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Sample records for renin inhibition activity

  1. Vanadate-induced inhibition of renin secretion is unrelated to inhibition Na,K-ATPase activity

    Energy Technology Data Exchange (ETDEWEB)

    Churchill, P.C.; Rossi, N.F.; Churchill, M.C.; Ellis, V.R. (Wayne State Univ. School of Medicine, Detroit, MI (USA))

    1990-01-01

    There is evidence that three inhibitors of Na,K-ATPase activity-ouabain, K-free extracellular fluid, and vanadate--inhibit renin secretion by increasing Ca{sup 2+} concentration in juxtaglomerular cells, but in the case of vanadate, it is uncertain whether the increase in Ca{sup 2+} is due to a decrease in Ca{sup 2+} efflux or to an increase in Ca{sup 2+} influx through potential operated Ca channels. In the present experiments, the rat renal cortical slice preparation was used to compare and contrast the effects of ouabain, of K-free fluid, and of vanadate on renin secretion, in the absence and presence of methoxyverapamil, A Ca channel blocker. Basal renin secretory rate averaged 7.7 {plus minus} 0.3 GU/g/60 min, and secretory rate was reduced to nearly zero by 1 mM ouabain, by K-free fluid, by 0.5 mM vanadate, and by K-depolarization. Although 0.5 {mu}M methoxyverapamil completely blocked the inhibitory effect of K-depolarization, it failed to antagonize the inhibitory effects of ouabain, of K-free fluid, and of vanadate.

  2. Chronic renin inhibition lowers blood pressure and reduces upright muscle sympathetic nerve activity in hypertensive seniors

    Science.gov (United States)

    Okada, Yoshiyuki; Jarvis, Sara S; Best, Stuart A; Bivens, Tiffany B; Adams-Huet, Beverley; Levine, Benjamin D; Fu, Qi

    2013-01-01

    Cardiovascular risk remains high in patients with hypertension even with adequate blood pressure (BP) control. One possible mechanism may be sympathetic activation via the baroreflex. We tested the hypothesis that chronic inhibition of renin reduces BP without sympathetic activation, but diuresis augments sympathetic activity in elderly hypertensives. Fourteen patients with stage-I hypertension (66 ± 5 (SD) years) were treated with a direct renin inhibitor, aliskiren (n= 7), or a diuretic, hydrochlorothiazide (n= 7), for 6 months. Muscle sympathetic nerve activity (MSNA), BP, direct renin and aldosterone were measured during supine and a graded head-up tilt (HUT; 5 min 30° and 20 min 60°), before and after treatment. Sympathetic baroreflex sensitivity (BRS) was assessed. Both groups had similar BP reductions after treatment (all P < 0.01), while MSNA responses were different between hydrochlorothiazide and aliskiren (P= 0.006 pre/post × drug). Both supine and upright MSNA became greater after hydrochlorothiazide treatment (supine, 72 ± 18 post vs. 64 ± 15 bursts (100 beats)−1 pre; 60° HUT, 83 ± 10 vs. 78 ± 13 bursts (100 beats)−1; P= 0.002). After aliskiren treatment, supine MSNA remained unchanged (69 ± 13 vs. 64 ± 8 bursts (100 beats)−1), but upright MSNA was lower (74 ± 15 vs. 85 ± 10 bursts (100 beats)−1; P= 0.012 for pre/post × posture). Direct renin was greater after both treatments (both P < 0.05), while upright aldosterone was greater after hydrochlorothiazide only (P= 0.002). The change in upright MSNA by the treatment was correlated with the change of aldosterone (r= 0.74, P= 0.002). Upright sympathetic BRS remained unchanged after either treatment. Thus, chronic renin inhibition may reduce upright MSNA through suppressed renin activity, while diuresis may evoke sympathetic activation via the upregulated renin–angiotensin–aldosterone system, without changing intrinsic sympathetic baroreflex function in elderly hypertensive

  3. Direct renin inhibition in chronic kidney disease

    DEFF Research Database (Denmark)

    Persson, Frederik; Rossing, Peter; Parving, Hans-Henrik

    2013-01-01

    that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need....... In addition, combination treatment seemed safe and effective also in patients with impaired kidney function. These initial findings formed the basis for the design of a large morbidity and mortality trial investigating aliskiren as add-on to standard treatment. The study has just concluded, but was terminated...... early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic...

  4. Active immunization against renin in normotensive marmoset

    International Nuclear Information System (INIS)

    Michel, J.B.; Guettier, C.; Philippe, M.; Galen, F.X.; Corvol, P.; Menard, J.

    1987-01-01

    Primate renins (human and monkey) are very similar. We used pure human renin to immunize marmosets (Callithrix jacchus) and thereby produce a chronic blockade of the renin-angiotensinogen reaction. After a control period of 2 months, five male marmosets, on their usual sodium-poor diet, were immunized against pure human renin by three subcutneous injections of 30 μg each, with complete and then incomplete Freund's adjuvant. Three marmosets were injected with adjuvant only and served as controls. Blood sampling and blood pressure measurements were performed weekly. After the third injection, the five marmosets immunized against renin developed a high titer of renin antibodies (50% binding of 125 I-labeled human renin at a dilution of ≥ 1:10,000). The antibodies inhibited the enzymatic activity of both marmoset and human renins. At the same time, systolic blood pressure decreased significantly. Plasma renin enzyme activity was undetectable in the animals. Plasma aldosterone decreased significantly. After 1-4 months with low blood pressure, a normal urinary output, and a normal plasma creatinine, the five marmosets became sick and died within one month. At autopsy an immunological renal disease, characterize by the presence of immunoglobulin and macrophage infiltration colocalized with renin, was found. No immunoglobulin was detectable in extrarenal vessels or in other organs. These experiments demonstrate that, in this primate, a chronic blockade of the renin-angiotensin system can be achieved by active immunization against homologous renin, but this blockade is associated with the development of an autoimmune disease localized in the kidney

  5. Radioimmunoassay for plasma renin activity

    International Nuclear Information System (INIS)

    1975-01-01

    A radioimmunoassay for the determination of renin activity in blood plasma is described. The plasma sample is mixed with a generator buffer solution also containing an inhibitor for enzymes which convert angiotensin I into other substances. The renin in the plasma sample converts angiotensinogen into angiotensin I. The amount of angiotensin I is then measured with a competitive binding method using 125 I-labelled angiotensin I and antibodies to angiotensin I

  6. Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes

    DEFF Research Database (Denmark)

    Persson, F; Rossing, P; Schjoedt, K J

    2008-01-01

    Inhibition of renin with an active site inhibitor, aliskiren, lowers blood pressure (BP) in diabetic patients. Here, we studied the time course of the antihypertensive and antiproteinuric effect of renin inhibition in 15 patients with type 2 diabetes and elevated urinary albumin/creatinine ratios...

  7. Influence of Aging on Plasma Renin Activity

    International Nuclear Information System (INIS)

    Cho, K. W.; Kim, S. H.; Kang, S. K.; Choi, H. Y.

    1982-01-01

    Influence of aging on plasma renin activity was evaluated in healthy normotensive subjects(age range 21-63 years, 413 males) devoid of cardiorenal or endocrinological problems. The age-related decrease of plasma renin activity in the subjects between 21-28 years group and 36-42 years group was slight, but over the 43 years groups was significantly different. The age-related suppression of plasma renin activity was much more smooth and continuous all over the age ranges evaluated. The sexual difference in plasma renin activity was noticed between the subjects of 22 years old group (34 males) and 19 years group (34 females) (p<0.003). The data suggest that the age-related suppression of plasma renin activity appeared in healthy normotensive subjects should be considered in the case of evaluation of low renin essential hypertension.

  8. Direct renin inhibition — a new way of targeting the renin system

    Directory of Open Access Journals (Sweden)

    Morris J Brown

    2006-06-01

    Full Text Available The renin system plays a key role in the pathology of hypertension and is influenced, both directly and indirectly, by most antihypertensive agents. The system is the target of several established classes of antihypertensive agents including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers. Of currently available drugs, only the beta-blockers suppress renin secretion, but these also reduce heart rate and cardiac output. Calcium channel blockers and diuretics cause a modest activation of the renin system secondary to the fall in renal afferent arteriolar pressure and reduction in filtered sodium load. Aliskiren is the first orally available direct inhibitor that blocks the renin system at its rate limiting step and is shown to reduce angiotensin I and II and plasma renin activity.

  9. Plasma Renin Activity in Diabetes Mellitus

    International Nuclear Information System (INIS)

    Pyo, Heui Jung; Park Jung Sik; Kim, Sung Kwon; Choi, Kang Won; Lee, Jung Sang; Lee, Mun Ho

    1979-01-01

    To evaluate the renin-angiotensin-aldosterone system in diabetes mellitus, basal plasma renin activity (PRA) and its response to intravenous furosemide were determined in 40 diabetic subjects. The diabetics were divided into 4 groups according to the presence of nephropathy and/or hypertension. Uncomplicated diabetics (Group I) were taken as control group and the results of the other groups were compared to this group. In diabetics with nephropathy alone (Group II), and with nephropathy and hypertension (Group III), basal PRA values were 0.63±0.59 ng/ml/hr., and 0.79±0.62 ng/ml/hr., respectively, both significantly lower than control group. (1.53±1.09 ng/ml/hr.). (p<0.05) In both of the above groups, the responses to intravenous furosemide tended to be blunted. On the other hand, in diabetics, with hypertension only (Group IV), the basal and stimulated PRA were not significantly different from control. Above results suggests that nephropathy may be one of the factors which suppress renin activity in diabetes mellitus

  10. Plasma Renin Activity in Diabetes Mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Pyo, Heui Jung; Sik, Park Jung; Kim, Sung Kwon; Choi, Kang Won; Lee, Jung Sang; Lee, Mun Ho [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1979-03-15

    To evaluate the renin-angiotensin-aldosterone system in diabetes mellitus, basal plasma renin activity (PRA) and its response to intravenous furosemide were determined in 40 diabetic subjects. The diabetics were divided into 4 groups according to the presence of nephropathy and/or hypertension. Uncomplicated diabetics (Group I) were taken as control group and the results of the other groups were compared to this group. In diabetics with nephropathy alone (Group II), and with nephropathy and hypertension (Group III), basal PRA values were 0.63+-0.59 ng/ml/hr., and 0.79+-0.62 ng/ml/hr., respectively, both significantly lower than control group. (1.53+-1.09 ng/ml/hr.). (p<0.05) In both of the above groups, the responses to intravenous furosemide tended to be blunted. On the other hand, in diabetics, with hypertension only (Group IV), the basal and stimulated PRA were not significantly different from control. Above results suggests that nephropathy may be one of the factors which suppress renin activity in diabetes mellitus

  11. Plasma renin activity profile in normal and hypertensive Filipinos

    International Nuclear Information System (INIS)

    Guevara, R.; Torres, J. Jr.; Abundo, H.P.; Perez, A.P.

    To establish a base line profile of plasma renin activity in normotensive and hypertensive Filipinos, 1.019 cases, 479 males and 540 females with an age range 14 - 89 years (mean - 46 + -20) were studied at the Santo Tomas University Hospital of various life styles from the Metro-Manila area, 248 comprised the normotensive group (male - 122 or 49.2 %, female 126 or 50.8 %) and 771 were hypertensive. Of these, 711 (92.6 %) has essential hypertension and are presented in this report. Plasma Renin Activity was determined by radioimmunoassay using Dainabot Renin-Ricket. Concurrent 24 hr. urine sodium and potassium were determined. Nomograms of plasma renin activity as related to urine sodium excretion were drawn after computerized statistical analysis of data. The normal mean value of plasma renin activity was found to be 1.64 + - 0.81 ng./ml./hr. in the upright position and 1.15 + - .68 ng./ml./hr. in the supine position. Based on the nomogram derived, the values obtained in the 711 cases of essential hypertension were classified into High Renin - 14.3 % Normal Renin - 56.1 % and Low Renin - 29.6 %. This study establishes normal levels of plasma renin activity as well as define and classify same renin activity among hypertensive Filipinos, a useful and practicable guide for treatment and can be of prognostic significance. (author)

  12. Iminopyrimidinones: A novel pharmacophore for the development of orally active renin inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    McKittrick, Brian A.; Caldwell, John P.; Bara, Thomas; Boykow, George; Chintala, Madhu; Clader, John; Czarniecki, Michael; Courneya, Brandy; Duffy, Ruth; Fleming, Linda; Giessert, Rachel; Greenlee, William J.; Heap, Charles; Hong, Liwu; Huang, Ying; Iserloh, Ulrich; Josien, Hubert; Khan, Tanweer; Korfmacher, Walter; Liang, Xian; Mazzola, Robert; Mitra, Soumya; Moore, Kristina; Orth, Peter; Rajagopalan, Murali; Roy, Sudipta; Sakwa, Samuel; Strickland, Corey; Vaccaro, Henry; Voigt, Johannes; Wang, Hongwu; Wong, Jesse; Zhang, Rumin; Zych, Andrew (Merck); (Albany MR)

    2015-04-01

    The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.

  13. Effect of additive renin inhibition with aliskiren on renal blood flow in patients with Chronic Heart Failure and Renal Dysfunction (Additive Renin Inhibition with Aliskiren on renal blood flow and Neurohormonal Activation in patients with Chronic Heart Failure and Renal Dysfunction).

    Science.gov (United States)

    Schroten, Nicolas F; Damman, Kevin; Hemmelder, Marc H; Voors, Adriaan A; Navis, Gerjan; Gaillard, Carlo A J M; van Veldhuisen, Dirk J; Van Gilst, Wiek H; Hillege, Hans L

    2015-05-01

    We examined the effect of the renin inhibitor, aliskiren, on renal blood flow (RBF) in patients with heart failure with reduced ejection fraction (HFREF) and decreased glomerular filtration rate (GFR). Renal blood flow is the main determinant of GFR in HFREF patients. Both reduced GFR and RBF are associated with increased mortality. Aliskiren can provide additional renin-angiotensin-aldosterone system inhibition and increases RBF in healthy individuals. Patients with left ventricular ejection fraction ≤45% and estimated GFR 30 to 75 mL/min per 1.73 m(2) on optimal medical therapy were randomized 2:1 to receive aliskiren 300 mg once daily or placebo. Renal blood flow and GFR were measured using radioactive-labeled (125)I-iothalamate and (131)I-hippuran at baseline and 26 weeks. After 41 patients were included, the trial was halted based on an interim safety analysis showing futility. Mean age was 68 ± 9 years, 82% male, GFR (49 ± 16 mL/min per 1.73 m(2)), RBF (294 ± 77 mL/min per 1.73 m(2)), and NT-proBNP 999 (435-2040) pg/mL. There was a nonsignificant change in RBF after 26 weeks in the aliskiren group compared with placebo (-7.1 ± 30 vs +14 ± 54 mL/min per 1.73 m(2); P = .16). However, GFR decreased significantly in the aliskiren group compared with placebo (-2.8 ± 6.0 vs +4.4 ± 9.6 mL/min per 1.73 m(2); P = .01) as did filtration fraction (-2.2 ± 3.3 vs +1.1 ± 3.1%; P = .01). There were no significant differences in plasma aldosterone, NT-proBNP, urinary tubular markers, or adverse events. Plasma renin activity was markedly reduced in the aliskiren group versus placebo throughout the treatment phase (P = .007). Adding aliskiren on top of optimal HFREF medical therapy did not improve RBF and was associated with a reduction of GFR and filtration fraction. Copyright © 2015 Mosby, Inc. All rights reserved.

  14. Plasma Renin Activity in Children with Protein Energy Malnutrition ...

    African Journals Online (AJOL)

    Plasma renin activity was measured by bio-assay in 100 children with kwashiorkor and in 20 healthy children, and also by radio-immunoassay in another 26 children with kwashiorkor and in another 20 healthy children. Both methods showed that (compared with healthy children) renin activity was significantly increased in ...

  15. Calcium channel blocker prevents stress-induced activation of renin and aldosterone in conscious pig

    International Nuclear Information System (INIS)

    Ceremuzynski, L.K.; Klos, J.; Barcikowski, B.; Herbaczynska-Cedro, K.

    1991-01-01

    A considerable amount of data suggest the involvement of calcium-mediated processes in the activation of the renin-angiotensin-aldosterone (RAA) cascade. To investigate the effect of calcium-channel inhibition on the RAA system, the authors studied 21 conscious pigs. Blood renin and aldosterone levels increased by subjecting animals to 24 hours of immobilization stress. Renin and aldosterone levels were repeatedly measured by radioimmunoassay in blood samples taken periodically over 24 hours from a chronically implanted arterial cannula. Pretreatment of the animals (N = 11) with nisoldipine, 2 x 20 mg p.o. daily for 2 days before and on the day of immobilization, transiently attenuated the stress-induced increase of plasma renin activity and completely prevented the rise of aldosterone, as compared to nontreated controls (N = 10). The finding that nisoldipine suppresses RAA activation induced by a nonpharmacologic stimulus in the conscious intact animal may have clinical implications

  16. Prevention of atrial fibrillation by Renin-Angiotensin system inhibition a meta-analysis

    DEFF Research Database (Denmark)

    Schneider, Markus; Hua, Tsushung A; Böhm, Michael

    2010-01-01

    The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective.......The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective....

  17. A Study on Plasma Renin Activity in Essential Hypertension

    International Nuclear Information System (INIS)

    Choe, Kang Won; Lee, Jung Sang; Cho, Bo Yeon; Koh, Chang Soon; Lee, Mun Ho

    1975-01-01

    Radioimmunoassay for the measurement of plasma renin activity (PRA) was performed in 43 normal Koreans and 45 patients with essential hypertension. Plasma samples were drawn in supine position in the morning and after upright posture for 4 hours. Urinary sodium excretion rates were measured in the concurrent 24 hour urine samples, an index of their sodium balance. The results were as follows: 1) There was an inverse correlation between 24 hr sodium excretion and PRA. The normal values of PRA in supine position ranged from 1.0 to 7.0 ng/ml/hr. when 24 hour sodium excretion were between 50 to 150 mEq. PRA in elderly tended to be low. 2) When stimulated by 4 hour upright posture, PRA increased by 2.6 times from the baseline value. 3) Of the 45 patients with essential hypertension, PRA was low in 10 cases (22.2%), normal in 28 cases (62.2%), and high in 7 cases (15.6%). 4) In the normal and high renin groups, who tended to be younger in ages, mean diastolic blood pressure and BUN were higher than in low renin group. Though hypertensive retinopathy and left ventricular hypertrophy in ECG were more prevalent in the former, no significant differences were noted as in the case of serum cholesterol. 5) There were 8 cases of cardiovascular complications (7 with cerebral vascular accident, 1 with myocardial infarction); 3 in low renin group (30%), 2 in normal renin (7.1%) and 3 in higher renin group (42.9%). This figure indicated higher rate of cardiovascular complications in higher renin groups, and lower rate in normal renin group. But the incidence of the complication was not significantly low in low renin group.

