantin; Lewis, Diana; Walter, Jochen; Messing, Albee

    2015-01-01

    Alexander disease is a fatal neurodegenerative disease caused by mutations in the astrocyte intermediate filament glial fibrillary acidic protein (GFAP). The disease is characterized by elevated levels of GFAP and the formation of protein aggregates, known as Rosenthal fibers, within astrocytes. Lithium has previously been shown to decrease protein aggregates by increasing the autophagy pathway for protein degradation. In addition, lithium has also been reported to decrease activation of the transcription factor STAT3, which is a regulator of GFAP transcription and astrogliogenesis. Here we tested whether lithium treatment would decrease levels of GFAP in a mouse model of Alexander disease. Mice with the Gfap-R236H point mutation were fed lithium food pellets for 4 to 8 weeks. Four weeks of treatment with LiCl at 0.5% in food pellets decreased GFAP protein and transcripts in several brain regions, although with mild side effects and some mortality. Extending the duration of treatment to 8 weeks resulted in higher mortality, and again with a decrease in GFAP in the surviving animals. Indicators of autophagy, such as LC3, were not increased, suggesting that lithium may decrease levels of GFAP through other pathways. Lithium reduced the levels of phosphorylated STAT3, suggesting this as one pathway mediating the effects on GFAP. In conclusion, lithium has the potential to decrease GFAP levels in Alexander disease, but with a narrow therapeutic window separating efficacy and toxicity.

  2. Lithium Decreases Glial Fibrillary Acidic Protein in a Mouse Model of Alexander Disease

    PubMed Central

    LaPash Daniels, Christine M.; Paffenroth, Elizabeth; Austin, Elizabeth V.; Glebov, Konstantin; Lewis, Diana; Walter, Jochen; Messing, Albee

    2015-01-01

    Alexander disease is a fatal neurodegenerative disease caused by mutations in the astrocyte intermediate filament glial fibrillary acidic protein (GFAP). The disease is characterized by elevated levels of GFAP and the formation of protein aggregates, known as Rosenthal fibers, within astrocytes. Lithium has previously been shown to decrease protein aggregates by increasing the autophagy pathway for protein degradation. In addition, lithium has also been reported to decrease activation of the transcription factor STAT3, which is a regulator of GFAP transcription and astrogliogenesis. Here we tested whether lithium treatment would decrease levels of GFAP in a mouse model of Alexander disease. Mice with the Gfap-R236H point mutation were fed lithium food pellets for 4 to 8 weeks. Four weeks of treatment with LiCl at 0.5% in food pellets decreased GFAP protein and transcripts in several brain regions, although with mild side effects and some mortality. Extending the duration of treatment to 8 weeks resulted in higher mortality, and again with a decrease in GFAP in the surviving animals. Indicators of autophagy, such as LC3, were not increased, suggesting that lithium may decrease levels of GFAP through other pathways. Lithium reduced the levels of phosphorylated STAT3, suggesting this as one pathway mediating the effects on GFAP. In conclusion, lithium has the potential to decrease GFAP levels in Alexander disease, but with a narrow therapeutic window separating efficacy and toxicity. PMID:26378915

  3. Taurine decreased uric acid levels in hyperuricemic rats and alleviated kidney injury.

    PubMed

    Feng, Ying; Sun, Fang; Gao, Yongchao; Yang, Jiancheng; Wu, Gaofeng; Lin, Shumei; Hu, Jianmin

    2017-07-29

    Hyperuricemia can lead to direct kidney damage. Taurine participates in several renal physiological processes and has been shown as a renoprotective agent. It has been reported that taurine could reduce uric acid levels in diabetic rats, but to date there was no research on the effects of taurine on hyperuricemic rats with kidney injury. In present study, hyperuricemic rat models were induced by intragastric administration of adenine and ethambutol hydrochloride for 10 days, and taurine (1% or 2%) were added in the drinking water 7 days in advance for consecutively 17 days. The results showed that taurine alleviated renal morphological and pathological changes as well as kidney dysfunction in hyperuricemic rats. Taurine could efficiently decrease the elevated xanthine oxidase activities in hyperuricemic rats, indicating its effect on the regulation of uric acid formation. The reabsorption and secretion of uric acid are dependent on a number of urate transporters. Expressions of three urate transporters were significantly down-regulated in hyperuricemic rats, while taurine prevented the decrease of mRNA and protein expression levels of these urate transporters. The results indicate that taurine might play a role in the regulation of renal uric acid excretion. Therefore, taurine could be a promising agent for the treatment of hyperuricemia. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Decreased eicosapentaenoic acid levels in acne vulgaris reveals the presence of a proinflammatory state.

    PubMed

    Aslan, İbrahim; Özcan, Filiz; Karaarslan, Taner; Kıraç, Ebru; Aslan, Mutay

    2017-01-01

    This study aimed to determine circulating levels of polyunsaturated fatty acids (PUFAs), secretory phospholipase A2 (sPLA2), lipoprotein lipase (LPL) and measure circulating protein levels of angiopoietin-like protein 3 (ANGPTL3), ANGPTL4, cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in patients with acne vulgaris. Serum from 21 control subjects and 31 acne vulgaris patients were evaluated for levels of arachidonic acid (AA, C20:4n- 6), dihomo-gamma-linolenic acid (DGLA, C20:3n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3). PUFA levels were determined by an optimized multiple reaction monitoring (MRM) method using ultra fast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Lipid profile, routine biochemical and hormone parameters were assayed by standard kit methods Serum EPA levels were significantly decreased while AA/EPA and DGLA/EPA ratio were significantly increased in acne vulgaris patients compared to controls. Serum levels of AA, DGLA and DHA showed no significant difference while activity of sPLA2 and LPL were significantly increased in acne vulgaris compared to controls. Results of this study reveal the presence of a proinflammatory state in acne vulgaris as shown by significantly decreased serum EPA levels and increased activity of sPLA2, AA/EPA and DGLA/EPA ratio. Increased LPL activity in the serum of acne vulgaris patients can be protective through its anti-dyslipidemic actions. This is the first study reporting altered EPA levels and increased sPLA2 activity in acne vulgaris and supports the use of omega-3 fatty acids as adjuvant treatment for acne patients.

  5. Decrease in Circulating Fatty Acids Is Associated with Islet Dysfunction in Chronically Sleep-Restricted Rats

    PubMed Central

    Zhan, Shanshan; Wu, Yangyang; Sun, Peng; Lin, Haiyan; Zhu, Yunxia; Han, Xiao

    2016-01-01

    Previous studies have shown that sleep restriction-induced environmental stress is associated with abnormal metabolism, but the underlying mechanism is poorly understood. In the current study, we investigated the possible lipid and glucose metabolism patterns in chronically sleep-restricted rat. Without changes in food intake, body weight was decreased and energy expenditure was increased in sleep-restricted rats. The effects of chronic sleep disturbance on metabolites in serum were examined using 1H NMR metabolomics and GC-FID/MS analysis. Six metabolites (lipoproteins, triglycerides, isoleucine, valine, choline, and phosphorylcholine) exhibited significant alteration, and all the fatty acid components were decreased, which suggested fatty acid metabolism was impaired after sleep loss. Moreover, increased blood glucose, reduced serum insulin, decreased glucose tolerance, and impaired glucose-stimulated insulin secretion of islets were also observed in sleep-restricted rats. The islet function of insulin secretion could be partially restored by increasing dietary fat to sleep-disturbed rats suggested that a reduction in circulating fatty acids was related to islet dysfunction under sleep deficiency-induced environmental stress. This study provides a new perspective on the relationship between insufficient sleep and lipid/glucose metabolism, which offers insights into the role of stressful challenges in a healthy lifestyle. PMID:27983645

  6. The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation.

    PubMed

    Graffner, H; Gillberg, P-G; Rikner, L; Marschall, H-U

    2016-01-01

    Reabsorption of bile acids from the intestine by ileal bile acid transporter is pivotal for the enterohepatic circulation of BAs and sterol homoeostasis. To assess tolerability and study, bile acid metabolism in a phase 1 trial with the selective ileal bile acid transporter inhibitor A4250. A randomised double-blind, single-ascending dose (SAD) and multiple-ascending-dose study consisting of five cohorts comprising 40 individuals with a single administration of A4250 (0.1, 0.3, 1, 3, or 10 mg) or placebo and three cohorts comprising 24 individuals with a 1-week administration of A4250 (1 or 3 mg once daily or 1.5 mg twice daily) or placebo. For the multiple-ascending-dose study, bile acids were measured by HPLC-MS in plasma and faeces, and fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) were measured in plasma. No serious adverse events occurred and all participants finished the trial per protocol. At the end of the multiple-ascending-dose study, plasma total bile acids and FGF19 decreased by 47% and 76%, respectively, at 3 mg/day (P < 0.01), and by 15% and 16%, respectively, at 1.5 mg twice daily (P < 0.05). Plasma C4 and faecal bile acids increased at all dose regimens, by 555%, 664%, 292% and 338%, 421%, 420%, respectively (P < 0.01-0.05). The primary bile acids cholic and chenodeoxycholic acids constituted the majority of faecal bile acids in the A4250-treated groups. A4250 is well tolerated. By blocking ileal bile acid transporter in the terminal ileum, it highly efficiently interrupts the enterohepatic circulation of BAs, and should be of benefit to patients with cholestatic liver diseases. Clinical Trial registration EudraCT 2013-001175-21. © 2015 John Wiley & Sons Ltd.

  7. Acute effects of different alcoholic beverages on vascular endothelium, inflammatory markers and thrombosis fibrinolysis system.

    PubMed

    Tousoulis, Dimitris; Ntarladimas, Ioannis; Antoniades, Charalambos; Vasiliadou, Carmen; Tentolouris, Costas; Papageorgiou, Nikos; Latsios, George; Stefanadis, Christodoulos

    2008-08-01

    Mild alcohol consumption has been associated with decreased cardiovascular risk, although the underlying mechanisms are still unclear. We compared the acute effects of several alcoholic beverages on endothelial function, inflammatory process and thrombosis/fibrinolysis system in young adults. In this randomized intervention trial, healthy young individuals with no risk factor for atherosclerosis were randomized into 5 equally sized groups and received an equal amount of alcohol (30 g), as red wine (264 ml), white wine (264 ml), beer (633 ml), whisky (79 ml) or water (250 ml). Forearm blood flow was determined by gauge-strain plethysmography, at baseline, 1 and 4 h after alcohol intake. Levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), fibrinogen (Fib), plasminogen activator inhibitor (PAI-1), von Willebrand factor (vWF) and tissue plasminogen activator (tPA) were determined at baseline and 4 h after alcohol consumption. Reactive hyperemia was significantly increased 1 h after beer and red wine consumption (p<0.05 for both), while it returned at baseline at 4 h (p=ns vs baseline) but remained unchanged in all the other groups. vWF was decreased in the beer and red wine groups (p<0.05 for both) only. PAI-1/tPA ratio remained unchanged only in red wine and control group. Inflammatory markers remained unchanged in all the groups. Acute consumption of red wine or beer improves endothelial function and decreases vWF levels, suggesting that the type of beverage may differently affect endothelial function and thrombosis/fibrinolysis system in healthy adults.

  8. Residual mitochondrial transmembrane potential decreases unsaturated fatty acid level in sake yeast during alcoholic fermentation.

    PubMed

    Sawada, Kazutaka; Kitagaki, Hiroshi

    2016-01-01

    Oxygen, a key nutrient in alcoholic fermentation, is rapidly depleted during this process. Several pathways of oxygen utilization have been reported in the yeast Saccharomyces cerevisiae during alcoholic fermentation, namely synthesis of unsaturated fatty acid, sterols and heme, and the mitochondrial electron transport chain. However, the interaction between these pathways has not been investigated. In this study, we showed that the major proportion of unsaturated fatty acids of ester-linked lipids in sake fermentation mash is derived from the sake yeast rather than from rice or koji (rice fermented with Aspergillus). Additionally, during alcoholic fermentation, inhibition of the residual mitochondrial activity of sake yeast increases the levels of unsaturated fatty acids of ester-linked lipids. These findings indicate that the residual activity of the mitochondrial electron transport chain reduces molecular oxygen levels and decreases the synthesis of unsaturated fatty acids, thereby increasing the synthesis of estery flavors by sake yeast. This is the first report of a novel link between residual mitochondrial transmembrane potential and the synthesis of unsaturated fatty acids by the brewery yeast during alcoholic fermentation.

  9. CONJUGATED LINOLEIC ACIDS (CLA) DECREASE THE BREAST CANCER RISK IN DMBA-TREATED RATS.

    PubMed

    Białek, Agnieszka; Tokarz, Andrzej; Zagrodzki, Paweł

    2016-01-01

    The aim of this study was to investigate how supplementation of diet of female Sprague-Dawley rats with different doses of conjugated linoleic acids and for a varied period of time influences breast cancer risk, fatty acids profile and lipids peroxidation in chemically induced mammary tumors. Animals were divided into nine groups with different modifications of diet (vegetable oil, 1.0 or 2.0% of CLA) and period of supplementation, which lasted after (A), before (B) and before and after (BA) carcinogenic agent--7,12-dimethylbenz[a]anthracene administration at 50th day of life. Mammary adenocarcinomas occurred in all groups, but CLA supplementation decreased the cancer morbidity. Two percent CLA seems to be excessive because of the coexisting cachexia. Two CLA isomers (9-cis, 11-trans and 10-trans, 12-cis) were detected in tumors but content of rumenic acid was higher. Dietary supplementation significantly influenced some unsaturated fatty acids content (C18:2 n-6 trans, C20:1, C20:5 n-3, C22:2), but the anti- or prooxidant properties of CLA were not confirmed. CLA can inhibit chemically induced mammary tumors development in female rats, but their cytotoxic action seems not to be connected with lipids peroxidation. CLA isomers differ with their incorporation into cancerous tissues and they influence the content of some other fatty acids.

  10. Influence of solar activity on fibrinolysis and fibrinogenolysis. [statistical correlation between solar flare and blood coagulation indices

    NASA Technical Reports Server (NTRS)

    Marchenko, V. I.

    1974-01-01

    During periods of high solar activity fibrinolysis and fibrinogenolysis are increased. A direct correlative relationship is established between the indices of fibrinolysis, fibrinogenolysis and solar flares which were recorded two days before the blood was collected for analysis.

  11. Influence of solar activity on fibrinolysis and fibrinogenolysis. [statistical correlation between solar flare and blood coagulation indices

    NASA Technical Reports Server (NTRS)

    Marchenko, V. I.

    1974-01-01

    During periods of high solar activity fibrinolysis and fibrinogenolysis are increased. A direct correlative relationship is established between the indices of fibrinolysis, fibrinogenolysis and solar flares which were recorded two days before the blood was collected for analysis.

  12. Experimental Warming Decreases the Average Size and Nucleic Acid Content of Marine Bacterial Communities

    PubMed Central

    Huete-Stauffer, Tamara M.; Arandia-Gorostidi, Nestor; Alonso-Sáez, Laura; Morán, Xosé Anxelu G.

    2016-01-01

    Organism size reduction with increasing temperature has been suggested as a universal response to global warming. Since genome size is usually correlated to cell size, reduction of genome size in unicells could be a parallel outcome of warming at ecological and evolutionary time scales. In this study, the short-term response of cell size and nucleic acid content of coastal marine prokaryotic communities to temperature was studied over a full annual cycle at a NE Atlantic temperate site. We used flow cytometry and experimental warming incubations, spanning a 6°C range, to analyze the hypothesized reduction with temperature in the size of the widespread flow cytometric bacterial groups of high and low nucleic acid content (HNA and LNA bacteria, respectively). Our results showed decreases in size in response to experimental warming, which were more marked in 0.8 μm pre-filtered treatment rather than in the whole community treatment, thus excluding the role of protistan grazers in our findings. Interestingly, a significant effect of temperature on reducing the average nucleic acid content (NAC) of prokaryotic cells in the communities was also observed. Cell size and nucleic acid decrease with temperature were correlated, showing a common mean decrease of 0.4% per °C. The usually larger HNA bacteria consistently showed a greater reduction in cell and NAC compared with their LNA counterparts, especially during the spring phytoplankton bloom period associated to maximum bacterial growth rates in response to nutrient availability. Our results show that the already smallest planktonic microbes, yet with key roles in global biogeochemical cycling, are likely undergoing important structural shrinkage in response to rising temperatures. PMID:27242747

  13. Experimental Warming Decreases the Average Size and Nucleic Acid Content of Marine Bacterial Communities.

    PubMed

    Huete-Stauffer, Tamara M; Arandia-Gorostidi, Nestor; Alonso-Sáez, Laura; Morán, Xosé Anxelu G

    2016-01-01

    Organism size reduction with increasing temperature has been suggested as a universal response to global warming. Since genome size is usually correlated to cell size, reduction of genome size in unicells could be a parallel outcome of warming at ecological and evolutionary time scales. In this study, the short-term response of cell size and nucleic acid content of coastal marine prokaryotic communities to temperature was studied over a full annual cycle at a NE Atlantic temperate site. We used flow cytometry and experimental warming incubations, spanning a 6°C range, to analyze the hypothesized reduction with temperature in the size of the widespread flow cytometric bacterial groups of high and low nucleic acid content (HNA and LNA bacteria, respectively). Our results showed decreases in size in response to experimental warming, which were more marked in 0.8 μm pre-filtered treatment rather than in the whole community treatment, thus excluding the role of protistan grazers in our findings. Interestingly, a significant effect of temperature on reducing the average nucleic acid content (NAC) of prokaryotic cells in the communities was also observed. Cell size and nucleic acid decrease with temperature were correlated, showing a common mean decrease of 0.4% per °C. The usually larger HNA bacteria consistently showed a greater reduction in cell and NAC compared with their LNA counterparts, especially during the spring phytoplankton bloom period associated to maximum bacterial growth rates in response to nutrient availability. Our results show that the already smallest planktonic microbes, yet with key roles in global biogeochemical cycling, are likely undergoing important structural shrinkage in response to rising temperatures.

  14. Decrease of brain phospholipid synthesis in free-moving n-3 fatty acid deficient rats.

    PubMed

    Gazzah, N; Gharib, A; Croset, M; Bobillier, P; Lagarde, M; Sarda, N

    1995-02-01

    The autoradiographic method with [14C]-docosahexaenoic acid ([14C]22:6 n-3) was used to determine whether a diet deficient in n-3 fatty acids, inducing a decrease in 22:6 n-3 circulating level, was associated with changes in local rates of phospholipid synthesis in the rat brain. As compared with rats fed a normal diet (peanut plus rapeseed oil), a n-3 fatty acid deficiency [peanut oil group (P group)] induced a generalized decrease (-35 to -76%) of 22:6 n-3 incorporation rates into phospholipids in all the regions examined. This effect was confirmed by using [3H]22:6 n-3 infusion by biochemical analysis and quantifications corrected for the contribution of docosahexaenoate derived from lipid store recycling to the unesterified pool, taken as the precursor pool for phospholipid synthesis in the whole brain. In normal or n-3 fatty acid-deficient rats, the values of the brain-to-plasma 22:6 n-3 specific activity ratio (psi) were similar (0.03), indicating that a considerable endogenous source of 22:6 n-3 (97%), likely derived from phospholipid degradation, dilutes the specific activity of the tracer coming from plasma. Using the specific activity of 22:6 n-3 in plasma instead of brain would thus lead to a gross underestimation of the rate of phospholipid synthesis. The results also demonstrate that the pattern of 14C or 3H distribution in brain lipids was not modified by the n-3 fatty acid-deficient diet. The major lipids labeled were phospholipids, particularly phosphatidylethanolamine. Nevertheless, the unesterified 22:6 n-3 concentrations in plasma and brain were significantly reduced (eight-and threefold, respectively) in the P group. In addition, the proportion of 22:6 n-3 in the brain total lipid fraction, total phospholipids, and phosphatidylcholine, -ethanolamine, and -serine was significantly decreased in n-3 fatty acid-deficient rats. This was partially compensated for by an increase in the 22:5 n-6 level. These results are discussed in relation to the

  15. Influence of synoptic processes on fibrinolysis and fibrinogenolysis in healthy persons. [meteorological effects on blood coagulation

    NASA Technical Reports Server (NTRS)

    Marchenko, V. I.

    1974-01-01

    It is shown that on days with frontal activity in the atmosphere the levels of fibrinolysis and fibrinogenolysis are increased. The reactions of fibrinolysis and fibrinogenolysis to the passage of warm and cold fronts varies with the season of the year.

  16. The influence of weather on fibrinolysis and fibrinogenolysis. [in human body

    NASA Technical Reports Server (NTRS)

    Marchenko, V. I.

    1974-01-01

    Analysis of fibrinolysis and fibrinogenolysis indices by month showed an increase in the activity of these processes from winter to summer (1967-1968). At all seasons of the year, fibrinolysis and fibrinogenolysis increase during weather of the cyclonic type with passage of fronts and sharp fluctuations in meteorological factors in the atmosphere.

  17. Fibrinolysis and fibrinogenolysis on magnetically-active days. [statistical correlation to magnetic storms

    NASA Technical Reports Server (NTRS)

    Marchenko, V. I.

    1974-01-01

    On magnetically-active days, activation of fibrinolysis and fibrinogenolysis is observed. The increase in fibrinolysis and fibrinogenolysis begins on the day of the onset of a magnetic storm, reaching a maximum in 24 hours. Activation is higher on days with magnetic storms with a sudden onset and a C index of 1.5-2.0.

  18. The influence of weather on fibrinolysis and fibrinogenolysis. [in human body

    NASA Technical Reports Server (NTRS)

    Marchenko, V. I.

    1974-01-01

    Analysis of fibrinolysis and fibrinogenolysis indices by month showed an increase in the activity of these processes from winter to summer (1967-1968). At all seasons of the year, fibrinolysis and fibrinogenolysis increase during weather of the cyclonic type with passage of fronts and sharp fluctuations in meteorological factors in the atmosphere.

  19. Influence of synoptic processes on fibrinolysis and fibrinogenolysis in healthy persons. [meteorological effects on blood coagulation

    NASA Technical Reports Server (NTRS)

    Marchenko, V. I.

    1974-01-01

    It is shown that on days with frontal activity in the atmosphere the levels of fibrinolysis and fibrinogenolysis are increased. The reactions of fibrinolysis and fibrinogenolysis to the passage of warm and cold fronts varies with the season of the year.

  20. Fibrinolysis and fibrinogenolysis on magnetically-active days. [statistical correlation to magnetic storms

    NASA Technical Reports Server (NTRS)

    Marchenko, V. I.

    1974-01-01

    On magnetically-active days, activation of fibrinolysis and fibrinogenolysis is observed. The increase in fibrinolysis and fibrinogenolysis begins on the day of the onset of a magnetic storm, reaching a maximum in 24 hours. Activation is higher on days with magnetic storms with a sudden onset and a C index of 1.5-2.0.

  1. Phytic acid decreases deoxynivalenol and fumonisin B1-induced changes on swine jejunal explants.

    PubMed

    da Silva, Elisângela Olegário; Gerez, Juliana Rubira; do Carmo Drape, Thalisie; Bracarense, Ana Paula F R L

    2014-01-01

    The purpose of the present study was to investigate the effects of phytic acid (IP6) on morphological and immunohistochemical parameters on intestinal explants exposed to deoxynivalenol (DON) and fumonisin B1 (FB1). The jejunal explants were exposed for 4 h to different treatments: control, DON (10 μM), DON plus 2.5 mM or 5 mM IP6, FB1 (70 μM), and FB1 plus 2.5 mM or 5 mM IP6. Both mycotoxins induced significant intestinal lesions and decreased villi height. The presence of 2.5 mM and 5 mM IP6 significantly inhibited the morphological changes caused by the mycotoxins. DON induced a significant increase in caspase-3 (83%) and cyclooxygenase-2 (71.3%) expression compared with the control. The presence of 5 mM IP6 induced a significant decrease in caspase-3 (43.7%) and Cox-2 (48%) expression compared with the DON group. FB1 induced a significant increase in caspase-3 expression (47%) compared to the control, whereas IP6 induced no significant change in this expression. A significant decrease in cell proliferation was observed when explants were exposed to 5 mM of IP6 in comparison with the DON and FB1 groups. The present data provide evidence that phytic acid modulates the toxic effects induced by DON and FB1 on intestinal tissue.

  2. Retinoic acid treatment of fibroblasts causes a rapid decrease in ( sup 3 H)inositol uptake

    SciTech Connect

    Sinha, R.; Creek, K.E.; Silverman-Jones, C.; de Luca, L.M. )

    1989-04-01

    NIH 3T3 fibroblasts treated with all-trans-retinoic acid (RA) showed a dramatic decrease in the uptake of ({sup 3}H)inositol compared to solvent-treated controls. The onset of RA-induced inhibition of ({sup 3}H)inositol uptake was rapid with a 10-15% decrease occurring after 2-3 h of RA exposure and 60-70% reduction after 16 h of RA treatment. A progressive dose-dependent decrease in inositol uptake was found as the concentration of RA increased from 10{sup {minus}8} to 10{sup {minus}5} M and the effect was fully reversible within 48 h after RA removal. RA inhibition of inositol uptake was also observed in 3T3-Swiss and Balb/3T3 cells but not in two virally transformed 3T3 cell lines. Phlorizin, amiloride, and monensin inhibited inositol uptake by 66, 74, and 58%, respectively, and this inhibition was additive when the cells were treated with RA as well as these inhibitors. A decreased incorporation of ({sup 3}H)inositol into polyphosphoinositides was also observed in RA-treated cells but not to the same extent as for ({sup 3}H)inositol uptake. In conclusion, RA treatment of 3T3 fibroblasts decreases the uptake of ({sup 3}H)inositol by up to 70% within 8 to 10 h at near physiological concentrations in a reversible and specific manner.

  3. Formulating gels for decreased mucociliary transport using rheologic properties: polyacrylic acids.

    PubMed

    Shah, Ankur J; Donovan, Maureen D

    2007-04-20

    The purpose of these studies was to identify the rheologic properties of polyacrylic acid gels necessary for optimal reductions in mucociliary clearance. The mucociliary transport of 2 bioadhesive polyacrylic acid polymers, polycarbophil and carbopol, was assessed in vitro by measuring their clearance rates across explants of ciliated bovine tracheal tissue. The viscoelastic properties of polymer gels were measured in the presence of mucus using controlled stress rheometry. Combinations of apparent viscosity (eta) and complex modulus (G*) were found to be the most useful parameters in the identification of polyacrylic acid formulations capable of decreasing mucociliary transport rate (MTR). A narrow range of eta and G* values suitable for reducing mucociliary clearance, while remaining sufficiently fluid for intranasal administration, were identified. The correlations between the rheologic parameters of the polycarbophil gels and their mucociliary transport rates were used to identify other polyacrylic acid gels that also had suitable mucociliary clearance properties, demonstrating that these parameters can be used to direct the optimization of formulations using simple in vitro rheologic testing.

  4. Changes in soil pH across England and Wales in response to decreased acid deposition

    NASA Astrophysics Data System (ADS)

    Kirk, G. J. D.; Bellamy, P. H.

    2009-04-01

    In our recent analysis of data from the National Soil Inventory of England and Wales, we found widespread changes in soil pH across both countries between the two samplings of the Inventory. In general, soil pH increased - i.e. soils became less acid - under all land uses. The Inventory was first sampled in 1978-83 on a 5-km grid over the whole area. This yielded about 6,000 sites of which 5,662 could be sampled for soil. Roughly 40% of the sites were re-sampled at intervals from 12 to 25 years after the original sampling - in 1994/96 for agricultural land and in 2002/03 for non-agricultural. Exactly the same sampling and analytical protocols were used in the two samplings. In arable soils, the increase in pH was right across the range, whereas in grassland soils the main increase was at the acid end of the scale (pH < 5.5) with a small increase above pH 7. Some part of the change is likely to have been due to changes in land management. This includes better targeting of agricultural lime on acid soils; changes in nitrogen fertilizer use; deeper ploughing bringing up more calcareous subsoil on soils on calcareous materials; and so forth. However a major driver appears to have been decreased acid deposition to land. The total amounts of nitrogen compounds deposited were relatively unchanged over the survey period, but the amounts of acidifying sulphur compounds decreased by approximately 50%. We constructed a linear regression model to assess the relation between the rate of change in pH (normalised to an annual basis) and the rate of change in acid deposition, as modified by soil properties (pH, clay content, organic matter content), rainfall and past acid deposition. We used data on rainfall and acid deposition over the survey period on the same 5-km grid as the NSI data. We fitted the model separately for each land use category. The results for arable land showed a significant effect of the change in rate of acid deposition, though a significant part of the

  5. Phenylboronic acid selectively inhibits human prostate and breast cancer cell migration and decreases viability.

    PubMed

    Bradke, Tiffany M; Hall, Casey; Carper, Stephen W; Plopper, George E

    2008-01-01

    We compared the in vitro effect of boric acid (BA) versus phenylboronic acid (PBA) on the migration of prostate and breast cancer cell lines and non-tumorigenic cells from the same tissues. Treatment at 24 hours with BA (< or =500 microM) did not inhibit chemotaxis on fibronectin in any cell line. However, treatment over the same time course with concentrations of PBA as low as 1 muM significantly inhibited cancer cell migration without effecting non-tumorigenic cell lines. The compounds did not affect cell adhesion or viability at 24 hours but did alter morphology; both decreased cancer cell viability at eight days. These results suggest that PBA is more potent than BA in targeting the metastatic and proliferative properties of cancer cells.

  6. Toxicity of valproic acid in mice with decreased plasma and tissue carnitine stores.

    PubMed

    Knapp, Andrea Caroline; Todesco, Liliane; Beier, Konstantin; Terracciano, Luigi; Sägesser, Hans; Reichen, Jürg; Krähenbühl, Stephan

    2008-02-01

    The aim of this study was to investigate whether a decrease in carnitine body stores is a risk factor for valproic acid (VPA)-associated hepatotoxicity and to explore the effects of VPA on carnitine homeostasis in mice with decreased carnitine body stores. Therefore, heterozygous juvenile visceral steatosis (jvs)(+/-) mice, an animal model with decreased carnitine stores caused by impaired renal reabsorption of carnitine, and the corresponding wild-type mice were treated with subtoxic oral doses of VPA (0.1 g/g b.wt./day) for 2 weeks. In jvs(+/-) mice, but not in wild-type mice, treatment with VPA was associated with the increased plasma activity of aspartate aminotransferase and alkaline phosphatase. Furthermore, jvs(+/-) mice revealed reduced palmitate metabolism assessed in vivo and microvesicular steatosis of the liver. The creatine kinase activity was not affected by treatment with VPA. In liver mitochondria isolated from mice that were treated with VPA, oxidative metabolism of l-glutamate, succinate, and palmitate, as well as beta-oxidation of palmitate, were decreased compared to vehicle-treated wild-type mice or jvs(+/-) mice. In comparison to vehicle-treated wild-type mice, vehicle-treated jvs(+/-) mice had decreased carnitine plasma and tissue levels. Treatment with VPA was associated with an additional decrease in carnitine plasma (wild-type mice and jvs(+/-) mice) and tissue levels (jvs(+/-) mice) and a shift of the carnitine pools toward short-chain acylcarnitines. We conclude that jvs(+/-) mice reveal a more accentuated hepatic toxicity by VPA than the corresponding wild-type mice. Therefore, decreased carnitine body stores can be regarded as a risk factor for hepatotoxicity associated with VPA.

  7. Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes

    PubMed Central

    Xu, Dan; Li, Feng; Zhang, Mian; Zhang, Ji; Liu, Can; Hu, Meng-yue; Zhong, Ze-yu; Jia, Ling-ling; Wang, Da-wei; Wu, Jie; Liu, Li; Liu, Xiao-dong

    2014-01-01

    Aim: Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes. Methods: Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR. Results: After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp. Conclusion: Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake. PMID:25152023

  8. Decreased solubilization of Pu(IV) polymers by humic acids under anoxic conditions

    NASA Astrophysics Data System (ADS)

    Xie, Jinchuan; Lin, Jianfeng; Liang, Wei; Li, Mei; Zhou, Xiaohua

    2016-11-01

    Pu(IV) polymer has a very low solubility (log[Pu(IV)aq]total = -10.4 at pH 7.2 and I = 0). However, some aspects of their environmental fate remain unclear. Humic acids are able to complex with Pu4+ ions and their dissolved species (<10 kD) in the groundwater (neutral to alkaline pH) may cause solubilization of the polymers. Also, humic acids have the native reducing capacity and potentially reduce the polymeric Pu(IV) to Pu(III)aq (log[Pu(III)aq]total = -5.3 at pH 7.2 and I = 0). Solubilization and reduction of the polymers can enhance their mobility in subsurface environments. Nevertheless, humic acids readily coat the surfaces of metal oxides via electrostatic interaction and ligand exchange mechanisms. The humic coatings are expected to prevent both solubilization and reduction of the polymers. Experiments were conducted under anoxic and slightly alkaline (pH 7.2) conditions in order to study whether humic acids have effects on stability of the polymers. The results show that the polymeric Pu(IV) was almost completely transformed into aqueous Pu(IV) in the presence of EDTA ligands. In contrast, the dissolved humic acids did not solubilize the polymers but in fact decreased their solubility by one order of magnitude. The humic coatings were responsible for the decreased solubilization. Such coatings limited the contact between the polymers and EDTA ligands, especially at the relatively high concentrations of humic acids (>0.57 mg/L). Solubilization of the humic-coated polymers was thus inhibited to a significant extent although EDTA, having the great complexation ability, was present in the humic solutions. Reduction of Pu(IV) polymers by the humic acids was also not observed in the absence of EDTA. In the presence of EDTA, the polymers were partially reduced to Pu(III)aq by the humic acids of 0.57 mg/L and the percentage of Pu(III)aq accounted for 51.7% of the total aqueous Pu. This demonstrates that the humic acids were able to reduce the aqueous Pu

  9. Ozone oxidation of oleic acid surface films decreases aerosol cloud condensation nuclei activity

    NASA Astrophysics Data System (ADS)

    Schwier, A. N.; Sareen, N.; Lathem, T. L.; Nenes, A.; McNeill, V. F.

    2011-08-01

    Heterogeneous oxidation of aerosols composed of pure oleic acid (C18H34O2, an unsaturated fatty acid commonly found in continental and marine aerosol) by gas-phase O3 is known to increase aerosol hygroscopicity and activity as cloud condensation nuclei (CCN). Whether this trend is preserved when the oleic acid is internally mixed with other electrolytes is unknown and addressed in this study. We quantify the CCN activity of sodium salt aerosols (NaCl and Na2SO4) internally mixed with sodium oleate (SO) and oleic acid (OA). We find that particles containing roughly one monolayer of SO/OA show similar CCN activity to pure salt particles, whereas a tenfold increase in organic concentration slightly depresses CCN activity. O3 oxidation of these multicomponent aerosols has little effect on the critical diameter for CCN activation for unacidified particles at all conditions studied, and the activation kinetics of the CCN are similar in each case to those of pure salts. SO-containing particles which are acidified to atmospherically relevant pH before analysis in order to form oleic acid, however, show depressed CCN activity upon oxidation. This effect is more pronounced at higher organic concentrations. The behavior after oxidation is consistent with the disappearance of the organic surface film, supported by Köhler Theory Analysis (KTA). The κ-Köhler calculations show a small decrease in hygroscopicity after oxidation. The important implication of this finding is that oxidative aging may not always enhance the hygroscopicity of internally mixed inorganic-organic aerosols.

  10. Decreased formation of branched-chain short fatty acids in Bacillus amyloliquefaciens by metabolic engineering.

    PubMed

    Chen, Yangyang; Liu, Mengjie; Chen, Shouwen; Wei, Xuetuan

    2017-04-01

    To reduce the unpleasant odor during 1-deoxynojirimycin (DNJ) production, the genes of leucine dehydrogenase (bcd) and phosphate butryltransferase (ptb) were deleted from Bacillus amyloliquefaciens HZ-12, and the concentrations of branched-chain short fatty acids (BCFAs) and DNJ were compared. By knockout of the ptb gene, 1.01 g BCFAs kg(-1) was produced from fermented soybean by HZ-12Δptb. This was a 56% decrease compared with that of HZ-12 (2.27 g BCFAs kg(-1)). Moreover, no significant difference was found in the DNJ concentration (0.7 g kg(-1)). After further deletion of the bcd gene from HZ-12Δptb, no BCFAs was detected in fermented soybeans with HZ-12ΔptbΔbcd, while the DNJ yield decreased by 26% compared with HZ-12. HZ-12Δptb had decreased BCFAs formation but also maintained the stable DNJ yield, which contributed to producing DNJ-rich products with decreased unpleasant smell.

  11. Release of alpha 2-plasmin inhibitor from plasma fibrin clots by activated coagulation factor XIII. Its effect on fibrinolysis.

    PubMed Central

    Mimuro, J; Kimura, S; Aoki, N

    1986-01-01

    When blood coagulation takes place in the presence of calcium ions, alpha 2-plasmin inhibitor (alpha 2PI) is cross-linked to fibrin by activated coagulation Factor XIII (XIIIa) and thereby contributes to the resistance of fibrin to fibrinolysis. It was previously shown that the cross-linking reaction is a reversible one, since the alpha 2PI-fibrinogen cross-linked complex could be dissociated. In the present study we have shown that the alpha 2PI-fibrin cross-linking reaction is also a reversible reaction and alpha 2PI which had been cross-linked to fibrin can be released from fibrin by disrupting the equilibrium, resulting in a decrease of its resistance to fibrinolysis. When the fibrin clot formed from normal plasma in the presence of calcium ions was suspended in alpha 2PI-deficient plasma of buffered saline, alpha 2PI was gradually released from fibrin on incubation. When alpha 2PI was present in the suspending milieu, the release was decreased inversely to the concentrations of alpha 2PI in the suspending milieu. The release was accelerated by supplementing XIIIa or the presence of a high concentration of the NH2-terminal 12-residue peptide of alpha 2PI (N-peptide) which is cross-linked to fibrin in exchange for the release of alpha 2PI. When the release of alpha 2PI from fibrin was accelerated by XIIIa or N-peptide, the fibrin became less resistant to the fibrinolytic process, resulting in an acceleration of fibrinolysis which was proportional to the degree of the release of alpha 2PI. These results suggest the possibility that alpha 2PI could be released from fibrin in vivo by disrupting the equilibrium of the alpha 2PI-fibrin cross-linking reaction, and that the release would result in accelerated thrombolysis. Images PMID:2419360

  12. Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis.

    PubMed

    Shinto, L; Marracci, G; Baldauf-Wagner, S; Strehlow, A; Yadav, V; Stuber, L; Bourdette, D

    2009-01-01

    The primary objective was to evaluate the effect of omega-3 fatty acids (omega-3 FA) on matrix metalloproteinase-9 (MMP-9) production by immune cells in multiple sclerosis (MS). Quality of life, fatty acid levels, and safety were also evaluated. Ten participants with relapsing-remitting MS (RRMS) received omega-3 FA supplementation (9.6g/day fish oil) in an open-label study. Participants were evaluated at four time points, baseline, after 1 month of omega-3 FA supplementation, after 3 months of omega-3 FA supplementation, and after a 3-month wash out. Immune cell secretion of MMP-9 decreased by 58% after 3 months of omega-3 FA supplementation when compared with baseline levels (p<0.01). This effect was coupled with a significant increase in omega-3 FA levels in red blood cell membranes. Omega-3 FA significantly decreased MMP-9 levels in RRMS and may act as an immune-modulator that has potential therapeutic benefit in MS patients.

  13. Downregulation of Clock in circulatory system leads to an enhancement of fibrinolysis in mice.

    PubMed

    Cheng, Shuting; Jiang, Zhou; Zou, Yan; Chen, Chen; Wang, Yuhui; Liu, Yanyou; Xiao, Jing; Guo, Huiling; Wang, Zhengrong

    2011-09-01

    As a main component of circadian genes, clock plays not only an important role in circadian rhythm but also in the regulation of many physiological systems. The dysfunction of clock genes is associated with the development of various disorders. Many studies have investigated the association between clock genes and blood coagulation and the fibrinolytic system. The present study was designed to investigate the effect of downregulation of circulatory Clock on blood coagulation and fibrinolysis at the initial stage of active phase in male mice. Downregulation of the expression of the Clock gene by siRNA and, subsequently, its effect on the thrombotic potential and the expression of relative coagulative and/or fibrinolytic factors were investigated. It was found that the Clock interfered mice were less liable to thrombosis and showed prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) at Zeitgeber time (ZT) 15. Meanwhile, these mice also showed an increase in factor VII (FVII) and a decrease in thrombomodulin (TM) and plasminogen activator inhibitor 1 (PAI-1) at ZT 15 at both transcriptional and translational levels. PT, APTT and mRNA expressions of fvii, tm and pai-1 were analyzed with the least-squares fit of a 24-h cosine function by single cosinor method; no circadian rhythm was determined in PT and APTT, and a higher amplitude of fvii in the Clock RNAi group was found with a circadian phase shift, while lower amplitudes of tm and pai-1 were found in the Clock RNAi group with nearly no phase shift. All these results suggest that downregulation of the Clock gene in circulatory system has an effect on factors involved in both blood coagulation and fibrinolysis resulting in an enhancement in mice. This may be considered as an indication that Clock regulates thrombotic homeostasis through the fibrinolytic system.

  14. Strictosidinic acid, isolated from Psychotria myriantha Mull. Arg. (Rubiaceae), decreases serotonin levels in rat hippocampus.

    PubMed

    Farias, F M; Passos, C S; Arbo, M D; Barros, D M; Gottfried, C; Steffen, V M; Henriques, A T

    2012-09-01

    Psychotria is a complex genus whose neotropical species are known by the presence of glucosidic monoterpene indole alkaloids. These compounds are able to display a large range of effects on the central nervous system, such as anxiolytic, antidepressant, analgesic, and impairment of learning and memory acquisition. The aims of this study were to investigate the effects displayed by strictosidinic acid, isolated from Psychotria myriantha Mull. Arg. (Rubiaceae) leaves, on monoamine levels in rat hippocampus and on monoamine oxidase activity. A significance (p<0.01) of 83.5% reduction in 5-HT levels was observed after intra-hippocampal injection (20 μg/μl). After treatment by intraperitoneal route (10 mg/kg), a 63.4% reduction in 5-HT levels and a 67.4% reduction in DOPAC values were observed. The results indicate that strictosidinic acid seems to act on 5-HT system in rat hippocampus, possibly inhibiting precursor enzymes of 5-HT biosynthesis. The decrease verified in DOPAC levels suggests a role of strictosidinic acid in the dopaminergic transmission, probably due to an inhibition of monoamine oxidase activity, confirmed by the enzymatic assay, which demonstrated an inhibitory effect on MAO A in rat brain mitochondria. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Folic Acid Transport to the Human Fetus Is Decreased in Pregnancies with Chronic Alcohol Exposure

    PubMed Central

    Hutson, Janine R.; Stade, Brenda; Lehotay, Denis C.; Collier, Christine P.; Kapur, Bhushan M.

    2012-01-01

    Background During pregnancy, the demand for folic acid increases since the fetus requires this nutrient for its rapid growth and cell proliferation. The placenta concentrates folic acid into the fetal circulation; as a result the fetal levels are 2 to 4 times higher than the maternal level. Animal and in vitro studies have suggested that alcohol may impair transport of folic acid across the placenta by decreasing expression of transport proteins. We aim to determine if folate transfer to the fetus is altered in human pregnancies with chronic alcohol consumption. Methodology/Principal Findings Serum folate was measured in maternal blood and umbilical cord blood at the time of delivery in pregnancies with chronic and heavy alcohol exposure (n = 23) and in non-drinking controls (n = 24). In the alcohol-exposed pairs, the fetal∶maternal serum folate ratio was ≤1.0 in over half (n = 14), whereas all but one of the controls were >1.0. Mean folate in cord samples was lower in the alcohol-exposed group than in the controls (33.15±19.89 vs 45.91±20.73, p = 0.04). Conclusions/Significance Our results demonstrate that chronic and heavy alcohol use in pregnancy impairs folate transport to the fetus. Altered folate concentrations within the placenta and in the fetus may in part contribute to the deficits observed in the fetal alcohol spectrum disorders. PMID:22666445

  16. Folic acid transport to the human fetus is decreased in pregnancies with chronic alcohol exposure.

    PubMed

    Hutson, Janine R; Stade, Brenda; Lehotay, Denis C; Collier, Christine P; Kapur, Bhushan M

    2012-01-01

    During pregnancy, the demand for folic acid increases since the fetus requires this nutrient for its rapid growth and cell proliferation. The placenta concentrates folic acid into the fetal circulation; as a result the fetal levels are 2 to 4 times higher than the maternal level. Animal and in vitro studies have suggested that alcohol may impair transport of folic acid across the placenta by decreasing expression of transport proteins. We aim to determine if folate transfer to the fetus is altered in human pregnancies with chronic alcohol consumption. Serum folate was measured in maternal blood and umbilical cord blood at the time of delivery in pregnancies with chronic and heavy alcohol exposure (n = 23) and in non-drinking controls (n = 24). In the alcohol-exposed pairs, the fetal:maternal serum folate ratio was ≤ 1.0 in over half (n = 14), whereas all but one of the controls were >1.0. Mean folate in cord samples was lower in the alcohol-exposed group than in the controls (33.15 ± 19.89 vs 45.91 ± 20.73, p = 0.04). Our results demonstrate that chronic and heavy alcohol use in pregnancy impairs folate transport to the fetus. Altered folate concentrations within the placenta and in the fetus may in part contribute to the deficits observed in the fetal alcohol spectrum disorders.

  17. Effect of pneumatic compression on fibrinolysis after total hip arthroplasty.

    PubMed

    Macaulay, William; Westrich, Geoffrey; Sharrock, Nigel; Sculco, Thomas P; Jhon, Peter H; Peterson, Margaret G E; Salvati, Eduardo A

    2002-06-01

    The purpose of this prospective randomized clinical study was to investigate the enhanced systemic fibrinolysis mechanism of venous thrombosis prevention by pneumatic compression after total hip arthroplasty. Fifty patients were randomized into one of two groups (one with pneumatic compression [n=25] and one without [n=25]). Blood was drawn from a radial arterial line immediately preoperatively (baseline), at skin closure, and 8 hours and 22 hours after the baseline sample. Serum determinations of antigen of tissue plasminogen activator and plasminogen activator inhibitor-1 were done using enzyme-linked immunosorbent assays. These data do not support the enhancement of systemic fibrinolysis mechanism for lowering thromboembolic risk after total hip arthroplasty by pneumatic compression devices. The results of this study showed no differences that were statistically significant between the two groups. The greatest difference was observed 8 hours after surgery for the plasminogen activator inhibitor-1 marker, (28.12 with compression versus 22.07 ng/mL without); however, this result was not statistically significant. The beneficial effect of mechanical compression is more likely achieved through increased flow, local fibrinolytic effects, or both.

  18. Breaking boundaries—coagulation and fibrinolysis at the neurovascular interface

    PubMed Central

    Bardehle, Sophia; Rafalski, Victoria A.; Akassoglou, Katerina

    2015-01-01

    Blood proteins at the neurovascular unit (NVU) are emerging as important molecular determinants of communication between the brain and the immune system. Over the past two decades, roles for the plasminogen activation (PA)/plasmin system in fibrinolysis have been extended from peripheral dissolution of blood clots to the regulation of central nervous system (CNS) functions in physiology and disease. In this review, we discuss how fibrin and its proteolytic degradation affect neuroinflammatory, degenerative and repair processes. In particular, we focus on novel functions of fibrin—the final product of the coagulation cascade and the main substrate of plasmin—in the activation of immune responses and trafficking of immune cells into the brain. We also comment on the suitability of the coagulation and fibrinolytic systems as potential biomarkers and drug targets in diseases, such as multiple sclerosis (MS), Alzheimer’s disease (AD) and stroke. Studying coagulation and fibrinolysis as major molecular pathways that regulate cellular functions at the NVU has the potential to lead to the development of novel strategies for the detection and treatment of neurologic diseases. PMID:26441525

  19. Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity.

    PubMed

    Yu, Jinghua; Lo, Jane-L; Huang, Li; Zhao, Annie; Metzger, Edward; Adams, Alan; Meinke, Peter T; Wright, Samuel D; Cui, Jisong

    2002-08-30

    Bile salt export pump (BSEP) is a major bile acid transporter in the liver. Mutations in BSEP result in progressive intrahepatic cholestasis, a severe liver disease that impairs bile flow and causes irreversible liver damage. BSEP is a target for inhibition and down-regulation by drugs and abnormal bile salt metabolites, and such inhibition and down-regulation may result in bile acid retention and intrahepatic cholestasis. In this study, we quantitatively analyzed the regulation of BSEP expression by FXR ligands in primary human hepatocytes and HepG2 cells. We demonstrate that BSEP expression is dramatically regulated by ligands of the nuclear receptor farnesoid X receptor (FXR). Both the endogenous FXR agonist chenodeoxycholate (CDCA) and synthetic FXR ligand GW4064 effectively increased BSEP mRNA in both cell types. This up-regulation was readily detectable at as early as 3 h, and the ligand potency for BSEP regulation correlates with the intrinsic activity on FXR. These results suggest BSEP as a direct target of FXR and support the recent report that the BSEP promoter is transactivated by FXR. In contrast to CDCA and GW4064, lithocholate (LCA), a hydrophobic bile acid and a potent inducer of cholestasis, strongly decreased BSEP expression. Previous studies did not identify LCA as an FXR antagonist ligand in cells, but we show here that LCA is an FXR antagonist with partial agonist activity in cells. In an in vitro co-activator association assay, LCA decreased CDCA- and GW4064-induced FXR activation with an IC(50) of 1 microm. In HepG2 cells, LCA also effectively antagonized GW4064-enhanced FXR transactivation. These data suggest that the toxic and cholestatic effect of LCA in animals may result from its down-regulation of BSEP through FXR. Taken together, these observations indicate that FXR plays an important role in BSEP gene expression and that FXR ligands may be potential therapeutic drugs for intrahepatic cholestasis.

  20. Homocysteine mediated decrease in bone blood flow and remodeling: role of folic acid.

    PubMed

    Tyagi, Neetu; Kandel, Madhavi; Munjal, Charu; Qipshidze, Natia; Vacek, Jonathan C; Pushpakumar, Sathnur B; Metreveli, Naria; Tyagi, Suresh C

    2011-10-01

    Deficiencies in folate lead to increased serum concentrations of homocysteine (Hcy), which is known as hyperhomocysteinemia (HHcy), is associated with bone disorders. Although, Hcy accumulates collagen in bone and contribute to decrease in bone strength. The mechanism of Hcy induced bone loss and remodeling is unclear. Therefore, the present study was aimed to determine the role of folic acid (FA) in genetically HHcy-associated decrease in bone blood flow and remodeling. Wild type (WT) and cystathionine-β-synthase heterozygous (CBS+/-) mice were used in this study and supplemented with or without FA (300 mg/kg, Hcy reducing agent) in drinking water for 6 weeks. The tibial bone blood flow was measured by laser Doppler and ultrasonic flow probe method. The tibial bone density (BD) was assessed by dual energy X-ray absorptiometry. The bone homogenates were analyzed for oxidative stress, NOX-4 as oxidative marker and thioredoxin-1 (Trx-1) as anti-oxidant marker, bone remodeling (MMP-9) and bio-availability of nitric oxide (eNOS/iNOS/NO) by Western blot method. The results suggested that there was decrease in tibial blood flow in CBS+/- mice. The BD was also reduced in CBS+/- mice. There was an increase in NOX-4, iNOS, MMP-9 protein as well as MMP-9 activity in CBS+/- mice and decrease in Trx-1, eNOS protein levels, in part by decreasing NO bio-availability in CBS+/- mice. Interestingly, these effects were ameliorated by FA and suggested that FA supplementation may have therapeutic potential against genetically HHcy induced bone loss.

  1. Poly-lactic-glycolic-acid surface nanotopographies selectively decrease breast adenocarcinoma cell functions

    NASA Astrophysics Data System (ADS)

    Zhang, Lijuan; Webster, Thomas J.

    2012-04-01

    The ability of poly(lactic-co-glycolic acid) (PLGA, 50:50 PLG/PGA, wt%) nanotopographies to decrease lung epithelial carcinoma cell functions (including adhesion, proliferation, apoptosis and vascular endothelial growth factor (VEGF) secretion) has been previously reported. Specifically, results demonstrated decreased lung epithelial carcinoma cell VEGF synthesis on 23 nm surface-featured PLGA compared to traditional nanosmooth PLGA. However, clearly, different cell lines could have different behaviors on similar biomaterials. Thus, to investigate the universality of nanopatterned PLGA substrates to inhibit numerous cancer cell functions, here, breast epithelial adenocarcinoma cell (MCF-7) adhesion, proliferation, apoptosis and VEGF secretion were determined on different PLGA nanometer surface topographies. To isolate surface nanotopographical effects from all other surface properties, PLGA surfaces with various nanotopographies but similar chemistry and hydrophobicity were fabricated here. Atomic force microscopy (AFM) verified the varied nanotopographies on the PLGA surfaces prepared in this study. Importantly, results demonstrated for the first time significantly decreased breast adenocarcinoma cell functions (including decreased proliferation rate, increased apoptosis and decreased VEGF synthesis) on 23 nm featured PLGA surfaces compared to all other PLGA surface topographies fabricated (specifically, nanosmooth, 300 and 400 nm surface-featured PLGA surfaces). In contrast, healthy breast epithelial cells proliferated more (24%) on the 23 nm featured PLGA surfaces compared to all other PLGA samples. In summary, these results provided further insights into understanding the role PLGA surface nanotopographies can have on cancer cell functions and, more importantly, open the possibility of using polymer nanotopographies for a wide range of anticancer regenerative medicine applications (without resorting to the use of chemotherapeutics).

  2. Estriol-induced fibrinolysis due to the activation of plasminogen to plasmin by nitric oxide synthesis in platelets.

    PubMed

    Jana, Pradipta; Maiti, Smarajit; Kahn, Nighat N; Sinha, Asru K

    2015-04-01

    Estriol, an oestrogen, at 0.6 nmol/l was reported to inhibit ADP-induced platelet aggregation through nitric oxide synthesis. As nitric oxide has been reported to cause fibrinolysis due to the activation of plasminogen to plasmin, the role of estriol as a fibrinolytic agent was investigated. Also, the mechanism of estriol-induced nitric oxide synthesis in anucleated platelets was investigated. The estriol-induced lysis of platelet-rich plasma (PRP) clot was determined by photography of the clot lysis and by the assay of fibrin degradation products in the lysate and was obtained by SDS-PAGE. Nitric oxide was determined by methemoglobin method. The platelet membrane protein was isolated from the platelets by using Triton X-100 (0.05% v/v). The binding of estriol to the protein was determined by Scatchard plot by using an ELISA for estriol. Estriol at 0.6 nmol/l was found to lyse the clotted PRP due to fibrinolysis that produced fibrin degradation products in the lysate. The amino acid analysis of the platelet membrane protein, which resembles with nitric oxide synthase (NOS) activity, was activated nearly 10-fold over the control in the presence of estriol and was identified to be a human serum albumin precursor (Mr. 69 kDa) that binds to estriol with Kd1 of 6.0 × 10 mol/l and 39 ± 2 molecules of estriol bound the NOS molecule. The estriol-induced nitric oxide is capable of inducing fibrinolysis of the clotted PRP. The binding of estriol to platelet membrane NOS activated the enzyme in the absence of DNA in the platelet.

  3. Thrombin activatable fibrinolysis inhibitor (TAFI) levels in hypertensive patients and a comparison of the effects of amlodipine and ramipril on TAFI levels.

    PubMed

    Ozkan, Gulsum; Ulusoy, Sukru; Sönmez, Mehmet; Karahan, S Caner; Menteşe, Ahmet; Kaynar, Kubra; Bektaş, Ozlen

    2013-01-01

    Hypertension is associated with fibrinolysis abnormality. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a novel molecule-linking coagulation and fibrinolysis. The aim of this study was to investigate the levels of TAFI in primary hypertensive patients and to compare the effects of amlodipine and ramipril on TAFI levels. The study was performed with 58 hypertensive subjects and 27 healthy volunteers. Biochemical and hematological parameters and TAFI levels were measured at baseline and after 1-month follow-up. TAFI concentrations increased in hypertensive patients compared with the controls (P = .030). Additionally, TAFI levels decreased with blood pressure control at 1-month follow-up (P = .026). There was no significant difference between TAFI levels in the amlodipine and ramipril groups at baseline. However, after 1-month follow-up, TAFI levels were decreased in the amlodipine group (P = .037) but not in the ramipril group. Our study is the first in the literature to determine increased TAFI levels in primary hypertension patients. In addition, we determined a decrease in TAFI levels in the amlodipine group after 1 month, but none in the ramipril group.

  4. Abscisic acid metabolizing rhizobacteria decrease ABA concentrations in planta and alter plant growth.

    PubMed

    Belimov, Andrey A; Dodd, Ian C; Safronova, Vera I; Dumova, Valentina A; Shaposhnikov, Alexander I; Ladatko, Alexander G; Davies, William J

    2014-01-01

    Although endogenous phytohormones such as abscisic acid (ABA) regulate root growth, and many rhizobacteria can modulate root phytohormone status, hitherto there have been no reports of rhizobacteria mediating root ABA concentrations and growth by metabolising ABA. Using a selective ABA-supplemented medium, two bacterial strains were isolated from the rhizosphere of rice (Oryza sativa) seedlings grown in sod-podzolic soil and assigned to Rhodococcus sp. P1Y and Novosphingobium sp. P6W using partial 16S rRNA gene sequencing and phenotypic patterns by the GEN III MicroPlate test. Although strain P6W had more rapid growth in ABA-supplemented media than strain P1Y, both could utilize ABA as a sole carbon source in batch culture. When rice seeds were germinated on filter paper in association with bacteria, root ABA concentration was not affected, but shoot ABA concentration of inoculated plants decreased by 14% (strain P6W) and 22% (strain P1Y). When tomato (Solanum lycopersicum) genotypes differing in ABA biosynthesis (ABA deficient mutants flacca - flc, and notabilis - not and the wild-type cv. Ailsa Craig, WT) were grown in gnotobiotic cultures on nutrient solution agar, rhizobacterial inoculation decreased root and/or leaf ABA concentrations, depending on plant and bacteria genotypes. Strain P6W inhibited primary root elongation of all genotypes, but increased leaf biomass of WT plants. In WT plants treated with silver ions that inhibit ethylene perception, both ABA-metabolising strains significantly decreased root ABA concentration, and strain P6W decreased leaf ABA concentration. Since these changes in ABA status also occurred in plants that were not treated with silver, it suggests that ethylene was probably not involved in regulating bacteria-mediated changes in ABA concentration. Correlations between plant growth and ABA concentrations in planta suggest that ABA-metabolising rhizobacteria may stimulate growth via an ABA-dependent mechanism.

  5. Retinoic acid decreases ATF-2 phosphorylation and sensitizes melanoma cells to taxol-mediated growth inhibition.

    PubMed

    Huang, Ying; Minigh, Jennifer; Miles, Sarah; Niles, Richard M

    2008-02-12

    Cutaneous melanoma is often resistant to chemo- and radiotherapy. This resistance has recently been demonstrated to be due, at least in part, to high activating transcription factor 2 (ATF-2) activity in these tumors. In concordance with these reports, we found that B16 mouse melanoma cells had higher levels of ATF-2 than immortalized, but non-malignant mouse melanocytes. In addition, the melanoma cells had a much higher amount of phosphorylated (active) ATF-2 than the immortalized melanocytes. In the course of determining how retinoic acid (RA) stimulates activating protein-1 (AP-1) activity in B16 melanoma, we discovered that this retinoid decreased the phosphorylation of ATF-2. It appears that this effect is mediated through p38 MAPK, because RA decreased p38 phosphorylation, and a selective inhibitor of p38 MAPK (SB203580) also inhibited the phosphorylation of ATF-2. Since ATF-2 activity appears to be involved in resistance of melanoma to chemotherapy, we tested the hypothesis that treatment of the melanoma cells with RA would sensitize them to the growth-inhibitory effect of taxol. We found that pretreatment of B16 cells with RA decreased the IC50 from 50 nM to 1 nM taxol. On the basis of these findings and our previous work on AP-1, we propose a model in which treatment of B16 cells with RA decreases the phosphorylation of ATF-2, which results in less dimer formation with Jun. The "freed-up" Jun can then form a heterodimer with Fos, resulting in the increased AP-1 activity observed in RA-treated B16 cells. Shifting the balance from predominantly ATF-2:Jun dimers to a higher amount of Jun:Fos dimers could lead a change in target gene expression that reduces resistance to chemotherapeutic drugs and contributes to the pathway by which RA arrests proliferation and induces differentiation.

  6. Imaging analyses of coagulation-dependent initiation of fibrinolysis on activated platelets and its modification by thrombin-activatable fibrinolysis inhibitor.

    PubMed

    Brzoska, Tomasz; Suzuki, Yuko; Sano, Hideto; Suzuki, Seiichirou; Tomczyk, Martyna; Tanaka, Hiroki; Urano, Tetsumei

    2017-04-03

    Using intravital confocal microscopy, we observed previously that the process of platelet phosphatidylserine (PS) exposure, fibrin formation and lysine binding site-dependent plasminogen (plg) accumulation took place only in the centre of thrombi, not at their periphery. These findings prompted us to analyse the spatiotemporal regulatory mechanisms underlying coagulation and fibrinolysis. We analysed the fibrin network formation and the subsequent lysis in an in vitro experiment using diluted platelet-rich plasma supplemented with fluorescently labelled coagulation and fibrinolytic factors, using confocal laser scanning microscopy. The structure of the fibrin network formed by supplemented tissue factor was uneven and denser at the sites of coagulation initiation regions (CIRs) on PS-exposed platelets. When tissue-type plasminogen activator (tPA; 7.5 nM) was supplemented, labelled plg (50 nM) as well as tPA accumulated at CIRs, from where fibrinolysis started and gradually expanded to the peripheries. The lysis time at CIRs and their peripheries (50 µm from the CIR) were 27.9 ± 6.6 and 44.4 ± 9.7 minutes (mean ± SD, n=50 from five independent experiments) after the addition of tissue factor, respectively. Recombinant human soluble thrombomodulin (TMα; 2.0 nM) attenuated the CIR-dependent plg accumulation and strongly delayed fibrinolysis at CIRs. A carboxypeptidase inhibitor dose-dependently enhanced the CIR-dependent fibrinolysis initiation, and at 20 µM it completely abrogated the TMα-induced delay of fibrinolysis. Our findings are the first to directly present crosstalk between coagulation and fibrinolysis, which takes place on activated platelets' surface and is further controlled by thrombin-activatable fibrinolysis inhibitor (TAFI).

  7. Eicosapentaenoic acid decreases TNF-α and protects dystrophic muscles of mdx mice from degeneration.

    PubMed

    Machado, Rafael Ventura; Mauricio, Adriana Fogagnolo; Taniguti, Ana Paula Tiemi; Ferretti, Renato; Neto, Humberto Santo; Marques, Maria Julia

    2011-03-01

    In dystrophin-deficient fibers of mdx mice and in Duchenne muscular dystrophy, inflammation and increased production of tumor necrosis factor alpha (TNF-α) contribute to myonecrosis. We examined the effects of eicosapentaenoic acid (EPA) on dystrophic muscle degeneration. Mdx mice (14 days old) received EPA for 16 days. The sternomastoid, diaphragm and biceps brachii muscles were removed. Control mdx mice received vehicle. EPA decreased creatine kinase and myonecrosis and reduced the levels of TNF-α. These results suggest that EPA plays a protective role in dystrophic muscle degeneration, possibly by reducing TNF-α, and support further investigations of EPA as a potential therapy for dystrophinopathies. Copyright © 2010 Elsevier B.V. All rights reserved.

  8. Inhibition of neutral sphingomyelinase decreases arachidonic acid mediated inflammation in liver ischemia-reperfusion injury

    PubMed Central

    Aslan, Mutay; Özcan, Filiz; Tuzcu, Hazal; Kıraç, Ebru; Elpek, Gulsum O

    2014-01-01

    This study aimed to determine the role of selective neutral sphingomyelinase (N-SMase) inhibition on arachidonic acid (AA) mediated inflammation following liver ischemia-reperfusion (IR) injury. Selective N-SMase inhibitor was administered via intraperitoneal injections. Liver IR injury was created by clamping blood vessels supplying the median and left lateral hepatic lobes for 60 min, followed by 60 min reperfusion. Levels of AA in liver tissue were determined by multiple reaction monitoring (MRM) using ultra fast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Phospholipase A2 (PLA2), cyclooxygenase (COX) and prostaglandin E2 (PGE2) were measured in liver tissue. Arachidonic acid levels, activity of PLA2, COX and PGE2 levels were significantly increased in postischemic liver tissue compared to nonischemic controls. N-SMase inhibition significantly decreased COX activity and PGE2 levels in postischemic liver. Future studies evaluating agents blocking N-SMase activity can facilitate the development of treatment strategies to alleviate inflammation in liver I/R injury. PMID:25550821

  9. A decrease in phytic acid content substantially affects the distribution of mineral elements within rice seeds.

    PubMed

    Sakai, Hiroaki; Iwai, Toru; Matsubara, Chie; Usui, Yuto; Okamura, Masaki; Yatou, Osamu; Terada, Yasuko; Aoki, Naohiro; Nishida, Sho; Yoshida, Kaoru T

    2015-09-01

    Phytic acid (myo-inositol hexakisphosphate; InsP6) is the storage compound of phosphorus and many mineral elements in seeds. To determine the role of InsP6 in the accumulation and distribution of mineral elements in seeds, we performed fine mappings of mineral elements through synchrotron-based X-ray microfluorescence analysis using developing seeds from two independent low phytic acid (lpa) mutants of rice (Oryza sativa L.). The reduced InsP6 in lpa seeds did not affect the translocation of mineral elements from vegetative organs into seeds, because the total amounts of phosphorus and the other mineral elements in lpa seeds were identical to those in the wild type (WT). However, the reduced InsP6 caused large changes in mineral localization within lpa seeds. Phosphorus and potassium in the aleurone layer of lpa greatly decreased and diffused into the endosperm. Zinc and copper, which were broadly distributed from the aleurone layer to the inner endosperm in the WT, were localized in the narrower space around the aleurone layer in lpa mutants. We also confirmed that similar distribution changes occurred in transgenic rice with the lpa phenotype. Using these results, we discussed the role of InsP6 in the dynamic accumulation and distribution patterns of mineral elements during seed development.

  10. Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders.

    PubMed

    Burrage, Lindsay C; Jain, Mahim; Gandolfo, Laura; Lee, Brendan H; Nagamani, Sandesh C S

    2014-01-01

    Sodium phenylbutyrate (NaPBA) is a commonly used medication for the treatment of patients with urea cycle disorders (UCDs). Previous reports involving small numbers of patients with UCDs have shown that NaPBA treatment can result in lower plasma levels of the branched-chain amino acids (BCAA) but this has not been studied systematically. From a large cohort of patients (n=553) with UCDs enrolled in the Longitudinal Study of Urea Cycle Disorders, a collaborative multicenter study of the Urea Cycle Disorders Consortium, we evaluated whether treatment with NaPBA leads to a decrease in plasma BCAA levels. Our analysis shows that NaPBA use independently affects the plasma BCAA levels even after accounting for multiple confounding covariates. Moreover, NaPBA use increases the risk for BCAA deficiency. This effect of NaPBA seems specific to plasma BCAA levels, as levels of other essential amino acids are not altered by its use. Our study, in an unselected population of UCD subjects, is the largest to analyze the effects of NaPBA on BCAA metabolism and potentially has significant clinical implications. Our results indicate that plasma BCAA levels should to be monitored in patients treated with NaPBA since patients taking the medication are at increased risk for BCAA deficiency. On a broader scale, these findings could open avenues to explore NaPBA as a therapy in maple syrup urine disease and other common complex disorders with dysregulation of BCAA metabolism.