  18. Active renin mass concentration to determine aldosterone-to-renin ratio in screening for primary aldosteronism

    Directory of Open Access Journals (Sweden)

    Corbin F

    2011-07-01

    Full Text Available François Corbin1, Pierre Douville2, Marcel Lebel3 1Division of Biochemistry, l'Université de Sherbrooke, Sherbrooke, Quebec, Canada; 2Division of Biochemistry; 3Division of Nephrology, L'Hôtel-Dieu de Québec Hospital and l'Université Laval, Quebec, CanadaBackground: Active renin mass concentration (ARC is independent of the endogenous level of angiotensinogen, and less variable and more reproducible than plasma renin activity. Reference values for the aldosterone-to-renin ratio (ARR using ARC are still undefined. The objective of the present study was to determine the threshold of ARR using ARC measurement to screen for primary aldosteronism.Methods: A total of 211 subjects were included in the study, comprising 78 healthy normotensive controls, 95 patients with essential hypertension, and 38 patients with confirmed primary aldosteronism (20 with surgery-confirmed aldosterone-producing adenoma and 18 with idiopathic adrenal hyperplasia. Blood samples were drawn from ambulatory patients and volunteers in the mid-morning without specific dietary restriction for measuring plasma aldosterone concentration, ARC, and serum potassium.Results: Most normotensive controls and essential hypertension patients had ARR results below 100 pmol/ng, a value which corresponded to 3.3 times the median of these two groups.Conclusion: Patients with ARR values above this level should be considered for further investigation (confirmatory tests or for repeat testing should ARR values be borderline. This study indicates that ARC can be used reliably in determining ARR for primary aldosteronism screening.Keywords: primary aldosteronism, active renin mass concentration, aldosterone-to-renin ratio

  19. The renin-angiotensin system in malignant hypertension revisited: plasma renin activity, microangiopathic hemolysis, and renal failure in malignant hypertension

    NARCIS (Netherlands)

    van den Born, Bert-Jan H.; Koopmans, Richard P.; van Montfrans, Gert A.

    2007-01-01

    BACKGROUND: Malignant hypertension is a renin-dependent form of hypertension. However, the variations in renin-angiotensin system (RAS) activation in malignant hypertension are not completely understood. A proposed mechanism for ongoing RAS activation is the presence of microangiopathic hemolysis

  20. Increased activity of digoxin-like substance in low-renin hypertension in acromegaly

    Energy Technology Data Exchange (ETDEWEB)

    Soszynski, P.; Slowinska-Srzednicka, J.; Zgliczynski, S. (Medical Center for Postgraduate Education, Warsaw (Poland))

    1990-01-01

    Arterial hypertension is common in acromegaly, but the pathogenesis of this complication remains unknown. To determine the role of an endogenous Na,K pump inhibitor/digoxin-like substance (DLS) in the pathogenesis of hypertension in acromegaly 76 subjects: 28 with acromegaly, 20 with essential hypertension and 28 healthy controls were studied. Serum DLS was measured with the use of radioimmunoassay and bioassay by the inhibition of digoxin-sensitive erythrocyte 86-Rb uptake. In acromegaly, the activity of DLS was significantly increased and plasma renin activity decreased in the hypertensive group, as compared with that of the normotensive group and controls. Moreover, DLS was elevated in the low-renin group of essential hypertension, as compared with that of the normal/high-renin group or controls. The activity of DLS correlated positively with mean arterial pressure and negatively with plasma renin activity, but not with growth hormone levels. In conclusion, an endogenous sodium pump inhibitor/digoxin-like substance may play a role in the pathogenesis of low-renin hypertension in acromegaly.

  1. Increased activity of digoxin-like substance in low-renin hypertension in acromegaly

    International Nuclear Information System (INIS)

    Soszynski, P.; Slowinska-Srzednicka, J.; Zgliczynski, S.

    1990-01-01

    Arterial hypertension is common in acromegaly, but the pathogenesis of this complication remains unknown. To determine the role of an endogenous Na,K pump inhibitor/digoxin-like substance (DLS) in the pathogenesis of hypertension in acromegaly 76 subjects: 28 with acromegaly, 20 with essential hypertension and 28 healthy controls were studied. Serum DLS was measured with the use of radioimmunoassay and bioassay by the inhibition of digoxin-sensitive erythrocyte 86-Rb uptake. In acromegaly, the activity of DLS was significantly increased and plasma renin activity decreased in the hypertensive group, as compared with that of the normotensive group and controls. Moreover, DLS was elevated in the low-renin group of essential hypertension, as compared with that of the normal/high-renin group or controls. The activity of DLS correlated positively with mean arterial pressure and negatively with plasma renin activity, but not with growth hormone levels. In conclusion, an endogenous sodium pump inhibitor/digoxin-like substance may play a role in the pathogenesis of low-renin hypertension in acromegaly

  2. Hyperpotassemia and bradycardia in a bedridden elderly woman with selective hypoaldosteronism associated with low renin activity.

    Science.gov (United States)

    Inada, Mitsuo; Iwasaki, Keiko; Imai, Chihiro; Hashimoto, Satoshi

    2010-01-01

    A bedridden 85-year-old woman had hyperpotassemia (7.7 mEq/L) and bradycardia (30/min). Endocrinologic findings revealed a decrease in the renin-aldosterone system and normal adrenoglucocorticoid function. The results were consistent with the abnormalities seen in selective hypoaldosteronism with low renin activity. In addition, 9 of 11 patients, selected randomly from 72 bedridden elderly patients with normal serum sodium and potassium levels in our hospital, had diminished plasma renin activity (PRA) and plasma aldosterone concentration (PAC). The present patient was prescribed nonsteroidal anti-inflammatory drug (NSAID). NSAID reduces renal potassium excretion through the inhibition of renal prostaglandin synthesis. Therefore, the use of NSAID in bedridden elderly patients might intensify the underlying asymptomatic hypoaldosteronism and cause life-threatening hyperpotassemia.

  3. Interleukin-1 inhibits renin gene expression in As4.1 cells but not in native juxtaglomerular cells

    DEFF Research Database (Denmark)

    Jensen, B L; Lehle, U; Müller, Maja

    1998-01-01

    ) cells and in the mouse tumor cell line As4.1, which expresses renin mRNA. Renin mRNA levels and secretion of active renin were not significantly changed by IL-1beta in native JG cells. Activation of adenylyl cyclase by forskolin increased renin secretion and renin mRNA levels three- and fivefold......, respectively. These stimulatory responses to forskolin were not altered by IL-1beta. In contrast to native JG cells, renin mRNA abundance was markedly suppressed by IL-1beta in As4.1 cells, whereas secretion of active renin and the stability of renin mRNA were not changed. In As4.1 cells forskolin did...... not change renin secretion or renin mRNA abundance in the absence or in the presence of IL-1beta. These findings suggest that IL-1beta has no direct influence on renin secretion and renin mRNA abundance at the level of native JG cells....

  4. Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure

    NARCIS (Netherlands)

    D. Westermann (Dirk); A. Riad (Alexander); O. Lettau (Olga); A.J.M. Roks (Anton); K. Sawatis (Konstantinos); P.M. Becher (Peter Moritz); F. Escher (Felicitas); A.H.J. Danser (Jan); H.P. Schultheiss (Heinz-Peter); C. Tschöpe (Carsten)

    2008-01-01

    textabstractPharmacological renin inhibition with aliskiren is an effective antihypertensive drug treatment, but it is currently unknown whether aliskiren is able to attenuate cardiac failure independent of its blood pressure-lowering effects. We investigated the effect of aliskiren on cardiac

  5. Blockade of chloride channels by DIDS stimulates renin release and inhibits contraction of afferent arterioles

    DEFF Research Database (Denmark)

    Jensen, B L; Skøtt, O

    1996-01-01

    or without ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid] and DIDS were not additive. In the absence of chloride, basal renin release was suppressed and the stimulatory effect of DIDS was abolished. The DIDS-induced enhancement of renin release was not dependent on bicarbonate....... Norepinephrine (5 x 10(-7)-1 x 10(-6) M) and angiotensin II (1 x 10(-8)-10(-6) M) evoked reversible and dose-dependent contractions of microperfused rabbit afferent arterioles. DIDS (0.5 mM) did not affect the basal diameter of the arterioles but strongly inhibited the response to angiotensin II and attenuated...

  6. Plasma renin activity in patients with ischaemic heart disease

    International Nuclear Information System (INIS)

    Urbanek, J.; Hofman, O.; Reisenauer, R.; Slaby, A.

    1977-01-01

    Plasma renin activity (PRA) stimulated by upright posture was measured in 300 men aged 45-64 years using a radioimmunoassay of angiotensin-I. The examined subjects were normotensive or patients with benign essential hypertension and were divided into 6 groups according to the absence of manifest atherosclerosis, the presence of definite angina pectoris or a history of myocardial infarction. Each group contained 50 unselected subjects, with a comparable mean age. Significant differences in mean PRA were found between corresponding groups of hypertensives and normotensives, the values in hypertensives being lower. The percentage of low renin values was higher in hypertensives with ischaemic heart disease than in other groups. It is suggested that this finding might be explained by functional disturbances in the kidneys in hypertensives with ischaemic heart disease. (orig.) [de

  7. Plasma renin activity in patients with ischaemic heart disease

    Energy Technology Data Exchange (ETDEWEB)

    Urbanek, J; Hofman, O; Reisenauer, R; Slaby, A [Karlova Universita, Prague (Czechoslovakia). Inst. of Biophysics and Nuclear Medicine; Karlova Universita, Prague (Czechoslovakia). IV. Dept. of Internal Medicine; Vyzkumny Ustav Endokrinologicky, Prague [Czechoslovakia

    1977-04-01

    Plasma renin activity (PRA) stimulated by upright posture was measured in 300 men aged 45 to 64 years using a radioimmunoassay of angiotensin-I. The examined subjects were normotensive or patients with benign essential hypertension and were divided into 6 groups according to the absence of manifest atherosclerosis, the presence of definite angina pectoris or a history of myocardial infarction. Each group contained 50 unselected subjects, with a comparable mean age. Significant differences in mean PRA were found between corresponding groups of hypertensives and normotensives, the values in hypertensives being lower. The percentage of low renin values was higher in hypertensives with ischaemic heart disease than in other groups. It is suggested that this finding might be explained by functional disturbances in the kidneys in hypertensives with ischaemic heart disease.

  8. Effect of additive renin inhibition with aliskiren on renal blood flow in patients with Chronic Heart Failure and Renal Dysfunction (Additive Renin Inhibition with Aliskiren on renal blood flow and Neurohormonal Activation in patients with Chronic Heart Failure and Renal Dysfunction)

    NARCIS (Netherlands)

    Schroten, Nicolas F.; Damman, Kevin; Hemmelder, Marc H.; Voors, Adriaan A.; Navis, Gerjan; Gaillard, Carlo A. J. M.; van Veldhuisen, Dirk J.; van Gilst, Wiek H.; Hillege, Hans L.

    AIMS: We examined the effect of the renin inhibitor, aliskiren, on renal blood flow (RBF) in patients with heart failure with reduced ejection fraction (HFREF) and decreased glomerular filtration rate (GFR). Renal blood flow is the main determinant of GFR in HFREF patients. Both reduced GFR and RBF

  9. Neuronal nitric oxide synthase supports Renin release during sodium restriction through inhibition of phosphodiesterase 3

    DEFF Research Database (Denmark)

    Sällström, Johan; Jensen, Boye L; Skøtt, Ole

    2010-01-01

    NOS supports renin release by cyclic guanosine monophosphate (cGMP)-mediated inhibition of cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase 3 (PDE3) in juxtaglomerular (JG) cells. METHODS: The experiments were performed in conscious nNOS⁻(/)⁻ and wild types after 10 days on a low-sodium diet...... by measurements of inulin- and para-amino hippuric acid (PAH) clearances, respectively. RESULTS: The basal PRC was reduced in nNOS⁻(/)⁻ compared to the wild types. Administration of milrinone caused a more pronounced PRC increase in nNOS⁻(/)⁻, resulting in normalized renin levels, whereas PDE5 inhibition did...... not affect PRC in any genotype. The blood pressure was similar in both genotypes, and milrinone did not affect blood pressure compared to vehicle. GFR and RPF were similar at baseline and were reduced by milrinone. CONCLUSIONS: The present study provides in vivo evidence supporting the view that NO...

  10. Impact of glycaemic control on the effect of direct renin inhibition in the AVOID study

    DEFF Research Database (Denmark)

    Persson, Frederik; Lewis, Julia B; Lewis, Edmund J

    2012-01-01

    Hyperglycaemia induces development and progression of microvascular complications in diabetes. A direct link between high glucose levels and intrarenal renin-angiotensin activation has been demonstrated. This post-hoc analysis assessed the influence of baseline glycaemic control on the reduction ...

  11. Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells

    Directory of Open Access Journals (Sweden)

    Andrade A.Q.

    2002-01-01

    Full Text Available Renin is an enzyme involved in the stepwise generation of angiotensin II. Juxtaglomerular cells are the main source of plasma renin, but renin activity has been detected in other cell types. In the present study we evaluated the presence of renin mRNA in adult male Wistar rat and mouse (C-57 Black/6 mesangial cells (MC and their ability to process, store and release both the active and inactive forms of the enzyme. Active renin and total renin content obtained after trypsin treatment were estimated by angiotensinogen consumption analyzed by SDS-PAGE electrophoresis and quantified by angiotensin I generation by HPLC. Renin mRNA, detected by RT-PCR, was present in both rat and mouse MC under basal conditions. Active renin was significantly higher (P<0.05 in the cell lysate (43.5 ± 5.7 ng h-1 10(6 cells than in the culture medium (12.5 ± 2.5 ng h-1 10(6 cells. Inactive prorenin content was similar for the intra- and extracellular compartments (9.7 ± 3.1 and 3.9 ± 0.9 ng h-1 10(6 cells. Free active renin was the predominant form found in both cell compartments. These results indicate that MC in culture are able to synthesize and translate renin mRNA probably as inactive prorenin which is mostly processed to active renin inside the cell. MC secrete both forms of the enzyme but at a lower level compared with intracellular content, suggesting that the main role of renin synthesized by MC may be the intracellular generation of angiotensin II.

  12. A Study on Plasma Renin Activity in Korean Hemorrhagic Fever

    International Nuclear Information System (INIS)

    Kim, Suhng Gwon; Cho, Bo Yun; Lee, Jung Sang; Koh, Won Soon; Lee, Mun Ho; Kim, Won Dong; Yun, Hong Jin

    1976-01-01

    To evaluate the possible pathophysiologic role of renin in acute renal failure observed in Korean hemorrhagic fever (KHF), the author measured the basal plasma renin activity (PRA) and the stimulated PRA by radioimmunoassay for angiotensin I in 15 normal controls and 42 KHF patients who are admitted in Seoul National University Hospital and Nation Army Hospital from Jan. 1975 to Jan. 1976. The results obtained were as follows:The mean basal PRA in normal control group was 2.9±2.16 ng/ml/hr in the patients during the oliguric phase of KHF, the mean basal PRA was 4.7±2.13 ng/ml/hr, and there was statistically significant increase compared to the normal control. In the patients during the diuretic phase of KHF, the mean basal PRA was 3.4±2.09 ng/ml/hr, and there was statistically significant decrease compared to the oliguric phase of KHF. In normal control group, the mean basal PRA was 2.9±2.16 ng/ml/hr. And the PRA 1 hour after the administration of Lasix 40 mg intravenously (stimulated PRA) was 5.3±2.20 ng/ml/hr and there was statistically significant increase compared to basal level. In oliguric phase of KHF, the mean basal PRA was 4.6±2.01 ng/ml/hr. And stimulated PRA was 4.4±2.34 ng/ml/hr and there was no significant changes. In diuretic phase of KHF, the mean basal PR was 3.3±1.86 ng/ml/hr. And stimulated PRA was 5.2±2.58 ng/ml/hr and there was statistically significant increase compared to basal level. There were statistically no significant correlations between basal PRA and stimulated PRA and serum creatinine. BUN, urine volume and peritoneal dialysis.

  13. Effects of long-term inhibition of neuronal nitric oxide synthase on blood pressure and renin release

    DEFF Research Database (Denmark)

    Ollerstam, A.; Skøtt, O.; Ek, J.

    2001-01-01

    Nitric oxide (NO) produced by neuronal NO-synthase (nNOS) in macula densa cells may be involved in the control of renin release. 7-Nitro indazole (7-NI) inhibits nNOS, and we investigated the effect of short- (4 days) and long-term (4 weeks) 7-NI treatment on blood pressure (BP), plasma renin...... LS rats (107 +/- 15 vs. 56 +/- 1 mGU mL(-1)). Stimulation of PRC in LS rats was further enhanced by 7-NI after 4 days of treatment, but not affected in rats treated for 4 weeks. This suggests that inhibition of nNOS stimulates renin release but that this stimulatory effect in the long run might...

  14. Renin release

    DEFF Research Database (Denmark)

    Schweda, Frank; Friis, Ulla; Wagner, Charlotte

    2007-01-01

    in the walls of renal afferent arterioles at the entrance of the glomerular capillary network. It has been known for a long time that renin synthesis and secretion are stimulated by the sympathetic nerves and the prostaglandins and are inhibited in negative feedback loops by angiotensin II, high blood pressure...

  15. Peptides and neurotransmitters that affect renin secretion

    Science.gov (United States)

    Ganong, W. F.; Porter, J. P.; Bahnson, T. D.; Said, S. I.

    1984-01-01

    Substance P inhibits renin secretion. This polypeptide is a transmitter in primary afferent neurons and is released from the peripheral as well as the central portions of these neurons. It is present in afferent nerves from the kidneys. Neuropeptide Y, which is a cotransmitter with norepinephrine and epinephrine, is found in sympathetic neurons that are closely associated with and presumably innervate the juxtagolmerular cells. Its effect on renin secretion is unknown, but it produces renal vasoconstriction and natriuresis. Vasoactive intestinal polypeptide (VIP) is a cotransmitter with acetylocholine in cholinergic neurons, and this polypeptide stimulates renin secretion. We cannot find any evidence for its occurence in neurons in the kidneys, but various stimuli increase plasma VIP to levels comparable to those produced by doses of exogenous VIP which stimulated renin secretion. Neostigmine increases plasma VIP and plasma renin activity, and the VIP appears to be responsible for the increase in renin secretion, since the increase is not blocked by renal denervation or propranolol. Stimulation of various areas in the brain produces sympathetically mediated increases in plasma renin activity associated with increases in blood pressure. However, there is pharmacological evidence that the renin response can be separated from the blood pressure response. In anaesthetized dogs, drugs that increase central serotonergic discharge increase renin secretion without increasing blood pressure. In rats, activation of sertonergic neurons in the dorsal raphe nucleus increases renin secretion by a pathway that projects from this nucleus to the ventral hypothalamus, and from there to the kidneys via the sympathetic nervous system. The serotonin releasing drug parachloramphetamine also increases plasma VIP, but VIP does not appear to be the primary mediator of the renin response. There is preliminary evidence that the serotonergic neurons in the dorsal raphe nucleus are part of the

  16. Effect of Diuresis on Plasma Renin Activity and Aldosterone Concentration in Normal and Toxemic Pregnancy

    Energy Technology Data Exchange (ETDEWEB)

    Sung, H. K.; Lee, H. S.; Cho, S. S.; Koh, J. H.; Lee, J. K.; Kim, H. S. [Korea Atomic Emergy Research Institute, Seoul (Korea, Republic of)

    1973-03-15

    The changes of plasma renin activity, aldosterone concentration, serum sodium, and potassium levels were studied before and after the water loading followed by diuretics injection. The materials were: 13 non-, 11 normal-, and 11 toxemic pregnancy cases. The plasma renin activity and aldosterone concentration of the cord and postpartum blood were also measured. Following were the results: 1. The plasma renin activity was elevated significantly in normal pregnancy, and slightly in toxemic pregnancy. The serum sodium levels were decreased in pregnancy. 2. The plasma aldosterone concentration was slightly decreased in normal pregnancy, and slightly increased in toxemic pregnancy, however, statistically insignificant. 3. The plasma renin activity of the cord and postpartum blood were lower than those of pregnancy cases. 4. The changes of plasma renin activity after the diuretic administration showed an initial increase, which recovered within 2 hours. These changes were the least in normal pregnancy, and the most in toxemic pregnancy. 5. The changes of plasma aldosterone concentration after the diuretic administration were similar to those of plasma renin activity, although the variations were not so wide.