  11. Pyrrole-hyaluronic acid conjugates for decreasing cell binding to metals and conducting polymers

    PubMed Central

    Lee, Jae Young; Schmidt, Christine E.

    2010-01-01

    Surface modification of electrically conductive biomaterials has been studied to improve biocompatibility for a number of applications, such as implantable sensors and microelectrode arrays. In this study, we electrochemically coated electrodes with biocompatible and non-cell adhesive hyaluronic acid (HA) to reduce cellular adhesion for potential use in neural prostheses. To this end, pyrrole-conjugated hyaluronic acid (PyHA) was synthesized and employed for electrochemical coating of platinum, indium-tin-oxide, and polystyrene sulfonate-doped polypyrrole electrodes. This PyHA conjugate consists of (1) a pyrrole moiety that allows the compound to be electrochemically deposited onto a conductive substrate and (2) non-adhesive HA to minimize cell adhesion and to potentially decrease inflammatory tissue responses. Our characterization results showed the presence of a hydrophilic p(PyHA) layer on the modified electrode, and impedance measurements revealed impedance that was statistically the same as the unmodified electrode. We found that the p(PyHA)-coated electrodes minimized adhesion and migration of fibroblasts and astrocytes for a minimum of up to 3 months. Also, the coating was stable in physiological solution for 3 months and also stable against enzymatic degradation by hyaluronidase. These studies suggest that this p(PyHA)-coating has the potential to be used to mask conducting electrodes from adverse glial responses that occur upon implantation. In addition, electrochemical coating with PyHA can be potentially extended for the surface modification of other metallic and conducting substances such as stents and biosensors. PMID:20558330

  12. Arachidonic acid incorporation and turnover is decreased in sympathetically denervated rat heart.

    PubMed

    Patrick, Casey B; McHowat, Jane; Rosenberger, Thad A; Rapoport, Stanley I; Murphy, Eric J

    2005-06-01

    Heart sympathetic denervation can accompany Parkinson's disease, but the effect of this denervation on cardiac lipid-mediated signaling is unknown. To address this issue, rats were sympathetically denervated with 6-hydroxydopamine (6-OHDA, 50 mg/kg ip) and infused with 170 muCi/kg of either [1-(14)C]palmitic acid ([1-(14)C]16:0) or [1-(14)C]arachidonic acid ([1-(14)C]20:4 n-6), and kinetic parameters were assessed using a steady-state radiotracer model. Heart norepinephrine and epinephrine levels were decreased 82 and 85%, respectively, in denervated rats, and this correlated with a 34% reduction in weight gain in treated rats. Fatty acid tracer uptake was not significantly different between groups for either tracer, although the dilution coefficient lambda was increased in [1-(14)C]20:4 n-6-infused rats, which indicates that less 20:4 n-6 was recycled in denervated rats. In [1-(14)C]16:0-infused rats, incorporation rate and turnover values of 16:0 in stable lipid compartments were unchanged, which is indicative of preservation of beta-oxidation. In [1-(14)C]20:4 n-6-infused rats, there were dramatic reductions in incorporation rate (60-84%) and turnover value (56-85%) in denervated rats that were dependent upon the lipid compartment. In addition, phospholipase A(2) activity was reduced 40% in treated rats, which is consistent with the reduction observed in 20:4 n-6 turnover. These results demonstrate marked reductions in 20:4 n-6 incorporation rate and turnover in sympathetic denervated rats and thereby suggest an effect on lipid-mediated signal transduction mediated by a reduction in phospholipase A(2) activity.

  13. Chlorogenic acid moderately decreases the quality of whey proteins in rats.

    PubMed

    Petzke, Klaus J; Schuppe, Stefanie; Rohn, Sascha; Rawel, Harshadrai M; Kroll, Jürgen

    2005-05-04

    During processing and storage, phenolic compounds (PCs) may react with food protein bound amino acids (AAs). Such reactions have been reported to change physicochemical and to decrease in vitro digestion properties of proteins. A rat growth and nitrogen (N) balance study was conducted to prove whether derivatization with chlorogenic acid (CA) affects the nutritional quality of beta-lactoglobulin (beta-LG). Test diets (10% protein level) contained nonderivatized beta-LG (LG, treated under omission of CA), low derivatization level beta-LG (LGL), high derivatization level beta-LG (LGH), or casein supplemented with l-methionine (0.3% of diet; C+met) as an internal standard. An additional group received untreated beta-LG supplemented with pure CA (1.03% of diet; LG+CA). The AA composition of test proteins, plasma AAs, and liver glutathione (GSH) concentrations were determined. Protein digestibility-corrected amino acid score (PDCAAS) was calculated using human or rat AA requirement patterns and rat fecal digestibility values. N excretion was significantly higher in feces and lower in urine of rats fed with LGH as compared to LG and LGL. Consequently, true N digestibility (TND) was significantly lower with LGH as compared to LG and LGL. The lower content of methionine, cysteine, lysine, and tryptophan in LGH corresponded to a reduced TND. Net protein utilization (NPU) was not different between treated beta-LG fed diet groups but was lower than in LG+CA and C+met fed groups. Only at a relatively high level of derivatization with CA, the otherwise good nutritional quality of beta-LG is affected so that TND is reduced, while NPU still remains unaffected. Derivatization of beta-LG with CA does not seem to lead to an additional deficiency in a specific indispensable AA in growing rats fed with 10% protein.

  14. Suppression of long chain acyl-CoA synthetase 3 decreases hepatic de novo fatty acid synthesis through decreased transcriptional activity.

    PubMed

    Bu, So Young; Mashek, Mara T; Mashek, Douglas G

    2009-10-30

    Long chain acyl-CoA synthetases (ACSL) and fatty acid transport proteins (FATP) activate fatty acids to acyl-CoAs in the initial step of fatty acid metabolism. Numerous isoforms of ACSL and FATP exist with different tissue distribution patterns, intracellular locations, and substrate preferences, suggesting that each isoform has distinct functions in channeling fatty acids into different metabolic pathways. Because fatty acids, acyl-CoAs, and downstream lipid metabolites regulate various transcription factors that control hepatic energy metabolism, we hypothesized that ACSL or FATP isoforms differentially regulate hepatic gene expression. Using small interference RNA (siRNA), we knocked down each liver-specific ACSL and FATP isoform in rat primary hepatocyte cultures and subsequently analyzed reporter gene activity of numerous transcription factors and performed quantitative mRNA analysis of their target genes. Compared with control cells, which were transfected with control siRNA, knockdown of acyl-CoA synthetase 3 (ACSL3) significantly decreased reporter gene activity of several lipogenic transcription factors such as peroxisome proliferator activation receptor-gamma, carbohydrate-responsive element-binding protein, sterol regulatory element-binding protein-1c, and liver X receptor-alpha and the expression of their target genes. These findings were further supported by metabolic labeling studies that showed [1-(14)C]acetate incorporation into lipid extracts was decreased in cells treated with ACSL3 siRNAs and that ACSL3 expression is up-regulated in ob/ob mice and mice fed a high sucrose diet. ACSL3 knockdown decreased total acyl-CoA synthetase activity without substantially altering the expression of other ACSL isoforms. In summary, these results identify a novel role for ACSL3 in mediating transcriptional control of hepatic lipogenesis.

  15. Ascorbic acid decreases morphine self-administration and withdrawal symptoms in rats.

    PubMed

    Alaei, H; Esmaeili, M; Nasimi, A; Pourshanazari, A

    2005-09-01

    Recent studies have indicated that the glutamatergic system is involved in the motivational aspects during the initiation of drug self-administration. Ascorbic acid (AA), an antioxidant vitamin, is released from glutamatergic neurons, and it modulates the synaptic action of dopamine and glutamate. In this study the AA effects on the self-administration of morphine and on the morphine withdrawal syndrome have been investigated. Wistar rats were allowed to self-administer morphine (1 mg/infusion) during 10 consecutive days for 2 h/session. The number of lever pressings was recorded. An intrapritoneal AA injection (500 mg/kg, i.p.), 30 min before morphine self-administration produced a significant decrease in the initiation of morphine self administration during all sessions. After the last test session morphine withdrawal symptom signs (MWS) were recorded after naloxone precipitation. Most of MWS (but not all) were decreased by AA application. In conclusion, AA may change the motivational processes underlying the morphine self-administration.

  16. Massive Pulmonary Embolism: Treatment with Thrombus Fragmentation and Local Fibrinolysis with Recombinant Human-Tissue Plasminogen Activator

    SciTech Connect

    Stock, Klaus Wilhelm; Jacob, Augustinus Ludwig; Schnabel, Karl Jakob; Bongartz, Georg; Steinbrich, Wolfgang

    1997-09-15

    Purpose: To report the results of thrombus fragmentation in combination with local fibrinolysis using recombinant human-tissue plasminogen activator (rtPA) in patients with massive pulmonary embolism. Methods: Five patients with massive pulmonary embolism were treated with thrombus fragmentation followed by intrapulmonary injection of rtPA. Clot fragmentation was performed with a guidewire, angiographic catheter, and balloon catheter. Three patients had undergone recent surgery; one of them received a reduced dosage of rtPA. Results: All patients survived and showed clinical improvement with a resultant significant (p < 0.05) decrease in the pulmonary blood pressure (mean systolic pulmonary blood pressure before treatment, 49 mmHg; 4 hr after treatment, 28 mmHg). Angiographic follow-up in three patients revealed a decrease in thrombus material and an increase in pulmonary perfusion. Two patients developed retroperitoneal hematomas requiring transfusion. Conclusion: Clot fragmentation and local fibrinolysis with rtPA was an effective therapy for massive pulmonary embolism. Bleeding at the puncture site was a frequent complication.

  17. Increased physical activity decreases hepatic free fatty acid uptake: a study in human monozygotic twins

    PubMed Central

    Hannukainen, Jarna C; Nuutila, Pirjo; Ronald, Borra; Kaprio, Jaakko; Kujala, Urho M; Janatuinen, Tuula; Heinonen, Olli J; Kapanen, Jukka; Viljanen, Tapio; Haaparanta, Merja; Rönnemaa, Tapani; Parkkola, Riitta; Knuuti, Juhani; Kalliokoski, Kari K

    2007-01-01

    Exercise is considered to be beneficial for free fatty acid (FFA) metabolism, although reports of the effects of increased physical activity on FFA uptake and oxidation in different tissues in vivo in humans have been inconsistent. To investigate the heredity-independent effects of physical activity and fitness on FFA uptake in skeletal muscle, the myocardium, and liver we used positron emission tomography (PET) in nine healthy young male monozygotic twin pairs discordant for physical activity and fitness. The cotwins with higher physical activity constituting the more active group had a similar body mass index but less body fat and 18 ± 10% higher V˙O2,max (P < 0.001) compared to the less active brothers with lower physical activity. Low-intensity knee-extension exercise increased skeletal muscle FFA and oxygen uptake six to 10 times compared to resting values but no differences were observed between the groups at rest or during exercise. At rest the more active group had lower hepatic FFA uptake compared to the less active group (5.5 ± 4.3 versus 9.0 ± 6.1 μmol (100 ml)−1 min−1, P = 0.04). Hepatic FFA uptake associated significantly with body fat percentage (P = 0.05). Myocardial FFA uptake was similar between the groups. In conclusion, in the absence of the confounding effects of genetic factors, moderately increased physical activity and aerobic fitness decrease body adiposity even in normal-weighted healthy young adult men. Further, increased physical activity together with decreased intra-abdominal adiposity seems to decrease hepatic FFA uptake but has no effects on skeletal muscle or myocardial FFA uptake. PMID:17053033

  18. Developmental PCB Exposure Increases Audiogenic Seizures and Decreases Glutamic Acid Decarboxylase in the Inferior Colliculus.

    PubMed

    Bandara, Suren B; Eubig, Paul A; Sadowski, Renee N; Schantz, Susan L

    2016-02-01

    Previously, we observed that developmental polychlorinated biphenyl (PCB) exposure resulted in an increase in audiogenic seizures (AGSs) in rats. However, the rats were exposed to loud noise in adulthood, and were not tested for AGS until after 1 year of age, either of which could have interacted with early PCB exposure to increase AGS susceptibility. This study assessed susceptibility to AGS in young adult rats following developmental PCB exposure alone (without loud noise exposure) and investigated whether there was a decrease in GABA inhibitory neurotransmission in the inferior colliculus (IC) that could potentially explain this effect. Female Long-Evans rats were dosed orally with 0 or 6 mg/kg/day of an environmentally relevant PCB mixture from 28 days prior to breeding until the pups were weaned at postnatal day 21. One male-female pair from each litter was retained for the AGS study whilst another was retained for Western blot analysis of glutamic acid decarboxylase (GAD) and GABAAα1 receptor in the IC, the site in the auditory midbrain where AGS are initiated. There was a significant increase in the number and severity of AGSs in the PCB groups, with females somewhat more affected than males. GAD65 was decreased but there was no change in GAD67 or GABAAα1 in the IC indicating decreased inhibitory regulation in the PCB group. These results confirm that developmental PCB exposure alone is sufficient to increase susceptibility to AGS, and provide the first evidence for a possible mechanism of action at the level of the IC. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. Developmental PCB Exposure Increases Audiogenic Seizures and Decreases Glutamic Acid Decarboxylase in the Inferior Colliculus

    PubMed Central

    Bandara, Suren B.; Eubig, Paul A.; Sadowski, Renee N.; Schantz, Susan L.

    2016-01-01

    Previously, we observed that developmental polychlorinated biphenyl (PCB) exposure resulted in an increase in audiogenic seizures (AGSs) in rats. However, the rats were exposed to loud noise in adulthood, and were not tested for AGS until after 1 year of age, either of which could have interacted with early PCB exposure to increase AGS susceptibility. This study assessed susceptibility to AGS in young adult rats following developmental PCB exposure alone (without loud noise exposure) and investigated whether there was a decrease in GABA inhibitory neurotransmission in the inferior colliculus (IC) that could potentially explain this effect. Female Long-Evans rats were dosed orally with 0 or 6 mg/kg/day of an environmentally relevant PCB mixture from 28 days prior to breeding until the pups were weaned at postnatal day 21. One male-female pair from each litter was retained for the AGS study whilst another was retained for Western blot analysis of glutamic acid decarboxylase (GAD) and GABAAα1 receptor in the IC, the site in the auditory midbrain where AGS are initiated. There was a significant increase in the number and severity of AGSs in the PCB groups, with females somewhat more affected than males. GAD65 was decreased but there was no change in GAD67 or GABAAα1 in the IC indicating decreased inhibitory regulation in the PCB group. These results confirm that developmental PCB exposure alone is sufficient to increase susceptibility to AGS, and provide the first evidence for a possible mechanism of action at the level of the IC. PMID:26543103

  20. The role of coagulation/fibrinolysis during Streptococcus pyogenes infection

    PubMed Central

    Loof, Torsten G.; Deicke, Christin; Medina, Eva

    2014-01-01

    The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis and is a host defense mechanism that protects the integrity of the vascular system after tissue injury. During bacterial infections, the coagulation system cooperates with the inflammatory system to eliminate the invading pathogens. However, pathogenic bacteria have frequently evolved mechanisms to exploit the hemostatic system components for their own benefit. Streptococcus pyogenes, also known as Group A Streptococcus, provides a remarkable example of the extraordinary capacity of pathogens to exploit the host hemostatic system to support microbial survival and dissemination. The coagulation cascade comprises the contact system (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway), both leading to fibrin formation. During the early phase of S. pyogenes infection, the activation of the contact system eventually leads to bacterial entrapment within a fibrin clot, where S. pyogenes is immobilized and killed. However, entrapped S. pyogenes can circumvent the antimicrobial effect of the clot by sequestering host plasminogen on the bacterial cell surface that, after conversion into its active proteolytic form, plasmin, degrades the fibrin network and facilitates the liberation of S. pyogenes from the clot. Furthermore, the surface-localized fibrinolytic activity also cleaves a variety of extracellular matrix proteins, thereby enabling S. pyogenes to migrate across barriers and disseminate within the host. This review summarizes the knowledge gained during the last two decades on the role of coagulation/fibrinolysis in host defense against S. pyogenes as well as the strategies developed by this pathogen to evade and exploit these host mechanisms for its own benefit. PMID:25309880

  1. Synergy between low-dose ranitidine and antacid in decreasing gastric and oesophageal acidity and relieving meal-induced heartburn.

    PubMed

    Robinson, M; Rodriguez-Stanley, S; Ciociola, A A; Filinto, J; Zubaidi, S; Miner, P B; Gardner, J D

    2001-09-01

    The pathophysiology of recurrent postprandial heartburn and the basis for the effectiveness of antacids or low doses of histamine H2-receptor antagonists have not been well studied. The selected subjects (n=26) had heartburn more than four times a week for at least 2 months, which was responsive to antacids. Gastric pH and oesophageal pH were measured for 1 h before, during, and 4.5 h after ingestion of a meal over 0.5 h. Heartburn severity was assessed at 15-min intervals beginning at the end of the meal. Each subject randomly received placebo, 75 mg ranitidine, 420 mg calcium carbonate, and ranitidine plus calcium carbonate. Values for pH were converted to acid concentration (mM) and integrated acidity was calculated from the cumulative, time-weighted means of the acid concentrations for every second of the postprandial recording period. There was a close temporal relationship between heartburn and oesophageal acidity. Most oesophageal acid exposure occurred over a 90-min period that began approximately 45 min after the end of the meal. During this period the gastric acid concentration was less than 5% of maximal. Ranitidine significantly decreased gastric but not oesophageal acidity, whilst antacid significantly decreased oesophageal but not gastric acidity. Ranitidine plus antacid significantly decreased both gastric and oesophageal acidity. Antacid alone and ranitidine plus antacid significantly decreased heartburn severity. Determining integrated gastric and oesophageal acidity provides novel information regarding the pathophysiology of meal-induced heartburn as well as the actions of low-dose ranitidine and antacid. For subjects with meal-induced heartburn, treatment with low-dose ranitidine plus antacid is particularly effective in decreasing gastric and oesophageal acidity as well as heartburn severity.

  2. Salicylic acid alleviates decreases in photosynthesis under heat stress and accelerates recovery in grapevine leaves

    PubMed Central

    2010-01-01

    Background Although the effect of salicylic acid (SA) on photosynthesis of plants including grapevines has been investigated, very little is yet known about the effects of SA on carbon assimilation and several components of PSII electron transport (donor side, reaction center and acceptor side). In this study, the impact of SA pretreatment on photosynthesis was evaluated in the leaves of young grapevines before heat stress (25°C), during heat stress (43°C for 5 h), and through the following recovery period (25°C). Photosynthetic measures included gas exchange parameters, PSII electron transport, energy dissipation, and Rubisco activation state. The levels of heat shock proteins (HSPs) in the chloroplast were also investigated. Results SA did not significantly (P < 0.05) influence the net photosynthesis rate (Pn) of leaves before heat stress. But, SA did alleviate declines in Pn and Rubisco activition state, and did not alter negative changes in PSII parameters (donor side, acceptor side and reaction center QA) under heat stress. Following heat treatment, the recovery of Pn in SA-treated leaves was accelerated compared with the control (H2O-treated) leaves, and, donor and acceptor parameters of PSII in SA-treated leaves recovered to normal levels more rapidly than in the controls. Rubisco, however, was not significantly (P < 0.05) influenced by SA. Before heat stress, SA did not affect level of HSP 21, but the HSP21 immune signal increased in both SA-treated and control leaves during heat stress. During the recovery period, HSP21 levels remained high through the end of the experiment in the SA-treated leaves, but decreased in controls. Conclusion SA pretreatment alleviated the heat stress induced decrease in Pn mainly through maintaining higher Rubisco activition state, and it accelerated the recovery of Pn mainly through effects on PSII function. These effects of SA may be related in part to enhanced levels of HSP21. PMID:20178597

  3. Maternal docosahexaenoic acid supplementation decreases lung inflammation in hyperoxia-exposed newborn mice.

    PubMed

    Rogers, Lynette K; Valentine, Christina J; Pennell, Michael; Velten, Markus; Britt, Rodney D; Dingess, Kelly; Zhao, Xuilan; Welty, Stephen E; Tipple, Trent E

    2011-02-01

    DHA is a long-chain fatty acid that has potent antiinflammatory properties. Whereas maternal DHA dietary supplementation has been shown to improve cognitive development in infants fed DHA-supplemented milk, the antiinflammatory effects of maternal DHA supplementation on the developing fetus and neonate have not been extensively explored. Pregnant C3H/HeN dams were fed purified control or DHA-supplemented diets (~0.25% of total fat) at embryonic d 16 and consumed these diets throughout the study. At birth, the nursing mouse pups were placed in room air (RA; 21% O(2)) or >95% O(2) (hyperoxia) for up to 7 d. These studies tested the hypothesis that maternal DHA supplementation would decrease inflammation and improve alveolarization in the lungs of newborn mouse pups exposed to hyperoxia. Survival, inflammatory responses, and lung growth were compared among control diet/RA, DHA/RA, control/O(2), and DHA/O(2) pups. There were fewer neutrophils and macrophages in lung tissues from pups nursed by DHA-supplemented dams than in those nursed by dams fed the control diet at 7 d of hyperoxia exposure (P < 0.015). Although differences due to hyperoxia exposure were observed, maternal diet did not affect keratinocyte-derived chemokine, macrophage inflammatory protein-2, IL-1β, or TNFα mRNA levels in pup tissues. Hyperoxia also induced NF-κB activity, but maternal diet did not affect NF-κB or PPARγ activities. In mice, DHA supplementation decreases leukocyte infiltration in the offspring exposed to hyperoxia, suggesting a potential role for DHA supplementation as a therapy to reduce inflammation in preterm infants.

  4. Photodynamic therapy mediated by 5-aminolevulinic acid suppresses gliomas growth by decreasing the microvessels.

    PubMed

    Yi, Wei; Xu, Hai-tao; Tian, Dao-feng; Wu, Li-quan; Zhang, Shen-qi; Wang, Long; Ji, Bao-wei; Zhu, Xiao-nan; Okechi, Humphrey; Liu, Gang; Chen, Qian-xue

    2015-04-01

    Although 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy (PDT) has been demonstrated to be a novel and effective therapeutic modality for some human malignancies, its effect and mechanism on glioma are still controversial. Previous studies have reported that 5-ALA-PDT induced necrosis of C6 rat glioma cells in vitro. The aim of this study was to further investigate the effect and mechanism of 5-ALA-PDT on C6 gliomas implanted in rats in vivo. Twenty-four rats bearing similar size of subcutaneously implanted C6 rat glioma were randomly divided into 3 groups: receiving 5-ALA-PDT (group A), laser irradiation (group B), and mock procedures but without any treatment (group C), respectively. The growth, histology, microvessel density (MVD), and apoptosis of the grafts in each group were determined after the treatments. As compared with groups B and C, the volume of tumor grafts was significantly reduced (P<0.05), MVD was significantly decreased (P<0.001), and the cellular necrosis was obviously increased in group A. There was no significant difference in apoptosis among the three groups. The in vivo studies confirmed that 5-ALA-PDT may be an effective treatment for gliomas by inhibiting the tumor growth. The mechanism underlying may involve increasing the cellular necrosis but not inducing the cellular apoptosis, which may result from the destruction of the tumor microvessels.

  5. Tranexamic acid decreases blood loss in shoulder arthroplasty: A meta-analysis.

    PubMed

    Yu, Bin-Feng; Yang, Guo-Jing; Li, Qi; Liu, Liang-le

    2017-08-01

    The objective of this meta-analysis was to evaluate the efficacy and safety of tranexamic acid (TXA) in shoulder arthroplasty (SA). Academic articles were identified from the Cochrane Library, Medline (1966-2017.2), PubMed (1966-2017.2), Embase (1980-2017.2), and ScienceDirect (1966-2017.2). Randomized controlled trials (RCTs) and non-RCTs studying TXA in SA were included. Two independent reviewers conducted independent data abstraction. The I statistic was used to assess heterogeneity. Fixed- or random-effects models were used for meta-analysis. Two RCTs and 2 non-RCTs met the inclusion criteria. This meta-analysis found significant differences in postoperative hemoglobin reduction (MD = -0.71 g/dL), drainage volume (MD = -133.21 mL), and total blood loss (MD = -226.82 mL) between TXA groups and controls. There were no significant differences in blood transfusion requirements, operation time, or length of hospital stay. The use of TXA in SA decreases postoperative hemoglobin reduction, drainage volume, and total blood loss and does not increase the risk of complications. Because of the limited high-quality evidence currently available, additional randomized controlled trials are required.

  6. TRPV1 temperature activation is specifically sensitive to strong decreases in amino acid hydrophobicity.

    PubMed

    Sosa-Pagán, Jason O; Iversen, Edwin S; Grandl, Jörg

    2017-04-03

    Several transient receptor potential (TRP) ion channels can be directly activated by hot or cold temperature with high sensitivity. However, the structures and molecular mechanism giving rise to their high temperature sensitivity are not fully understood. One hypothesized mechanism assumes that temperature activation is driven by the exposure of hydrophobic residues to solvent. This mechanism further predicts that residues are exposed to solvent in a coordinated fashion, but without necessarily being located in close proximity to each other. However, there is little experimental evidence supporting this mechanism in TRP channels. Here, we combined high-throughput mutagenesis, functional screening, and deep sequencing to identify mutations from a total of ~7,300 TRPV1 random mutant clones. We found that strong decreases in hydrophobicity of amino acids are better tolerated for activation by capsaicin than for activation by hot temperature, suggesting that strong hydrophobicity might be specifically required for temperature activation. Altogether, our work provides initial correlative support for a previously hypothesized temperature mechanism in TRP ion channels.

  7. Decrease of intracellular pH as possible mechanism of embryotoxicity of glycol ether alkoxyacetic acid metabolites.

    PubMed

    Louisse, Jochem; Bai, Yanqing; Verwei, Miriam; van de Sandt, Johannes J M; Blaauboer, Bas J; Rietjens, Ivonne M C M

    2010-06-01

    Embryotoxicity of glycol ethers is caused by their alkoxyacetic acid metabolites, but the mechanism underlying the embryotoxicity of these acid metabolites is so far not known. The present study investigates a possible mechanism underlying the embryotoxicity of glycol ether alkoxyacetic acid metabolites using the methoxyacetic acid (MAA) metabolite of ethylene glycol monomethyl ether as the model compound. The results obtained demonstrate an MAA-induced decrease of the intracellular pH (pH(i)) of embryonic BALB/c-3T3 cells as well as of embryonic stem (ES)-D3 cells, at concentrations that affect ES-D3 cell differentiation. These results suggest a mechanism for MAA-mediated embryotoxicity similar to the mechanism of embryotoxicity of the drugs valproic acid and acetazolamide (ACZ), known to decrease the pH(i)in vivo, and therefore used as positive controls. The embryotoxic alkoxyacetic acid metabolites ethoxyacetic acid, butoxyacetic acid and phenoxyacetic acid also caused an intracellular acidification of BALB/c-3T3 cells at concentrations that are known to inhibit ES-D3 cell differentiation. Two other embryotoxic compounds, all-trans-retinoic acid and 5-fluorouracil, did not decrease the pH(i) of embryonic cells at concentrations that affect ES-D3 cell differentiation, pointing at a different mechanism of embryotoxicity of these compounds. MAA and ACZ induced a concentration-dependent inhibition of ES-D3 cell differentiation, which was enhanced by amiloride, an inhibitor of the Na(+)/H(+)-antiporter, corroborating an important role of the pH(i) in the embryotoxic mechanism of both compounds. Together, the results presented indicate that a decrease of the pH(i) may be the mechanism of embryotoxicity of the alkoxyacetic acid metabolites of the glycol ethers.

  8. Decrease of intracellular pH as possible mechanism of embryotoxicity of glycol ether alkoxyacetic acid metabolites

    SciTech Connect

    Louisse, Jochem; Verwei, Miriam; Sandt, Johannes J.M. van de; Rietjens, Ivonne M.C.M.

    2010-06-01

    Embryotoxicity of glycol ethers is caused by their alkoxyacetic acid metabolites, but the mechanism underlying the embryotoxicity of these acid metabolites is so far not known. The present study investigates a possible mechanism underlying the embryotoxicity of glycol ether alkoxyacetic acid metabolites using the methoxyacetic acid (MAA) metabolite of ethylene glycol monomethyl ether as the model compound. The results obtained demonstrate an MAA-induced decrease of the intracellular pH (pH{sub i}) of embryonic BALB/c-3T3 cells as well as of embryonic stem (ES)-D3 cells, at concentrations that affect ES-D3 cell differentiation. These results suggest a mechanism for MAA-mediated embryotoxicity similar to the mechanism of embryotoxicity of the drugs valproic acid and acetazolamide (ACZ), known to decrease the pH{sub i}in vivo, and therefore used as positive controls. The embryotoxic alkoxyacetic acid metabolites ethoxyacetic acid, butoxyacetic acid and phenoxyacetic acid also caused an intracellular acidification of BALB/c-3T3 cells at concentrations that are known to inhibit ES-D3 cell differentiation. Two other embryotoxic compounds, all-trans-retinoic acid and 5-fluorouracil, did not decrease the pH{sub i} of embryonic cells at concentrations that affect ES-D3 cell differentiation, pointing at a different mechanism of embryotoxicity of these compounds. MAA and ACZ induced a concentration-dependent inhibition of ES-D3 cell differentiation, which was enhanced by amiloride, an inhibitor of the Na{sup +}/H{sup +}-antiporter, corroborating an important role of the pH{sub i} in the embryotoxic mechanism of both compounds. Together, the results presented indicate that a decrease of the pH{sub i} may be the mechanism of embryotoxicity of the alkoxyacetic acid metabolites of the glycol ethers.

  9. [Pharmacological studies of FUT-175, nafamstat mesilate. IV. Effects on coagulation, platelets and fibrinolysis].

    PubMed

    Koshiyama, Y; Ozeki, M; Motoyoshi, A; Fujita, M; Iwaki, M; Aoyama, T

    1984-11-01

    Inhibitory effects of FUT-175 (nafamstat mesilate) on coagulation, platelets and fibrinolysis were examined. FUT-175 prolonged activated partial thromboplastin time, thrombin time and prothrombin time in rabbit plasma. FUT-175 prolonged these coagulation times in human plasma at lower concentration than in rabbit plasma. FUT-175 inhibited platelet aggregation induced by a variety of aggregation agents in rabbit platelet-rich plasma (PRP). In human PRP, FUT-175 inhibited platelet aggregation induced by a variety of aggregation agents at lower concentration than in rabbit PRP. Lipopolysaccharide induced a dose-dependent platelet aggregation in dog PRP. FUT-175 showed an inhibitory effect on this aggregation. FUT-175 inhibited clot retraction in rabbit plasma. The fibrinolysis activity was measured on fibrinolysis of rabbit plasma activated by urokinase. FUT-175 prolonged this fibrinolysis time. Inhibitory effects on coagulation and fibrinolysis were also found ex vivo. FUT-175 prolonged bleeding time in mice. These results indicate that FUT-175 has potent inhibitory effects on coagulation, platelets and fibrinolysis.

  10. Effects of weight loss from a high-calcium energy-reduced diet on biomarkers of inflammatory stress, fibrinolysis, and endothelial function in obese subjects.

    PubMed

    Torres, Márcia Regina Simas Gonçalves; Sanjuliani, Antonio Felipe

    2013-01-01

    Obesity is characterized by chronic subclinical inflammation, which is critical to endothelial dysfunction. Weight loss, induced by lifestyle interventions, is associated with a decline in biomarkers of inflammation and endothelial dysfunction. There is little evidence that high dietary calcium intake may reduce inflammation and improve endothelial function. The purpose of this study was to evaluate the effects of weight loss from a high-calcium energy-reduced diet on biomarkers of inflammation, fibrinolysis, and endothelial function in obese individuals. In this randomized clinical trial, we analyzed the data from 35 obese adults who lost at least 3% of initial body weight, during a period of 16 wk of energy restriction (-800 Kcal/d). Individuals were randomized into the following dietary regimens: (1) a high calcium diet (HCD; 1200-1300 mg/d) or (2) a low-calcium diet (LCD; <500 mg/d). After 16 wk of intervention subjects on HCD compared with those on LCD exhibited greater reduction in waist circumference and waist-to-hip ratio. Participants on HCD presented a significant reduction in all biomarkers of endothelial dysfunction evaluated in the study (intracellular adhesion molecule-1, vascular cell adhesion molecule 1, and E-Selectin), whereas subjects on LCD showed a significant decrease in intracellular adhesion molecule-1 and E-Selectin. Biomarkers of inflammation and fibrinolysis were reduced in both diets, although without reaching statistical significance. The reduction in all markers of inflammation, fibrinolysis, and endothelial dysfunction was similar in both diets. The findings of this study suggest that increased calcium intake during weight loss has no benefits with respect to biomarkers of inflammation, fibrinolysis, and endothelial function. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. The Response of Stream and Soil Chemistry to Decreases in Acid Deposition in the Catskill Mountains, New York, USA

    NASA Astrophysics Data System (ADS)

    McHale, M. R.; Burns, D. A.; Siemion, J.; Antidormi, M. R.

    2016-12-01

    The Catskill Mountains have been adversely impacted by decades of acid deposition, however, since the early 1990s, acid deposition levels have decreased sharply as a result of decreases in emissions of sulfur dioxide and nitrogen oxides. The purpose of this study is to provide updated trends in acid deposition and stream-water chemistry in the southeastern Catskill Mountains and to examine whether soil chemistry has shown signs of recovery during the past 2 decades. We measured significant reductions in acid deposition in the region during the 23 year period from 1992 to 2014. The reductions were reflected in significant improvement in stream-water quality in all 5 of the streams included in this study. The largest and most significant trends were for sulfate (SO42-) concentrations (mean trend of -2.5 μeq L-1 yr-1 for 5 sites); hydrogen ion (H+) also decreased significantly as did inorganic monomeric aluminum (Alim) which is toxic to some aquatic biota (mean trends of -0.3 μeq L-1 yr-1 for H+ and -0.1 μeq L-1 yr-1 for Alim for the 3 most acidic sites). Acid neutralizing capacity (ANC) increased a mean of 0.65 μeq L-1 yr-1 for all 5 sites, which was 4 fold less than the decrease in SO42- concentrations. These upward trends in ANC were limited in part by coincident decreases in base cations (-1.3 μeq L-1 yr-1 for calcium + magnesium). No significant trends were detected in stream-water nitrate (NO3-) concentrations despite significant decreasing trends in NO3- deposition. This incongruity is likely caused by the large biological demand and complex cycling processes of nitrogen. Despite the decreases in stream-water acidity, we measured no recovery in soil chemistry which we attributed to soils with low buffering capacity that have been further depleted by decades of acid deposition. Tightly coupled decreasing trends in stream-water silicon (Si) (-0.2 μeq L-1 yr-1) and base cations suggest a decrease in the soil mineral weathering rate. We hypothesize that a

  12. A first-in-human study of DS-1040, an inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor, in healthy subjects.

    PubMed

    Zhou, J; Kochan, J; Yin, O; Warren, V; Zamora, C; Atiee, G; Pav, J; Orihashi, Y; Vashi, V; Dishy, V

    2017-05-01

    Essentials DS-1040 inhibits the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa). Infusion of DS-1040 was safe and well tolerated in healthy young and elderly subjects. DS-1040 substantially decreased TAFIa activity but had no impact on bleeding time. DS-1040 may provide an option of safer thrombolytic therapy. Background Current treatments for acute ischemic stroke and venous thromboembolism, such as recombinant tissue-type plasminogen activator and thrombectomy, are limited by a narrow time window and the risk of bleeding. DS-1040 is a novel low molecular weight compound that inhibits the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa), and was developed as a fibrinolysis enhancer for the treatment of thromboembolic diseases. Objectives This first-in-human, randomized, placebo-controlled, three-part, phase 1 study was conducted to evaluate the safety, pharmacokinetics and pharmacodynamics of DS-1040 in healthy subjects. Subjects/Methods Young (18-45 years) or elderly (65-75 years) subjects (N = 103) were randomized to receive single ascending doses of DS-1040 ranging from 0.1 mg to 40 mg, or placebo, administered either as a 0.5-h intravenous infusion or as a 24-h continuous infusion. Results All doses of DS-1040 were tolerated, and no serious adverse events (AEs) or discontinuations resulting from AEs occurred during the study. Bleeding time remained within the normal range for all doses tested in all subjects. Plasma exposure of DS-1040 increased proportionally with increase in dose. Elderly subjects had higher exposures to DS-1040 and prolonged elimination times, probably because of decreased renal clearance. DS-1040 caused a substantial dose-dependent and time-dependent decrease in TAFIa activity and in 50% clot lysis time. The levels of D-dimer, indicative of endogenous fibrinolysis, increased in some individuals following DS-1040 treatment. No effects of DS-1040 on coagulation parameters or platelet

  13. Gallic acid decreases hepatitis C virus expression through its antioxidant capacity

    PubMed Central

    GOVEA-SALAS, MAYELA; RIVAS-ESTILLA, ANA MARIA; RODRÍGUEZ-HERRERA, RAUL; LOZANO-SEPÚLVEDA, SONIA A.; AGUILAR-GONZALEZ, CRISTOBAL N.; ZUGASTI-CRUZ, ALEJANDRO; SALAS-VILLALOBOS, TANYA B.; MORLETT-CHÁVEZ, JESUS ANTONIO

    2016-01-01

    Gallic acid (GA) is a natural phenolic compound that possesses various biological effects, including antioxidant, anti-inflammatory, antibiotic, anticancer, antiviral and cardiovascular protection activities. In addition, numerous studies have reported that antioxidants possess antiviral activities. Hepatitis C virus (HCV) is one of the most important causes of chronic liver diseases worldwide, but until recently, only a small number of antiviral agents had been developed against HCV. Therefore, the present study investigated whether GA exhibits an anti-HCV activity. The effects of GA on HCV expression were examined using a subgenomic HCV replicon cell culture system that expressed HCV nonstructural proteins (NSs). In addition, GA cytotoxicity was evaluated at concentrations between 100–600 mg/ml using an MTT assay. Huh-7 replicon cells were incubated with 300 mg/ml GA for different times, and the HCV-RNA and protein levels were measured by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Pyrrolidine dithiocarbamate (PDTC) was used as an antioxidant control and reactive oxygen species (ROS) production was measured during the exposure. The results indicated that GA did not produce a statistically significant cytotoxicity in parental and HCV replicon cells. Furthermore, GA downregulated the expression levels of NS5A-HCV protein (~55%) and HCV-RNA (~50%) in a time-dependent manner compared with the levels in untreated cells. Notably, GA treatment decreased ROS production at the early time points of exposure in cells expressing HCV proteins. Similar results were obtained upon PDTC exposure. These findings suggest that the antioxidant capacity of GA may be involved in the downregulation of HCV replication in hepatoma cells. PMID:26893656

  14. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury.

    PubMed

    Idell, Steven

    2003-04-01

    To review: a) the role of extravascular fibrin deposition in the pathogenesis of acute lung injury; b) the abnormalities in the coagulation and fibrinolysis pathways that promote fibrin deposition in the acutely injured lung; and c) the pathways that contribute to the regulation of the fibrinolytic system via the lung epithelium, including newly recognized posttranscriptional and urokinase-dependent pathways. Another objective was to determine how novel anticoagulant or fibrinolytic strategies may be used to protect against acute inflammation or accelerated fibrosis in acute lung injury. Published medical literature. Alveolar fibrin deposition is characteristic of diverse forms of acute lung injury. Intravascular thrombosis or disseminated intravascular coagulation can also occur in the acutely injured lung. Extravascular fibrin deposition promotes lung dysfunction and the acute inflammatory response. In addition, transitional fibrin in the alveolar compartment undergoes remodeling leading to accelerated pulmonary fibrosis similar to the events associated with wound healing, or desmoplasia associated with solid neoplasms. In acute lung injury, alveolar fibrin deposition is potentiated by consistent changes in endogenous coagulation and fibrinolytic pathways. Procoagulant activity is increased in conjunction with depression of fibrinolytic activity in the alveolar compartment. Initiation of the procoagulant response occurs as a result of local overexpression of tissue factor associated with factor VII. Depression of fibrinolytic activity occurs as a result of inhibition of urokinase plasminogen activator (uPA) by plasminogen activators, or series inhibition of plasmin by antiplasmins. Locally increased amplification of plasminogen activator inhibitor-1 (PAI-1) is largely responsible for this fibrinolytic defect. Newly described pathways by which lung epithelial cells regulate expression of uPA, its receptor uPAR, and PAI-1 at the posttranscriptional level have been

  15. Ursodeoxycholic Acid Suppresses Lipogenesis in Mouse Liver: Possible Role of the Decrease in β-Muricholic Acid, a Farnesoid X Receptor Antagonist.

    PubMed

    Fujita, Kyosuke; Iguchi, Yusuke; Une, Mizuho; Watanabe, Shiro

    2017-03-17

    The farnesoid X receptor (FXR) is a major nuclear receptor of bile acids; its activation suppresses sterol regulatory element-binding protein 1c (SREBP1c)-mediated lipogenesis and decreases the lipid contents in the liver. There are many reports showing that the administration of ursodeoxycholic acid (UDCA) suppresses lipogenesis and reduces the lipid contents in the liver of experimental animals. Since UDCA is not recognized as an FXR agonist, these effects of UDCA cannot be readily explained by its direct activation of FXR. We observed that the dietary administration of UDCA in mice decreased the expression levels of SREBP1c and its target lipogenic genes. Alpha- and β-muricholic acids (MCA) and cholic acid (CA) were the major bile acids in the mouse liver but their contents decreased upon UDCA administration. The hepatic contents of chenodeoxycholic acid and deoxycholic acid (DCA) were relatively low but were not changed by UDCA. UDCA did not show FXR agonistic or antagonistic potency in in vitro FXR transactivation assay. Taking these together, we deduced that the above-mentioned change in hepatic bile acid composition induced upon UDCA administration might cause the relative increase in the FXR activity in the liver, mainly by the reduction in the content of β-MCA, a farnesoid X receptor antagonist, which suggests a mechanism by which UDCA suppresses lipogenesis and decreases the lipid contents in the mouse liver.

  16. Decreased Anterior Cingulate Cortex γ-Aminobutyric Acid in Youth With Tourette's Disorder.

    PubMed

    Freed, Rachel D; Coffey, Barbara J; Mao, Xiangling; Weiduschat, Nora; Kang, Guoxin; Shungu, Dikoma C; Gabbay, Vilma

    2016-12-01

    γ-Aminobutyric acid has been implicated in the pathophysiology of Tourette's disorder. The present study primarily sought to examine in vivo γ-aminobutyric acid levels in the anterior cingulate cortex in psychotropic medication-free adolescents and young adults. Secondarily, we sought to determine associations between γ-aminobutyric acid in the anterior cingulate cortex and measures of tic severity, tic-related impairment, and anxiety and depression symptoms. γ-Aminobutyric acid levels were measured using proton magnetic resonance spectroscopy. Analysis of covariance compared γ-aminobutyric acid levels in 15 youth with Tourette's disorder (mean age = 15.0, S.D. = 2.7) and 36 healthy comparison subjects (mean age = 15.9, S.D. = 2.1). Within the Tourette disorder group, we examined correlations between γ-aminobutyric acid levels and tic severity and tic-related impairment, as well as anxiety and depression severity. Anterior cingulate cortex γ-aminobutyric acid levels were lower in participants with Tourette's disorder compared with control subjects. Within the Tourette disorder group, γ-aminobutyric acid levels did not correlate with any clinical measures. Our findings support a role for γ-aminobutyric acid in Tourette's disorder. Larger prospective studies will further elucidate this role. Copyright © 2016. Published by Elsevier Inc.

  17. Frost decreases content of sugars, ascorbic acid and some quercetin glycosides but stimulates selected carotenes in Rosa canina hips.

    PubMed

    Cunja, Vlasta; Mikulic-Petkovsek, Maja; Zupan, Anka; Stampar, Franci; Schmitzer, Valentina

    2015-04-15

    Primary and secondary metabolites of Rosa canina hips were determined by HPLC/MS during ripening and after frost damage. Rose hips were harvested six times from the beginning of September until the beginning of December. Color parameters a*, b* and L* decreased during maturation. Glucose and fructose were the predominant sugars representing up to 92% total sugars, and citric acid was the major organic acid detected in rose hips (constituting up to 58% total organic acids). Total sugar and ascorbic acid content significantly decreased after frost damage; from 42.2 to 25.9 g 100 g(-1) DW for sugars and from 716.8 to 176.0 mg 100 g(-1) DW for ascorbic acid. Conversely, β-carotene and lycopene levels increased in frostbitten rose hips to 22.1 and 113.2 mg 100 g(-1) DW, respectively. In addition to cyanidin-3-glucoside (highest level in hips was 125.7 μg 100 g (-1) DW), 45 different phenolic compounds have been identified. The most abundant were proanthocyanidins (their levels amounted up to 90% of total flavanol content) and their content showed no significant differences during maturation. The levels of catechin, phloridzin, flavanones and several quercetin glycosides were highest on the first three sampling dates and decreased after frost. Antioxidant capacity similarly decreased in frostbitten rose hips. Total phenolic content increased until the third sampling and decreased on later samplings. Copyright © 2015 Elsevier GmbH. All rights reserved.

  18. Supplementation with Folic Acid, but Not Creatine, Increases Plasma Betaine, Decreases Plasma Dimethylglycine, and Prevents a Decrease in Plasma Choline in Arsenic-Exposed Bangladeshi Adults123

    PubMed Central

    Hall, Megan N; Liu, Xinhua; Caudill, Marie A; Malysheva, Olga; Ilievski, Vesna; Lomax-Luu, Angela M; Parvez, Faruque; Siddique, Abu B; Shahriar, Hasan; Uddin, Mohammad N; Islam, Tariqul; Graziano, Joseph H; Gamble, Mary V

    2016-01-01

    Background: Folic acid (FA) supplementation facilitates urinary excretion of arsenic, a human carcinogen. A better understanding of interactions between one-carbon metabolism intermediates may improve the ability to design nutrition interventions that further facilitate arsenic excretion. Objective: The objective was to determine if FA and/or creatine supplementation increase choline and betaine and decrease dimethylglycine (DMG). Methods: We conducted a secondary analysis of the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults (n = 605, aged 24–55 y, 50.3% male) who received arsenic-removal water filters. We examined treatment effects of FA and/or creatine supplementation on plasma choline, betaine, and DMG concentrations, measured by LC–tandem mass spectrometry at baseline and at week 12. Group comparisons were between 1) 400 and 800 μg FA/d (FA400 and FA800, respectively) compared with placebo, 2) creatine (3 g/d) compared with placebo, and 3) creatine plus FA400 compared with FA400. Results: Choline decreased in the placebo group (−6.6%; 95% CI: −10.2%, −2.9%) but did not change in the FA groups (FA400: 2.5%; 95% CI: −0.9%, 6.1%; FA800: 1.4%; 95% CI: −2.5%, 5.5%; P < 0.05). Betaine did not change in the placebo group (−3.5%; 95% CI: −9.3%, 2.6%) but increased in the FA groups (FA400: 14.1%; 95% CI: 9.4%, 19.0%; FA800: 13.0%; 95% CI: 7.2%, 19.1%; P < 0.01). The decrease in DMG was greater in the FA groups (FA400: −26.7%; 95% CI: −30.9%, −22.2%; FA800: −27.8%; 95% CI: −31.8%, −23.4%) than in the placebo group (−12.3%; 95% CI: −18.1%, −6.2%; P < 0.01). The percentage change in choline, betaine, and DMG did not differ between creatine treatment arms and their respective reference groups. Conclusion: Supplementation for 12 wk with FA, but not creatine, increases plasma betaine, decreases plasma DMG, and prevents a decrease in plasma choline in arsenic-exposed Bangladeshi adults. This trial

  19. Supplementation with Folic Acid, but Not Creatine, Increases Plasma Betaine, Decreases Plasma Dimethylglycine, and Prevents a Decrease in Plasma Choline in Arsenic-Exposed Bangladeshi Adults.

    PubMed

    Hall, Megan N; Howe, Caitlin G; Liu, Xinhua; Caudill, Marie A; Malysheva, Olga; Ilievski, Vesna; Lomax-Luu, Angela M; Parvez, Faruque; Siddique, Abu B; Shahriar, Hasan; Uddin, Mohammad N; Islam, Tariqul; Graziano, Joseph H; Gamble, Mary V

    2016-05-01

    Folic acid (FA) supplementation facilitates urinary excretion of arsenic, a human carcinogen. A better understanding of interactions between one-carbon metabolism intermediates may improve the ability to design nutrition interventions that further facilitate arsenic excretion. The objective was to determine if FA and/or creatine supplementation increase choline and betaine and decrease dimethylglycine (DMG). We conducted a secondary analysis of the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults (n = 605, aged 24-55 y, 50.3% male) who received arsenic-removal water filters. We examined treatment effects of FA and/or creatine supplementation on plasma choline, betaine, and DMG concentrations, measured by LC-tandem mass spectrometry at baseline and at week 12. Group comparisons were between 1) 400 and 800 μg FA/d (FA400 and FA800, respectively) compared with placebo, 2) creatine (3 g/d) compared with placebo, and 3) creatine plus FA400 compared with FA400. Choline decreased in the placebo group (-6.6%; 95% CI: -10.2%, -2.9%) but did not change in the FA groups (FA400: 2.5%; 95% CI: -0.9%, 6.1%; FA800: 1.4%; 95% CI: -2.5%, 5.5%; P < 0.05). Betaine did not change in the placebo group (-3.5%; 95% CI: -9.3%, 2.6%) but increased in the FA groups (FA400: 14.1%; 95% CI: 9.4%, 19.0%; FA800: 13.0%; 95% CI: 7.2%, 19.1%; P < 0.01). The decrease in DMG was greater in the FA groups (FA400: -26.7%; 95% CI: -30.9%, -22.2%; FA800: -27.8%; 95% CI: -31.8%, -23.4%) than in the placebo group (-12.3%; 95% CI: -18.1%, -6.2%; P < 0.01). The percentage change in choline, betaine, and DMG did not differ between creatine treatment arms and their respective reference groups. Supplementation for 12 wk with FA, but not creatine, increases plasma betaine, decreases plasma DMG, and prevents a decrease in plasma choline in arsenic-exposed Bangladeshi adults. This trial was registered at clinicaltrials.gov as NCT01050556. © 2016 American Society for

  20. Plasma pentraxin-3 and coagulation and fibrinolysis variables during acute Puumala hantavirus infection and associated thrombocytopenia.

    PubMed

    Laine, Outi K; Koskela, Sirpa M; Outinen, Tuula K; Joutsi-Korhonen, Lotta; Huhtala, Heini; Vaheri, Antti; Hurme, Mikko A; Jylhävä, Juulia; Mäkelä, Satu M; Mustonen, Jukka T

    2014-09-01

    Thrombocytopenia and altered coagulation characterize all hantavirus infections. To further assess the newly discovered predictive biomarkers of disease severity during acute Puumala virus (PUUV) infection, we studied the associations between them and the variables reflecting coagulation, fibrinolysis and endothelial activation. Nineteen hospital-treated patients with serologically confirmed acute PUUV infection were included. Acutely, plasma levels of pentraxin-3 (PTX3), cell-free DNA (cf-DNA), complement components SC5b-9 and C3 and interleukin-6 (IL-6) were recorded as well as platelet ligands and markers of coagulation and fibrinolysis. High values of plasma PTX3 associated with thrombin formation (prothrombin fragments F1+2; r = 0.46, P = 0.05), consumption of platelet ligand fibrinogen (r = -0.70, P < 0.001) and natural anticoagulants antithrombin (AT) (r = -0.74, P < 0.001), protein C (r = -0.77, P < 0.001) and protein S free antigen (r = -0.81, P < 0.001) and a decreased endothelial marker ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 domain 13) (r = -0.48, P = 0.04). Plasma level of AT associated with C3 (r = 0.76, P < 0.001), IL-6 (r = -0.56, P = 0.01) and cf-DNA (r = -0.47, P = 0.04). High cf-DNA coincided with increased prothrombin fragments F1+2 (r = 0.47, P = 0.04). Low C3 levels reflecting the activation of complement system through the alternative route predicted loss of all natural anticoagulants (for protein C r = 0.53, P = 0.03 and for protein S free antigen r = 0.64, P = 0.004). Variables depicting altered coagulation follow the new predictive biomarkers of disease severity, especially PTX3, in acute PUUV infection. The findings are consistent with the previous observations of these biomarkers also being predictive for low platelet count and underline the cross-talk of inflammation and coagulation systems in acute PUUV infection.

  1. Dietary Omega-3 Fatty Acids Increase Survival and Decrease Bacterial Load in Mice Subjected to Staphylococcus aureus-Induced Sepsis

    PubMed Central

    Ulleryd, Marcus A.; Grahnemo, Louise; Ståhlman, Marcus; Borén, Jan; Nilsson, Staffan; Jansson, John-Olov

    2016-01-01

    Sepsis caused by Staphylococcus aureus is increasing in incidence. With the alarming use of antibiotics, S. aureus is prone to become methicillin resistant. Antibiotics are the only widely used pharmacological treatment for sepsis. Interestingly, mice fed high-fat diet (HFD) rich in polyunsaturated fatty acids have better survival of S. aureus-induced sepsis than mice fed HFD rich in saturated fatty acids (HFD-S). To investigate what component of polyunsaturated fatty acids, i.e., omega-3 or omega-6 fatty acids, exerts beneficial effects on the survival of S. aureus-induced sepsis, mice were fed HFD rich in omega-3 or omega-6 fatty acids for 8 weeks prior to inoculation with S. aureus. Further, mice fed HFD-S were treated with omega-3 fatty acid metabolites known as resolvins. Mice fed HFD rich in omega-3 fatty acids had increased survival and decreased bacterial loads compared to those for mice fed HFD-S after S. aureus-induced sepsis. Furthermore, the bacterial load was decreased in resolvin-treated mice fed HFD-S after S. aureus-induced sepsis compared with that in mice treated with vehicle. Dietary omega-3 fatty acids increase the survival of S. aureus-induced sepsis by reversing the deleterious effect of HFD-S on mouse survival. PMID:26857576

  2. Dietary Omega-3 Fatty Acids Increase Survival and Decrease Bacterial Load in Mice Subjected to Staphylococcus aureus-Induced Sepsis.

    PubMed

    Svahn, Sara L; Ulleryd, Marcus A; Grahnemo, Louise; Ståhlman, Marcus; Borén, Jan; Nilsson, Staffan; Jansson, John-Olov; Johansson, Maria E

    2016-04-01

    Sepsis caused by Staphylococcus aureus is increasing in incidence. With the alarming use of antibiotics,S. aureus is prone to become methicillin resistant. Antibiotics are the only widely used pharmacological treatment for sepsis. Interestingly, mice fed high-fat diet (HFD) rich in polyunsaturated fatty acids have better survival of S. aureus-induced sepsis than mice fed HFD rich in saturated fatty acids (HFD-S). To investigate what component of polyunsaturated fatty acids, i.e., omega-3 or omega-6 fatty acids, exerts beneficial effects on the survival of S. aureus-induced sepsis, mice were fed HFD rich in omega-3 or omega-6 fatty acids for 8 weeks prior to inoculation with S. aureus Further, mice fed HFD-S were treated with omega-3 fatty acid metabolites known as resolvins. Mice fed HFD rich in omega-3 fatty acids had increased survival and decreased bacterial loads compared to those for mice fed HFD-S after S. aureus-induced sepsis. Furthermore, the bacterial load was decreased in resolvin-treated mice fed HFD-S after S. aureus-induced sepsis compared with that in mice treated with vehicle. Dietary omega-3 fatty acids increase the survival of S. aureus-induced sepsis by reversing the deleterious effect of HFD-S on mouse survival.

  3. Three conazoles increase hepatic microsomal retinoic acid metabolism and decrease mouse hepatic retinoic acid levels in vivo

    SciTech Connect

    Chen, P.-J.; Padgett, William T.; Moore, Tanya; Winnik, Witold; Lambert, Guy R.; Thai, Sheau-Fung; Hester, Susan D.; Nesnow, Stephen

    2009-01-15

    Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with cancer-preventative properties (Ward et al., Toxicol. Pathol. 2006; 34:863-78). The goals of this study were to examine effects of propiconazole, triadimefon, and myclobutanil, three triazole-containing conazoles, on the microsomal metabolism of atRA, the associated hepatic cytochrome P450 (P450) enzyme(s) involved in atRA metabolism, and their effects on hepatic atRA levels in vivo. The in vitro metabolism of atRA was quantitatively measured in liver microsomes from male CD-1 mice following four daily intraperitoneal injections of propiconazole (210 mg/kg/d), triadimefon (257 mg/kg/d) or myclobutanil (270 mg/kg/d). The formation of both 4-hydroxy-atRA and 4-oxo-atRA were significantly increased by all three conazoles. Propiconazole-induced microsomes possessed slightly greater metabolizing activities compared to myclobutanil-induced microsomes. Both propiconazole and triadimefon treatment induced greater formation of 4-hydroxy-atRA compared to myclobutanil treatment. Chemical and immuno-inhibition metabolism studies suggested that Cyp26a1, Cyp2b, and Cyp3a, but not Cyp1a1 proteins were involved in atRA metabolism. Cyp2b10/20 and Cyp3a11 genes were significantly over-expressed in the livers of both triadimefon- and propiconazole-treated mice while Cyp26a1, Cyp2c65 and Cyp1a2 genes were over-expressed in the livers of either triadimefon- or propiconazole-treated mice, and Cyp2b10/20 and Cyp3a13 genes were over-expressed in the livers of myclobutanil-treated mice. Western blot analyses indicated conazole induced-increases in Cyp2b and Cyp3a proteins. All three conazoles decreased hepatic atRA tissue levels ranging from 45-67%. The possible implications of these changes in hepatic atRA levels

  4. Local Fibrinolysis in Spontaneous Supratentorial Hematomas: Comparison with Surgical and Medical Treatment

    PubMed Central

    Condrea, Eugeniu; Timirgaz, Valeriu; Groppa, Stanislav; Codreanu, Ion; Rotaru, Natalia

    2016-01-01

    Objective To evaluate the effectiveness of minimally invasive craniopuncture with local fibrinolysis in the management of supratentorial spontaneous intracerebral hemorrhage (SICH). Methods The study included 218 consecutive patients with supratentorial SICH who were assigned to one of three groups: treated with minimally invasive craniopuncture with local fibrinolysis, treated with craniotomy or other minimally invasive techniques without local fibrinolysis, or receiving conservative management alone. Results Minimally invasive craniopuncture with local fibrinolysis was associated with a lower rate of assisted ventilation, a shorter period of in-hospital stay, a more frequent initiation of early rehabilitation, and a lower mortality rate at all periods of assessment. The overall mortality at 12 months was 19.4% (vs. 50.0 and 33.3% in the two other therapy groups). Lobar (subcortical and cortical) SICHs treated with local fibrinolysis had an overall mortality of 4.8% (vs. 43.5 and 41.7% in the two other therapy groups). On the other hand, SICHs having mixed (basal ganglia and lobar) locations treated with medical therapy alone had an overall mortality of 28.6%, while associated surgery with or without local fibrinolysis increased the overall mortality to over 65%. Conclusions The study demonstrated the applicability of minimally invasive craniopuncture with local fibrinolysis for the management of supratentorial SICHs and the advantages it may have in certain categories of patients. The method proved particularly useful in lobar SICHs, being associated with the lowest mortality. Mixed SICHs do not represent a predilection for surgical interventions; however, the results related to mixed supratentorial locations need confirmation in larger cohorts. PMID:27781045

  5. Oral branched-chain amino acids decrease whole-body proteolysis

    NASA Technical Reports Server (NTRS)

    Ferrando, A. A.; Williams, B. D.; Stuart, C. A.; Lane, H. W.; Wolfe, R. R.

    1995-01-01

    BACKGROUND: This study reports the effects of ingesting branched-chain amino acids (leucine, valine, and isoleucine) on protein metabolism in four men. METHODS: To calculate leg protein synthesis and breakdown, we used a new model that utilized the infusion of L-[ring-13C6]phenylalanine and the sampling of the leg arterial-venous difference and muscle biopsies. In addition, protein-bound enrichments provided for the direct calculation of muscle fractional synthetic rate. Four control subjects ingested an equivalent amount of essential amino acids (threonine, methionine, and histidine) to discern the effects of branched-chain amino acid nitrogen vs the effects of essential amino acid nitrogen. Each drink also included 50 g of carbohydrate. RESULTS: Consumption of the branched-chain and the essential amino acid solutions produced significant threefold and fourfold elevations in their respective arterial concentrations. Protein synthesis and breakdown were unaffected by branched-chain amino acids, but they increased by 43% (p < .05) and 36% (p < .03), respectively, in the group consuming the essential amino acids. However, net leg balance of phenylalanine was unchanged by either drink. Direct measurement of protein synthesis by tracer incorporation into muscle protein (fractional synthetic rate) revealed no changes within or between drinks. Whole-body phenylalanine flux was significantly suppressed by each solution but to a greater extent by the branched-chain amino acids (15% and 20%, respectively) (p < .001). CONCLUSIONS: These results suggest that branched-chain amino acid ingestion suppresses whole-body proteolysis in tissues other than skeletal muscle in normal men.

  6. Oral branched-chain amino acids decrease whole-body proteolysis

    NASA Technical Reports Server (NTRS)

    Ferrando, A. A.; Williams, B. D.; Stuart, C. A.; Lane, H. W.; Wolfe, R. R.

    1995-01-01

    BACKGROUND: This study reports the effects of ingesting branched-chain amino acids (leucine, valine, and isoleucine) on protein metabolism in four men. METHODS: To calculate leg protein synthesis and breakdown, we used a new model that utilized the infusion of L-[ring-13C6]phenylalanine and the sampling of the leg arterial-venous difference and muscle biopsies. In addition, protein-bound enrichments provided for the direct calculation of muscle fractional synthetic rate. Four control subjects ingested an equivalent amount of essential amino acids (threonine, methionine, and histidine) to discern the effects of branched-chain amino acid nitrogen vs the effects of essential amino acid nitrogen. Each drink also included 50 g of carbohydrate. RESULTS: Consumption of the branched-chain and the essential amino acid solutions produced significant threefold and fourfold elevations in their respective arterial concentrations. Protein synthesis and breakdown were unaffected by branched-chain amino acids, but they increased by 43% (p < .05) and 36% (p < .03), respectively, in the group consuming the essential amino acids. However, net leg balance of phenylalanine was unchanged by either drink. Direct measurement of protein synthesis by tracer incorporation into muscle protein (fractional synthetic rate) revealed no changes within or between drinks. Whole-body phenylalanine flux was significantly suppressed by each solution but to a greater extent by the branched-chain amino acids (15% and 20%, respectively) (p < .001). CONCLUSIONS: These results suggest that branched-chain amino acid ingestion suppresses whole-body proteolysis in tissues other than skeletal muscle in normal men.

  7. The response of soil and stream chemistry to decreases in acid deposition in the Catskill Mountains, New York, USA.

    PubMed

    McHale, Michael R; Burns, Douglas A; Siemion, Jason; Antidormi, Michael R

    2017-10-01

    The Catskill Mountains have been adversely impacted by decades of acid deposition, however, since the early 1990s, levels have decreased sharply as a result of decreases in emissions of sulfur dioxide and nitrogen oxides. This study examines trends in acid deposition, stream-water chemistry, and soil chemistry in the southeastern Catskill Mountains. We measured significant reductions in acid deposition and improvement in stream-water quality in 5 streams included in this study from 1992 to 2014. The largest, most significant trends were for sulfate (SO4(2-)) concentrations (mean trend of -2.5 μeq L(-1) yr(-1)); hydrogen ion (H(+)) and inorganic monomeric aluminum (Alim) also decreased significantly (mean trends of -0.3 μeq L(-1) yr(-1) for H(+) and -0.1 μeq L(-1) yr(-1) for Alim for the 3 most acidic sites). Acid neutralizing capacity (ANC) increased by a mean of 0.65 μeq L(-1) yr(-1) for all 5 sites, which was 4 fold less than the decrease in SO4(2-) concentrations. These upward trends in ANC were limited by coincident decreases in base cations (-1.3 μeq L(-1) yr(-1) for calcium + magnesium). No significant trends were detected in stream-water nitrate (NO3(-)) concentrations despite significant decreasing trends in NO3(-) wet deposition. We measured no recovery in soil chemistry which we attributed to an initially low soil buffering capacity that has been further depleted by decades of acid deposition. Tightly coupled decreasing trends in stream-water silicon (Si) (-0.2 μeq L(-1) yr(-1)) and base cations suggest a decrease in the soil mineral weathering rate. We hypothesize that a decrease in the ionic strength of soil water and shallow groundwater may be the principal driver of this apparent decrease in the weathering rate. A decreasing weathering rate would help to explain the slow recovery of stream pH and ANC as well as that of soil base cations. Published by Elsevier Ltd.

  8. A decrease of the rabbit's physiologic IOP after the application of specific amino acids and double combination of antiglaucomatics mixture.

    PubMed

    Olah, Z; Veselovsky, J

    2013-01-01

    To compare the effect of amino acids mixtures to a double combination of antiglaucomatics on the physiologic intraocular pressure (IOP) in rabbits. Experimental evaluations were performed on 5 female rabbits of the New Zealand White species. 1) After instillation of 10 % L-arginine. HCl in the double combination of antiglaucomatics: a) 0.5 % Timolol with 0.005 % Xalatan mixture, the biphasic IOP decrease was measured. The mean decrease in 24 hours was - 2.9 torr; b) 2 % Trusopt with 0.005 % Xalatane mixture in 24 hours, the biphasic decrease of the IOP was measured. The mean decrease in 24 hours was - 4.2 torr; c) Fixed combination COSOPT the mean IOP value decrease was - 1.8 torr. 2) The IOP decrease achieved during 24 hours by instillation of the amino acid 10 % L-taurine.HCl and the double combination of antiglaucomatics: 0.5% Timolol with 0.005% Xalatane mixture was in average - 2.8 torr. The pupilar diameter was not changed. We assume that after the interaction of the selected amino acids 10 % L-arginin or 10 % L-taurin with the double combination of antiglaucomatics (Trusopt and Xalatan, COSOPT or Timoptol and Xalatan) a new substance was formed. The effect of this substance is not separate or additive but acts as a newly formed substance. In vivo, it is only a weak interaction with the free amino acids of the conjunctival sac and the antiglaucomatics. The amino acids interacted in vitro with the double combination of antiglaucomatics resulting in a new "bio-antiglaucomatic" better penetrating into the target area. This new substance was responsible for a more significant decrease and regulation IOP after the mixture application compared to the antiglaucomatics alone (Fig. 1, Ref. 23).

  9. Thrombin-activatable fibrinolysis inhibitor is degraded by Salmonella enterica and Yersinia pestis.

    PubMed

    Valls Serón, M; Haiko, J; DE Groot, P G; Korhonen, T K; Meijers, J C M

    2010-10-01

     Pathogenic bacteria modulate the host coagulation system to evade immune responses or to facilitate dissemination through extravascular tissues. In particular, the important bacterial pathogens Salmonella enterica and Yersinia pestis intervene with the plasminogen/fibrinolytic system. Thrombin-activatable fibrinolysis inhibitor (TAFI) has anti-fibrinolytic properties as the active enzyme (TAFIa) removes C-terminal lysine residues from fibrin, thereby attenuating accelerated plasmin formation.  Here, we demonstrate inactivation and cleavage of TAFI by homologous surface proteases, the omptins Pla of Y. pestis and PgtE of S. enterica. We show that omptin-expressing bacteria decrease TAFI activatability by thrombin-thrombomodulin and that the anti-fibrinolytic potential of TAFIa was reduced by recombinant Escherichia coli expressing Pla or PgtE. The functional impairment resulted from C-terminal cleavage of TAFI by the omptins.  Our results indicate that TAFI is degraded directly by the omptins PgtE of S. enterica and Pla of Y. pestis. This may contribute to the ability of PgtE and Pla to damage tissue barriers, such as fibrin, and thereby to enhance spread of S. enterica and Y. pestis during infection. © 2010 International Society on Thrombosis and Haemostasis.