  17. Effect of Diuresis on Plasma Renin Activity and Aldosterone Concentration in Normal and Toxemic Pregnancy

    International Nuclear Information System (INIS)

    Sung, H. K.; Lee, H. S.; Cho, S. S.; Koh, J. H.; Lee, J. K.; Kim, H. S.

    1973-01-01

    The changes of plasma renin activity, aldosterone concentration, serum sodium, and potassium levels were studied before and after the water loading followed by diuretics injection. The materials were: 13 non-, 11 normal-, and 11 toxemic pregnancy cases. The plasma renin activity and aldosterone concentration of the cord and postpartum blood were also measured. Following were the results: 1. The plasma renin activity was elevated significantly in normal pregnancy, and slightly in toxemic pregnancy. The serum sodium levels were decreased in pregnancy. 2. The plasma aldosterone concentration was slightly decreased in normal pregnancy, and slightly increased in toxemic pregnancy, however, statistically insignificant. 3. The plasma renin activity of the cord and postpartum blood were lower than those of pregnancy cases. 4. The changes of plasma renin activity after the diuretic administration showed an initial increase, which recovered within 2 hours. These changes were the least in normal pregnancy, and the most in toxemic pregnancy. 5. The changes of plasma aldosterone concentration after the diuretic administration were similar to those of plasma renin activity, although the variations were not so wide.

  18. Urinary renin and angiotensinogen in type 2 diabetes

    DEFF Research Database (Denmark)

    Persson, Frederik; Lu, Xifeng; Rossing, Peter

    2013-01-01

    Urinary levels of renin-angiotensin-aldosterone system (RAAS) components may reflect renal RAAS activity and/or the renal efficacy of RAAS inhibition. Our aim was to determine whether urinary angiotensinogen and renin are circulating RAAS-independent markers during RAAS blockade.......Urinary levels of renin-angiotensin-aldosterone system (RAAS) components may reflect renal RAAS activity and/or the renal efficacy of RAAS inhibition. Our aim was to determine whether urinary angiotensinogen and renin are circulating RAAS-independent markers during RAAS blockade....

  19. Cortisol-induced inhibition of ovine renin and aldosterone responses to hypotension

    International Nuclear Information System (INIS)

    Wood, C.E.; Silbiger, J.

    1987-01-01

    Previous studies from this laboratory have demonstrated that in preterm fetal sheep increases in plasma cortisol (F) concentration equal in amplitude to fetal F stress responses suppress plasma renin activity (PRA). The purpose of this study was to investigate the possibility that this negative interaction exists in adult sheep. Cortisol was measured by radioimmunoassay. Five conscious ewes with chronically prepared carotid arterial loops were infused intravenously with F or vehicle for 5 h. One hour after the end of F or vehicle infusion, renin secretion was stimulated by hypotension produced by infusion of sodium nitroprusside. F infusion increased plasma F; during vehicle infusion plasma F did not change. F infusion decreased hematocrit from 29 +/- 2 to 26 +/- 1%. Basal PRA in vehicle- and F-infused groups were 0.4 +/- 0 and 0.2 +/- 0.1 ng angiotensin I-ml -1 -h -1 and did not change. In vehicle-infused ewes, PRA increased from 0.4 +/- 0 to 4.6 +/- 0.4 and plasma aldosterone from 26.0 +/- 1.0 to 173.1 +/- 21.8 pg/ml, while in F-infused ewes, PRA increased from 0.2 +/- 1 to 3.3 +/- 0.4 ng angiotensin I-ml -1 -h -1 and aldosterone from 25.0 +/- 0 to 48.2 +/- 23.2 pg/ml, significantly smaller responses. These results suggest that repeated stress may modulate the responses of the renin-angiotensin system in this species

  20. Control plasma renin activity and changes in sympathetic tone as determinants of minoxidil-induced increase in plasma renin activity.

    Science.gov (United States)

    O'Malley, K; Velasco, M; Wells, J; McNay, J L

    1975-01-01

    A study was made of the possible mechanism(s) underlying minoxidil-induced increase in plasma renin activity (PRA). 10 patients with essential hypertension were treated with minoxidil and subsequently with a combination of minoxidil plus propranolol. Minoxidil lowered mean arterial pressure 31.6 plus or minus 3.3 mm Hg, mean plus or minus SEM. There was an associated increase in both PRA, 6.26 plus or minus 2.43 NG/ML/H, and heart rate, 21.4 plus or minus 2.7 beats/min. The changes in PRA and heart rate were positively correlated, r, 0.79. Addition of propranolol reduced mean arterial pressure by a further 10.1 plus or minus 1.5 mm Hg and returned heart rate to control levels. Propranolol reduced PRA significantly but not to control levels. Control PRA positively correlated with PRA on minoxidil, r, 0.97, and with PRA on minoxidil plus propranolol, r, 0.98. We conclude that control PRA is a major determinant of change in PRA with minoxidil. Minoxidil increased PRA by at least two mechanisms: (a) an adrenergic mechanism closely related to change in heart rate and blocked by propranolol, and (b) a mechanism(s) not sensitive to propranolol and possibly related to decrease in renal perfusion pressure. PMID:1127099

  1. Renal hemodynamics and renin-angiotensin system activity in humans with multifocal renal artery fibromuscular dysplasia.

    Science.gov (United States)

    van Twist, Daan J L; Houben, Alphons J H M; de Haan, Michiel W; de Leeuw, Peter W; Kroon, Abraham A

    2016-06-01

    Fibromuscular dysplasia (FMD) is the second most common cause of renovascular hypertension. Nonetheless, knowledge on the renal microvasculature and renin-angiotensin system (RAS) activity in kidneys with FMD is scarce. Given the fairly good results of revascularization, we hypothesized that the renal microvasculature and RAS are relatively spared in kidneys with FMD. In 58 hypertensive patients with multifocal renal artery FMD (off medication) and 116 matched controls with essential hypertension, we measured renal blood flow (Xenon washout method) per kidney and drew blood samples from the aorta and both renal veins to determine renin secretion and glomerular filtration rate per kidney. We found that renal blood flow and glomerular filtration rate in FMD were comparable to those in controls. Although systemic renin levels were somewhat higher in FMD, renal renin secretion was not elevated. Moreover, in patients with unilateral FMD, no differences between the affected and unaffected kidney were observed with regard to renal blood flow, glomerular filtration rate, or renin secretion. In men, renin levels and renin secretion were higher as compared with women. The renal blood flow response to RAS modulation (by intrarenal infusion of angiotensin II, angiotensin-(1-7), an angiotensin II type 1 receptor blocker, or a nitric oxide synthase blocker) was also comparable between FMD and controls. Renal blood flow, glomerular filtration, and the response to vasoactive substances in kidneys with multifocal FMD are comparable to patients with essential hypertension, suggesting that microvascular function is relatively spared. Renin secretion was not increased and the response to RAS modulation was not affected in kidneys with FMD.

  2. Pharmacokinetic/Pharmacodynamic Modeling of Renin-Angiotensin Aldosterone Biomarkers Following Angiotensin-Converting Enzyme (ACE) Inhibition Therapy with Benazepril in Dogs.

    Science.gov (United States)

    Mochel, Jonathan P; Fink, Martin; Peyrou, Mathieu; Soubret, Antoine; Giraudel, Jérôme M; Danhof, Meindert

    2015-06-01

    The objective of this research was to provide a comprehensive description of the effect of benazepril on the dynamics of the renin-angiotensin aldosterone system (RAAS) in dogs. Blood specimens for renin activity (RA), angiotensin II (AII), and aldosterone (ALD) quantitation in plasma were drawn from 12 healthy adult beagle dogs randomly allocated to 2 treatment groups: (i) benazepril 5 mg PO, q24 h (n: 6) and (ii) placebo (n: 6), in a cross-over design. A mechanism-based pharmacokinetic/pharmacodynamic model, which includes the periodic nature of RA, AII, and ALD during placebo treatment and the subsequent changes in dynamics following repeated dosing with benazepril, was developed. The disposition kinetics of benazepril active metabolite, benazeprilat, was characterized using a saturable binding model to the angiotensin converting enzyme. The modulatory effect of benazeprilat on the RAAS was described using a combination of immediate response models. Our data show that benazepril noticeably influences the dynamics of the renin cascade, resulting in a substantial decrease in AII and ALD, while increasing RA throughout the observation span. The model provides a quantitative framework for better understanding the effect of ACE inhibition on the dynamics of the systemic RAAS in dogs.

  3. Combination inhibition of the renin-angiotensin system: is more better?

    Science.gov (United States)

    Krause, Michelle W; Fonseca, Vivian A; Shah, Sudhir V

    2011-08-01

    Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are considered the standard of care for treatment of cardiovascular disease and chronic kidney disease. Combination therapy with both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers effectively inhibits the renin-angiotensin system as well as potentiates the vasodilatory effects of bradykinin. It has been advocated that this dual blockade approach theoretically should result in improved clinical outcomes in both cardiovascular disease and chronic kidney disease. Clinical trial evidence for the use of combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in cardiovascular disease has provided conflicting results in hypertension, congestive heart failure, and ischemic heart disease. Clinical trial evidence to support combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chronic kidney disease has largely been based on proteinuria reduction as a surrogate marker for clinically meaningful outcomes. Recent large-scale randomized clinical trials have not been able to validate protection in halting progression in chronic kidney disease with a dual blockade approach. This review serves as an appraisal on the clinical evidence of combination angiotensin-converting enzyme inhibition and angiotensin II receptor blockade in both cardiovascular disease and chronic kidney disease.

  4. Activity assays and immunoassays for plasma Renin and prorenin: information provided and precautions necessary for accurate measurement

    DEFF Research Database (Denmark)

    Campbell, Duncan J; Nussberger, Juerg; Stowasser, Michael

    2009-01-01

    into focus the differences in information provided by activity assays and immunoassays for renin and prorenin measurement and has drawn attention to the need for precautions to ensure their accurate measurement. CONTENT: Renin activity assays and immunoassays provide related but different information...... provided by these assays and of the precautions necessary to ensure their accuracy....

  5. The adipose renin-angiotensin system modulates sysemic markers of insulin sensitivity activates the intrarenal renin-angiotensin system

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Suyeon [University of Tennessee, Knoxville (UTK); Soltani-Bejnood, Morvarid [University of Tennessee, Knoxville (UTK); Quignard-Boulange, Annie [Centre Biomedical des Cordeliers, Paris, France; Massiera, Florence [Centre de Biochimie, Nice, France; Teboul, Michele [Centre de Biochimie, Nice, France; Ailhaud, Gerard [Centre de Biochimie, Nice, France; Kim, Jung [University of Tennessee, Knoxville (UTK); Moustaid-Moussa, Naima [University of Tennessee, Knoxville (UTK); Voy, Brynn H [ORNL

    2006-07-01

    BACKGROUND: A growing body of data provides increasing evidence that the adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass. Beyond its paracrine actions within adipose tissue, adipocyte-derived angiotensin II (Ang II) may also impact systemic functions such as blood pressure and metabolism. METHODS AND RESULTS: We used a genetic approach to manipulate adipose RAS activity in mice and then study the consequences on metabolic parameters and on feedback regulation of the RAS. The models included deletion of the angiotensinogen (Agt) gene (Agt-KO), its expression solely in adipose tissue under the control of an adipocyte-specific promoter (aP2-Agt/ Agt-KO), and overexpression in adipose tissue of wild type mice (aP2-Agt). Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. Overexpression of Agt in adipose tissue resulted in increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also markedly elevated in kidney of aP2-Agt mice, suggesting that hypertension in these animals may be in part due to stimulation of the intrarenal RAS. CONCLUSIONS: Taken together, the results from this study demonstrate that alterations in adipose RAS activity significantly alter both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.

  6. Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells

    DEFF Research Database (Denmark)

    Desch, Michael; Schreiber, Andrea; Schweda, Frank

    2010-01-01

    We recently found that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome proliferator-activated receptor (PPAR)gamma stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARgamma. The mouse re...

  7. ANGIOTONIN-ACTIVATOR, RENIN- AND ANGIOTONIN-INHIBITOR, AND THE MECHANISM OF ANGIOTONIN TACHYPHYLAXIS IN NORMAL, HYPERTENSIVE, AND NEPHRECTOMIZED ANIMALS.

    Science.gov (United States)

    Page, I H; Helmer, O M

    1940-03-31

    1. Angiotonin does not exert its vasoconstrictor effect in the absence of a substance contained in red blood cells and serum which we have called "angiotonin-activator." A fraction has been separated from blood in which angiotonin-activator is concentrated. It contains little or no reninactivator. 2. Repeated intravenous injections of angiotonin into animals causes the pressor response gradually to lessen and finally to disappear (the phenomenon of tachyphylaxis), but much more slowly than when renin is injected. When the response to angiotonin is abolished, renin also fails to act. Large doses of renin reduce and finally abolish the responsiveness to angiotonin. Exhaustion of renin-activator in the blood abolishes the response to renin without abolishing the response to angiotonin. 3. Blood from animals made tachyphylactic by infusion of angiotonin contains greatly reduced amounts of angiotonin-activator. An inhibitor also appears in the blood. 4. Bilateral nephrectomy prolongs and greatly enhances the rise of arterial pressure following injection of angiotonin and renin. The enhancement reaches a maximum in from 24 to 30 hours after operation. Blood from these animals exhibits greatly increased ability to activate angiotonin and renin when tested in isolated perfused organs. Large amounts of angiotonin are required to reduce the amount of activator in their blood. Renin-activator is simultaneously but little affected. 5. Tranfusion of blood from an animal made tachyphylactic to angiotonin into a nephrectomized dog reduces the response of the latter to angiotonin. Angiotonin when added to the blood of the recipient of the transfusion and perfused through a rabbit's ear also exhibits greatly reduced vasoconstrictor action. 6. Transfusion of normal blood in large amounts into nephrectomized or hypertensive dogs reduces the recipient's response to renin. If renintachyphylaxis is established in the donor, transfusion abolishes the response to renin in the recipient

  8. Control of the renal renin system by local factors

    DEFF Research Database (Denmark)

    Wagner, C; Jensen, B L; Krämer, B K

    1998-01-01

    prostanoid, both stimulate renin secretion and renin gene expression by activating cAMP formation in JG cells. Although the direct effect of NO on JG cells is less clear, its overall effect in vivo seems to be to stimulate the renin system. Evidence is emerging that stimulation by NO is related to the c......AMP pathway, and cGMP-induced inhibition of cAMP-phosphodiesterase III (PDE-III) may mediate this effect. ETs, on the other hand, appear to inhibit the renin system, in particular in those pathways activated by cAMP, acting via Ca2+- and protein kinase C-related mechanisms. There is increasing evidence...... that both NO and PGs could be involved in the physiological regulatory mechanisms by which salt intake affects the renin system....

  9. Interaction of renin-angiotensin system and adenosine monophosphate-activated protein kinase signaling pathway in renal carcinogenesis of uninephrectomized rats.

    Science.gov (United States)

    Yang, Ke-Ke; Sui, Yi; Zhou, Hui-Rong; Zhao, Hai-Lu

    2017-05-01

    Renin-angiotensin system and adenosine monophosphate-activated protein kinase signaling pathway both play important roles in carcinogenesis, but the interplay of renin-angiotensin system and adenosine monophosphate-activated protein kinase in carcinogenesis is not clear. In this study, we researched the interaction of renin-angiotensin system and adenosine monophosphate-activated protein kinase in renal carcinogenesis of uninephrectomized rats. A total of 96 rats were stratified into four groups: sham, uninephrectomized, and uninephrectomized treated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Renal adenosine monophosphate-activated protein kinase and its downstream molecule acetyl coenzyme A carboxylase were detected by immunohistochemistry and western blot at 10 months after uninephrectomy. Meanwhile, we examined renal carcinogenesis by histological transformation and expressions of Ki67 and mutant p53. During the study, fasting lipid profiles were detected dynamically at 3, 6, 8, and 10 months. The results indicated that adenosine monophosphate-activated protein kinase expression in uninephrectomized rats showed 36.8% reduction by immunohistochemistry and 89.73% reduction by western blot. Inversely, acetyl coenzyme A carboxylase expression increased 83.3% and 19.07% in parallel to hyperlipidemia at 6, 8, and 10 months. The histopathology of carcinogenesis in remnant kidneys was manifested by atypical proliferation and carcinoma in situ, as well as increased expressions of Ki67 and mutant p53. Intervention with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker significantly prevented the inhibition of adenosine monophosphate-activated protein kinase signaling pathway and renal carcinogenesis in uninephrectomized rats. In conclusion, the novel findings suggest that uninephrectomy-induced disturbance in adenosine monophosphate-activated protein kinase signaling pathway resulted in hyperlipidemia and

  10. Inhibition of calcineurin phosphatase promotes exocytosis of renin from juxtaglomerular cells

    DEFF Research Database (Denmark)

    Madsen, Kirsten; Friis, Ulla Glenert; Gooch, Jennifer L

    2010-01-01

    . Simultaneous exposure to EGTA and CsA had no additive effect. The protein kinase A (PKA) blocker RpcAMPs had no effect on the CsA-induced increase in membrane capacitance. Intra- and extracellular application of tacrolimus did not alter membrane capacitance. A calmodulin antagonist (calmidazolium) and Cs...... after CsA treatment of the A-alpha knockout, while renin mRNA was suppressed. We conclude that calcineurin and calcium/calmodulin suppress exocytosis of renin from juxtaglomerular cells independent of PKA....

  11. Plasma volume, osmolality, vasopressin, and renin activity during graded exercise in man

    Science.gov (United States)

    Convertino, V. A.; Keil, L. C.; Bernauer, E. M.; Greenleaf, J. E.

    1981-01-01

    The influence of work intensity on plasma volume, osmolality, vasopressin and renin activity and the interrelationships between these responses are investigated. Plasma volume, renin activity and osmotic, sodium and arginine vasopressin concentrations were measured in venous blood samples taken from 15 healthy male subjects before and after six minutes of bicycle ergometer exercise at 100, 175 and 225 W. Plasma volume is found to decrease significantly with increasing work intensity, while increases in Na(+) concentration, osmolality and vasopressin are only observed to be significant when the work intensity exceeds 40% maximal aerobic capacity and plasma resin activity increased linearly at all work levels. In addition, significant correlations are observed between plasma volume and osmolality and sodium changes, and between vasopressin and osmolality and sodium content changes. Data thus support the hypotheses that (1) vasopressin may be the primary controlling endocrine for fluid and electrolyte levels following exercise; (2) an exercise intensity greater than 40% maximal aerobic capacity is required to stimulate vasopressin release through changes in plasma osmolality; and (3) the stimulation of the renin-angiotensin system is a more general stress response.