  10. Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification

    PubMed Central

    Yuasa, Masato; Mignemi, Nicholas A.; Nyman, Jeffry S.; Duvall, Craig L.; Schwartz, Herbert S.; Okawa, Atsushi; Yoshii, Toshitaka; Bhattacharjee, Gourab; Zhao, Chenguang; Bible, Jesse E.; Obremskey, William T.; Flick, Matthew J.; Degen, Jay L.; Barnett, Joey V.; Cates, Justin M.M.; Schoenecker, Jonathan G.

    2015-01-01

    Bone formation during fracture repair inevitably initiates within or around extravascular deposits of a fibrin-rich matrix. In addition to a central role in hemostasis, fibrin is thought to enhance bone repair by supporting inflammatory and mesenchymal progenitor egress into the zone of injury. However, given that a failure of efficient fibrin clearance can impede normal wound repair, the precise contribution of fibrin to bone fracture repair, whether supportive or detrimental, is unknown. Here, we employed mice with genetically and pharmacologically imposed deficits in the fibrin precursor fibrinogen and fibrin-degrading plasminogen to explore the hypothesis that fibrin is vital to the initiation of fracture repair, but impaired fibrin clearance results in derangements in bone fracture repair. In contrast to our hypothesis, fibrin was entirely dispensable for long-bone fracture repair, as healing fractures in fibrinogen-deficient mice were indistinguishable from those in control animals. However, failure to clear fibrin from the fracture site in plasminogen-deficient mice severely impaired fracture vascularization, precluded bone union, and resulted in robust heterotopic ossification. Pharmacological fibrinogen depletion in plasminogen-deficient animals restored a normal pattern of fracture repair and substantially limited heterotopic ossification. Fibrin is therefore not essential for fracture repair, but inefficient fibrinolysis decreases endochondral angiogenesis and ossification, thereby inhibiting fracture repair. PMID:26214526

  11. Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease.

    PubMed

    Kunkel, Steven D; Elmore, Christopher J; Bongers, Kale S; Ebert, Scott M; Fox, Daniel K; Dyle, Michael C; Bullard, Steven A; Adams, Christopher M

    2012-01-01

    Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness.

  12. Ursolic Acid Increases Skeletal Muscle and Brown Fat and Decreases Diet-Induced Obesity, Glucose Intolerance and Fatty Liver Disease

    PubMed Central

    Kunkel, Steven D.; Elmore, Christopher J.; Bongers, Kale S.; Ebert, Scott M.; Fox, Daniel K.; Dyle, Michael C.; Bullard, Steven A.; Adams, Christopher M.

    2012-01-01

    Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness. PMID:22745735

  13. Decreased vitamin B12 and folic Acid concentrations in acne patients after isotretinoin therapy: a controlled study.

    PubMed

    Gökalp, Hilal; Bulur, I; Gürer, Ma

    2014-11-01

    Oral isotretinoin treatment might influence the levels of vitamin B12 and folic acid. The aim of this study is to compare vitamin B12 and folic acid levels in patients with moderate and severe acne vulgaris with those of the healthy control group and to investigate the effect of isotretinoin treatment on these vitamins. Patients who completed 6 months of isotretinoin therapy for moderate and severe forms of acne vulgaris and a control group consisting of healthy individuals between February 2011 and March 2012 were included in the study. Before isotretinoin therapy and at 6.- months of the therapy, serum vitamin B12 and folic acid levels were measured. In the healthy control group, vitamin B12 and folic acid levels were assessed only once. In total, 120 patients with moderate and severe acne vulgaris who completed 6 months isotretinoin therapy and 100 healthy individuals who constituted the control group were included in the study. Pre-treatment vitamin B12 values of the patient group were found to be statistically significantly higher (P = 0.002), but any statistically significant difference was not detected in folic acid measurements (P = 0.566). A statistically significant decrease was detected in post-treatment vitamin B12 and folic acid levels (P < 0.05). Vitamin B12/folic acid treatment should be given under medical surveillance before and during isotretinoin therapy. Supplementation of these vitamins should be recommended in cases of their deficiency, so as to decrease the risks of neuropsychiatric and occlusive vascular diseases.

  14. A specific protein-enriched enteral formula decreases cortisolemia and improves plasma albumin and amino acid concentrations in elderly patients

    PubMed Central

    2010-01-01

    Background Old age is associated with an involuntary and progressive but physiological loss of muscle mass. The aim of this study was to evaluate the effects of exclusive consumption for 6 months of a protein-enriched enteral diet with a relatively high content of branched-chain amino acids on albuminemia, cortisolemia, plasma amino acids, insulin resistance, and inflammation biomarkers in elderly patients. Methods Thirty-two patients from the Clinical Nutrition Outpatient Unit at our hospital exclusively consumed a protein-enriched enteral diet for 6 months. Data were collected at baseline and at 3 and 6 months on anthropometric and biochemical parameters and on plasma concentrations of amino acids, cortisol, adrenocorticotropic hormone, urea, creatinine, insulin resistance, and inflammation biomarkers. Results The percentage of patients with albumin concentration below normal cut-off values decreased from 18% to 0% by the end of the study. At 6 months, concentrations of total plasma (p = 0.008) and essential amino acids (p = 0.011), especially branched-chain amino acids (p = 0.031), were higher versus baseline values, whereas 3-methylhistidine (p = 0.001), cortisol (p = 0.001) and adrenocorticotropic hormone (p = 0.004) levels were lower. Conclusions Regular intake of specific protein-enriched enteral formula increases plasma essential amino acids, especially branched-chain amino acids, and decreases cortisol and 3-methylhistidine, while plasma urea and creatinine remain unchanged. PMID:20626909

  15. Gallic acid decreases vacuous chewing movements induced by reserpine in rats.

    PubMed

    Reckziegel, Patrícia; Peroza, Luis Ricardo; Schaffer, Larissa Finger; Ferrari, Mayara Calegaro; de Freitas, Catiuscia Molz; Bürger, Marilise Escobar; Fachinetto, Roselei

    2013-03-01

    Involuntary oral movements are present in several diseases and pharmacological conditions; however, their etiology and efficient treatments remain unclear. Gallic acid is a natural polyphenolic acid found in gall nuts, sumac, oak bark, tea leaves, grapes and wine, with potent antioxidant and antiapoptotic activity. Thus, the present study investigated the effects of gallic acid on vacuous chewing movements (VCMs) in an animal model induced by reserpine. Rats received either vehicle or reserpine (1mg/kg/day, s.c.) during three days, followed by treatment with water or different doses of gallic acid (4.5, 13.5 or 40.5mg/kg/day, p.o.) for three more days. As result, reserpine increased the number of VCMs in rats, and this effect was maintained for at least three days after its withdrawal. Gallic acid at two different doses (13.5 and 40.5mg/kg/day) has reduced VCMs in rats previously treated with reserpine. Furthermore, we investigated oxidative stress parameters (DCFH-DA oxidation, TBARS and thiol levels) and Na(+),K(+)-ATPase activity in striatum and cerebral cortex, however, no changes were observed. These findings show that gallic acid may have promissory use in the treatment of involuntary oral movements. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Ultrasound enhancement of fibrinolysis at frequencies of 27 to 100 kHz.

    PubMed

    Suchkova, Valentina; Carstensen, Edwin L; Francis, Charles W

    2002-03-01

    Ultrasound (US) accelerates enzymatic fibrinolysis in vitro and in animal models, and may be a useful adjunctive therapy for clinical thrombolysis. Successful clinical application will depend on the selection of appropriate US parameters to optimize fibrinolytic enhancement while limiting adverse effects, including heating. Most studies have been done at megahertz frequencies, but tissue penetration is better and heating less at lower frequencies. We have, therefore, now investigated the effects of continuous-wave and pulsed US on fibrinolysis at midkilohertz frequencies. Fibrinolysis with tissue plasminogen activator (t-PA) was measured by solubilization of radiolabeled fibrin exposed to a calibrated US field in a temperature-controlled water bath. There was significant enhancement of fibrinolysis at frequencies of 27, 40 and 100 kHz, with the greatest effect observed at 27 kHz. The largest effect was observed with continuous-wave US, but significant acceleration was also observed with peak intensities of 1 W/cm(2) duty cycles of 10% and 1%. At a 10% duty cycle, there was approximately 60% of the fibrinolytic enhancement observed with continuous-wave exposure, indicating a clear advantage of pulsing to optimize fibrinolytic effect and limit exposure. We conclude that US in the range of 27 to 100 kHz is effective in accelerating fibrinolysis at intensities and pulsing conditions that minimize the probability of heating and cavitation in clinical applications.

  17. n-3 Essential fatty acids decrease weight gain in genetically obese mice.

    PubMed

    Cunnane, S C; McAdoo, K R; Horrobin, D F

    1986-07-01

    1. Lean (ln/ln) and obese (ob/ob) mice were given diets containing a fat source of 100 g evening primrose (Oenothera biennis) oil (fatty acids 18:2n-6, 18:3n-6; EPO) or 100 g cod liver oil (20:5n-3, 22:6n-3; CLO)/kg diet. 2. Weight gain was lower in the ob/ob mice fed on CLO, an effect unrelated to food intake. 3. In the ob/ob mice fed on CLO, thromboxane synthesis by clotting platelets was reduced compared with that in ob/ob mice fed on EPO. 4. The ob/ob CLO-fed mice had lower arachidonic acid but higher levels of n-3 fatty acids in liver, brown adipose tissue and white adipose tissue. 5. The n-3 fatty acids in CLO therefore replaced the n-6 fatty acids in tissue lipids and reduced synthesis of '2 series' prostaglandins in addition to causing lower weight gain in the CLO-fed ob/ob mice.

  18. The role of arbuscular mycorrhizas in decreasing aluminium phytotoxicity in acidic soils: a review.

    PubMed

    Seguel, Alex; Cumming, Jonathan R; Klugh-Stewart, Katrina; Cornejo, Pablo; Borie, Fernando

    2013-04-01

    Soil acidity is an impediment to agricultural production on a significant portion of arable land worldwide. Low productivity of these soils is mainly due to nutrient limitation and the presence of high levels of aluminium (Al), which causes deleterious effects on plant physiology and growth. In response to acidic soil stress, plants have evolved various mechanisms to tolerate high concentrations of Al in the soil solution. These strategies for Al detoxification include mechanisms that reduce the activity of Al3+ and its toxicity, either externally through exudation of Al-chelating compounds such as organic acids into the rhizosphere or internally through the accumulation of Al-organic acid complexes sequestered within plant cells. Additionally, root colonization by symbiotic arbuscular mycorrhizal (AM) fungi increases plant resistance to acidity and phytotoxic levels of Al in the soil environment. In this review, the role of the AM symbiosis in increasing the Al resistance of plants in natural and agricultural ecosystems under phytotoxic conditions of Al is discussed. Mechanisms of Al resistance induced by AM fungi in host plants and variation in resistance among AM fungi that contribute to detoxifying Al in the rhizosphere environment are considered with respect to altering Al bioavailability.

  19. Lowered fasting chenodeoxycholic acid correlated with the decrease of fibroblast growth factor 19 in Chinese subjects with impaired fasting glucose.

    PubMed

    Zhang, Jing; Li, Huating; Zhou, Hu; Fang, Li; Xu, Jingjing; Yan, Han; Chen, Shuqin; Song, Qianqian; Zhang, Yinan; Xu, Aimin; Fang, Qichen; Ye, Yang; Jia, Weiping

    2017-07-20

    The gut-derived hormone Fibroblast growth factor 19 (FGF19) could regulate glucose metabolism and is induced by bile acids (BAs) through activating Farnesoid X Receptor (FXR). FGF19 was found to decrease in subjects with isolated-impaired fasting glucose (I-IFG) and type 2 diabetes mellitus (T2DM). However, the reason for the change of FGF19 in subjects with different glucometabolic status remained unclear. Here we measured six BAs including chenodeoxycholic acid (CDCA), cholic acid, deoxycholic acid, their glycine conjugates and FGF19 levels during oral glucose tolerance test (OGTT) in normal glucose tolerance (NGT), isolated-impaired glucose tolerance, I-IFG, combined glucose intolerance (CGI) and T2DM subjects. After OGTT, serum FGF19 peaked at 120 min in all subjects. Glycine conjugated BAs peaked at 30 min, while free BAs did not elevated significantly. Consistent with the decrease trend in FGF19 levels, fasting serum CDCA levels in subjects with I-IFG, CGI and T2DM were significantly lower than NGT subjects (P < 0.05). Fasting serum CDCA was independently associated with FGF19. CDCA strongly upregulated FGF19 mRNA levels in LS174T cells in a dose- and time-dependent manner. These results suggest that the decrease of FGF19 in subjects with I-IFG was at least partially due to their decrease of CDCA acting via FXR.

  20. Dopamine receptor alterations in female rats with diet-induced decreased brain docosahexaenoic acid (DHA): interactions with reproductive status

    PubMed Central

    Davis, Paul F.; Ozias, Marlies K.; Carlson, Susan E.; Reed, Gregory A.; Winter, Michelle K.; McCarson, Kenneth E.; Levant, Beth

    2010-01-01

    Decreased tissue levels of n-3 (omega-3) fatty acids, particularly docosahexaenoic acid (DHA), are implicated in the etiologies of non-puerperal and postpartum depression. This study examined the effects of a diet-induced loss of brain DHA content and concurrent reproductive status on dopaminergic parameters in adult female Long–Evans rats. An α-linolenic acid-deficient diet and breeding protocols were used to produce virgin and parous female rats with cortical phospholipid DHA levels 20–22% lower than those fed a control diet containing adequate α-linolenic acid. Decreased brain DHA produced a significant main effect of decreased density of ventral striatal D2-like receptors. Virgin females with decreased DHA also exhibited higher density of D1-like receptors in the caudate nucleus than virgin females with normal DHA. These receptor alterations are similar to those found in several rodent models of depression, and are consistent with the proposed hypodopaminergic basis for anhedonia and motivational deficits in depression. PMID:20670471

  1. Long-term recovery of lakes in the Adirondack region of New York to decreases in acidic deposition

    NASA Astrophysics Data System (ADS)

    Waller, Kristin; Driscoll, Charles; Lynch, Jason; Newcomb, Dani; Roy, Karen

    2012-01-01

    After years of adverse impacts to the acid-sensitive ecosystems of the eastern United States, the Acid Rain Program and Nitrogen Budget Program were developed to control sulfur dioxide (SO 2) and nitrogen oxide (NO x) emissions through market-based cap and trade systems. We used data from the National Atmospheric Deposition Program's National Trends Network (NTN) and the U.S. EPA Temporally Integrated Monitoring of Ecosystems (TIME) program to evaluate the response of lake-watersheds in the Adirondack region of New York to changes in emissions of sulfur dioxide and nitrogen oxides resulting from the Acid Rain Program and the Nitrogen Budget Program. TIME is a long-term monitoring program designed to sample statistically selected subpopulations of lakes and streams across the eastern U.S. to quantify regional trends in surface water chemistry due to changes in atmospheric deposition. Decreases in wet sulfate deposition for the TIME lake-watersheds from 1991 to 2007 (-1.04 meq m -2-yr) generally corresponded with decreases in estimated lake sulfate flux (-1.46 ± 0.72 meq m -2-yr), suggesting declines in lake sulfate were largely driven by decreases in atmospheric deposition. Decreases in lake sulfate and to a lesser extent nitrate have generally coincided with increases in acid neutralizing capacity (ANC) resulting in shifts in lakes among ANC sensitivity classes. The percentage of acidic Adirondack lakes (ANC <0 μeq L -1) decreased from 15.5% (284 lakes) to 8.3% (152 lakes) since the implementation of the Acid Rain Program and the Nitrogen Budget Program. Two measures of ANC were considered in our analysis: ANC determined directly by Gran plot analysis (ANC G) and ANC calculated by major ion chemistry (ANC calc = CB - CA). While these two metrics should theoretically show similar responses, ANC calc (+2.03 μeq L -1-yr) increased at more than twice the rate as ANC G (+0.76 μeq L -1-yr). This discrepancy has important implications for assessments of lake recovery

  2. Three Conazoles Increase Hepatic Microsomal Retinoic Acid Metabolism and Decrease Mouse Hepatic Retinoic Acid Levels In Vivo

    EPA Science Inventory

    Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with...

  3. Three Conazoles Increase Hepatic Microsomal Retinoic Acid Metabolism and Decrease Mouse Hepatic Retinoic Acid Levels In Vivo

    EPA Science Inventory

    Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with...

  4. Aspirin and salicylic acid decrease c-Myc expression in cancer cells: a potential role in chemoprevention.

    PubMed

    Ai, Guoqiang; Dachineni, Rakesh; Muley, Pratik; Tummala, Hemachand; Bhat, G Jayarama

    2016-02-01

    Epidemiological studies have demonstrated a significant correlation between regular aspirin use and reduced colon cancer incidence and mortality; however, the pathways by which it exerts its anti-cancer effects are still not fully explored. We hypothesized that aspirin's anti-cancer effect may occur through downregulation of c-Myc gene expression. Here, we demonstrate that aspirin and its primary metabolite, salicylic acid, decrease the c-Myc protein levels in human HCT-116 colon and in few other cancer cell lines. In total cell lysates, both drugs decreased the levels of c-Myc in a concentration-dependent fashion. Greater inhibition was observed in the nucleus than the cytoplasm, and immunofluorescence studies confirmed these observations. Pretreatment of cells with lactacystin, a proteasome inhibitor, partially prevented the downregulatory effect of both aspirin and salicylic acid, suggesting that 26S proteasomal pathway is involved. Both drugs failed to decrease exogenously expressed DDK-tagged c-Myc protein levels; however, under the same conditions, the endogenous c-Myc protein levels were downregulated. Northern blot analysis showed that both drugs caused a decrease in c-Myc mRNA levels in a concentration-dependent fashion. High-performance liquid chromatography (HPLC) analysis showed that aspirin taken up by cells was rapidly metabolized to salicylic acid, suggesting that aspirin's inhibitory effect on c-Myc may occur through formation of salicylic acid. Our result suggests that salicylic acid regulates c-Myc level at both transcriptional and post-transcription levels. Inhibition of c-Myc may represent an important pathway by which aspirin exerts its anti-cancer effect and decrease the occurrence of cancer in epithelial tissues.

  5. Dietary supplementation of conjugated linoleic acid in horses increases plasma conjugated linoleic acid and decreases plasma arachidonic acid but does not alter body fat.

    PubMed

    Headley, S; Coverdale, J A; Jenkins, T C; Klein, C M; Sharp, J L; Vernon, K L

    2012-12-01

    Studies using dietary supplementation of eicosapentaenoic and docosahexaenoic fatty acids (FA) in horses report inconsistent anti-inflammatory results but consistently report an increase in plasma arachidonic acid (C20:4), the major substrate of cyclooxygenase (COX) II inflammatory pathway. Conjugated linoleic acid has shown anti-inflammatory effects in laboratory and food animal species, but effects of CLA supplementation in horses have not been reported. Our objective was to determine the effects of CLA supplementation on plasma CLA and C20:4 and body fat in healthy horses at maintenance. In a crossover study, 12 mature mares were blocked by breed, age, and BCS and separated into 2 treatment groups (n = 6/group). Groups were fed CLA and corn oil (CO; isocaloric control) for two 6-wk feeding periods, separated by a 4-wk period during which treatment was withheld. Corn oil or CLA supplement (55% mixed CLA isomers) was incorporated into diets at 0.01% BW/d. Mares were fed individually and restricted to dry lots to control forage intake. Rump fat thickness (RFT), BW, and BCS were measured before (d 0) and after (d 42) each feeding period. Blood was collected on d 0, 14, 28, and 42 of each 6-wk period for GLC analysis of plasma CLA isomers (cis-9, trans-11; trans-10, cis-12; and trans-9, trans-11) and C20:4. An ANOVA was conducted to compare the response of RFT, BW, and BCS of CLA-treated and control mares. A mixed methods analysis with repeated measures was used to detect differences in plasma FA concentrations. There were no differences in BW, RFT, or BCS between treatment groups. All CLA isomers present in the CLA supplement were greater in plasma of horses fed CLA compared with controls (P < 0.01). Additionally, plasma concentrations of C20:4 were decreased in horses fed CLA (P < 0.05). This decline in C20:4 may impact the COX II pathway and warrants further investigation. These results suggest that in an equine model, dietary CLA increases circulating

  6. Blood coagulation activation and fibrinolysis during a downhill marathon run.

    PubMed

    Sumann, Günther; Fries, Dietmar; Griesmacher, Andrea; Falkensammer, Gerda; Klingler, Anton; Koller, Arnold; Streif, Werner; Greie, Sven; Schobersberger, Beatrix; Schobersberger, Wolfgang

    2007-07-01

    Prolonged physical exercise is associated with multiple changes in blood hemostasis. Eccentric muscle activation induces microtrauma of skeletal muscles, inducing an inflammatory response. Since there is a link between inflammation and coagulation we speculated that downhill running strongly activates the coagulation system. Thirteen volunteers participated in the Tyrolean Speed Marathon (42,195 m downhill race, 795 m vertical distance). Venous blood was collected 3 days (T1) and 3 h (T2) before the run, within 30 min after finishing (T3) and 1 day thereafter (T4). We measured the following key parameters: creatine kinase, myoglobin, thrombin-antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin-alpha(2)-antiplasmin complexes, tissue-type plasminogen activator antigen, plasminogen-activator-inhibitor-1 antigen and thrombelastography with ROTEM [intrinsic pathway (InTEM) clotting time, clot formation time, maximum clot firmness, alpha angle]. Thrombin generation was evaluated by the Thrombin Dynamic Test and the Technothrombin TGA test. Creatine kinase and myoglobin were elevated at T3 and further increased at T4. Thrombin-antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin-alpha(2)-antiplasmin complexes, tissue-type plasminogen activator antigen and plasminogen-activator-inhibitor-1 antigen were significantly increased at T3. ROTEM analysis exhibited a shortening of InTEM clotting time and clot formation time after the marathon, and an increase in InTEM maximum clot firmness and alpha angle. Changes in TGA were indicative for thrombin generation after the marathon. We demonstrated that a downhill marathon induces an activation of coagulation, as measured by specific parameters for coagulation, ROTEM and thrombin generation assays. These changes were paralleled by an activation of fibrinolysis indicating a preserved hemostatic balance.

  7. [Use of allikor for the normalization of fibrinolysis and hemostasis in patients with chronic cerebrovascular diseases].

    PubMed

    Andrianova, I V; Ionova, V G; Demina, E G; Shabalina, A A; Karabasova, Ia A; Liutova, L I; Povorinskaia, T E; Orekhov, A N

    2001-01-01

    A new form of garlic preparation--long-acting tablets of garlic powder allicor has been studied in patients with cerebral atherosclerosis (CA) complicated by chronic cerebrovascular pathology. A double blind placebo-controlled trial examined allicor effects on hemostasis and fibrinolysis in cross-over groups at two stages. At the first stage patients of group 1 (n = 15) received allicor in a dose 600 mg/day; patients of group 2 (n = 14) were given placebo. At the second stage group 1 received place and group 2 allicor in the same regimen. Before the treatment allicor effects on platelet aggregation and fibrinolysis were studied in vitro (20 patients). Allicor significantly inhibited ADP-induced platelet aggregation in vitro and ex vivo, reduced blood fibrinogen, normalized initially low fibrinolytic activity and fibrinolysis index. Due to the above properties allicor can be used for prevention and treatment of CA complicated by chronic cerebrovascular pathology.

  8. Endogenous Fibrinolysis: An Important Mediator of Thrombus Formation and Cardiovascular Risk.

    PubMed

    Okafor, Osita N; Gorog, Diana A

    2015-04-28

    Most acute cardiovascular events are attributable to arterial thrombosis. Plaque rupture or erosion stimulates platelet activation, aggregation, and thrombosis, whilst simultaneously activating enzymatic processes that mediate endogenous fibrinolysis to physiologically maintain vessel patency. Interplay between these pathways determines clinical outcome. If proaggregatory factors predominate, the thrombus may propagate, leading to vessel occlusion. However, if balanced by a healthy fibrinolytic system, thrombosis may not occur or cause lasting occlusion. Despite abundant evidence for the fibrinolytic system regulating thrombosis, it has been overlooked compared with platelet reactivity, partly due to a lack of techniques to measure it. We evaluate evidence for endogenous fibrinolysis in arterial thrombosis and review techniques to assess it, including biomarkers and global assays, such as thromboelastography and the Global Thrombosis Test. Global assays, simultaneously assessing proaggregatory and fibrinolytic pathways, could play a role in risk stratification and in identifying impaired fibrinolysis as a potential target for pharmacological modulation.

  9. Selection of a Bifidobacterium animalis subsp. lactis Strain with a Decreased Ability To Produce Acetic Acid

    PubMed Central

    Margolles, Abelardo

    2012-01-01

    We have characterized a new strain, Bifidobacterium animalis subsp. lactis CECT 7953, obtained by random UV mutagenesis, which produces less acetic acid than the wild type (CECT 7954) in three different experimental settings: De Man-Rogosa-Sharpe broth without sodium acetate, resting cells, and skim milk. Genome sequencing revealed a single Phe-Ser substitution in the acetate kinase gene product that seems to be responsible for the strain's reduced acid production. Accordingly, acetate kinase specific activity was lower in the low acetate producer. Strain CECT 7953 produced less acetate, less ethanol, and more yoghourt-related volatile compounds in skim milk than the wild type did. Thus, CECT 7953 shows promising potential for the development of dairy products fermented exclusively by a bifidobacterial strain. PMID:22389372

  10. Selection of a Bifidobacterium animalis subsp. lactis strain with a decreased ability to produce acetic acid.

    PubMed

    Margolles, Abelardo; Sánchez, Borja

    2012-05-01

    We have characterized a new strain, Bifidobacterium animalis subsp. lactis CECT 7953, obtained by random UV mutagenesis, which produces less acetic acid than the wild type (CECT 7954) in three different experimental settings: De Man-Rogosa-Sharpe broth without sodium acetate, resting cells, and skim milk. Genome sequencing revealed a single Phe-Ser substitution in the acetate kinase gene product that seems to be responsible for the strain's reduced acid production. Accordingly, acetate kinase specific activity was lower in the low acetate producer. Strain CECT 7953 produced less acetate, less ethanol, and more yoghourt-related volatile compounds in skim milk than the wild type did. Thus, CECT 7953 shows promising potential for the development of dairy products fermented exclusively by a bifidobacterial strain.

  11. Can 5-aminosalicylic acid suppository decrease the pain after rectal band ligation?

    PubMed Central

    Kayhan, Burcak; Ozer, Digdem; Akdogan, Meral; Ozaslan, Ersan; Yuksel, Osman

    2008-01-01

    AIM: To investigate the effect of 5-aminosalicylic acid (5-ASA) suppositories on rectal band ligation-induced pain. METHODS: Sixty patients were randomized into two treatment groups. RESULTS: Our results showed that there was no difference between 5-ASA suppository group and the control group for pain control. CONCLUSION: 5-ASA may be an alternative treatment for hemorrhoids; however, it does not affect the rectal band ligation-induced pain. PMID:18567081

  12. Glycyrrhizic Acid Decreases Gentamicin-Resistance in Vancomycin-Resistant Enterococci.

    PubMed

    Schmidt, Sebastian; Heymann, Kerstin; Melzig, Matthias F; Bereswill, Stefan; Heimesaat, Markus M

    2016-12-01

    The resistance of commensal bacteria against first and second line antibiotics has reached an alarming level in many parts of the world and endangers the effective treatment of infectious diseases. Particularly vancomycin-resistant Enterococcus faecium represents an increasing clinical problem in the treatment of infectious diseases and hinders adequate antibiotic stewardship. In consideration of the lack of novel antibiotic compounds, the development of resistance-modifying agents, however, can mitigate the spread of bacterial drug resistance and might possibly extend the useful application indices of an existing licensed antibiotic. Given that saponins modify the local chemical environment at cell membranes and might modify the uptake or mode of action of antibiotics in bacteria, we investigated the influence of the triterpenoid saponin glycyrrhizic acid of Glycyrrhiza glabra on the susceptibility of vancomycin-resistant enterococci against the aminoglycoside antibiotic gentamicin in 47 clinical isolates by applying the checkerboard method. The fractional inhibitory concentration indices values were determined between 0.016 and ≤ 0.5 (synergy is accepted with values ≤ 0.5). Glycyrrhizic acid at the subinhibitory concentration of 2.4 mM was found to reduce the minimal inhibitory concentration of gentamicin in intrinsically resistant E. faecium strains down to 6.25 % of the minimal inhibitory concentration of gentamicin alone, whereas relatively low concentrations of glycyrrhizic acid (18 µM) resulted in increased susceptibilities for some E. faecium isolates to gentamicin. In conclusion, our study points towards a therapeutic potential of glycyrrhizic acid in co-application with gentamicin for defined local bacterial infections caused by vancomycin resistant Enterococcus strains. Georg Thieme Verlag KG Stuttgart · New York.

  13. Amino Acid Correction of Regulatory Volume Decrease Evoked by Hypotonic Stress in Mouse Oocytes In Vitro.

    PubMed

    Pogorelova, M A; Golichenkov, V A; Pogorelova, V N; Panait, A I; Smirnov, A A; Pogorelov, A G

    2015-05-01

    Regulatory volume decrease in response to hypotonic stress is typical of the oocytes and early mouse embryos. Changes in the kinetics of osmotic reaction can be used as a marker of the modulating effect of the incubation medium on transmembrane transport in embryonic cells. Quantitative laser scanning microtomography (QLSM) was used to measure oocyte volume. In this paper, it is shown that addition of 5 μM glycine, taurine, or GABA, as well as ATP to Dulbecco's medium abolished the regulatory volume decrease in mature mouse oocytes.

  14. Thoracoscopic decortication vs tube thoracostomy with fibrinolysis for empyema in children: a prospective, randomized trial

    PubMed Central

    St. Peter, Shawn D.; Tsao, Kuojen; Harrison, Christopher; Jackson, Mary Ann; Spilde, Troy L.; Keckler, Scott J.; Sharp, Susan W.; Andrews, Walter S.; Holcomb, George W.; Ostlie, Daniel J.

    2011-01-01

    Purpose Management of empyema has been debated in the literature for decades. Although both primary video-assisted thoracoscopic surgery (VATS) and tube thoracostomy with pleural instillation of fibrinolytics have been shown to result in early resolution when compared to tube thoracostomy alone, there is a lack of comparative data between these modes of management. Therefore, we conducted a prospective, randomized trial comparing VATS to fibrinolytic therapy in children with empyema. Methods After Institutional Review Board approval, children defined as having empyema by either loculation on imaging or more than 10,000 white blood cells/μL were treated with VATS or fibrinolysis. Based on our retrospective data using length of postoperative hospitalization as the primary end point, a sample size of 36 patients was calculated for an α of .5 and a power of 0.8. Fibrinolysis consisted of inserting a 12F chest tube followed by infusion of 4 mg tissue plasminogen activator mixed with 40 mL of normal saline at the time of tube placement followed by 2 subsequent doses 24 hours apart. Results At diagnosis, there were no differences between groups in age, weight, degree of oxygen support, white blood cell count, or days of symptoms. The outcome data showed no difference in days of hospitalization after intervention, days of oxygen requirement, days until afebrile, or analgesic requirements. Video-assisted thoracoscopic surgery was associated with significantly higher charges. Three patients (16.6%) in the fibrinolysis group subsequently required VATS for definitive therapy. Two patients in the VATS group required ventilator support after therapy, one of whom required temporary dialysis. No patient in the fibrinolysis group clinically worsened after initiation of therapy. Conclusions There are no therapeutic or recovery advantages between VATS and fibrinolysis for the treatment of empyema; however, VATS resulted in significantly greater charges. Fibrinolysis may pose less

  15. Fatty acid amide supplementation decreases impulsivity in young adult heavy drinkers

    PubMed Central

    van Kooten, Maria J.; Veldhuizen, Maria G.; de Araujo, Ivan E.; O’Malley, Stephanie; Small, Dana M.

    2016-01-01

    Compromised dopamine signaling in the striatum has been associated with the expression of impulsive behaviors in addiction, obesity and alcoholism. In rodents, Intragastric infusion of the fatty acid amide oleoylethanolamide increases striatal extracellular dopamine levels via vagal afferent signaling. Here we tested whether supplementation with PhosphoLean™, a dietary supplement that contains the precursor of the fatty acid amide oleoylethanolamide (N-oleyl-phosphatidylethanolamine), would reduce impulsive responding and alcohol use in heavy drinking young adults. Twenty-two individuals were assigned to a three-week supplementation regimen with PhosphoLean™ or placebo. Impulsivity was assessed with self-report questionnaires and behavioral tasks pre- and post-supplementation. Although self-report measures of impulsivity did not change, supplementation with PhosphoLean™, but not placebo, significantly reduced false alarm rate on a Go/No-Go task. In addition, an association was found between improved sensitivity on the Go/No-Go task and reduced alcohol intake. These findings provide preliminary evidence that promoting fatty acid derived gut-brain dopamine communication may have therapeutic potential for reducing impulsivity in heavy drinkers. PMID:26656766

  16. Failure of various agents to decrease oleic acid pulmonary albumin leak.

    PubMed

    Sugerman, H J; Blocher, C R; Hirsch, J I; Strash, A M; Tatum, J L

    1983-05-01

    Computerized pulmonary gamma scintigraphy has been shown to be a sensitive technique for the measurement of albumin flux in oleic acid pulmonary microvascular injury. In this technique technetium-99m-tagged human serum albumin is administered intravenously and lung:heart radioactivity ratios are constructed. This ratio remains constant unless there is a net flux of albumin from the vascular space into the lung, when a rising ratio is seen, called the "slope of injury" or SI. Gamma scintigraphy provides a method to rapidly screen the ability of various possible therapeutic agents to reduce the flux of albumin in experimental ARDS. In this study, 0.05 ml/kg oleic acid produced a significant increase in the SI. None of the agents tested (30 mg/kg methylprednisolone, 12.5 mg/kg ibuprofen, 4 mg/kg MK-447, a superoxide radical scavenger, or 140 mg/kg calcium gluconate) were able to alter the scintigraphically measured increased albumin flux produced by 0.05 ml/kg oleic acid.

  17. Teneligliptin Decreases Uric Acid Levels by Reducing Xanthine Dehydrogenase Expression in White Adipose Tissue of Male Wistar Rats

    PubMed Central

    2016-01-01

    We investigated the effects of teneligliptin on uric acid metabolism in male Wistar rats and 3T3-L1 adipocytes. The rats were fed with a normal chow diet (NCD) or a 60% high-fat diet (HFD) with or without teneligliptin for 4 weeks. The plasma uric acid level was not significantly different between the control and teneligliptin groups under the NCD condition. However, the plasma uric acid level was significantly decreased in the HFD-fed teneligliptin treated rats compared to the HFD-fed control rats. The expression levels of xanthine dehydrogenase (Xdh) mRNA in liver and epididymal adipose tissue of NCD-fed rats were not altered by teneligliptin treatment. On the other hand, Xdh expression was reduced significantly in the epididymal adipose tissue of the HFD-fed teneligliptin treated rats compared with that of HFD-fed control rats, whereas Xdh expression in liver did not change significantly in either group. Furthermore, teneligliptin significantly decreased Xdh expression in 3T3-L1 adipocytes. DPP-4 treatment significantly increased Xdh expression in 3T3-L1 adipocytes. With DPP-4 pretreatment, teneligliptin significantly decreased Xdh mRNA expression compared to the DPP-4-treated 3T3-L1 adipocytes. In conclusion, our studies suggest that teneligliptin reduces uric acid levels by suppressing Xdh expression in epididymal adipose tissue of obese subjects. PMID:27652270

  18. Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.

    PubMed

    Puy, H; Deybach, J C; Bogdan, A; Callebert, J; Baumgartner, M; Voisin, P; Nordmann, Y; Touitou, Y

    1996-01-01

    Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. This study using a rat experimental model was designed to produce a pattern of TRP and melatonin production similar to that in AIP patients. Pineal melatonin production was measured in response to: (a) a heme synthesis inhibitor, succinylacetone, (b) a heme precursor, delta-aminolevulinic acid (Ala), (c) a structural analogue of Ala, gamma-aminobutyric acid. Studies were performed in intact rats, perifused pineal glands, and pinealocyte cultures. Ala, succinylacetone, and gamma-aminobutyric acid significantly decreased plasma melatonin levels independently of blood TRP concentration. In the pineal gland, the key enzyme activities of melatonin synthesis were unchanged for hydroxyindole-O-methyltransferase and decreased for N-acetyltransferase. Our results strongly suggest that Ala overproduced by the liver acts by mimicking the effect of gamma-aminobutyric acid on pineal melatonin in AIP. They also support the view that Ala acts as a toxic element in the pathophysiology of AIP.

  19. Silencer-of-Death Domain Mediates Acid-Induced Decrease in Cell Apoptosis in Barrett's Associated Esophageal Adenocarcinoma Cells.

    PubMed

    Li, Dan; Hong, Jie; Cao, Weibiao

    2017-01-01

    We have shown that NADPH oxidase (NOX)5-S may mediate the acid-induced decrease in cell apoptosis. However, mechanisms of NOX5-S-dependent decrease in cell apoptosis are not fully understood. In this study, we found that silencer-of-death domain (SODD) was significantly increased in esophageal adenocarcinoma (EA) tissues, EA cell lines FLO and OE33, and a dysplastic cell line CP-B. Strong SODD immunostaining was significantly higher in low-grade dysplasia (66.7%), high-grade dysplasia (81.2%), and EA (71.2%) than in Barrett's mucosa (10.5%). Acid treatment significantly increased SODD protein and mRNA expression and promoter activity in FLO cells, an increase that was significantly decreased by the knockdown of NOX5-S and nuclear factor κB (NF-κB)1 p50 with their small interfering RNAs. Similarly, acid-induced increase of SODD mRNA was blocked by knockdown of NOX5-S and p50 in a BE cell line CP-A. Overexpression of NOX5-S significantly increased SODD protein expression in FLO cells. Moreover, overexpression of NOX5-S or p50 significantly increased the SODD promoter activity and decreased the caspase 9 activity or apoptosis. NOX5-S overexpression-induced increase in SODD promoter activity was significantly decreased by knockdown of p50. In addition, acid treatment significantly decreased the caspase 9 activity, a decrease that was significantly inhibited by knockdown of SODD. Furthermore, chromatin immunoprecipitation assay showed that NF-κB1 p50 bound to SODD genomic DNA containing a NF-κB-binding element GGGGACACCCT. This binding element was further confirmed by a gel mobility shift assay. We conclude that acid-induced increase in SODD expression and decrease in cell apoptosis may depend on the activation of NOX5-S and NF-κB1 p50 in FLO cells. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  20. Acute Ischemia due to Superficial Femoral Artery Thrombosis: Results of In Situ Fibrinolysis.

    PubMed

    Arsicot, Matthieu; Della Schiava, Nellie; Boudjelit, Tarek; Rouvière, Olivier; Feugier, Patrick; Lermusiaux, Patrick; Millon, Antoine

    2016-05-01

    The management of acute ischemia due to the thrombosis superficial femoral artery (SFA) stents is complex. In situ arterial fibrinolysis, still not evaluated in this indication, would allow, by lifting the ischemia and uncovering its cause, to avoid thrombectomy, endovascular recanalization, or arterial bypass. The purpose of the study was to evaluate the effectiveness, the complications, and the assisted secondary patency of in situ fibrinolysis for thrombosis of SFA stents. We conducted a retrospective monocentric study with prospective collection of the data. Between October 2011 and December 2014, 86 in situ fibrinolysis procedures were carried out for acute lower limb ischemia. Twelve procedures were carried out for acute ischemia due to the thrombosis of SFA stents. Clinical success was defined by the lifting of acute ischemia. The causes of thromboses, the complications related to the fibrinolysis, and the secondary assisted patency were analyzed. The mean age of the patients was 66.3 (55-90) years. The average length of the stents was 119.3 (18-270) mm. In 10 patients, the thrombosis extended in the full length of the artery. The average time between the implantation of the stent and the initiation of the fibrinolysis was 180 (11-369) days. The average time between the beginning of the symptoms and fibrinolysis was 5 (0-12) days. The average duration of treatment was 46 (24-72) hr. Clinical success was obtained in all the patients. Diagnosed isolated or associated lesions were a progression of the atheromatous disease upstream or downstream of the stent in 6 cases, and an isolated intrastent restenosis in 3 cases. In 2 cases, no obvious cause was found. One or more additional endovascular procedures were carried out in 9 cases at the end of the fibrinolysis, and consisted of a transluminal intrastent angioplasty with an active balloon in 5 cases, an additional stenting in 3 cases, and the stenting of upstream or downstream arteries in 5 cases. Secondary

  1. Disseminated Intravascular Coagulation and Excessive Fibrinolysis (DIC XFL) Syndrome in Prostate Cancer: A Rare Complicated Disorder

    PubMed Central

    Hamzah, Azhar Bin Amir; Choo, Yew Maw; Saleem, Fahad; Verma, Ashutosh Kumar

    2017-01-01

    Disseminated Intravascular Coagulation (DIC) develops in patient with prostate cancer, which is manifested by systemic, intracranial, intracavitary or intracutaneous bleeding indicating uncompensated or excessive fibrinolysis (XFL). This case report is a description of a 61-year-old male with metastatic prostate cancer that progressed to manifest DIC. The condition is rare in clinical practice, and even rarer when is coupled with XFL. Treatment was mainly replenishing coagulation factors, platelets and controlling the disease progression with aggressive hormonal therapy. The patient progressed to coagulopathy further with fibrinolysis, hence leading to mortality. This case study discusses the pathophysiology of this complication and various methods to monitor the disease progression are discussed. PMID:28274032

  2. The role of ACTH and glucocorticoids in nonenzymatic fibrinolysis during immobilization stress in animals

    NASA Technical Reports Server (NTRS)

    Kudryashov, B. A.; Shapiro, F. B.; Lomovskaya, E. G.; Lyapina, L. A.

    1980-01-01

    The role of the altered hormonal status of an organism in the activation of the anticoagulative system during stress is investigated. The 30 minute immobilization stress was shown to raise significantly the nonenzymatic fibrinolytic activity of blood in rats. Combined with adrenocorticotropin (ACTH) the effect is still greater. Intravenous administration of 0.2 m1 0.01 percent solution of protamine sulphate prevented the nonenzymatic fibrinolysis induced by the stress. Administration of ACTH after protomine sulphate again raised the fibrinolysis. This suggests that ACTH stimulates the release of heparin.

  3. Decreased Vitamin B12 and Folic Acid Concentrations in Acne Patients After Isotretinoin Therapy: A Controlled Study

    PubMed Central

    Gökalp, Hilal; Bulur, I; Gürer, MA

    2014-01-01

    Background: Oral isotretinoin treatment might influence the levels of vitamin B12 and folic acid. Aims and Objectives: The aim of this study is to compare vitamin B12 and folic acid levels in patients with moderate and severe acne vulgaris with those of the healthy control group and to investigate the effect of isotretinoin treatment on these vitamins. Materials and Methods: Patients who completed 6 months of isotretinoin therapy for moderate and severe forms of acne vulgaris and a control group consisting of healthy individuals between February 2011 and March 2012 were included in the study. Before isotretinoin therapy and at 6.- months of the therapy, serum vitamin B12 and folic acid levels were measured. In the healthy control group, vitamin B12 and folic acid levels were assessed only once. Results: In total, 120 patients with moderate and severe acne vulgaris who completed 6 months isotretinoin therapy and 100 healthy individuals who constituted the control group were included in the study. Pre-treatment vitamin B12 values of the patient group were found to be statistically significantly higher (P = 0.002), but any statistically significant difference was not detected in folic acid measurements (P = 0.566). A statistically significant decrease was detected in post-treatment vitamin B12 and folic acid levels (P < 0.05). Conclusion: Vitamin B12/folic acid treatment should be given under medical surveillance before and during isotretinoin therapy. Supplementation of these vitamins should be recommended in cases of their deficiency, so as to decrease the risks of neuropsychiatric and occlusive vascular diseases. PMID:25484410

  4. Determining and surveying the role of carnitine and folic acid to decrease fatigue in β-thalassemia minor subjects.

    PubMed

    Tabei, Seyed Mohammad Bagher; Mazloom, Maryam; Shahriari, Mahdi; Zareifar, Soheila; Azimi, Ali; Hadaegh, Amirhossein; Karimi, Mehran

    2013-11-01

    Beta-thalassemia minor (BTM) patients usually experience fatigue, bone pain complaint, and muscle weakness. Carnitine is an essential protein for transportation of long-chain fatty acids to the matrix for beta-oxidation. BTM patients have abnormally low plasma carnitine concentrations, which results in deficient ATP production. Carnitine and folic acid together may have a role in preventing bone pain complaint and fatigue in these patients. The aim of this study is to determine the effect of carnitine and folic acid supplementation in subjects with BTM. Seventy three BTM (mean age 11.06 ± 5.46 years) and 23 healthy controls (mean age 8.48 ± 3.78 years) were enrolled in the study. Fasting blood was drawn to determine baseline free and total carnitine levels, red blood cell folate concentration, and hemoglobin level. BTM were divided into three groups and received different types of supplementation for 3 months: Group 1, 50 mg/kg/day carnitine; Group 2, 50 mg/kg/day carnitine plus 1 mg/day folic acid; and Group 3, 1 mg/day folic acid. Controls did not receive supplementation. Laboratory parameters were again evaluated after 3 months' supplementation. A detailed quality of life questionnaire was designed to investigate muscle symptoms before and after supplementation. Free and total plasma carnitine concentration and hemoglobin levels in BTM subjects increased significantly after carnitine supplementation (P < .0001). Bone pain complaint and muscle weakness decreased with carnitine. Red blood cell folate level increased after folic acid supplementation. Carnitine and folic acid supplementation resulted in a decrease in bone pain complaint and muscle weakness in cases with β-thalassemia minor.

  5. Serum saturated fatty acid decreases plasma adiponectin and increases leptin throughout pregnancy independently of BMI.

    PubMed

    Lepsch, Jaqueline; Farias, Dayana Rodrigues; Vaz, Juliana Dos Santos; de Jesus Pereira Pinto, Thatiana; da Silva Lima, Natália; Freitas Vilela, Ana Amélia; Cunha, Marcelo; Factor-Litvak, Pam; Kac, Gilberto

    2016-01-01

    The aim of this study was to investigate whether serum concentrations of total saturated fatty acids (SFAs), polyunsaturated fatty acids (PUFAs), and their fractions are associated with plasma adiponectin and leptin concentrations throughout pregnancy. A prospective cohort of 201 pregnant women was followed from gestational weeks 5 to 13, 20 to 26, and 30 to 36. Blood samples were collected at the three visits after 12 h of fasting. Fatty acid concentrations were determined using fast gas-liquid chromatography. Plasma adiponectin (μg/mL) and leptin (ng/dL) concentrations were evaluated using enzyme-linked immunosorbent assay kits. Statistical analyses included median adipokine concentrations according to the tertiles of fatty acid distribution and multiple linear mixed-effect models adjusted for body mass index, gestational age, total energy intake, alcohol consumption, and smoking. Women classified in the third SFA concentration tertile had lower median values of adiponectin compared with those in the first tertile ([first trimester: first tertile = 5.36; third tertile = 5.00]; [second trimester: first tertile = 6.39; third tertile = 4.47]; [third trimester: first tertile = 6.46; third tertile = 4.60]). Similar trends were observed for the 14:0, 16:0 and 18:0 fractions. In the multiple longitudinal models, total SFA (β = -41.039; P = 0.008) and 16:0 were negatively associated with plasma adiponectin (16:0, β = -0.511; P = 0.001). Total PUFA ω-6 (β = 28.961; P = 0.002) and 18:2 ω-6 (β = 0.259, P = 0.006) were positively associated with the adiponectin. Total SFA (β = 0.110, P = 0.007), 14:0 (β = 0.072, P = 0.011), and 20:3 ω-6 (β = 0.039; P = 0.035) were positively associated with plasma leptin. Total serum SFA and the 16:0 fraction were negatively associated with plasma adiponectin and positively associated with leptin concentrations. Total ω-6 PUFA was positively associated only with plasma adiponectin

  6. Saturated fatty acid intake decreases serum adiponectin levels in subjects with type 1 diabetes.

    PubMed

    Eccel Prates, Raquel; Beretta, Mileni V; Nascimento, Filipe V; Bernaud, Fernanda R; de Almeira, Jussara Carnevale; Rodrigues, Ticiana C

    2016-06-01

    Adiponectin is a protein secreted by adipose tissue. It plays a key role in insulin resistance and has anti-inflammatory and anti-atherogenic functions. Changes in diet can influence adiponectin levels. Different dietary interventions, especially those altering fatty acid intake, have been reported as possible mediators of adiponectin levels. We conducted a cross-sectional study of 122 subjects with type 1 diabetes (T1DM). Dietary intake was evaluated by 3-day weighed-diet records. Adiponectin levels were categorized into tertiles (T1, <10.260μg/mL; T2, 10.261-18.280μg/mL; T3, >18.281μg/mL). Mean age was 38±11years, and mean duration of diabetes was 17±9years. After multiple regression analysis, waist-to-hip ratio (WHR) (r=-0.19, p = 0.03), age (r=-0.22, p=0.01), systolic blood pressure (SBP) (r=-0.27, p=0.002), diastolic blood pressure (DBP) (r=-0.19, p=0.30), total lipid intake (g) (r=-0.20, p=0.02), saturated fatty acid (SFA) intake (r=-0.25, p=0.004), monounsaturated fatty acid (MUFA) intake (r=-0.21, p=0.02), cholesterol intake (mg) (r=-0.20, p=0.021), sodium intake (g) (r=-0.19, p=0.03), and urinary albumin excretion rate (UAE) (μg/24h) (r=0.26, p=0.02) correlated with adiponectin levels. Even after adjustment for age, SBP or DBP, UAE, and WHR in all models, inverse associations between adiponectin levels and intake of total SFA and MUFA and polyunsaturated fatty acid fractions were observed. Subjects in the first and third tertiles of adiponectin exhibited the greatest differences between adiponectin levels, with a trend toward increasing levels with higher SFA intake. The present study suggests that high SFA intake may be associated with lower adiponectin levels in patients with T1DM. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Reduced thrombin activatable fibrinolysis inhibitor and enhanced proinflammatory cytokines in acute coronary syndrome.

    PubMed

    Pang, H; Zhang, C; Liu, F; Gong, X; Jin, X; Su, C

    2016-12-27

    A study was made of the changes in the serum levels of thrombin activatable fibrinolysis inhibitor (TAFI), proinflammatory cytokines and acute phase proteins in the acute stage of acute coronary syndrome (ACS), in order to explore the possibility of using TAFI as a biomarker for ACS risk assessment. A total of 211 patients with ACS were enrolled, and healthy subjects were used as controls. Blood samples were taken within 24h after admission. Serum TAFI levels were determined by immunoturbidimetry. Serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were determined by enzyme linked immunosorbent assay (ELISA). Procalcitonin (PCT) and C-reactive protein (CRP) levels were measured by gold-immunochromatographic assay. Serum TAFI levels in ACS patients were significantly decreased versus the controls. The IL-1β, IL-6, TNF-α, PCT and CRP levels were markedly higher in the ACS patients than in the controls. Correlation analysis revealed a strong negative correlation between TAFI concentration and the IL-1β, IL-6, TNF-а, PCT and CRP levels in ACS patients and in controls. Multivariate logistic regression analysis suggested decreased serum TAFI to be an independent risk factor for ACS (OR 9.459; 95% CI 2.306-38.793; P=0.002). The area under the receiver operating characteristic (ROC) curve for TAFI was 0.872 (95% CI 0.787-0.909; P<0.001). The optimum TAFI cutoff point for the prediction of ACS was 24μg/ml, with a sensitivity of 75.83% and a specificity of 72.57%. These findings suggest that TAFI can be useful as a potential biomarker for ACS risk assessment. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

  8. Increased anaplerosis of the tricarboxylic acid cycle decreased meal size and energy intake of cows in the postpartum period.

    PubMed

    Gualdrón-Duarte, Laura B; Allen, Michael S

    2017-03-22

    The objective of this study was to determine the effects of anaplerosis of the tricarboxylic acid cycle on feeding behavior and energy intake of cows in the postpartum period. We infused propionic acid (PA) and glycerol (GL) continuously into the abomasum and hypothesized that PA will decrease meal size and energy intake compared with GL because PA enters the tricarboxylic acid cycle, likely stimulating oxidation of acetyl CoA and satiety compared with GL. Three experiments (Exp.) were conducted using 20 Holstein cows between 3 and 22 d postpartum (8 cows in Exp. 1 and 6 cows each for Exp. 2 and 3). Treatments were compared using isoenergetic (Exp. 1, 193 kcal/h) and isomolar (Exp. 2, ∼0.5 mol/h) continuous infusions of PA (99.5%) and GL (99.7%) to the abomasum using a double crossover design with four 2-d infusion periods each, and 2 mol of PA or GL pulse-dosed to the abomasum using a crossover design (Exp. 3). Treatment sequences were assigned alternately to cows based upon date of parturition. Feeding behavior was recorded by a computerized data acquisition system for Exp. 1 and 2. Propionic acid decreased dry matter intake (DMI) compared with GL 16.7 and 23.4% in Exp. 1 and 2, respectively. The decrease in DMI was because PA decreased meal size compared with GL by 12.6 and 15.3% in Exp. 1 and 2, respectively. Propionic acid decreased total metabolizable energy intake (diet plus treatment infusions) compared with GL for both experiments. Compared with PA, GL increased plasma glucose and insulin concentrations for Exp. 2 only. In Exp. 3, PA decreased hepatic acetyl CoA content 34%, whereas GL increased hepatic acetyl CoA content 32%, resulting in lower hepatic acetyl CoA content for PA compared with GL at 30 min (18.0 vs. 36.9 nmol/g), which persisted at 60 min after dosing (21.9 vs. 32.8 nmol/g). Consistent with our hypothesis, the obligatory anaplerotic metabolite PA decreased meal size, DMI, and total metabolizable energy intake compared with GL, likely

  9. Flufenamic acid decreases neuronal excitability through modulation of voltage-gated sodium channel gating.

    PubMed

    Yau, Hau-Jie; Baranauskas, Gytis; Martina, Marco

    2010-10-15

    The electrophysiological phenotype of individual neurons critically depends on the biophysical properties of the voltage-gated channels they express. Differences in sodium channel gating are instrumental in determining the different firing phenotypes of pyramidal cells and interneurons; moreover, sodium channel modulation represents an important mechanism of action for many widely used CNS drugs. Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug that has been long used as a blocker of calcium-dependent cationic conductances. Here we show that FFA inhibits voltage-gated sodium currents in hippocampal pyramidal neurons; this effect is dose-dependent with IC(50) = 189 μm. We used whole-cell and nucleated patch recordings to investigate the mechanisms of FFA modulation of TTX-sensitive voltage-gated sodium current. Our data show that flufenamic acid slows down the inactivation process of the sodium current, while shifting the inactivation curve ~10 mV toward more hyperpolarized potentials. The recovery from inactivation is also affected in a voltage-dependent way, resulting in slower recovery at hyperpolarized potentials. Recordings from acute slices demonstrate that FFA reduces repetitive- and abolishes burst-firing in CA1 pyramidal neurons. A computational model based on our data was employed to better understand the mechanisms of FFA action. Simulation data support the idea that FFA acts via a novel mechanism by reducing the voltage dependence of the sodium channel fast inactivation rates. These effects of FFA suggest that it may be an effective anti-epileptic drug.

  10. Nitric oxide-induced rapid decrease of abscisic acid concentration is required in breaking seed dormancy in Arabidopsis.

    PubMed

    Liu, Yinggao; Shi, Lin; Ye, Nenghui; Liu, Rui; Jia, Wensuo; Zhang, Jianhua

    2009-01-01

    Nitric oxide (NO) has been reported to be involved in breaking seed dormancy but its mechanism of action is unclear. Here, we report that a rapid accumulation of NO induced an equally rapid decrease of abscisic acid (ABA) that is required for this action in Arabidopsis. Results of quantitative real-time polymerase chain reaction (QRT-PCR) and Western blotting indicate that the NO-induced ABA decrease correlates with the regulation of CYP707A2 transcription and (+)-abscisic acid 8'-hydroxylase (encoded by CYP707A2) protein expression. By analysing cyp707a1, cyp707a2 and cyp707a3 mutants, we found that CYP707A2 plays a major role in ABA catabolism during the first stage of imbibition. Fluorescent images demonstrate that NO is released rapidly in the early hours at the endosperm layer during imbibition. Evidently, such response precedes the enhancement of ABA catabolism which is required for subsequent seed germination.

  11. Incremental amounts of ground flaxseed decrease milk yield but increase n-3 fatty acids and conjugated linoleic acids in dairy cows fed high-forage diets(1).

    PubMed

    Resende, T L; Kraft, J; Soder, K J; Pereira, A B D; Woitschach, D E; Reis, R B; Brito, A F

    2015-07-01

    The objective of this study was to investigate the effect of incremental amounts of ground flaxseed (GFX) on milk yield and concentrations and yields of milk components, milk fatty acids (FA) profile, ruminal metabolism, and nutrient digestibility in dairy cows fed high-forage diets. Twelve multiparous Jersey cows averaging (mean ± SD) 112±68d in milk and 441±21kg of body weight and 8 primiparous Jersey cows averaging 98±43d in milk and 401±43kg of body weight were randomly assigned to treatment sequences in a replicated 4×4 Latin square design. Each period lasted 21d with 14d for diet adaptation and 7d for data and sample collection. Treatments were fed as a total mixed ration (63:37 forage-to-concentrate ratio) with corn meal and soybean meal replaced by incremental levels (i.e., 0, 5, 10, or 15% diet dry matter) of GFX. The ruminal molar proportions of acetate and butyrate decreased linearly with GFX supplementation, whereas the ruminal molar proportion of propionate increased linearly resulting in decreased acetate-to-propionate ratio. Apparent total-tract digestibilities of nutrients either decreased (dry matter) or tended to decrease (organic matter, neutral detergent fiber, acid detergent fiber) linearly in cows fed GFX. Milk yield decreased linearly in cows fed increasing amounts of GFX, which is explained by the linear reduction in dry matter intake. Except for the concentrations of milk protein and urea N, which decreased linearly with GFX supplementation, no other changes in the concentration of milk components were observed. However, yields of milk protein and fat decreased linearly with GFX supplementation. The linear decrease in the yields of milk fat and protein are explained by reduced milk yield, whereas that in milk urea N is explained by decreased crude protein intake. No treatment effects were observed for plasma urea N and nonesterified fatty acids, serum cortisol, and body weight change. Milk odd- and branched-chain FA and saturated FA

  12. [Succinic semialdehyde dehydrogenase deficiency: decrease in 4-OH-butyric acid levels with low doses of vigabatrin].

    PubMed

    Escalera, G Iglesias; Ferrer, I; Marina, Ll Carrasco; Sala, P Ruiz; Salomons, G S; Jakobs, C; Pérez-Cerdá, C

    2010-02-01

    Succinic semialdehyde dehydrogenase deficiency (gamma-hydroxybutyric aciduria) is a rare neurometabolic disease caused by a deficiency in gamma-aminobutyric degradation, resulting in an increase in gamma-hydroxybutyric acid in biological fluids. The clinical spectrum is heterogeneous, including a variety of neurological manifestations and psychiatric symptoms. The treatment usually used is vigabatrin, but its clinical efficacy is under discussion. We present two affected siblings. The older brother was examined when he was 2.5 years old due to psychomotor and developmental delay, disturbances in motor coordination, axial hypotonia and language disability. His younger brother had mild axial hypotonia when 5 months old. Metabolic studies demonstrated a high plasma and urine concentration of gamma-hydroxybutyric acid. Mutation analysis of the gene ALDH5A1 confirmed the disease. After 1 year of treatment with low-doses of vigabatrin of the older patient, a decrease in gamma-hydroxybutyric acid plasma levels and a slow clinical improvement were observed.

  13. Bile acid receptor TGR5 overexpression is associated with decreased intestinal mucosal injury and epithelial cell proliferation in obstructive jaundice.

    PubMed

    Ji, Chen-Guang; Xie, Xiao-Li; Yin, Jie; Qi, Wei; Chen, Lei; Bai, Yun; Wang, Na; Zhao, Dong-Qiang; Jiang, Xiao-Yu; Jiang, Hui-Qing

    2017-04-01

    Bile acids stimulate intestinal epithelial proliferation in vitro. We sought to investigate the role of the bile acid receptor TGR5 in the protection of intestinal epithelial proliferation in obstructive jaundice. Intestinal tissues and serum samples were obtained from patients with malignant obstructive jaundice and from bile duct ligation (BDL) rats. Intestinal permeability and morphological changes in the intestinal mucosa were observed. The functions of TGR5 in cell proliferation in intestinal epithelial injury were determined by overexpression or knockdown studies in Caco-2 and FHs 74 Int cells pretreated with lipopolysaccharide (LPS). Internal biliary drainage was superior to external biliary drainage in recovering intestinal permeability and mucosal histology in patients with obstructive jaundice. In BDL rats, feeding of chenodeoxycholic acid (CDCA) decreased intestinal mucosa injury. The levels of PCNA, a marker of proliferation, increased in response to CDCA feeding and were paralleled by elevated TGR5 expression. CDCA upregulated TGR5 expression and promoted proliferation in Caco-2 and FHs 74 Int cells pretreated with LPS. Overexpression of TGR5 resulted in increased PCNA, cell viability, EdU incorporation, and the proportion of cells in S phase, whereas knockdown of TGR5 had the opposite effect. Our data indicate that bile acids promote intestinal epithelial cell proliferation and decrease mucosal injury by upregulating TGR5 expression in obstructive jaundice. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Consumption of pomegranate juice decreases blood lipid peroxidation and levels of arachidonic acid in women with metabolic syndrome.

    PubMed

    Kojadinovic, Milica I; Arsic, Aleksandra C; Debeljak-Martacic, Jasmina D; Konic-Ristic, Aleksandra I; Kardum, Nevena Dj; Popovic, Tamara B; Glibetic, Marija D

    2017-04-01

    Pomegranate juice is a rich source of polyphenols and is thus a promising dietary antioxidant with numerous health-promoting effects. These include a beneficial impact on cardiovascular health that could be partly attributed to the effects of polyphenols on lipid metabolism. The aim of this study was to investigate whether consumption of pomegranate juice for 6 weeks could modify lipid peroxidation and phospholipid fatty acid composition of plasma and erythrocytes in subjects with metabolic syndrome. Twenty-three women, aged 40-60 years, were enrolled and randomly assigned into two groups: the intervention group, in which each participant consumed 300 mL of juice per day for 6 weeks; and a control group. A statistically significant decrease in the relative amount of arachidonic acid (P < 0.05) and an increase in the relative amount of saturated fatty acids (P < 0.05) were observed in the intervention group at the end of the consumption period. In addition, pomegranate juice significantly increased the relative amount of total mono-unsaturated fatty acids (P < 0.05), and significantly decreased the levels of thiobarbituric acid reactive substances in erythrocytes (P < 0.05). The status of blood lipids and the values for blood pressure were not changed during the study. The results obtained indicate a positive impact of the consumption of pomegranate juice on lipid peroxidation and fatty acid status in subjects with metabolic syndrome and suggest potential anti-inflammatory and cardio-protective effects. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

  15. Consumption of acidic water alters the gut microbiome and decreases the risk of diabetes in NOD mice.

    PubMed

    Wolf, Kyle J; Daft, Joseph G; Tanner, Scott M; Hartmann, Riley; Khafipour, Ehsan; Lorenz, Robin G

    2014-04-01

    Infant formula and breastfeeding are environmental factors that influence the incidence of Type 1 Diabetes (T1D) as well as the acidity of newborn diets. To determine if altering the intestinal microbiome is one mechanism through which an acidic liquid plays a role in T1D, we placed non-obese diabetic (NOD)/ShiLtJt mice on neutral (N) or acidified H2O and monitored the impact on microbial composition and diabetes incidence. NOD-N mice showed an increased development of diabetes, while exhibiting a decrease in Firmicutes and an increase in Bacteroidetes, Actinobacteria, and Proteobacteria from as early as 2 weeks of age. NOD-N mice had a decrease in the levels of Foxp3 expression in CD4(+)Foxp3(+) cells, as well as decreased CD4(+)IL17(+) cells, and a lower ratio of IL17/IFNγ CD4+ T-cells. Our data clearly indicates that a change in the acidity of liquids consumed dramatically alters the intestinal microbiome, the presence of protective Th17 and Treg cells, and the incidence of diabetes. This data suggests that early dietary manipulation of intestinal microbiota may be a novel mechanism to delay T1D onset in genetically pre-disposed individuals.

  16. Warming decreased and grazing increased plant uptake of amino acids in an alpine meadow.

    PubMed

    Ma, Shuang; Zhu, Xiaoxue; Zhang, Jing; Zhang, Lirong; Che, Rongxiao; Wang, Fang; Liu, Hanke; Niu, Haishan; Wang, Shiping; Cui, Xiaoyong

    2015-09-01

    Organic nitrogen (N) uptake by plants has been recognized as a significant component of terrestrial N cycle. Several studies indicated that plants have the ability to switch their preference between inorganic and organic forms of N in diverse environments; however, research on plant community response in organic nitrogen uptake to warming and grazing is scarce. Here, we demonstrated that organic N uptake by an alpine plant community decreased under warming with (13)C-(15)N-enriched glycine addition method. After 6 years of treatment, warming decreased plant organic N uptake by 37% as compared to control treatment. Under the condition of grazing, warming reduced plant organic N uptake by 44%. Grazing alone significantly increased organic N absorption by 15%, whereas under warming condition grazing did not affect organic N uptake by the Kobresia humilis community on Tibetan Plateau. Besides, soil NO 3-N content explained more than 70% of the variability observed in glycine uptake, and C:N ratio in soil dissolved organic matter remarkably increased under warming treatment. These results suggested warming promoted soil microbial activity and dissolved organic N mineralization. Grazing stimulated organic N uptake by plants, which counteracted the effect of warming.

  17. Decreased lipases and fatty acid and glycerol transporter could explain reduced fat in diabetic morbidly obese.

    PubMed

    Ferrer, Roser; Pardina, Eva; Rossell, Joana; Baena-Fustegueras, Juan Antonio; Lecube, Albert; Balibrea, José María; Caubet, Enric; González, Oscar; Vilallonga, Ramón; Fort, Jose Manuel; Peinado-Onsurbe, Julia

    2014-11-01

    The possible differences were investigated in 32 morbidly obese patients depending on whether they were "healthy" or had dyslipidemia and/or type 2 diabetes. Lipid metabolism and insulin resistance were analyzed in subcutaneous (SAT) and visceral adipose tissue (VAT) before and during 6 and 12 months after Roux-en-Y gastric bypass. Significant differences have been found in lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) activities in SAT from the different obese group versus normal weight (control) but not between them. The reduced lipase activities in VAT were 43 and 19% smaller (22 and 4% smaller, respectively, vs. control) than the "healthy" obese group for LPL and HSL, respectively, and were accompanied with a reduced expression of these lipases, as well as decreased expression of FAT/CD36, FABP4, and AQ7 in that tissue. In addition, the expression of the other genes measured showed a downregulation not only versus the "healthy" obese but also versus the normal weight group. Being obese is not "healthy," but it is even less so if morbidly obese patients with diabetes and dyslipidemia were considered. The reduced fat accumulation in these patients may be attributed to the decrease of the expression and activity of the lipases of their adipose tissue. © 2014 The Obesity Society.