  12. Plasma renin activity, aldosterone and catecholamine levels when swimming and running.

    Science.gov (United States)

    Guezennec, C Y; Defer, G; Cazorla, G; Sabathier, C; Lhoste, F

    1986-01-01

    The purpose of this study was to determine the response of plasma renin activity (PRA), plasma aldosterone concentration (PAC) and catecholamines to two graded exercises differing by posture. Seven male subjects (19-25 years) performed successively a running rest on a treadmill and a swimming test in a 50-m swimming pool. Each exercise was increased in severity in 5-min steps with intervals of 1 min. Oxygen consumption, heart rate and blood lactate, measured every 5 min, showed a similar progression in energy expenditure until exhaustion, but there was a shorter time to exhaustion in the last step of the running test. PRA, PAC and catecholamines were increased after both types of exercise. The PRA increase was higher after the running test (20.9 ng AngI X ml-1 X h-1) than after swimming (8.66 ng AngI X ml-1 X h-1). The PAC increase was slightly greater after running (123 pg X ml-1) than swimming (102 pg X ml-1), buth the difference was not significant. Plasma catecholamine was higher after the swimming test. These results suggest that the volume shift induced by the supine position and water pressure during swimming decreased the PRA response. The association after swimming compared to running of a decreased PRA and an enhanced catecholamine response rule out a strict dependence of renin release under the effect of plasma catecholamines and is evidence of the major role of neural pathways for renin secretion during physical exercise.

  13. Sodium butyrate suppresses angiotensin II-induced hypertension by inhibition of renal (pro)renin receptor and intrarenal renin-angiotensin system.

    Science.gov (United States)

    Wang, Lei; Zhu, Qing; Lu, Aihua; Liu, Xiaofen; Zhang, Linlin; Xu, Chuanming; Liu, Xiyang; Li, Haobo; Yang, Tianxin

    2017-09-01

    Butyrate, a short-chain fatty acid, is the end product of the fermentation of complex carbohydrates by the gut microbiota. Recently, sodium butyrate (NaBu) has been found to play a protective role in a number of chronic diseases. However, it is still unclear whether NaBu has a therapeutic potential in hypertension. The present study was aimed to investigate the role of NaBu in angiotensin II (Ang II)-induced hypertension and to further explore the underlying mechanism. Ang II was infused into uninephrectomized Sprague-Dawley rats with or without intramedullary infusion of NaBu for 14 days. Mean arterial blood pressure was recorded by the telemetry system. Renal tissues, serum samples, and 24-h urine samples were collected to examine renal injury and the regulation of the (pro)renin receptor (PRR) and renin. Intramedullary infusion of NaBu in Sprague-Dawley rats lowered the Ang II-induced mean arterial pressure from 129 ± 6 mmHg to 108 ± 4 mmHg (P renal injury, including urinary albumin, glomerulosclerosis, and renal fibrosis, as well as the expression of inflammatory mediators tumor necrosis factor α, interleukin 6. The renal expression of PRR, angiotensinogen, angiotensin I-converting enzyme and the urinary excretion of soluble PRR, renin, and angiotensinogen were all increased by Ang II infusion but decreased by NaBu treatment. In cultured innermedullary collecting duct cells, NaBu treatment attenuated Ang II-induced expression of PRR and renin. These results demonstrate that NaBu exerts an antihypertensive action, likely by suppressing the PRR-mediated intrarenal renin-angiotensin system.

  14. Renin-angiotensin system inhibition ameliorates CCl4-induced liver fibrosis in mice through the inactivation of nuclear transcription factor kappa B.

    Science.gov (United States)

    Saber, Sameh; Mahmoud, Amr A A; Helal, Noha S; El-Ahwany, Eman; Abdelghany, Rasha H

    2018-06-01

    Therapeutic interventions for liver fibrosis are still limited due to the complicated molecular pathogenesis. Renin-angiotensin system (RAS) seems to contribute to the development of hepatic fibrosis. Therefore, we aimed to examine the effect of RAS inhibition on CCl 4 -induced liver fibrosis. Mice were treated with silymarin (30 mg·kg -1 ), perindopril (1 mg·kg -1 ), fosinopril (2 mg·kg -1 ), or losartan (10 mg·kg -1 ). The administration of RAS inhibitors improved liver histology and decreased protein expression of alpha smooth muscle actin (α-SMA) and hepatic content of hydroxyproline. These effects found to be mediated via inactivation of nuclear transcription factor kappa B (NFκB) pathway by the inhibition of NFκB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of nuclear factor kappa-B inhibitor alpha (NFκBia) subsequently inhibited NFκB-induced TNF-α and TGF-β1, leading to lower levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF). We concluded that the tissue affinity of the angiotensin converting enzyme inhibitors (ACEIs) has no impact on its antifibrotic activity and that interfering the RAS either through the inhibition of ACE or the blockade of AT1R has the same therapeutic benefit. These results suggest RAS inhibitors as promising candidates for further clinical trials in the management of hepatic fibrosis.

  15. Controlled treatment of primary hypertension with propranolol and spironolactone. A crossover study with special reference to initial plasma renin activity.

    Science.gov (United States)

    Karlberg, B E; Kågedal, B; Tegler, L; Tolagen, K; Bergman, B

    1976-03-31

    Twenty-seven patients with hypertension were randomly allocated to a 10 month crossover study. Treatment consisted of spironolactone (200 mg/day for 2 months), propranolol (320 mg/day for 2 months) and combined administration of both drugs at half the dosage. Between treatment periods placebo was given for 2 months. Fourteen patients were previously untreated. The average pretreatment blood pressure for the entire group was 188/114 +/- 16/7(mean +/- standard deviation) mm Hg supine and 188/118 +/- 20/9 mm Hg standing. Both spironolactone and propranolol reduced blood pressure significantly in both the supine and standing positions. Upright plasma renin activity was determined by radioimmunoassay of angiotensin I. The average initial level was 1.9 +/- 1.2 (range 0.4 to 5.0) ng/ml/hr. There was a close correlation between plasma renin activity and the effects of the drugs: With increasing renin level the response to propranolol was better whereas the opposite was true for spironolactone. The combination of spironolactone and propranolol decreased the blood pressure still further in the supine and standing positions, irrespective of initial plasma renin activity. All patients achieved a normal supine pressure. Blood pressure and plasma renin activity returned toward pretreatment values during placebo administration. It is concluded that pretreatment levels of plasma renin activity can predict the antihypertensive response to propranolol and spironolactone. The combination of the two drugs, which have different modes of action, will effectively reduce blood pressure in hypertension. The results support the concept that the renin-angiotensin-aldo-sterone system may be involved in primary hypertension.

  16. Severe hypoglycaemia during pregnancy in women with type 1 diabetes: possible role of renin-angiotensin system activity?

    DEFF Research Database (Denmark)

    Nielsen, L Ringholm; Pedersen-Bjergaard, U; Thorsteinsson, B

    2009-01-01

    AIMS: To investigate whether increased risk of severe hypoglycaemia in early pregnancy is related to pregnancy-induced changes in renin-angiotensin system (RAS) activity in women with type 1 diabetes (T1DM). METHODS: Severe hypoglycaemic events the year preceding pregnancy were recorded...... retrospectively in 107 consecutive pregnant women with T1DM. Events during pregnancy were recorded prospectively. Measurements of ACE, renin and angiotensinogen were determined at 8, 14, 21, 27 and 33 weeks and postpartum. RESULTS: The rate of severe hypoglycaemia was 1.1 and 5.3 events/patient-year the year...... preceding pregnancy and postpartum ACE activity (relative rate of severe hypoglycaemia above versus below median ACE activity: 4.4 (CI: 1.7-11.9), p=0.003). No association was found between severe hypoglycaemia during pregnancy and renin angiotensin system activity at 8 weeks. CONCLUSIONS: In early...

  17. Hypertrophic response to hemodynamic overload: role of load vs. renin-angiotensin system activation

    Science.gov (United States)

    Koide, M.; Carabello, B. A.; Conrad, C. C.; Buckley, J. M.; DeFreyte, G.; Barnes, M.; Tomanek, R. J.; Wei, C. C.; Dell'Italia, L. J.; Cooper, G. 4th; hide

    1999-01-01

    Myocardial hypertrophy is one of the basic mechanisms by which the heart compensates for hemodynamic overload. The mechanisms by which hemodynamic overload is transduced by the cardiac muscle cell and translated into cardiac hypertrophy are not completely understood. Candidates include activation of the renin-angiotensin system (RAS) and angiotensin II receptor (AT1) stimulation. In this study, we tested the hypothesis that load, independent of the RAS, is sufficient to stimulate cardiac growth. Four groups of cats were studied: 14 normal controls, 20 pulmonary artery-banded (PAB) cats, 7 PAB cats in whom the AT1 was concomitantly and continuously blocked with losartan, and 8 PAB cats in whom the angiotensin-converting enzyme (ACE) was concomitantly and continuously blocked with captopril. Losartan cats had at least a one-log order increase in the ED50 of the blood pressure response to angiotensin II infusion. Right ventricular (RV) hypertrophy was assessed using the RV mass-to-body weight ratio and ventricular cardiocyte size. RV hemodynamic overload was assessed by measuring RV systolic and diastolic pressures. Neither the extent of RV pressure overload nor RV hypertrophy that resulted from PAB was affected by AT1 blockade with losartan or ACE inhibition with captopril. RV systolic pressure was increased from 21 +/- 3 mmHg in normals to 68 +/- 4 mmHg in PAB, 65 +/- 5 mmHg in PAB plus losartan and 62 +/- 3 mmHg in PAB plus captopril. RV-to-body weight ratio increased from 0.52 +/- 0.04 g/kg in normals to 1.11 +/- 0.06 g/kg in PAB, 1.06 +/- 0.06 g/kg in PAB plus losartan and 1.06 +/- 0.06 g/kg in PAB plus captopril. Thus 1) pharmacological modulation of the RAS with losartan and captopril did not change the extent of the hemodynamic overload or the hypertrophic response induced by PAB; 2) neither RAS activation nor angiotensin II receptor stimulation is an obligatory and necessary component of the signaling pathway that acts as an intermediary coupling load to the

  18. [Renin-angiotensin-aldosterone system activity during head-up tilt testing in patients with vasovagal syncope].

    Science.gov (United States)

    Gajek, Jacek; Zyśko, Dorota; Mazurek, Walentyna

    2005-08-01

    The stimulation of renin-angiotensin-aldosterone (RAA) system during tilt table test is caused by sympathetic nervous system activation by orthostatic stress and a serotonin release as well. In healthy individuals increase of plasma renin activity during test with maximal values on the peak of the test was described. The aim of the study was to assess the activation of RAAS in patients with neurally mediated syncope during the tilt table test by means of plasma renin activity and serum aldosterone levels. The study was carried out in 31 patients aged 39.4 +/- 15.0 years (18 women and 13 men) with neurally mediated syncope during tilt test. Plasma renin activity was assessed in the baseline conditions, immediately after the test and 10 minutes after the test using radioenzymatic assay. Aldosterone concentrations were measured radioimmunologically, twice: after 30 minutes supine rest and after the syncope. Plasma renin activity during supine rest was 2.2 +/- 2.4 ng/ml/h, rose after the syncope 2.5-fold to 5.2 +/- 4.5 ng/ml/h (p < 0.001 comparing to baseline) stayed on similar level approximately for the next 10 minutes--4.9 +/- 5.5 ng/ml/h (p = n.s.). In 11 patients (35%) 10 minutes after the test even further increase of PRA was observed. Serum aldosterone level increased significantly immediately after tilt test (90.0 +/- 72.9 vs 178.8 +/- 150.1 pg/ml, p < 0.01). Authors showed, that in patients with NMS plasma renin activity increases and this increase lasts for 10 minutes after the syncope and the concentration of aldosterone increases immediately after tilt test.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    BACKGROUND: There are breed differences in several blood variables in healthy dogs. OBJECTIVE: Investigate breed variation in plasma endothelin-1 (ET-1) concentration, plasma renin activity, and serum cortisol concentration. ANIMALS: Five-hundred and thirty-one healthy dogs of 9 breeds examined...... at 5 centers (2-4 breeds/center). METHODS: Prospective observational study. Circulating concentrations of ET-1 and cortisol, and renin activity, were measured using commercially available assays. Absence of organ-related or systemic disease was ensured by thorough clinical investigations, including...

  20. Low plasma aldosterone despite normal plasma renin activity in uncomplicated type 1 diabetes mellitus : effects of RAAS stimulation

    NARCIS (Netherlands)

    Luik, PT; Kerstens, MN; Hoogenberg, K; Navis, GJ; Dullaart, RPF

    Background Data on levels and responsiveness of PRA and aldosterone in type 1 diabetes mellitus are conflicting. Earlier studies were not standardized with respect to the type of diabetes mellitus, the presence of diabetic complications or sodium intake. Therefore, we studied plasma renin activity

  1. The effect of postural changes on plasma renin activity during normal and pathologic pregnancies.

    Science.gov (United States)

    Brandes, J M; Abramovici, H; Katz, M; Diengott, D; Spindel, A; Kahana, L

    1978-11-01

    A study of the effect of posture on plasma renin activity (PRA) in the third trimester in 27 gravidas revealed a significantly greater increase in PRA in the supine position, compared to the left lateral. The women were classified into 3 groups: normal pregnancy, preeclampsia, intrauterine fetal death. There was no statistical difference in PRA among the 3 groups. It is assumed that the increase of PRA in the supine position was due mainly to mechanical pressure by the gravid uterus on the great vessels (regardless of whether the fetus was dead or alive) and that effective circulatory volume was thus reduced. However, low PRA in the left lateral position in women with preeclampsia seemed to correlate with more severe disease in these women.

  2. Living alone and activation of the renin-angiotensin-aldosterone-system: Differential effects depending on alexithymic personality features.

    Science.gov (United States)

    Terock, Jan; Hannemann, Anke; Janowitz, Deborah; Völzke, Henry; Nauck, Matthias; Freyberger, Harald-Jürgen; Wallaschofski, Henri; Grabe, Hans Jörgen

    2017-05-01

    Living alone is considered as a chronic stress factor predicting different health conditions and particularly cardiovascular disease (CVD). Alexithymia is associated with increased psychological distress, less social skills and fewer close relationships, making alexithymic subjects particularly susceptible to chronic stress imposed by "living alone". Only few studies investigated the renin-angiotensin-aldosterone-system (RAAS) activity in response to chronic stress. We aimed at evaluating the effects of "living alone" as a paradigm for chronic stress on RAAS activity and putatively differential effects depending on alexithymic personality features. Alexithymia and serum concentrations of renin and aldosterone were measured in 944 subjects from the population-based SHIP-1 study. Subgroups were formed using the median of the Toronto Alexithymia Scale-20 (TAS-20) and a cohabitation status of "living alone" or "living together". Analyses were adjusted for various psychosocial, behavioral and metabolic risk factors. "Living alone" was associated with elevated plasma renin (p<0.01, β=0.138) but not aldosterone concentrations in the total sample. On subgroup level, we found associations of "living alone" and elevated renin concentrations only in subjects low in TAS-20 scores (p<0.01, β=0.219). Interactional effects of alexithymia×cohabitation status were found for the aldosterone-to-renin ratio (p=0.02, β=-0.234). The association of chronic stress imposed by "living alone" with increased RAAS activity contributes to explain the relationship of this psychosocial stress condition and increased risk for CVD. In contrast, alexithymic subjects may be less affected by the deleterious effects of "living alone". Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Aldosterone breakthrough with benazepril in furosemide-activated renin-angiotensin-aldosterone system in normal dogs.

    Science.gov (United States)

    Lantis, A C; Ames, M K; Atkins, C E; DeFrancesco, T C; Keene, B W; Werre, S R

    2015-02-01

    Pilot studies in our laboratory revealed that furosemide-induced renin-angiotensin-aldosterone system (RAAS) activation was not attenuated by the subsequent co-administration of benazepril. This study was designed to evaluate the effect of benazepril on angiotensin-converting enzyme (ACE) activity and furosemide-induced circulating RAAS activation. Our hypothesis was that benazepril suppression of ACE activity would not suppress furosemide-induced circulating RAAS activation, indicated by urinary aldosterone concentration. Ten healthy hound dogs were used in this study. The effect of furosemide (2 mg/kg p.o., q12h; Group F; n = 5) and furosemide plus benazepril (1 mg/kg p.o., q24h; Group FB; n = 5) on circulating RAAS was determined by plasma ACE activity, 4-6 h posttreatment, and urinary aldosterone to creatinine ratio (UAldo:C) on days -1, -2, 1, 3, and 7. There was a significant increase in the average UAldo:C (μg/g) after the administration of furosemide (Group F baseline [average of days -1 and -2] UAldo:C = 0.41, SD 0.15; day 1 UAldo:C = 1.1, SD 0.56; day 3 UAldo:C = 0.85, SD 0.50; day 7 UAldo:C = 1.1, SD 0.80, P Benazepril suppressed ACE activity (U/L) in Group FB (Group FB baseline ACE = 16.4, SD 4.2; day 1 ACE = 3.5, SD 1.4; day 3 ACE = 1.6, SD 1.3; day 7 ACE = 1.4, SD 1.4, P Benazepril decreased plasma ACE activity but did not prevent furosemide-induced RAAS activation, indicating aldosterone breakthrough (escape). This is particularly noteworthy in that breakthrough is observed at the time of initiation of RAAS suppression, as opposed to developing after months of therapy. © 2014 John Wiley & Sons Ltd.

  4. [Differences of blood plasma renin activity, angiotensin II and aldosterone levels in essential or secondary hypertension].

    Science.gov (United States)

    Song, Ai-ling; Zeng, Zheng-pei; Tong, An-li; Lu, Lin; Chen, Shi; Li, Ming; Fu, Chun-li; Wang, Yong-hui; Sun, Mei-li

    2012-04-01

    To study on the difference of plasma renin activity (PRA), angiotensin II (Ang II), and aldosterone levels in patients with essential hypertension (EH) or primary aldosteronism (PA) or pheochromocytoma (PHEO), and to analyze the sensitivity and specificity on the diagnosis of PA among patients with hypertension with aldosterone/PRA ratio (ARR). The plasma aldosterone, Ang II and PRA concentrations in supine and upright positions were measured by radioimmunoassay from 413 patients including idiopathic hyperaldosteronism (IHA, n = 111), aldosterone-producing adenoma (APA, n = 118), PHEO (n = 98) and EH (n = 86). ARR was calculated. Plasma aldosterone concentrations in both of supine and upright positions in PHEO group [374 (294, 465) pmol/L and 629 (449, 997) pmol/L] and PA group [471 (346, 632) pmol/L and 673 (499, 825) pmol/L] were higher than those in EH group [277 (224, 332) pmol/L and 427 (341, 501) pmol/L] (P 0.05). The PRA level in both positions of each group were PHEO group [0.3 (0.2, 1.0) µg · L(-1) · h(-1) and 1.4 (0.6, 3.4) µg · L(-1) · h(-1)] > EH group [0.2 (0.1, 0.4) µg · L(-1) · h(-1) and 0.6 (0.4, 1.0) µg · L(-1) · h(-1)] (P PA group [0.1 (0.1, 0.1) µg · L(-1) · h(-1) and 0.2 (0.1, 0.3) µg · L(-1) · h(-1)] (P < 0.01), and APA group [0.1 (0.1, 0.1) µg · L(-1) · h(-1) and 0.1 (0.1, 0.3) µg · L(-1) · h(-1)] < IHA group [0.1 (0.1, 0.2) µg · L(-1) · h(-1) and 0.2 (0.1, 0.3) µg · L(-1) · h(-1)] (supine P < 0.01; upright P < 0.05). APA was divided into 2 types with renin-Ang II-responsive APA (n = 26) and unresponsive APA (n = 92). The plasma aldosterone concentration was lower in supine position but higher in upright position in renin-Ang II-responsive APA than in unresponsive APA patients. ARR in upright was higher in PA group (P < 0.01) but lower in PHEO group (P < 0.05) compared with EH. ARR was higher in APA than in IHA (P < 0.01). The sensitivity and specificity of ARR as 40 (aldosterone unit: ng/dl; PRA unit: µg · L(-1

  5. Genetic variation and activity of the renin-angiotensin system and severe hypoglycemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, U.; Dhamrait, S.S.; Sethi, A.A.