  18. Decreased ovarian reserve in female Sprague-Dawley rats induced by isotretinoin (retinoic acid) exposure.

    PubMed

    Abali, Remzi; Yuksel, Mehmet Aytac; Aktas, Cevat; Celik, Cem; Guzel, Savas; Erfan, Gamze; Sahin, Onder

    2013-08-01

    Isotretinoin is a retinoid widely used for the treatment of severe nodulocystic acne. Although it has broad side effects, there is no well-designed study about its effects on the ovary. This study investigated possible toxic effects of isotretinoin on female gonads. A total of 30 female rats were randomly divided into three equal groups according to the dose of isotretinoin they were administered: 0 mg/kg/day (group 1), 7.5 mg/kg/day (group 2) or 15 mg/kg/day (group 3). Thirty days after the treatment, the effects of isotretinoin on the ovaries were evaluated with serum anti-Müllerian hormone (AMH) concentrations, apoptosis by TUNEL assay and immunohistochemical observations by proliferating cell nuclear antigen (PCNA). The percentage of atretic follicles was calculated for each stage of folliculogenesis. The serum AMH concentrations were found to be lower in both isotretinoin groups. The percentage of atretic follicles in both isotretinoin groups was higher than the control. The number of PCNA-positive granulosa cells was decreased in the isotretinoin groups. The number of ovarian follicles with apoptotic granulosa cells was increased in the experimental groups. These data are the first to identify that exposure of isotretinoin may be responsible for decreased ovarian reserve and toxic effects on rat ovaries.

  19. [Decreased insulin resistance with amino acids, extracts and antioxidants in patients with polycystic ovary syndrome].

    PubMed

    Hernández-Valencia, Marcelino; Hernández-Quijano, Tomás; Vargas-Girón, Antonio; Vargas-López, Carlos; Arturo-Zárate

    2013-10-01

    The polycystic ovary syndrome (PCOS) it is a metabolic disorder with insulin resistance associated. Have been recently described contributor factors in the presence of insulin resistance that need to be studied. These factors can be the nutrients in the daily diet, final products of the advanced glycated end-products (AGEs), reactive derivatives of non enzymatic glucose-protein reactions either produced endogenously or ingested from dietary sources. The aim was to modifies the food intake to know the contribution on improve insulin resistance. Compare different diets and changes in insulin resistance in patients with polycystic ovary syndrome. As longitudinal, prospective and descriptive study, were included women with age among 18 to 40 years who received a compound with amino acids, extracts and anti-oxidants to dose of 660mg every 8 hours for 6 months. The inclusion approaches included the insulin resistance presence HOMA-IR > 2.6, elevated LH, and presence of ovaries with cysts by ultrasound. Statistical analysis with ANOVA one way to p <0.05. Were included a total of 30 patients, of which 28 patients had improvement in the insulin resistance from the 3 months, but until the 6 months they had significant difference (p<0.05), compared with 24 women from control group. With this result is demonstrated that it is necessary to modify the diet and to offer alimentary support to avoid the oxidative stress that takes impairment the insulin signaling with the subsequent insulin resistance.

  20. Valproic acid decreases the reparation capacity of irradiated MOLT-4 cells.

    PubMed

    Muthna, D; Vavrova, J; Lukasova, E; Tichy, A; Knizek, J; Kohlerova, R; Mazankova, N; Rezacova, M

    2012-01-01

    The aim of our work was to evaluate mechanisms leading to radiosensitization of MOLT-4 leukemia cells following valproic acid (VA) treatment. Cells were pretreated with 2 mM VA for 24 h followed by irradiation with a dose of 0.5 or 1 Gy. The effect of both noxae, alone and combined, was detected 1 and 24 hours after the irradiation. Induction of apoptosis was evaluated by a flow cytometry. The extent of DNA damage was further determined by phosphorylation of histone H2AX using confocal microscopy. Changes in protein expression were identified by SDS-PAGE/immunoblotting. Two-millimolar VA increased apoptosis induction after irradiation as well as phosphorylation of H2AX and provokes an increase in the level of p53 and its phosphorylation at Ser392 in 4 h post-irradiation. Likewise, p21 protein reached its maximal expression in 4 h after the irradiation of VA-treated cells. Twenty four hours later, only the p53 phosphorylated at Ser15 was detected. At the same time, the protein mdm2 (negative regulator of p53) was maximally activated. The 24-hour treatment of MOLT-4 leukemia cells with 2 mM VA results in radiosensitizing, increases apoptosis induction, H2AX phosphorylation, and also p53 and p21 activation.

  1. Deletion of fabN in Enterococcus faecalis results in unsaturated fatty acid auxotrophy and decreased release of inflammatory cytokines.

    PubMed

    Diederich, Ann-Kristin; Duda, Katarzyna A; Romero-Saavedra, Felipe; Engel, Regina; Holst, Otto; Huebner, Johannes

    2016-05-01

    The Gram-positive bacterium Enterococcus faecalis can cause life-threatening infections and is resistant to several commonly used antibiotics. The type II fatty acid pathway in bacteria is discussed as a potential target for antimicrobial therapy. However, it was shown that inhibition or deletion of its enzymes can be rescued in Gram-positive bacteria by supplementation with fatty acids. Here we show that by deletion of the fabN gene, which is essential for unsaturated fatty acid (UFA) synthesis in E. faecalis, growth is impaired but can be rescued by supplementation with oleic acid or human serum. Nonetheless, we demonstrate alterations of the UFA profile after supplementation with oleic acid in the ΔfabN mutant using a specific glycolipid. In addition, we demonstrate that cytokine release in vitro is almost abolished after stimulation of mouse macrophages by the mutant in comparison to the wild type. The results indicate that fabN is not a suitable target for antimicrobials as UFA auxotrophy can be overcome. However, deletion of fabN resulted in a decreased inflammatory response indicating that fabN and resulting UFA synthesis are relevant for virulence.

  2. Not all boronic acids with a five-membered cycle induce tremor, neuronal damage and decreased dopamine.

    PubMed

    Pérez-Rodríguez, Maribel; García-Mendoza, Esperanza; Farfán-García, Eunice D; Das, Bhaskar C; Ciprés-Flores, Fabiola J; Trujillo-Ferrara, José G; Tamay-Cach, Feliciano; Soriano-Ursúa, Marvin A

    2017-06-06

    Several striatal toxins can be used to induce motor disruption. One example is MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), whose toxicity is accepted as a murine model of parkinsonism. Recently, 3-Thienylboronic acid (3TB) was found to produce motor disruption and biased neuronal damage to basal ganglia in mice. The aim of this study was to examine the toxic effects of four boronic acids with a close structural relationship to 3TB (all having a five-membered cycle), as well as boric acid and 3TB. These boron-containing compounds were compared to MPTP regarding brain access, morphological disruption of the CNS, and behavioral manifestations of such disruption. Data was collected through acute toxicity evaluations, motor behavior tests, necropsies, determination of neuronal survival by immunohistochemistry, Raman spectroscopic analysis of brain tissue, and HPLC measurement of dopamine in substantia nigra and striatum tissue. Each compound showed a distinct profile for motor disruption. For example, motor activity was not disrupted by boric acid, but was decreased by two boronic acids (caused by a sedative effect). 3TB, 2-Thienyl and 2-furanyl boronic acid gave rise to shaking behavior. The various manifestations generated by these compounds can be linked, in part, to different levels of dopamine (measured by HPLC) and degrees of neuronal damage in the basal ganglia and cerebellum. Clearly, motor disruption is not induced by all boronic acids with a five-membered cycle as substituent. Possible explanations are given for the diverse chemico-morphological changes and degrees of disruption of the motor system, considering the role of boron and the structure-toxicity relationship. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Crude glycerin decreases nonesterified fatty acid concentration in ewes during late gestation and early lactation.

    PubMed

    Polizel, D M; Susin, I; Gentil, R S; Ferreira, E M; de Souza, R A; Freire, A P A; Pires, A V; Ferraz, M V C; Rodrigues, P H M; Eastridge, M L

    2017-02-01

    Crude glycerin is a gluconeogenic substrate in ruminants and may help to decrease the occurrence of pregnancy toxemia. The objective in this trial was to determine the effects of feeding a diet containing crude glycerin on DMI, milk yield, milk composition, and blood metabolites in periparturient ewes and lamb performance. One hundred eighteen 90 (±1.1)-d pregnant Santa Inês ewes were used. After lambing, 32 ewes (62.8 ± 1.3 kg BW) were allotted in a randomized complete block design defined by prelambing diet, BW, BCS, lambing date, type of birth (single or twin), and sex of offspring. Diets were isonitrogenous (13.0 ± 0.3% CP, DM basis), composed of concentrate and raw sugarcane bagasse (70:30 ratio, DM basis), and fed ad libitum daily. Crude glycerin (83.6% glycerol) levels were 0 or 10% (DM basis), corresponding to the experimental diets G0 and G10, respectively. From 8 until 56 d of lactation, DMI was determined. In the same period, once a week at 1000 h, the ewes were separated from the lambs and mechanically milked after intravenous administration of 10 IU of synthetic oxytocin. Three hours after the first milking, ewes were milked again and milk yield and composition were determined. Glucose, NEFA, and β-hydroxybutyrate (BHBA) were determined at -14, -7, 0, 7, 14, 28, and 56 d relative to lambing and insulin was determined at -14, -7, 0, and 7 d. Crude glycerin did not affect DMI (2.2 kg/d for G0 vs. 2.2 kg/d for G10; = 0.93) or milk production (171 g/3 h for G0 vs. 164 g/3 h for G10; = 0.66). However, there was a decrease ( = 0.01) in milk fat percentage (8.1% for G0 vs. 7.0% for G10) for ewes fed glycerin. Ewes fed the G10 diet had decreased ( < 0.01) NEFA concentration (0.27 mmol/L for G0 vs. 0.18 mmol/L for G10). There was an interaction between diet × time for glucose ( = 0.04), insulin ( = 0.05), and BHBA ( = 0.01); feeding glycerin increased glucose (5.61 mmol/L for G0 vs. 7.42 mmol/L for G10; < 0.01) and insulin concentrations (10.5 μIU for G0

  4. Oral folic acid supplementation decreases palate and/or lip cleft occurrence in Pug and Chihuahua puppies and elevates folic acid blood levels in pregnant bitches.

    PubMed

    Domosławska, A; Jurczak, A; Janowski, T

    2013-01-01

    The aim of this study was to compare the frequency of the occurrence of lip and/or palate cleft (CL/CP) in new-borns of two breeds, Pugs and Chihuahuas, and to measure the folic acid blood levels in bitches during gestations both with and without folic acid oral supplementation. Bitches of 13 Pugs and 17 Chihuahuas with CL/CP cases were used in the study. In trial 1, the animals of the experimental group (n=25) were given additional folic acid from the onset of heat till the 40th day of gestation. The females of the control group (n=12) were fed a traditional diet. From all the animals blood was collected at the onset of heat, 14 days later and on the 30th day of the gestation to estimate folic acid concentration. In trial 2, the prevalence of CP/CL cases in litters from pregnancies before and after supplementation was compared. The percentage of puppies with CL/CP after supplementation decreased in both Pugs and Chihuahua puppies (10.86% and 15.78% vs. 4.76% and 4.8% respectively). On Day 0, the concentrations of folic acid were at a low physiological level (around 8 ng/ml) in all the animals. In bitches of the experimental group the blood level of folic acid on day 14th and 30th of the treatment showed an increase in both breeds (13.65 +/- 4.27 ng/ml in Pugs, 10.79 +/- 2.84 ng/ml in Chihuahuas, and 14.94 +/- 3.22 ng/ml in Pugs, 12.95 +/- 3.58 in Chihuahuas, respectively) while in the control group, this level decreased with time of gestation both in Pugs and in Chihuahuas (around 6 ng/ml). Folic acid supplementation seems to be a simple, effective preventive method to reduce the risk of CL/CP, especially in the predisposed breeds.

  5. Individual Amino Acid Supplementation Can Improve Energy Metabolism and Decrease ROS Production in Neuronal Cells Overexpressing Alpha-Synuclein.

    PubMed

    Delic, Vedad; Griffin, Jeddidiah W D; Zivkovic, Sandra; Zhang, Yumeng; Phan, Tam-Anh; Gong, Henry; Chaput, Dale; Reynes, Christian; Dinh, Vinh B; Cruz, Josean; Cvitkovic, Eni; Placides, Devon; Frederic, Ernide; Mirzaei, Hamed; Stevens, Stanley M; Jinwal, Umesh; Lee, Daniel C; Bradshaw, Patrick C

    2017-06-15

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein accumulation and loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. Increased levels of alpha-synuclein have been shown to result in loss of mitochondrial electron transport chain complex I activity leading to increased reactive oxygen species (ROS) production. WT alpha-synuclein was stably overexpressed in human BE(2)-M17 neuroblastoma cells resulting in increased levels of an alpha-synuclein multimer, but no increase in alpha-synuclein monomer levels. Oxygen consumption was decreased by alpha-synuclein overexpression, but ATP levels did not decrease and ROS levels did not increase. Treatment with ferrous sulfate, a ROS generator, resulted in decreased oxygen consumption in both control and alpha-synuclein overexpressing cells. However, this treatment only decreased ATP levels and increased ROS production in the cells overexpressing alpha-synuclein. Similarly, paraquat, another ROS generator, decreased ATP levels in the alpha-synuclein overexpressing cells, but not in the control cells, further demonstrating how alpha-synuclein sensitized the cells to oxidative insult. Proteomic analysis yielded molecular insights into the cellular adaptations to alpha-synuclein overexpression, such as the increased abundance of many mitochondrial proteins. Many amino acids and citric acid cycle intermediates and their ester forms were individually supplemented to the cells with L-serine, L-proline, L-aspartate, or L-glutamine decreasing ROS production in oxidatively stressed alpha-synuclein overexpressing cells, while diethyl oxaloacetate or L-valine supplementation increased ATP levels. These results suggest that dietary supplementation with individual metabolites could yield bioenergetic improvements in PD patients to delay loss of dopaminergic neurons.

  6. Chlorogenic Acid Decreases Intestinal Permeability and Increases Expression of Intestinal Tight Junction Proteins in Weaned Rats Challenged with LPS

    PubMed Central

    Ruan, Zheng; Liu, Shiqiang; Zhou, Yan; Mi, Shumei; Liu, Gang; Wu, Xin; Yao, Kang; Assaad, Houssein; Deng, Zeyuan; Hou, Yongqing; Wu, Guoyao; Yin, Yulong

    2014-01-01

    Chlorogenic acid, a natural phenolic acid present in fruits and plants, provides beneficial effects for human health. The objectives of this study were to investigate whether chlorogenic acid (CHA) could improve the intestinal barrier integrity for weaned rats with lipopolysaccharide (LPS) challenge. Thirty-two weaned male Sprague Dawley rats (21±1 d of age; 62.26±2.73 g) were selected and randomly allotted to four treatments, including weaned rat control, LPS-challenged and chlorogenic acid (CHA) supplemented group (orally 20 mg/kg and 50 mg/kg body). Dietary supplementation with CHA decreased (P<0.05) the concentrations of urea and albumin in the serum, compared to the LPS-challenged group. The levels of IFN-γ and TNF-α were lower (P<0.05) in the jejunal and colon of weaned rats receiving CHA supplementation, in comparison with the control group. CHA supplementation increased (P<0.05) villus height and the ratio of villus height to crypt depth in the jejunal and ileal mucosae under condictions of LPS challenge. CHA supplementation decreased (P<0.05) intestinal permeability, which was indicated by the ratio of lactulose to mannitol and serum DAO activity, when compared to weaned rats with LPS challenge. Immunohistochemical analysis of tight junction proteins revealed that ZO-1 and occludin protein abundances in the jejunum and colon were increased (P<0.05) by CHA supplementation. Additionally, results of immunoblot analysis revealed that the amount of occludin in the colon was also increased (P<0.05) in CHA-supplemented rats. In conclusion, CHA decreases intestinal permeability and increases intestinal expression of tight junction proteins in weaned rats challenged with LPS. PMID:24887396

  7. Chlorogenic acid decreases intestinal permeability and increases expression of intestinal tight junction proteins in weaned rats challenged with LPS.

    PubMed

    Ruan, Zheng; Liu, Shiqiang; Zhou, Yan; Mi, Shumei; Liu, Gang; Wu, Xin; Yao, Kang; Assaad, Houssein; Deng, Zeyuan; Hou, Yongqing; Wu, Guoyao; Yin, Yulong

    2014-01-01

    Chlorogenic acid, a natural phenolic acid present in fruits and plants, provides beneficial effects for human health. The objectives of this study were to investigate whether chlorogenic acid (CHA) could improve the intestinal barrier integrity for weaned rats with lipopolysaccharide (LPS) challenge. Thirty-two weaned male Sprague Dawley rats (21 ± 1 d of age; 62.26 ± 2.73 g) were selected and randomly allotted to four treatments, including weaned rat control, LPS-challenged and chlorogenic acid (CHA) supplemented group (orally 20 mg/kg and 50 mg/kg body). Dietary supplementation with CHA decreased (P<0.05) the concentrations of urea and albumin in the serum, compared to the LPS-challenged group. The levels of IFN-γ and TNF-α were lower (P<0.05) in the jejunal and colon of weaned rats receiving CHA supplementation, in comparison with the control group. CHA supplementation increased (P<0.05) villus height and the ratio of villus height to crypt depth in the jejunal and ileal mucosae under condictions of LPS challenge. CHA supplementation decreased (P<0.05) intestinal permeability, which was indicated by the ratio of lactulose to mannitol and serum DAO activity, when compared to weaned rats with LPS challenge. Immunohistochemical analysis of tight junction proteins revealed that ZO-1 and occludin protein abundances in the jejunum and colon were increased (P<0.05) by CHA supplementation. Additionally, results of immunoblot analysis revealed that the amount of occludin in the colon was also increased (P<0.05) in CHA-supplemented rats. In conclusion, CHA decreases intestinal permeability and increases intestinal expression of tight junction proteins in weaned rats challenged with LPS.

  8. Over-expression of SlJA2 decreased heat tolerance of transgenic tobacco plants via salicylic acid pathway.

    PubMed

    Liu, Zhong-Ming; Yue, Meng-Meng; Yang, Dong-Yue; Zhu, Shao-Bo; Ma, Na-Na; Meng, Qing-Wei

    2017-04-01

    Over-expression of SlJA2 decreased the accumulation of SA, which resulted in significant physiological and gene expression changes in transgenic tobacco plants, leading to the decreased heat tolerance of transgenic tobacco. NAC family, the largest transcription factors in plants, responses to different environmental stimuli. Here, we isolated a typical NAC transcription factor (SlJA2) from tomato and got transgenic tobacco with SlJA2 over-expression. Expression of SlJA2 was induced by heat stress (42 °C), chilling stress (4 °C), drought stress, osmotic stress, abscisic acid, and salicylic acid. Over-expression of SlJA2 decreased the accumulation of salicylic acid by regulating expression of salicylic acid degradation gene under heat stress. Compared to WT plants, stomatal apertures and water loss increased in transgenic plants, and the damage of photosynthetic apparatus and chlorophyll breakdown were more serious in transgenic plants under heat stress. Meanwhile, more H2O2 and O2(·-) were accumulated transgenic plants and proline synthesis was restricted, which resulted in more serious oxidative damage compared to WT. qRT-PCR analysis showed that over-expression of SlJA2 could down-regulate genes involved in reactive oxygen species scavenging, proline biosynthesis, and response to heat stress. All the above results indicated that SlJA2 may be a negative regulator responded to plant's heat tolerance. Thus, this study provides new insight into roles of NAC family member in plant response to abiotic stress.

  9. Acute and chronic administration of the branched-chain amino acids decreases nerve growth factor in rat hippocampus.

    PubMed

    Scaini, Giselli; Mello-Santos, Lis Mairá; Furlanetto, Camila B; Jeremias, Isabela C; Mina, Francielle; Schuck, Patrícia F; Ferreira, Gustavo C; Kist, Luiza W; Pereira, Talita C B; Bogo, Maurício R; Streck, Emilio L

    2013-12-01

    Maple syrup urine disease (MSUD) is a neurometabolic disorder caused by deficiency of the activity of the mitochondrial enzyme complex branched-chain α-keto acid dehydrogenase leading to accumulation of the branched-chain amino acids (BCAA) and their corresponding branched-chain α-keto acids. In this study, we examined the effects of acute and chronic administration of BCAA on protein levels and mRNA expression of nerve growth factor (NGF) considering that patients with MSUD present neurological dysfunction and cognitive impairment. Considering previous observations, it is suggested that oxidative stress may be involved in the pathophysiology of the neurological dysfunction of MSUD. We also investigated the influence of antioxidant treatment (N-acetylcysteine and deferoxamine) in order to verify the influence of oxidative stress in the modulation of NGF levels. Our results demonstrated decreased protein levels of NGF in the hippocampus after acute and chronic administration of BCAA. In addition, we showed a significant decrease in the expression of ngf in the hippocampus only following acute administration in 10-day-old rats. Interestingly, antioxidant treatment was able to prevent the decrease in NGF levels by increasing ngf expression. In conclusion, the results suggest that BCAA is involved in the regulation of NGF in the developing rat. Thus, it is possible that alteration of neurotrophin levels during brain maturation could be of pivotal importance in the impairment of cognition provoked by BCAA. Moreover, the decrease in NGF levels was prevented by antioxidant treatment, reinforcing that the hypothesis of oxidative stress can be an important pathophysiological mechanism underlying the brain damage observed in MSUD.

  10. Dry matter intake is decreased more by abomasal infusion of unsaturated free fatty acids than by unsaturated triglycerides.

    PubMed

    Litherland, N B; Thire, S; Beaulieu, A D; Reynolds, C K; Benson, J A; Drackley, J K

    2005-02-01

    Previous experiments from our group have demonstrated that abomasal infusion of unsaturated free fatty acids (FFA) markedly decreases dry matter intake (DMI) in dairy cows. In contrast, experiments from other groups have noted smaller decreases in DMI when unsaturated triglycerides (TG) were infused postruminally. Our hypothesis was that unsaturated FFA would be more potent inhibitors of DMI than an equivalent amount of unsaturated TG. Four Holstein cows in late lactation were used in a single reversal design. Cows were fed a total mixed ration containing (DM basis) 23% alfalfa silage, 23% corn silage, 40.3% ground shelled corn, and 10.5% soybean meal. Two cows received soy FFA (UFA; 0, 200, 400, 600 g/d) and 2 received soy oil (TG) in the same amounts; cows then were switched to the other lipid source. Cows were abomasally infused with each amount for 5-d periods. The daily amount of lipid was pulse-dosed in 4 equal portions at 0600, 1000, 1700, and 2200 h; no emulsifiers were used and there was no sign of digestive disturbance. Both lipid sources linearly decreased DMI, with a significant interaction between lipid source and amount. Slope-ratio analysis indicated that UFA were about 2 times more potent in decreasing DMI than were TG. Decreased DMI led to decreased milk production. Milk fat content was increased linearly by lipid infusion. Milk fat yield decreased markedly for UFA infusion but was relatively unaffected by infusion of TG. Contents of short- and medium-chain fatty acids in milk fat decreased as the amount of either infusate increased. Contents of C(18:2) and C(18:3) in milk fat were increased linearly by abomasal infusion of either fat source; cis-9 C(18:1) was unaffected. Transfer of infused C(18:2) to milk fat was 35.6, 42.5, and 27.8% for 200, 400, and 600 g/d of UFA, and 34.3, 39.6, and 34.0% for respective amounts of TG. Glucagon-like peptide-1 (7-36) amide (GLP-1) concentration in plasma significantly increased as DMI decreased with increasing

  11. [Primary angioplasty versus fibrinolysis in patients at a distance from a hospital with a catheterization laboratory].

    PubMed

    Aboal, Jaime; Núñez, María; Bosch, Daniel; Tirón, Coloma; Brugada, Ramón; Loma-Osorio, Pablo

    2017-01-01

    Long distance from a hospital with a catheterization laboratory is associated with a poorer prognosis in patients who undergo primary angioplasty for ST-elevation myocardial infarction (STEMI). An invasive pharmacologic strategy could offer an alternative treatment for these patients. We aimed to establish whether prognosis was better with primary angioplasty or fibrinolysis for reperfusion in cases of STEMI occurring far from a catheterization laboratory. Prospective registry study of patients with STEMI admitted to our cardiology critical care unit. Patients were included over a 5-year period if they received reperfusion therapy and had required transport of more than 50 km to reach a hospital with a catheterization laboratory. We recorded characteristics of the STEMI event, treatment times, and short- and long-term mortality. The data was used for survival analysis. We registered 584 patients; 194 were treated with primary angioplasty and 390 with fibrinolysis. The mean time between first physician contact and balloon insertion was 160 minutes. The mean time between first physician contact and needle insertion for fibrinolysis was 30 minutes. The 2-year mortality rate was higher in patients treated with angioplasty (12.2%) than with those who underwent fibrinolysis (7.0%) ) (P=.04). Survival analysis showed that risk for death was higher in the primary angioplasty group (hazard ratio, 1.97 (95% CI, 0.64-0.95; P=.001). When STEMI occurs more than 50 km from a catheterization laboratory, reperfusion by means of balloon angioplasty delays care considerably and is associated with a higher mortality rate than reperfusion by fibrinolysis.

  12. Simultaneous measurement of thrombin and plasmin generation to assess the interplay between coagulation and fibrinolysis.

    PubMed

    Matsumoto, Tomoko; Nogami, Keiji; Shima, Midori

    2013-10-01

    Normal haemostasis is maintained by a controlled balance between coagulation and fibrinolysis, involving thrombin and plasmin the respective key enzymes. Simultaneous evaluation of both enzymes facilitates, therefore, an overall understanding of normal and pathological haemostasis. Combined thrombin and plasmin generation (T/P-G) assays have been recently described, and we have adapted the technique to investigate the interplay between coagulation and fibrinolysis in patients with various haemostatic disorders. Our modified T/P-G was initiated by the addition of a mixture of optimised lower concentrations of tissue factor and tissue-type plasminogen activator. Thrombin generation (TG) and plasmin generation (PG) were monitored simultaneously using individual fluorescent substrates in separate microtitre wells. The relationship between coagulation and fibrinolysis was demonstrated by analysing the effects of thrombin inhibitors, activated protein C and thrombomodulin. The most evident impairments in TG were observed with plasma samples deficient of coagulation factors participating in the prothrombinase complex. Defects in PG were observed with deficiencies of factor (F)V, FX, fibrinogen, and plasminogen. TG appeared to be a prerequisite for the initiation of PG, and overall PG was governed by fibrinogen concentration. TG in patients with haemophilia A correlated with levels of FVIII activity, but there was no significant relationship between PG and FVIII:C, confirming that the abnormal haemostasis in haemophilia A results in a severe imbalance between coagulation and fibrinolysis. The findings demonstrate that global haemostasis depends on a sensitive balance between coagulation and fibrinolysis, and that the modified T/P-G assay could provide an enhanced understanding of haemorrhage and thrombosis in clinical practice.

  13. Effectiveness of anchovy substrate application on decreasing acid solubility of Sprague Dawley rats’ tooth enamel (in vivo)

    NASA Astrophysics Data System (ADS)

    Triputra, F.; Puspitawati, R.; Gunawan, H. A.

    2017-08-01

    Anchovies (Stolephorus insularis), a natural resource of Indonesia, contain fluoride in the form of CaF2 and can function as a fluoridation material to prevent dental caries. The aim of this study is to study the effectiveness of anchovy substrate, through food or topical application, in decreasing the acid solubility of tooth enamel. This research used 14 Sprague Dawley rats as subjects divided into the following 5 groups: baseline, experimental feeding, experimental smearing, and their negative controls. After 15 days of anchovy substrate application, lower incisors were extracted and the acid solubility of enamel was analyzed qualitatively and quantitatively using a stereo microscope and a Micro-Vickers Hardness Tester. Analysis of enamel surface destruction and enamel surface microscopic hardness shifting after a 60 sec application of H2PO4 (50% concentration) resulted in a decrease in acid solubility of enamel treated with anchovy substrate. This result can be seen with both the chewing and smearing method. S. insularis can be used as an alternative material for fluoridation.

  14. Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells.

    PubMed

    Rzeski, Wojciech; Stepulak, Andrzej; Szymański, Marek; Sifringer, Marco; Kaczor, Józef; Wejksza, Katarzyna; Zdzisińska, Barbara; Kandefer-Szerszeń, Martyna

    2006-10-01

    Betulinic acid (BA) is a pentacyclic triterpene found in many plant species, among others in the bark of white birch Betula alba. BA was reported to display a wide range of biological effects, including antiviral, antiparasitic, antibacterial and anti-inflammatory activities, and in particular to inhibit growth of cancer cells. The aim of the study was further in vitro characterization of BA anticancer activity. In this study, we demonstrated a remarkable antiproliferative effect of BA in all tested tumor cell cultures including neuroblastoma, rabdomyosarcoma-medulloblastoma, glioma, thyroid, breast, lung and colon carcinoma, leukemia and multiple myeloma, as well as in primary cultures isolated from ovarian carcinoma, cervical carcinoma and glioblastoma multiforme. Furthermore, we have shown that BA decreased cancer cell motility and induced apoptotic cell death. We also observed decrease of bcl2 and cyclin D1 genes expression, and increase of bax gene expression after betulinic acid treatment. These findings demonstrate the anticancer potential of betulinic acid and suggest that it may be taken into account as a supportive agent in the treatment of cancers with different tissue origin.

  15. Cognitive deficits and decreased locomotor activity induced by single-walled carbon nanotubes and neuroprotective effects of ascorbic acid.

    PubMed

    Liu, Xudong; Zhang, Yuchao; Li, Jinquan; Wang, Dong; Wu, Yang; Li, Yan; Lu, Zhisong; Yu, Samuel C T; Li, Rui; Yang, Xu

    2014-01-01

    Single-walled carbon nanotubes (SWCNTs) have shown increasing promise in the field of biomedicine, especially in applications related to the nervous system. However, there are limited studies available on the neurotoxicity of SWCNTs used in vivo. In this study, neurobehavioral changes caused by SWCNTs in mice and oxidative stress were investigated. The results of ethological analysis (Morris water maze and open-field test), brain histopathological examination, and assessments of oxidative stress (reactive oxygen species [ROS], malondialdehyde [MDA], and glutathione [GSH]), inflammation (nuclear factor κB, tumor necrosis factor α, interleukin-1β), and apoptosis (cysteine-aspartic acid protease 3) in brains showed that 6.25 and 12.50 mg/kg/day SWCNTs in mice could induce cognitive deficits and decreased locomotor activity, brain histopathological alterations, and increased levels of oxidative stress, inflammation, and apoptosis in mouse brains; however, 3.125 mg/kg/day SWCNTs had zero or minor adverse effects in mice, and these effects were blocked by concurrent administration of ascorbic acid. Down-regulation of oxidative stress, inflammation, and apoptosis were proposed to explain the neuroprotective effects of ascorbic acid. This work suggests SWCNTs could induce cognitive deficits and decreased locomotor activity, and provides a strategy to avoid the adverse effects.

  16. Phosphate decreases urine calcium and increases calcium balance: A meta-analysis of the osteoporosis acid-ash diet hypothesis

    PubMed Central

    Fenton, Tanis R; Lyon, Andrew W; Eliasziw, Michael; Tough, Suzanne C; Hanley, David A

    2009-01-01

    Background The acid-ash hypothesis posits that increased excretion of "acidic" ions derived from the diet, such as phosphate, contributes to net acidic ion excretion, urine calcium excretion, demineralization of bone, and osteoporosis. The public is advised by various media to follow an alkaline diet to lower their acidic ion intakes. The objectives of this meta-analysis were to quantify the contribution of phosphate to bone loss in healthy adult subjects; specifically, a) to assess the effect of supplemental dietary phosphate on urine calcium, calcium balance, and markers of bone metabolism; and to assess whether these affects are altered by the b) level of calcium intake, c) the degree of protonation of the phosphate. Methods Literature was identified through computerized searches regarding phosphate with surrogate and/or direct markers of bone health, and was assessed for methodological quality. Multiple linear regression analyses, weighted for sample size, were used to combine the study results. Tests of interaction included stratification by calcium intake and degree of protonation of the phosphate supplement. Results Twelve studies including 30 intervention arms manipulated 269 subjects' phosphate intakes. Three studies reported net acid excretion. All of the meta-analyses demonstrated significant decreases in urine calcium excretion in response to phosphate supplements whether the calcium intake was high or low, regardless of the degree of protonation of the phosphate supplement. None of the meta-analyses revealed lower calcium balance in response to increased phosphate intakes, whether the calcium intake was high or low, or the composition of the phosphate supplement. Conclusion All of the findings from this meta-analysis were contrary to the acid ash hypothesis. Higher phosphate intakes were associated with decreased urine calcium and increased calcium retention. This meta-analysis did not find evidence that phosphate intake contributes to demineralization

  17. Phosphate decreases urine calcium and increases calcium balance: a meta-analysis of the osteoporosis acid-ash diet hypothesis.

    PubMed

    Fenton, Tanis R; Lyon, Andrew W; Eliasziw, Michael; Tough, Suzanne C; Hanley, David A

    2009-09-15

    The acid-ash hypothesis posits that increased excretion of "acidic" ions derived from the diet, such as phosphate, contributes to net acidic ion excretion, urine calcium excretion, demineralization of bone, and osteoporosis. The public is advised by various media to follow an alkaline diet to lower their acidic ion intakes. The objectives of this meta-analysis were to quantify the contribution of phosphate to bone loss in healthy adult subjects; specifically, a) to assess the effect of supplemental dietary phosphate on urine calcium, calcium balance, and markers of bone metabolism; and to assess whether these affects are altered by the b) level of calcium intake, c) the degree of protonation of the phosphate. Literature was identified through computerized searches regarding phosphate with surrogate and/or direct markers of bone health, and was assessed for methodological quality. Multiple linear regression analyses, weighted for sample size, were used to combine the study results. Tests of interaction included stratification by calcium intake and degree of protonation of the phosphate supplement. Twelve studies including 30 intervention arms manipulated 269 subjects' phosphate intakes. Three studies reported net acid excretion. All of the meta-analyses demonstrated significant decreases in urine calcium excretion in response to phosphate supplements whether the calcium intake was high or low, regardless of the degree of protonation of the phosphate supplement. None of the meta-analyses revealed lower calcium balance in response to increased phosphate intakes, whether the calcium intake was high or low, or the composition of the phosphate supplement. All of the findings from this meta-analysis were contrary to the acid ash hypothesis. Higher phosphate intakes were associated with decreased urine calcium and increased calcium retention. This meta-analysis did not find evidence that phosphate intake contributes to demineralization of bone or to bone calcium excretion

  18. Elevated serum alpha-linolenic acid levels are associated with decreased chance of pregnancy after in vitro fertilization

    PubMed Central

    Jungheim, Emily S.; Macones, George A.; Odem, Randall R.; Patterson, Bruce W.; Moley, Kelle H.

    2011-01-01

    Study Objective To analyze relationships between serum free fatty acid (FFA) concentrations and pregnancy. Design Prospective cohort Setting University hospital Patients 91 women undergoing in vitro fertilization (IVF) Interventions Serum was analyzed for total and specific serum FFAs including myristic, palmitic, stearic, oleic, linoleic and α-linolenic acids. Main outcome measures Univariate analyses were used to identify specific FFAs and other factors associated with pregnancy after IVF. Logistic regression was performed modeling relationships between identified factors and chance of pregnancy. Results In unadjusted analyses, women with elevated serum α-linolenic (ALA) levels (highest quartile) demonstrated a decreased chance of pregnancy compared to women with the lowest levels (OR:0.24, 95% CI:0.052–0.792, p=0.022). No associations between other FFAs and pregnancy were identified. In a multivariable regression model, associations between elevated serum ALA levels and decreased chance of pregnancy remained after adjusting for patient age, body mass index, and history of endometriosis or previous live birth (adjusted OR:0.139, 95% CI:0.028–0.686, p=0.015). Conclusions Elevated serum ALA levels are associated with decreased chance of pregnancy in women undergoing IVF. Further work is needed to determine if ALA is involved in early reproductive processes and if the relationship between ALA and pregnancy is associated with excess ALA intake, impaired ALA metabolism or both. PMID:21840520

  19. Rapid decrease in amino acid metabolism in prolactin-secreting pituitary adenomas after bromocriptine treatment: a PET study

    SciTech Connect

    Bergstroem, M.M.; Muhr, C.; Lundberg, P.O.; Bergstroem, K.G.; Gee, A.D.; Fasth, K.J.; Langstroem B5

    1987-09-01

    Four patients with prolactin-secreting pituitary adenomas were examined with positron emission tomography using L-(/sup 11/C)methionine to monitor the effect of dopamine agonist treatment on the amino acid metabolism in the tumors. Within the first few hours after intramuscular injection of bromocriptine retard (50 mg) the amino acid metabolism decreased by 40%. Two of the patients were reexamined 7 and 9 days later and showed a 70% reduction in the metabolism of the adenomas. This metabolic effect was later accompanied by significant tumor shrinkage in all adenomas. It is suggested that bromocriptine has a general and rapid effect on the protein synthesis of the prolactin-secreting pituitary adenoma cells.

  20. Rosiglitazone increases fatty acid Δ9-desaturation and decreases elongase activity index in human skeletal muscle in vivo.

    PubMed

    Mai, Knut; Andres, Janin; Bobbert, Thomas; Assmann, Anke; Biedasek, Katrin; Diederich, Sven; Graham, Ian; Larson, Tony R; Pfeiffer, Andreas F H; Spranger, Joachim

    2012-01-01

    The ratio of unsaturated to saturated long-chain fatty acids (LC-FAs) in skeletal muscle has been associated with insulin resistance. Some animal data suggest a modulatory effect of peroxisome proliferator receptor γ (PPARγ) stimulation on stearoyl-CoA desaturase 1 (SCD1) and LC-FA composition in skeletal muscle, but human data are rare. We here investigate whether treatment with a PPARγ agonist affects myocellular SCD1 expression and modulates the intramyocellular fatty acid profile in individuals with impaired glucose tolerance. Muscle biopsies and hyperinsulinemic-euglycemic clamps were performed in 7 men before and after 8 weeks of rosiglitazone treatment. Intramyocellular saturated, monounsaturated, and polyunsaturated intramuscular fatty acid profiles were measured by gas chromatography. Effects on SCD1 messenger RNA expression were analyzed in C2C12 cells and in human biopsies before and after rosiglitazone treatment. As expected, treatment with the PPARγ activator rosiglitazone improved insulin sensitivity in humans. Myocellular SCD1 messenger RNA expression was increased in human biopsies and C2C12 cells. Although the total content of myocellular LC-FA was unchanged, a relative shift from saturated LC-FAs to unsaturated LC-FAs was observed in human biopsies. Particularly, the amount of stearate was reduced, whereas the amounts of palmitoleate as well as oleate and vaccenate were increased, after rosiglitazone therapy. These changes resulted in an increased fatty acid Δ9-desaturation index (16:1/16:0 and 18:1/18:0) in skeletal muscle and a decreased elongase activity index (18:0/16:0). The PPARγ associated phenotypes may be partially explained by an increased Δ9-desaturation and a decreased elongase activity of skeletal muscle. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. A single session of exhaustive exercise markedly decreases circulating levels of guanidinoacetic acid in healthy men and women.

    PubMed

    Stajer, Valdemar; Trivic, Tatjana; Drid, Patrik; Vranes, Milan; Ostojic, Sergej M

    2016-07-19

    We evaluated the effects of exercise on circulating concentrations of guanidinoacetic acid (GAA) and creatine in 23 healthy volunteers subjected to running to exhaustion and free-weight bench-press to volitional failure. Blood was taken before and following each exercise session. Running induced a significant decrease in serum GAA by 20.1% (P < 0.001), while free-weight exercise reduced GAA by 11.7% (P < 0.001), suggesting the possible use of serum GAA as a novel biomarker of exhaustion.

  2. Comparison of oleic acid metabolism in the soybean (Glycine max (L. ) Merr. ) genotypes Williams and A5, a mutant with decreased linoleic acid in the seed

    SciTech Connect

    Martin, B.A.; Rinne, R.W.

    1986-05-01

    The metabolism of oleoyl coenzyme A (CoA) was examined in developing seed from two soybean (Glycine max (L.) Merr.) genotypes: Williams, a standard cultivar and A5, a mutant containing nearly twice the oleic acid (18:1) content of Williams. The in vitro rates of esterification of oleoyl-CoA to lysophosphatides by acyl-CoA: lysophosphatidylcholine acyltransferase was similar in both genotypes and lysophosphatidyl-ethanolamine was a poor substrate. Crude extracts desaturated exogenous (1-/sup 14/C)dioleoyl phosphatidylcholine at 14% of the rate achieved with (1-/sup 14/C)oleoyl-CoA, and 50 micromolar lysophosphaatidylcholine. The desaturase enzyme also required NADH for full activity. Extracts from Williams contained 1.5-fold more oleoyl phosphatidylcholine desaturase activity, on a fresh weight basis, than did A5 and appeared to have a similar affinity for oleoyl-CoA. There was 1.2- to 1.9-fold more linoleic acid (18:2) in phosphatidylcholine from Williams than from A5, measured at two stages of development, but both genotypes had a similar distribution of fatty acids in the one and two positions. Phosphatidylethanolamine in A5 contained relatively more linoleic acid (18:2) in the one position than did Williams. The increased oleic acid (18:1) content in A5 appeared to be a result of decreased rates of 18:1 desaturation of oleoyl-phosphatidylcholine in this genotype.

  3. Decreased susceptibility to copper-induced oxidation of rat-lipoproteins after fibrate treatment: influence of fatty acid composition.

    PubMed Central

    Vázquez, M.; Merlos, M.; Adzet, T.; Laguna, J. C.

    1996-01-01

    1. The effect of clofibrate (CFB), bezafibrate (BFB), and gemfibrozil (GFB) on plasma lipoprotein (VLDL and LDL) concentration, composition and resistance to copper-induced oxidation has been studied in male Sprague-Dawley rats after a 15 day treatment. 2. Plasma triglyceride levels were reduced by CFB (41%) and BFB (39%). This effect was related to a significant reduction (67% for CFB and 56% for BFB) in the amount of circulating VLDL-protein. 3. Plasma total cholesterol was reduced by 28% and 45% in CFB- and BFB-treated animals, respectively, mainly by modification of the cholesteryl ester fraction. In contrast, GFB significantly increased total cholesterol (27%). No modification in the LDL protein or lipid content was introduced by fibrates, although GFB decreased the proportion of LDL-triglycerides, at the expense of an increase in total cholesterol. 4. The fatty acid species carried by VLDL and LDL were affected after fibrate treatment. In general, both particles showed an increase in monounsaturated fatty acids (MUFA) (18:1) and a decrease in polyunsaturated fatty acids (PUFA) species (18:2 n-6, 20:4 n-6, 18:3 n-3, 20:5 n-3). As a consequence, the ratio of PUFA/(SFA+MUFA) for the whole lipoproteins was markedly reduced. 5. The degree of copper-induced VLDL- and LDL-oxidation was assessed by means of the analysis of lysine content, thiobarbituric acid reactive substances (TBARS) production and conjugated dienes formation. Lipoproteins obtained from fibrate-treated rats were more resistant to the oxidative challenge. For each lipoprotein, BFB was the most effective drug, followed by CFB and GFB. 6. The observed antioxidant effect can be ascribed to two independent phenomena produced by fibrates: the reduction of the amount of substrate for the oxidation process due to their hypolipidemic activity, and the alteration in the type of fatty acids transported by the lipoproteins towards an enrichment in species resistant to the oxidation process. 7. As similar

  4. Decreased susceptibility to copper-induced oxidation of rat-lipoproteins after fibrate treatment: influence of fatty acid composition.

    PubMed

    Vázquez, M; Merlos, M; Adzet, T; Laguna, J C

    1996-03-01

    1. The effect of clofibrate (CFB), bezafibrate (BFB), and gemfibrozil (GFB) on plasma lipoprotein (VLDL and LDL) concentration, composition and resistance to copper-induced oxidation has been studied in male Sprague-Dawley rats after a 15 day treatment. 2. Plasma triglyceride levels were reduced by CFB (41%) and BFB (39%). This effect was related to a significant reduction (67% for CFB and 56% for BFB) in the amount of circulating VLDL-protein. 3. Plasma total cholesterol was reduced by 28% and 45% in CFB- and BFB-treated animals, respectively, mainly by modification of the cholesteryl ester fraction. In contrast, GFB significantly increased total cholesterol (27%). No modification in the LDL protein or lipid content was introduced by fibrates, although GFB decreased the proportion of LDL-triglycerides, at the expense of an increase in total cholesterol. 4. The fatty acid species carried by VLDL and LDL were affected after fibrate treatment. In general, both particles showed an increase in monounsaturated fatty acids (MUFA) (18:1) and a decrease in polyunsaturated fatty acids (PUFA) species (18:2 n-6, 20:4 n-6, 18:3 n-3, 20:5 n-3). As a consequence, the ratio of PUFA/(SFA+MUFA) for the whole lipoproteins was markedly reduced. 5. The degree of copper-induced VLDL- and LDL-oxidation was assessed by means of the analysis of lysine content, thiobarbituric acid reactive substances (TBARS) production and conjugated dienes formation. Lipoproteins obtained from fibrate-treated rats were more resistant to the oxidative challenge. For each lipoprotein, BFB was the most effective drug, followed by CFB and GFB. 6. The observed antioxidant effect can be ascribed to two independent phenomena produced by fibrates: the reduction of the amount of substrate for the oxidation process due to their hypolipidemic activity, and the alteration in the type of fatty acids transported by the lipoproteins towards an enrichment in species resistant to the oxidation process. 7. As similar

  5. A Novel Approach to Decrease Sialic Acid Expression in Cells by a C-3-modified N-Acetylmannosamine*

    PubMed Central

    Wratil, Paul R.; Rigol, Stephan; Solecka, Barbara; Kohla, Guido; Kannicht, Christoph; Reutter, Werner; Giannis, Athanassios; Nguyen, Long D.

    2014-01-01

    Due to its position at the outermost of glycans, sialic acid is involved in a myriad of physiological and pathophysiological cell functions such as host-pathogen interactions, immune regulation, and tumor evasion. Inhibitors of cell surface sialylation could be a useful tool in cancer, immune, antibiotic, or antiviral therapy. In this work, four different C-3 modified N-acetylmannosamine analogs were tested as potential inhibitors of cell surface sialylation. Peracetylated 2-acetylamino-2-deoxy-3-O-methyl-d-mannose decreases cell surface sialylation in Jurkat cells in a dose-dependent manner up to 80%, quantified by flow cytometry and enzyme-linked lectin assays. High-performance liquid chromatography experiments revealed that not only the concentration of membrane bound but also of cytosolic sialic acid is reduced in treated cells. We have strong evidence that the observed reduction of sialic acid expression in cells is caused by the inhibition of the bifunctional enzyme UDP-GlcNAc-2-epimerase/ManNAc kinase. 2-Acetylamino-2-deoxy-3-O-methyl-d-mannose inhibits the human ManNAc kinase domain of the UDP-GlcNAc-2-epimerase/ManNAc kinase. Binding kinetics of the inhibitor and human N-acetylmannosamine kinase were evaluated using surface plasmon resonance. Specificity studies with human N-acetylglucosamine kinase and hexokinase IV indicated a high specificity of 2-acetylamino-2-deoxy-3-O-methyl-d-mannose for MNK. This substance represents a novel class of inhibitors of sialic acid expression in cells, targeting the key enzyme of sialic acid de novo biosynthesis. PMID:25278018

  6. Catha Edulis (Khat) Chewing Decreases Serum Levels of Iron, Ferritin and Vitamin B12 and Increases Folic Acid.

    PubMed

    Al-Dubai, Waled; Al-Ghazaly, Jameel; Al-Habori, Molham; Saif-Ali, Riyadh; Mohammed, Ahmed

    2014-01-01

    Catha edulis (Khat) is customarily chewed to attain a state of stimulation and reduce physical fatigue. In view of the reported common adverse effects of Khat, the aim of this study was to evaluate the levels of iron, ferritin, folic acid, vitamin B(12) and body mass index (BMI) as nutritive indicators in Yemeni Khat chewers. This study was a prospective cohort study, carried out on 90 male workers aged 19 - 23 years old; 45 were healthy non-Khat chewers serving as control group and 45 were regular Khat chewers. Serum iron, ferritin, folic acid, vitamin B(12) and body mass index were measured at baseline and after a year of follow up. Serum iron and BMI were significantly (p < 0.01) lower at baseline in Khat chewers by 9 % and 6 %, respectively; whereas ferritin, folic acid and vitamin B(12) were non-significantly different from non-Khat chewers. In the follow-up one year later, serum iron, ferritin, vitamin B(12) and BMI were significantly (p < 0.001) lower in Khat chewers by 19.0, 31.4, 20.6 and 10.7 %; whereas folic acid was significantly (p = 0.007) higher by 26.7 %. Comparison within groups showed serum iron, ferritin, and BMI to be significantly (p < 0.01) decreased after one year in the Khat chewers with respect to its baseline; whereas folic acid significantly (p < 0.001) increased. This study shows Khat chewers to be more susceptible to malnutrition, which should be considered by the general population and the public health authorities.

  7. Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension.

    PubMed

    Fogari, Roberto; Zoppi, Annalisa; Salvadeo, Sibilla A T; Mugellini, Amedeo; Lazzari, Pierangelo; Santoro, Tara; Derosa, Giuseppe

    2011-04-01

    The aim of this study was to evaluate the effects of imidapril and candesartan on fibrinolysis and insulin sensitivity in normoweight hypertensive patients. After a 2-week wash-out period, 61 patients with mild-to-moderate hypertension were randomized to imidapril or candesartan for 12 weeks. Blood pressure (BP), plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen activities were evaluated at baseline and during treatment. The patients underwent a euglycemic-hyperinsulinemic clamp (insulin sensitivity was evaluated as glucose infusion rate during the last 30 min) and a desmopressin test (with desmopressin infusion in the brachial artery) to evaluate endothelial ability to release t-PA. Imidapril and candesartan induced similar systolic/diastolic BP reductions (-16/12.6 and -16.1/12.2 mm Hg, respectively, P<0.001 vs. baseline). Imidapril increased glucose infusion rate (+1.1 mg min(-1) per kg, P<0.02), whereas candesartan did not change it. Both drugs decreased PAI-1 antigen activity after 4 weeks of treatment; subsequently, only the decreasing effect of imidapril was sustained throughout the 12 weeks, whereas candesartan increased PAI-1 activity at week 12 (P<0.05 vs. baseline, P<0.01 vs. imidapril). Activity of t-PA decreased with candesartan (from 0.48±0.16 to 0.43±0.14 IU ml(-1), P<0.05) but not with imidapril. Activity of t-PA in response to desmopressin was increased more by imidapril (+4.45 IU ml(-1)) than by candesartan (+2.73 IU ml(-1), P<0.01 vs. imidapril). These results indicate that in normoweight hypertensive patients, despite similar BP reduction, imidapril but not candesartan improved the fibrinolytic balance, suggesting that mechanisms other than Ang II inhibition, possibly including bradykinin-mediated effects on insulin sensitivity and endothelial function, may be responsible for these different effects.

  8. Dietary conjugated linoleic acids increase intramuscular fat deposition and decrease subcutaneous fat deposition in Yellow Breed × Simmental cattle.

    PubMed

    Zhang, Haibo; Dong, Xianwen; Wang, Zhisheng; Zhou, Aiming; Peng, Quanhui; Zou, Huawei; Xue, Bai; Wang, Lizhi

    2016-04-01

    This study was conducted to estimate the effect of dietary conjugated linoleic acids (CLA) on intramuscular and subcutaneous fat deposition in Yellow Breed × Simmental cattle. The experiment was conducted for 60 days. The results showed that the average backfat thickness, (testicles + kidney + pelvic) fat percentage and subcutaneous fat percentage in dietary CLA were significantly lower than in the control group, while intramuscular the fat percentage was significantly higher. Compared to the control group, the Longissimus muscle enzyme activities of lipoprotein lipase (LPL), fatty acid synthase (FAS) and acetyl-coenzyme A carboxylase (ACC) in dietary CLA and the subcutaneous fat enzyme activities of LPL, hormone-sensitive lipase (HSL) and carnitine palmitoyltransferase-1 (CPT-1) were significantly increased. Similarly, compared to the control group, the Longissimus muscle sterol regulatory element binding protein 1 (SREBP-1), FAS, stearoyl-coenzyme A desaturase (SCD), ACC, peroxisome proliferator-activated receptor γ (PPARγ), heart fatty-acid binding protein (H-FABP) and LPL gene expression in dietary CLA were significant increased, as were the subcutaneous fat of PPARγ, H-FABP, LPL, CPT-1 and HSL in dietary CLA. These results indicated that dietary CLA increases IMF deposition mainly by the up-regulation of lipogenic gene expression, while decreasing subcutaneous fat deposition mainly by the up-regulation of lipolytic gene expression. © 2015 Japanese Society of Animal Science.

  9. cAMP and forskolin decrease. gamma. -aminobutyric acid-gated chloride flux in rat brain synaptoneurosomes

    SciTech Connect

    Heuschneider, G.; Schwartz, R.D. )

    1989-04-01

    The effects of the cyclic nucleotide cAMP on {gamma}-aminobutyric acid-gated chloride channel function were investigated. The membrane-permeant cAMP analog N{sup 6}, O{sup 2{prime}}-dibutyryladenosine 3{prime},5{prime}-cyclic monophosphate inhibited muscimol-induced {sup 36}Cl{sup {minus}} uptake into rat cerebral cortical synaptoneurosomes in a concentration-dependent manner. The inhibition was due to a decrease in the maximal effect of muscimol, with no change in potency. Similar effects were observed with 8-(4-chlorophenylthio)adenosine 3{prime},5{prime}-cyclic monophosphate, 8-bromoadenosine 3{prime},5{prime}-cyclic monophosphate, and the phosphodiesterase inhibitor isobutylmethylxanthine. The effect of endogenous cAMP accumulation on the {gamma}-aminobutyric acid-gated Cl{sup {minus}} channel was studied with forskolin, an activator of adenylate cyclase. Under identical conditions, in the intact synaptoneurosomes, forskolin inhibited muscimol-induced {sup 36}Cl{sup {minus}} uptake and generated cAMP with similar potencies. Surprisingly, 1,9-dideoxyforskolin, which does not activate adenylate cyclase, also inhibited the muscimol response, suggesting that forskolin and its lipophilic derivatives may interact with the Cl{sup {minus}} channel directly. The data suggest that {gamma}-aminobutyric acid (GABA{sub A}) receptor function in brain can be regulated by cAMP-dependent phosphorylation.

  10. Melinjo (Gnetum gnemon L.) Seed Extract Decreases Serum Uric Acid Levels in Nonobese Japanese Males: A Randomized Controlled Study

    PubMed Central

    Kanai, Yoshiaki; Katagiri, Mikiyuki; Mori, Akemi; Tatefuji, Tomoki

    2013-01-01

    Melinjo (Gnetum gnemon L.) seed extract (MSE) containing trans-resveratrol (3,5,4′-trihydroxy-trans-stilbene) and other derivatives exerts various beneficial effects. However, its mechanism of action in humans remains unknown. In this study, we aimed to investigate beneficial effects of MSE in healthy adult males. In this double-blind, randomized controlled study, 30 males aged 35–70 years with ≤10% flow-mediated dilatation received placebo or 750 mg MSE powder for 8 weeks, and twenty-nine males (45.1 ± 8.8 years old) completed the trial. There was a significant difference in the melinjo and placebo groups. Compared with the placebo control, MSE significantly reduced serum uric acid at 4 weeks and 8 weeks (n = 14 and 15, resp.). HDL cholesterol was significantly increased in the melinjo group. To clarify the mechanism of MSE for reducing uric acid, we investigated xanthine oxidase inhibitory activity, angiotensin II type 1 (AT1) receptor binding inhibition rate, and agonistic activities for PPARα and PPARγ. MSE, trans-resveratrol, and a resveratrol dimer, gnetin C (GC), significantly inhibit AT1 receptor binding and exhibit mild agonistic activities for PPARα and PPARγ. In conclusion, MSE may decrease serum uric acid regardless of insulin resistance and may improve lipid metabolism by increasing HDL cholesterol. PMID:24454499

  11. Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction.

    PubMed

    Naidoo, V; Swan, G E

    2009-04-01

    Diclofenac (DF), a non-steroidal anti-inflammatory drug (NSAID), is largely regarded as one of the most devastating environmental toxicant in recent times, after accidental exposure via their food-chain lead to massive mortalities in three vulture species on the Asian subcontinent. Although the use of diclofenac was recently banned on the Indian subcontinent, following the favourable safety profile of meloxicam, its mechanism of toxicity remains unknown. In an attempt to establish this mechanism, we test three hypotheses using models established from either the domestic chicken (Gallus domesticus) or the African White-backed vulture (Gyps africanus). We demonstrate that both DF and meloxicam are toxic to renal tubular epithelial (RTE) cells following 12 h of exposure, due to an increase in production of reactive oxygen species (ROS), which could be temporarily ameliorated by pre-incubation with uric acid (UA). When cultures were incubated with either drug for only 2 h, meloxicam showed no toxicity in contrast to diclofenac. In both cases no increase in ROS production was evident. In addition, diclofenac decreased the transport of uric acid, by interfering with the p-amino-hippuric acid (PAH) channel. We conclude that vulture susceptibility to diclofenac results from a combination of an increased ROS, interference with UA transport and the duration of exposure.

  12. Presumed case of "stiff-horse syndrome" caused by decreased gamma-aminobutyric acid (GABA) production in an American Paint mare.

    PubMed

    Purcell, Tawna Backman; Sellers, Ann Davidson; Goehring, Lutz S

    2012-01-01

    Glutamic acid decarboxylase (GAD) converts glutamic acid into the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Increased serum GAD (auto) antibody concentrations were found in a mare with increased postural musculature tone resulting in stiffness and recumbence. The mare was treated with dexamethasone which resulted in resolution of clinical signs and decreased GAD antibody concentrations.

  13. Decreased long-chain fatty acid oxidation impairs postischemic recovery of the insulin-resistant rat heart.

    PubMed

    Harmancey, Romain; Vasquez, Hernan G; Guthrie, Patrick H; Taegtmeyer, Heinrich

    2013-10-01

    Diabetic patients with acute myocardial infarction are more likely to die than nondiabetic patients. In the present study we examined the effect of insulin resistance on myocardial ischemia tolerance. Hearts of rats, rendered insulin resistant by high-sucrose feeding, were subjected to ischemia/reperfusion ex vivo. Cardiac power of control hearts from chow-fed rats recovered to 93%, while insulin-resistant hearts recovered only to 80% (P<0.001 vs. control). Unexpectedly, impaired contractile recovery did not result from an impairment of glucose oxidation (576±36 vs. 593±42 nmol/min/g dry weight; not significant), but from a failure to increase and to sustain oxidation of the long-chain fatty acid oleate on reperfusion (1878±56 vs. 2070±67 nmol/min/g dry weight; P<0.05). This phenomenon was due to a reduced ability to transport oleate into mitochondria and associated with a 38-58% decrease in the mitochondrial uncoupling protein 3 (UCP3) levels. Contractile function was rescued by replacing oleate with a medium-chain fatty acid or by restoring UCP3 levels with 24 h of food withdrawal. Lastly, the knockdown of UCP3 in rat L6 myocytes also decreased oleate oxidation by 13-18% following ischemia. Together the results expose UCP3 as a critical regulator of long-chain fatty acid oxidation in the stressed heart postischemia and identify octanoate as an intervention by which myocardial metabolism can be manipulated to improve function of the insulin-resistant heart.

  14. Hippocampal interneurons expressing glutamic acid decarboxylase and calcium-binding proteins decrease with aging in Fischer 344 rats.

    PubMed

    Shetty, A K; Turner, D A

    1998-05-04

    Aging leads to alterations in the function and plasticity of hippocampal circuitry in addition to behavioral changes. To identify critical alterations in the substrate for inhibitory circuitry as a function of aging, we evaluated the numbers of hippocampal interneurons that were positive for glutamic acid decarboxylase and those that expressed calcium-binding proteins (parvalbumin, calbindin, and calretinin) in young adult (4-5 months old) and aged (23-25 months old) male Fischer 344 rats. Both the overall interneuron population and specific subpopulations of interneurons demonstrated a commensurate decline in numbers throughout the hippocampus with aging. Interneurons positive for glutamic acid decarboxylase were significantly depleted in the stratum radiatum of CA1, the strata oriens, radiatum and pyramidale of CA3, the dentate molecular layer, and the dentate hilus. Parvalbumin interneurons showed significant reductions in the strata oriens and pyramidale of CA1, the stratum pyramidale of CA3, and the dentate hilus. The reductions in calbindin interneurons were more pronounced than other calcium-binding protein-positive interneurons and were highly significant in the strata oriens and radiatum of both CA1 and CA3 subfields and in the dentate hilus. Calretinin interneurons were decreased significantly in the strata oriens and radiatum of CA3, in the dentate granule cell and molecular layers, and in the dentate hilus. However, the relative ratio of parvalbumin-, calbindin-, and calretinin-positive interneurons compared with glutamic acid decarboxylase-positive interneurons remained constant with aging, suggesting actual loss of interneurons expressing calcium-binding proteins with age. This loss contrasts with the reported preservation of pyramidal neurons with aging in the hippocampus. Functional decreases in inhibitory drive throughout the hippocampus may occur due to this loss, particularly alterations in the processing of feed-forward information through the

  15. Relationship of decreased hepatic lipase activity and lipoprotein abnormalities to essential fatty acid deficiency in cystic fibrosis patients.

    PubMed

    Lévy, E; Lepage, G; Bendayan, M; Ronco, N; Thibault, L; Galéano, N; Smith, L; Roy, C C

    1989-08-01

    Polyunsaturated fatty acids are known to affect plasma lipids and lipoproteins but there is no information on the effect of essential fatty acid (EFA) deficiency on lipoprotein composition. The purpose of this study was to characterize lipoproteins from 17 cystic fibrosis (CF) patients in relationship to their EFA status (eicosatrienoic/arachidonic acid ratio) and compare them with those of 10 healthy siblings (SIB) and of 10 unrelated controls. In 7 EFA-deficient (EFAD) and 10 EFA-sufficient (EFAS) patients, hypocholesterolemia was associated with a decrease of HDL-cholesterol and of LDL-cholesterol which was more marked in the EFAD group. Similarly, although triglyceride enrichment of VLDL, LDL, HDL2, and HDL3 with a concomitant reduction of cholesteryl esters from all particles except HDL2 was observed in both CF groups, it was more sizable in the EFAD patients. These changes led to an increase in the particle size of VLDL, LDL, and HDL2 whereas the distribution of HDL3 was skewed to smaller particles. Alterations in the apoprotein composition of particles were greater in EFAD than in EFAS. A decrease of total postheparin lipolytic activity was observed in the two groups of CF patients as well as in siblings. It was entirely accounted for by hepatic lipase (mumol FFA/ml per h) which was more severely diminished in EFAD (2.8 +/- 0.6) than in EFAS (4.4 +/- 0.7) and SIB (5.1 +/- 0.5). Although the two groups of CF children differed in terms of growth, severity of malabsorption, and vitamin E status, these data suggest that disturbance of lipoprotein concentration, composition, size, and metabolism (hepatic lipase) may be in part related to EFA deficiency. Further studies are necessary to explore the effect of EFA deficiency on hepatic lipase activity.

  16. An unprotected conjugated linoleic acid supplement decreases milk production and secretion of milk components in grazing dairy ewes.

    PubMed

    Oliveira, D E; Gama, M A S; Fernandes, D; Tedeschi, L O; Bauman, D E

    2012-03-01

    Feeding conjugated linoleic acid (CLA) in a rumen-inert form to dairy ewes has been shown to increase milk production, alter milk composition, and increase the milk fat CLA content. However, few studies have tested ruminally unprotected CLA sources. The objective of this study was to evaluate the effects of an unprotected CLA supplement (29.8% of cis-9,trans-11 and 29.9% of trans-10,cis-12 isomers as methyl esters) on milk yield and composition of dairy ewes. Twenty-four lactating Lacaune ewes were used in a crossover design and received 2 dietary treatments: (1) control: basal diet containing no supplemental lipid and (2) basal diet plus CLA (30 g/d). The CLA supplement was mixed into the concentrate and fed in 2 equal meals after morning and afternoon milkings. Each experimental period consisted of 21 d: 7 d for adaptation and 14 d for data collection. The CLA supplement decreased milk fat content and yield by 31.3 and 38.0%, respectively. Milk yield and secretion of milk lactose and protein were decreased by 8.0, 9.8, and 5.6%, respectively. On the other hand, milk protein content and linear SCC score were 1.8 and 17.7% higher in ewes fed the CLA supplement. The concentration of milk fatty acids originating from de novo synthesis (decreased by 25%, whereas the concentration of milk fatty acids taken up preformed from the plasma (>C16) was increased by 22.6% in ewes fed the CLA supplement. The CLA supplement decreased C14:1/C14:0, C16:1/C16:0, and C18:1/C18:0 desaturase indexes by 25, 18.7, and 0.1%, respectively, but increased the cis-9,trans-11 CLA/trans-11 C18:1 ratio by 8.6%. The concentrations of trans-10,cis-12 CLA and cis-9,trans-11 CLA in milk fat was 309 and 33.4% higher in ewes fed CLA. Pronounced milk fat depression coupled with the deleterious effects on milk yield, milk SCC, and secretion of all milk solids observed in ewes fed an unprotected CLA supplement is likely to be associated with high doses of trans-10,cis-12 CLA reaching the

  17. Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression.

    PubMed

    Clarke, John D; Hardwick, Rhiannon N; Lake, April D; Canet, Mark J; Cherrington, Nathan J

    2014-03-01

    Simvastatin (SIM)-induced myopathy is a dose-dependent adverse drug reaction (ADR) that has been reported to occur in 18.2% of patients receiving a 40- to 80-mg dose. The pharmacokinetics of SIM hydroxy acid (SIMA), the bioactive form of SIM, and the occurrence of SIM-induced myopathy are linked to the function of the organic anion transporting polypeptide (Oatp) hepatic uptake transporters. Genetic polymorphisms in SLCO1B1, the gene for human hepatic OATP1B1, cause decreased elimination of SIMA and increased risk of developing myopathy. Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease, and is known to alter drug transporter expression and drug disposition. The purpose of this study was to assess the metabolism and disposition of SIM in a diet-induced rodent model of NASH. Rats were fed a methionine- and choline-deficient diet for 8 weeks to induce NASH and SIM was administered intravenously. Diet-induced NASH caused increased plasma retention and decreased biliary excretion of SIMA due to decreased protein expression of multiple hepatic Oatps. SIM exhibited increased volume of distribution in NASH as evidenced by increased muscle, decreased plasma, and no change in biliary concentrations. Although Cyp3a and Cyp2c11 proteins were decreased in NASH, no alterations in SIM metabolism were observed. These data, in conjunction with our previous data showing that human NASH causes a coordinated downregulation of hepatic uptake transporters, suggest that NASH-mediated transporter regulation may play a role in altered SIMA disposition and the occurrence of myopathy.

  18. Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid.

    PubMed

    Nicolini, Chiara; Ahn, Younghee; Michalski, Bernadeta; Rho, Jong M; Fahnestock, Margaret

    2015-01-20

    The molecular mechanisms underlying autistic behaviors remain to be elucidated. Mutations in genes linked to autism adversely affect molecules regulating dendritic spine formation, function and plasticity, and some increase the mammalian target of rapamycin, mTOR, a regulator of protein synthesis at spines. Here, we investigated whether the Akt/mTOR pathway is disrupted in idiopathic autism and in rats exposed to valproic acid, an animal model exhibiting autistic-like behavior. Components of the mTOR pathway were assayed by Western blotting in postmortem fusiform gyrus samples from 11 subjects with idiopathic autism and 13 controls and in valproic acid versus saline-exposed rat neocortex. Additionally, protein levels of brain-derived neurotrophic factor receptor (TrkB) isoforms and the postsynaptic organizing molecule PSD-95 were measured in autistic versus control subjects. Full-length TrkB, PI3K, Akt, phosphorylated and total mTOR, p70S6 kinase, eIF4B and PSD-95 were reduced in autistic versus control fusiform gyrus. Similarly, phosphorylated and total Akt, mTOR and 4E-BP1 and phosphorylated S6 protein were decreased in valproic acid- versus saline-exposed rats. However, no changes in 4E-BP1 or eIF4E were found in autistic brains. In contrast to some monogenic disorders with high rates of autism, our data demonstrate down-regulation of the Akt/mTOR pathway, specifically via p70S6K/eIF4B, in idiopathic autism. These findings suggest that disruption of this pathway in either direction is widespread in autism and can have adverse consequences for synaptic function. The use of valproic acid, a histone deacetylase inhibitor, in rats successfully modeled these changes, implicating an epigenetic mechanism in these pathway disruptions.