    2008-01-01

    BACKGROUND: The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system...... are similarly associated. METHODS: Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma...... associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation Udgivelsesdato: 2008/3...

  6. Renin-Angiotensin Activation and Oxidative Stress in Early Heart Failure with Preserved Ejection Fraction

    Directory of Open Access Journals (Sweden)

    Smita I. Negi

    2015-01-01

    Full Text Available Animal models have suggested a role of renin-angiotensin system (RAS activation and subsequent cardiac oxidation in heart failure with preserved ejection fraction (HFpEF. Nevertheless, RAS blockade has failed to show efficacy in treatment of HFpEF. We evaluated the role of RAS activation and subsequent systemic oxidation in HFpEF. Oxidative stress markers were compared in 50 subjects with and without early HFpEF. Derivatives of reactive oxidative metabolites (DROMs, F2-isoprostanes (IsoPs, and ratios of oxidized to reduced glutathione (Eh GSH and cysteine (Eh CyS were measured. Angiotensin converting enzyme (ACE levels and activity were measured. On univariate analysis, HFpEF was associated with male sex (p=0.04, higher body mass index (BMI (p=0.003, less oxidized Eh CyS (p=0.001, lower DROMs (p=0.02, and lower IsoP (p=0.03. Higher BMI (OR: 1.3; 95% CI: 1.1–1.6 and less oxidized Eh CyS (OR: 1.2; 95% CI: 1.1–1.4 maintained associations with HFpEF on multivariate analysis. Though ACE levels were higher in early HFpEF (OR: 1.09; 95% CI: 1.01–1.05, ACE activity was similar to that in controls. HFpEF is not associated with significant systemic RAS activation or oxidative stress. This may explain the failure of RAS inhibitors to alter outcomes in HFpEF.

  7. Renin blood test

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/003698.htm Renin blood test To use the sharing features on this page, ... renin test measures the level of renin in blood. How the Test is Performed A blood sample is needed . How ...

  8. Differences in cortical and pituitary activity in response to hypoglycaemia and cognitive testing in healthy men with different basal activity of the renin-angiotensin system

    DEFF Research Database (Denmark)

    Bie-Olsen, Lise G; Pedersen-Bjergaard, Ulrik; Kjaer, Troels W

    2010-01-01

    INTRODUCTION: High renin-angiotensin system (RAS) activity has been associated with a high risk of severe hypoglycaemia in patients with type 1 diabetes and with cognitive deterioration during experimental hypoglycaemia in healthy subjects. The aim of this study was to describe possible differenc...

  9. Effect of PTA on blood pressure, renal plasma flow and renal venous renin activity in renovascular hypertension

    International Nuclear Information System (INIS)

    Arlart, I.P.; Dewitz, H. von; Rosenthal, J.

    1983-01-01

    Percutaneous transluminal angioplasty (PTA) is more and more accepted for interventional management of renal artery stenosis in hypertensive patients. This study was carried out to assess the behaviour of arterial blood-pressure, renal plasma flow and renal venous rening activity in renovascular hypertension following catheter dilatation. Using the data the possibility is calculated to predict the effect of PTA on blood pressure preinterventionally. The results demonstrate that a successful employment of PTA depends on a normal contralateral renal plasma flow and a normalization of plasma flow of the poststenotic kidney. Determination of plasma renin activity is only of restricted value. (orig.)

  10. Intramuscular renin-angiotensin system is activated in human muscular dystrophy.

    Science.gov (United States)

    Sun, Guilian; Haginoya, Kazuhiro; Dai, Hongmei; Chiba, Yoko; Uematsu, Mitsugu; Hino-Fukuyo, Naomi; Onuma, Akira; Iinuma, Kazuie; Tsuchiya, Shigeru

    2009-05-15

    To investigate the role of the muscular renin-angiotensin system (RAS) in human muscular dystrophy, we used immunohistochemistry and Western blotting to examine the cellular localization of angiotensin-converting enzyme (ACE), the angiotensin II type 1 receptor (AT1) and the angiotensin II type 2 receptor (AT2) in muscle biopsies from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and congenital muscular dystrophy (CMD). In normal muscle, ACE was expressed in vascular endothelial cells and neuromuscular junctions (NMJs), whereas AT1 was immunolocalized to the smooth muscle cells of blood vessels and intramuscular nerve twigs. AT2 was immunolocalized in the smooth muscle cells of blood vessels. These findings suggest that the RAS has a functional role in peripheral nerves and NMJs. ACE and AT1, but AT2 immunoreactivity were increased markedly in dystrophic muscle as compared to controls. ACE and the AT1 were strongly expressed in the cytoplasm and nuclei of regenerating muscle fibers, fibroblasts, and in macrophages infiltrating necrotic fibers. Double immunolabeling revealed that activated fibroblasts in the endomysium and perimysium of DMD and CMD muscle were positive for ACE and AT1. Triple immunolabeling demonstrated that transforming growth factor-beta1 (TGF-beta1) and ACE were colocalized on the cytoplasm of activated fibroblasts in dystrophic muscle. Furthermore, Western blotting showed increases in the expression of AT1 and TGF-beta1 protein in dystrophic muscle, which coincided with our immunohistochemical results. The overexpression of ACE and AT1 in dystrophic muscle would likely result in the increased production of Ang II, which may act on these cells in an autocrine manner via AT1. The activation of AT1 may induce fibrous tissue formation through overexpression of TGF-beta1, which potently activates fibrogenesis and suppresses regeneration. In conclusion, our results imply that the intramuscular RAS-TGF-beta1 pathway

  11. Study of prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves

    Directory of Open Access Journals (Sweden)

    Divya Bhadoo

    2015-01-01

    Full Text Available Aims: Study on prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves. Materials and Methods: Antenatally diagnosed hydronephrosis patients were included. Postnatally, they were divided into two groups, posterior urethral valve (PUV and non-PUV. The studied parameters were: Gestational age at detection, surgical intervention, ultrasound findings, cord blood and follow up plasma renin activity (PRA values, vesico-ureteric reflux (VUR, renal scars, and glomerular filtration rate (GFR. Results: A total of 25 patients were included, 10 PUV and 15 non-PUV. All infants with PUV underwent primary valve incision. GFR was less than 60 ml/min/1.73 m 2 body surface area in 4 patients at last follow-up. Keyhole sign, oligoamnios, absent bladder cycling, and cortical cysts were not consistent findings on antenatal ultrasound in PUV. Cord blood PRA was significantly higher (P < 0.0001 in PUV compared to non-PUV patients. Gestational age at detection of hydronephrosis, cortical cysts, bladder wall thickness, and amniotic fluid index were not significantly correlated with GFR while PRA could differentiate between poor and better prognosis cases with PUV. Conclusions: Ultrasound was neither uniformly useful in diagnosing PUV antenatally, nor differentiating it from cases with non-PUV hydronephrosis. In congenital hydronephrosis, cord blood PRA was significantly higher in cases with PUV compared to non-PUV cases and fell significantly after valve ablation. Cord blood PRA could distinguish between poor and better prognosis cases with PUV.

  12. Cognitive performance, symptoms and counter-regulation during hypoglycaemia in patients with type 1 diabetes and high or low renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Høi-Hansen, Thomas; Pedersen-Bjergaard, Ulrik; Andersen, Rikke Due

    2009-01-01

    INTRODUCTION: High basal renin-angiotensin system (RAS) activity is associated with increased risk of severe hypoglycaemia in type 1 diabetes. We tested whether this might be explained by more pronounced cognitive dysfunction during hypoglycaemia in patients with high RAS activity than in patient...

  13. Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure.

    Science.gov (United States)

    Wei, Shun-Guang; Yu, Yang; Weiss, Robert M; Felder, Robert B

    2016-10-01

    We previously reported that endoplasmic reticulum (ER) stress is induced in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) of heart failure (HF) rats and is reduced by inhibition of mitogen-activated protein kinase (MAPK) signaling. The present study further examined the relationship between brain MAPK signaling, ER stress, and sympathetic excitation in HF. Sham-operated (Sham) and HF rats received a 4-wk intracerebroventricular (ICV) infusion of vehicle (Veh) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10 μg/day). Lower mRNA levels of the ER stress biomarkers GRP78, ATF6, ATF4, and XBP-1s in the SFO and PVN of TUDCA-treated HF rats validated the efficacy of the TUDCA dose. The elevated levels of phosphorylated p44/42 and p38 MAPK in SFO and PVN of Veh-treated HF rats, compared with Sham rats, were significantly reduced in TUDCA-treated HF rats as shown by Western blot and immunofluorescent staining. Plasma norepinephrine levels were higher in Veh-treated HF rats, compared with Veh-treated Sham rats, and were significantly lower in the TUDCA-treated HF rats. TUDCA-treated HF rats also had lower mRNA levels for angiotensin converting enzyme, angiotensin II type 1 receptor, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and NF-κB p65, and a higher mRNA level of IκB-α, in the SFO and PVN than Veh-treated HF rats. These data suggest that ER stress contributes to the augmented sympathetic activity in HF by inducing MAPK signaling, thereby promoting inflammation and renin-angiotensin system activity in key cardiovascular regulatory regions of the brain.

  14. Anti-stress and nootropic activity of drugs affecting the renin-angiotensin system in rats based on indirect biochemical evidence.

    Science.gov (United States)

    Anil Kumar, K V; Nagwar, Shrasti; Thyloor, Rama; Satyanarayana, Sreemantula

    2015-12-01

    Various stress hormones are responsible for bringing out stress-related changes and are implicated in learning and memory processes. The extensive clinical experience of angiotensin receptor blockers (ARBs) and direct renin inhibitor as antihypertensive agents provides anecdotal evidence of improvements in cognition. The neurochemical basis underlying the anti-stress and nootropic effects are unclear. This study was aimed to determine the effects of aliskiren, valsartan and their combination on the neuromediators of the central nervous system (CNS) and periphery as well as on cognitive function. Groups of rats were subjected to a forced swim stress for one hour after daily treatment with aliskiren, valsartan and their combination. The 24 h urinary excretion of vanillylmandellic acid (VMA), 5-hydroxyindoleacetic acid (5-HIAA), 6-β-hydroxycortisol (6-β-OH) cortisol and homovanillic acid (HVA) was determined in all groups under normal and stressed conditions. Nootropic activity was studied using cook's pole climbing apparatus and acetylcholinesterase (AChE) inhibitory activity by Ellman's method. Administration of aliskiren (10 mg/kg), valsartan (20 mg/kg) and their combination at a dose of 5 and 10 mg/kg respectively reduced the urinary metabolite levels. Further, all drugs showed significant improvement in scopolamine-impaired performance and produced inhibition of the AChE enzyme. The present study provides scientific support for the anti-stress and nootropic activities of aliskiren, valsartan and their combination. © The Author(s) 2014.

  15. Effect of maternal renin-angiotensin-aldosterone system activation on social coping strategies and gene expression of oxytocin and vasopressin in the brain of rat offspring in adulthood.

    Science.gov (United States)

    Senko, Tomáš; Svitok, Pavel; Kršková, Lucia

    2017-10-01

    The intrauterine condition in which the mammalian foetus develops has an important role in prenatal programming. The aim of this study was to determine the extent to which activation of the maternal renin-angiotensin-aldosterone system (RAAS) could influence social behaviour strategies in offspring via changes in social neurotransmitters in the brain. Pregnant female Wistar rats were implanted with osmotic minipumps which continually released angiotensin II for 14 days at concentration of 2 μg/kg/h. The adult offspring (angiotensin and control groups) underwent a social interaction test. The mRNA expression of vasopressin, oxytocin and the oxytocin receptor in selected brain areas was measured by in situ hybridisation. Prenatal exposure to higher levels of angiotensin II resulted in a strong trend toward decreased total social interaction time and significantly decreased time spent in close proximity and frequency of mutual sniffing. The angiotensin group showed no changes in oxytocin mRNA expression in the hypothalamic paraventricular or supraoptic nuclei, but this group had reduced vasopressin mRNA expression in the same areas. We concluded that maternal activation of RAAS (via higher levels of angiotensin II) caused inhibition of some socio-cohesive indicators and decreased vasopressinergic activity of offspring. Taken together, these results suggest a reactive rather than proactive social coping strategy.

  16. Direct Renin Inhibition with Aliskiren Improves Ischemia-Induced Neovasculogenesis in Diabetic Animals via the SDF-1 Related Mechanism.

    Directory of Open Access Journals (Sweden)

    Ting-Ting Chang

    Full Text Available Aliskiren is a direct renin inhibitor which is suggested to modify proangiogenic cells in addition to lower blood pressure. Given that angiogenesis is impaired in the presence of diabetes mellitus, we would like to investigate whether and how aliskiren enhances endothelial progenitor cells (EPCs and improves ischemic-induced neovasculogenesis by an effect independent of blood pressure reduction in diabetic animals.Streptozotocin-induced diabetic mice were administered with either aliskiren (5 or 25 mg/kg/day using an osmotic pump or hydralazine (2 or 10 mg/kg/day given in drinking water for two weeks prior to a hind-limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and the circulating levels of EPCs, respectively.In streptozotocin-induced diabetic mice, aliskiren enhanced the recovery of limb perfusion and capillary density, increased the number of circulating Sca-1+/Flk-1+ EPC-like cells, and elevated the levels of the plasma vascular endothelial growth factor (VEGF and stromal cell-derived factor (SDF-1α in a dose-dependent manner, whereas there were no such effects in hydralazine-treated mice. Intraperitoneal administration of anti-SDF-1 neutralizing monoclonal antibodies abolished the effects of aliskiren.Independent of the reduction of blood pressure, aliskiren enhanced ischemia-induced neovasculogenesis in a dose-dependent manner via VEGF/SDF-1α related mechanisms in diabetic mice.

  17. Comparative biochemistry of renins and angiotensins in the vertebrates.

    Science.gov (United States)

    Nakajima, T; Khosla, M C; Sakakibara, S

    1978-09-01

    Comparative biochemistry of renins and angiotensins was discussed. Renin extracted from hog kidney was different from that from mouse submaxillary glands in immunoreactivity and carbohydrate content. Rat kidney renin was also different from hog kidney renin in the amino acid composition. The presence of big and big-big renins was pointed out immunochemically. These big renins were considered to be precursors of kidney renin. Angiotensins in mammalian and nonmammalian species produced by renal or extrarenal renin have been differentiated by some biochemical and pharmacological criteria. Some of these angiotensins were analyzed sequentially. The replacements of amino acid residues at positions 1, 5, and/or 9 of angiotensin I have been demonstrated in nonmammalian species. Specific pressor activities have been determined using synthetic angiotensins by a 4 point assay in rat. Specific pressor activities of various angiotensins were obtained from the dose-blood pressure-response curves using a single angiotensin sample per assay rat.

  18. Aldosterone to Active Renin Ratio Is Associated With Nocturnal Blood Pressure in Obese and Treated Hypertensive Patients: The Styrian Hypertension Study

    NARCIS (Netherlands)

    Grubler, M.R.; Kienreich, K.; Gaksch, M.; Verheyen, N.; Fahrleitner-Pammer, A.; Schmid, J.; Grogorenz, J.; Ablasser, K.; Pieske, B.; Tomaschitz, A.; Pilz, S.

    2014-01-01

    High aldosterone levels are considered to play a key role in arterial hypertension. Data on the relationship between the aldosterone to active renin ratio (AARR), a quantity of aldosterone excess, and ambulatory blood pressure (BP) monitoring (ABPM) during the night are, however, sparse.

  19. The Effect of the Arg389Gly Beta-1 Adrenoceptor Polymorphism on Plasma Renin Activity and Heart Rate and the Genotype-Dependent Response to Metoprolol Treatment

    DEFF Research Database (Denmark)

    Petersen, Morten; Andersen, Jon T; Jimenez-Solem, Espen

    2012-01-01

    A gene-drug interaction has been indicated between beta-1 selective beta-blockers and the Arg389Gly polymorphism (rs1801253) in the adrenergic beta-1 receptor gene (ADRB1). We studied the effect of the ADRB1 Arg389Gly polymorphism on plasma renin activity (PRA) and heart rate (HR) and the genotype...

  20. The influence of a tilt training programme on the renin-angiotensin-aldosterone system activity in patients with vasovagal syncope.

    Science.gov (United States)

    Gajek, Jacek; Zyśko, Dorota; Krzemińska, Sylwia; Mazurek, Walentyna

    2009-08-01

    We assessed the influence of short-term and long-term tilt training on the activity of the renin-angiotensin-aldosterone system (RAAS) in vasovagal patients. Thirty-nine patients (28 F, 11 M) aged 39.7 +/- 11.2 years with a history of vasovagal syncope and a positive head-up tilt test (HUT) were studied. Blood samples for plasma renin activity (PRA) and aldosterone (ALDO) concentration were drawn at the baseline, immediately after HUT and 10 min after HUT, during the diagnostic, the negative short-term (2-5 days) follow-up HUT and long-term (1-3 months) follow-up HUT. Tilt training was started after diagnostic HUT. In diagnostic HUT, PRA increased significantly immediately after HUT comparing to the baseline, during recovery the values did not change. ALDO concentration increased after HUT comparing to baseline and further increased during recovery. After short-term tilt training, PRA and ALDO concentrations did not significantly change compared to their corresponding values in diagnostic HUT. After long-term tilt training, PRA did not significantly change compared to the values in the diagnostic and short-term follow-up HUT. ALDO concentration also did not change significantly at the baseline and immediately after HUT, and 10 min after HUT ALDO concentration was significantly lower than after diagnostic HUT. Tilt training changes the response of RAAS to the prolonged orthostasis in vasovagal patients. The coupling between PRA and ALDO after diagnostic HUT has been found to be altered and the physiological relationship was restored after long-term tilt training. The beneficial effect of tilt training depends partially on changed RAAS activation.

  1. Effects of high doses of enalapril and benazepril on the pharmacologically activated renin-angiotensin-aldosterone system in clinically normal dogs.

    Science.gov (United States)

    Ames, Marisa K; Atkins, Clarke E; Lee, Seunggon; Lantis, Andrea C; zumBrunnen, James R

    2015-12-01

    To determine whether high doses of enalapril and benazepril would be more effective than standard doses of these drugs in suppressing the furosemide-activated renin-angiotensin-aldosterone system (RAAS). 6 healthy Beagles. 2 experiments were conducted; each lasted 10 days, separated by a 2-week washout period. In experiment 1, all dogs received furosemide (2 mg/kg, PO, q 12 h) and enalapril (1 mg/kg, PO, q 12 h) for 8 days (days 0 through 7). In experiment 2, dogs received furosemide (2 mg/kg, PO, q 12 h) and benazepril (1 mg/kg, PO, q 12 h) for 8 days. Effects on the RAAS were determined by assessing serum angiotensin-converting enzyme (ACE) activity on days -1, 3, and 7; serum aldosterone concentration on days -2, -1, 1, 3, and 7; and the urinary aldosterone-creatinine ratio (UAldo:C) in urine collected in the morning and evening of days -2, -1, 1, 3, and 7. High doses of enalapril and benazepril caused significant reductions in serum ACE activity on all days but were not more effective than standard doses used in other studies. Mean UAldo:C remained significantly higher on days 2 through 7, compared with baseline values. Serum aldosterone concentration also increased after drug administration, which mirrored changes in the UAldo:C. In this study, administration of high doses of enalapril and benazepril significantly inhibited ACE activity, yet did not prevent increases in mean urine and serum aldosterone concentrations resulting from furosemide activation of RAAS. This suggested that aldosterone breakthrough from ACE inhibition was a dose-independent effect of ACE inhibitors.