  19. Decreased Hepatocyte Growth Factor (HGF) and Gamma Aminobutyric Acid (GABA) in Individuals with Obsessive-Compulsive Disorder (OCD).

    PubMed

    Russo, Anthony J; Pietsch, Stefanie C

    2013-01-01

    There is support for the role of gamma aminobutyric acid (GABA) in the etiology of mood disorders. Recent research has shown that hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility. This study was designed to determine and correlate plasma levels of HGF and GABA as well as symptom severity in individuals with obsessive-compulsive disorder (OCD). Plasma from 15 individuals with OCD (9 males, 6 females;, mean age 38.7 years) and 17 neurotypical controls (10 males, 7 females; mean age 35.2 years) was assessed for HGF, GABA, urokinase plasminogen activator (uPA), and urokinase plasminogen activator receptor (uPAR) concentration using enzyme-linked immunosorbest assays ELISAs. Symptom severity was assessed in these OCD individuals and compared with HGF and GABA concentrations. In this preliminary study, individuals with OCD had significantly decreased HGF levels, decreased plasma levels of GABA and decreased uPA. We found that both uPA and uPAR levels correlate with HGF. Both low uPA and low uPAR levels correlate with high symptom severity in individuals with OCD. Low GABA levels in OCD individuals also correlate with high symptom severity. These results demonstrate a preliminary association between HGF, GABA, uPA levels, and OCD and suggest that plasma GABA and uPA levels are related to symptom severity in individuals with OCD.

  20. D-dimer: An Overview of Hemostasis and Fibrinolysis, Assays, and Clinical Applications.

    PubMed

    Olson, John D

    2015-01-01

    D-dimer is the smallest fibrinolysis-specific degradation product found in the circulation. The origins, assays, and clinical use of D-dimer will be addressed. Hemostasis (platelet and vascular function, coagulation, fibrinolysis, hemostasis) is briefly reviewed. D-dimer assays are reviewed. The D-dimer is very sensitive to intravascular thrombus and may be markedly elevated in disseminated intravascular coagulation, acute aortic dissection, and pulmonary embolus. Because of its exquisite sensitivity, negative tests are useful in the exclusion venous thromboembolism. Elevations occur in normal pregnancy, rising two- to fourfold by delivery. D-dimer also rises with age, limiting its use in those >80 years old. There is a variable rise in D-dimer in active malignancy and indicates increased thrombosis risk in active disease. Elevated D-dimer following anticoagulation for a thrombotic event indicates increased risk of recurrent thrombosis. These and other issues are addressed.

  1. Fibrinolysis during anaphylaxis, and its spontaneous resolution, as demonstrated by thromboelastography.

    PubMed

    Iqbal, A; Morton, C; Kong, K-L

    2010-08-01

    A large and ever-growing number of agents used in anaesthesia can precipitate acute anaphylactic reactions after their administration. Anaphylaxis is a sudden onset (or rapidly progressive), severe systemic allergic reaction, affecting multiple organ systems. The number of people who suffer severe systemic allergic reactions is increasing. The incidence is about 1-3 reactions per 10 000 population per annum, although anaphylaxis is not always recognized; therefore, certain UK studies may underestimate the incidence. In this case report, we present an episode of acute fibrinolysis associated with life-threatening anaphylaxis, demonstrated by thromboelastography (TEG) and resolving spontaneously. This is despite an added fibrinolytic insult in the form of cardiopulmonary bypass. There is a paucity of literature detailing fibrinolysis occurring during anaphylaxis, most likely due to the limited availability of TEG in the acute setting and the primary clinical focus of delivering life-saving interventions.

  2. Hormone-sensitive lipase activity and triacylglycerol hydrolysis are decreased in rat soleus muscle by cyclopiazonic acid.

    PubMed

    Watt, Matthew J; Steinberg, Gregory R; Heigenhauser, G J F; Spriet, Lawrence L; Dyck, David J

    2003-08-01

    Cyclopiazonic acid (CPA) is a sarcoplasmic reticulum Ca2+-ATPase inhibitor that increases intracellular calcium. The role of CPA in regulating the oxidation and esterification of palmitate, the hydrolysis of intramuscular lipids, and the activation of hormone-sensitive lipase (HSL) was examined in isolated rat soleus muscles at rest. CPA (40 micro M) was added to the incubation medium to levels that resulted in subcontraction increases in muscle tension, and lipid metabolism was monitored using the previously described pulse-chase procedure. CPA did not alter the cellular energy state, as reflected by similar muscle contents of ATP, phosphocreatine, free AMP, and free ADP. CPA increased total palmitate uptake into soleus muscle (11%, P < 0.05) and was without effect on palmitate oxidation. This resulted in greater esterification of exogenous palmitate into the triacylglycerol (18%, P < 0.05) and phospholipid (89%, P < 0.05) pools. CPA decreased (P < 0.05) intramuscular lipid hydrolysis, and this occurred as a result of reduced HSL activity (20%, P < 0.05). Incubation of muscles with 3 mM caffeine, which is also known to increase Ca2+ without affecting the cellular energy state, reduced HSL activity (24%, P < 0.05). KN-93, a calcium/calmodulin-dependent kinase inhibitor (CaMKII), blocked the effects of CPA and caffeine, and HSL activity returned to preincubation values. The results of the present study demonstrate that CPA simultaneously decreases intramuscular triacylglycerol (IMTG) hydrolysis and promotes lipid storage in isolated, intact soleus muscle. The decreased IMTG hydrolysis is likely mediated by reduced HSL activity, possibly via the CaMKII pathway. These responses are not consistent with the increased hydrolysis and decreased esterification observed in contracting muscle when substrate availability and the hormonal milieu are tightly controlled. It is possible that more powerful signals or a higher [Ca2+] may override the lipid-storage effect of the CPA

  3. The impact of angiotensin II receptor blockade and the DASH diet on markers of endogenous fibrinolysis.

    PubMed

    Erlinger, T P; Conlin, P R; Macko, R F; Bohannon, A D; Miller, E R; Moore, T J; Svetkey, L P; Appel, L J

    2002-06-01

    Hypertension is associated with impaired fibrinolysis. Both angiotensin receptor blockers (ARB) and the DASH (Dietary Approaches to Stop Hypertension) diet effectively lower blood pressure in hypertensive patients. Some evidence suggests that treatment with ARBs could increase fibrinolysis, however, data is conflicting. The impact of the DASH diet on fibrinolytic parameters is not known. Fifty-five hypertensive participants (35 African-American, 20 white) were randomly assigned to receive 8 weeks of either a control diet or the DASH diet. The diets did not differ in sodium content (approximately 3 g/day). Within each diet, individuals were randomly assigned to receive losartan or placebo for 4 weeks in double-blind, cross-over fashion. Tissue plasminogen activator (t-PA) antigen, t-PA activity, plasminogen activator inhibitor-1 (PAI-1) activity and plasma renin activity (PRA) were measured at the end of a 2-week run-in period on the control diet and after each treatment period. The DASH diet did not affect markers of fibrinolysis. Losartan significantly lowered t-PA antigen levels (-1.8 ng/mL, P = 0.045), but had no effect on t-PA or PAI-1 activities. This effect was more pronounced in whites (-4.1 ng/mL (P = 0.003)) compared with African-Americans (-0.3 ng/mL (P = 0.7), P-interaction = 0.03). Results were not materially affected by adjustment for basline values or changes in blood pressure. This study demonstrates that losartan reduces t-PA antigen levels in white, but not African-American hypertensive individuals. In contrast, the DASH diet had no significant effect on markers of fibrinolysis in whites or African-Americans.

  4. Phospholipid barrier to fibrinolysis: role for the anionic polar head charge and the gel phase crystalline structure.

    PubMed

    Váradi, Balázs; Kolev, Krasimir; Tenekedjiev, Kiril; Mészáros, Gyöngyi; Kovalszky, Ilona; Longstaff, Colin; Machovich, Raymund

    2004-09-17

    The massive presence of phospholipids is demonstrated in frozen sections of human arterial thrombi. Purified platelet phospholipids and synthetic phospholipids retard in vitro tissue-type plasminogen activator (tPA)-induced fibrinolysis through effects on plasminogen activation and plasmin function. The inhibition of plasminogen activation on the surface of fibrin correlates with the fraction of anionic phospholipid. The phospholipids decrease the amount of tPA penetrating into the clot by 75% and the depth of the reactive surface layer occupied by the activator by up to 30%, whereas for plasmin both of these parameters decrease by approximately 50%. The phospholipids are not only a diffusion barrier, they also bind the components of the fibrinolytic system. Isothermal titration calorimetry shows binding characterized with dissociation constants in the range 0.35-7.64 microm for plasmin and tPA (lower values with more negative phospholipids). The interactions are endothermic and thermodynamically driven by an increase in entropy, probably caused by the rearrangements in the ordered gel structure of the phospholipids (in line with the stronger inhibition at gel phase temperatures compared with liquid crystalline phase temperatures). These findings show a phospholipid barrier, which should be overcome during lysis of arterial thrombi.

  5. Decrease of Population Divergence in Eurasian Perch (Perca fluviatilis) in Browning Waters: Role of Fatty Acids and Foraging Efficiency.

    PubMed

    Scharnweber, Kristin; Strandberg, Ursula; Karlsson, Konrad; Eklöv, Peter

    2016-01-01

    Due to altered biogeochemical processes related to climate change, highly colored dissolved organic carbon (DOC) from terrestrial sources will lead to a water "brownification" in many freshwater systems of the Northern Hemisphere. This will create deteriorated visual conditions that have been found to affect habitat-specific morphological variations in Eurasian perch (Perca fluviatilis) in a previous study. So far, potential drivers and ultimate causes of these findings have not been identified. We conducted a field study to investigate the connection between morphological divergence and polyunsaturated fatty acid (PUFA) composition of perch from six lakes across a gradient of DOC concentration. We expected a decrease in the prevalence of PUFAs, which are important for perch growth and divergence with increasing DOC concentrations, due to the restructuring effects of DOC on aquatic food webs. In general, rate of morphological divergence in perch decreased with increasing DOC concentrations. Proportions of specific PUFAs (22:6n-3, 18:3n-3, 20:5n-3, and 20:4n-6) identified to primarily contribute to overall differences between perch caught in clear and brown-water lakes tended to be connected to overall decline of morphological divergence. However, no overall significant relationship was found, indicating no severe limitation of essential fatty acids for perch inhabiting brown water lakes. We further broaden our approach by conducting a laboratory experiment on foraging efficiency of perch. Therefore, we induced pelagic and littoral phenotypes by differences in habitat-structure and feeding mode and recorded attack rate in a feeding experiment. Generally, fish were less efficient in foraging on littoral prey (Ephemeroptera) when visual conditions were degraded by brown water color. We concluded that browning water may have a strong effect on the forager's ability to find particular food resources, resulting in the reduced development of evolutionary traits, such as

  6. Decrease of Population Divergence in Eurasian Perch (Perca fluviatilis) in Browning Waters: Role of Fatty Acids and Foraging Efficiency

    PubMed Central

    Scharnweber, Kristin; Strandberg, Ursula; Karlsson, Konrad; Eklöv, Peter

    2016-01-01

    Due to altered biogeochemical processes related to climate change, highly colored dissolved organic carbon (DOC) from terrestrial sources will lead to a water “brownification” in many freshwater systems of the Northern Hemisphere. This will create deteriorated visual conditions that have been found to affect habitat-specific morphological variations in Eurasian perch (Perca fluviatilis) in a previous study. So far, potential drivers and ultimate causes of these findings have not been identified. We conducted a field study to investigate the connection between morphological divergence and polyunsaturated fatty acid (PUFA) composition of perch from six lakes across a gradient of DOC concentration. We expected a decrease in the prevalence of PUFAs, which are important for perch growth and divergence with increasing DOC concentrations, due to the restructuring effects of DOC on aquatic food webs. In general, rate of morphological divergence in perch decreased with increasing DOC concentrations. Proportions of specific PUFAs (22:6n-3, 18:3n-3, 20:5n-3, and 20:4n-6) identified to primarily contribute to overall differences between perch caught in clear and brown-water lakes tended to be connected to overall decline of morphological divergence. However, no overall significant relationship was found, indicating no severe limitation of essential fatty acids for perch inhabiting brown water lakes. We further broaden our approach by conducting a laboratory experiment on foraging efficiency of perch. Therefore, we induced pelagic and littoral phenotypes by differences in habitat-structure and feeding mode and recorded attack rate in a feeding experiment. Generally, fish were less efficient in foraging on littoral prey (Ephemeroptera) when visual conditions were degraded by brown water color. We concluded that browning water may have a strong effect on the forager’s ability to find particular food resources, resulting in the reduced development of evolutionary traits

  7. A Conjugate of Two tPA-Binding RNA Aptamers Efficiently Inhibits Fibrinolysis.

    PubMed

    Bjerregaard, Nils; Dupont, Daniel M; Andreasen, Peter A

    2017-04-01

    Uncontrolled bleeding is a major cause of mortality. Lysine analogues are routinely used in the management of bleeding, but several studies indicate a risk of serious detrimental effects upon their administration. In this study, we report a bivalent conjugate "3218" of two RNA aptamers selected for binding to the serine protease tissue-type plasminogen activator (tPA), the principal initiator of fibrinolysis in mammals. The constituent monomeric aptamers, K32v2 and K18v2, were previously demonstrated to weakly inhibit fibrinolysis. We now show that K32v2 and K18v2 recognize distinct binding sites, presumably in the A- and B-chain of tPA, respectively. Both aptamers bind tPA with low nanomolar affinity and inhibit tPA-mediated activities in a way that is consistent with the proposed localization of their binding sites. The 3218 conjugate possesses the inhibitory activities of both K32v2 and K18v2 and additionally exhibits increased inhibitory efficiency relative to the monomeric aptamers. The 3218 conjugate proved an efficient inhibitor of fibrinolysis and may find application in the management of bleeding as a substitute for, or in combination with, currently used lysine analogues.

  8. [Intra-arterial fibrinolysis in acute thrombosis of the basilar artery].

    PubMed

    Solaz, J; Martínez-Rodrigo, J; Lonjedo, E; Poyatos, C; Vega, M; Palmero, J

    1998-12-01

    Ischemia in the territory of the basilar artery presents with a variable clinical picture of hemiparesia-tetraplegia, progressive deterioration of level of consciousness, irregular respiration and apnea leading to irreversible coma and death in between 75% and 86% of cases. The usual treatment is supportive. We present the case of a 49 year old woman with acute thrombosis of the basilar artery and a progressive course leading to coma. No bulbar lesions were seen on the CT scan done in the Emergency Department. Thrombosis of the basilar artery and permeable bilateral carotid systems were shown on arteriography. There were no contra-indications to fibrinolysis. Following local fibrinolytic treatment with urokinase the patient had full recovery from her neurological disorder and no sequelae. The basilar artery remained permeable six months later. Emergency treatment with cerebral intra-arterial fibrinolysis within the first six hours, in a case of neurological deficit progressing in the basilar artery territory, with persistence of brain-stem functions and no signs of decerebration (provided there are no contra-indications to fibrinolysis and the initial cerebral CT scan shows no bulbar lesions) may save the patient's life, with total or partial recovery of brain-stem function.

  9. In vivo inhibition of acylpeptide hydrolase by carbapenem antibiotics causes the decrease of plasma concentration of valproic acid in dogs.

    PubMed

    Suzuki, Eiko; Nakai, Daisuke; Ikenaga, Hidenori; Fusegawa, Keiichi; Goda, Ryoya; Kobayashi, Nobuhiro; Kuga, Hiroshi; Izumi, Takashi

    2016-01-01

    1. Our previous in vitro studies suggest that inhibition of the acylpeptide hydrolase (APEH) activity as valproic acid glucuronide (VPA-G) hydrolase by carbapenems in human liver cytosol is a key process for clinical drug-drug interaction (DDI) of valproic acid (VPA) with carbapenems. Here, we investigated whether in vivo DDI of VPA with meropenem (MEPM) was caused via inhibition of APEH in dogs. 2. More rapid decrease of plasma VPA levels and increased urinary excretion of VPA-G were observed after co-administration with MEPM compared with those after without co-administration, whereas the plasma level and bile excretion of VPA-G showed no change. 3. Dog VPA-G hydrolase activity, inhibited by carbapenems, was mainly located in cytosol from both the liver and kidney. APEH-immunodepleted cytosols lacked VPA-G hydrolase activity. Hepatic and renal APEH activity was negligible even at 24 h after dosing of MEPM to a dog. 4. In conclusion, DDI of VPA with carbapenems in dogs is caused by long-lasting inhibition of APEH-mediated VPA-G hydrolysis by carbapenems, which could explain the delayed recovery of plasma VPA levels to the therapeutic window even after discontinuation of carbapenems in humans.

  10. Oleic acid increases mitochondrial reactive oxygen species production and decreases endothelial nitric oxide synthase activity in cultured endothelial cells.

    PubMed

    Gremmels, Hendrik; Bevers, Lonneke M; Fledderus, Joost O; Braam, Branko; van Zonneveld, Anton Jan; Verhaar, Marianne C; Joles, Jaap A

    2015-03-15

    Elevated plasma levels of free fatty acids (FFA) are associated with increased cardiovascular risk. This may be related to FFA-induced elevation of oxidative stress in endothelial cells. We hypothesized that, in addition to mitochondrial production of reactive oxygen species, endothelial nitric oxide synthase (eNOS)-mediated reactive oxygen species production contributes to oleic acid (OA)-induced oxidative stress in endothelial cells, due to eNOS uncoupling. We measured reactive oxygen species production and eNOS activity in cultured endothelial cells (bEnd.3) in the presence of OA bound to bovine serum albumin, using the CM-H2DCFDA assay and the L-arginine/citrulline conversion assay, respectively. OA induced a concentration-dependent increase in reactive oxygen species production, which was inhibited by the mitochondrial complex II inhibitor thenoyltrifluoroacetone (TTFA). OA had little effect on eNOS activity when stimulated by a calcium-ionophore, but decreased both basal and insulin-induced eNOS activity, which was restored by TTFA. Pretreatment of bEnd.3 cells with tetrahydrobiopterin (BH4) prevented OA-induced reactive oxygen species production and restored inhibition of eNOS activity by OA. Elevation of OA levels leads to both impairment in receptor-mediated stimulation of eNOS and to production of mitochondrial-derived reactive oxygen species and hence endothelial dysfunction.

  11. The antidiabetic drug metformin decreases mitochondrial respiration and tricarboxylic acid cycle activity in cultured primary rat astrocytes.

    PubMed

    Hohnholt, Michaela C; Blumrich, Eva-Maria; Waagepetersen, Helle S; Dringen, Ralf

    2017-03-19

    Metformin is an antidiabetic drug that is used daily by millions of patients worldwide. Metformin is able to cross the blood-brain barrier and has recently been shown to increase glucose consumption and lactate release in cultured astrocytes. However, potential effects of metformin on mitochondrial tricarboxylic acid (TCA) cycle metabolism in astrocytes are unknown. We investigated this by mapping (13) C labeling in TCA cycle intermediates and corresponding amino acids after incubation of primary rat astrocytes with [U-(13) C]glucose. The presence of metformin did not compromise the viability of cultured astrocytes during 4 hr of incubation, but almost doubled cellular glucose consumption and lactate release. Compared with control cells, the presence of metformin dramatically lowered the molecular (13) C carbon labeling (MCL) of the cellular TCA cycle intermediates citrate, α-ketoglutarate, succinate, fumarate, and malate, as well as the MCL of the TCA cycle intermediate-derived amino acids glutamate, glutamine, and aspartate. In addition to the total molecular (13) C labeling, analysis of the individual isotopomers of TCA cycle intermediates confirmed a severe decline in labeling and a significant lowering in TCA cycling ratio in metformin-treated astrocytes. Finally, the oxygen consumption of mitochondria isolated from metformin-treated astrocytes was drastically reduced in the presence of complex I substrates, but not of complex II substrates. These data demonstrate that exposure to metformin strongly impairs complex I-mediated mitochondrial respiration in astrocytes, which is likely to cause the observed decrease in labeling of mitochondrial TCA cycle intermediates and the stimulation of glycolytic lactate production. © 2017 Wiley Periodicals, Inc.

  12. Decreased bile-acid synthesis in livers of hepatocyte-conditional NADPH-cytochrome P450 reductase-null mice results in increased bile acids in serum.

    PubMed

    Cheng, Xingguo; Zhang, Youcai; Klaassen, Curtis D

    2014-10-01

    NADPH-cytochrome P450 reductase (Cpr) is essential for the function of microsomal cytochrome P450 monooxygenases (P450), including those P450s involved in bile acid (BA) synthesis. Mice with hepatocyte-specific deletion of NADPH-cytochrome P450 reductase (H-Cpr-null) have been engineered to understand the in vivo function of hepatic P450s in the metabolism of xenobiotics and endogenous compounds. However, the impact of hepatic Cpr on BA homeostasis is not clear. The present study revealed that H-Cpr-null mice had a 60% decrease in total BA concentration in liver, whereas the total BA concentration in serum was almost doubled. The decreased level of cholic acid (CA) in both serum and livers of H-Cpr-null mice is likely due to diminished enzyme activity of Cyp8b1 that is essential for CA biosynthesis. Feedback mechanisms responsible for the reduced liver BA concentrations and/or increased serum BA concentrations in H-Cpr-null mice included the following: 1) enhanced alternative BA synthesis pathway, as evidenced by the fact that classic BA synthesis is diminished but chenodeoxycholic acid still increases in both serum and livers of H-Cpr-null mice; 2) inhibition of farnesoid X receptor activation, which increased the mRNA of Cyp7a1 and 8b1; 3) induction of intestinal BA transporters to facilitate BA absorption from the intestine to the circulation; 4) induction of hepatic multidrug resistance-associated protein transporters to increase BA efflux from the liver to blood; and 5) increased generation of secondary BAs. In summary, the present study reveals an important contribution of the alternative BA synthesis pathway and BA transporters in regulating BA concentrations in H-Cpr-null mice.

  13. Decreased Bile-Acid Synthesis in Livers of Hepatocyte-Conditional NADPH–Cytochrome P450 Reductase–Null Mice Results in Increased Bile Acids in Serum

    PubMed Central

    Cheng, Xingguo; Zhang, Youcai

    2014-01-01

    NADPH–cytochrome P450 reductase (Cpr) is essential for the function of microsomal cytochrome P450 monooxygenases (P450), including those P450s involved in bile acid (BA) synthesis. Mice with hepatocyte-specific deletion of NADPH–cytochrome P450 reductase (H-Cpr-null) have been engineered to understand the in vivo function of hepatic P450s in the metabolism of xenobiotics and endogenous compounds. However, the impact of hepatic Cpr on BA homeostasis is not clear. The present study revealed that H-Cpr-null mice had a 60% decrease in total BA concentration in liver, whereas the total BA concentration in serum was almost doubled. The decreased level of cholic acid (CA) in both serum and livers of H-Cpr-null mice is likely due to diminished enzyme activity of Cyp8b1 that is essential for CA biosynthesis. Feedback mechanisms responsible for the reduced liver BA concentrations and/or increased serum BA concentrations in H-Cpr-null mice included the following: 1) enhanced alternative BA synthesis pathway, as evidenced by the fact that classic BA synthesis is diminished but chenodeoxycholic acid still increases in both serum and livers of H-Cpr-null mice; 2) inhibition of farnesoid X receptor activation, which increased the mRNA of Cyp7a1 and 8b1; 3) induction of intestinal BA transporters to facilitate BA absorption from the intestine to the circulation; 4) induction of hepatic multidrug resistance–associated protein transporters to increase BA efflux from the liver to blood; and 5) increased generation of secondary BAs. In summary, the present study reveals an important contribution of the alternative BA synthesis pathway and BA transporters in regulating BA concentrations in H-Cpr-null mice. PMID:25034404

  14. Urinary coagulation-fibrinolysis, kallirein-kinin systems and kininase in cases of preclampsia.

    PubMed

    Mutoh, S; Kobayashi, M; Hirata, J; Itoh, N; Maki, M; Komatsu, Y; Yoshida, A; Sasa, H; Kuroda, K; Kikuchi, Y

    1992-01-01

    Urinary kallikrein and kallikrein activity significantly decreased in cases of preeclampsia (u-kall./CRE.index 42.39 +/- 9.66 ng/mg, u-kall. act./CRE.index 0.26 +/- 0.06 ng/min/mg), and urinary kininase II and kininase activity significantly increased (u-kininase/CRE.index 10.91 +/- 1.26 x 10(-3) IU/min/mg, u-kininase act./CRE.index 506.37 +/- 178.45 pg/min/mg) when compared with those of normal gravidas from 28 weeks to 42 weeks of gestation (u-kall./CRE.index 189.31 +/- 14.17 ng/mg, u-kall. act./CRE index 1.08 +/- 0.10 ng/min/mg, u-kininase/CRE.index 6.24 +/- 0.31 x 10(-3) IU/min/mg, u-kininase act./CRE.index 15.64 +/- 0.10 pg/min/mg). Urinary FPA, B beta 5-42, alpha 2-PI, and alpha 2PI-plasmin-complex (PIC) significantly increased in preeclampsia (u-FPA/CRE.index 23.59 +/- 8.47 ng/mg, u-B beta/CRE.index 105.26 +/- 29.30 ng/mg, u-alpha 2PI/CRE.index 121.53 +/- 43.57 ng/mg, u-PIC/CRE index 278.39 +/- 60.50 ng/mg) when compared with those of normal control group (u-FPA/CRE.index 0.92 +/- 0.04 ng/mg, u-B beta/CRE.index 12.15 +/- 0.44 ng/mg, u-alpha 2PI/CRE.index 4.18 +/- 0.33 ng/mg, u-PIC/CRE.index 5.98 +/- 1.15 ng/mg). Urinary urokinase markedly increased and urinary D-dimer was detected in severe cases of preeclampsia (u-UK/CRE.index 58.20 +/- 43.69 ng/mg, u-D-dimer 54.76 +/- 9.89 ng/ml) when compared with those of normal control group. These findings suggest that deficiency in urinary kinin excretion may induce hypertension in addition to the changes of urinary coagulation-fibrinolysis system that represents the occurrence of either the endothelial cell injury in the glomerulus or the renal tulbular damage in mild cases of preeclampsia, eventually resulting in the intra-renal vascular coagulation.

  15. Estradiol decreases taurine level by reducing cysteine sulfinic acid decarboxylase via the estrogen receptor-α in female mice liver.

    PubMed

    Ma, Qiwang; Zhao, Jianjun; Cao, Wei; Liu, Jiali; Cui, Sheng

    2015-02-15

    Cysteine sulfinic acid decarboxylase (CSAD) and cysteine dioxygenase (CDO) are two rate-limiting enzymes in taurine de novo synthesis, and their expressions are associated with estrogen concentration. The present study was designed to determine the relationship between 17β-estradiol (E₂) and taurine in female mice liver. We initially observed the mice had lower levels of CSAD, CDO, and taurine during estrus than diestrus. We then, respectively, treated the ovariectomized mice, the cultured hepatocytes, and Hep G2 cells with different doses of E₂, and the CSAD and CDO expressions and taurine levels were analyzed. The results showed that E₂ decreased taurine level in the serum and the cultured cells by inhibiting CSAD and CDO expressions. Furthermore, we identified the molecular receptor types through which E₂ plays its role in regulating taurine synthesis, and our results showed that estrogen receptor-α (ERα) expression was much higher than estrogen receptor-β (ERβ) in the liver and hepatocytes, and the inhibiting effects of E₂ on CSAD, CDO, and taurine level were partially abrogated in the ICI-182,780-pretreated liver and hepatocytes, and in ERα knockout mice. These results indicate that estradiol decreases taurine content by reducing taurine biosynthetic enzyme expression in mice liver.

  16. [Characteristics of the indicators of the blood coagulation and fibrinolysis systems in the pre-clinical stage of ischemic heart disease].

    PubMed

    Andreenko, G V; Panchenko, V M; Lisina, A N; Liutova, L V

    1978-10-01

    Signs of dysfunction of the coagulation system and fibrinolysis were determined in 45 healthy young individuals who had such risk factors in relation to ischemic heart disease as arterial hypertension, hypercholesterolemia, smoking, aggravated heredity, permanent emotional overstress, etc. These signs were manifested by a tendency to augmentation of blood coagulation and compensatory activation of fibrinolysis. Ischemic-type changes were detected on the ECG after a physical load. It is assumed that dysfunction of the coagulation system and fibrinolysis is an additional risk factor in relation to ischemic heart disease, while derangement of compensatory fibrinolysis tension with the subsequent tension of its components may lead to the development of coronary thrombosis.

  17. All-trans retinoic acid decreases susceptibility of a gastric cancer cell line to lymphokine-activated killer cytotoxicity.

    PubMed Central

    Chao, T. Y.; Jiang, S. Y.; Shyu, R. Y.; Yeh, M. Y.; Chu, T. M.

    1997-01-01

    All-trans retinoic acid (RA) was previously shown to regulate the growth of gastric cancer cells derived from the cell line SC-M1. This study was designed to investigate the effect of RA on the sensitivity of SC-M1 cells to lymphokine-activated killer (LAK) activity. RA at the concentration range of 0.001-10 microM was shown to induce SC-M1 cells to exhibit resistance to LAK activity in a dose-dependent manner. A kinetics study indicated that a significantly increased resistance was detected after 2 days of co-culturing SC-M1 cells with RA and reached a maximum after 6 days of culture. Similar results were obtained from two other cancer cell lines: promyelocytic leukaemia HL-60 and hepatic cancer Hep 3B. A binding assay demonstrated that the binding efficacy between target SC-M1 cells and effector LAK cells was not altered by RA. Flow cytometric analyses revealed that RA exhibited no effect on the expression of cell surface molecules, including HLA class I and class II antigens, intercellular adhesion molecule-1 and -2, and lymphocyte function antigen-3. Cell cycle analysis revealed that culture of SC-M1 cells with RA resulted in an increase in G0/G1 phase and a decrease in S phase, accompanied by a decrease in cyclin A and cyclin B1 mRNA as determined by Northern blot analysis. Additionally, RA was shown to enhance the expression of retinoic acid receptor alpha (RAR alpha) in SC-M1 cells, and to have no effect on the expression of RARbeta or RARgamma. Taken together, these results indicate that RA can significantly increase gastric cancer cells SC-M1 to resist LAK cytotoxicity by means of a cytostatic effect through a mechanism relating to cell cycle regulation. The prevailing ideas, such as a decrease in effector to target cell binding, a reduced MHC class I antigen expression or an altered RARbeta expression, are not involved. Images Figure 4 Figure 5 PMID:9155047

  18. In-vitro study of methylglyoxal and aspirin effects on fibrinolysis parameters.

    PubMed

    Pouya, Fahima D; Zavar-Reza, Javad; Jalali, Beman A

    2013-10-01

    Methylglyoxal is a reactive α, β dicarbonyl aldehyde compound that originates from various biochemical pathways. Some studies suggest that increased methylglyoxal in blood leads to changes in fibrinolysis; however, the precise mechanism is not clear. The aim of this study was to compare different concentrations of methylglyoxal and aspirin on fibrinolysis in the plasma of healthy individuals in vitro. Different concentrations of methylglyoxal (5, 50, 100, and 500 μmol/l) and aspirin (1, 10, and 100 mg/l) were added to the plasma citrate. They were incubated at 37°C for 24 h. Then, fibrinolysis parameters were analyzed by the turbidimetric procedure at 405 nm. The Independent Samples t-test was utilized to compare them (P < 0.05). Findings revealed that methylglyoxal at 500 μmol/l with aspirin 100 mg/l had significant changes in the maximum lysis velocity (0.163 ± 0.003), half-time lysis (240 ± 10.00), the total lysis time (485 ± 5.00), lag time in lysis (126 ± 5.77), compared with methylglyoxal at 500 μmol/l (0.104 ± 0.005), (276 ± 5.77), (570 ± 10.00), and (186 ± 5.77), respectively (P < 0.05). Methylglyoxal at 500 μmol/l with aspirin 1 mg/l did not significantly change in either parameter (P > 0.05). Methylglyoxal at 100 μmol/l with aspirin 1 mg/l did not significantly change in either fibrinolysis parameter (P > 0.05), compared with methylglyoxal at 100 μmol/l. Methylglyoxal at 5 μmol/l with aspirin (1, 10, 100  mg/l) changed in all fibrinolysis parameters (P < 0.05), compared with methylglyoxal at 5 μmol/l. The other concentrations were compared in the same way. Aspirin (more than 1 mg/l) had more effect on higher concentrations of methylglyoxal. It increased the velocity of lysis of the clot and shortened clot lysis.

  19. Iron and carbon monoxide attenuate Crotalus atrox venom-enhanced tissue-type plasminogen activator-initiated fibrinolysis.

    PubMed

    Nielsen, Vance G; Boyer, Leslie V; Matika, Ryan W; Amos, Quinlan; Redford, Daniel T

    2016-07-01

    In addition to degrading fibrinogen as a source of consumptive coagulopathy, rattlesnake venom has also been demonstrated to enhance fibrinolysis and degrade alpha-2-antiplasmin. The goals of this investigation was to characterize the kinetic fibrinolytic profile of Crotalus atrox venom in the absence and presence of tissue-type plasminogen activator (tPA), and to also ascertain if iron and carbon monoxide (CO, a positive modulator of alpha-2-antiplasmin) could attenuate venom-enhanced fibrinolysis. Utilizing thrombelastographic methods, the coagulation and fibrinolytic kinetic profiles of human plasma exposed to C. atrox venom (0-2 μg/ml) were determined in the absence or presence of tPA (0-100 IU/ml). Then, either separately or in combination, plasma was exposed to iron (ferric chloride, 10 μmol/l) or CO (carbon monoxide-releasing molecule-2, 100 μmol/l) prior to incubation with venom; the plasma sample was subsequently subjected to thrombelastographic analysis with addition of tPA. Venom exposure in the absence of tPA did not result in detectable fibrinolysis. In the presence of tPA, venom markedly enhanced fibrinolysis. Iron and CO, markedly attenuated venom enhancement of fibrinolysis. C. atrox venom enhances tPA-mediated fibrinolysis, and interventions that enhance/protect alpha-2-antiplasmin activity significantly attenuate venom-enhanced fibrinolysis. Future preclinical investigation is required to determine if iron and CO can attenuate venom-mediated degradation of alpha-2-antiplasmin-dependent fibrinolytic resistance.

  20. Baseline plasma fibrinolysis and its correlation with clinical manifestations in patients with Raynaud's phenomenon.

    PubMed Central

    Lau, C S; McLaren, M; Mackay, I; Belch, J J

    1993-01-01

    OBJECTIVES--(1) To assess if patients with various forms of Raynaud's phenomenon (RP) have abnormal plasma fibrinolysis that may contribute to diminished digital blood flow; (2) to assess whether patients with RP with evidence of endothelial damage have abnormal plasma fibrinolysis; (3) to determine the clinical relevance of abnormalities, if any, in plasma fibrinolysis in patients with RP. METHODS--One hundred and sixty eight patients with significant RP were studied--46 had primary Raynaud's disease (RD), 32 had suspected Raynaud's syndrome secondary to an undifferentiated connective tissue disorder (undifferentiated CTD), 25 had Raynaud's syndrome associated with atherosclerosis (athero RS), and 65 had an underlying connective tissue disease (CTD RS). All attended in the morning after a low fat light breakfast. After a clinical history was obtained, venous blood samples were collected without stasis for assays of plasma fibrinolysis and factor VIII von Willebrand factor antigen (fVIII vWF Ag). Results were compared with those obtained from normal subjects matched for sex and age. As patients with athero RS were significantly older than the other patients with Raynaud's phenomenon, two groups of control subjects were recruited--namely, 'old' and 'young' control subjects. RESULTS--Patients with CTD RS and athero RS had higher concentrations of fVIII vWF Ag (CTD RS median 174.5 range (45-370)% v 100 (38-202)%, p < 0.001; athero RS 182-5 (100-240)% v 100 (50-158)%, p < 0.001). Both had raised fibrinogen (CTD RS 3.25 (1.9-6.8) g/l v 2.4 (1.2-4.2) g/l, p < 0.001; athero RS 3.4 (2.2-6.2) g/l v 2.5 (1.8-3.9) g/l, p < 0.001) and both had diminished fibrinolysis with reduced plasminogen activator activity (CTD RS 79.5 (31-72) mm2 v 92 (37-197) mm2, p < 0.04; athero RS 73 (45-125) mm2 v 98 (41-197) mm2, p < 0.03). Patients with CTD RS also had raised plasminogen activity (3.3 (2.3-5.8) cU/ml v 2.9 (1.5-5.4) cU/ml, p < 0.001). On the contrary, patients with primary RD and

  1. Lower ω-6/ω-3 Polyunsaturated Fatty Acid Ratios Decrease Fat Deposition by Inhibiting Fat Synthesis in Gosling.

    PubMed

    Yu, Lihuai; Wang, Shunan; Ding, Luoyang; Liang, Xianghuan; Wang, Mengzhi; Dong, Li; Wang, Hongrong

    2016-10-01

    The objective of the current study was to investigate the effects of dietary ω-6/ω-3 polyunsaturated fatty acid (PUFA) ratios on lipid metabolism in goslings. One hundred and sixty 21-day-old Yangzhou geese of similar weight were randomly divided into 4 groups. They were fed different PUFA-supplemented diets (the 4 diets had ω-6/ω-3 PUFA ratios of 12:1, 9:1, 6:1, or 3:1). The geese were slaughtered and samples of liver and muscle were collected at day 70. The activities and the gene expression of enzymes involved in lipid metabolism were measured. The results show that the activities of acetyl coenzyme A carboxylase (ACC), malic enzyme (ME), and fatty acid synthase (FAS) were lower (p<0.05), but the activities of hepatic lipase (HL) and lipoprotein lipase (LPL) were higher (p<0.05), in the liver and the muscle from the 3:1 and 6:1 groups compared with those in the 9:1 and 12:1 groups. Expression of the genes for FAS (p<0.01), ME (p<0.01) and ACC (p<0.05) were higher in the muscle of groups fed diets with higher ω-6/ω-3 PUFA ratios. Additionally, in situ hybridization tests showed that the expression intensities of the high density lipoprotein (HDL-R) gene in the 12:1 and 9:1 groups were significantly lower (p<0.01) than that of the 3:1 group in the muscle of goslings. In conclusion, diets containing lower ω-6/ω-3 PUFA ratios (3:1 or 6:1) could decrease fat deposition by inhibiting fat synthesis in goslings.

  2. Lower ω-6/ω-3 Polyunsaturated Fatty Acid Ratios Decrease Fat Deposition by Inhibiting Fat Synthesis in Gosling

    PubMed Central

    Yu, Lihuai; Wang, Shunan; Ding, Luoyang; Liang, Xianghuan; Wang, Mengzhi; Dong, Li; Wang, Hongrong

    2016-01-01

    The objective of the current study was to investigate the effects of dietary ω-6/ω-3 polyunsaturated fatty acid (PUFA) ratios on lipid metabolism in goslings. One hundred and sixty 21-day-old Yangzhou geese of similar weight were randomly divided into 4 groups. They were fed different PUFA-supplemented diets (the 4 diets had ω-6/ω-3 PUFA ratios of 12:1, 9:1, 6:1, or 3:1). The geese were slaughtered and samples of liver and muscle were collected at day 70. The activities and the gene expression of enzymes involved in lipid metabolism were measured. The results show that the activities of acetyl coenzyme A carboxylase (ACC), malic enzyme (ME), and fatty acid synthase (FAS) were lower (p<0.05), but the activities of hepatic lipase (HL) and lipoprotein lipase (LPL) were higher (p<0.05), in the liver and the muscle from the 3:1 and 6:1 groups compared with those in the 9:1 and 12:1 groups. Expression of the genes for FAS (p<0.01), ME (p<0.01) and ACC (p<0.05) were higher in the muscle of groups fed diets with higher ω-6/ω-3 PUFA ratios. Additionally, in situ hybridization tests showed that the expression intensities of the high density lipoprotein (HDL-R) gene in the 12:1 and 9:1 groups were significantly lower (p<0.01) than that of the 3:1 group in the muscle of goslings. In conclusion, diets containing lower ω-6/ω-3 PUFA ratios (3:1 or 6:1) could decrease fat deposition by inhibiting fat synthesis in goslings. PMID:27189638

  3. Thrombin activatable fibrinolysis inhibitor (TAFI) - A possible link between coagulation and complement activation in the antiphospholipid syndrome (APS).

    PubMed

    Grosso, Giorgia; Vikerfors, Anna; Woodhams, Barry; Adam, Mariette; Bremme, Katarina; Holmström, Margareta; Ågren, Anna; Eelde, Anna; Bruzelius, Maria; Svenungsson, Elisabet; Antovic, Aleksandra

    2017-06-24

    Thrombosis and complement activation are pathogenic features of antiphospholipid syndrome (APS). Their molecular link is Plasma carboxypeptidase-B, also known as thrombin activatable fibrinolysis inhibitor (TAFIa), which plays a dual role: anti-fibrinolytic, by cleaving carboxyl-terminal lysine residues from partially degraded fibrin, and anti-inflammatory, by downregulating complement anaphylatoxins C3a and C5a. To investigate the levels of TAFI (proenzyme) and TAFIa (active enzyme) in relation to complement activation, fibrin clot permeability and fibrinolytic function in clinical and immunological subsets of 52 APS patients and 15 controls. TAFI (p<0.001), TAFIa (p<0.05) and complement factor C5a (p<0.001) were increased, while fibrin permeability (p<0.01) was decreased and clot lysis time (CLT) was prolonged (p<0.05) in APS patients compared to controls. Furthermore, TAFIa was increased (p<0.01) in samples from APS patients affected by arterial thrombosis compared to other APS-phenotypes. Positive associations were found between TAFI and age, fibrinogen and C5a, and between TAFIa and age, fibrinogen and thrombomodulin. TAFI and TAFIa levels were increased in patients with APS as a potential response to complement activation. Interestingly, TAFI activation was associated with arterial thrombotic APS manifestations. Thus, TAFIa may be considered a novel biomarker for arterial thrombosis in APS. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Short-term supplementation with Aronia melanocarpa extract improves platelet aggregation, clotting, and fibrinolysis in patients with metabolic syndrome.

    PubMed

    Sikora, Joanna; Broncel, Marlena; Markowicz, Magdalena; Chałubiński, Maciej; Wojdan, Katarzyna; Mikiciuk-Olasik, Elżbieta

    2012-08-01

    A diet rich in berries is believed to play a distinct role in the prevention of metabolic diseases associated with obesity. So far, there have been no published clinical observations evaluating the influence of Aronia melanocarpa on hemostasis. The aim of our study was to investigate the effects of A. melanocarpa extract (AM) supplementation on platelet aggregation, clot formation, and lysis in patients with metabolic syndrome (MS). Middle-aged non-medicated subjects with MS (n = 38) and 14 healthy volunteers were included in this study. Patients with MS were treated with 100 mg of AM three times daily for 2 months. We observed a significant reduction in the concentration of TC, LDL-C, and TG after AM supplementation. Beneficial changes in coagulation parameters were also observed. After 1 month of AM administration, we noticed significant inhibition of platelet aggregation. However, this effect became less pronounced after 2 months of supplementation. In the case of coagulation induced by endogenic thrombin, a significant decrease in the overall potential for coagulation was induced after 1 or 2 months of supplementation. Moreover, after 1 month of AM extract supplementation, we observed a beneficial reduction in the overall potential for clot formation and fibrinolysis. We observed the normalization of hemostasis parameters in MS patients after both 1 and 2 months of AM administration. After 1 month of AM supplementation, we found favorable changes in regards to the overall potential for plasma clotting, clot formation, and lysis, as well as in the lipid profiles of subjects.

  5. DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes: the OmegAD study.

    PubMed

    Karimi, Mohsen; Vedin, Inger; Freund Levi, Yvonne; Basun, Hans; Faxén Irving, Gerd; Eriksdotter, Maria; Wahlund, Lars-Olof; Schultzberg, Marianne; Hjorth, Erik; Cederholm, Tommy; Palmblad, Jan

    2017-08-30

    Background: Dietary fish oils, rich in long-chain n-3 (ω-3) fatty acids (FAs) [e.g., docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3)], modulate inflammatory reactions through various mechanisms, including gene expression, which is measured as messenger RNA concentration. However, the effects of long-term treatment of humans with DHA and EPA on various epigenetic factors-such as DNA methylation, which controls messenger RNA generation-are poorly described.Objective: We wanted to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global DNA methylation of peripheral blood leukocytes (PBLs) and the relation to plasma EPA and DHA concentrations in Alzheimer disease (AD) patients.Design: In the present study, DNA methylation in four 5'-cytosine-phosphate-guanine-3' (CpG) sites of long interspersed nuclear element-1 repetitive sequences was assessed in a group of 63 patients (30 given the n-3 FA preparation and 33 given placebo) as an estimation of the global DNA methylation in blood cells. Patients originated from the randomized, double-blind, placebo-controlled OmegAD study, in which 174 AD patients received either 1.7 g DHA and 0.6 g EPA (the n-3 FA group) or placebo daily for 6 mo.Results: At 6 mo, the n-3 FA group displayed marked increases in DHA and EPA plasma concentrations (2.6- and 3.5-fold), as well as decreased methylation in 2 out of 4 CpG sites (P < 0.05 for all), respectively. This hypomethylation in CpG2 and CpG4 sites showed a reverse correlation to changes in plasma EPA concentration (r = -0.25, P = 0.045; and r = -0.26, P = 0.041, respectively), but not to changes in plasma DHA concentration, and were not related to apolipoprotein E-4 allele frequency.Conclusion: Supplementation with n-3 FA for 6 mo was associated with global DNA hypomethylation in PBLs. Our data may be of importance in measuring various effects of marine oils, including gene expression, in patients with AD

  6. Gamma-Aminobutyric Acid Increases the Production of Short-Chain Fatty Acids and Decreases pH Values in Mouse Colon.

    PubMed

    Xie, Min; Chen, Hai-Hong; Nie, Shao-Ping; Yin, Jun-Yi; Xie, Ming-Yong

    2017-04-20

    Gamma-Aminobutyric acid (GABA) could regulate physiological functions in the gastrointestinal tract. The present study aimed to investigate the effect of GABA on colon health in mice. The female Kunming mice were given GABA at doses of 5, 10, 20 and 40 mg/kg/d for 14 days. Afterwards, the short-chain fatty acids (SCFAs) concentrations, pH values, colon index, colon length and weight of colonic and cecal contents were determined to evaluate the effects of GABA on colon health. The results showed that intake of GABA could increase the concentrations of acetate, propionate, butyrate and total SCFAs in colonic and cecal contents, as well as the weight of colonic and cecal contents. The colon index and length of the 40 mg/kg/d GABA-treated group were significantly higher than those of the control group (p < 0.05). In addition, decrease of pH values in colonic and cecal contents was also observed. These results suggest that GABA may improve colon health.

  7. Developmental subchronic exposure to diphenylarsinic acid induced increased exploratory behavior, impaired learning behavior, and decreased cerebellar glutathione concentration in rats.

    PubMed

    Negishi, Takayuki; Matsunaga, Yuki; Kobayashi, Yayoi; Hirano, Seishiro; Tashiro, Tomoko

    2013-12-01

    In Japan, people using water from the well contaminated with high-level arsenic developed neurological, mostly cerebellar, symptoms, where diphenylarsinic acid (DPAA) was a major compound. Here, we investigated the adverse effects of developmental exposure to 20mg/l DPAA in drinking water (early period [0-6 weeks of age] and/or late period [7-12]) on behavior and cerebellar development in male rats. In the open field test at 6 weeks of age, early exposure to DPAA significantly increased exploratory behaviors. At 12 weeks of age, late exposure to DPAA similarly increased exploratory behavior independent of the early exposure although a 6-week recovery from DPAA could reverse that change. In the passive avoidance test at 6 weeks of age, early exposure to DPAA significantly decreased the avoidance performance. Even at 12 weeks of age, early exposure to DPAA significantly decreased the test performance, which was independent of the late exposure to DPAA. These results suggest that the DPAA-induced increase in exploratory behavior is transient, whereas the DPAA-induced impairment of passive avoidance is long lasting. At 6 weeks of age, early exposure to DPAA significantly reduced the concentration of cerebellar total glutathione. At 12 weeks of age, late, but not early, exposure to DPAA also significantly reduced the concentration of cerebellar glutathione, which might be a primary cause of oxidative stress. Early exposure to DPAA induced late-onset suppressed expression of NMDAR1 and PSD95 protein at 12 weeks of age, indicating impaired glutamatergic system in the cerebellum of rats developmentally exposed to DPAA.

  8. Developmental Subchronic Exposure to Diphenylarsinic Acid Induced Increased Exploratory Behavior, Impaired Learning Behavior, and Decreased Cerebellar Glutathione Concentration in Rats

    PubMed Central

    Negishi, Takayuki; Matsunaga, Yuki

    2013-01-01

    In Japan, people using water from the well contaminated with high-level arsenic developed neurological, mostly cerebellar, symptoms, where diphenylarsinic acid (DPAA) was a major compound. Here, we investigated the adverse effects of developmental exposure to 20mg/l DPAA in drinking water (early period [0–6 weeks of age] and/or late period [7–12]) on behavior and cerebellar development in male rats. In the open field test at 6 weeks of age, early exposure to DPAA significantly increased exploratory behaviors. At 12 weeks of age, late exposure to DPAA similarly increased exploratory behavior independent of the early exposure although a 6-week recovery from DPAA could reverse that change. In the passive avoidance test at 6 weeks of age, early exposure to DPAA significantly decreased the avoidance performance. Even at 12 weeks of age, early exposure to DPAA significantly decreased the test performance, which was independent of the late exposure to DPAA. These results suggest that the DPAA-induced increase in exploratory behavior is transient, whereas the DPAA-induced impairment of passive avoidance is long lasting. At 6 weeks of age, early exposure to DPAA significantly reduced the concentration of cerebellar total glutathione. At 12 weeks of age, late, but not early, exposure to DPAA also significantly reduced the concentration of cerebellar glutathione, which might be a primary cause of oxidative stress. Early exposure to DPAA induced late-onset suppressed expression of NMDAR1 and PSD95 protein at 12 weeks of age, indicating impaired glutamatergic system in the cerebellum of rats developmentally exposed to DPAA. PMID:24008832

  9. Periodontal therapy decreases serum levels of adipocyte fatty acid-binding protein in systemically healthy subjects: a pilot clinical trial.

    PubMed

    Li, X; Tse, H F; Yiu, K H; Zhang, C; Jin, L J

    2013-06-01

    Adipocyte fatty acid-binding protein (A-FABP) is expressed in adipocytes, macrophages and microvascular endothelial cells, and it plays a central role in inflammation, atherosclerosis and metabolic responses. This pilot study investigated the effect of nonsurgical periodontal therapy on the serum levels of A-FABP in subjects with chronic periodontitis. A pilot clinical trial was conducted in 24 otherwise healthy Chinese subjects with moderate to severe chronic periodontitis. The treatment group (n = 12) received nonsurgical periodontal therapy immediately, whereas in the control group (n = 12) the treatment was delayed for 3 months. The serum levels of A-FABP were measured by ELISAs. Other inflammatory and endothelial biomarkers and periodontal conditions were evaluated at baseline and at the 3-month follow-up appointment. A-FABP levels decreased significantly in the treatment group compared with the control group (treatment effect: -1.7 ng/mL; 95% confidence interval: -2.8 to -0.6; p = 0.003). The treatment also significantly improved periodontal conditions but had no significant effect on other biomarkers. In the multivariable regression model, the change in the percentage of sites with detectable plaque was significantly associated with the change in the level of A-FABP (beta: 0.04, 95% confidence interval: 0.01-0.06, p = 0.004). Within the limitations of this pilot study, the current findings suggest that treatment of periodontitis may significantly decrease the serum levels of A-FABP. Further longitudinal study with a large sample size is warranted to confirm this finding and elaborate the relevant clinical implications. © 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass☆,☆☆

    PubMed Central

    Gennero, Isabelle; Laurencin-Dalicieux, Sara; Conte-Auriol, Françoise; Briand-Mésange, Fabienne; Laurencin, Danielle; Rue, Jackie; Beton, Nicolas; Malet, Nicole; Mus, Marianne; Tokumura, Akira; Bourin, Philippe; Vico, Laurence; Brunel, Gérard; Oreffo, Richard O. C.; Chun, Jerold; Salles, Jean Pierre

    2013-01-01

    Lysophosphatidic acid (LPA) is a lipid mediator that acts in paracrine systems via interaction with a subset of G protein-coupled receptors (GPCRs). LPA promotes cell growth and differentiation, and has been shown to be implicated in a variety of developmental and pathophysiological processes. At least 6 LPA GPCRs have been identified to date: LPA1–LPA6. Several studies have suggested that local production of LPA by tissues and cells contributes to paracrine regulation, and a complex interplay between LPA and its receptors, LPA1 and LPA4, is believed to be involved in the regulation of bone cell activity. In particular, LPA1may activate both osteoblasts and osteoclasts. However, its role has not as yet been examined with regard to the overall status of bone in vivo. We attempted to clarify this role by defining the bone phenotype of LPA1(−/−) mice. These mice demonstrated significant bone defects and low bone mass, indicating that LPA1 plays an important role in osteogenesis. The LPA1(−/−) mice also presented growth and sternal and costal abnormalities, which highlights the specific roles of LPA1 during bone development. Microcomputed tomography and histological analysis demonstrated osteoporosis in the trabecular and cortical bone of LPA1(−/−) mice. Finally, bone marrow mesenchymal progenitors from these mice displayed decreased osteoblastic differentiation. These results suggest that LPA1 strongly influences bone development both qualitatively and quantitatively and that, in vivo, its absence results in decreased osteogenesis with no clear modification of osteoclasis. They open perspectives for a better understanding of the role of the LPA/LPA1 paracrine pathway in bone pathophysiology. PMID:21569876

  11. Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass.

    PubMed

    Gennero, Isabelle; Laurencin-Dalicieux, Sara; Conte-Auriol, Françoise; Briand-Mésange, Fabienne; Laurencin, Danielle; Rue, Jackie; Beton, Nicolas; Malet, Nicole; Mus, Marianne; Tokumura, Akira; Bourin, Philippe; Vico, Laurence; Brunel, Gérard; Oreffo, Richard O C; Chun, Jerold; Salles, Jean Pierre

    2011-09-01

    Lysophosphatidic acid (LPA) is a lipid mediator that acts in paracrine systems via interaction with a subset of G protein-coupled receptors (GPCRs). LPA promotes cell growth and differentiation, and has been shown to be implicated in a variety of developmental and pathophysiological processes. At least 6 LPA GPCRs have been identified to date: LPA1-LPA6. Several studies have suggested that local production of LPA by tissues and cells contributes to paracrine regulation, and a complex interplay between LPA and its receptors, LPA1 and LPA4, is believed to be involved in the regulation of bone cell activity. In particular, LPA1 may activate both osteoblasts and osteoclasts. However, its role has not as yet been examined with regard to the overall status of bone in vivo. We attempted to clarify this role by defining the bone phenotype of LPA1((-/-)) mice. These mice demonstrated significant bone defects and low bone mass, indicating that LPA1 plays an important role in osteogenesis. The LPA1((-/-)) mice also presented growth and sternal and costal abnormalities, which highlights the specific roles of LPA1 during bone development. Microcomputed tomography and histological analysis demonstrated osteoporosis in the trabecular and cortical bone of LPA1((-/-)) mice. Finally, bone marrow mesenchymal progenitors from these mice displayed decreased osteoblastic differentiation. These results suggest that LPA1 strongly influences bone development both qualitatively and quantitatively and that, in vivo, its absence results in decreased osteogenesis with no clear modification of osteoclasis. They open perspectives for a better understanding of the role of the LPA/LPA1 paracrine pathway in bone pathophysiology. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Omega-3 fatty acid ethyl ester supplementation decreases very-low-density lipoprotein triacylglycerol secretion in obese men.

    PubMed

    Wong, Annette T Y; Chan, Dick C; Ooi, Esther M M; Ng, Theodore W K; Watts, Gerald F; Barrett, P Hugh R

    2013-03-13

    Dysregulated VLDL-TAG (very-low-density lipoprotein triacylglycerol) metabolism in obesity may account for hypertriacylglycerolaemia and increased cardiovascular disease. ω-3 FAEEs (omega-3 fatty acid ethyl esters) decrease plasma TAG and VLDL concentrations, but the mechanisms are not fully understood. In the present study, we carried out a 6-week randomized, placebo-controlled study to examine the effect of high-dose ω-3 FAEE supplementation (3.2 g/day) on the metabolism of VLDL-TAG in obese men using intravenous administration of d5-glycerol. We also explored the relationship of VLDL-TAG kinetics with the metabolism of VLDL-apo (apolipoprotein) B-100 and HDL (high-density lipoprotein)-apoA-I. VLDL-TAG isotopic enrichment was measured using gas chromatography-mass spectrometry. Kinetic parameters were derived using a multicompartmental model. Compared with placebo, ω-3 FAEE supplementation significantly lowered plasma concentrations of total (-14%, P<0.05) and VLDL-TAG (-32%, P<0.05), as well as hepatic secretion of VLDL-TAG (-32%, P<0.03). The FCR (fractional catabolic rate) of VLDL-TAG was not altered by ω-3 FAEEs. There was a significant association between the change in secretion rates of VLDL-TAG and VLDL-apoB-100 (r=0.706, P<0.05). However, the change in VLDL-TAG secretion rate was not associated with change in HDL-apoA-I FCR (r=0.139, P>0.05). Our results suggest that the TAG-lowering effect of ω-3 FAEEs is associated with the decreased VLDL-TAG secretion rate and hence lower plasma VLDL-TAG concentration in obesity. The changes in VLDL-TAG and apoB-100 kinetics are closely coupled.

  13. [Results of the IOP decrease after application of some mixtures of amino acids and antiglaucomatics in rabbits (a review of experimental publications)].

    PubMed

    Oláh, Z; Veselovský, J

    2011-01-01

    To summarise of experimental results performed on rabbit eyes focused to influence the physiological intraocular pressure (lOP) after application of some amino acids mixture with some regularly used antiglaucomatics. The experiments were performed on adult rabbits (female of the New Zealand White species). The applicated substances were: 10% solution of amino acids (L-lysin.2HCl.2H2O, L-arginine.HCL or L-glycine.HCL) in antiglau-comatics 0.5% timolol (Timoptol) or 0.005% latanoprost (Xalatan). This mixture was applicated to the left eye; right eye was used as control. The measurement of IOP and pupil diameter was performed before instillation, in 15th, 30th, 60th, 180th, 240th minute and 24 hours after application. Functional bioactivity of the used antiglaucomatics in case of decreased lOP is rising after interaction with the relevant specific amino acid. Glycine in timolol showed the highest effect on average decrease of the lOP physiological values (lOP decrease reached - 5,5 torr) followed by arginine in timolol (lOP decrease reached - 3,3 torr). The lOP decrease after other combinations of amino acids and antiglaucomatics was in average lower or nonsignificant. Through interaction between in vitro prepared mixture free amino acids and antiglaucomatics a new, biologically active substance (metabolite) is created. After instillation in experimental condition achieving stronger and longer decrease of the lOP compared with a single antiglaucomatic or amino acid.

  14. Abscisic acid signalling when soil moisture is heterogeneous: decreased photoperiod sap flow from drying roots limits abscisic acid export to the shoots.

    PubMed

    Dodd, Ian C; Egea, Gregorio; Davies, William J

    2008-09-01

    To investigate the contribution of different parts of the root system to total sap flow and leaf xylem abscisic acid (ABA) concentration ([X-ABA](leaf)), individual sunflower (Helianthus annuus L.) shoots were grafted onto the root systems of two plants grown in separate pots and sap flow through each hypocotyl measured below the graft union. During deficit irrigation (DI), both pots received the same irrigation volumes, while during partial root zone drying (PRD) one pot ('wet') was watered and another ('dry') was not. During PRD, once soil water content (theta) decreased below a threshold, the fraction of sap flow from drying roots declined. As theta declined, root xylem ABA concentration increased in both irrigation treatments, and [X-ABA](leaf) increased in DI plants, but [X-ABA](leaf) of PRD plants actually decreased within a certain theta range. A simple model that weighted ABA contributions of wet and dry root systems to [X-ABA](leaf) according to the sap flow from each, better predicted [X-ABA](leaf) of PRD plants than either [X-ABA](dry), [X-ABA](wet) or their mean. Model simulations revealed that [X-ABA](leaf) during PRD exceeded that of DI with moderate soil drying, but continued soil drying (such that sap flow from roots in drying soil ceased) resulted in the opposite effect.

  15. Alpha-2 adrenoreceptor-mediated decrease in gamma-aminobutyric acid outflow in cortical slices and synaptosomes during morphine tolerance.

    PubMed

    Beani, L; Bianchi, C; Ferraro, L; Morari, M; Simonato, M; Spalluto, G; Tanganelli, S

    1991-08-01

    Morphine tolerance has proven to be accompanied by alterations in the efficiency of many neuronal signals, as well as by an inversion of the noradrenergic signal response of cortical acetylcholine terminals and gamma-aminobutyric acid (GABA) neurons in vivo (decreased acetylcholine and increased GABA release in normal animals, vice versa in tolerant). The latter observation may be relevant in interpreting morphine withdrawal, because the noradrenergic neuron firing rate increases dramatically during its course. This study was designed as an attempt to anatomically localize the inversion of the GABA response to norepinephrine. Because this phenomenon is observed in cortical slices and synaptosomes, it can be postulated that it occurs in the neocortex at the level of the intracortical GABA nerve terminals. Pharmacological analysis demonstrates that although the stimulation observed in controls is alpha-1 adrenoreceptor-mediated, the inhibition in tolerant animals is exerted via alpha-2 adrenoreceptors. Therefore, an increase in number or an improved coupling to the transduction system of alpha-2 adrenoreceptors is hypothesized. This observation gives a clue to a molecular interpretation of the inversion of GABA response to norepinephrine in tolerant animals, which may be of heuristic value in terms of biological interpretation of morphine tolerance.

  16. Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

    PubMed Central

    Kim, Jae; John, Joel; Langford, Dianne; Walker, Ellen; Ward, Sara; Rawls, Scott M.

    2015-01-01

    The β-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the β-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the β-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine’s reinforcing efficacy at 100-fold lower doses than CTX. PMID:26543027

  17. Deficiency of glycerol-3-phosphate acyltransferase 1 decreases triacylglycerol storage and induces fatty acid oxidation in insect fat body.

    PubMed

    Alves-Bezerra, Michele; Ramos, Isabela B; De Paula, Iron F; Maya-Monteiro, Clarissa M; Klett, Eric L; Coleman, Rosalind A; Gondim, Katia C

    2017-03-01

    Glycerol-3-phosphate acyltransferases (GPAT) catalyze the initial and rate-limiting step for the de novo synthesis of triacylglycerol (TAG). Four mammalian GPAT isoforms have been identified: the mitochondria-associated GPAT1 and 2, and the endoplasmic reticulum (ER)-associated GPAT3 and 4. In the insect Rhodnius prolixus, a vector of Chagas' disease, we previously predicted a mitochondrial-like isoform (RhoprGPAT1) from genomic data. In the current study, we clone the RhoprGPAT1 coding sequence and identify an ER-associated GPAT (RhoprGPAT4) as the second isoform in the insect. RhoprGPAT1 contributes 15% of the total GPAT activity in anterior midgut, 50% in posterior midgut and fat body, and 70% in the ovary. The RhoprGpat1 gene is the predominant transcript in the midgut and fat body. To evaluate the physiological relevance of RhoprGPAT1, we generate RhoprGPAT1-deficient insects. The knockdown of RhoprGpat1 results in 50% and 65% decrease in TAG content in the posterior midgut and fat body, respectively. RhoprGpat1-deficient insects also exhibits impaired lipid droplet expansion and a 2-fold increase in fatty acid β-oxidation rates in the fat body. We propose that the RhoprGPAT1 mitochondrial-like isoform is required to channel fatty acyl chains towards TAG synthesis and away from β-oxidation. Such a process is crucial for the insect lipid homeostasis.

  18. Serum bile acids and GLP-1 decrease following telemetric induced weight loss: results of a randomized controlled trial

    PubMed Central

    Biemann, Ronald; Penner, Marina; Borucki, Katrin; Westphal, Sabine; Luley, Claus; Rönicke, Raik; Biemann, Kathleen; Weikert, Cornelia; Lux, Anke; Goncharenko, Nikolai; Marschall, Hanns-Ulrich; Schneider, Jochen G.; Isermann, Berend

    2016-01-01

    Bile acids (BAs) are increasingly recognised as metabolic regulators, potentially improving insulin sensitivity following bariatric surgery. However, physiological relevance of such observations remains unknown. Hence, we analysed serum BA composition and associated gut-derived hormone levels following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). 74 non-smoking men (45–55 yr) with MetS were randomised to a lifestyle-induced weight loss program (supervision via telemonitoring) or to a control arm. Before and after a 6 months intervention period clinical and laboratory parameters, body composition, serum BA profile, FGF-19, and GLP-1 concentrations were determined in fasting blood samples. 30 participants in the control and 33 participants in the treatment arm completed the study and were included in the data analysis. In participants of the treatment arm lifestyle-induced weight loss resulted in markedly improved insulin sensitivity. Serum levels of BA species and total GLP-1 decreased, while FGF-19 remained stable. Serum BA composition changed towards an increased 12α-hydroxylated/non-12α-hydroxylated ratio. None of these parameters changed in participants of the control arm. Our results demonstrate that improved metabolic control by lifestyle modifications lowers serum levels of BAs and GLP-1 and changes serum BA composition towards an increased 12α/non-12α ratio (ICTRP Trial Number: U1111-1158-3672). PMID:27452603

  19. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis

    PubMed Central

    Pinkosky, Stephen L.; Newton, Roger S.; Day, Emily A.; Ford, Rebecca J.; Lhotak, Sarka; Austin, Richard C.; Birch, Carolyn M.; Smith, Brennan K.; Filippov, Sergey; Groot, Pieter H.E.; Steinberg, Gregory R.; Lalwani, Narendra D.

    2016-01-01

    Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve sufficient LDL-C lowering due to muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended to lower LDL-C in hypercholesterolemic patients, and has been previously shown to modulate both ATP-citrate lyase (ACL) and AMP-activated protein kinase (AMPK) activity in rodents. However, its mechanism for LDL-C lowering, efficacy in models of atherosclerosis and relevance in humans are unknown. Here we show that ETC-1002 is a prodrug that requires activation by very long-chain acyl-CoA synthetase-1 (ACSVL1) to modulate both targets, and that inhibition of ACL leads to LDL receptor upregulation, decreased LDL-C and attenuation of atherosclerosis, independently of AMPK. Furthermore, we demonstrate that the absence of ACSVL1 in skeletal muscle provides a mechanistic basis for ETC-1002 to potentially avoid the myotoxicity associated with statin therapy. PMID:27892461

  20. Inhibition of fatty acid oxidation activates transforming growth factor-beta in cerebrospinal fluid and decreases spontaneous motor activity.