  2. Role of the renin-angiotensin system in cardiac hypertrophy induced in rats by hyperthyroidism.

    Science.gov (United States)

    Kobori, H; Ichihara, A; Suzuki, H; Takenaka, T; Miyashita, Y; Hayashi, M; Saruta, T

    1997-08-01

    This study was conducted to examine whether the renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy without involving the sympathetic nervous system. Sprague-Dawley rats were divided into control-innervated, control-denervated, hyperthyroid-innervated, and hyperthyroid-denervated groups using intraperitoneal injections of thyroxine and 6-hydroxydopamine. After 8 wk, the heart-to-body weight ratio increased in hyperthyroid groups (63%), and this increase was only partially inhibited by sympathetic denervation. Radioimmunoassays and reverse transcription-polymerase chain reaction revealed increased cardiac levels of renin (33%) and angiotensin II (53%) and enhanced cardiac expression of renin mRNA (225%) in the hyperthyroid groups. These increases were unaffected by sympathetic denervation or 24-h bilateral nephrectomy. In addition, losartan and nicardipine decreased systolic blood pressure to the same extent, but only losartan caused regression of thyroxine-induced cardiac hypertrophy. These results suggest that thyroid hormone activates the cardiac renin-angiotensin system without involving the sympathetic nervous system or the circulating renin-angiotensin system; the activated renin-angiotensin system contributes to cardiac hypertrophy in hyperthyroidism.

  3. Effect of hypovolemia, infusion, and oral rehydration on plasma electrolytes, ADH, renin activity, and +G/z/ tolerance

    Science.gov (United States)

    Greenleaf, J. E.; Brock, P. J.; Haines, R. F.; Rositano, S. A.; Montgomery, L. D.; Keil, L. C.

    1977-01-01

    Effects on plasma volume, electrolyte shifts, and +G(z) tolerance induced by: (1) blood withdrawal; (2) blood infusion; and (3) oral fluid intake, were determined at 0.5 G/min in centrifugation tests of six ambulatory male patients, aged 21 to 27 yrs. Hypovolemia induced by withdrawal of 400 ml blood, blood infusion followed by repeated centrifugation, effects of consuming an isotonic drink (0.9% NaCl) to achieve oral rehydration, and donning of red adaptation goggles were studied for effects on acceleration tolerance, pre-acceleration and post-acceleration plasma renin activity (PRA) and plasma vasopressin levels. No significant changes in post-acceleration PRA compared to pre-acceleration PRA were found, and administration of oral rehydration is found as effective as blood replacement in counteracting hypovolemic effects.

  4. Renal renin secretion as regulator of body fluid homeostasis

    DEFF Research Database (Denmark)

    Damkjær, Mads; Isaksson, Gustaf L; Stubbe, Jane

    2013-01-01

    The renin-angiotensin system is essential for body fluid homeostasis and blood pressure regulation. This review focuses on the homeostatic regulation of the secretion of active renin in the kidney, primarily in humans. Under physiological conditions, renin secretion is determined mainly by sodium...

  5. Pituitary adenylate cyclase-activating polypeptide stimulates renin secretion via activation of PAC1 receptors

    DEFF Research Database (Denmark)

    Hautmann, Matthias; Friis, Ulla G; Desch, Michael

    2007-01-01

    Besides of its functional role in the nervous system, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in the regulation of cardiovascular function. Therefore, PACAP is a potent vasodilator in several vascular beds, including the renal vasculature. Because...

  6. Correlations of plasma renin activity and aldosterone concentration with ambulatory blood pressure responses to nebivolol and valsartan, alone and in combination, in hypertension.

    Science.gov (United States)

    Giles, Thomas D; Bakris, George; Oparil, Suzanne; Weber, Michael A; Li, Huiling; Mallick, Madhuja; Bharucha, David B; Chen, ChunLin; Ferguson, William G

    2015-11-01

    After demonstration of the antihypertensive efficacy of the combination of the beta-blocker nebivolol and the angiotensin receptor blocker valsartan in an 8-week, randomized, placebo-controlled trial (N = 4161), we now report the effects of this treatment on the renin-angiotensin-aldosterone system in a substudy (n = 805). Plasma renin activity increased with valsartan (54%-73%) and decreased with nebivolol (51%-65%) and the combination treatment (17%-39%). Plasma aldosterone decreased with individual treatments (valsartan, 11%-22%; nebivolol, 20%-26%), with the largest reduction (35%) observed with maximum combination dose (20 mg nebivolol/320 mg valsartan). Baseline ln(plasma renin activity) correlated with the 8-week reductions in 24-hour systolic and diastolic BP following treatments with the combination (all doses combined, P = .003 and P valsartan. Baseline ln(aldosterone) correlated with 24-hour systolic and diastolic BP reductions following combination treatment only (P < .001 and P = .005). The implications of the renin-angiotensin-aldosterone system effects of this beta blocker-angiotensin receptor blocker combination should be explored further. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Stimulatory effects of neuronally released norepinephrine on renin release in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Matsumura, Yasuo; Kawazoe, Shinka; Ichihara, Toshio; Shinyama, Hiroshi; Kageyama, Masaaki; Morimoto, Shiro (Osaka Univ. of Pharmaceutical Sciences (Japan))

    1988-10-01

    Extracellular high potassium inhibits renin release in vitro by increasing calcium concentrations in the juxtaglomerular cells. The authors found that the decreased response of renin release from rat kidney cortical slices in high potassium solution changed to a strikingly increased one in the presence of nifedipine at doses over 10{sup {minus}6} M. They then examined the stimulatory effect of extracellular high potassium in the presence of nifedipine on renin release. The enhancement of release was significantly suppressed either by propranolol or by metoprolol but not by prazosin. High potassium plus nifedipine-induced increase in renin release was markedly attenuated by renal denervation. The enhancing effect was not observed when the slices were incubated in calcium-free medium. Divalent cations such as Cd{sup 2+}, Co{sup 2+}, and Mn{sup 2+} blocked this enhancement in a concentration-dependent manner. High potassium elicited an increase in {sup 3}H efflux from the slices preloaded with ({sup 3}H)-norepinephrine. The increasing effect was not influenced by nifedipine but was abolished by the removal of extracellular calcium or by the addition of divalent cations. These observations suggest to us that the high potassium plus nifedipine-induced increase in renin release from the slices is mediated by norepinephrine derived from renal sympathetic nerves and that this neuronally released norepinephrine stimulates renin release via activation of {beta}-adrenoceptors.

  8. Graz Endocrine Causes of Hypertension (GECOH study: a diagnostic accuracy study of aldosterone to active renin ratio in screening for primary aldosteronism

    Directory of Open Access Journals (Sweden)

    Dobnig Harald

    2009-04-01

    Full Text Available Abstract Background Primary aldosteronism (PA affects approximately 5 to 10% of all patients with arterial hypertension and is associated with an excess rate of cardiovascular complications that can be significantly reduced by a targeted treatment. There exists a general consensus that the aldosterone to renin ratio should be used as a screening tool but valid data about the accuracy of the aldosterone to renin ratio in screening for PA are sparse. In the Graz endocrine causes of hypertension (GECOH study we aim to prospectively evaluate diagnostic procedures for PA. Methods and design In this single center, diagnostic accuracy study we will enrol 400 patients that are routinely referred to our tertiary care center for screening for endocrine hypertension. We will determine the aldosterone to active renin ratio (AARR as a screening test. In addition, all study participants will have a second determination of the AARR and will undergo a saline infusion test (SIT as a confirmatory test. PA will be diagnosed in patients with at least one AARR of ≥ 5.7 ng/dL/ng/L (including an aldosterone concentration of ≥ 9 ng/dL who have an aldosterone level of ≥ 10 ng/dL after the saline infusion test. As a primary outcome we will calculate the receiver operating characteristic curve of the AARR in diagnosing PA. Secondary outcomes include the test characteristics of the saline infusion test involving a comparison with 24 hours urine aldosterone levels and the accuracy of the aldosterone to renin activity ratio in diagnosing PA. In addition we will evaluate whether the use of beta-blockers significantly alters the accuracy of the AARR and we will validate our laboratory methods for aldosterone and renin. Conclusion Screening for PA with subsequent targeted treatment is of great potential benefit for hypertensive patients. In the GECOH study we will evaluate a standardised procedure for screening and diagnosing of this disease.

  9. Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial.

    Science.gov (United States)

    McMullan, Ciaran J; Borgi, Lea; Fisher, Naomi; Curhan, Gary; Forman, John

    2017-05-08

    Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting. In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping. Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m 2 ) from baseline to 8 weeks, was -4 (-25 to 32) in the probenecid group ( P =0.83), -4 (-16 to 9) in the allopurinol group ( P =0.32), and 1 (-21 to 17) in the placebo group ( P =0.96), with no significant treatment effect ( P =0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was -1.6±10.1 with probenecid ( P =0.43), -0.4±6.1 with allopurinol ( P =0.76), and 0.5±6.0 with placebo ( P =0.65); there was no significant treatment effect ( P =0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively. In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney

  10. Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

    Science.gov (United States)

    Ishigaki, Sayaka; Ohashi, Naro; Isobe, Shinsuke; Tsuji, Naoko; Iwakura, Takamasa; Ono, Masafumi; Sakao, Yukitoshi; Tsuji, Takayuki; Kato, Akihiko; Miyajima, Hiroaki; Yasuda, Hideo

    2016-12-01

    Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb). Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (β = -0.31, p = 0.044) and U-Alb (β = -0.25, p = 0.025) only at night. Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.

  11. Vascular endothelial growth factor during hypoglycemia in patients with type 1 diabetes mellitus: relation to cognitive function and renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Kristensen, Peter Lommer; Høi-Hansen, Thomas; Boomsma, Frans

    2009-01-01

    hypoglycemia. High activity in the renin-angiotensin system (RAS) is associated with an increased risk of severe hypoglycemia in patients with type 1 diabetes mellitus. Renin-angiotensin system possibly exerts its mechanism in hypoglycemia via VEGF. We studied the impact of mild hypoglycemia on plasma VEGF...... in patients with type 1 diabetes mellitus and high or low RAS activity and analyzed associations between VEGF levels and cognitive function during hypoglycemia. Eighteen patients with type 1 diabetes mellitus-9 with high and 9 with low RAS activity-underwent a single-blinded, placebo-controlled, crossover...... study with either mild hypoglycemia or stable glycemia. Cognitive function was assessed by the California Cognitive Assessment Package and the Alzheimer Quick Test. Nadir plasma glucose was 2.2 (0.3) mmol/L. During the control study, plasma VEGF did not change. During hypoglycemia, plasma VEGF increased...

  12. Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Cao, Wei; Li, Aiqing; Li, Jiawen; Wu, Chunyi; Cui, Shuang; Zhou, Zhanmei; Liu, Youhua; Wilcox, Christopher S; Hou, Fan Fan

    2017-09-01

    A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

  13. Combined use of drugs inhibiting the renin-angiotensin system: prescribing patterns and risk of acute kidney injury in German nursing home residents.

    Science.gov (United States)

    Dörks, Michael; Herget-Rosenthal, Stefan; Hoffmann, Falk; Jobski, Kathrin

    2018-01-01

    In 2012, the European Medicines Agency reviewed the safety of dual renin-angiotensin system (RAS) blockade because of potentially increased risks for inter alia acute kidney injury (AKI). Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade. Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CI) were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities. Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7%) who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%). Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%), followed by angiotensin II receptor blockers (21.6%) and aliskiren (0.2%). Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8-11.8) in 2010 to 4.7 (95% CI 4.0-5.4) per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77-5.17). However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27-9.47), chronic kidney disease (4.74; 1.24-18.13) or both (11.17; 2.65-47.15). Prescribing of drugs inhibiting the RAS is common in German nursing homes. Though the prevalence of dual RAS blockade declined, our study showed an increased risk of AKI in patients with diabetes and/or chronic kidney disease. Therefore, cautious use is warranted in these vulnerable patients.

  14. Effect of antigravity suit inflation on cardiovascular, PRA, and PVP responses in humans. [Plasma Renin Activity and Plasma VasoPressin

    Science.gov (United States)

    Kravik, S. E.; Keil, L. C.; Geelen, G.; Wade, C. E.; Barnes, P. R.

    1986-01-01

    The effects of lower body and abdominal pressure, produced by antigravity suit inflation, on blood pressure, pulse rate, fluid and electrolyte shift, plasma vasopressin and plasma renin activity in humans in upright postures were studied. Five men and two women stood upright for 3 hr with the suit being either inflated or uninflated. In the control tests, the suit was inflated only during the latter part of the trials. Monitoring was carried out with a sphygnomanometer, with sensors for pulse rates, and using a photometer and osmometer to measure blood serum characteristics. The tests confirmed earlier findings that the anti-g suit eliminates increases in plasma renin activity. Also, the headward redistribution of blood obtained in the tests commends the anti-g suit as an alternative to water immersion or bed rest for initial weightlessness studies.

  15. A local renal renin-angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats.

    Science.gov (United States)

    Tojo, Akihiro; Kinugasa, Satoshi; Fujita, Toshiro; Wilcox, Christopher S

    2016-01-01

    The mechanism of activation of local renal renin-angiotensin system (RAS) has not been clarified in diabetes mellitus (DM). We hypothesized that the local renal RAS will be activated via increased glomerular filtration and tubular uptake of prorenin and angiotensinogen in diabetic kidney with microalbuminuria. Streptozotocin (STZ)-induced DM and control rats were injected with human prorenin and subsequently with human angiotensinogen. Human prorenin uptake was increased in podocytes, proximal tubules, macula densa, and cortical collecting ducts of DM rats where prorenin receptor (PRR) was expressed. Co-immunoprecipitation of kidney homogenates in DM rats revealed binding of human prorenin to the PRR and to megalin. The renal uptake of human angiotensinogen was increased in DM rats at the same nephron sites as prorenin. Angiotensin-converting enzyme was increased in podocytes, but decreased in the proximal tubules in DM rats, which may have contributed to unchanged renal levels of angiotensin despite increased angiotensinogen. The systolic blood pressure increased more after the injection of 20 μg of angiotensinogen in DM rats than in controls, accompanied by an increased uptake of human angiotensinogen in the vascular endothelium. In conclusion, endocytic uptake of prorenin and angiotensinogen in the kidney and vasculature in DM rats was contributed to increased tissue RAS and their pressor response to angiotensinogen.

  16. Differences in cortical and pituitary activity in response to hypoglycaemia and cognitive testing in healthy men with different basal activity of the renin-angiotensin system

    DEFF Research Database (Denmark)

    Bie-Olsen, Lise G; Pedersen-Bjergaard, Ulrik; Kjaer, Troels W

    2010-01-01

    in cerebral activity during hypoglycaemia and cognitive testing in two groups of healthy men with different basal RAS activity. METHODS: Ten healthy men with high RAS activity and 10 with low activity underwent six oxygen-15-labelled water positron emission tomography scans: twice during normoglycaemia, twice......INTRODUCTION: High renin-angiotensin system (RAS) activity has been associated with a high risk of severe hypoglycaemia in patients with type 1 diabetes and with cognitive deterioration during experimental hypoglycaemia in healthy subjects. The aim of this study was to describe possible differences...... during insulin-induced hypoglycaemia and twice during post-hypoglycaemia. During the scans, the subjects performed a computer-based reaction time test. RESULTS: Occipital areas were consistently more activated in the low RAS group than in the high RAS group throughout all three conditions. During...

  17. High fat diet exacerbates neuroinflammation in an animal model of multiple sclerosis by activation of the Renin Angiotensin system.

    Science.gov (United States)

    Timmermans, Silke; Bogie, Jeroen F J; Vanmierlo, Tim; Lütjohann, Dieter; Stinissen, Piet; Hellings, Niels; Hendriks, Jerome J A

    2014-03-01

    Epidemiological studies suggest a positive correlation between the incidence and severity of multiple sclerosis (MS) and the intake of fatty acids. It remains to be clarified whether high fat diet (HFD) indeed can exacerbate the disease pathology associated with MS and what the underlying mechanisms are. In this study, we determined the influence of HFD on the severity and pathology of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Mice were fed either normal diet (ND) or HFD and subsequently induced with EAE. Immunohistochemical staining and real-time PCR were used to determine immune cell infiltration and inflammatory mediators in the central nervous system (CNS). Our data show that HFD increases immune cell infiltration and inflammatory mediator production in the CNS and thereby aggravates EAE. Moreover, our data demonstrate that activation of the renin angiotensin system (RAS) is associated with the HFD-mediated effects on EAE severity. These results show that HFD exacerbates an autoreactive immune response within the CNS. This indicates that diets containing excess fat have a significant influence on neuroinflammation in EAE, which may have important implications for the treatment and prevention of neuroinflammatory disorders.

  18. Renin release from isolated juxtaglomerular apparatus depends on macula densa chloride transport

    DEFF Research Database (Denmark)

    Lorenz, J N; Weihprecht, H; Schnermann, J

    1991-01-01

    salts to inhibit renin secretion, starting from a stimulated value produced by low-NaCl perfusion. Perfusion with a high-NaCl solution decreased renin secretion from 58.9 to 14.8 nGU/min, which served as a positive control. Addition of choline chloride decreased renin secretion from 42.7 to 16.6 n...

  19. Role of Nitric Oxide in the Regulation of Renin and Vasopressin Secretion

    Science.gov (United States)

    Reid, Ian A.

    1994-01-01

    Research during recent years has established nitric oxide as a unique signaling molecule that plays important roles in the regulation of the cardiovascular, nervous, immune, and other systems. Nitric oxide has also been implicated in the control of the secretion of hormones by the pancreas, hypothalamus, and anterior pituitary gland, and evidence is accumulating that it contributes to the regulation of the secretion of renin and vasopressin, hormones that play key roles in the control of sodium and water balance. Several lines of evidence have implicated nitric oxide in the control of renin secretion. The enzyme nitric oxide synthase is present in vascular and tubular elements of the kidney, particularly in cells of the macula densa, a structure that plays an important role in the control of renin secretion. Guanylyl cyclase, a major target for nitric oxide, is also present in the kidney. Drugs that inhibit nitric oxide synthesis generally suppress renin release in vivo and in vitro, suggesting a stimulatory role for the L-arginine/nitric oxide pathway in the control of renin secretion. Under some conditions, however, blockade of nitric oxide synthesis increases renin secretion. Recent studies indicate that nitric oxide not only contributes to the regulation of basal renin secretion, but also participates in the renin secretory responses to activation of the renal baroreceptor, macula densa, and beta adrenoceptor mechanisms that regulate renin secretion. Histochemical and immunocytochemical studies have revealed the presence of nitric oxide synthase in the supraoptic and paraventricular nuclei of the hypothalamus and in the posterior pituitary gland. Colocalization of nitric oxide synthase and vasopressin has been demonstrated in some hypothalamic neurons. Nitric oxide synthase activity in the hypothalamus and pituitary is increased by maneuvers known to stimulate vasopressin secretion, including salt loading and dehydration, Administration of L-arginine and nitric

  20. The secretory phospholipase A2 group IIA: a missing link between inflammation, activated renin-angiotensin system, and atherogenesis?