    PubMed

    Fujikawa, Teppei; Fujita, Ryo; Iwaki, Yoko; Matsumura, Shigenobu; Fushiki, Tohru; Inoue, Kazuo

    2010-10-05

    We have previously reported that transforming growth factor (TGF)-beta in the cerebrospinal fluid (CSF) is involved in the mechanism underlying the regulation of spontaneous motor activity (SMA) by the central nervous system after exercise. However, it remained unclear what physiological condition triggers the activation of TGF-beta. We hypothesized that the shortage of energy derived from fatty acid (FA) oxidation observed in the early phase of exercise activated TGF-beta in the CSF. To test this hypothesis, we investigated whether mercaptoacetate (MA), an inhibitor of FA oxidation, could induce an activation of TGF-beta in the CSF and a decrease in SMA. Intraperitoneal (i.p.) administration of MA activated TGF-beta in CSF in rats and depressed SMA; 2-deoxyglucose, an inhibitor of carbohydrate oxidation, on the other hand, depressed SMA but failed to activate CSF TGF-beta. Intracisternal administration of anti-TGF-beta antibody abolished the depressive effect of MA on SMA. We also found that the depression of SMA and the activation of TGF-beta in the CSF by i.p. MA administration were eliminated by vagotomy. Our data suggest that TGF-beta in the CSF is activated by the inhibition of FA oxidation via the vagus nerve and that this subsequently induces depression of SMA.

  1. Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice.

    PubMed

    Kim, Jae; John, Joel; Langford, Dianne; Walker, Ellen; Ward, Sara; Rawls, Scott M

    2016-03-01

    The β-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the β-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the β-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine's reinforcing efficacy at 100-fold lower doses than CTX.

  2. Increased Dietary Intake of Saturated Fatty Acid Heptadecanoic Acid (C17:0) Associated with Decreasing Ferritin and Alleviated Metabolic Syndrome in Dolphins.

    PubMed

    Venn-Watson, Stephanie K; Parry, Celeste; Baird, Mark; Stevenson, Sacha; Carlin, Kevin; Daniels, Risa; Smith, Cynthia R; Jones, Richard; Wells, Randall S; Ridgway, Sam; Jensen, Eric D

    2015-01-01

    Similar to humans, bottlenose dolphins (Tursiops truncatus) can develop metabolic syndrome and associated high ferritin. While fish and fish-based fatty acids may protect against metabolic syndrome in humans, findings have been inconsistent. To assess potential protective factors against metabolic syndrome related to fish diets, fatty acids were compared between two dolphin populations with higher (n = 30, Group A) and lower (n = 19, Group B) mean insulin (11 ± 12 and 2 ± 5 μIU/ml, respectively; P < 0.0001) and their dietary fish. In addition to higher insulin, triglycerides, and ferritin, Group A had lower percent serum heptadecanoic acid (C17:0) compared to Group B (0.3 ± 0.1 and 1.3 ± 0.4%, respectively; P < 0.0001). Using multivariate stepwise regression, higher percent serum C17:0, a saturated fat found in dairy fat, rye, and some fish, was an independent predictor of lower insulin in dolphins. Capelin, a common dietary fish for Group A, had no detectable C17:0, while pinfish and mullet, common in Group B's diet, had C17:0 (41 and 67 mg/100g, respectively). When a modified diet adding 25% pinfish and/or mullet was fed to six Group A dolphins over 24 weeks (increasing the average daily dietary C17:0 intake from 400 to 1700 mg), C17:0 serum levels increased, high ferritin decreased, and blood-based metabolic syndrome indices normalized toward reference levels. These effects were not found in four reference dolphins. Further, higher total serum C17:0 was an independent and linear predictor of lower ferritin in dolphins in Group B dolphins. Among off the shelf dairy products tested, butter had the highest C17:0 (423mg/100g); nonfat dairy products had no detectable C17:0. We hypothesize that humans' movement away from diets with potentially beneficial saturated fatty acid C17:0, including whole fat dairy products, could be a contributor to widespread low C17:0 levels, higher ferritin, and metabolic syndrome.

  3. Increased Dietary Intake of Saturated Fatty Acid Heptadecanoic Acid (C17:0) Associated with Decreasing Ferritin and Alleviated Metabolic Syndrome in Dolphins

    PubMed Central

    Venn-Watson, Stephanie K.; Parry, Celeste; Baird, Mark; Stevenson, Sacha; Carlin, Kevin; Daniels, Risa; Smith, Cynthia R.; Jones, Richard; Wells, Randall S.; Ridgway, Sam; Jensen, Eric D.

    2015-01-01

    Similar to humans, bottlenose dolphins (Tursiops truncatus) can develop metabolic syndrome and associated high ferritin. While fish and fish-based fatty acids may protect against metabolic syndrome in humans, findings have been inconsistent. To assess potential protective factors against metabolic syndrome related to fish diets, fatty acids were compared between two dolphin populations with higher (n = 30, Group A) and lower (n = 19, Group B) mean insulin (11 ± 12 and 2 ± 5 μIU/ml, respectively; P < 0.0001) and their dietary fish. In addition to higher insulin, triglycerides, and ferritin, Group A had lower percent serum heptadecanoic acid (C17:0) compared to Group B (0.3 ± 0.1 and 1.3 ± 0.4%, respectively; P < 0.0001). Using multivariate stepwise regression, higher percent serum C17:0, a saturated fat found in dairy fat, rye, and some fish, was an independent predictor of lower insulin in dolphins. Capelin, a common dietary fish for Group A, had no detectable C17:0, while pinfish and mullet, common in Group B’s diet, had C17:0 (41 and 67 mg/100g, respectively). When a modified diet adding 25% pinfish and/or mullet was fed to six Group A dolphins over 24 weeks (increasing the average daily dietary C17:0 intake from 400 to 1700 mg), C17:0 serum levels increased, high ferritin decreased, and blood-based metabolic syndrome indices normalized toward reference levels. These effects were not found in four reference dolphins. Further, higher total serum C17:0 was an independent and linear predictor of lower ferritin in dolphins in Group B dolphins. Among off the shelf dairy products tested, butter had the highest C17:0 (423mg/100g); nonfat dairy products had no detectable C17:0. We hypothesize that humans’ movement away from diets with potentially beneficial saturated fatty acid C17:0, including whole fat dairy products, could be a contributor to widespread low C17:0 levels, higher ferritin, and metabolic syndrome. PMID:26200116

  4. Decreased arachidonic acid content and metabolism in tissues of NZB/W F1 females fed a diet containing 0. 45% dehydroisoandrosterone (DHA)

    SciTech Connect

    Matsunaga, A.; Cottam, G.L.

    1987-05-01

    A diet containing 0.45% DHA fed to NZB/W mice, a model of systemic lupus erythematosus, delays the time of onset, improves survival and decreases the formation of antibodies to ds-DNA. Essential fatty acid-deficient diets or inclusion of eicosapentaenoic acid have similar beneficial effects and led them to investigate arachidonic acid metabolism in response to feeding DHA. The arachidonic acid content of plasma cholesteryl ester decreased from 37.4 +/- 2.2 to 28.2 +/- 1.3 mg%. In total liver phospholipid the value decreased from 18.1 +/- 0.52 to 13.7 +/- 1.3 mg%, in total kidney phospholipid the value decreased from 24.10 +/- 0.87 to 20.7 +/- 0.32 mg% and in resident peritoneal macrophages the value decreased from 15.4 +/- 4.6 to 3.6 +/- 1.4 mg%. The metabolism of exogenous (1-/sup 14/C)arachidonic acid by resident peritoneal macrophages in response to Zymosan stimulation for 2 hr was examined by extraction of metabolites and separation by HPLC. Cells isolated from DHA-fed animals produced less PGE2 than controls, yet similar amounts of 6-keto PGF1..cap alpha.. were produced. Arachidonic acid metabolites have significant effects on the immune system and may be a mechanism involved in the benefits obtained by inclusion of DHA in the diet.

  5. Olive oil and haemostasis: platelet function, thrombogenesis and fibrinolysis.

    PubMed

    Delgado-Lista, Javier; Garcia-Rios, Antonio; Perez-Martinez, Pablo; Lopez-Miranda, Jose; Perez-Jimenez, Francisco

    2011-01-01

    Mediterranean diet is one of the healthiest nutritional models used in developed countries. The actual interest in this dietary model is based in two main premises. First, the high palatability for the consumer, which aids to the adherence to the model on a life-long basis, and second, the mounting evidence on the beneficial properties that its consumption provokes in cardiovascular risk factors, cancer and cognitive age associated decline. Olive oil is the principal component of Mediterranean diet, both by its predominant position as the main energy source, and its presence in almost all cooked and/or seasoned food. The influence of the olive oil on the beneficial effects of the Mediterranean diet is well known. Albeit an initial stage in which monounsaturated fatty acids (mainly oleic acid) were studied as the sole player of these effects, the knowledge about the micronutrients has evolved to a much more complex model in which the processing of the oil and the content in some minor contents of the virgin olive oil play a fundamental role. In this article we will review the current evidences that relate olive oil with the haemostatic system.

  6. High Insulin Combined With Essential Amino Acids Stimulates Skeletal Muscle Mitochondrial Protein Synthesis While Decreasing Insulin Sensitivity in Healthy Humans

    PubMed Central

    Robinson, Matthew M.; Soop, Mattias; Sohn, Tae Seo; Morse, Dawn M.; Schimke, Jill M.; Klaus, Katherine A.

    2014-01-01

    Context: Insulin and essential amino acids (EAAs) regulate skeletal muscle protein synthesis, yet their independent effects on mitochondrial protein synthesis (MiPS) and oxidative function remain to be clearly defined. Objective: The purpose of this study was to determine the effects of high or low insulin with or without EAAs on MiPS. Design: Thirty participants were randomized to 3 groups of 10 each with each participant studied twice. Study groups comprised (1) low and high insulin, (2) low insulin with and without EAAs, and (3) high insulin with and without EAAs. Setting: The study was conducted in an in-patient clinical research unit. Participants: Eligible participants were 18 to 45 years old, had a body mass index of <25 kg/m2, and were free of diseases and medications that might impair mitochondrial function. Intervention: Low (∼6 μU/mL) and high (∼40 μU/mL) insulin levels were maintained by iv insulin infusion during a somatostatin clamp while maintaining euglycemia (4.7–5.2 mM) and replacing GH and glucagon. The EAA infusion was 5.4% NephrAmine. l-[ring-13C6]Phenylalanine was infused, and muscle needle biopsies were performed. Main Outcomes: Muscle MiPS, oxidative enzymes, and plasma amino acid metabolites were measured. Results: MiPS and oxidative enzyme activities did not differ between low and high insulin (MiPS: 0.07 ± 0.009 vs 0.07 ± 0.006%/h, P = .86) or between EAAs and saline during low insulin (MiPS: 0.05 ± 0.01 vs 0.07 ± 0.01, P = .5). During high insulin, EAAs in comparison with saline increased MiPS (0.1 ± 0.01 vs 0.06 ± 0.01, P < .05) and cytochrome c oxidase activity (P < .05) but not citrate synthase (P = .27). EAA infusion decreased (P < .05) the glucose infusion rates needed to maintain euglycemia during low (∼40%) and high insulin (∼24%). Conclusion: EAAs increased MiPS and oxidative enzyme activity only with high insulin concentrations. PMID:25222757

  7. Improved fibrinolysis by an intensive lifestyle intervention in subjects with impaired glucose tolerance. The Finnish Diabetes Prevention Study.

    PubMed

    Hämäläinen, H; Rönnemaa, T; Virtanen, A; Lindström, J; Eriksson, J G; Valle, T T; Ilanne-Parikka, P; Keinänen-Kiukaanniemi, S; Rastas, M; Aunola, S; Uusitupa, M; Tuomilehto, J

    2005-11-01

    The aim of this study was to investigate the effects of lifestyle intervention on the levels of plasminogen activator inhibitor (PAI-1) and fibrinogen in subjects participating in the Finnish Diabetes Prevention Study (DPS). In five DPS centres, 321 subjects with impaired glucose tolerance (intervention group, n=163; control group, n=158) had their PAI-1 and fibrinogen levels measured at baseline and at the 1-year follow-up. Additional 3-year follow-up assessments were carried out in a sample of 97 subjects in one of the DPS centres (Turku). The intervention programme included an intensive lifestyle intervention aiming at weight reduction, healthy diet and increased physical activity. During the first intervention year, PAI-1 decreased by 31% in the intervention group but showed no change in the control group (p<0.0001). In the Turku subgroup, the decrease in PAI-1 persisted throughout the 3-year follow-up. Changes in PAI-1 were associated with the number of lifestyle changes made during the first year (p=0.008). Weight reduction was the most important factor explaining the decrease in PAI-1. Changes in fibrinogen levels did not differ between the groups. In addition to the previously reported reduction in the risk of type 2 diabetes in DPS participants with impaired glucose tolerance, the intensive dietary and exercise intervention had beneficial long-term effects on fibrinolysis as indicated by the reduced levels of PAI-1. These results suggest that elevated PAI-1 levels in obese subjects with impaired glucose tolerance are mostly reversible by lifestyle changes, especially those geared to weight reduction.

  8. Spray-dried milk supplemented with alpha-linolenic acid or eicosapentaenoic acid and docosahexaenoic acid decreases HMG Co A reductase activity and increases biliary secretion of lipids in rats.

    PubMed

    Ramaprasad, Talahalli R; Srinivasan, Krishnapura; Baskaran, Vallikannan; Sambaiah, Kari; Lokesh, Belur R

    2006-05-01

    In our earlier study, we have shown that rats fed spray-dried milk containing alpha-linolenic acid (LNA 18:3 n-3) or eicosapentaenoic acid (EPA 20:5 n-3) and docosahexaenoic acid (DHA 22:6 n-3) had significantly lower amounts of serum and liver cholesterol. To evaluate the mechanism for hypocholesterolemic effect of n-3 fatty acids containing milk formulation, we fed male Wistar rats with spray-dried milk containing linseed oil (LSO) (source of LNA) or fish oil (FO) (source of EPA+DHA) for 8 weeks. Feeding n-3 fatty acid containing milk formulation lowered the hepatic 3-hydroxy-methylglutaryl coenzyme A (HMG Co A) activity by 17-22% compared to rats given control diet devoid of n-3 fatty acids. The cholesterol level in liver microsomes was found to be decreased by 16% and 20%, respectively, in LSO and FO containing formulation fed rats. The bile flow was enhanced to an extent of 19-23% in experimental groups compared to control animals. The biliary cholesterol and phospholipid secretion was increased to an extent of 49-55% and 140-146%, respectively, in rats fed n-3 fatty acid containing formulation. The increase in the total bile acids secretion in bile was mainly reflected on an increase in the levels of taurine conjugated bile acids. These results indicated that n-3 fatty acid containing spray-dried milk formulation would bring about the hypocholesterolemic effect by lowering HMG Co A reductase activity in liver and by increasing the secretion of bile constituents.

  9. Amino acid substitutions of Na,K-ATPase conferring decreased sensitivity to cardenolides in insects compared to mammals.

    PubMed

    Dalla, Safaa; Swarts, Herman G P; Koenderink, Jan B; Dobler, Susanne

    2013-12-01

    Mutagenesis analyses and a recent crystal structure of the mammalian Na,K-ATPase have identified amino acids which are responsible for high affinity binding of cardenolides (such as ouabain) which at higher doses block the enzyme in the phosphorylated state. Genetic analysis of the Na,K-ATPase of insects adapted to cardenolides in their food plants revealed that some species possess substitutions which confer strongly increased resistance to ouabain in the mammalian enzyme such as the substitution T797A or combined substitutions at positions 111 and 122. To test for the effect of these mutations against the background of insect Na,K-ATPase, we here expressed the ouabain sensitive Na,K-ATPase α-subunit of Drosophila melanogaster together with the β-subunit Nrv3 in baculovirus-infected Sf9 cells and introduced the substitutions N122H, T797A, Q111T-N122H, Q111V-N122H, all of which have been observed in cardenolide-adapted insects. While all constructs showed similar expression levels, ouabain affinity of mutated Na,K-ATPases was reduced compared to the wild-type fly enzyme. Ouabain sensitivity of the ATPase activity in inhibition assays was significantly decreased by all mutations, yet whereas the IC₅₀ for the single mutations of N122H (61.0 μM) or T797A (63.3 μM) was increased roughly 250-fold relative to the wild-type (0.24 μM), the double mutations of Q111V-N122H (IC₅₀ 550 μM) and Q111T-N122H (IC₅₀ 583 μM) proved to be still more effective yielding a 2.250-fold increased resistance to ouabain. The double mutations identified in cardenolide-adapted insects are more effective in reducing ouabain sensitivity of the enzyme than those found naturally in the rat Na,K-ATPase (Q111R-N122D) or in mutagenesis screens of the mammalian enzyme. Obviously, the intense selection pressure on cardenolide exposed insects has resulted in very efficient substitutions that decrease cardenolide sensitivity extremely. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Blood coagulation and fibrinolysis after experimental subarachnoid hemorrhage.

    PubMed

    Larsen, Carl C; Hansen-Schwartz, Jacob; Nielsen, Jørn D; Astrup, Jens

    2010-09-01

    Aneurysmal rebleeding poses a serious risk in patients with subarachnoid hemorrhage (SAH). Studies have shown that antifibrinolytic therapy with tranexamic acid has a dramatic effect on the rate of rebleeding. Therefore, changes in the fibrinolytic system could be hypothesized. We have used an experimental SAH rat model to demonstrate serial changes in the haemostatic system as evaluated by Thromboelastography (TEG). In the SAH group, a shorter reaction time (R-time) and higher maximum amplitude (MA) were observed. In the saline group, only a shorter R-time was observed. The study has shown that a hypercoagulable state is present immediately after experimental SAH is induced as determined by TEG. The reduction in R-time and rise in MA observed in the SAH group indicate that blood in the subarachnoid space is necessary to accomplish a full systemic coagulation response. This abnormality in coagulation profile seems to be a response to the acute traumatic event caused by induction of SAH.

  11. Thrombin-Activatable Fibrinolysis Inhibitor in Human Abdominal Aortic Aneurysm Disease.

    PubMed

    Bridge, Katherine I; Bollen, Lize; Zhong, Jim; Hesketh, Mark; Macrae, Fraser L; Johnson, Anne; Philippou, Helen; Scott, D Julian; Gils, Ann; Ariёns, Robert A S

    2017-08-21

    Intra-luminal thrombosis is a key factor in Abdominal Aortic Aneurysms (AAA) growth. Patients with AAA form dense clots that are resistant to fibrinolysis. Thrombin-activatable fibrinolysis inhibitor (TAFI) has been shown to influence AAA development in murine models. The aim of this study is to characterise the role of TAFI in human AAA. Plasma levels of TAFI, TAFI activation peptide (TAFI-AP), activated/inactivated TAFI (TAFIa/ai) and plasmin-α2-antiplasmin complex were measured by ELISAs in patients with AAA (n=202) and controls (n=188). TAFIa/ai and TAFI-AP levels were higher in patients than controls (median (IQR): 20.3 (14.6-32.8) vs. 14.2 (11.2-19.3) and 355.0 (232.4-528.1) vs. 248.6 (197.1-328.1) ng/ml). TAFIa/ai was positively correlated with TAFI-AP (r=0.164). Intact TAFI levels were not different between patients and controls (13.4 (11.2-16.1) vs. 12.8 (10.6-15.4) μg/ml). Plasmin-α2-antiplasmin was higher in AAA patients than controls (690.0 (489.1-924.3) vs. 480.7 (392.6-555.3) ng/ml). The increase in TAFIa/ai and TAFI-AP suggest an increased TAFI activation in patients with AAA. Prospective studies are required to further elucidate the role of TAFI and fibrinolysis in AAA pathogenesis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  12. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease.

    PubMed

    Undas, A; Celinska-Löwenhoff, M; Löwenhoff, T; Szczeklik, A

    2006-05-01

    Aspirin increases fibrin clot porosity and susceptibility to lysis. It is unknown whether other drugs, in combination with aspirin, used in the treatment of coronary artery disease (CAD) might affect clot structure and resistance to lysis. The aim of the study was to assess the effects of statins, fibrates, or angiotensin-converting enzyme inhibitors (ACEIs) on fibrin clot properties. In a randomized double-blind study, men with advanced CAD taking low-dose aspirin were assigned to receive one of the four drugs: simvastatin 40 mg day(-1) (n = 13), atorvastatin 40 mg day(-1) (n = 12), fenofibrate 160 mg day(-1) (n = 12), and quinapril 10 mg day(-1) (n = 11) for 28 +/- 2 days. Moreover, CAD patients (n = 13) taking aspirin (75 mg day(-1)) for 8 weeks were studied after additional 4 weeks on an open-label basis. Thirty men served as healthy controls. Plasma clot permeability and tissue plasminogen activator-induced fibrinolysis were evaluated at baseline and after drug administration. Permeability increased following the administration of simvastatin (by 20%; P = 0.01), atorvastatin (by 22%; P = 0.001), fenofibrate (by 16%; P = 0.02), and quinapril (by 13%; P = 0.04) like for aspirin (P < 0.001). Turbidity analysis showed that administration of any of the drugs was associated with higher maximum absorbancy, suggesting thicker fibers, and shorter fibrinolysis time (P < 0.001). Post-treatment reduction in lysis time correlated with an increase in clot porosity in all the groups (r from 0.42 to 0.61; P from 0.01 to 0.001). Statins, fibrates, and ACEIs may increase plasma clot permeability and susceptibility to fibrinolysis in CAD patients receiving aspirin. This novel antithrombotic mechanism might contribute to clinical benefits of the drugs tested.

  13. [Superselective fibrinolysis for a middle cerebral artery embolism caused by a left atrial myxoma: case report].

    PubMed

    Yamanome, T; Yoshida, K; Miura, K; Ogawa, A

    2000-07-01

    A case of successful treatment by local fibrinolysis of a middle cerebral artery embolism caused by a thrombus from a left atrial myxoma is reported. A 62-year-old woman using a pacemaker and suffering from sick sinus syndrome was admitted on December 29th 1996, complaining of transient restlessness. CT and cerebral angiography revealed no abnormal vascular lesions. Eighteen months after the initial episode, she suffered a sudden onset of left hemiparesis and loss of consciousness. CT scan performed during the second episode revealed no lesions and, in particular, no early CT infarction sign, but emergent cerebral angiography revealed a right middle cerebral artery embolic occlusion. Local fibrinolysis using a tissue plasminogen activator was performed within 3 hours after the beginning of the episode, and partial recanalization was obtained within one hour after initiation of the fibrinolytic therapy. On the first hospital day, though CT revealed a small low-density area in the right basal ganglia, motor deficits gradually improved. Considering the possibility of a cardiac source of the embolism, trans-esophageal echocardiography was performed and revealed a left atrial tumor suspected to be a myxoma. It was removed by surgery on the 34th hospital day. Histological examination proved it to be a myxoma. Nine months after local fibrinolytic therapy, the patient returned to work. The diagnosis of cerebral embolism caused by cardiac myxoma is difficult to make at the time when the patient is first examined after admission. It is also hard to discover during emergent cerebral angiography with fibrinolytic therapy. Therefore, in the case of patients with cerebral embolism for which local fibrinolysis is ineffective, it should be presumed that cardiac myxoma is the source of the embolus. Direct PTA alone may be effective for such tumoral embolism.

  14. Abnormalities in blood coagulation, fibrinolysis, and platelet activation in adult patients after the Fontan procedure.

    PubMed

    Tomkiewicz-Pajak, Lidia; Hoffman, Piotr; Trojnarska, Olga; Lipczyńska, Magdalena; Podolec, Piotr; Undas, Anetta

    2014-04-01

    Thrombosis occurs in up to 30% of patients with various forms of congenital single ventricle after the Fontan procedure. We investigated hemostatic abnormalities in adult Fontan patients. Forty-eight Fontan patients between ages 18 and 40 years, including 10 (21%) patients with previous thromboembolism 5 to 15 years after surgery, and 35 control subjects matched for age and sex were studied. Coagulation factors and inhibitors, together with markers of fibrinolysis, platelets, and endothelial activation, were determined in peripheral venous blood plasma. Compared with control subjects, Fontan patients showed lower, although mostly within normal ranges, values of all coagulation factors, as well as reduced free protein S, in association with higher antithrombin and free tissue factor pathway inhibitor levels. Thrombin generation, reflected by prothrombin fragment 1.2, and platelet activation markers were increased in Fontan patients. The plasma clot lysis time was prolonged in Fontan patients, which was associated with an increased activity of thrombin-activatable fibrinolysis inhibitor. Fontan patients with previous thromboembolism had lower oxygen saturation, coagulation factors V and VIII, and free protein S, and increased von Willebrand factor, soluble CD40 ligand, and P-selectin. Other laboratory or clinical parameters were not associated with prior thrombotic episodes. Adult Fontan patients are characterized by enhanced platelet activation and endothelial injury, heightened thrombin formation, and impaired fibrinolysis. Patients showed reduced free protein S levels, increased platelet activation, and endothelial damage after thromboembolic events observed late after Fontan surgery. Our findings indicate novel prothrombotic mechanisms in adult Fontan patients, which might help to optimize thromboprophylaxis. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  15. [Activators and inhibitors of fibrinolysis in chronic glomerulonephritis and amyloidosis].

    PubMed

    Podorol'skaia, L V; Andreenko, G V; Poliantseva, L R; Bumblite, I D

    1996-01-01

    Functional activities of plasminogen activators (FPAA) and their inhibitors and plasminogen activators's (PA), antigen level were determined in 31 patients with chronic glomerulonephritis, 23 patients with amyloidosis and 15 healthy persons. High FPAA correlated with favourable prognosis of diseases, elevated PA antigen level and diminished alpha 1-antitrypsin, alpha 2-macroglobulin and antiactivator activities. There were decreased PA antigen level and increased inhibitor's activities in group with zero FPAA. Protein loaded functional probe demonstrated the presence of PA reserves in high FPAA patients and "pathological proteolysis" in zero FPAA patients. The last phenomenon was likely connected to nonspecific proteases differed from PA.

  16. n-3 polyunsaturated fatty acids supplementation decreases asymmetric dimethyl arginine and arachidonate accumulation in aging spontaneously hypertensive rats.

    PubMed

    Raimondi, Laura; Lodovici, Maura; Visioli, Francesco; Sartiani, Laura; Cioni, Laura; Alfarano, Chiara; Banchelli, Grazia; Pirisino, Renato; Cecchi, Enrica; Cerbai, Elisabetta; Mugelli, Alessandro

    2005-09-01

    Plasma accumulation of asymmetric dimethyl arginine (ADMA) is considered as a risk factor for endothelial dysfunction and a strong predictor for coronary heart diseases. Eicosapentaenoic (EPA) and docosahexaenoic (DHA) increasing plasma levels have been positively associated with reduced cardiovascular mortality with a mechanism( s) yet unclear. We hypothesised that ADMA reduction might be a part of EPA and DHA beneficial effects on the cardiovascular system. To verify this hypothesis we measured ADMA plasma levels in aged spontaneously hypertensive rats (SHR) supplemented for 8 weeks with EPA and DHA. 16-month-old SHR were supplemented with EPA and DHA (EPA-DHA) or with olive oil (1 g/kg/day; OLIVE). At the end of the treatments, the plasma of each animal was analysed for 1) the total fatty acid composition, by gas-cromatography, 2) ADMA levels, by high pressure liquid chromatography, 3) nitrite and homocysteine concentration by chemiluminescence and by polarisation immunoassay respectively. Moreover, the activity of dimethyl arginine dimethyl amino hydrolase, the main enzyme involved in ADMA metabolism, was measured spectrophotometrically in the kidney from each rat. Animals supplemented with EPA and DHA showed: 1) lower ADMA and arachidonate plasma levels (587.4 +/- 113.7 nM and 0.49 +/- 0.11 mM respectively) than the values found in OLIVE rats (1365 +/- 399 nM and 1.07 +/- 0.07 mM respectively) 2) higher nitrite content (0.73 +/- 0.05 microM) than OLIVE (0.23 +/- 0.08 microM). EPA and DHA supplementation reduced ADMA accumulation in SHR in parallel with a decrease of arachidonate availability. This finding suggests that the control of the inflammatory ground of endothelium might play an important role in EPA and DHA effect on this novel and highly predictive cardiovascular risk factor.

  17. Effects of three cobra venoms on blood coagulation, platelet aggregation, and fibrinolysis

    PubMed Central

    MacKay, N.; Ferguson, J. C.; McNicol, G. P.

    1969-01-01

    The effects of the venoms of Naja melanoleuca, Naja nigricollis, and Ophiophagus hannah on blood coagulation, platelet aggregation, and fibrinolysis were studied in vitro. All three venoms were shown to be anticoagulant. This action appeared to be due to an effect on both the extrinsic and blood thromboplastin mechanisms. Platelet aggregation in Chandler's tubes and adenosine diphosphate reactivity were inhibited by the three venoms, although in the case of Ophiophagus hannah venom they were inhibited only with intermediate concentrations. The three venoms possessed proteolytic properties, but when incorporated into purified caseinolytic systems and euglobulin clot lysis systems inhibition of plasmin activity was observed. PMID:5814735

  18. Pesticins III. Expression of Coagulase and Mechanism of Fibrinolysis1

    PubMed Central

    Beesley, E. D.; Brubaker, R. R.; Janssen, W. A.; Surgalla, M. J.

    1967-01-01

    Mutational loss of pesticin I, a bacteriocin-like substance produced by Pasteurella pestis, is known to result in concomitant loss of a coagulase and fibrinolytic factor. No relationship was detected between pesticinogeny and other tested properties either associated with virulence or peculiar to P. pestis. Pesticin I was distinguished from the coagulase and fibrinolytic activities on the basis of anatomical distribution, behavior during gel filtration, and sensitivity to heat. Coagulase and the fibrinolytic factor were not differentiated by these criteria. Spontaneous suppressor mutations causing reversion to pesticinogeny were not detected, nor were such mutants obtained by treatment with ultraviolet light or 2-aminopurine. Attempts to demonstrate a common activator of pesticin I, coagulase, or the fibrinolytic factor in extracts of pesticinogenic cells were not successful. These results are in accord with the hypothesis that at least two structural genes for the three activities reside on a replicon distinct from the chromosome proper. Fibrinolytic activity was significantly reduced in the presence of 0.003 m ε-aminocaproic acid and was nonexistent on fibrin films freed from endogenous plasminogen by treatment with heat. Fibrinolytic activity on heated films could be restored by addition of plasma or serum from six mammalian species. Accordingly, the plague fibrinolytic factor, like staphylokinase or urokinase, promotes the conversion of plasminogen to plasmin. Images PMID:6027989

  19. Decreased uric acid levels correlate with poor outcomes in acute ischemic stroke patients, but not in cerebral hemorrhage patients.

    PubMed

    Wu, Hongliang; Jia, Qian; Liu, Gaifen; Liu, Liping; Pu, Yuehua; Zhao, Xingquan; Wang, Chunxue; Wang, Yilong; Wang, Yongjun

    2014-03-01

    The relationship between uric acid and stroke prognosis is ambiguous. Some studies have explored this relationship in acute stroke but have different results. In this study, we explored the relationship between uric acid levels and 1-year outcomes and vascular events of acute ischemic stroke patients and cerebral hemorrhage patients. In all, 1452 continued first, acute ischemic stroke patients and 380 continued cerebral hemorrhage patients were admitted to our hospitals. Serum uric acid concentrations were measured in 1351 ischemic stroke patients and 380 cerebral hemorrhage patients at admission. We evaluated the relationship between uric acid levels and outcomes (modified Rankin scale [mRS] > 2, all-cause death, vascular events, stroke recurrent) at 14 days, 90 days, and 1 year after stroke onset. The median uric acid concentration was 303.0 μmol/L in ischemic stroke patients and 269 μmol/L in cerebral hemorrhage patients. In univariate analysis, uric acid levels were not correlated with outcomes in cerebral hemorrhage patients. We used multiple logistic regression analysis to show that lower serum uric acid levels independently predicted poor functional outcomes (mRS >2) at 1 year after ischemic stroke onset (odds ratio [OR] = .335, 95% confidence interval [CI]: .164-.684, P = .003). Also, lower serum uric acid levels were independently correlated with vascular events in the first year in ischemic stroke patients. By multiple cox proportional hazards analysis, we obtained data which reveal that serum uric acid levels were not correlated with all-cause death (OR = .992, 95% CI: .683-1.443, P = .969) in ischemic stroke patients. Serum uric acid may be neuroprotective in acute ischemic stroke patients. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  20. Decreased aortic early atherosclerosis in hypercholesterolemic hamsters fed oleic acid-rich TriSun oil compared to linoleic acid-rich sunflower oil.

    PubMed

    Nicolosi, Robert J.; Wilson, Thomas A.; Handelman, Garry; Foxall, Thomas; Keaney, John F.; Vita, Joseph A.

    2002-07-01

    Previous studies have demonstrated that low density lipoprotein (LDL) enriched in polyunsaturated fatty acids (PUFA) are more susceptible to oxidation (ex vivo) than those containing monounsaturated fatty acids (MUFA). To test whether this observation was associated with various parameters considered to be related with the development of early aortic atherosclerosis, hamsters were fed commercial hypercholesterolemic diets (HCD) containing either the PUFA, sunflower oil (SF) or the MUFA, TriSun oil (TS) at 10% with 0.4% cholesterol (wt/wt). LDL isolated from hamsters fed TS had significantly longer lag phase (30%, P < 0.05), a decreased propagation phase (-62%, P < 0.005), and fewer conjugated dienes formed (-37%, P < 0.007) compared to hamsters fed SF. Aortic vasomotor function, measured as degree of aortic relaxation, was significantly greater in the TS vs SF-fed hamsters whether acetylcholine or the calcium ionophore A23187 was used as the endothelium-dependent agonist. As a group, the SF-fed hamsters had significantly more early atherosclerosis than hamsters fed TS (46%, P < 0.006). When animals across the two diets were pair-matched by plasma LDL-C levels, there was an 82% greater mean difference (P < 0.002) in early atherosclerosis in the SF versus the TS-fed hamsters. While there were no significant associations with plasma lipids and lipoprotein cholesterol, early atherosclerosis was significantly correlated with lag phase (r = -0.67, p < 0.02), rate of LDL conjugated diene formation (r = 0.74, p < 0.006) and maximum dienes formed (r = 0.67, p < 0.02). Compared to TS-fed animals, aortic sections from hamsters fed the SF-containing diet revealed that the cytoplasm of numerous foam cells in the subendothelial space reacted positively with the monoclonal anti-bodies MDA-2 and NA59 antibody, epitopes found on oxidized forms of LDL. The present study suggests that compared to TS, hamsters fed the SF-diet demonstrated enhanced LDL oxidative susceptibility, reduced

  1. Changes in coagulation and fibrinolysis in the postoperative period immediately after kidney transplantation in patients receiving OKT3 or cyclosporine A as induction therapy.

    PubMed

    Deira, J; Alberca, I; Lerma, J L; Martín, B; Tabernero, J M

    1998-10-01

    Different immunosuppressive agents, in particular OKT3, have been implicated as causative factors in the risk for renal thrombosis in the period immediately after kidney transplantation. Also, in different types of vascular surgery, a state similar to hypercoagulation has been reported. To assess the extent to which OKT3, cyclosporine A (CsA), and surgery itself affect coagulation and fibrinolysis, a study was conducted of 20 patients divided into two groups: group A, 10 patients received OKT3 (first dose during the induction of anesthesia); and group B, 10 patients received CsA (first dose at least 2 hours before transplantation). Basal determinations and determinations at 2, 4, and 24 hours after the induction of anesthesia were made. No differences were found between the groups with respect to the clinical and usual coagulation parameters. The following were studied in both groups: (1) markers of coagulation activity (prekallikrein [PKK] levels and formation of thrombin-antithrombin complexes [TATc]), (2) inhibitors and suppressors of hemostasis (antithrombin III [AT-III] and protein C [PC] activity), (3) markers of fibrinolysis activation (levels of plasminogen [PLG] and of alpha2-antiplasmin [alpha2-APL]), and (4) markers of endothelial damage (tissue plasminogen activator [TPA] and thrombomodulin [TMD]). In both groups, an important formation of TATc was observed early, together with a decrease in PKK levels and consumption of both AT-III and PC, which reached their lowest levels at 24 hours. This points to an activation of coagulation through the intrinsic route and a secondary consumption of hemostasis inhibitors, both possibly caused by surgery. A consumption of PLG and alpha2-APL was also observed, reflecting stimulation of the fibrinolytic system and a physiological response to the activation of coagulation. A greater release of endothelial TPA was only observed in the patients receiving OKT3 (P < 0.0001), possibly signaling endothelial activation. It is

  2. The effects of intermittent pneumatic compression during cesarean delivery on fibrinolysis.

    PubMed

    Reddick, Keisha L B; Smrtka, Michael P; Grotegut, Chad A; James, Andra H; Brancazio, Leo R; Swamy, Geeta K

    2014-10-01

    Pregnancy is associated with increased risk for thromboembolic events. Intermittent pneumatic compression (IPC) devices are the method of thromboprophylaxis in a nonpregnant population. The aim of this study was to examine the effects of IPC on markers of fibrinolysis during cesarean delivery. We conducted a randomized controlled trial from April 2009 to March 2010 of women undergoing scheduled elective cesarean delivery. Forty-nine women were randomized to IPCs or usual care. All participants had three blood samples obtained: (1) baseline, (2) 1 hour after randomization, and (3) 30 minutes after cesarean delivery. Tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor-1 (PAI-1), and plasminogen activator inhibitor-2 (PAI-2) levels were analyzed in each sample using an enzyme-linked immunosorbent assay. Statistical analysis was performed using repeated measures two-way analysis of variance with α = 0.05. There was a time-dependent change in tPA, uPA, and PAI-1 levels following delivery but no difference in TAT and PAI-2 levels with time. There were no differences between women randomized to IPCs or usual care. Markers of fibrinolysis were not significantly altered by IPCs in this study of low-risk pregnant women. Further research regarding the mechanism and efficacy of IPCs in pregnant women is warranted. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  3. Pulsed transthrombotic fibrinolysis: technique and results in the management of occluded lower limb bypass grafts.

    PubMed

    Payelle, G; Maiza, D; Coffin, O; Alachkar, F; Alweis, S; Courtheoux, P; Khayat, M C; Gérard, J L; Théron, J

    1997-03-01

    Between March 1987 and March 1993 we used pulsed transthrombotic fibrinolysis to treat 58 symptomatic thrombotic occlusions of lower limb bypass grafts in 45 patients. There were 17 suprainguinal grafts and 28 infrainguinal grafts. Treatment consisted of pulsed infusion of fibrinolytic agents into the thrombus followed by continuous infusion using an electric pump. Minor percutaneous or surgical procedures were often associated. The mean delay to treatment was 7 days. The mean duration of treatment was 150 +/- 66 minutes. Immediate patency was achieved in 88% of cases with no significant difference between suprainguinal and infrainguinal grafts. The clinical success rate was 55%. Actuarial patency at 1 year was 54% +/- 11% for suprainguinal grafts and 26% +/- 7% for infrainguinal grafts. The probability of patency was much lower in patients whose grafts had been implanted within 3 months before occlusion and in patients in whom an adjuvant procedure had not been performed. This study demonstrates that, in cases not requiring immediate surgery, pulsed transthrombotic fibrinolysis can achieve durable patency by treating both the bypass and distal arterial network. This technique allows identification of lesions causing thrombosis and adaptation of treatment specifically to these lesions.

  4. Shrimp Alpha-2-Macroglobulin Prevents the Bacterial Escape by Inhibiting Fibrinolysis of Blood Clots

    PubMed Central

    Chaikeeratisak, Vorrapon; Somboonwiwat, Kunlaya; Tassanakajon, Anchalee

    2012-01-01

    Proteomic analysis of the hemocytic proteins of Penaeus monodon (Pm) has previously shown that alpha-2-macroglobulin (A2M) was among the proteins that showed substantially altered expression levels upon Vibrio harveyi infection. Therefore, in this study its potentially important role in the response of shrimp to bacterial infection was further characterized. The yeast two-hybrid system revealed that the receptor binding domain of PmA2M interacted with the carboxyl-terminus of one or both of the transglutaminase type II isoforms, which are key enzymes involved in the shrimp clotting system. In accord with this, PmA2M was found to be localized on the extracellular blood clots and to colocalize with clottable proteins. RNA interference (RNAi)-mediated knockdown of A2M transcript levels reduced the PmA2M transcript levels (∼94%) and significantly reduced the bacterial seizing ability of the clotting system, resulting in an up to 3.3-fold higher number of V. harveyi that systemically disseminated into the circulatory system at 5 min post-infection before subsequent clearance by the immune system. Furthermore, an appearance of PmA2M depleted clots in the presence of V. harveyi strikingly demonstrated fibrinolysis zones surrounding the bacteria. This study provides the first evidence of the vital role of PmA2M in enhancing bacterial sequestration by protecting blood clots against fibrinolysis. PMID:23082160

  5. Blood coagulation and fibrinolysis in aortic valve stenosis: links with inflammation and calcification.

    PubMed

    Natorska, J; Undas, A

    2015-08-01

    Aortic valve stenosis (AS) increasingly afflicts our aging population. However, the pathobiology of the disease is still poorly understood and there is no effective pharmacotherapy for treating those at risk for clinical progression. The progression of AS involves complex inflammatory and fibroproliferative processes that resemble to some extent atherosclerosis. Accumulating evidence indicates that several coagulation proteins and its inhibitors, including tissue factor, tissue factor pathway inhibitor, prothrombin, factor XIII, von Willebrand factor, display increased expression within aortic stenotic valves, predominantly on macrophages and myofibroblasts around calcified areas. Systemic impaired fibrinolysis, along with increased plasma and valvular expression of plasminogen activator inhibitor-1, has also been observed in patients with AS in association with the severity of the disease. There is an extensive cross-talk between inflammation and coagulation in stenotic valve tissue which contributes to the calcification and mineralisation of the aortic valve leaflets. This review summarises the available data on blood coagulation and fibrinolysis in AS with the emphasis on their interactions with inflammation and calcification.

  6. Plasmatic coagulation and fibrinolysis in healthy and Otostrongylus-affected Northern elephant seals (Mirounga angustirostris).

    PubMed

    Kaye, Sarrah; Johnson, Shawn; Rios, Carlos; Fletcher, Daniel J

    2017-09-13

    Prepatent Otostrongylus arteritis results in hemorrhagic diathesis in free-ranging Northern elephant seals (Mirounga angustirostris) attributed to aberrant larval migration of the lungworm, Otostrongylus circumlitus. Clinical signs are often nonspecific, including lethargy, anorexia, and blepharospasm, but can progress to spontaneous frank hemorrhage and death within 72 hours of onset. Previously published case reports describe coagulopathy with prolonged PT and APTT, normal to elevated platelet counts, normal antithrombin concentrations, and low concentrations of fibrinogen degradation products. Disseminated intravascular coagulation was proposed as the cause of hemorrhage, but is inconsistent with some of the reported clinicopathologic changes. The purpose of this study was to compare plasmatic coagulation and fibrinolysis in healthy and Otostrongylus-affected elephant seals, in order to identify potential therapy. We hypothesized that hyperfibrinolysis contributed to hemorrhage in these cases. Citrated plasma samples were collected from 3- to 4-month-old Northern elephant seals in a wildlife rehabilitation hospital. The sampled population included 25 healthy, prerelease seals and 32 clinically ill seals diagnosed with presumptive Otostrongylus arteritis. Twenty-one of the included seals had Otostrongylus infestation confirmed at necropsy. Standard coagulation tests and plasma thromboelastography were performed for a complete assessment of coagulation and fibrinolysis. Northern elephant seals with definitive Otostrongylus infestation were hypocoagulable and hypofibrinolytic compared to healthy controls. Results were most consistent with disseminated intravascular coagulation. Treatment with antifibrinolytic drugs to control hemorrhage may be unrewarding; alternative therapies such as plasma transfusions or coagulation factor concentrates should be investigated. © 2017 American Society for Veterinary Clinical Pathology.

  7. Cyclosporin A-sensitive decrease in the transmembrane potential across the inner membrane of liver mitochondria induced by low concentrations of fatty acids and Ca2+.

    PubMed

    Bodrova, M E; Brailovskaya, I V; Efron, G I; Starkov, A A; Mokhova, E N

    2003-04-01

    At low Ca2+ concentrations the pore of the inner mitochondrial membrane can open in substates with lower permeability (Hunter, D. R., and Haworth, R. A. (1979) Arch. Biochem. Biophys., 195, 468-477). Recently, we showed that Ca2+ loading of mitochondria augments the cyclosporin A-dependent decrease in transmembrane potential (DeltaPsi) across the inner mitochondrial membrane caused by 10 micro M myristic acid but does not affect the stimulation of respiration by this fatty acid. We have proposed that in our experiments the pore opened in a substate with lower permeability rather than in the "classic" state (Bodrova, M. E., et al. (2000) IUBMB Life, 50, 189-194). Here we show that under conditions lowering the probability of "classic pore" opening in Ca2+-loaded mitochondria myristic acid induces the cyclosporin A-sensitive DeltaPsi decrease and mitochondrial swelling more effectively than uncoupler SF6847 does, though their protonophoric activities are equal. In the absence of P(i) and presence of succinate and rotenone (with or without glutamate) cyclosporin A either reversed or only stopped DeltaPsi decrease induced by 5 micro M myristic acid and 5 micro M Ca2+. In the last case nigericin, when added after cyclosporin A, reversed the DeltaPsi decrease, and the following addition of EGTA produced only a weak (if any) DeltaPsi increase. In P(i)-containing medium (in the presence of glutamate and malate) cyclosporin A reversed the DeltaPsi decrease. These data show that the cyclosporin A-sensitive decrease in DeltaPsi by low concentrations of fatty acids and Ca2+ cannot be explained by specific uncoupling effect of fatty acid. We propose that: 1) low concentrations of Ca2+ and fatty acid induce the pore opening in a substate with a selective cation permeability, and the cyclosporin A-sensitive DeltaPsi decrease results from a conversion of DeltaPsi to pH gradient due to the electrogenic cation transport in mitochondria; 2) the ADP/ATP-antiporter is involved in this

  8. Protoporphyrinaemia and decreased activities of 5-aminolevulinic acid dehydrase and uroporphyrinogen I synthetase in erythrocytes of a Vitamin B6-deficient epileptic boy given valproic acid and carbamazepine.

    PubMed

    Haust, H L; Poon, H C; Carson, R; VanDeWetering, C; Peter, F

    1989-06-01

    Carbamazepine (CBMZP) has been implicated as an inhibitor of the activities of 5-aminolaevulinic acid dehydratase (ALA-D) and uroporphyrinogen I synthetase (URO-S). In an epileptic boy undergoing long-term treatment with valproic acid (VPA), 1.3 g/d, CBMZP, 0.9 g/d and folic acid, 7.5 mg/d, decreased activities of ALA-D and URO-S coincided with increased levels of erythrocyte protoporphyrin (EP) in the absence of Pb poisoning, iron depletion and erythropoietic protoporphyria. A progressive fall in plasma pyridoxal 5'-phosphate (B6-P) to 7.7 nmol/L (lower reference limit, 14.6 nmol/L) prompted implementation of pyridoxine HCl (B6-HCl), 87.5 mg/d followed by administration of both B6-HCl and preformed B6-P (50 mg/d each). This permitted the eventual withdrawal of VPA and a net reduction of CBMZP to 450 mg/d. During these manipulations, ALA-D and URO-S activities, EP and urinary porphyrins and their precursors were measured serially. An assay system utilizing red cell ALA-D for generation of porphobilinogen (PBG) from added ALA at pH 7.4 was used for determination of ALA-D and URO-S activities in separate aliquots of the same assay mixture both in the absence and presence of Zn and dithiothreitol (DTT). One unit (U) for ALA-D = 1 nmol PBG/L RBC/s; for URO-S = 1 nmol porphyrin/L/s; minimum normal level for ALA-D = 135 U; for URO-S = 6 U. B6-HCl alone entailed increases in ALA-D and URO-S prior to any reduction of CBMZP. After administration of both B6-HCl and B6-P and withdrawal of VPA, the overall increase in ALA-D was from 54.59 to 197.2 U (-Zn; -DTT) and from 50.76 to 217.3 U (+Zn; +DTT). The overall increase in URO-S was from 2.67 to 8.90 U (-Zn; -DTT) and from 3.02 to 8.66 U (+Zn; +DTT). During stepwise reduction of VPA, EP remained elevated to values as high as 2.48 mumol/L (upper reference limit, 1.33 mumol/L). Only after permanent withdrawal of VPA did concentrations of EP fall to normal levels. Values for porphyrins and their precursors in urine were normal

  9. Lifelong treatment with atenolol decreases membrane fatty acid unsaturation and oxidative stress in heart and skeletal muscle mitochondria and improves immunity and behavior, without changing mice longevity.

    PubMed

    Gómez, Alexia; Sánchez-Roman, Ines; Gomez, Jose; Cruces, Julia; Mate, Ianire; Lopez-Torres, Mónica; Naudi, Alba; Portero-Otin, Manuel; Pamplona, Reinald; De la Fuente, Monica; Barja, Gustavo

    2014-06-01

    The membrane fatty acid unsaturation hypothesis of aging and longevity is experimentally tested for the first time in mammals. Lifelong treatment of mice with the β1-blocker atenolol increased the amount of the extracellular-signal-regulated kinase signaling protein and successfully decreased one of the two traits appropriately correlating with animal longevity, the membrane fatty acid unsaturation degree of cardiac and skeletal muscle mitochondria, changing their lipid profile toward that present in much more longer-lived mammals. This was mainly due to decreases in 22:6n-3 and increases in 18:1n-9 fatty acids. The atenolol treatment also lowered visceral adiposity (by 24%), decreased mitochondrial protein oxidative, glycoxidative, and lipoxidative damage in both organs, and lowered oxidative damage in heart mitochondrial DNA. Atenolol also improved various immune (chemotaxis and natural killer activities) and behavioral functions (equilibrium, motor coordination, and muscular vigor). It also totally or partially prevented the aging-related detrimental changes observed in mitochondrial membrane unsaturation, protein oxidative modifications, and immune and behavioral functions, without changing longevity. The controls reached 3.93 years of age, a substantially higher maximum longevity than the best previously described for this strain (3.0 years). Side effects of the drug could have masked a likely lowering of the endogenous aging rate induced by the decrease in membrane fatty acid unsaturation. We conclude that it is atenolol that failed to increase longevity, and likely not the decrease in membrane unsaturation induced by the drug.

  10. Protein Restriction with Amino Acid-Balanced Diets Shrinks Circulating Pool Size of Amino Acid by Decreasing Expression of Specific Transporters in the Small Intestine

    PubMed Central

    Luo, Min; Zhang, Xin; Sun, Wen Juan; Jiao, Ning; Li, De Fa; Yin, Jing Dong

    2016-01-01

    Dietary protein restriction is not only beneficial to health and longevity in humans, but also protects against air pollution and minimizes feeding cost in livestock production. However, its impact on amino acid (AA) absorption and metabolism is not quite understood. Therefore, the study aimed to explore the effect of protein restriction on nitrogen balance, circulating AA pool size, and AA absorption using a pig model. In Exp.1, 72 gilts weighting 29.9 ± 1.5 kg were allocated to 1 of the 3 diets containing 14, 16, or 18% CP for a 28-d trial. Growth (n = 24), nitrogen balance (n = 6), and the expression of small intestinal AA and peptide transporters (n = 6) were evaluated. In Exp.2, 12 barrows weighting 22.7 ± 1.3 kg were surgically fitted with catheters in the portal and jejunal veins as well as the carotid artery and assigned to a diet containing 14 or 18% CP. A series of blood samples were collected before and after feeding for determining the pool size of circulating AA and AA absorption in the portal vein, respectively. Protein restriction did not sacrifice body weight gain and protein retention, since nitrogen digestibility was increased as dietary protein content reduced. However, the pool size of circulating AA except for lysine and threonine, and most AA flux through the portal vein were reduced in pigs fed the low protein diet. Meanwhile, the expression of peptide transporter 1 (PepT-1) was stimulated, but the expression of the neutral and cationic AA transporter systems was depressed. These results evidenced that protein restriction with essential AA-balanced diets, decreased AA absorption and reduced circulating AA pool size. Increased expression of small intestinal peptide transporter PepT-1 could not compensate for the depressed expression of jejunal AA transporters for AA absorption. PMID:27611307

  11. Dietary ɛ-Polylysine Decreased Serum and Liver Lipid Contents by Enhancing Fecal Lipid Excretion Irrespective of Increased Hepatic Fatty Acid Biosynthesis-Related Enzymes Activities in Rats

    PubMed Central

    Hosomi, Ryota; Yamamoto, Daiki; Otsuka, Ren; Nishiyama, Toshimasa; Yoshida, Munehiro; Fukunaga, Kenji

    2015-01-01

    ɛ-Polylysine (EPL) is used as a natural preservative in food. However, few studies have been conducted to assess the beneficial functions of dietary EPL. The purpose of this study was to elucidate the mechanism underlying the inhibition of neutral and acidic sterol absorption and hepatic enzyme activity-related fatty acid biosynthesis following EPL intake. EPL digest prepared using an in vitro digestion model had lower lipase activity and micellar lipid solubility and higher bile acid binding capacity than casein digest. Male Wistar rats were fed an AIN-93G diet containing 1% (wt/wt) EPL or l-lysine. After 4 weeks of feeding these diets, the marked decrease in serum and liver triacylglycerol contents by the EPL diet was partly attributed to increased fecal fatty acid excretion. The activities of hepatic acetyl-coenzyme A carboxylase and glucose-6-phosphate dehydrogenase, which are key enzymes of fatty acid biosynthesis, were enhanced in rats fed EPL diet. The increased fatty acid biosynthesis activity due to dietary EPL may be prevented by the enhancement of fecal fatty acid excretion. The hypocholesterolemic effect of EPL was mediated by increased fecal neutral and acidic sterol excretions due to the EPL digest suppressing micellar lipid solubility and high bile acid binding capacity. These results show that dietary EPL has beneficial effects that could help prevent lifestyle-related diseases such as hyperlipidemia and atherosclerosis. PMID:25866749

  12. Retinol and riboflavin supplementation decreases the prevalence of anemia in Chinese pregnant women taking iron and folic Acid supplements.

    PubMed

    Ma, Ai G; Schouten, Evert G; Zhang, Feng Z; Kok, Frans J; Yang, Fang; Jiang, Dian C; Sun, Yong Y; Han, Xiu X

    2008-10-01

    In rural China, many pregnant women in their third trimester suffer from anemia (48%) and iron deficiency (ID; 42%), often with coexisting deficiencies of retinol and riboflavin. We investigated the effect of retinol and riboflavin supplementation in addition to iron plus folic acid on anemia and subjective well-being in pregnant women. The study was a 2-mo, double-blind, randomized trial. Subjects (n = 366) with anemia [hemoglobin (Hb) acid. The iron+folic acid (IF) group (n = 93) served as reference, the iron+folic acid+retinol group (IFA) (n = 91) was treated with 2000 mug retinol, the iron+folic acid+riboflavin group (IFB) (n = 91) with 1.0 mg riboflavin, and the iron+folic acid+retinol+riboflavin group (IFAB) (n = 91) with retinol and riboflavin. After the 2-mo intervention, the Hb concentration increased in all 4 groups (P < 0.001). The increase in the IFAB group was 5.4 +/- 1.1 g/L greater than in the IF group (P < 0.001). The reduced prevalence of anemia (Hb < 110g/L) and ID anemia were significantly greater in the groups supplemented with retinol and /or riboflavin than in the IF group. Moreover, gastrointestinal symptoms were less prevalent in the IFA group than in the IF group (P < 0.05) and improved well-being was more prevalent in the groups receiving additional retinol and/or riboflavin than in the IF group (P < 0.05). Thus, a combination of iron, folic acid, retinol, and riboflavin was more effective than iron plus folic acid alone. Multimicronutrient supplementation may be worthwhile for pregnant women in rural China.

  13. Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats

    PubMed Central

    Cummings, Bethany P.; Bettaieb, Ahmed; Graham, James L.; Kim, Jaehyoung; Ma, Fangrui; Shibata, Noreene; Stanhope, Kimber L.; Giulivi, Cecilia; Hansen, Frederik; Jelsing, Jacob; Vrang, Niels; Kowala, Mark; Chouinard, Michael L.; Haj, Fawaz G.; Havel, Peter J.

    2013-01-01

    SUMMARY Post-operative increases in circulating bile acids have been suggested to contribute to the metabolic benefits of bariatric surgery; however, their mechanistic contributions remain undefined. We have previously reported that ileal interposition (IT) surgery delays the onset of type 2 diabetes in UCD-T2DM rats and increases circulating bile acids, independently of effects on energy intake or body weight. Therefore, we investigated potential mechanisms by which post-operative increases in circulating bile acids improve glucose homeostasis after IT surgery. IT, sham or no surgery was performed on 2-month-old weight-matched male UCD-T2DM rats. Animals underwent an oral fat tolerance test (OFTT) and serial oral glucose tolerance tests (OGTT). Tissues were collected at 1.5 and 4.5 months after surgery. Cell culture models were used to investigate interactions between bile acids and ER stress. IT-operated animals exhibited marked improvements in glucose and lipid metabolism, with concurrent increases in postprandial glucagon-like peptide-1 (GLP-1) secretion during the OFTT and OGTTs, independently of food intake and body weight. Measurement of circulating bile acid profiles revealed increases in circulating total bile acids in IT-operated animals, with a preferential increase in circulating cholic acid concentrations. Gut microbial populations were assessed as potential contributors to the increases in circulating bile acid concentrations, which revealed proportional increases in Gammaproteobacteria in IT-operated animals. Furthermore, IT surgery decreased all three sub-arms of ER stress signaling in liver, adipose and pancreas tissues. Amelioration of ER stress coincided with improved insulin signaling and preservation of β-cell mass in IT-operated animals. Incubation of hepatocyte, adipocyte and β-cell lines with cholic acid decreased ER stress. These results suggest that postoperative increases in circulating cholic acid concentration contribute to

  14. Low Temperature-Induced Decrease in trans-Δ3-Hexadecenoic Acid Content Is Correlated with Freezing Tolerance in Cereals 1

    PubMed Central

    Huner, Norman P. A.; Williams, John P.; Maissan, Ellen E.; Myscich, Elizabeth G.; Krol, Marianna; Laroche, Andre; Singh, Jasbir

    1989-01-01

    The effect of growth at 5°C on the trans-Δ3-hexadecenoic acid content of phosphatidyl(d)glycerol was examined in a total of eight cultivars of rye (Secale cereale L.) and what (Triticum aestivum L.) of varying freezing tolerance. In these monocots, low temperature growth caused decreases in the trans-Δ3-hexadecenoic acid content of between 0 and 74% with concomitant increases in the palmitic acid content of phosphatidyl(d)glycerol. These trends were observed for whole leaf extracts as well as isolated thylakoids. The low growth temperature-induced decrease in the trans-Δ3-hexadecenoic acid content was shown to be a linear function (r2 = 0.954) of freezing tolerance in these cultivars. Of the six cold tolerant dicotyledonous species examined, only Brassica and Arabidopsis thaliana L. cv Columbia exhibited a 42% and 65% decrease, respectively, in trans-Δ3-hexadecenoic acid content. Thus, the relationship between the change in trans-Δ3-hexadecenoic acid content of phosphatidyl(d)glycerol and freezing tolerance cannot be considered a general one for all cold tolerant plant species. However, species which exhibited a low growth temperature-induced decrease in trans-Δ3-hexadecenoic acid also exhibited a concomitant shift in the in vitro organization of the light harvesting complex II from a predominantly oligomeric form to the monomeric form. We conclude that the proposed role of phosphatidyl(d)glycerol in modulating the organization of light harvesting complex II as a function of growth temperature manifests itself to varying degrees in different plant species. A possible physiological role for this phenomenon with respect to low temperature acclimation and freezing tolerance in cereals is discussed. PMID:16666505

  15. Decreased levels of alpha-1-acid glycoprotein are related to the mortality of septic patients in the emergency department

    PubMed Central

    Barroso-Sousa, Romualdo; Lobo, Romulo R.; Mendonça, Patricia R.; Memória, Renan R.; Spiller, Fernando; Cunha, Fernando Q.; Pazin-Filho, Antonio

    2013-01-01

    OBJECTIVE: To determine the validity of alpha-1-acid glycoprotein as a novel biomarker for mortality in patients with severe sepsis. METHODS: We prospectively included patients with severe sepsis or septic shock at the emergency department at a single tertiary referral teaching hospital. All of the patients were enrolled within the first 24 hours of emergency department admission, and clinical data and blood samples were obtained. As the primary outcome, we investigated the association of serum levels of alpha-1-acid glycoprotein and 96-hour mortality with logistic regression analysis and generalized estimating equations adjusted for age, sex, shock status and Acute Physiology and Chronic Health Evaluation II score. RESULTS: Patients with septic shock had lower alpha-1-acid glycoprotein levels at the time of emergency department admission compared to patients without shock (respectively, 149.1±42.7 vs. 189.8±68.6; p = 0.005). Similarly, non-survivors in the first 96 hours were also characterized by lower levels of alpha-1-acid glycoprotein at the time of emergency department admission compared to survivors (respectively, 132.18±50.2 vs. 179.8±61.4; p = 0.01). In an adjusted analysis, alpha-1-acid glycoprotein levels ≤120 mg/dL were significantly associated with 96-hour mortality (odds ratio = 14.37; 95% confidence interval = 1.58 to 130.21). CONCLUSION: Septic shock patients exhibited lower circulating alpha-1-acid glycoprotein levels than patients without shock. Alpha-1-acid glycoprotein levels were independently associated with 96-hour mortality in individuals with severe sepsis. PMID:24037010

  16. Decreased levels of alpha-1-acid glycoprotein are related to the mortality of septic patients in the emergency department.

    PubMed

    Barroso-Sousa, Romualdo; Lobo, Romulo R; Mendonça, Patricia R; Memória, Renan R; Spiller, Fernando; Cunha, Fernando Q; Pazin-Filho, Antonio

    2013-01-01

    To determine the validity of alpha-1-acid glycoprotein as a novel biomarker for mortality in patients with severe sepsis. We prospectively included patients with severe sepsis or septic shock at the emergency department at a single tertiary referral teaching hospital. All of the patients were enrolled within the first 24 hours of emergency department admission, and clinical data and blood samples were obtained. As the primary outcome, we investigated the association of serum levels of alpha-1-acid glycoprotein and 96-hour mortality with logistic regression analysis and generalized estimating equations adjusted for age, sex, shock status and Acute Physiology and Chronic Health Evaluation II score. Patients with septic shock had lower alpha-1-acid glycoprotein levels at the time of emergency department admission compared to patients without shock (respectively, 149.1 ±42.7 vs. 189.8 ±68.6; p = 0.005). Similarly, non-survivors in the first 96 hours were also characterized by lower levels of alpha-1-acid glycoprotein at the time of emergency department admission compared to survivors (respectively, 132.18 ±50.2 vs. 179.8 ±61.4; p = 0.01). In an adjusted analysis, alpha-1-acid glycoprotein levels ≤120 mg/dL were significantly associated with 96-hour mortality (odds ratio = 14.37; 95% confidence interval = 1.58 to 130.21). Septic shock patients exhibited lower circulating alpha-1-acid glycoprotein levels than patients without shock. Alpha-1-acid glycoprotein levels were independently associated with 96-hour mortality in individuals with severe sepsis.

  17. Temperature Shift Experiments Suggest That Metabolic Impairment and Enhanced Rates of Photorespiration Decrease Organic Acid Levels in Soybean Leaflets Exposed to Supra-Optimal Growth Temperatures.

    PubMed

    Sicher, Richard C

    2015-08-05

    Elevated growth temperatures are known to affect foliar organic acid concentrations in various plant species. In the current study, citrate, malate, malonate, fumarate and succinate decreased 40 to 80% in soybean leaflets when plants were grown continuously in controlled environment chambers at 36/28 compared to 28/20 °C. Temperature effects on the above mentioned organic acids were partially reversed three days after plants were transferred among optimal and supra-optimal growth temperatures. In addition, CO2 enrichment increased foliar malate, malonate and fumarate concentrations in the supra-optimal temperature treatment, thereby mitigating effects of high temperature on respiratory metabolism. Glycerate, which functions in the photorespiratory pathway, decreased in response to CO2 enrichment at both growth temperatures. The above findings suggested that diminished levels of organic acids in soybean leaflets upon exposure to high growth temperatures were attributable to metabolic impairment and to changes of photorespiratory flux. Leaf development rates differed among temperature and CO2 treatments, which affected foliar organic acid levels. Additionally, we report that large decreases of foliar organic acids in response to elevated growth temperatures were observed in legume species.

  18. Tranexamic acid suppresses ultraviolet B eye irradiation-induced melanocyte activation by decreasing the levels of prohormone convertase 2 and alpha-melanocyte-stimulating hormone.

    PubMed

    Hiramoto, Keiichi; Yamate, Yurika; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

    2014-12-01

    Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medicinal amino acid used in skin whitening care. This study examined the effects of tranexamic acid on the melanocyte activation of the skin induced by an ultraviolet (UV) B eye irradiation. The eye or ear was locally exposed to UVB at a dose of 1.0 kJ/m(2) using a 20SE sunlamp after covering the remaining body surface with aluminum foil. UVB eye irradiation induced melanocyte activation of the skin, similar to that observed following UVB ear irradiation, which was suppressed by the administration of tranexamic acid treatment. The plasma α-melanocyte-stimulating hormone (α-MSH) content was increased by UVB irradiation of the eye; however, the increase in α-MSH was suppressed by tranexamic acid treatment. In addition, UVB eye irradiation induced the up-regulation of prohormone convertase (PC) 2 in the pituitary gland. Meanwhile, the increase in PC2 induced by UVB eye irradiation was suppressed by tranexamic acid treatment. These results clearly indicate that tranexamic acid decreases the expression of PC2, which cleavages from proopiomelanocortin to α-MSH in the pituitary gland, thereby suppressing melanocyte activation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Alpha-lipoic acid induces adipose triglyceride lipase expression and decreases intracellular lipid accumulation in HepG2 cells.

    PubMed

    Kuo, Yung-Ting; Lin, Ting-Han; Chen, Wei-Lu; Lee, Horng-Mo

    2012-10-05

    Non-alcoholic fatty liver disease can be attributed to the imbalance between lipogenesis and lipolysis in the liver. Alpha-lipoic acid has been shown to activate the 5'-AMP-activated protein kinase (AMPK) signalling pathway and to effectively inhibit the lipogenesis pathway in liver. However, whether alpha-lipoic acid stimulates lipolysis remains unclear. Recently, adipose triglyceride lipase (ATGL) was shown to be responsible for triacylglycerol hydrolase activity in cells. In the present study, we established a fatty liver cell model by incubating HepG2 cells in a high glucose (30mM glucose) and high fat (0.1mM palmitate) medium. We found that the activation of the AMPK signalling pathway induced ATGL protein expression and enhanced lipid hydrolysis. Similarly, treatment of the fatty liver cell model with alpha-lipoic acid reduced intracellular lipid accumulation in HepG2 cells, increased AMPK phosphorylation, and induced ATGL expression. We showed that insulin phosphorylates the transcription factor forkhead box O1 (FOXO1), which regulates ATGL expression and inhibits FOXO1 translocation into the nucleus. In contrast, alpha-lipoic acid dephosphorylated FOXO1 and reversed the nuclear exclusion of FOXO1. These data suggest that alpha-lipoic acid can effectively ameliorate intracellular lipid accumulation and induce ATGL expression through the FOXO1/ATGL pathway in liver cells. Thus, alpha-lipoic acid may be a potential therapeutic agent for treating fatty liver disease. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

  20. 18:1 n7 fatty acids inhibit growth and decrease inositol phosphate release in HT-29 cells compared to n9 fatty acids.

    PubMed

    Awad, A B; Herrmann, T; Fink, C S; Horvath, P J

    1995-05-04

    Studies have shown that trans fatty acids may play a role in the development of chronic diseases such as heart disease and cancer. The objective of the present project was to examine the effect of supplementation with 18:1 isomers, both positional and geometrical, as compared to 18:0 on the growth, membrane fatty acid composition and the phosphoinositide cycle of HT-29 human colon cancer cells. Cells were supplemented with 30 microM stearic acid (18:0), elaidic acid (18:1, n9, trans), oleic acid (18:1, n9, cis), vaccenic acid (18:1, n7, cis) or trans-vaccenic acid (18:1, n7, trans) as sodium salts complexed to fatty acid-free bovine serum. Cells were grown in these media for 9 days. Cell growth was examined by counting the number of cells and expressed as percentage of control (18:0 supplemented cells). The phosphoinositide (PI) cycle was examined by measuring the inositol phosphate (IP) released from phosphoinositides in the absence (basal) or presence of stimuli (0.1 mM carbachol, 0.1 mM A23187 or 20 mM NaF). The results obtained indicated that cis and trans n7 fatty acids inhibited the growth of HT-29 cells by 11% and 23%, respectively, as compared to 18:0 supplementation. 18:1, n9 had no effect on tumor growth. Supplementation with all forms of 18:1 resulted in an increase in IP and IP2 production as compared to 18:0 supplemented cells without influencing IP3. The presence of the double bond at the 9 position in the supplemented fatty acid increases total IP production by 59% and in the cis form by 37% above the control. The breakdown of phosphoinositides in the absence and presence of several stimuli supports the observed finding on IP. Trans fatty acid supplementation resulted in lower hydrolysis of PI as compared to cis fatty acids. It is concluded that the observed inhibition of tumor growth by the vaccenic acids may be mediated by their effect(s) on the PI cycle which may be associated with their incorporation into membrane lipids.

  1. Chicoric acid binds to two sites and decreases the activity of the YopH bacterial virulence factor.

    PubMed

    Kuban-Jankowska, Alicja; Sahu, Kamlesh K; Gorska, Magdalena; Tuszynski, Jack A; Wozniak, Michal

    2016-01-19

    Chicoric acid (CA) is a phenolic compound present in dietary supplements with a large spectrum of biological properties reported ranging from antioxidant, to antiviral, to immunostimulatory properties. Due to the fact that chicoric acid promotes phagocytic activity and was reported as an allosteric inhibitor of the PTP1B phosphatase, we examined the effect of CA on YopH phosphatase from pathogenic bacteria, which block phagocytic processes of a host cell. We performed computational studies of chicoric acid binding to YopH as well as validation experiments with recombinant enzymes. In addition, we performed similar studies for caffeic and chlorogenic acids to compare the results. Docking experiments demonstrated that, from the tested compounds, only CA binds to both catalytic and secondary binding sites of YopH. Our experimental results showed that CA reduces activity of recombinant YopH phosphatase from Yersinia enterocolitica and human CD45 phosphatase. The inhibition caused by CA was irreversible and did not induce oxidation of catalytic cysteine. We proposed that inactivation of YopH induced by CA is involved with allosteric inhibition by interacting with essential regions responsible for ligand binding.

  2. Chicoric acid binds to two sites and decreases the activity of the YopH bacterial virulence factor

    PubMed Central

    Kuban-Jankowska, Alicja; Sahu, Kamlesh K.; Gorska, Magdalena; Tuszynski, Jack A.; Wozniak, Michal

    2016-01-01

    Chicoric acid (CA) is a phenolic compound present in dietary supplements with a large spectrum of biological properties reported ranging from antioxidant, to antiviral, to immunostimulatory properties. Due to the fact that chicoric acid promotes phagocytic activity and was reported as an allosteric inhibitor of the PTP1B phosphatase, we examined the effect of CA on YopH phosphatase from pathogenic bacteria, which block phagocytic processes of a host cell. We performed computational studies of chicoric acid binding to YopH as well as validation experiments with recombinant enzymes. In addition, we performed similar studies for caffeic and chlorogenic acids to compare the results. Docking experiments demonstrated that, from the tested compounds, only CA binds to both catalytic and secondary binding sites of YopH. Our experimental results showed that CA reduces activity of recombinant YopH phosphatase from Yersinia enterocolitica and human CD45 phosphatase. The inhibition caused by CA was irreversible and did not induce oxidation of catalytic cysteine. We proposed that inactivation of YopH induced by CA is involved with allosteric inhibition by interacting with essential regions responsible for ligand binding. PMID:26735581

  3. Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy.

    PubMed

    Chapman, Michael P; Moore, Ernest E; Ramos, Christopher R; Ghasabyan, Arsen; Harr, Jeffrey N; Chin, Theresa L; Stringham, John R; Sauaia, Angela; Silliman, Christopher C; Banerjee, Anirban

    2013-12-01

    The acute coagulopathy of trauma is present in up to one third of patients by the time of admission, and the recent CRASH-2 and MATTERs trials have focused worldwide attention on hyperfibrinolysis as a component of acute coagulopathy of trauma. Thromboelastography (TEG) is a powerful tool for analyzing fibrinolyis, but a clinically relevant threshold for defining hyperfibrinolysis has yet to be determined. Recent data suggest that the accepted normal upper bound of 7.5% for 30-minute fibrinolysis (LY30) by TEG is inappropriate in severe trauma, as the risk of death rises at much lower levels of clot lysis. We wished to determine the validity of this hypothesis and establish a threshold value to treat fibrinolysis, based on prediction of massive transfusion requirement and risk of mortality. Patients with uncontrolled hemorrhage, meeting the massive transfusion protocol (MTP) criteria at admission (n = 73), represent the most severely injured trauma population at our center (median Injury Severity Score [ISS], 30; interquartile range, 20-38). Citrated kaolin TEG was performed at admission blood samples from this population, stratified by LY30, and evaluated for transfusion requirement and 28-day mortality. The same analysis was conducted on available field blood samples from all non-MTP trauma patients (n = 216) in the same period. These represent the general trauma population. Within the MTP-activating population, the cohort of patients with LY30 of 3% or greater was shown to be at much higher risk for requiring a massive transfusion (90.9% vs. 30.5%, p = 0.0008) and dying of hemorrhage (45.5% vs. 4.8%, p = 0.0014) than those with LY30 less than 3%. Similar trends were seen in the general trauma population. LY30 of 3% or greater defines clinically relevant hyperfibrinolysis and strongly predicts the requirement for massive transfusion and an increased risk of mortality in trauma patients presenting with uncontrolled hemorrhage. This threshold value for LY30

  4. A single amino acid substitution in ORF1 dramatically decreases L1 retrotransposition and provides insight into nucleic acid chaperone activity

    PubMed Central

    Martin, Sandra L.; Bushman, Diane; Wang, Fei; Li, Patrick Wai-Lun; Walker, Ann; Cummiskey, Jessica; Branciforte, Dan; Williams, Mark C.

    2008-01-01

    L1 is a ubiquitous interspersed repeated sequence in mammals that achieved its high copy number by autonomous retrotransposition. Individual L1 elements within a genome differ in sequence and retrotransposition activity. Retrotransposition requires two L1-encoded proteins, ORF1p and ORF2p. Chimeric elements were used to map a 15-fold difference in retrotransposition efficiency between two L1 variants from the mouse genome, TFC and TFspa, to a single amino acid substitution in ORF1p, D159H. The steady-state levels of L1 RNA and protein do not differ significantly between these two elements, yet new insertions are detected earlier and at higher frequency in TFC, indicating that it converts expressed L1 intermediates more effectively into new insertions. The two ORF1 proteins were purified and their nucleic acid binding and chaperone activities were examined in vitro. Although the RNA and DNA oligonucleotide binding affinities of these two ORF1 proteins were largely indistinguishable, D159 was significantly more effective as a nucleic acid chaperone than H159. These findings support a requirement for ORF1p nucleic acid chaperone activity at a late step during L1 retrotransposition, extend the region of ORF1p that is known to be critical for its functional interactions with nucleic acids, and enhance understanding of nucleic acid chaperone activity. PMID:18790804

  5. Decreased Membrane Integrity in Aging Typha latifolia L.Pollen (Accumulation of Lysolipids and Free Fatty Acids).

    PubMed Central

    Van Bilsen, DGJL.; Hoekstra, F. A.

    1993-01-01

    Aging of cattail (Typha latifolia L.) pollen was studied at 24[deg]C under conditions of 40 and 75% relative humidity (RH). The decline of viability coincides with increased leakage at imbibition; both processes develop much faster at the higher humidity condition. During aging phospholipids are deesterified and free fatty acids (FFAs) and lysophospholipids (LPLs) accumulate, again, much more rapidly at 75% RH than at 40% RH. The fatty acid composition of the remaining phospholipids hardly changes during aging, which suggests limited involvement of lipid peroxidation in the degradation process. Tests with phospholipase A2 revealed that the saturated fatty acids occur at the sn-1 position of the glycerol backbone of the phospholipids. The fatty acid composition of the LPLs is similar to that of the phospholipids from which they were formed, indicating that the deesterification occurs at random. This favors involvement of free radicals instead of phospholipases in the deesterification process. Liposome studies were carried out to characterize components in the lipid fraction that might account for the leakage associated with aging. Entrapped carboxyfluorescein leaked much more from liposomes when they were partly made up from total lipids from aged pollen than from nonaged pollen. The components causing the leakage were found in both the polar and the neutral lipid fractions. Further purification and subsequent interchanging of the FFAs and LPLs between extracts from aged and nonaged pollen revealed that in neutral lipid extracts the FFAs are entirely responsible for the leakage, whereas in the phospholipid fraction the LPLs are largely responsible for the leakage. The leakage from the liposomes is not caused by fusion. We suggest that the observed loss of viability and increased leakage during aging are due to the nonenzymic accumulation of FFAs and LPLs in the pollen membranes. PMID:12231723

  6. Oleogels, a promising structured oil for decreasing saturated fatty acid concentrations: Production and food-based applications.

    PubMed

    Pehlivanoğlu, Halime; Demirci, Mehmet; Toker, Omer Said; Konar, Nevzat; Karasu, Salih; Sagdic, Osman

    2016-11-10

    Oils and fats are widely used in the food formulations in order to improve nutritional and some quality characteristics of food products. Solid fats produced from oils by hydrogenization, interesterification, and fractionation processes are widely used in different foodstuffs for these aims. In recent years, consumer awareness of relation between diet and health has increased which can cause worry about solid fat including products in terms of their high saturated fatty acid and trans fatty acid contents. Therefore, different attempts have been carried out to find alternative ways to produce solid fat with low saturated fatty acid content. One of the promising ways is using oleogels, structuring oils with oleogelators. In this review, history, raw materials and production methods of the oleogels and their functions in oleogel quality were mentioned. Moreover, studies related with oleogel usage in different products were summarized and positive and negative aspects of oleogel were also mentioned. Considering the results of the related studies, it can be concluded that oleogels can be used in the formulation of bakery products, breakfast spreads, margarines, chocolates and chocolate-derived products and some of the meat products.

  7. Plasminogen-independent fibrinolysis by proteases produced by transformed chick embryo fibroblasts.

    PubMed Central

    Chen, L B; Buchanan, J M

    1975-01-01

    The fibrinolytic activity of proteases secreted by chick embryo fibroblasts infected with Rous sarcoma virus was studied by use of a procedure in which a fibrin clot was formed with highly purified fibrinogen and thrombin above the cell layer. This procedure results in the formation of fibrin that is apparently a more suitable substrate for studies on fibrinolysis than is fibrin prepared by other methods. Since neither plasminogen nor serum were included in the assay system in the present studies, the fibrinolytic activity observed cannot be ascribed to the conversion of the plasminogen in serum to plasmin by a plasminogen activator produced by transformed cells. Our procedure, therefore, measures proteolytic activities other than those reported by previous investigators. Maintenance of some of the transformed phenotypes of Rous sarcoma virus transformed chick embryo fibroblasts such as morpholigical change and increased rate of glucose uptake apparently does not depend on the presence of plasminogen in the culture medium. Images PMID:165484

  8. Storage of Fruits and Vegetables in Refrigerator Increases their Phenolic Acids but Decreases the Total Phenolics, Anthocyanins and Vitamin C with Subsequent Loss of their Antioxidant Capacity.

    PubMed

    Galani, Joseph H Y; Patel, Jalpesh S; Patel, Nilesh J; Talati, Jayant G

    2017-07-24

    It is of paramount importance for consumers, scientists and industrialists to understand how low-temperature storage of food items affects their bioactive compounds and properties. This study evaluated the effects of cold storage on total phenolics (TP), phenolic acids profile (PA), total anthocyanins (TA), total ascorbic acid (Vit. C) and antioxidant activity (AA) of 19 fruits and vegetables, collected from local Indian markets and stored in refrigerator (4 °C) during 15 days. Content of TP was highest in dill and amaranth and decreased (up to 29.67%) with storage. Leafy vegetables (amaranth, dill, onion, fenugreek and spinach) contained higher amounts of the 12 PA revealed by UPLC-UV; ellagic, gallic, sinapic and vanillic acids levels were the highest; chlorogenic acid (ρ = 0.423), syringic acid (ρ = 0.403) and sinapic acid (ρ = 0.452) mostly correlated with TP; and the PA increased during storage. Highest contents of Vit C estimated by AOAC, DCPIP and DNP methods were found in amaranth, dill and pomegranate, and decreased with storage. Pomegranate showed highest TA levels and low-temperature storage did not significantly increase TA, which was the largest contributor of TP in fruits and vegetables (ρ = 0.661). Storage induced a drastic decrease of AA, which mostly correlated with TP (ρ = 0.808, 0.690 and 0.458 for DPPH, ABTS and FRAP assays, respectively). Spearman's correlation confirmed by principal component analysis demonstrated that dill, pomegranate and amaranth had the highest overall antioxidant capacity, whereas orange juice and carrot showed the lowest. The results provide support for a key-role of TP, followed by Vit. C and TA in antioxidant capacity of fruits and vegetables, which could be interesting dietary sources of natural antioxidants for prevention of diseases caused by oxidative stress.

  9. Storage of Fruits and Vegetables in Refrigerator Increases their Phenolic Acids but Decreases the Total Phenolics, Anthocyanins and Vitamin C with Subsequent Loss of their Antioxidant Capacity

    PubMed Central

    Patel, Nilesh J.; Talati, Jayant G.

    2017-01-01

    It is of paramount importance for consumers, scientists and industrialists to understand how low-temperature storage of food items affects their bioactive compounds and properties. This study evaluated the effects of cold storage on total phenolics (TP), phenolic acids profile (PA), total anthocyanins (TA), total ascorbic acid (Vit. C) and antioxidant activity (AA) of 19 fruits and vegetables, collected from local Indian markets and stored in refrigerator (4 °C) during 15 days. Content of TP was highest in dill and amaranth and decreased (up to 29.67%) with storage. Leafy vegetables (amaranth, dill, onion, fenugreek and spinach) contained higher amounts of the 12 PA revealed by UPLC-UV; ellagic, gallic, sinapic and vanillic acids levels were the highest; chlorogenic acid (ρ = 0.423), syringic acid (ρ = 0.403) and sinapic acid (ρ = 0.452) mostly correlated with TP; and the PA increased during storage. Highest contents of Vit C estimated by AOAC, DCPIP and DNP methods were found in amaranth, dill and pomegranate, and decreased with storage. Pomegranate showed highest TA levels and low-temperature storage did not significantly increase TA, which was the largest contributor of TP in fruits and vegetables (ρ = 0.661). Storage induced a drastic decrease of AA, which mostly correlated with TP (ρ = 0.808, 0.690 and 0.458 for DPPH, ABTS and FRAP assays, respectively). Spearman’s correlation confirmed by principal component analysis demonstrated that dill, pomegranate and amaranth had the highest overall antioxidant capacity, whereas orange juice and carrot showed the lowest. The results provide support for a key-role of TP, followed by Vit. C and TA in antioxidant capacity of fruits and vegetables, which could be interesting dietary sources of natural antioxidants for prevention of diseases caused by oxidative stress. PMID:28737734

  10. Omega-3 fatty acids decreases oxidative stress, tumor necrosis factor-alpha, and interleukin-1 beta in hyperthyroidism-induced hepatic dysfunction rat model.

    PubMed

    Gomaa, Asmaa M S; Abd El-Aziz, Ebtihal A

    2016-12-01

    Hyperthyroidism is associated with abnormalities of the liver. Omega-3 polyunsaturated fatty acids, especially their long-chain forms: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have beneficial health effects. The objectives of the present study were to assess hyperthyroidism-induced hepatic dysfunction in adult male rats and to evaluate the ameliorative effects of omega-3 on hyperthyroidism-induced hepatic dysfunction and the underlying mechanisms. Twenty four adult male rats were randomly divided into three equal groups; control group which received water for 6 weeks, hyperthyroid group which received L-thyroxine orally for 6 weeks and hyperthyroid omega-3 treated group which received L-thyroxine for 2 weeks and then co-treated with L-thyroxine and omega-3 oral compound containing 18% of EPA and 12% of DHA for 4 weeks. Hyperthyroid omega-3 treated group showed significantly increased final body weight and body weight gain, decreased liver weight to body weight ratio, decreased serum triiodo-l-thyronine level, increased serum thyroid stimulating hormone level, decreased serum levels of alanine transaminase, aspartate transaminase and tumor necrosis factor-alpha, increased hepatic levels of total antioxidant capacity and decreased hepatic levels of total peroxide and interleukin-1 beta when compared with the hyperthyroid group. Furthermore, histopathological studies revealed also marked improvement. We concluded that omega-3 had encouraging therapeutic effects against hyperthyroidism-induced hepatic dysfunction attributable to more than one mechanism: antioxidant, anti-inflammatory and anti-fibrotic effects.

  11. Low level of trans-10, cis-12 conjugated linoleic acid decreases adiposity and increases browning independent of inflammatory signaling in overweight Sv129 mice

    PubMed Central

    Shen, Wan; Baldwin, Jessie; Collins, Brian; Hixson, Lindsay; Lee, Kuan-Ting; Herberg, Timothy; Starnes, Joseph; Cooney, Paula; Chuang, Chia-Chi; Hopkins, Robin; Reid, Tanya; Gupta, Sat; McIntosh, Michael

    2015-01-01

    The objective of this study was to determine the extent to which a low level of trans-10, cis-12 (10,12) conjugated linoleic acid (CLA) decreases adiposity and increases browning in overweight mice, its dependence on inflammatory signaling, and potential synergistic effects of daily exercise. Young, Sv129 male mice were fed a high fat diet for 5 wk to make them fat and glucose intolerant, and then switch them to a low fat diet with or without 0.1% 10,12 CLA, sodium salicylate, or exercise for another 7 wk. 10,12 CLA decreased white adipose tissue (WAT) and brown adipose tissue mass, and increased the mRNA and protein levels, and activities of enzymes associated with thermogenesis or fatty acid oxidation in WAT. Mice fed 10,12 CLA had lower body temperatures compared to controls during cold exposure, which coincided with decreased adiposity. Although sodium salicylate decreased 10,12 CLA-mediated increases in markers of inflammation in WAT, it did not affect other outcomes. Exercise had no further effect on the outcomes measured. Collectively, these data indicate that 10,12 CLA-mediated reduction of adiposity is independent of inflammatory signaling, and possibly due to up-regulation of fatty acid oxidation and heat production in order to regulate body temperature. Although this low level of 10,12 CLA reduced adiposity in overweight mice, hepatomegaly and inflammation are major health concerns. PMID:25801353

  12. Low level of trans-10, cis-12 conjugated linoleic acid decreases adiposity and increases browning independent of inflammatory signaling in overweight Sv129 mice.

    PubMed

    Shen, Wan; Baldwin, Jessie; Collins, Brian; Hixson, Lindsay; Lee, Kuan-Ting; Herberg, Timothy; Starnes, Joseph; Cooney, Paula; Chuang, Chia-Chi; Hopkins, Robin; Reid, Tanya; Gupta, Sat; McIntosh, Michael

    2015-06-01

    The objective of this study was to determine the extent to which a low level of trans-10, cis-12 (10,12) conjugated linoleic acid (CLA) decreases adiposity and increases browning in overweight mice, its dependence on inflammatory signaling and potential synergistic effects of daily exercise. Young, Sv129 male mice were fed a high-fat diet for 5 weeks to make them fat and glucose intolerant and then switch them to a low-fat diet with or without 0.1% 10,12 CLA, sodium salicylate or exercise for another 7 weeks. 10,12 CLA decreased white adipose tissue (WAT) and brown adipose tissue mass, and increased the messenger RNA and protein levels, and activities of enzymes associated with thermogenesis or fatty acid oxidation in WAT. Mice fed 10,12 CLA had lower body temperatures compared to controls during cold exposure, which coincided with decreased adiposity. Although sodium salicylate decreased 10,12 CLA-mediated increases in markers of inflammation in WAT, it did not affect other outcomes. Exercise had no further effect on the outcomes measured. Collectively, these data indicate that 10,12 CLA-mediated reduction of adiposity is independent of inflammatory signaling, and possibly due to up-regulation of fatty acid oxidation and heat production in order to regulate body temperature. Although this low level of 10,12 CLA reduced adiposity in overweight mice, hepatomegaly and inflammation are major health concerns. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Effect of Two Lipoprotein (a)-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis.

    PubMed

    Wang, Hong; Hong, Chan E; Lewis, Joshua P; Zhu, Yanbei; Wang, Xing; Chu, Xin; Backman, Joshua; Hu, Ziying; Yang, Peixing; Still, Christopher D; Gerhard, Glenn S; Fu, Mao

    2016-09-07

    Two genetic variants (rs3798220 and rs10455872) in the apolipoprotein (a) gene (LPA) have been implicated in cardiovascular disease (CVD), presumably through their association with Lipoprotein (a) (Lp(a)) levels. While Lp(a) is recognized as a lipoprotein with atherogenic and thrombogenic characteristics, it is unclear whether or not the two Lp(a)-associated genetic variants are also associated with markers of thrombosis (i.e. plasminogen levels and fibrinolysis). In the present study, we genotyped the two genetic variants in 2919 subjects of the Old Order Amish (OOA) and recruited 146 subjects according the carrier and non-carrier status for rs3798220 and rs10455872, and also matched for gender and age. We measured plasma Lp(a) and plasminogen levels in these subjects, and found that the concentrations of plasma Lp(a) were 2.62 and 1.73 fold higher in minor allele carriers of rs3798220 and rs10455872, respectively, compared with non-carriers (P = 2.04 × 10(-17) and P = 1.64 × 10(-6), respectively). By contrast, there was no difference in plasminogen concentrations between carriers and non-carriers of rs3798220 and rs10455872. Furthermore, we observed no association between carrier status of rs3798220 or rs10455872 with clot lysis time. Finally, plasminogen mRNA expression in liver samples derived from 76 Caucasian subjects was not significantly different between carriers and non-carriers of these two genetic variants. Our results provide further insight into the mechanism of action behind two genetic variants previously implicated in CVD risk and show that these polymorphisms are not major modulating factors for plasma plasminogen levels and fibrinolysis.

  14. Effect of Two Lipoprotein (a)-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis

    PubMed Central

    Wang, Hong; Hong, Chan E.; Lewis, Joshua P.; Zhu, Yanbei; Wang, Xing; Chu, Xin; Backman, Joshua; Hu, Ziying; Yang, Peixin; Still, Christopher D.; Gerhard, Glenn S.; Fu, Mao

    2016-01-01

    Two genetic variants (rs3798220 and rs10455872) in the apolipoprotein (a) gene (LPA) have been implicated in cardiovascular disease (CVD), presumably through their association with lipoprotein (a) [Lp(a)] levels. While Lp(a) is recognized as a lipoprotein with atherogenic and thrombogenic characteristics, it is unclear whether or not the two Lp(a)-associated genetic variants are also associated with markers of thrombosis (i.e., plasminogen levels and fibrinolysis). In the present study, we genotyped the two genetic variants in 2919 subjects of the Old Order Amish (OOA) and recruited 146 subjects according to the carrier and noncarrier status for rs3798220 and rs10455872, and also matched for gender and age. We measured plasma Lp(a) and plasminogen levels in these subjects, and found that the concentrations of plasma Lp(a) were 2.62- and 1.73-fold higher in minor allele carriers of rs3798220 and rs10455872, respectively, compared with noncarriers (P = 2.04 × 10−17 and P = 1.64 × 10−6, respectively). By contrast, there was no difference in plasminogen concentrations between carriers and noncarriers of rs3798220 and rs10455872. Furthermore, we observed no association between carrier status of rs3798220 or rs10455872 with clot lysis time. Finally, plasminogen mRNA expression in liver samples derived from 76 Caucasian subjects was not significantly different between carriers and noncarriers of these two genetic variants. Our results provide further insight into the mechanism of action behind two genetic variants previously implicated in CVD risk and show that these polymorphisms are not major modulating factors for plasma plasminogen levels and fibrinolysis. PMID:27605514

  15. A principal component analysis of postinjury viscoelastic assays: clotting factor depletion versus fibrinolysis.

    PubMed

    Chin, Theresa L; Moore, Ernest E; Moore, Hunter B; Gonzalez, Eduardo; Chapman, Michael P; Stringham, John R; Ramos, Christopher R; Banerjee, Anirban; Sauaia, Angela

    2014-09-01

    The mechanisms driving trauma-induced coagulopathy (TIC) remain to be defined, and its therapy demands an orchestrated replacement of specific blood products. Thrombelastography (TEG) is a tool to guide the TIC multicomponent therapy. Principal component analysis (PCA) is a statistical approach that identifies variable clusters; thus, we hypothesize that PCA can identify specific combinations of TEG-generated values that reflect TIC mechanisms. Adult trauma patients admitted from September 2010 to October 2013 for whom a massive transfusion protocol was activated were included. Rapid TEG values obtained within the first 6 hours after injury were included in the PCA. PCA components with an eigenvalue >1 were retained, and, within components, variable loadings (equivalent to correlation coefficients) >|60| were considered significant. Component scorings for each patient were calculated and clinical characteristics of patients with high and low scores were compared. Of 98 enrolled patients, 67% were male and 70% suffered blunt trauma. Median age was 41 years (interquartile range 28-55) and median Injury Severity Score was 31.5 (interquartile range 24-43). PCA identified three principal components (PCs) that together explained 93% of the overall variance. PC1 reflected global coagulopathy with depletion of platelets and fibrinogen whereas PC3 indicated hyperfibrinolysis. PC2 may represent endogenous anticoagulants such as the activation of protein C. PCA suggests depletion coagulopathy is independent from fibrinolytic coagulopathy. Furthermore, the distribution of mortality suggests that low levels of fibrinolysis may be beneficial in a select group of injured patients. These data underscore the potential of risk for concurrent presumptive treatment for preserved depletion coagulopathy and possible fibrinolysis. Copyright © 2014 Mosby, Inc. All rights reserved.

  16. The rate of fibrinolysis is increased by free retraction of human gingival fibroblast populated fibrin lattices.

    PubMed

    Lorimier, S; Bouthors, S; Droulle, C; Maquin, D L; Maquart, F X; Gillery, P; Emonard, H; Hornebeck, W

    1997-01-01

    We previously demonstrated that human gingival fibroblasts (HGF), but not their dermal counterparts, when seeded in retracting fibrin lattices induced intense fibrinolysis that was observed at the earliest stages of contraction and led to complete matrix degradation by day 7 of culture. Our aim was to examine the influence of mechanical forces in such fibrinolytic processes. HGF were seeded in retracting (R) e.g. free floating or non retracting (NR) e.g. anchored fibrin lattices (FL). Cultures were analysed from day 1-12 by phase contrast microscopy and scanning electron microscopy (s.e.m.). Levels of fibrin degradation products (FDP) and tissue plasminogen activator (tPA) accumulating in culture media were quantified by ELISA. Urokinase (uPA) and gelatinase A (MMP2) were identified by zymographic techniques. At the s.e.m. level, vacuolization around some HGF was noticed at the earliest stages of culture for RFL and complete degradation of lattices occurred at day 7. Formation of lysed matrix cavity was far less intense in NRFL even after 12 days of culture. FDP amounts at day 4 of culture were equal to 79 +/- 14 and 8.5 +/- 0.6 micrograms/10(5) cells for RFL and NRFL, respectively; tPA levels were equal to 5.8 +/- 0.6 (RFL) and 2.1 +/- 0.3 ng/10(5) cells (NRFL) and differences were still evident at day 7. The kinetics of tPA production were identical in either retracting fibrin or collagen lattices. On the contrary, uPA and proMMP2 productions were similar in RFL and NRFL. Isometric forces, but not the matrix support, were responsible for accelerated tPA production and fibrinolysis in HGF populated lattices.

  17. A novel highly potent autotaxin/ENPP2 inhibitor produces prolonged decreases in plasma lysophosphatidic acid formation in vivo and regulates urethral tension.

    PubMed

    Saga, Hiroshi; Ohhata, Akira; Hayashi, Akio; Katoh, Makoto; Maeda, Tatsuo; Mizuno, Hirotaka; Takada, Yuka; Komichi, Yuka; Ota, Hiroto; Matsumura, Naoya; Shibaya, Masami; Sugiyama, Tetsuya; Nakade, Shinji; Kishikawa, Katsuya

    2014-01-01

    Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation. The IC50 values of ONO-8540506 for lysophospholipase D activity were 6.4-19 nM for recombinant autotaxin/ENPP2 proteins and 4.7-11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration. Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia.

  18. MDMA decreases glutamic acid decarboxylase (GAD) 67-immunoreactive neurons in the hippocampus and increases seizure susceptibility: Role for glutamate.

    PubMed

    Huff, Courtney L; Morano, Rachel L; Herman, James P; Yamamoto, Bryan K; Gudelsky, Gary A

    2016-12-01

    3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented recently. In the present study, we tested the hypothesis that MDMA reduces glutamic acid decarboxylase (GAD) 67-IR, another biochemical marker of GABA neurons, in the hippocampus and that this reduction in GAD67-IR neurons and an accompanying increase in seizure susceptibility involve glutamate receptor activation. Repeated exposure to MDMA (3×10mg/kg, ip) resulted in a reduction of 37-58% of GAD67-IR cells in the dentate gyrus (DG), CA1, and CA3 regions, as well as an increased susceptibility to kainic acid-induced seizures, both of which persisted for at least 30days following MDMA treatment. Administration of the NMDA antagonist MK-801 or the glutamate transporter type 1 (GLT-1) inducer ceftriaxone prevented both the MDMA-induced loss of GAD67-IR neurons and the increased vulnerability to kainic acid-induced seizures. The MDMA-induced increase in the extracellular concentration of glutamate in the hippocampus was significantly diminished in rats treated with ceftriaxone, thereby implicating a glutamatergic mechanism in the neuroprotective effects of ceftriaxone. In summary, the present findings support a role for increased extracellular glutamate and NMDA receptor activation in the MDMA-induced loss of hippocampal GAD67-IR neurons and the subsequent increased susceptibility to evoked seizures.

  19. 17beta-estradiol treatment decreases steroidogenic enzyme messenger ribonucleic acid levels in the rainbow trout testis.

    PubMed

    Govoroun, M; McMeel, O M; Mecherouki, H; Smith, T J; Guiguen, Y

    2001-05-01

    In fish, estrogens are well known for their involvement in ovarian differentiation and have been shown to be very potent feminizing agents when administrated in vivo during early development. However, the mechanism of action of exogenous estrogens is poorly understood. We report here on the feminizing effects of estrogen treatment on the testicular levels of some steroidogenic enzyme messenger RNAs [mRNAs; cholesterol side-chain cleavage (P450scc), 17-hydroxylase/lyase (P450c17), 3beta-hydroxysteroid dehydrogenase (3betaHSD), 11beta-hydroxylase (P45011beta), and aromatase (P450aro)] in the rainbow trout, Oncorhynchus mykiss. Treatment was carried out by dietary administration of 17beta-estradiol (E(2); dosage of 20 mg/kg diet) to a genetically all male population. Steroidogenesis in the differentiating testis was demonstrated to be strongly altered by E(2), as this treatment resulted in considerable decrease in P450c17, 3betaHSD, and P45011beta mRNAs after only 10 days of treatment. In contrast, P450scc and P450aro mRNA levels were unaffected by E(2), with P450scc mRNA levels remaining unaltered and P450aro not stimulated by this feminizing estrogen treatment. To better characterize this E(2) effect, the same treatment was applied on postdifferentiating males, and roughly the same expression pattern was detected with a considerable decrease in testicular P450c17, 3betaHSD, and P45011beta mRNAs and a significant, but reduced, decrease in P450scc mRNA. In the interrenal, these steroidogenic enzyme mRNAs were not significantly affected by this E(2) treatment, except for a slight, but significant, decrease in P450scc mRNA. These results clearly demonstrate that estrogens have profound effects on testicular steroidogenesis and that they are acting specifically on the testis by decreasing mRNA steady state levels of many steroidogenic enzyme genes. The decrease in P45011beta mRNA, and thus inhibition of the synthesis of testicular 11-oxygenated androgens, may be an

  20. Response of drinking-water reservoir ecosystems to decreased acidic atmospheric deposition in SE Germany: trends of chemical reversal.

    PubMed

    Ulrich, Kai-Uwe; Paul, Lothar; Meybohm, Andreas

    2006-05-01

    This study evaluates chemical trends of seven acidified reservoirs and 22 tributaries in the Erzgebirge from 1993 to 2003. About 85% of these waters showed significantly (p < 0.05) declining concentrations of protons (-69%), nitrate (-41%), sulfate (-27%), and reactive aluminum (-50% on average). This reversal is attributed to the intense reduction of industrial SO2 and NOx emissions from formerly high levels, which declined by 99% and 82% in the German-Czech border region between 1993 and 1999. The deposition rates of protons and sulfur decreased by 70-90%. Since 1993, the dry deposition of total inorganic nitrogen diminished to a minor degree, but the wet deposition remained unchanged. The surface waters reflect a substantial decrease in Al exchange processes, a release of sulfur previously stored in soils, and an uptake of nitrate by forest vegetation. The latter effect may be supported by soil protection liming which contributed to the chemical reversal in almost 20% of the study waters.

  1. Dural afferents express acid-sensing ion channels: a role for decreased meningeal pH in migraine headache.

    PubMed

    Yan, Jin; Edelmayer, Rebecca M; Wei, Xiaomei; De Felice, Milena; Porreca, Frank; Dussor, Gregory

    2011-01-01

    Migraine headache is one of the most common neurological disorders. The pathological conditions that directly initiate afferent pain signaling are poorly understood. In trigeminal neurons retrogradely labeled from the cranial meninges, we have recorded pH-evoked currents using whole-cell patch-clamp electrophysiology. Approximately 80% of dural-afferent neurons responded to a pH 6.0 application with a rapidly activating and rapidly desensitizing ASIC-like current that often exceeded 20nA in amplitude. Inward currents were observed in response to a wide range of pH values and 30% of the neurons exhibited inward currents at pH 7.1. These currents led to action potentials in 53%, 30% and 7% of the dural afferents at pH 6.8, 6.9 and 7.0, respectively. Small decreases in extracellular pH were also able to generate sustained window currents and sustained membrane depolarizations. Amiloride, a non-specific blocker of ASIC channels, inhibited the peak currents evoked upon application of decreased pH while no inhibition was observed upon application of TRPV1 antagonists. The desensitization time constant of pH 6.0-evoked currents in the majority of dural afferents was less than 500ms which is consistent with that reported for ASIC3 homomeric or heteromeric channels. Finally, application of pH 5.0 synthetic-interstitial fluid to the dura produced significant decreases in facial and hind-paw withdrawal threshold, an effect blocked by amiloride but not TRPV1 antagonists, suggesting that ASIC activation produces migraine-related behavior in vivo. These data provide a cellular mechanism by which decreased pH in the meninges following ischemic or inflammatory events directly excites afferent pain-sensing neurons potentially contributing to migraine headache.

  2. Polyphenols and phenolic acids from strawberry and apple decrease glucose uptake and transport by human intestinal Caco-2 cells.

    PubMed

    Manzano, Susana; Williamson, Gary

    2010-12-01

    The effect of polyphenols, phenolic acids and tannins (PPTs) from strawberry and apple on uptake and apical to basolateral transport of glucose was investigated using Caco-2 intestinal cell monolayers. Substantial inhibition on both uptake and transport was observed by extracts from both strawberry and apple. Using sodium-containing (glucose transporters SGLT1 and GLUT2 both active) and sodium-free (only GLUT2 active) conditions, we show that the inhibition of GLUT2 was greater than that of SGLT1. The extracts were analyzed and some of the constituent PPTs were also tested. Quercetin-3-O-rhamnoside (IC₅₀ =31 μM), phloridzin (IC₅₀=146 μM), and 5-caffeoylquinic acid (IC₅₀=2570 μM) contributed 26, 52 and 12%, respectively, to the inhibitory activity of the apple extract, whereas pelargonidin-3-O-glucoside (IC₅₀=802 μM) contributed 26% to the total inhibition by the strawberry extract. For the strawberry extract, the inhibition of transport was non-competitive based on kinetic analysis, whereas the inhibition of cellular uptake was a mixed-type inhibition, with changes in both V(max) and apparent K(m) . The results in this assay show that some PPTs inhibit glucose transport from the intestinal lumen into cells and also the GLUT2-facilitated exit on the basolateral side.

  3. Acute dopamine depletion with branched chain amino acids decreases auditory top-down event-related potentials in healthy subjects.

    PubMed

    Neuhaus, Andres H; Goldberg, Terry E; Hassoun, Youssef; Bates, John A; Nassauer, Katharine W; Sevy, Serge; Opgen-Rhein, Carolin; Malhotra, Anil K

    2009-06-01

    Cerebral dopamine homeostasis has been implicated in a wide range of cognitive processes and is of great pathophysiological importance in schizophrenia. A novel approach to study cognitive effects of dopamine is to deplete its cerebral levels with branched chain amino acids (BCAAs) that acutely lower dopamine precursor amino acid availability. Here, we studied the effects of acute dopamine depletion on early and late attentive cortical processing. Auditory event-related potential (ERP) components N2 and P3 were investigated using high-density electroencephalography in 22 healthy male subjects after receiving BCAAs or placebo in a randomized, double-blind, placebo-controlled crossover design. Total free serum prolactin was also determined as a surrogate marker of cerebral dopamine depletion. Acute dopamine depletion increased free plasma prolactin and significantly reduced prefrontal ERP components N2 and P3. Subcomponent analysis of N2 revealed a significant attenuation of early attentive N2b over prefrontal scalp sites. As a proof of concept, these results strongly suggest that BCAAs are acting on basic information processing. Dopaminergic neurotransmission seems to be involved in auditory top-down processing as indexed by prefrontal N2 and P3 reductions during dopamine depletion. In healthy subjects, intact early cortical top-down processing can be acutely dysregulated by ingestion of BCAAs. We discuss the potential impact of these findings on schizophrenia research.

  4. Acute dopamine depletion with branched chain amino acids decreases auditory top-down event-related potentials in healthy subjects

    PubMed Central

    Neuhaus, Andres H.; Goldberg, Terry E.; Hassoun, Youssef; Bates, John A.; Nassauer, Katharine W.; Sevy, Serge; Opgen-Rhein, Carolin; Malhotra, Anil K.

    2013-01-01

    Cerebral dopamine homeostasis has been implicated in a wide range of cognitive processes and is of great pathophysiological importance in schizophrenia. A novel approach to study cognitive effects of dopamine is to deplete its cerebral levels with branched chain amino acids (BCAAs) that acutely lower dopamine precursor amino acid availability. Here, we studied the effects of acute dopamine depletion on early and late attentive cortical processing. Auditory event-related potential (ERP) components N2 and P3 were investigated using high-density electroencephalography in 22 healthy male subjects after receiving BCAAs or placebo in a randomized, double-blind, placebo-controlled crossover design. Total free serum prolactin was also determined as a surrogate marker of cerebral dopamine depletion. Acute dopamine depletion increased free plasma prolactin and significantly reduced prefrontal ERP components N2 and P3. Subcomponent analysis of N2 revealed a significant attenuation of early attentive N2b over prefrontal scalp sites. As a proof of concept, these results strongly suggest that BCAAs are acting on basic information processing. Dopaminergic neurotransmission seems to be involved in auditory top-down processing as indexed by prefrontal N2 and P3 reductions during dopamine depletion. In healthy subjects, intact early cortical top-down processing can be acutely dysregulated by ingestion of BCAAs. We discuss the potential impact of these findings on schizophrenia research. PMID:19356906

  5. Omega-3 fatty acids decreased irritability of patients with bipolar disorder in an add-on, open label study

    PubMed Central

    Sagduyu, Kemal; Dokucu, Mehmet E; Eddy, Bruce A; Craigen, Gerald; Baldassano, Claudia F; Yıldız, Ayşegül

    2005-01-01

    This is a report on a 37-patient continuation study of the open ended, Omega-3 Fatty Acid (O-3FA) add-on study. Subjects consisted of the original 19 patients, along with 18 new patients recruited and followed in the same fashion as the first nineteen. Subjects carried a DSM-IV-TR diagnosis of Bipolar Disorder and were visiting a Mood Disorder Clinic regularly through the length of the study. At each visit, patients' clinical status was monitored using the Clinical Monitoring Form. Subjects reported on the frequency and severity of irritability experienced during the preceding ten days; frequency was measured by way of percentage of days in which subjects experienced irritability, while severity of that irritability was rated on a Likert scale of 1 – 4 (if present). The irritability component of Young Mania Rating Scale (YMRS) was also recorded quarterly on 13 of the 39 patients consistently. Patients had persistent irritability despite their ongoing pharmacologic and psychotherapy. Omega-3 Fatty Acid intake helped with the irritability component of patients suffering from bipolar disorder with a significant presenting sign of irritability. Low dose (1 to 2 grams per day), add-on O-3FA may also help with the irritability component of different clinical conditions, such as schizophrenia, borderline personality disorder and other psychiatric conditions with a common presenting sign of irritability. PMID:15703073

  6. Increased dietary protein elevates plasma uric acid and is associated with decreased oxidative stress in rapidly-growing broilers.

    PubMed

    Machín, M; Simoyi, M F; Blemings, K P; Klandorf, H

    2004-03-01

    Uric acid is an important antioxidant and methods to elevate its plasma concentration may be important in animal health. In a first study, the effect of dietary protein on plasma uric acid (PUA) and glucose concentrations were determined in 3-week-old chicks. Twenty-four broiler chicks were randomly assigned to four diets: a commercial control diet (C, 20% crude protein), low protein (LP) containing 10% casein, medium protein (MP) containing 20% casein or high protein (HP) containing 45% casein for a 3-week experiment. PUA concentration increased (P<0.05) in chicks fed HP diet and declined (P<0.05) in chicks fed LP while plasma glucose concentrations were lower (P<0.05) in chicks fed the LP diet at the end of the study. In a second study, PUA and leukocyte oxidative activity (LOA) were determined in broilers fed C, LP, MP or HP diets for 4 weeks. As in the first study, dietary protein directly affected PUA concentrations. In birds consuming HP diets, PUA was negatively correlated (P=0.06) with lowered LOA. These data support the view that increases in dietary protein can increase PUA concentrations, which can ameliorate oxidative stress.

  7. Incremental amounts of ground flaxseed decreases milk production but increases n-3 fatty acids and conjugated linoleic acids in dairy cows fed high-forage diets

    USDA-ARS?s Scientific Manuscript database

    The objective of this study was to investigate the effect of incremental amounts of ground flaxseed (GFLAX) on milk yield and fatty acids (FA) profile, ruminal metabolism, and nutrient digestibility in dairy cows fed high-forage diets. Twelve multiparous Jersey cows averaging (mean ± SD) 112 ± 68 da...

  8. Minodronic acid (ONO-5920/YM529) prevents decrease in bone mineral density and bone strength, and improves bone microarchitecture in ovariectomized cynomolgus monkeys.

    PubMed

    Mori, Hiroshi; Tanaka, Makoto; Kayasuga, Ryoji; Masuda, Taisei; Ochi, Yasuo; Yamada, Hiroyuki; Kishikawa, Katsuya; Ito, Masako; Nakamura, Toshitaka

    2008-11-01

    This study examined the effect of the highly potent nitrogen-containing bisphosphonate, minodronic acid (ONO-5920/YM529), on bone mineral density (BMD), bone turnover, bone microarchitecture and bone strength in ovariectomized (OVX) cynomolgus monkeys. Skeletally mature female cynomolgus monkeys, aged 9-17 years, were ovariectomized or sham-operated. Minodronic acid was administered orally once a day in doses of 0, 0.015, and 0.15 mg/kg from the day after surgery for 17 months. Bone resorption markers (urinary N-terminal cross-linking telopeptide of type I collagen and deoxypyridinoline), bone formation markers (serum osteocalcin and bone alkaline phosphatase) and lumbar vertebral BMD were measured at baseline and at 4, 8, 12 and 16 months after surgery. Treatment with minodronic acid dose-dependently inhibited OVX-induced increase in bone turnover markers and decrease in lumbar vertebral BMD, and minodronic acid at 0.15 mg/kg completely prevented these changes. At 17 months after surgery, minodronic acid also suppressed bone resorption (Oc.S/BS and N.Oc/BS) and bone formation (OS/BS, MS/BS, MAR, BFR/BS, and BFR/BV) in the lumbar vertebral bodies and tibia. In the mechanical tests, ultimate load on lumbar vertebral bodies and femoral neck of the OVX-control animals were significantly reduced compared to the sham animals. Minodronic acid prevented these reductions in bone strength at 0.15 mg/kg. There was significant correlation between BMD and bone strength, suggesting that the increase in bone strength was associated with the increase in BMD produced by minodronic acid. In micro-CT analysis of the lumbar vertebral bodies, minodronic acid improved trabecular architecture, converting rod structures into plate structures, and preventing the increase in trabecular disconnectivity at 0.15 mg/kg. In conclusion, similar to patients with postmenopausal osteoporosis, reduction in bone strength of lumbar vertebral bodies and femoral neck was clearly demonstrated in OVX

  9. The decrease in Greenland ice-core δ15N of nitrate in the industrial period: influenced by changes in atmospheric acidity?

    NASA Astrophysics Data System (ADS)

    Geng, L.; Cole-Dai, J.; Alexander, B.; Steig, E. J.; Schauer, A. J.; Savarino, J.

    2012-12-01

    Previous study in a central Greenland ice core has revealed a decreasing trend in δ15N of nitrate (δ15N (nitrate)) starting as early as 1850 C.E.. Lake sediment cores from North America show a similar trend in δ15N of total nitrogen starting around 1895 C.E.. The decrease in δ15N has been proposed to be due to the increasing deposition of anthropogenically derived (i.e., fossil fuel combustion) nitrate in the industrial period. However, this interpretation is questioned by measurements of δ15N in NOx and atmospheric nitrate. Here, we present new, annually-resolved records of δ15N (nitrate) and major ion concentrations (Cl-, NO3-, SO42-, Na+, NH4+, K+, Mg2+, and Ca2+) obtained from two central Greenland ice cores. The results (Figure 1) indicate that the significant decrease in δ15N is coincident with an increase in acidity (H+ concentration estimated based on ionic balance) beginning around 1895 C.E., which is about 50 years earlier than the start of the increase in nitrate concentration (~1945 C.E.) . This observation suggests that it is likely the acidity change, instead of the input of anthropogenic nitrate, triggered the decrease in ice-core δ15N (nitrate). Atmospheric aerosol acidity influences the partitioning of atmospheric nitrate between its gaseous (HNO3) and particulate (p-NO3-) phases, resulting in a depletion of δ15N in HNO3 relative to p-NO3-. If atmospheric nitrate is transported to central Greenland preferentially in its gaseous form (HNO3), which is an open question, a decrease in ice-core δ15N (nitrate) would be expected with an increase in atmospheric acidity. We will examine the relationships between δ15N (nitrate) and the ice-core records of acidity, and HNO3, to discern the processes from changes in atmospheric acidity to the observed variability in ice core δ15N (nitrate) during the Industrial era.igure 1. The annual NO3- (blue curve), H+ (black curve) concentrations, and annual δ15N (nitrate) (red curve, y-axis is reversely

  10. Vitamin A deficiency disturbs collagen IV and laminin composition and decreases matrix metalloproteinase concentrations in rat lung. Partial reversibility by retinoic acid.

    PubMed

    Esteban-Pretel, Guillermo; Marín, M Pilar; Renau-Piqueras, Jaime; Sado, Yoshikazu; Barber, Teresa; Timoneda, Joaquín

    2013-01-01

    Vitamin A is essential for lung development and pulmonary cell differentiation. Its deficiency leads to altered lung structure and function and to basement membrane architecture and composition disturbances. Previously, we showed that lack of retinoids thickens the alveolar basement membrane and increases collagen IV, which are reversed by retinoic acid, the main biologically active vitamin A form. This study analyzed how vitamin A deficiency affects the subunit composition of collagen IV and laminin of lung basement membranes and pulmonary matrix metalloproteinase content, plus the recovering effect of all-trans-retinoic acid. Male weanling pups were fed a retinol-adequate/-deficient diet until 60 days old. A subgroup of vitamin-A-deficient pups received daily intraperitoneal all-trans-retinoic acid injections for 10 days. Collagen IV and laminin chain composition were modified in vitamin-A-deficient rats. The protein and mRNA contents of chains α1(IV), α3(IV) and α4(IV) increased; those of chains α2(IV) and α5(IV) remained unchanged; and the protein and mRNA contents of laminin chains α5, β1 and γ1 decreased. The mRNA of laminin chains α2 and α4 also decreased. Matrix metalloproteinases 2 and 9 decreased, but the tissue inhibitors of metalloproteinases 1 and 2 did not change. Treating vitamin-A-deficient rats with retinoic acid reversed all alterations, but laminin chains α2, α4 and α5 and matrix metalloproteinase 2 remained low. In conclusion, vitamin A deficiency alters the subunit composition of collagen IV and laminin and the lung's proteolytic potential, which are partly reverted by retinoic acid. These alterations could contribute to impaired lung function and predispose to pulmonary disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Epoxyeicosatrienoic acid agonist regulates human mesenchymal stem cell-derived adipocytes through activation of HO-1-pAKT signaling and a decrease in PPARγ.

    PubMed

    Kim, Dong Hyun; Vanella, Luca; Inoue, Kazuyoshi; Burgess, Angela; Gotlinger, Katherine; Manthati, Vijaya Lingam; Koduru, Sreenivasulu Reddy; Zeldin, Darryl C; Falck, John R; Schwartzman, Michal L; Abraham, Nader G

    2010-12-01

    Human mesenchymal stem cells (MSCs) expressed substantial levels of CYP2J2, a major CYP450 involved in epoxyeicosatrienoic acid (EET) formation. MSCs synthesized significant levels of EETs (65.8 ± 5.8 pg/mg protein) and dihydroxyeicosatrienoic acids (DHETs) (15.83 ± 1.62 pg/mg protein), suggesting the presence of soluble epoxide hydrolase (sEH). The addition of an sEH inhibitor to MSC culture decreased adipogenesis. EETs decreased MSC-derived adipocytes in a concentration-dependent manner, 8,9- and 14,15-EET having the maximum reductive effect on adipogenesis. We examined the effect of 12-(3-hexylureido)dodec-8(Z)-enoic acid, an EET agonist, on MSC-derived adipocytes and demonstrated an increased number of healthy small adipocytes, attenuated fatty acid synthase (FAS) levels (P < 0.01), and reduced PPARγ, C/EBPα, FAS, and lipid accumulation (P < 0.05). These effects were accompanied by increased levels of heme oxygenase (HO)-1 and adiponectin (P < 0.05), and increased glucose uptake (P < 0.05). Inhibition of HO activity or AKT by tin mesoporphyrin (SnMP) and LY2940002, respectively, reversed EET-induced inhibition of adipogenesis, suggesting that activation of the HO-1-adiponectin axis underlies EET effect in MSCs. These findings indicate that EETs decrease MSC-derived adipocyte stem cell differentiation by upregulation of HO-1-adiponectin-AKT signaling and play essential roles in the regulation of adipocyte differentiation by inhibiting PPARγ, C/EBPα, and FAS and in stem cell development. These novel observations highlight the seminal role of arachidonic acid metabolism in MSCs and suggest that an EET agonist may have potential therapeutic use in the treatment of dyslipidemia, diabetes, and the metabolic syndrome.

  12. Carbonate minerals in porous media decrease mobility of polyacrylic acid modified zero-valent iron nanoparticles used for groundwater remediation.

    PubMed

    Laumann, Susanne; Micić, Vesna; Lowry, Gregory V; Hofmann, Thilo

    2013-08-01

    The limited transport of nanoscale zero-valent iron (nZVI) in porous media is a major obstacle to its widespread application for in situ groundwater remediation. Previous studies on nZVI transport have mainly been carried out in quartz porous media. The effect of carbonate minerals, which often predominate in aquifers, has not been evaluated to date. This study assessed the influence of the carbonate minerals in porous media on the transport of polyacrylic acid modified nZVI (PAA-nZVI). Increasing the proportion of carbonate sand in the porous media resulted in less transport of PAA-nZVI. Predicted travel distances were reduced to a few centimeters in pure carbonate sand compared to approximately 1.6 m in quartz sand. Transport modeling showed that the attachment efficiency and deposition rate coefficient increased linearly with increasing proportion of carbonate sand. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Folic acid deficiency enhances abeta accumulation in APP/PS1 mice brain and decreases amyloid-associated miRNAs expression.

    PubMed

    Liu, Huan; Tian, Tian; Qin, Shanchun; Li, Wen; Zhang, Xumei; Wang, Xuan; Gao, Yuxia; Huang, Guowei

    2015-12-01

    Recent efforts have revealed the microRNA (miRNA) pathways in the pathogenesis of Alzheimer's disease (AD). Epidemiological studies have revealed an association between folic acid deficiency and AD risk. However, the effects of folic acid deficiency on miRNA expression in AD animals have not been observed. We aimed to find if folic acid deficiency may enhance amyloid-β (Aβ) peptide deposition and regulate amyloid-associated miRNAs and their target genes expression in APP/PS1 mice. APP/PS1 mice and N2a cells were treated with folic acid-deficient diet or medium. Cognitive function of mice was assessed using the Morris water maze. miRNA profile was tested by polymerase chain reaction (PCR) array. Different expressional miRNAs were validated by real-time PCR. The deposition of Aβ plaques was evaluated by immunohistochemistry and enzyme-linked immunosorbent assay. APP and BACE1 proteins in mice brain and N2a cells were determined by Western blot. Folic acid deficiency aggravated amyloid pathology in AD mice. The AD+FD group showed shorter time spent in the target zone during the probe test. Analysis of miRNAs predicted to target these genes revealed several miRNA candidates that were differentially modulated by folic acid deficiency. In APP/PS1 mice brains and N2a cells with folic acid-deficient treatment, miR-106a-5p, miR-200b-3p and miR-339-5p were down-regulated, and their target genes APP and BACE1 were up-regulated. In conclusion, folic acid deficiency can enhance Aβ accumulation in APP/PS1 mice brain and decrease amyloid-associated miRNAs expression.

  14. Administration of docosahexaenoic acid before birth and until aging decreases kainate-induced seizures in adult zebrafish.

    PubMed

    Sierra, Saleta; Alfaro, Juan M; Sánchez, Sonia; Burgos, Javier S

    2012-08-01

    Docosahexaeonic acid (DHA) is the final compound in the omega-3 polyunsaturated fatty acids (PUFA) synthetic pathway and the most abundant PUFA found in the brain. DHA plays an essential role in the development of the brain, and the intakes in pregnancy and early life affect growth and cognitive performance later in childhood. Recently, it has been proposed that dietary intake of DHA could be a non-pharmacological interventional strategy for the treatment of seizures in humans. However, to date, the experimental approaches to study the antiepileptic effect of DHA have been exclusively restricted to rodent models during short-to-medium periods of treatment. The purpose of the present study was to test the chronic anticonvulsivant effects of DHA supplementation in zebrafish from the pre-spawning stage to aging, taking advantage of our recently described kainate-induced seizure model using this animal. To that end, two groups of adult female zebrafish were fed with standard or 200mg/kg DHA-enriched diets during 1 month previous to the spawning, and offspring subdivided in two categories, and subsequently fed with standard or DHA diets, generating 4 groups of animals that were aged until 20 months. Afterward, KA was intraperitoneally administered and epileptic score determined. All the DHA-enriched groups presented antiepileptic effects compared to the control group, showing that DHA presents an anticonvulsant potential. Among the studied groups, zebrafish fed with DHA from the pre-spawning stage to aging presented the best antiepileptic profile. These results show a neuroprotective benefit in zebrafish fed with DHA-enriched diet before birth and during the whole life. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. BAPTA-AM decreases cellular pH, inhibits acidocalcisome acidification and autophagy in amino acid-starved T. brucei.

    PubMed

    Li, Feng-Jun; Tan, Kevin S W; He, Cynthia Y

    2017-04-01

    To investigate the role of Ca(2+) signaling in starvation-induced autophagy in Trypanosoma brucei, the causative agent of human African trypanosomiasis, we used cell-permeant Ca(2+) chelator BAPTA-AM and cell impermeant chelator EGTA, and examined the potential involvement of several intracellular Ca(2+) signaling pathways in T. brucei autophagy. The results showed an unexpected effect of BAPTA-AM in decreasing cellular pH and inhibiting acidocalcisome acidification in starved cells. The implication of these results in the role of Ca(2+) signaling and cellular/organellar pH in T. brucei autophagy is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Increased cardiac fatty acid uptake with dobutamine infusion in swine is accompanied by a decrease in malonyl CoA levels.

    PubMed

    Hall, J L; Lopaschuk, G D; Barr, A; Bringas, J; Pizzurro, R D; Stanley, W C

    1996-11-01

    Malonyl CoA is an important regulator of fatty acid oxidation in the heart secondary to its ability to inhibit carnitine palmitoyltransferase 1 (CPT 1). Malonyl CoA is produced from acetyl CoA in a reaction catalyzed by acetyl CoA carboxylase (ACC). In this study we determined if alterations in malonyl CoA regulation of fatty acid metabolism are involved in the increase in energy transduction seen following an increase in cardiac work. Anesthetized, open-chest, domestic swine were subjected to a 30 min control period followed by a 30 min treatment period with either dobutamine (15 micrograms.kg-1. min-1 i.v.) (n = 6) or saline (n = 6). Heart rate, left ventricular peak dp/dt, and MVO2, were significantly increased in the dobutamine group compared to the saline group during the treatment period. Free fatty acid and glucose uptake were increased 210 and 248%, respectively, in the dobutamine group during the treatment period. Malonyl CoA content was decreased by 55% (from 0.40 +/- 0.05 to 0.18 +/- 0.12 nmol/g wet wt; P < 0.05) with dobutamine treatment, but was not affected by saline treatment. ACC activity was not significantly different between groups (0.31 +/- 0.02 vs. 0.30 +/- 0.04 nmol. min-1. mg protein-1, respectively). The activity of AMP-dependent protein kinase (AMPK), which phosphorylates and inactivates ACC, was also not significantly different in the dobutamine hearts compared to the saline hearts (322 +/- 26 vs. 338 +/- 39 pmol. min-1. mg protein-1, respectively). The increased cardiac work following dobutamine infusion is accompanied by a decrease in malonyl CoA levels and an increase in fatty acid uptake. However, the decrease in malonyl CoA cannot be explained by a decrease in ACC activity.

  17. Higher thermostability of l-lactate dehydrogenases is a key factor in decreasing the optical purity of d-lactic acid produced from Lactobacillus coryniformis.

    PubMed

    Gu, Sol-A; Jun, Chanha; Joo, Jeong Chan; Kim, Seil; Lee, Seung Hwan; Kim, Yong Hwan

    2014-05-10

    Lactobacillus coryniformis is known to produce d-lactic acid as a dominant fermentation product at a cultivation temperature of approximately 30°C. However, the considerable production of l-lactic acid is observed when the fermentation temperature is greater than 40°C. Because optically pure lactates are synthesized from pyruvate by the catalysis of chiral-specific d- or l-lactate dehydrogenase, the higher thermostability of l-LDHs is assumed to be one of the key factors decreasing the optical purity of d-lactic acid produced from L. coryniformis at high temperature. To verify this hypothesis, two types of d-ldh genes and six types of l-ldh genes based on the genomic information of L. coryniformis were synthesized and expressed in Escherichia coli. Among the LDHs tested, five LDHs showed activity and were used to construct polyclonal antibodies. d-LDH1, l-LDH2, and l-LDH3 were found to be expressed in L. coryniformis by Western blotting analysis. The half-life values (t1/2) of the LDHs at 40°C were estimated to be 10.50, 41.76, and 2311min, and the T50(10) values were 39.50, 39.90, and 58.60°C, respectively. In addition, the Tm values were 36.0, 41.0, and 62.4°C, respectively, which indicates that l-LDH has greater thermostability than d-LDH. The higher thermostability of l-LDHs compared with that of d-LDH1 may be a major reason why the enantiopurity of d-lactic acid is decreased at high fermentation temperatures. The key enzymes characterized will suggest a direction for the design of genetically modified lactic acid bacteria to produce optically pure d-lactic acid.

  18. Decreased mental time travel to the past correlates with default-mode network disintegration under lysergic acid diethylamide.

    PubMed

    Speth, Jana; Speth, Clemens; Kaelen, Mendel; Schloerscheidt, Astrid M; Feilding, Amanda; Nutt, David J; Carhart-Harris, Robin L

    2016-04-01

    This paper reports on the effects of LSD on mental time travel during spontaneous mentation. Twenty healthy volunteers participated in a placebo-controlled crossover study, incorporating intravenous administration of LSD (75 μg) and placebo (saline) prior to functional magnetic resonance imaging (fMRI). Six independent, blind judges analysed mentation reports acquired during structured interviews performed shortly after the functional magnetic resonance imaging (fMRI) scans (approximately 2.5 h post-administration). Within each report, specific linguistic references to mental spaces for the past, present and future were identified. Results revealed significantly fewer mental spaces for the past under LSD and this effect correlated with the general intensity of the drug's subjective effects. No differences in the number of mental spaces for the present or future were observed. Consistent with the previously proposed role of the default-mode network (DMN) in autobiographical memory recollection and ruminative thought, decreased resting-state functional connectivity (RSFC) within the DMN correlated with decreased mental time travel to the past. These results are discussed in relation to potential therapeutic applications of LSD and related psychedelics, e.g. in the treatment of depression, for which excessive reflection on one's past, likely mediated by DMN functioning, is symptomatic.

  19. Manganese accumulation in membrane fractions of primary astrocytes is associated with decreased γ-aminobutyric acid (GABA) uptake, and is exacerbated by oleic acid and palmitate.

    PubMed

    Fordahl, Steve C; Erikson, Keith M

    2014-05-01

    Manganese (Mn) exposure interferes with GABA uptake; however, the effects of Mn on GABA transport proteins (GATs) have not been identified. We sought to characterize how Mn impairs GAT function in primary rat astrocytes. Astrocytes exposed to Mn (500 μM) had significantly reduced (3)H-GABA uptake despite no change in membrane or cytosolic GAT3 protein levels. Co-treatment with 100 μM oleic or palmitic acids (both known to be elevated in Mn neurotoxicity), exacerbated the Mn-induced decline in (3)H-GABA uptake. Mn accumulation in the membrane fraction of astrocytes was enhanced with fatty acid administration, and was negatively correlated with (3)H-GABA uptake. Furthermore, control cells exposed to Mn only during the experimental uptake had significantly reduced (3)H-GABA uptake, and the addition of GABA (50 μM) blunted cytosolic Mn accumulation. These data indicate that reduced GAT function in astrocytes is influenced by Mn and fatty acids accumulating at or interacting with the plasma membrane. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Streptozotocin-Induced Diabetes Decreases Mammary Gland Lipoprotein Lipase Activity and Messenger Ribonucleic Acid in Pregnant and Nonpregnant Rats

    PubMed Central

    Blanco-Dolado, Laura; Martín-Hidalgo, Antonia; Herrera, Emilio

    2002-01-01

    Diabetes mellitus is associated with a reduction of lipoprotein lipase (LPL) activity in adipose tissue and development of hypertriglyceridemia. To determine how a condition of severe insulin deficiency affects mammary gland LPL activity and mRNA expression during late pregnancy, streptozotocin (STZ) treated (40 mg/kg) and non-treated (control) virgin and 20 day pregnant rats were studied. In control rats, both LPL activity and mRNA were higher in pregnant than in virgin rats. When compared to control rats, STZ-treated rats, either pregnant or virgin, showed decreased LPL activity and mRNA content. Furthermore, mammary gland LPL activity was linearly correlated with mRNA content, and either variable was linearly correlated with plasma insulin levels. Thus, insulin deficiency impairs the expression of LPL in mammary glands, revealing the role of insulin as a modulator of the enzyme at the mRNA expression level. PMID:11900280

  1. Omega-3 Polyunsaturated Fatty Acids Inhibited Tumor Growth via Preventing the Decrease of Genomic DNA Methylation in Colorectal Cancer Rats.

    PubMed

    Huang, Qionglin; Wen, Juan; Chen, Guangzhao; Ge, Miaomiao; Gao, Yihua; Ye, Xiaoxia; Liu, Chunan; Cai, Chun

    2016-01-01

    Omge-3 polyunsaturated fatty acids (PUFAs) exhibited significant effect in inhibiting various tumors. However, the mechanisms of its anticancer role have not been fully demonstrated. The declination of 5-methylcytosine (5 mC) was closely associated with poor prognosis of tumors. To explore whether omega-3 PUFAs influences on DNA methylation level in tumors, colorectal cancer (CRC) rat model were constructed using N-methyl phosphite nitrourea and omega-3 PUFAs were fed to part of the rats during tumor induction. The PUFAs contents in the rats of 3 experimental groups were measured using gas chromatography and 5 mC level were detected by liquid chromatography tandem mass spectrometry. The results showed that tumor incidence in omega-3 treated rats was much lower than in CRC model rats, which confirmed significant antitumor role of omega-3 PUFAs. Six PUFA members categorized to omega-3 and omega-6 families were quantified and the ratio of omega-6/omega-3 PUFAs was remarkably lower in omega-3 PUFAs treatment group than in CRC model group. 5 mC content in omega-3 PUFAs treated rats was higher than in CRC model rats, suggesting omega-3 PUFAs promoted 5 mC synthesis. Therefore, omega-3 PUFAs probably inhibited tumor growth via regulating DNA methylation process, which provided a novel anticancer mechanism of omega-3 PUFAs from epigenetic view.

  2. The absence of myristic acid decreases membrane binding of p60src but does not affect tyrosine protein kinase activity.

    PubMed Central

    Buss, J E; Kamps, M P; Gould, K; Sefton, B M

    1986-01-01

    We have constructed two point mutants of Rous sarcoma virus in which the amino-terminal glycine residue of the transforming protein, p60src, was changed to an alanine or a glutamic acid residue. Both mutant proteins failed to become myristylated and, more importantly, no longer transformed cells. The lack of transformation could not be attributed to defects in the catalytic activity of the mutant p60src proteins. In vitro phosphorylation of the peptide angiotensin or of the cellular substrate proteins enolase and p36 revealed no significant differences in the Km or specific activity of the mutant and wild-type p60src proteins. However, when cellular fractions were prepared, less than 12% of the nonmyristylated p60src proteins was bound to membranes. In contrast, more than 82% of the wild-type protein was associated with membranes. Wild-type p60src was phosphorylated by protein kinase C, a protein kinase which associates with membranes when activated. The mutant proteins were not. This finding supports the idea that within the intact cell the nonmyristylated p60src proteins are cytoplasmic and suggests that this apparent solubility is not an artifact of the cell fractionation procedure. The myristyl groups of p60src apparently encourages a tight association between protein and membranes and, by determining the cellular location of the enzyme, allows transformation to occur. Images PMID:3009860

  3. N-3 Polyunsaturated Fatty Acids Decrease the Protein Expression of Soluble Epoxide Hydrolase via Oxidative Stress-Induced P38 Kinase in Rat Endothelial Cells.