    Directory of Open Access Journals (Sweden)

    Dimitar Divchev

    2008-06-01

    Full Text Available Dimitar Divchev, Bernhard SchiefferDepartment of Cardiology and Angiology, Medizinische Hochschule Hannover, GermanyAbstract: Inflammation, lipid peroxidation and chronic activation of the renin–angiotensin system (RAS are hallmarks of the development of atherosclerosis. Recent studies have suggested the involvement of the pro-inflammatory secretory phospholipase A2 (sPLA2-IIA in atherogenesis. This enzyme is produced by different cell types through stimulation by proinflammatory cytokines. It is detectable in the intima and in media smooth muscle cells, not only in atherosclerotic lesions but also in the very early stages of atherogenesis. sPLA2-IIA can hydrolyse the phospholipid monolayers of low density lipoproteins (LDL. Such modified LDL show increased affinity to proteoglycans. The modified particles have a greater tendency to aggregate and an enhanced ability to insert cholesterol into cells. This modification may promote macrophage LDL uptake leading to the formation of foam cells. Furthermore, sPLA2-IIA is not only a mediator for localized inflammation but may be also used as an independent predictor of adverse outcomes in patients with stable coronary artery disease or acute coronary syndromes. An interaction between activated RAS and phospholipases has been indicated by observations showing that inhibitors of sPLA2 decrease angiotensin (Ang II-induced macrophage lipid peroxidation. Meanwhile, various interactions between Ang II and oxLDL have been demonstrated suggesting a central role of sPLA2-IIA in these processes and offering a possible target for treatment. The role of sPLA2-IIA in the perpetuation of atherosclerosis appears to be the missing link between inflammation, activated RAS and lipidperoxidation.Keywords: secretory phospholipase A2, lipoproteins, renin-angiotensin system, inflammation, atherosclerosis

  1. Effects of adenosine on renin release from isolated rat glomeruli and kidney slices

    DEFF Research Database (Denmark)

    Skøtt, O; Baumbach, L

    1985-01-01

    was used. The specificity of the renin release process was validated by measuring adenylate kinase as a marker for cytoplasmatic leak. Adenosine (10 micrograms/ml) halved basal renin release from incubated KS as compared to controls (P less than 0.001, n = 8, 8). Renin release from LAG stimulated...... by calcium depletion was also inhibited (P less than 0.05, n = 8, 9) whereas basal release was not affected (n = 6, 12). No effect was detected neither on basal nor on calcium stimulated renin release from SAG. We conclude that adenosine inhibits renin release in vitro by a mechanism independent...

  2. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction

    DEFF Research Database (Denmark)

    Solomon, Scott D; Shin, Sung Hee; Shah, Amil

    2011-01-01

    Direct renin inhibitors provide an alternative approach to inhibiting the renin-angiotensin-aldosterone system (RAAS) at the most proximal, specific, and rate-limiting step. We tested the hypothesis that direct renin inhibition would attenuate left ventricular remodelling in patients following...

  3. Activation of Membrane-Bound Kallikrein and Renin in the Kidney.

    Science.gov (United States)

    1980-05-23

    included repeated washings with hypotonic buffer. Kallikrein activity in the PM fraction (PM-kallikrein) averaged 1.81 nmol of S-2266 hydrolyzed per min...thousand Fig. 1 times more active than lysolecithin on a molar basis. Lecithin and arachidonic acid were active only at a much higher concentration...taglandin E2 (11), arachidonic acid or lecithin . However, melittin, on a molar basis, was about three orders of magnitude more potent than

  4. Regulation of human renin expression in chorion cell primary cultures

    International Nuclear Information System (INIS)

    Duncan, K.G.; Haidar, M.A.; Baxter, J.D.; Reudelhuber, T.L.

    1990-01-01

    The human renin gene is expressed in the kidney, placenta, and several other sites. The release of renin or its precursor, prorenin, can be affected by several regulatory agents. In this study, primary cultures of human placental cells were used to examine the regulation of prorenin release and renin mRNA levels and of the transfected human renin promoter linked to chloramphenicol acetyltransferase reporter sequences. Treatment of the cultures with a calcium ionophore alone, calcium ionophore plus forskolin (that activates adenylate cyclase), or forskolin plus a phorbol ester increased prorenin release and renin mRNA levels 1.3 endash to 6 endash fold, but several classes of steroids did not affect prorenin secretion or renin RNA levels. These results suggest that (i) the first 584 base pairs of the renin gene 5'endash flanking DNA do not contain functional glucocorticoid or estrogen response elements, (ii) placental prorenin release and renin mRNA are regulated by calcium ion and by the combinations of cAMP with either C kinase or calcium ion, and (iii) the first 100 base pairs of the human renin 5'endash flanking DNA direct accurate initiation of transcription and can be regulated by cAMP. Thus, some control of renin release in the placenta (and by inference in other tissues) occurs via transcriptional influences on its promoter

  5. Cardiac repolarization during hypoglycaemia and hypoxaemia in healthy males: impact of renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Due-Andersen, Rikke; Høi-Hansen, Thomas; Olsen, Niels Vidiendal

    2008-01-01

    . Hypoglycaemia and hypoxaemia induced QTc prolongation (P VR increased as a function of hypoglycaemia, but were unaffected by hypoxaemia. Low RAS activity was associated with a steeper QT/RR slope in the recovery phase after both stimuli: hypoglycaemia: P = 0...

  6. Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme inhibition in patients with chronic systolic heart failure: rationale and design of the Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) study

    DEFF Research Database (Denmark)

    Krum, Henry; Massie, Barry; Abraham, William T

    2011-01-01

    AIMS: The renin-angiotensin-aldosterone system (RAAS) represents a key therapeutic target in heart failure (HF) management. However, conventional agents that block this system induce a reflex increase in plasma renin activity (PRA), which may lead to RAAS 'escape'. Direct renin inhibitors (DRIs......S for Patients with HEart failuRE (ATMOSPHERE) study is to evaluate the effect of both aliskiren and enalapril monotherapy and aliskiren/enalapril combination therapy on cardiovascular death and HF hospitalization in patients with chronic systolic HF, NYHA functional class II-IV symptoms, and elevated plasma...... levels of BNP. Methods Patients tolerant to at least 10 mg or equivalent of enalapril will undergo an open-label run-in period where they receive enalapril then aliskiren. Approximately 7000 patients tolerating this run-in period will then be randomized 1:1:1 to aliskiren monotherapy, enalapril...

  7. Influence of antihypertensive therapy, sodium intake and the concentration of potassium in plasma on concentration of aldosterone and plasma renin activity

    Directory of Open Access Journals (Sweden)

    Lalić Tijana

    2013-01-01

    Full Text Available Introduction: Primary aldosteronism (PA is a group of disorders which are characterized by inadequate and non-suppressible production of aldosterone. The prevalence of PA is increasing in hypertensive population. The golden standard of screening for primary aldosteronism, determination of aldosterone/plasma renin activity (ARR, is influenced by numerous exogenous and endogenous factors. Testing cannot always be conducted under optimal conditions. Objective: To determine influence of antihypertensive drugs and concentrations of potassium and sodium in blood and urine on values of aldosterone and plasma renin activity. Methods: In this retrospective study, we analyzed medical reports of patients admitted to Department of thyroid gland disease in the period from 2009 to 2011, with increased risk for primary aldosteronism. Body weight and height, sodium and potassium in serum and urine, plasma aldosterone concentrations and plasma renin activity, data on medicines and comorbidity were analyzed in all patients. In processing data, statistical methods descriptive analysis, Student T test and univariate linear regression were applied. Result: Of 137 patients, there were more patients with resistant hypertension (53,28% than with adrenal tumors (46,72%. Most patients used calcium channel blockers. Treatment with alpha blockers and calcium channel blockers does not influence ARR. Beta blockers and ACE inhibitors can influence ARR and diuretics and vasodilatators have definite influence. Diabetes mellitus can have higher risk of false negative results. Urine sodium excretion is significantly correlated with plasma aldosteron and serum potassium. Plasma aldosteron and PRA are significantly correlated with concentrations of electrolites in urine. Conclusion: Increased prevalence of primary aldosteronism necessitates need for accurate and better diagnostics.

  8. Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY)

    DEFF Research Database (Denmark)

    Lindhardt, Morten; Persson, Frederik; Currie, Gemma

    2016-01-01

    INTRODUCTION: Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment...... AND DISSEMINATION: The study will be conducted under International Conference on Harmonisation - Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy...

  9. Therapeutic vaccines against human and rat renin in spontaneously hypertensive rats.

    Directory of Open Access Journals (Sweden)

    Zhihua Qiu

    Full Text Available Vaccination provides a promising approach for treatment of hypertension and improvement in compliance. As the initiation factor of renin-angiotensin system, renin plays a critical role in hypertension. In this study, we selected six peptides (rR32, rR72, rR215, hR32, hR72, and hR215 belonging to potential epitopes of rat and human renin. The main criteria were as follows: (1 include one of renin catalytic sites or the flap sequence; (2 low/no-similarity when matched with the host proteome; (3 ideal antigenicity and hydrophilicity. The peptides were coupled to keyhole limpet hemocyanin and injected into SpragueDawley (SD rats, spontaneously hypertensive rats (SHRs and Wistar-Kyoto rats. The antisera titers and the binding capacity with renin were detected. The effects of the anti-peptides antibodies on plasma renin activity (PRA and blood pressure were also determined. All peptides elicited strong antibody responses. The antisera titers ranged from 1:32,000 to 1:80,000 in SD rats on day 63. All antisera could bind to renin in vitro. Compared with the control antibody, the antibodies against the rR32, hR32, rR72 and hR72 peptides inhibited PRA level by up to about 50%. Complete cross-reactivity of the anti-rR32 antibody and the anti-hR32 antibody was confirmed. The epitopes rR32 and hR32 vaccines significantly decreased systolic blood pressure (SBP of SHRs up to 15mmHg (175±2 vesus 190±3 mmHg, P = 0.035; 180±2 vesus 195±3 mmHg, P = 0.039, while no obvious effect on SD rats. Additionally, no significant immune-mediated damage was detected in the vaccinated animals. In conclusion, the antigenic peptide hR32 vaccine mimicking the (32Asp catalytic site of human renin may constitute a novel tool for the development of a renin vaccine.

  10. Free Fatty Acids Activate Renin-Angiotensin System in 3T3-L1 Adipocytes through Nuclear Factor-kappa B Pathway

    Directory of Open Access Journals (Sweden)

    Jia Sun

    2016-01-01

    Full Text Available The activity of a local renin-angiotensin system (RAS in the adipose tissue is closely associated with obesity-related diseases. However, the mechanism of RAS activation in adipose tissue is still unknown. In the current study, we found that palmitic acid (PA, one kind of free fatty acid, induced the activity of RAS in 3T3-L1 adipocytes. In the presence of fetuin A (Fet A, PA upregulated the expression of angiotensinogen (AGT and angiotensin type 1 receptor (AT1R and stimulated the secretion of angiotensin II (ANG II in 3T3-L1 adipocytes. Moreover, the activation of RAS in 3T3-L1 adipocytes was blocked when we blocked Toll-like receptor 4 (TLR4 signaling pathway using TAK242 or NF-κB signaling pathway using BAY117082. Together, our results have identified critical molecular mechanisms linking PA/TLR4/NF-κB signaling pathway to the activity of the local renin-angiotensin system in adipose tissue.

  11. Chronic activation of plasma renin is log-linearly related to dietary sodium and eliminates natriuresis in response to a pulse change in total body sodium

    DEFF Research Database (Denmark)

    Kjolby, Mads; Bie, Peter

    2008-01-01

    rate, urine flow, plasma potassium, and plasma renin activity did not change. The results indicate that sodium excretion is controlled by neurohumoral mechanisms that are quite resistant to acute changes in plasma volume and colloid osmotic pressure and are not down-regulated within 2 h. With previous......Cl administration increased PV (+6.3-8.9%) and plasma sodium concentration (~2%) and decreased plasma protein concentration (-6.4-8.1%). Plasma ANG II and aldosterone concentrations decreased transiently. Potassium excretion increased substantially. Sodium excretion, arterial blood pressure, glomerular filtration...

  12. A case of posterior reversible encephalopathy syndrome in the setting of post-partum preeclampsia with suppressed plasma aldosterone levels and plasma renin activity

    Directory of Open Access Journals (Sweden)

    Aurelio Negro

    2013-12-01

    Full Text Available Posterior reversible encephalopathy syndrome (PRES is characterized by headache, altered mental status, visual loss, and seizures. PRES is associated with neuroradiological findings: white matter abnormalities, predominantly in the parieto-occipital regions of the brain. PRES has been described in association with hypertensive encephalopathy, eclampsia, renal failure, or following immunosuppressive or anticancer therapy. We report a case of PRES in a severe preeclampsia occurring in the late postpartum period, with suppressed plasma aldosterone levels and plasma renin activity. These laboratory abnormalities may be due to an apparent mineralocorticoid excess syndrome.

  13. The role of the renin-angiotensin-aldosterone system in heart failure

    Directory of Open Access Journals (Sweden)

    Thomas Unger

    2004-03-01

    Full Text Available Activity of the renin-angiotensin-aldosterone system (RAAS is increased in patients with heart failure, and its maladaptive mechanisms may lead to adverse effects such as cardiac remodelling and sympathetic activation. Elevated renin activity has been demonstrated in patients with dilated cardiomyopathy. (Third-generation synthetic non-peptide renin inhibitors, with more favourable properties than earlier renin inhibitors, lower ambulatory blood pressure and may have a role to play in other cardiovascular disease. Chymase, a protease inhibitor stored in mast cells that generates angiotensin II (Ang II (in addition to angiotensin-converting enzyme [ACE], has been linked to extracellular matrix remodelling in heart failure. Again, chymase inhibitors have been developed to investigate its functions in vitro and in vivo. Bradykinin is thought to contribute to the cardioprotective effect of ACE inhibition through modification of nitric oxide release, calcium handling and collagen accumulation. Ang II is believed to influence a number of molecular and structural changes in the heart, mostly mediated through the AT1-receptor. The importance of the RAAS in heart failure is shown by the survival benefit conferred by treatment with ACE inhibitors.

  14. Regulation of renin secretion by renal juxtaglomerular cells

    DEFF Research Database (Denmark)

    Friis, Ulla G; Madsen, Kirsten; Stubbe, Jane

    2013-01-01

    A major rate-limiting step in the renin-angiotensin-aldosterone system is the release of active renin from endocrine cells (juxtaglomerular (JG) cells) in the media layer of the afferent glomerular arterioles. The number and distribution of JG cells vary with age and the physiological level...

  15. Influence of bicarbonate on the sensitivity of renin release to sodium chloride

    DEFF Research Database (Denmark)

    Skøtt, O; Jensen, B L

    1989-01-01

    glomeruli treated with bicarbonate/chloride exchange inhibitor (DNDS), NaCl/KCl cotransport inhibitor (bumetanide), or Na+/H+ antiport inhibitor (amiloride) in the presence or absence of bicarbonate. In addition, the sensitivity to increases in osmolality by addition of sucrose was tested in the presence...... or absence of bicarbonate. Renin release from time controls superfused with a bicarbonate-free Ringer was identical to release from glomeruli superfused with a bicarbonate Ringer. DNDS (0.11 or 1.1 mM) had no effect on renin release in a bicarbonate Ringer. 30 mM sucrose inhibited renin release independently...... of bicarbonate. 15 mM NaCl stimulated renin release when bicarbonate was absent, while it caused an inhibition in the presence of bicarbonate. When bicarbonate/chloride exchange was inhibited, addition of NaCl stimulated renin release even when bicarbonate was present. The effect of NaCl on renin release...

  16. Intracellular renin disrupts chemical communication between heart cells. Pathophysiological implications

    Directory of Open Access Journals (Sweden)

    Walmor eDe Mello

    2015-01-01

    Full Text Available The influence of intracellular renin on the process of chemical communication between cardiac cells was investigated in cell pairs isolated from the left ventricle of adult Wistar Kyoto rats. The enzyme together with Lucifer yellow CH was dialyzed into one cell of the pair using the whole cell clamp technique. The diffusion of the dye in the dialyzed and in non-dialyzed cell was followed by measuring the intensity of fluorescence in both cells as a function of time. The results indicated that; 1 under normal conditions, Lucifer Yellow flows from cell-to-cell through gap junctions; 2 the intracellular dialysis of renin (100nM disrupts chemical communication-an effect enhanced by simultaneous administration of angiotensinogen (100nM; 3 enalaprilat (10-9M administered to the cytosol together with renin reduced drastically the uncoupling action of the enzyme; 4 aliskiren (10-8M inhibited the effect of renin on chemical communication;5 the possible role of intracellular renin independently of angiotensin II (Ang II was evaluated including the increase of the inward calcium current elicited by the enzyme and the possible role of oxidative stress on the disruption of cell communication; 6 the possible harmful versus the beneficial effect of intracellular renin during myocardial infarction was discussed;7 the present results indicate that intracellular renin due to internalization or in situ synthesis, causes a severe impairment of chemical communication in the heart resulting in derangement of metabolic cooperation with serious consequences for heart function.

  17. Human renin biosynthesis and secretion in normal and ischemic kidneys

    International Nuclear Information System (INIS)

    Pratt, R.E.; Carleton, J.E.; Richie, J.P.; Heusser, C.; Dzau, V.J.

    1987-01-01

    The pathway of renin biosynthesis and secretion in normal and ischemic human kidneys has been investigated by pulse-labeling experiments. The results indicate that in normal human kidney, preprorenin is rapidly processed to 47-kDa prorenin. Microradiosequencing showed that this molecule was generated by cleavage between Gly-23 and Leu-24, yielding a 43-amino acid proregion. Analysis of prorenin secreted by the kidney tissue yielded an identical sequence, indicating that prorenin is secreted without any further proteolysis. An examination of the kinetics of processing and secretion suggested that a majority of the newly synthesized prorenin is quickly secreted, while only a small fraction is processed intracellularly to the mature renin. The differences in secretion kinetics between prorenin and mature renin and the selective inhibition of prorenin secretion by monensin suggest that they are secreted independently via two pathways: a constitutive pathway probably from the Golgi or protogranules that rapidly release prorenin and a regulated pathway that secretes mature renin from the mature granules. A comparison of the kinetics of processing between normal and ischemic tissues suggests that renal ischemia leads to an overall increase in the rate of processing or prorenin to mature renin. In addition, prolonged biosynthetic labeling of renin in the ischemic kidney yielded two smaller molecular weight immunoreactive forms suggestive of renin fragments that may be degradative products. These fragments were not detected in normal kidney tissue labeled for similar lengths of time

  18. Giant renin secretory granules in beige mouse renal afferent arterioles

    DEFF Research Database (Denmark)

    Jensen, B L; Rasch, Ruth; Nyengaard, Jens Randel

    1997-01-01

    The mutant beige mouse (C57BL/6 bg) has a disease characterised by abnormally enlarged cytoplasmic granules in a variety of cells. With the purpose of establishing a suitable cellular model for studying renin secretion, the present study was undertaken to compare renin granule morphology in beige...... (average granular volume 0.681 microm3), whereas 1-2 large granules were present per cell in beige mice. The volume of afferent arteriole that contained secretory granules was lower in the beige mice. We conclude that the beige mouse synthesizes, stores and releases active renin. Renin secretory granules...... in beige mice are grossly enlarged with 1-2 granules per juxtaglomerular cell. Compared with control mice, a similar amount of total renin granule volume per afferent arteriole is contained in a smaller part of beige mouse afferent arteriole. Granular cells from beige mice could therefore be a valuable...