    PubMed

    Okada, Takashi; Morino, Katsutaro; Nakagawa, Fumiyuki; Tawa, Masashi; Kondo, Keiko; Sekine, Osamu; Imamura, Takeshi; Okamura, Tomio; Ugi, Satoshi; Maegawa, Hiroshi

    2017-06-24

    N-3 polyunsaturated fatty acids (PUFAs) improve endothelial function. The arachidonic acid-derived metabolites (epoxyeicosatrienoic acids (EETs)) are part of the endothelial hyperpolarization factor and are vasodilators independent of nitric oxide. However, little is known regarding the regulation of EET concentration by docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in blood vessels. Sprague-Dawley rats were fed either a control or fish oil diet for 3 weeks. Compared with the control, the fish oil diet improved acetylcholine-induced vasodilation and reduced the protein expression of soluble epoxide hydrolase (sEH), a key EET metabolic enzyme, in aortic strips. Both DHA and EPA suppressed sEH protein expression in rat aorta endothelial cells (RAECs). Furthermore, the concentration of 4-hydroxy hexenal (4-HHE), a lipid peroxidation product of n-3 PUFAs, increased in n-3 PUFA-treated RAECs. In addition, 4-HHE treatment suppressed sEH expression in RAECs, suggesting that 4-HHE (derived from n-3 PUFAs) is involved in this phenomenon. The suppression of sEH was attenuated by the p38 kinase inhibitor (SB203580) and by treatment with the antioxidant N-acetyl-L-cysteine. In conclusion, sEH expression decreased after n-3 PUFAs treatment, potentially through oxidative stress and p38 kinase. Mild oxidative stress induced by n-3 PUFAs may contribute to their cardio-protective effect.

  4. Folic acid protects against lead acetate-induced hepatotoxicity by decreasing NF-κB, IL-1β production and lipid peroxidation mediataed cell injury.

    PubMed

    Abd Allah, Eman S H; Badary, Dalia M

    2017-03-01

    Folic acid plays an important role in cellular metabolic activities. The present study was designed to investigate the protective effect of folic acid against lead acetate-induced hepatotoxicity. Twenty four male Wistar albino rats were randomly divided into four groups, six animals each. Negative control group received the vehicle, positive control group received 1mg/kg folic acid for five consecutive days/week for 4 weeks orally, lead-exposed group received 10mg/kg lead acetate intraperitoneally (IP) for five consecutive days/week for 4 weeks, and lead-treated group received 10mg/kg lead acetate IP and 1mg/kg folic acid orally for five consecutive days/week for 4 weeks concurrently. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ- glutamyltransferase (GGT) were measured. Hepatic total peroxide and interleukin-1β (IL-1β) were also investigated. Histopathological studies using hematoxylin-eosin (H&E) and periodic acid shiff's (PAS) were carried out. The expression of nuclear factor kappa B (NF-κB) was evaluated using immunohistochemistry. Serum AST, ALT and GGT and hepatic total peroxide and IL-1β were significantly increased in lead-exposed group and were positively correlated with hepatic lead level. Moreover, lead-exposed rats showed hydropic degeneration, nuclear vesiculation, high lymphocytic infiltration, depletion of glycogen content and NF-κB expression. Concomitant folic acid administration resulted in a significant alleviation of biochemical and structural alteration-induced by lead. This was associated with reduction of hepatic total peroxide and IL-1β and reduction of NF-κB expression. In conclusion, folic acid protects against lead acetate-induced hepatotoxicity by decreasing NF-κB, IL-1β production and lipid peroxidation mediataed cell injury.

  5. Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA2β (VIA)-deficient mice

    PubMed Central

    Basselin, Mireille; Rosa, Angelo O.; Ramadan, Epolia; Cheon, Yewon; Chang, Lisa; Chen, Mei; Greenstein, Deanna; Wohltmann, Mary; Turk, John; Rapoport, Stanley I.

    2010-01-01

    Ca2+-independent phospholipase A2β (iPLA2β) selectively hydrolyzes docosahexaenoic acid (DHA, 22:6n-3) in vitro from phospholipid. Mutations in the PLA2G6 gene encoding this enzyme occur in patients with idiopathic neurodegeneration plus brain iron accumulation and dystonia-parkinsonism without iron accumulation, whereas mice lacking PLA2G6 show neurological dysfunction and neuropathology after 13 months. We hypothesized that brain DHA metabolism and signaling would be reduced in 4-month-old iPLA2β-deficient mice without overt neuropathology. Saline or the cholinergic muscarinic M1,3,5 receptor agonist arecoline (30 mg/kg) was administered to unanesthetized iPLA2β−/−, iPLA2β+/−, and iPLA2β+/+ mice, and [1-14C]DHA was infused intravenously. DHA incorporation coefficients k* and rates Jin, representing DHA metabolism, were determined using quantitative autoradiography in 81 brain regions. iPLA2β−/− or iPLA2β+/− compared with iPLA2β+/+ mice showed widespread and significant baseline reductions in k* and Jin for DHA. Arecoline increased both parameters in brain regions of iPLA2β+/+ mice but quantitatively less so in iPLA2β−/− and iPLA2β+/− mice. Consistent with iPLA2β’s reported ability to selectively hydrolyze DHA from phospholipid in vitro, iPLA2β deficiency reduces brain DHA metabolism and signaling in vivo at baseline and following M1,3,5 receptor activation. Positron emission tomography might be used to image disturbed brain DHA metabolism in patients with PLA2G6 mutations. PMID:20686114

  6. Decreased expression of the glial water channel aquaporin-4 in the intrahippocampal kainic acid model of epileptogenesis

    PubMed Central

    Lee, Darrin J.; Hsu, Mike S.; Seldin, Marcus M.; Arellano, Janetta L.; Binder, Devin K.

    2012-01-01

    Recent evidence suggests that astrocytes may be a potential new target for the treatment of epilepsy. The glial water channel aquaporin-4 (AQP4) is expressed in astrocytes, and along with the inwardly-rectifying K+ channel Kir4.1 is thought to underlie the reuptake of H2O and K+ into glial cells during neural activity. Previous studies have demonstrated increased seizure duration and slowed potassium kinetics in AQP4−/− mice, and redistribution of AQP4 in hippocampal specimens from patients with chronic epilepsy. However, the regulation and role of AQP4 during epileptogenesis remain to be defined. In this study, we examined the expression of AQP4 and other glial molecules (GFAP, Kir4.1, glutamine synthetase) in the intrahippocampal kainic acid (KA) model of epilepsy and compared behavioral and histologic outcomes in wild-type mice vs. AQP4−/− mice. Marked and prolonged reduction in AQP4 immunoreactivity on both astrocytic fine processes and endfeet was observed following KA status epilepticus in multiple hippocampal layers. In addition, AQP4−/− mice had more spontaneous recurrent seizures than wild-type mice during the first week after KA SE as assessed by chronic video-EEG monitoring and blinded EEG analysis. While both genotypes exhibited similar reactive astrocytic changes, granule cell dispersion and CA1 pyramidal neuron loss, there were an increased number of fluorojade-positive cells early after KA SE in AQP4−/− mice. These results indicate a marked reduction of AQP4 following KA SE and suggest that dysregulation of water and potassium homeostasis occurs during early epileptogenesis. Restoration of astrocytic water and ion homeostasis may represent a novel therapeutic strategy. PMID:22361023

  7. Galbanic acid decreases androgen receptor abundance and signaling and induces G1 arrest in prostate cancer cells

    PubMed Central

    Zhang, Yong; Kim, Kwan-Hyun; Zhang, Wei; Guo, Yinglu; Kim, Sung-Hoon; Lü, Junxuan

    2011-01-01

    Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(−) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(−) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA down-regulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide, LNCaP cell culture assays did not detect agonist activity of GBA. GBA and bicalutamide exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G1 arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D1 without the causal involvement of CDK inhibitory proteins P21Cip1 and P27Kip1. In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and bicalutamide with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multi-targeting drug candidate for the prevention and therapy of PCa. PMID:21328348

  8. Laser-assisted delivery of vitamin C, vitamin E, and ferulic acid formula serum decreases fractional laser postoperative recovery by increased beta fibroblast growth factor expression.

    PubMed

    Waibel, Jill S; Mi, Qing-Sheng; Ozog, David; Qu, Le; Zhou, Li; Rudnick, Ashley; Al-Niaimi, Firas; Woodward, Julie; Campos, Valerie; Mordon, Serge

    2016-03-01

    Laser-assisted drug delivery is an emerging technology to achieve greater penetration by existing topical medications to reach desired targets in the tissue. The objective of this research was to study whether laser-assisted delivery of Vitamin C, E, and Ferulic immediately postoperatively of fractional ablative laser could improve wound healing. Secondary objectives were to evaluate the potential molecular markers involved in this wound-healing process. A double blinded, prospective, single center, randomized split face trial of Vitamin C, E, and Ferulic topical formula #740019 to decrease postoperative recovery time in fractional ablative laser resurfacing for photo damage. Fifteen healthy men and women of ages 30-55 years were treated with the Vitamin C, E, and Ferulic acid serum to one side of face and vehicle to the other side of face, within 2 minutes immediately after fractional ablative CO2 laser surgery and daily during the healing process. Patients were evaluated daily on days 1-7 using photographs, patient questionnaires, and molecular evaluation. Clinically, postoperative Vitamin C, E, and Ferulic delivery resulted in decreased edema versus vehicle on postoperative day 7 and decreased erythema versus vehicle on postoperative days 3 and 5. Molecularly, the expression of basic fibroblast growth factor (bFGF) was significantly increased at day 5 on the lesion treated with Vitamin C, E, and Ferulic acid serum compared to vehicle control on the other side. This is first study to show that Vitamin C, E, and Ferulic acid correlate with more rapid wound healing post-fractional ablative laser. Elevated bFGF could be involved in the Vitamin C, E, and Ferulic acid-induced rapid wound healing. © 2015 Wiley Periodicals, Inc.

  9. Locked nucleic acid-inhibitor of miR-205 decreases endometrial cancer cells proliferation in vitro and in vivo

    PubMed Central

    Torres, Anna; Kozak, Joanna; Korolczuk, Agnieszka; Rycak, Dominika; Wdowiak, Paulina; Maciejewski, Ryszard; Torres, Kamil

    2016-01-01

    Pathogenesis of endometrial cancer has been connected with alterations of microRNA expression and in particular miR-205 up–regulation was consistently reported in this carcinoma. Presented study aimed to investigate if inhibition of miR-205 expression using LNA-modified-nucleotide would attenuate endometrial cancer cells proliferation in vitro and in vivo. In the course of the study we found that the proliferation of endometrial cancer cells (HEC-1-B, RL-95, KLE, Ishikawa) transfected with LNA-miR-205-inhibitor and evaluated using real time cell monitoring as well as standard cell proliferation assay, was significantly decreased. Next, LNA-miR-205-inhibitor was used to assess the in vivo effects of miR-205 inhibition of endometrial cancer growth. Cby.Cg-Foxn1/cmdb mice bearing endometrial cancer xenografts were intraperitoneally injected with nine dosages of 25mg/kg of miR-205-LNA-inhibitor or scramble control or phosphatase buffered saline and were observed for 32 days. We found that systemic administration of miR-205-LNA-inhibitor was technically possible, and exerted inhibitory effect on endometrial cancer xenograft growth in vivo with only mild toxic effects in treated animals. In conclusion our results suggest that systemic delivery of miR-205-LNA-inhibitor is feasible, devoid of significant toxicity, and could be a promising treatment strategy for endometrial cancer. Therefore it warrants further studies in other animal models. PMID:27655663

  10. Locked nucleic acid-inhibitor of miR-205 decreases endometrial cancer cells proliferation in vitro and in vivo.

    PubMed

    Torres, Anna; Kozak, Joanna; Korolczuk, Agnieszka; Rycak, Dominika; Wdowiak, Paulina; Maciejewski, Ryszard; Torres, Kamil

    2016-11-08

    Pathogenesis of endometrial cancer has been connected with alterations of microRNA expression and in particular miR-205 up-regulation was consistently reported in this carcinoma. Presented study aimed to investigate if inhibition of miR-205 expression using LNA-modified-nucleotide would attenuate endometrial cancer cells proliferation in vitro and in vivo.In the course of the study we found that the proliferation of endometrial cancer cells (HEC-1-B, RL-95, KLE, Ishikawa) transfected with LNA-miR-205-inhibitor and evaluated using real time cell monitoring as well as standard cell proliferation assay, was significantly decreased. Next, LNA-miR-205-inhibitor was used to assess the in vivo effects of miR-205 inhibition of endometrial cancer growth. Cby.Cg-Foxn1/cmdb mice bearing endometrial cancer xenografts were intraperitoneally injected with nine dosages of 25mg/kg of miR-205-LNA-inhibitor or scramble control or phosphatase buffered saline and were observed for 32 days. We found that systemic administration of miR-205-LNA-inhibitor was technically possible, and exerted inhibitory effect on endometrial cancer xenograft growth in vivo with only mild toxic effects in treated animals.In conclusion our results suggest that systemic delivery of miR-205-LNA-inhibitor is feasible, devoid of significant toxicity, and could be a promising treatment strategy for endometrial cancer. Therefore it warrants further studies in other animal models.

  11. Wheat germ extract decreases glucose uptake and RNA ribose formation but increases fatty acid synthesis in MIA pancreatic adenocarcinoma cells.

    PubMed

    Boros, L G; Lapis, K; Szende, B; Tömösközi-Farkas, R; Balogh, A; Boren, J; Marin, S; Cascante, M; Hidvégi, M

    2001-08-01

    The fermented wheat germ extract with standardized benzoquinone composition has potent tumor propagation inhibitory properties. The authors show that this extract induces profound metabolic changes in cultured MIA pancreatic adenocarcinoma cells when the [1,2-13C2]glucose isotope is used as the single tracer with biologic gas chromatography-mass spectrometry. MIA cells treated with 0.1, 1, and 10 mg/mL wheat germ extract showed a dose-dependent decrease in cell glucose consumption. uptake of isotope into ribosomal RNA (2.4%, 9.4%, and 28.0%), and release of 13CO2. Conversely, direct glucose oxidation and ribose recycling in the pentose cycle showed a dose-dependent increase of 1.2%, 20.7%, and 93.4%. The newly synthesized fraction of cell palmitate and the 13C enrichment of acetyl units were also significantly increased with all doses of wheat germ extract. The fermented wheat germ extract controls tumor propagation primarily by regulating glucose carbon redistribution between cell proliferation-related and cell differentiation-related macromolecules. Wheat germ extract treatment is likely associated with the phosphorylation and transcriptional regulation of metabolic enzymes that are involved in glucose carbon redistribution between cell proliferation-related structural and functional macromolecules (RNA, DNA) and the direct oxidative degradation of glucose, which have devastating consequences for the proliferation and survival of pancreatic adenocarcinoma cells in culture.

  12. Fibrinolysis and Proliferative Endarteritis: Two Related Processes in Chronic Infections? The Model of the Blood-Borne Pathogen Dirofilaria immitis

    PubMed Central

    González-Miguel, Javier; Morchón, Rodrigo; Siles-Lucas, Mar; Simón, Fernando

    2015-01-01

    The interaction between blood-borne pathogens and fibrinolysis is one of the most important mechanisms that mediate invasion and the establishment of infectious agents in their hosts. However, overproduction of plasmin (final product of the route) has been related in other contexts to proliferation and migration of the arterial wall cells and degradation of the extracellular matrix. We have recently identified fibrinolysis-activating antigens from Dirofilaria immitis, a blood-borne parasite whose key pathological event (proliferative endarteritis) is produced by similar mechanisms to those indicated above. The objective of this work is to study how two of this antigens [actin (ACT) and fructose-bisphosphate aldolase (FBAL)] highly conserved in pathogens, activate fibrinolysis and to establish a relationship between this activation and the development of proliferative endarteritis during cardiopulmonary dirofilariasis. We demonstrate that both proteins bind plasminogen, enhance plasmin generation, stimulate the expression of the fibrinolytic activators tPA and uPA in endothelial cell cultures and are located on the surface of the worm in contact with the host’s blood. ELISA, western blot and immunofluorescence techniques were employed for this purpose. Additionally, the implication of lysine residues in this interaction was analyzed by bioinformatics. The involvement of plasmin generated by the ACT/FBAL and plasminogen binding in cell proliferation and migration, and degradation of the extracellular matrix were shown in an “in vitro” model of endothelial and smooth muscle cells in culture. The obtained results indicate that ACT and FBAL from D. immitis activate fibrinolysis, which could be used by the parasite like a survival mechanism to avoid the clot formation. However, long-term overproduction of plasmin can trigger pathological events similar to those described in the emergence of proliferative endarteritis. Due to the high degree of evolutionary

  13. Long-term temporal trends and spatial patterns in the acid-base chemistry of lakes in the Adirondack region of New York in response to decreases in acidic deposition

    NASA Astrophysics Data System (ADS)

    Driscoll, Charles T.; Driscoll, Kimberley M.; Fakhraei, Habibollah; Civerolo, Kevin

    2016-12-01

    We examined the response of lake water chemistry in the Adirondack Mountains of New York State, USA to decreases in acid deposition. Striking declines in the concentrations and fluxes of sulfate and hydrogen ion in wet deposition have been observed since the late 1970s, while significant decreases in nitrate have been evident since the early 2000s. Decreases in estimated dry sulfur and nitrate deposition have also occurred in the Adirondacks, but with no change in dry to wet deposition ratios. These patterns follow long-term decreases in anthropogenic emissions of sulfur dioxide and nitrogen oxides in the U.S. over the same interval. All of the 48 lakes monitored through the Adirondack Long-Term Monitoring program since 1992 have exhibited significant declines in sulfate concentrations, consistent with reductions in atmospheric deposition of sulfur. Nitrate concentrations have also significantly diminished at variable rates in many (33 of 48) lakes. Decreases in concentrations of sulfate plus nitrate (48 of 48) in lakes have driven widespread increases in acid neutralizing capacity (ANC; 42 of 48) and lab pH (33 of 48), and decreases in the toxic fraction, inorganic monomeric Al (45 of 48). Coincident with decreases in acid deposition, concentrations of dissolved organic carbon (DOC) have also increased in some (29 of 48) lakes. While recovery from elevated acid deposition is evident across Adirondack lakes, highly sensitive and impacted mounded seepages lakes and thin till drainage lakes are recovering most rapidly. Future research might focus on how much additional recovery could be achieved given the current deposition relative to future deposition anticipated under the Clean Power Plan, ecosystem effects of increased mobilization of dissolved organic matter, and the influence of changing climate on recovery from acidification.

  14. Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Guo, Liang; Zhou, Shui-Rong; Wei, Xiang-Bo; Liu, Yuan; Chang, Xin-Xia; Liu, Yang; Ge, Xin; Dou, Xin; Huang, Hai-Yan; Qian, Shu-Wen; Li, Xi; Lei, Qun-Ying

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein α-subunit (MTPα) functions as a critical enzyme for fatty acid β-oxidation, but whether dysregulation of MTPα is pathogenically connected to NAFLD is poorly understood. We show that MTPα is acetylated at lysine residues 350, 383, and 406 (MTPα-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTPα-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTPα. Replacement of MTPα-3K with either MTPα-3KR or MTPα-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTPα-3K mutant expression in mouse livers, and MTPα-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTPα and MTPα-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTPα regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD. PMID:27457618

  15. Involvement of CD36 in Modulating the Decrease of NPY and AgRP Induced by Acute Palmitic Acid Stimulation in N1E-115 Cells

    PubMed Central

    Ma, Yan; Wang, Xiaoyi; Yang, Hongying; Zhang, Xu; Yang, Nianhong

    2017-01-01

    Central nervous system (CNS) fatty acid sensing plays an important role in the regulation of food intake, and palmitic acid (PA) is the most important long chain fatty acid (LCFA) in the mammalian diet. To explore the effect of PA on central neuropeptide expression and the role of the cluster of the differentiation of 36 (CD36) in the process, N1E-115 cells were cultured with PA in the presence or absence of sulfosuccinimidyl-oleate (SSO), a CD36 inhibitor. Results showed that 10 μmol/L PA significantly reduced NPY and AgRP mRNA expression after 20 min of exposure, while the expression of CD36 was upregulated. The presence of SSO significantly attenuated the decrease of NPY and AgRP expression that was induced by PA alone, although no notable effect on PA- induced CD36 gene expression was observed. In conclusion, our study suggests the involvement of CD36 in the PA-induced decrease of NPY and AgRP in N1E-115 cells. PMID:28629148

  16. Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats.

    PubMed

    Roglans, Núria; Sanguino, Elena; Peris, Cristina; Alegret, Marta; Vázquez, Manuel; Adzet, Tomás; Díaz, Cristina; Hernández, Gonzalo; Laguna, Juan C; Sánchez, Rosa M

    2002-07-01

    We aimed to investigate the effect of atorvastatin (5 and 30 mg/kg/day for 2 weeks) on hepatic lipid metabolism in a well established model of dietary hypertriglyceridemia, the fructose-fed rat. Fructose feeding (10% fructose in drinking water for 2 weeks) induced hepatic lipogenesis and reduced peroxisome proliferator-activated receptor alpha (PPARalpha) expression and fatty acid oxidation. As a result, plasma and liver triglyceride and plasma apolipoprotein B (apoB) levels were increased. Atorvastatin, 5 and 30 mg/kg during 2 weeks, markedly reduced plasma triglyceride, but decreased apoB levels only at the highest dose tested (50%). Triglyceride biosynthetic enzymes and microsomal triglyceride transfer protein were unchanged, whereas liver PPARalpha, acyl-CoA oxidase, and carnitine palmitoyltransferase I mRNA levels (1.9-, 1.25-, and 3.4-fold, respectively) and hepatic fatty acid beta-oxidation activity (1.25-fold) were increased by atorvastatin at 30 mg/kg. Furthermore, hepatic triglyceride content (45%) and plasma nonesterified fatty acids (NEFAs) (49%) were reduced. These results show for the first time that liver triglyceride increase in fructose-fed rats is linked to decreased expression of PPARalpha, which is prevented by atorvastatin treatment. The increase in PPARalpha expression caused by atorvastatin was associated with reduced liver triglyceride and plasma NEFA levels.

  17. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study.

    PubMed

    Piazza, Gregory; Hohlfelder, Benjamin; Jaff, Michael R; Ouriel, Kenneth; Engelhardt, Tod C; Sterling, Keith M; Jones, Noah J; Gurley, John C; Bhatheja, Rohit; Kennedy, Robert J; Goswami, Nilesh; Natarajan, Kannan; Rundback, John; Sadiq, Immad R; Liu, Stephen K; Bhalla, Narinder; Raja, M Laiq; Weinstock, Barry S; Cynamon, Jacob; Elmasri, Fakhir F; Garcia, Mark J; Kumar, Mark; Ayerdi, Juan; Soukas, Peter; Kuo, William; Liu, Ping-Yu; Goldhaber, Samuel Z

    2015-08-24

    This study conducted a prospective, single-arm, multicenter trial to evaluate the safety and efficacy of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis, using the EkoSonic Endovascular System (EKOS, Bothell, Washington). Systemic fibrinolysis for acute pulmonary embolism (PE) reduces cardiovascular collapse but causes hemorrhagic stroke at a rate exceeding 2%. Eligible patients had a proximal PE and a right ventricular (RV)-to-left ventricular (LV) diameter ratio ≥0.9 on chest computed tomography (CT). We included 150 patients with acute massive (n = 31) or submassive (n = 119) PE. We used 24 mg of tissue-plasminogen activator (t-PA) administered either as 1 mg/h for 24 h with a unilateral catheter or 1 mg/h/catheter for 12 h with bilateral catheters. The primary safety outcome was major bleeding within 72 h of procedure initiation. The primary efficacy outcome was the change in the chest CT-measured RV/LV diameter ratio within 48 h of procedure initiation. Mean RV/LV diameter ratio decreased from baseline to 48 h post-procedure (1.55 vs. 1.13; mean difference, -0.42; p < 0.0001). Mean pulmonary artery systolic pressure (51.4 mm Hg vs. 36.9 mm Hg; p < 0.0001) and modified Miller Index score (22.5 vs. 15.8; p < 0.0001) also decreased post-procedure. One GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries)-defined severe bleed (groin hematoma with transient hypotension) and 16 GUSTO-defined moderate bleeding events occurred in 15 patients (10%). No patient experienced intracranial hemorrhage. Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis decreased RV dilation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and minimized intracranial hemorrhage in patients with acute massive and submassive PE. (A Prospective, Single-arm, Multi-center Trial of EkoSonic® Endovascular System and Activase for Treatment of Acute Pulmonary Embolism (PE) [SEATTLE II]; NCT

  18. Coagulation and fibrinolysis are in balance after moderate exercise in middle-aged participants.

    PubMed

    Menzel, Kathleen; Hilberg, Thomas

    2009-01-01

    Increased age is associated with a higher risk of thrombotic events. The aim of this study was to investigate the age-related changes in hemostasis before and after moderate exercise controlled by individual anaerobic threshold as recommended for rehabilitation training. In this study, 24 young (25 +/- 1 years) and 24 middle-aged healthy nonsmokers (48 +/- 1 years) underwent an individualized exercise test with 80% of individual anaerobic threshold (young individuals: 127 +/- 6 W; middle-aged individuals: 128 +/- 5 W; values are expressed as mean +/- standard error of mean) for 60 minutes. The blood samples were collected before and after the exercise. The age-related higher (P < or = .05) levels could be detected in factors II, VII, VIII, IX, XI, XII, prothrombin fragment 1+2, in tissue plasminogen activator antigen and activity, as well as in plasminogen. The relative exercise-induced increases in these parameters were similar in both groups, although beginning at a higher level for those in the middle-aged group.A statistically enhanced increase after exercise in the middle-aged group could be shown in prothrombin fragment 1+2 (young individuals: 98 +/- 6 to 102 +/- 6 pmol/L; middle-aged individuals: 138 +/- 7 to 156 +/- 8 pmol/L) and in thrombin-antithrombin complex (young individuals: 2.2 +/- 0.1 to 3.1 +/- 0.2 microg/L; middle-aged individuals: 2.4 +/- 0.3 to 3.9 +/- 0.6 microg/L); the latter only showing a tendency. The data show the age-related changes with a rise in blood coagulation and fibrinolysis in a healthy middle-aged group compared with younger participants. Moderate exercise leads to comparably relative increases in hemostatic parameters but starting at higher levels. However, the exercise-induced thrombin generation (prothrombin fragment 1+2) is enhanced in the middle-aged participants in comparison with younger participants, but may be compensated by a sufficient fibrinolysis, and therefore the hemostatic system remains in balance.

  19. Ruminal Infusions of Cobalt EDTA Modify Milk Fatty Acid Composition via Decreases in Fatty Acid Desaturation and Altered Gene Expression in the Mammary Gland of Lactating Cows.

    PubMed

    Leskinen, Heidi; Viitala, Sirja; Mutikainen, Mervi; Kairenius, Piia; Tapio, Ilma; Taponen, Juhani; Bernard, Laurence; Vilkki, Johanna; Shingfield, Kevin J

    2016-05-01

    Intravenous or ruminal infusion of lithium salt of cobalt EDTA (Co-EDTA) or cobalt-acetate alters milk fat composition in cattle, but the mechanisms involved are not known. The present study evaluated the effect of ruminal Co-EDTA infusion on milk FA composition, mammary lipid metabolism, and mammary lipogenic gene expression. For the experiment, 4 cows in midlactation and fitted with rumen cannulae were used in a 4 × 4 Latin square with 28-d periods. Co-EDTA was administered in the rumen to supply 0, 1.5, 3.0, or 4.5 g Co/d over an 18-d interval with a 10-d washout between experimental periods. Milk production was recorded daily, and milk FA composition was determined on alternate days. Mammary tissue was biopsied on day 16, and arteriovenous differences of circulating lipid fractions and FA uptake across the mammary gland were measured on day 18. Co-EDTA had no effect on intake, proportions of rumen volatile FA, or milk production but caused dose-dependent changes in milk FA composition. Alterations in milk fat composition were evident within 3 d of infusion and characterized by linear or quadratic decreases (P < 0.05) in FAs containing a cis-9 double bond, an increase in 4:0 and 16:0, and linear decreases in milk 8:0, 10:0, 12:0, and 14:0 concentrations. Co-EDTA progressively decreased (P < 0.05) the stearoyl-CoA desaturase (SCD)-catalyzed desaturation of FAs in the mammary gland by up to 72% but had no effect on mammary SCD1 mRNA or SCD protein abundance. Changes in milk FA composition were accompanied by altered expression of specific genes involved in de novo FA and triacylglycerol synthesis. Ruminal infusion of Co-EDTA alters milk FA composition in cattle via a mechanism that involves decreases in the desaturation of FAs synthesized de novo or extracted from blood and alterations in mammary lipogenic gene expression, without affecting milk fat yield. © 2016 American Society for Nutrition.

  20. Cinnamic acid-inhibited ribulose-1,5-bisphosphate carboxylase activity is mediated through decreased spermine and changes in the ratio of polyamines in cowpea.

    PubMed

    Huang, Xingxue; Bie, Zhilong

    2010-01-01

    This study investigated the effects of cinnamic acid (CA) on ribulose-1,5-bisphosphate carboxylase (RuBPC) activity and the endogenous polyamine levels of cowpea leaves. The results show that 0.1 mM CA treatment decreased photosynthetic rate (P(n)) and RuBPC activity, but it did not affect the maximal photochemical efficiency of PSII (F(v)/F(m)), the actual photochemical efficiency of PSII (PhiPSII), intercellular CO(2) concentration (C(i)), and relative chlorophyll content. These suggest that the decrease in P(n) is at least partially attributed to a lowered RuBPC activity. In addition, 0.1 mM CA treatment increased the putrescine (Put) level, but decreased spermidine (Spd) and spermine (Spm) levels, thereby reducing the (Spd+Spm)/Put (PAs) ratio in the leaves. The exogenous application of 1 mM Spd markedly reversed these CA-induced effects for polyamine and partially restored the PAs ratio and RuBPC activity in leaves. Methylglyoxal-bis (guanylhydrazone) (MGBG), which is an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), results in the inability of activated cells to synthesize Spd and exacerbates the negative effects induced by CA. The exogenous application of 1 mM D-arginine (D-Arg), which is an inhibitor of Put biosynthesis, decreased the levels of Put, but increased the PAs ratio and RuBPC activity in leaves. These results suggest that 0.1 mM CA inhibits RuBPC activity by decreasing the levels of endogenous free and perchloric acid soluble (PS) conjugated Spm, as well as the PAs ratio.

  1. Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction

    PubMed Central

    Liepinsh, E; Makrecka-Kuka, M; Kuka, J; Vilskersts, R; Makarova, E; Cirule, H; Loza, E; Lola, D; Grinberga, S; Pugovics, O; Kalvins, I; Dambrova, M

    2015-01-01

    Background and Purpose The important pathological consequences of ischaemic heart disease arise from the detrimental effects of the accumulation of long-chain acylcarnitines in the case of acute ischaemia-reperfusion. The aim of this study is to test whether decreasing the L-carnitine content represents an effective strategy to decrease accumulation of long-chain acylcarnitines and to reduce fatty acid oxidation in order to protect the heart against acute ischaemia–reperfusion injury. Key Results In this study, we used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (Methyl-GBB), which inhibits γ-butyrobetaine dioxygenase (IC50 3 μM) and organic cation transporter 2 (OCTN2, IC50 3 μM), and, in turn, decreases levels of L-carnitine and acylcarnitines in heart tissue. Methyl-GBB reduced both mitochondrial and peroxisomal palmitate oxidation rates by 44 and 53% respectively. In isolated hearts treated with Methyl-GBB, uptake and oxidation rates of labelled palmitate were decreased by 40%, while glucose oxidation was increased twofold. Methyl-GBB (5 or 20 mg·kg−1) decreased the infarct size by 45–48%. In vivo pretreatment with Methyl-GBB (20 mg·kg−1) attenuated the infarct size by 45% and improved 24 h survival of rats by 20–30%. Conclusions and Implications Reduction of L-carnitine and long-chain acylcarnitine content by the inhibition of OCTN2 represents an effective strategy to protect the heart against ischaemia–reperfusion-induced damage. Methyl-GBB treatment exerted cardioprotective effects and increased survival by limiting long-chain fatty acid oxidation and facilitating glucose metabolism. PMID:25363063

  2. Decreased fatty acid beta-oxidation in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase-deficient patients is associated with an increase in uncoupling protein-3.

    PubMed

    Russell, Aaron P; Schrauwen, Patrick; Somm, Emmanuel; Gastaldi, Giacomo; Hesselink, Matthijs K C; Schaart, Gert; Kornips, Esther; Lo, Sing Kai; Bufano, Daniela; Giacobino, Jean-Paul; Muzzin, Patrick; Ceccon, Mara; Angelini, Corrado; Vergani, Lodovica

    2003-12-01

    Riboflavin-responsive, multiple acylcoenzyme A dehydrogenase deficiency (RR-MAD), a lipid storage myopathy, is characterized by, among others, a decrease in fatty acid (FA) beta-oxidation capacity. Muscle uncoupling protein 3 (UCP3) is up-regulated under conditions that either increase the levels of circulating free FA and/or decrease FA beta-oxidation. Using a relatively large cohort of seven RR-MAD patients, we aimed to better characterize the metabolic disturbances of this disease and to explore the possibility that it might increase UCP3 expression. A battery of biochemical and molecular tests were performed, which demonstrated decreases in FA beta-oxidation and in the activities of respiratory chain complexes I and II. These metabolic alterations were associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All parameters were restored to control values after riboflavin treatment. We postulate that the up-regulation of UCP3 in RR-MAD is due to the accumulation of muscle FA/acylCoA. RR-MAD is an optimal model to support the hypothesis that UCP3 is involved in the outward translocation of an excess of FA from the mitochondria and to show that, in humans, the effects of FA on UCP3 expression are direct and independent of fatty acid beta-oxidation.

  3. Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp −/− mice[S

    PubMed Central

    Newberry, Elizabeth P.; Kennedy, Susan M.; Xie, Yan; Luo, Jianyang; Crooke, Rosanne M.; Graham, Mark J.; Fu, Jin; Piomelli, Daniele; Davidson, Nicholas O.

    2012-01-01

    The tissue-specific sources and regulated production of physiological signals that modulate food intake are incompletely understood. Previous work showed that L-Fabp−/− mice are protected against obesity and hepatic steatosis induced by a high-fat diet, findings at odds with an apparent obesity phenotype in a distinct line of aged L-Fabp−/− mice. Here we show that the lean phenotype in L-Fabp−/− mice is recapitulated in aged, chow-fed mice and correlates with alterations in hepatic, but not intestinal, fatty acid amide metabolism. L-Fabp−/− mice exhibited short-term changes in feeding behavior with decreased food intake, which was associated with reduced abundance of key signaling fatty acid ethanolamides, including oleoylethanolamide (OEA, an agonist of PPARα) and anandamide (AEA, an agonist of cannabinoid receptors), in the liver. These reductions were associated with increased expression and activity of hepatic fatty acid amide hydrolase-1, the enzyme that degrades both OEA and AEA. Moreover, L-Fabp−/− mice demonstrated attenuated responses to OEA administration, which was completely reversed with an enhanced response after administration of a nonhydrolyzable OEA analog. These findings demonstrate a role for L-Fabp in attenuating obesity and hepatic steatosis, and they suggest that hepatic fatty acid amide metabolism is altered in L-Fabp−/− mice. PMID:22327204

  4. Herbivore perception decreases photosynthetic carbon assimilation and reduces stomatal conductance by engaging 12-oxo-phytodienoic acid, mitogen-activated protein kinase 4 and cytokinin perception.

    PubMed

    Meza-Canales, Ivan D; Meldau, Stefan; Zavala, Jorge A; Baldwin, Ian T

    2017-07-01

    Herbivory-induced changes in photosynthesis have been documented in many plant species; however, the complexity of photosynthetic regulation and analysis has thwarted progress in understanding the mechanism involved, particularly those elicited by herbivore-specific elicitors. Here, we analysed the early photosynthetic gas exchange responses in Nicotiana attenuata plants after wounding and elicitation with Manduca sexta oral secretions and the pathways regulating these responses. Elicitation with M. sexta oral secretions rapidly decreased photosynthetic carbon assimilation (AC ) in treated and systemic (untreated, vascularly connected) leaves, which were associated with changes in stomatal conductance, rather than with changes in Rubisco activity and 1-5 ribulose-1,5-bisphosphate turnover. Phytohormone profiling and gas exchange analysis of oral secretion-elicited transgenic plants altered in phytohormone regulation, biosynthesis and perception, combined with micrografting techniques, revealed that the local photosynthetic responses were mediated by 12-oxo-phytodienoic acid, while the systemic responses involved interactions among jasmonates, cytokinins and abscisic acid signalling mediated by mitogen-activated protein kinase 4. The analysis also revealed a role for cytokinins interacting with mitogen-activated protein kinase 4 in CO2 -mediated stomatal regulation. Hence, oral secretions, while eliciting jasmonic acid-mediated defence responses, also elicit 12-oxo-phytodienoic acid-mediated changes in stomatal conductance and AC , an observation illustrating the complexity and economy of the signalling that regulates defence and carbon assimilation pathways in response to herbivore attack. © 2016 John Wiley & Sons Ltd.

  5. Schinus terebinthifolius Raddi extract and linoleic acid from Passiflora edulis synergistically decrease melanin synthesis in B16 cells and reconstituted epidermis.

    PubMed

    Jorge, A T S; Arroteia, K F; Santos, I A; Andres, E; Medina, S P H; Ferrari, C R; Lourenço, C B; Biaggio, R M T T; Moreira, P L

    2012-10-01

    Several treatments for skin whitening are available today, but few of them are completely adequate, especially owing to the carcinogenic potential attributed to classical drugs like hydroquinone, arbutin and kojic acid. To provide an alternative and safer technology for whitening, we developed two botanical compounds originated from Brazilian biodiversity, an extract of Schinus terebinthifolius Raddi and a linoleic acid fraction isolated from Passiflora edulis oil. The whitening effect of these compounds was assessed using biochemical assays and in vitro models including cellular assays and equivalent skin. The results showed that S. terebinthifolius Raddi extract is able to reduce the tyrosinase activity in vitro, and the combination of this extract with linoleic acid is able to decrease the level of melanin produced by B16 cells cultured with melanocyte-stimulating hormone. Furthermore, melanin was also reduced in human reconstituted epidermis (containing melanocytes) treated with the compounds. The combination of the compounds may provide a synergistic positive whitening effect rather than their isolated use. Finally, we demonstrated that the performance of these mixed compounds is comparable to classical molecules used for skin whitening, as kojic acid. This new natural mixture could be considered an alternative therapeutic agent for treating hyperpigmentation and an effective component in whitening cosmetics.

  6. Mutations in the Arabidopsis Lst8 and Raptor genes encoding partners of the TOR complex, or inhibition of TOR activity decrease abscisic acid (ABA) synthesis.

    PubMed

    Kravchenko, Alena; Citerne, Sylvie; Jéhanno, Isabelle; Bersimbaev, Rakhmetkazhi I; Veit, Bruce; Meyer, Christian; Leprince, Anne-Sophie

    2015-11-27

    The Target of Rapamycin (TOR) kinase regulates essential processes in plant growth and development by modulation of metabolism and translation in response to environmental signals. In this study, we show that abscisic acid (ABA) metabolism is also regulated by the TOR kinase. Indeed ABA hormone level strongly decreases in Lst8-1 and Raptor3g mutant lines as well as in wild-type (WT) Arabidopsis plants treated with AZD-8055, a TOR inhibitor. However the growth and germination of these lines are more sensitive to exogenous ABA. The diminished ABA hormone accumulation is correlated with lower transcript levels of ZEP, NCED3 and AAO3 biosynthetic enzymes, and higher transcript amount of the CYP707A2 gene encoding a key-enzyme in abscisic acid catabolism. These results suggest that the TOR signaling pathway is implicated in the regulation of ABA accumulation in Arabidopsis. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Decrease of acidity inside zymogen granules inhibits acetylcholine- or inositol trisphosphate-evoked cytosolic Ca2+ spiking in pancreatic acinar cells.

    PubMed

    Titievsky, A V; Takeo, T; Tepikin, A V; Petersen, O H

    1996-09-01

    In isolated pancreatic acinar cells application of the proton-potassium ionophore nigericin or the proton-sodium ionophore monensin led to a reduction of acidity inside the zymogen granules which could be visualized in an imaging system by a rapid reduction in the intragranular quinacrine fluorescence. Cytosolic Ca2+ spikes in response to acetylcholine stimulation or intracellular inositol trisphosphate application were assessed by recording Ca2+ -sensitive ionic currents in the patch clamp whole-cell recording configuration. Both nigericin and monensin evoked marked reductions in frequency and amplitude of spikes and in many experiments abolished spiking altogether. The Ca2+ -sensitive membrane currents could still be activated after nigericin or monensin treatment since subsequent application of the Ca2+ ionophore ionomycin evoked a large current response. The decrease in intragranular acidity would appear to inhibit intracellular Ca2+ release perhaps due to a reduction in the free intragranular Ca2+ concentration.

  8. Decrease of aquaporin-4 and excitatory amino acid transporter-2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV-associated neurocognitive disorders.

    PubMed

    Xing, Hui Qin; Zhang, Yu; Izumo, Kimiko; Arishima, Shiho; Kubota, Ryuji; Ye, Xiang; Xu, Qiping; Mori, Kazuyasu; Izumo, Shuji

    2017-02-01

    Human immunodeficiency virus (HIV) encephalitis and degeneration of cerebral cortex are established histopathologies of HIV-associated neurocognitive disorders (HAND). We previously reported decreased excitatory amino acid transporter-2 (EAAT-2) and astrocytic apoptosis in cortical degeneration using SIVmac239 and simian-human immunodeficiency virus (SHIV)-infected macaques and human AIDS autopsy cases. In the present study, we added highly pathogenic SIVsm543-3-infected macaques. These animals showed similar degenerative changes in the frontal cortex. Using 11 SIV-infected macaques, three SIVsm543-3, five SIVmac239 and three SHIV, we compared brain pathology caused by three different viruses and further analyzed the pathogenic process of HAND. We noticed vacuolar changes in perivascular processes of astrocytes by electron microscopy, and examined expression of astrocyte-specific protein aquaporin-4 (AQP4) by immunohistochemistry. APQ4 was diffusely positive in the neuropil and perivascular area in control brains. There was patchy or diffuse decrease of AQP4 staining in the neuropil of SIV-infected macaques, which was associated with EAAT-2 staining by double immunostaining. A quantitative analysis demonstrated significant positive correlation between areas of AQP4 and EAAT-2. Some astrocytes express EAAT-2 but not AQP4, and decrease of EAAT-2 expression tended to be less than the decrease of AQP4. Active-caspase-3 immunostaining demonstrated apoptosis of neurons and astrocytes in the area of AQP4/EAAT-2 reduction. These results suggest that AQP4 is damaged first and decrease of EAAT-2 may follow in pathogenesis of cortical degeneration. This is the first demonstration of decrease of AQP4 and its association with EAAT-2 decrease in AIDS brain, suggesting a role in the pathogenesis of HAND. © 2016 Japanese Society of Neuropathology.

  9. Carrot Juice Administration Decreases Liver Stearoyl-CoA Desaturase 1 and Improves Docosahexaenoic Acid Levels, but Not Steatosis in High Fructose Diet-Fed Weanling Wistar Rats

    PubMed Central

    Mahesh, Malleswarapu; Bharathi, Munugala; Reddy, Mooli Raja Gopal; Kumar, Manchiryala Sravan; Putcha, Uday Kumar; Vajreswari, Ayyalasomayajula; Jeyakumar, Shanmugam M.

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases associated with an altered lifestyle, besides genetic factors. The control and management of NAFLD mostly depend on lifestyle modifications, due to the lack of a specific therapeutic approach. In this context, we assessed the effect of carrot juice on the development of high fructose-induced hepatic steatosis. For this purpose, male weanling Wistar rats were divided into 4 groups, fed either a control (Con) or high fructose (HFr) diet of AIN93G composition, with or without carrot juice (CJ) for 8 weeks. At the end of the experimental period, plasma biochemical markers, such as triglycerides, alanine aminotransferase, and β-hydroxy butyrate levels were comparable among the 4 groups. Although, the liver injury marker, aspartate aminotransferase, levels in plasma showed a reduction, hepatic triglycerides levels were not significantly reduced by carrot juice ingestion in the HFr diet-fed rats (HFr-CJ). On the other hand, the key triglyceride synthesis pathway enzyme, hepatic stearoyl-CoA desaturase 1 (SCD1), expression at mRNA level was augmented by carrot juice ingestion, while their protein levels showed a significant reduction, which corroborated with decreased monounsaturated fatty acids (MUFA), particularly palmitoleic (C16:1) and oleic (C18:1) acids. Notably, it also improved the long chain n-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA; C22:6) content of the liver in HFr-CJ. In conclusion, carrot juice ingestion decreased the SCD1-mediated production of MUFA and improved DHA levels in liver, under high fructose diet-fed conditions. However, these changes did not significantly lower the hepatic triglyceride levels. PMID:27752492

  10. Probiotics decreased the bioavailability of the bile acid analog, monoketocholic acid, when coadministered with gliclazide, in healthy but not diabetic rats.

    PubMed

    Al-Salami, Hani; Butt, Grant; Tucker, Ian; Golocorbin-Kon, Svetlana; Mikov, Momir

    2012-06-01

    In recent studies we showed that gliclazide has no hypoglycemic effect on type 1 diabetic (T1D) rats while MKC does, and their combination exerted a better hypoglycemic effect than MKC alone. We also showed that the most hypoglycemic effect was noticed when T1D rats were treated with probiotics then gavaged with MKC + gliclazide (blood glucose decreased from 24 ± 3 to 10 ± 2 mmol/l). The aim of this study is to investigate the influence of probiotics on MKC pharmacokinetics when coadministered with gliclazide, in T1D rats. 80 male Wistar rats (weight 350 ± 50 g) were randomly allocated into 8 groups (10 rats/group), 4 of which were injected with alloxan (30 mg/kg) to induce T1D. Group 1 was healthy and group 2 was diabetic. Groups 3 (healthy) and 4 (diabetic) were gavaged with probiotics (75 mg/kg) every 12 h for 3 days and 12 h later all groups received a single oral dose of MKC + gliclazide (4 and 20 mg/kg respectively). The remaining 4 groups were treated in the same way but administered MKC + gliclazide via the i.v. route. Blood samples collected from T1D rats prior to MKC + gliclazide revealed that probiotic treatment alone reduced blood glucose levels twofold. When coadministered with gliclazide, the bioavailability of MKC was reduced in healthy rats treated with probiotics but remained the same in diabetic pretreated rats. The decrease in MKC bioavailability, when administered with gliclazide, caused by probiotic treatment in healthy but not diabetic rats suggests that probiotic treatment induced MKC metabolism or impaired its absorption, only in healthy animals. The different MKC bioavailability in healthy and diabetic rats could be explained by different induction of presystemic elimination of MKC in the gut by probiotic treatment.

  11. Suppression of Aflatoxin Biosynthesis in Aspergillus flavus by 2-Phenylethanol Is Associated with Stimulated Growth and Decreased Degradation of Branched-Chain Amino Acids.

    PubMed

    Chang, Perng-Kuang; Hua, Sui Sheng T; Sarreal, Siov Bouy L; Li, Robert W

    2015-09-24

    The saprophytic soil fungus Aspergillus flavus infects crops and produces aflatoxin. Pichia anomala, which is a biocontrol yeast and produces the major volatile 2-phenylethanol (2-PE), is able to reduce growth of A. flavus and aflatoxin production when applied onto pistachio trees. High levels of 2-PE are lethal to A. flavus and other fungi. However, at low levels, the underlying mechanism of 2-PE to inhibit aflatoxin production remains unclear. In this study, we characterized the temporal transcriptome response of A. flavus to 2-PE at a subinhibitory level (1 μL/mL) using RNA-Seq technology and bioinformatics tools. The treatment during the entire 72 h experimental period resulted in 131 of the total A. flavus 13,485 genes to be significantly impacted, of which 82 genes exhibited decreased expression. They included those encoding conidiation proteins and involved in cyclopiazonic acid biosynthesis. All genes in the aflatoxin gene cluster were also significantly decreased during the first 48 h treatment. Gene Ontology (GO) analyses showed that biological processes with GO terms related to catabolism of propionate and branched-chain amino acids (valine, leucine and isoleucine) were significantly enriched in the down-regulated gene group, while those associated with ribosome biogenesis, translation, and biosynthesis of α-amino acids OPEN ACCESS Toxins 2015, 7 3888 were over-represented among the up-regulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that metabolic pathways negatively impacted among the down-regulated genes parallel to those active at 30 °C, a condition conducive to aflatoxin biosynthesis. In contrast, metabolic pathways positively related to the up-regulated gene group resembled those at 37 °C, which favors rapid fungal growth and is inhibitory to aflatoxin biosynthesis. The results showed that 2-PE at a low level stimulated active growth of A. flavus but concomitantly rendered decreased activities in

  12. Activation of Markers of Inflammation, Coagulation and Fibrinolysis in Musculoskeletal Trauma

    PubMed Central

    Reikerås, Olav; Borgen, Pål

    2014-01-01

    Background Traumatic injury induces changes in mediators of inflammation and coagulation, but the pivotal roles of inflammation and coagulation has not been precisely clarified. Therefore we have studied markers of inflammation and coagulation after a standardized musculoskeletal trauma like total hip replacement surgery. Methods We allocated 21 patients aged 50 to 84 years who underwent total hip replacement surgery. Releases of TNF-α, IL-1β, IL-6, IL-8 and IL-10 and protrombin fragment F1.2 and plasmin-antiplasmin complex (PAP) were examined during surgery and up 6 days postoperatively, and systemic releases were compared to pre-operative values. Surgery induced significant increments in serum levels of IL-6 at 6 hours and at 1 day after surgery and in levels of IL-8 at 6 hours after surgery. There were no significant changes in serum levels of TNF-α, IL-1β or IL-10. There were significant increments in blood levels of F1.2 and PAP up to 6 days postoperatively with highest levels at 6 hours after surgery. There were only week correlations between IL-6 and IL-8 and F1.2 and PAP. Conclusion Major musculoskeletal surgery causes changes of the inflammatory, coagulatory and fibrinolytic cascades in stable patients, but with no correlations between inflammation and coagulation and fibrinolysis. PMID:25364904

  13. Hemostasis and fibrinolysis in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a systematic review

    PubMed Central

    Boluijt, Jacoline; Meijers, Joost CM; Rinkel, Gabriel JE; Vergouwen, Mervyn DI

    2015-01-01

    Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) has been associated with microthrombosis, which can result from activated hemostasis, inhibited fibrinolysis, or both. We systematically searched the PUBMED and EMBASE databases to identify hemostatic or fibrinolytic parameters that can be used for the prediction or diagnosis of DCI, or that inform on the pathogenesis of DCI and may serve as treatment targets. We included 24 studies that fulfilled predefined criteria and described 39 biomarkers. Only one study fulfilled predefined criteria for high quality. Since no parameter on admission was associated with DCI and in none of the included studies blood was drawn at the time of clinical deterioration, none of the studied parameters can presently be used for the prediction or diagnosis of DCI. Regarding the pathogenesis of DCI, it was shown that compared with patients without DCI those with DCI had higher levels of von Willebrand factor and platelet activating factor in plasma 5 to 9 days after aSAH, membrane tissue factor in cerebrospinal fluid 5 to 9 days after aSAH, and D-dimer in plasma 11 to 14 days after aSAH. Confirmation in high-quality studies is needed to investigate whether these parameters can serve as targets for new intervention studies. PMID:25690473

  14. Hemostasis and fibrinolysis in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a systematic review.

    PubMed

    Boluijt, Jacoline; Meijers, Joost C M; Rinkel, Gabriel J E; Vergouwen, Mervyn D I

    2015-05-01

    Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) has been associated with microthrombosis, which can result from activated hemostasis, inhibited fibrinolysis, or both. We systematically searched the PUBMED and EMBASE databases to identify hemostatic or fibrinolytic parameters that can be used for the prediction or diagnosis of DCI, or that inform on the pathogenesis of DCI and may serve as treatment targets. We included 24 studies that fulfilled predefined criteria and described 39 biomarkers. Only one study fulfilled predefined criteria for high quality. Since no parameter on admission was associated with DCI and in none of the included studies blood was drawn at the time of clinical deterioration, none of the studied parameters can presently be used for the prediction or diagnosis of DCI. Regarding the pathogenesis of DCI, it was shown that compared with patients without DCI those with DCI had higher levels of von Willebrand factor and platelet activating factor in plasma 5 to 9 days after aSAH, membrane tissue factor in cerebrospinal fluid 5 to 9 days after aSAH, and D-dimer in plasma 11 to 14 days after aSAH. Confirmation in high-quality studies is needed to investigate whether these parameters can serve as targets for new intervention studies.

  15. Sequentially combined estradiol valerate plus levonorgestrel therapy decreases 18:1 trans-fatty acid content of plasma lipids in healthy postmenopausal women.

    PubMed

    Jokela, Hannu; Kalela, Anne; Lilja, Mari; Salmi, Mia; Lehtimäki, Terho; Kunnas, Tarja; Teisala, Klaus; Punnonen, Reijo; Nikkari, Seppo T

    2005-12-01

    Trans-fatty acids (TFA) have been classified as atherogenic dietary constituents but the effect of hormone replacement therapy (HRT) on their concentrations is not known. We used a washout protocol to study the effect of long-term estrogen and combined estrogen-progestin HRT on plasma elaidate (18:1t), which is the trans isomer of oleate and the major TFA in the diet. The study group comprised 15 women receiving estradiol valerate HRT and 15 women receiving combined HRT with estradiol valerate and levonorgestrel. The concentrations of elaidate in plasma phospholipids, cholesteryl esters and triglycerides were determined by gas chromatography. At baseline, the total plasma elaidate concentration was lower in the combined HRT group than in the estradiol valerate HRT group (p < 0.01). In the combined HRT group, the concentration of elaidate increased significantly after withdrawal of HRT (p < 0.001) and decreased again to the baseline level after restart of therapy (p < 0.001). These changes were due to decreases in the concentrations of phospholipids and triglycerides; in phospholipids there was also a proportional decrease of elaidate. There were no changes in elaidate in women receiving estradiol valerate alone. Our results suggest that long-term combined HRT treatment decreases plasma TFA, which is not achieved by estrogen alone.

  16. Veno-occlusive disease in pediatric patients after hematopoietic stem cell transplantation: relevance of activated coagulation and fibrinolysis markers and natural anticoagulants.

    PubMed

    Jevtic, Dragana; Zecevic, Zeljko; Veljkovic, Dobrila; Dopsaj, Violeta; Radojicic, Zoran; Elezovic, Ivo

    2011-04-01

    Prediction of veno-occlusive disease (VOD), its precise diagnosis, and treatment have been the subject of various studies, but still remain unclear. Our goal was to investigate the levels of activated coagulation and fibrinolysis markers and natural anticoagulants in pediatric patients with VOD after hematopoietic stem cell transplantation (HSCT). We investigated 47 pediatric patients: 20 with neuroblastoma, 17 with leukemias, and 10 with lymphomas and measured the values of antithrombin (AT), protein C (PC), fibrinogen (FI), thrombin AT complex, prothrombin fragments 1+2 (F1+2), and D-dimer from day -7 to day +30 post-HSCT. Patients were monitored for the occurrence of VOD, and it occurred in 10 patients at a median post-HSCT day of 17.5 (range: 2 to 28 d). In the VOD group, at baseline the levels of FI were significantly lower, and on days +7 and +14 a relevant difference existed in F1+2 levels. The levels of PC were significantly lower on day +14. Logistic multivariate regression analysis between the groups showed significantly different D-dimer levels on day +14. On day +30, the levels of PC, AT, and F1+2 were different between these 2 groups of patients. The levels of D-dimer and F1+2 were increased, and PC and FI decreased before the clinical onset of VOD. The parameter differences may have a predictive value in VOD onset, which makes them candidates to be routinely monitored in patients after HSCT.

  17. Intracerebroventricular administration of α-ketoisocaproic acid decreases brain-derived neurotrophic factor and nerve growth factor levels in brain of young rats.

    PubMed

    Wisniewski, Miriam S W; Carvalho-Silva, Milena; Gomes, Lara M; Zapelini, Hugo G; Schuck, Patrícia F; Ferreira, Gustavo C; Scaini, Giselli; Streck, Emilio L

    2016-04-01

    Maple syrup urine disease (MSUD) is an inherited aminoacidopathy resulting from dysfunction of the branched-chain keto acid dehydrogenase complex, leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine as well as their corresponding transaminated branched-chain α-ketoacids. This disorder is clinically characterized by ketoacidosis, seizures, coma, psychomotor delay and mental retardation whose pathophysiology is not completely understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. However, the effect of accumulating α-ketoacids in MSUD on neurotrophic factors has not been investigated. Thus, the objective of the present study was to evaluate the effects of acute intracerebroventricular administration of α-ketoisocaproic acid (KIC) on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the brains of young male rats. Ours results showed that intracerebroventricular administration of KIC decreased BDNF levels in hippocampus, striatum and cerebral cortex, without induce a detectable change in pro-BDNF levels. Moreover, NGF levels in the hippocampus were reduced after intracerebroventricular administration of KIC. In conclusion, these data suggest that the effects of KIC on demyelination and memory processes may be mediated by reduced trophic support of BDNF and NGF. Moreover, lower levels of BDNF and NGF are consistent with the hypothesis that a deficit in this neurotrophic factor may contribute to the structural and functional alterations of brain underlying the psychopathology of MSUD, supporting the hypothesis of a neurodegenerative process in MSUD.

  18. UV decreases the synthesis of free fatty acids and triglycerides in the epidermis of human skin in vivo, contributing to development of skin photoaging.

    PubMed

    Kim, Eun Ju; Jin, Xing-Ji; Kim, Yeon Kyung; Oh, In Kyung; Kim, Ji Eun; Park, Chi-Hyun; Chung, Jin Ho

    2010-01-01

    Although fatty acids are known to be important in various skin functions, their roles on photoaging in human skin are poorly understood. We investigated the alteration of lipid metabolism in the epidermis by photoaging and acute UV irradiation in human skin. UV irradiated young volunteers (21-33 years, n=6) and elderly volunteers (70-75 years, n=7) skin samples were obtained by punch biopsy. Then the epidermis was separated from dermis and lipid metabolism was investigated. We observed that the amounts of free fatty acids (FFA) and triglycerides (TG) in the epidermis of photoaged or acutely UV irradiated human skin were significantly decreased. The expressions of genes related to lipid synthesis, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), sterol regulatory element binding proteins (SREBPs), and peroxisome proliferator-activated receptors (PPARgamma) were also markedly decreased. To elucidate the significance of these changes of epidermal lipids in human skin, we investigated the effects of TG or various inhibitors for the enzymes involved in TG synthesis on the expression of matrix metalloproteinase-1 (MMP-1) in cultured human epidermal keratinocytes. We demonstrated that triolein (TG) reduced basal and UV-induced MMP-1 mRNA expression. In addition, each inhibitor for various lipid synthesis enzymes, such as TOFA (ACC inhibitor), cerulenin (FAS inhibitor) and trans-10, cis-12-CLA (SCD inhibitor), increased the MMP-1 expression significantly in a dose-dependent manner. We also demonstrated that triolein could inhibit cerulenin-induced MMP-1 expression. Furthermore, topical application of triolein (10%) significantly prevented UV-induced MMP-13, COX-2, and IL-1beta expression in hairless mice. Our results suggest that TG and FFA may play important roles in photoaging of human skin. Copyright 2009 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  19. Dietary Caprylic Acid (C8:0) Does Not Increase Plasma Acylated Ghrelin but Decreases Plasma Unacylated Ghrelin in the Rat

    PubMed Central

    Lemarié, Fanny; Beauchamp, Erwan; Dayot, Stéphanie; Duby, Cécile; Legrand, Philippe; Rioux, Vincent

    2015-01-01

    Focusing on the caprylic acid (C8:0), this study aimed at investigating the discrepancy between the formerly described beneficial effects of dietary medium chain fatty acids on body weight loss and the C8:0 newly reported effect on food intake via ghrelin octanoylation. During 6 weeks, Sprague-Dawley male rats were fed with three dietary C8:0 levels (0, 8 and 21% of fatty acids) in three experimental conditions (moderate fat, caloric restriction and high fat). A specific dose-response enrichment of the stomach tissue C8:0 was observed as a function of dietary C8:0, supporting the hypothesis of an early preduodenal hydrolysis of medium chain triglycerides and a direct absorption at the gastric level. However, the octanoylated ghrelin concentration in the plasma was unchanged in spite of the increased C8:0 availability. A reproducible decrease in the plasma concentration of unacylated ghrelin was observed, which was consistent with a decrease in the stomach preproghrelin mRNA and stomach ghrelin expression. The concomitant decrease of the plasma unacylated ghrelin and the stability of its acylated form resulted in a significant increase in the acylated/total ghrelin ratio which had no effect on body weight gain or total dietary consumption. This enhanced ratio measured in rats consuming C8:0 was however suspected to increase (i) growth hormone (GH) secretion as an increase in the GH-dependent mRNA expression of the insulin like growth Factor 1 (IGF-1) was measured (ii) adipocyte diameters in subcutaneous adipose tissue without an increase in the fat pad mass. Altogether, these results show that daily feeding with diets containing C8:0 increased the C8:0 level in the stomach more than all the other tissues, affecting the acylated/total ghrelin plasma ratio by decreasing the concentration of circulating unacylated ghrelin. However, these modifications were not associated with increased body weight or food consumption. PMID:26196391

  20. Partial deletion of the αC-domain in the Fibrinogen Perth variant is associated with thrombosis, increased clot strength and delayed fibrinolysis.

    PubMed

    Westbury, Sarah K; Duval, Cédric; Philippou, Helen; Brown, Rebecca; Lee, Kurtis R; Murden, Sherina L; Phillips, Emma; Reilly-Stitt, Christopher; Whalley, Daniel; Ariëns, Robert A; Mumford, Andrew D

    2013-12-01

    Genetic fibrinogen (FGN) variants that are associated with bleeding or thrombosis may be informative about fibrin polymerisation, structure and fibrinolysis. We report a four generation family with thrombosis and heritable dysfibrinogenaemia segregating with a c.[1541delC];[=] variation in FGA (FGN-Perth). This deletion predicts a truncated FGN αC-domain with an unpaired terminal Cys at residue 517 of FGN-Aα. In keeping with this, SDS-PAGE of purified FGN-Perth identified a truncated FGN-Aα chain with increased co-purification of albumin, consistent with disulphide bonding to the terminal Cys of the variant FGN-Aα. Clot visco-elastic strength in whole blood containing FGN-Perth was greater than controls and tPA-mediated fibrinolysis was delayed. In FGN-Perth plasma and in purified FGN-Perth, there was markedly reduced final turbidity after thrombin-mediated clot generation. Consistent with this, FGN-Perth formed tighter, thinner fibrin fibres than controls indicating defective lateral aggregation of protofibrils. Clots generated with thrombin in FGN-Perth plasma were resistant to tPA-mediated fibrinolysis. FGN-Perth clot also displayed impaired tPA-mediated plasmin generation but incorporated α2-antiplasmin at a similar rate to control. Impaired fibrinolysis because of defective plasmin generation potentially explains the FGN-Perth clinical phenotype. These findings highlight the importance of the FGN αC-domain in the regulation of clot formation and fibrinolysis.

  1. Growth inhibition of fungus Phycomyces blakesleeanus by anion channel inhibitors anthracene-9-carboxylic and niflumic acid attained through decrease in cellular respiration and energy metabolites.

    PubMed

    Stanić, Marina; Križak, Strahinja; Jovanović, Mirna; Pajić, Tanja; Ćirić, Ana; Žižić, Milan; Zakrzewska, Joanna; Antić, Tijana Cvetić; Todorović, Nataša; Živić, Miroslav

    2017-03-01

    Increasing resistance of fungal strains to known fungicides has prompted identification of new candidates for fungicides among substances previously used for other purposes. We have tested the effects of known anion channel inhibitors anthracene-9-carboxylic acid (A9C) and niflumic acid (NFA) on growth, energy metabolism and anionic current of mycelium of fungus Phycomyces blakesleeanus. Both inhibitors significantly decreased growth and respiration of mycelium, but complete inhibition was only achieved by 100 and 500 µM NFA for growth and respiration, respectively. A9C had no effect on respiration of human NCI-H460 cell line and very little effect on cucumber root sprout clippings, which nominates this inhibitor for further investigation as a potential new fungicide. Effects of A9C and NFA on respiration of isolated mitochondria of P. blakesleeanus were significantly smaller, which indicates that their inhibitory effect on respiration of mycelium is indirect. NMR spectroscopy showed that both A9C and NFA decrease the levels of ATP and polyphosphates in the mycelium of P. blakesleeanus, but only A9C caused intracellular acidification. Outwardly rectifying, fast inactivating instantaneous anionic current (ORIC) was also reduced to 33±5 and 21±3 % of its pre-treatment size by A9C and NFA, respectively, but only in the absence of ATP. It can be assumed from our results that the regulation of ORIC is tightly linked to cellular energy metabolism in P. blakesleeanus, and the decrease in ATP and polyphosphate levels could be a direct cause of growth inhibition.

  2. Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes

    PubMed Central

    Hinder, Lucy M.; Vivekanandan-Giri, Anuradha; McLean, Lisa L.; Pennathur, Subramaniam; Feldman, Eva L.

    2013-01-01

    Diabetic neuropathy (DN) is the most common complication of diabetes and is characterized by distal-to-proximal loss of peripheral nerve axons. The idea of tissue-specific pathological alterations in energy metabolism in diabetic complications-prone tissues is emerging. Altered nerve metabolism in type 1 diabetes models is observed; however, therapeutic strategies based on these models offer limited efficacy to type 2 diabetic patients with DN. Therefore, understanding how peripheral nerves metabolically adapt to the unique type 2 diabetic environment is critical to develop disease-modifying treatments. In the current study, we utilized targeted LC/MS/MS to characterize the glycolytic and tricarboxylic acid (TCA) cycle metabolomes in sural nerve, sciatic nerve and dorsal root ganglia (DRG) from male type 2 diabetic mice (BKS.Cg-m+/+Leprdb; db/db) and controls (db/+). We report depletion of glycolytic intermediates in diabetic sural nerve and sciatic nerve (glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate (sural nerve only), 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, lactate), with no significant changes in DRG. Citrate and isocitrate TCA cycle intermediates were decreased in sural nerve, sciatic nerve and DRG from diabetic mice. Utilizing LC/ESI/MS/MS and HPLC methods, we also observed increased protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids, HODEs) in db/db tissue, with a proximal-to-distal increase in oxidative stress, with associated decreased aconitase enzyme activity. We propose a preliminary model, whereby the greater change in metabolomic profile, increase in oxidative stress, and decrease in TCA cycle enzyme activity may cause distal peripheral nerve to rely on truncated TCA cycle metabolism in the type 2 diabetes environment. PMID:23086140

  3. Exogenous abscisic acid application decreases cadmium accumulation in Arabidopsis plants, which is associated with the inhibition of IRT1-mediated cadmium uptake.

    PubMed

    Fan, Shi Kai; Fang, Xian Zhi; Guan, Mei Yan; Ye, Yi Quan; Lin, Xian Yong; Du, Shao Ting; Jin, Chong Wei

    2014-01-01

    Cadmium (Cd) contamination of agricultural soils is an increasingly serious problem. Measures need to be developed to minimize Cd entering the human food chain from contaminated soils. We report here that, under Cd exposure condition, application with low doses of (0.1-0.5 μM) abscisic acid (ABA) clearly inhibited Cd uptake by roots and decreased Cd level in Arabidopsis wild-type plants (Col-0). Expression of IRT1 in roots was also strongly inhibited by ABA treatment. Decrease in Cd uptake and the inhibition of IRT1 expression were clearly lesser pronounced in an ABA-insensitive double mutant snrk2.2/2.3 than in the Col-0 in response to ABA application. The ABA-decreased Cd uptake was found to correlate with the ABA-inhibited IRT1 expression in the roots of Col-0 plants fed two different levels of iron. Furthermore, the Cd upt