  19. Reduced plasma levels of angiotensin-(1-7 and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

    Directory of Open Access Journals (Sweden)

    E.P. Velloso

    2007-04-01

    Full Text Available The relationship between preeclampsia and the renin-angiotensin system (RAS is poorly understood. Angiotensin I-converting enzyme (ACE is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II and inactivating the vasodilator angiotensin-(1-7 (Ang-(1-7. ACE (I/D polymorphism is characterized by the insertion (I or deletion (D of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D polymorphism was correlated with plasma Ang-(1-7 levels and several RAS components in both preeclamptic (N = 20 and normotensive pregnant women (N = 20. The percentage of the ACE DD genotype (60% in the preeclamptic group was higher than that for the control group (35%; however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260. The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 ± 5.06 vs 27.6 ± 3.25 nmol Hip-His Leu-1 min-1 mL-1 in DD control patients; P = 0.0005. Plasma renin activity was markedly reduced in preeclampsia (0.81 ± 0.2 vs 3.43 ± 0.8 ng Ang I mL plasma-1 h-1 in DD normotensive patients; P = 0.0012. A reduced plasma level of Ang-(1-7 was also observed in preeclamptic women (15.6 ± 1.3 vs 22.7 ± 2.5 pg/mL in the DD control group; P = 0.0146. In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

  20. Reduced plasma levels of angiotensin-(1-7 and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

    Directory of Open Access Journals (Sweden)

    E.P. Velloso

    Full Text Available The relationship between preeclampsia and the renin-angiotensin system (RAS is poorly understood. Angiotensin I-converting enzyme (ACE is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II and inactivating the vasodilator angiotensin-(1-7 (Ang-(1-7. ACE (I/D polymorphism is characterized by the insertion (I or deletion (D of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D polymorphism was correlated with plasma Ang-(1-7 levels and several RAS components in both preeclamptic (N = 20 and normotensive pregnant women (N = 20. The percentage of the ACE DD genotype (60% in the preeclamptic group was higher than that for the control group (35%; however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260. The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 ± 5.06 vs 27.6 ± 3.25 nmol Hip-His Leu-1 min-1 mL-1 in DD control patients; P = 0.0005. Plasma renin activity was markedly reduced in preeclampsia (0.81 ± 0.2 vs 3.43 ± 0.8 ng Ang I mL plasma-1 h-1 in DD normotensive patients; P = 0.0012. A reduced plasma level of Ang-(1-7 was also observed in preeclamptic women (15.6 ± 1.3 vs 22.7 ± 2.5 pg/mL in the DD control group; P = 0.0146. In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

  1. Expression and nutritional regulation of the (pro)renin receptor in rat visceral adipose tissue.

    Science.gov (United States)

    Achard, V; Tassistro, V; Boullu-Ciocca, S; Grino, M

    2011-12-01

    Early life nutritional environment plays an important role in the development of visceral adipose tissue and interacts with nutritional regulations in adulthood, leading to metabolic dysregulations. We hypothesized that the renin-angiotensin system may play a role in the programming-induced development of visceral adipose tissue. We studied, using a model of programming of overweight and glucose intolerance, obtained by post-natal overfeeding with consecutive highfat diet, the status of plasma renin activity and mesenteric adipose renin-angiotensin system, including the recently identified (pro)renin receptor, in adult rats. Post-natal overfeeding or high-fat feeding lead to overweight with increased visceral fat mass and adipocytes surface. When both paradigms were associated, adipocytes surface showed a disproportionate increase. A strong immunoreactivity for (pro)renin receptor was found in stromal cells. Plasma renin activity increased in programmed animals whereas (pro)renin receptor expressing cells density was stimulated by high-fat diet. There was a positive, linear relationship between plasma renin activity and (pro)renin receptor expressing cells density and adipocytes surface. Our experiments demonstrate that association of post-natal overfeeding and high-fat diet increased plasma renin activity and adipose (pro)renin receptor expression. Such phenomenon could explain, at least in part, the associated disproportionate adipocyte hypertrophy and its accompanying increased glucose intolerance.

  2. Renin secretion from permeabilized juxtaglomerular cells requires a permeant cation

    DEFF Research Database (Denmark)

    Jensen, B L; Ellekvist, Peter; Skøtt, O

    1999-01-01

    The cytosolic concentration of chloride correlates directly with renin secretion from renal juxtaglomerular granular (JG) cells. In the present study, the mechanism by which chloride stimulates renin release was investigated in a preparation of permeabilized rat glomeruli with attached JG cells....... An isosmotic increase in the concentration of chloride by 129 mM stimulated renin release 16- to 20-fold. Substitution of K+ by the impermeant cation N-methyl-d-glucamine (NMDG) abolished this response, while substitution with Na+ caused marginal inhibition. Substitution with Cs+ had no effect. Addition...... of sucrose, which permeates the secretory granules poorly, also abolished the stimulation of renin secretion by KCl. The response to KCl was not affected by K+-channel antagonists or by agonists of K+ channels. Chloride channel blockers were also without effect on the secretory response to KCl. When the ATP...

  3. A case of low renin hyperaldosteronism considered to be aldosterone-producing adrenocortical adenoma by CT image of adrenal gland

    International Nuclear Information System (INIS)

    Hayashi, Kozo; Tsuchihashi, Yoshihiro; Ito, Kazuro; Ozono, Noboru

    1983-01-01

    A case was reported in which hypertension, hypopotassemia, low plasma renin activity and hyperaldosteronemia were observed. Imaging suggested adrenocortical adenoma, leading to the diagnosis of low renin hyperaldosteronism. (Chiba, N.)

  4. Renal Kallikrein Activation and Renoprotection after Dual Blockade of Renin-Angiotensin System in Diet-Induced Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Xia Zou

    2015-01-01

    Full Text Available Purpose. The objective of this study is to investigate the effect of dual blockage of renin-angiotensin system (RAS on renal kallikrein expression and inflammatory response in diabetic nephropathy (DN. Methods. Rats were randomly divided into 5 groups with 10 rats in each group: normal control; DN model induced by high fat and high sucrose diets; and DN treated with either benazepril 10 mg/kg/d, irbesartan 30 mg/kg/d, or both. After 8-week treatment, we examined changes in the kidney histopathology, function and immunohistochemical stain of kallikrein, macrophage marker CD68, and profibrotic markers transforming growth factor- (TGF- β and α-smooth muscle action (SMA. Results. DN rats showed enlarged kidneys with glomerulosclerosis, interstitial chronic inflammation and fibrosis, and proteinuria. All the pathological damage and functional impairments were improved after the RAS blockades (all P<0.05. Compared with monotherapy, combined treatment further alleviated the kidney impairments in parallel to increased tubular immunoreactivity for kallikrein and decreased immunopositive cells for CD68, TGF-β, and α-SMA. Conclusion. The renoprotective effects of the dual RAS blockade in diabetic nephropathy may be attributed to improved tubular kallikrein expression and interstitial inflammatory response.

  5. Radioimmunoassay - renin - angiotensin. Principles of radioimmunoassay and their application in measuring renin and angiotensin

    Energy Technology Data Exchange (ETDEWEB)

    Krause, D K; Hummerich, W; Poulsen, K [eds.

    1978-01-01

    Typical pitfalls such as impurity of 'standard', tracer damage, crossreactivity of antiserum, unspecific binding of protecting proteins, blank effects with negative results, charcoal stripping, invisible coprecipitate or uncertainty in the analysis of the calibration curve (graph, logit-log, polynormal or spline function) can occur in any type of radioimmunoassay; they are detailed in the general part of this book. The special position occupied by radioimmunological quantification of parameters of the renin-angiotensin system creates additional, even more serious problems. While the radioimmunological determination of the decapeptide angiotensin I no longer causes major obstacles, measurement of the biologically active octapeptide angiotensin II is still only possible in a few centers. The (indirect) determination of plasma renin is characterized by a situation where the enzyme renin may be clearly defined in theory as a specific 10-11-leucine-leucine-endopeptidase cleaving only a decapeptide, but the actual renin assay, however, measures various forms of renin and other angiotensin-forming (or angiotensin-destroying) enzymes at the same time.

  6. New sensitive direct radioimmunoassay for human plasma renin and its clinical application

    International Nuclear Information System (INIS)

    Higaki, J.; Ogihara, T.; Imai, N.; Kumahara, Y.; Hontani, S.; Nishiura, M.; Ogawa, H.; Hirose, S.; Murakami, K.

    1984-01-01

    A new sensitive direct radioimmunoassay for human plasma renin has been developed. Renin was purified from Haas' preparation utilizing a pepstatin-C 6 -Sepharose affinity chromatography. Antiserum, prepared by immunizing rabbits with the purified renin, was used for the direct radioimmunoassay at a final dilution of 1:30,000. The antibody was specific for human renal and plasma renin, but did not cross-react with cathepsin D, trypsin, or renins of mouse, dog, and rat. Radioimmunoassay was performed by the double antibody technique using the delayed tracer addition method. In this method, a standard curve was obtained over a range from 0.2 to 8.0 ng/ml. The values from this assay correlated well with total renin activity measured as the generation rate of angiotensin I after trypsin activation, but correlated weakly with active renin activity. This finding disclosed that both active and inactive renin were detected by this method. In normal participants, plasma renin concentration determined by direct radioimmunoassay was increased by standing and furosemide injection. The plasma renin concentration determined by direct radioimmunoassay of patients with essential hypertension was not significantly different from values in normal controls. The values were higher in patients with renovascular hypertension, malignant hypertension and Bartter's syndrome, but lower in patients with primary aldosteronism than in normal controls. 20 references, 7 figures

  7. Emerging drugs which target the renin-angiotensin-aldosterone system.

    Science.gov (United States)

    Steckelings, Ulrike Muscha; Paulis, Ludovit; Unger, Thomas; Bader, Michael

    2011-12-01

    The renin-angiotensin-aldosterone system (RAAS) is already the most important target for drugs in the cardiovascular system. However, still new developments are underway to interfere with the system on different levels. The novel strategies to interfere with RAAS aim to reduce the synthesis of the two major RAAS effector hormones, angiotensin (Ang) II and aldosterone, or interfere with their receptors, AT1 and mineralocorticoid receptor, respectively. Moreover, novel targets have been identified in RAAS, such as the (pro)renin receptor, and molecules, which counteract the classical actions of Ang II and are therefore beneficial in cardiovascular diseases. These include the AT2 receptor and the ACE2/Ang-(1-7)/Mas axis. The search for drugs activating these tissue-protective arms of RAAS is therefore the most innovative field in RAAS pharmacology. Most of the novel pharmacological strategies to inhibit the classical RAAS need to prove their superiority above the existing treatment in clinical trials and then have to compete against these now quite cheap drugs in a competitive market. The newly discovered targets have functions beyond the cardiovascular system opening up novel therapeutic areas for drugs interfering with RAAS components.

  8. Effect of Losartan on Right Ventricular Dysfunction: Results From the Double-Blind, Randomized REDEFINE Trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) in Adults With Repaired Tetralogy of Fallot.

    Science.gov (United States)

    Bokma, Jouke P; Winter, Michiel M; van Dijk, Arie P; Vliegen, Hubert W; van Melle, Joost P; Meijboom, Folkert J; Post, Martijn C; Berbee, Jacqueline K; Boekholdt, S Matthijs; Groenink, Maarten; Zwinderman, Aeilko H; Mulder, Barbara J M; Bouma, Berto J

    2018-04-03

    The effect of angiotensin II receptor blockers on right ventricular (RV) function is still unknown. Angiotensin II receptor blockers are beneficial in patients with acquired left ventricular dysfunction, and recent findings have suggested a favorable effect in symptomatic patients with systemic RV dysfunction. The current study aimed to determine the effect of losartan, an angiotensin II receptor blocker, on subpulmonary RV dysfunction in adults after repaired tetralogy of Fallot. The REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) is an investigator-initiated, multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled study. Adults with repaired tetralogy of Fallot and RV dysfunction (RV ejection fraction [EF] 0.30 for all). In predefined subgroup analyses, losartan did not have a statistically significant impact on RV EF in subgroups with symptoms, restrictive RV, RV EFtetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02010905. © 2017 American Heart Association, Inc.

  9. The renin-angiotensin system and its blockers

    Directory of Open Access Journals (Sweden)

    Igić Rajko

    2014-01-01

    Full Text Available Research on the renin-angiotensin system (RAS has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of cardiovascular diseases. This review offers a brief history of the RAS with an overview of its major components and their functions, as well as blockers of the RAS, their clinical usage and current research that targets various components of the RAS. Because angiotensin-converting enzyme (ACE metabolizes two biologically active peptides, one in the kallikrein-kinin system (KKS and one in the RAS, it is the essential connection between the two systems. ACE releases very powerful hypertensive agent, angiotensin II and also inactivates strong hypotensive peptide, bradykinin. Inhibition of ACE thus has a dual effect, resulting in decreased angiotensin II and increased bradykinin. We described the KKS as well.

  10. Role of (Pro)Renin Receptor in Albumin Overload-Induced Nephropathy in Rats.

    Science.gov (United States)

    Fang, Hui; Deng, Mokan; Zhang, Linlin; Lu, Aihua; Su, Jiahui; Xu, Chuanming; Zhou, Li; Wang, Lei; Ou, Jing-Song; Wang, Weidong; Yang, Tianxin

    2018-05-30

    Proteinuria is not only a common feature of chronic kidney diseases (CKD) but also an independent risk factor promoting CKD progression to end-stage renal failure. However, the underlying molecular mechanisms for protein overload-induced renal injury remain elusive. The present study examined the role of (pro)renin receptor (PRR) in pathogenesis of albumin overload (AO)-induced nephropathy and activation of intrarenal renin-angiotensin system (RAS) in rats. Wistar rats underwent unilateral nephrectomy and were treated for 7 weeks with vehicle, bovine serum albumin (5 g/kg/d via a single i.p. injection) alone or in conjunction with a PRR decoy inhibitor PRO20 (500 μg/kg/d via 3 s.c. injections). The AO rat model exhibited severe proteinuria, tubular necrosis, and interstitial fibrosis, oxidative stress, inflammation, accompanied by elevated urinary N-acetyl-beta-D-glucosaminidase activity and urinary β2-microglobulin secretion, all of which were significantly attenuated by PRO20. Urinary and renal levels of renin, angiotensinogen (AGT), and Ang II were elevated by AO and suppressed by PRO20, contrasting to largely unaltered plasma levels of the RAS parameters. The AO model also showed increased renal expression of full-length PRR and soluble PRR (sPRR) and urinary excretion of sPRR. Taken together, we conclude that PRR antagonism with PRO20 alleviates AO-induced nephropathy via inhibition of intrarenal RAS.

  11. Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells

    DEFF Research Database (Denmark)

    Friis, Ulla Glenert; Stubbe, Jane; Uhrenholt, Torben Rene

    2005-01-01

    /l), AE1-259-01 (1 nmol/l), EP4-selective agonist AE1-329 (1 nmol/l), and IP agonist iloprost (1 micromol/l) significantly increased C(m) mediated by PKA. The EP4 antagonist AE3-208 (10 nmol/l) blocked the effect of EP4 agonist but did not alter the response to PGE(2). Application of both EP4 antagonist....... The membrane potential hyperpolarized significantly after PGE(2), butaprost, AE1-329 and AE1-259 and outward current was augmented in a PKA-dependent fashion. PGE(2)-stimulated outward current, but not C(m) change, was abolished by the BK(Ca) channel inhibitor iberiotoxin (300 nmol/l). EP2 and EP4 m......RNA was detected in sampled JG cells, and the preglomerular and glomerular vasculature was immunopositive for EP4. Thus IP, EP2, and EP4 receptors are associated with JG cells, and their activation leads to rapid PKA-mediated exocytotic fusion and release of renin granules....

  12. Inhibition of intestinal disaccharidase activity by pentoses

    DEFF Research Database (Denmark)

    Halschou-Jensen, Kia

    on carbohydrate- ingesting enzymes activity in vitro and possible effects on human postprandial blood response. In paper 1 the effects of sugar beet polyphenols from molasses and the potential inhibition of sucrase activity in vitro, was investigated. Two different polyphenol-rich fractions from chromatographic...... separation of molasses from sugar beets and pure ferulic acid were tested. We found no effects of the two fractions of molasses. The pure ferulic acid indicated an inhibition of sucrase in vitr. Both in vitro and in vivo studies have investigated the effects of L-arabinose and D-xylose on carbohydrate...

  13. Anthology of the renin-angiotensin system: a one hundred reference approach to angiotensin II antagonists.

    Science.gov (United States)

    Ménard, J

    1993-04-01

    To provide a historical overview of the renin-angiotensin system as a guide to the introduction of a new therapeutic pathway, non-peptide inhibition of a angiotensin II. One hundred references were selected as a personal preference, for their originality or for their potential impact on medicine. This review raises the following questions for future research. (1) Will the long-term cardiovascular effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II antagonism and renin inhibition be similar or not, and dependent or independent of blood pressure levels? (2) What are the local-regional interactions between vasoconstrictor and vasodilator systems, and does the renin-angiotensin system synchronize these regional hemodynamic regulatory mechanisms? (3) If hypertension is the result of an interaction between genetic and environmental factors, do proteins secreted through constitutive pathways contribute to the genetic abnormality (prorenin, angiotensinogen, ACE) while regulated secretion (renin) and other regulatory mechanisms (angiotensin II receptors) provide biological support for the environmental effects?

  14. Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice.

    Science.gov (United States)

    Fukushima, Arata; Kinugawa, Shintaro; Takada, Shingo; Matsumoto, Junichi; Furihata, Takaaki; Mizushima, Wataru; Tsuda, Masaya; Yokota, Takashi; Matsushima, Shouji; Okita, Koichi; Tsutsui, Hiroyuki

    2016-05-15

    Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. NT-pro-BNP during hypoglycemia and hypoxemia in normal subjects: impact of renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Due-Andersen, R; Pedersen-Bjergaard, U; Høi-Hansen, T

    2008-01-01

    subjects with high-RAS activity and 10 subjects with low-RAS activity (age 26 +/- 1 yr; mean +/- SE) were studied in a single-blinded, randomized, counterbalanced, crossover study on three occasions separated by at least 3 wk: 1) hypoglycemia (mean nadir plasma glucose 2.7 +/- 0.5 mmol/l), 2) hypoxemia...

  16. Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcomes.

    Science.gov (United States)

    Clase, Catherine M; Barzilay, Joshua; Gao, Peggy; Smyth, Andrew; Schmieder, Roland E; Tobe, Sheldon; Teo, Koon K; Yusuf, Salim; Mann, Johannes F E

    2017-03-01

    Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  17. The renin-angiotensin system in kidney development

    DEFF Research Database (Denmark)

    Jensen, B L; Stubbe, J; Madsen, K

    2004-01-01

    Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data on the develo......Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data...... on the developmental changes of RAAS and COX-2 and the pathways by which they are activated; their possible interplay and the mechanisms by which they affect kidney development. Intrarenal and circulating renin and angiotensin II (ANG II) are stimulated at birth in most mammals. In rats, renin and ANG II stay...... glucocorticoid concentration and by a low NaCl intake. Studies with selective inhibitors of COX-2 and COX-2 null mice show that COX-2 activity stimulates renin secretion from JG-cells during postnatal kidney development and that lack of COX-2 activity leads to pathological change in cortical architecture...

  18. Effects of renal denervation on cardiac oxidative stress and local activity of the sympathetic nervous system and renin-angiotensin system in acute myocardial infracted dogs.

    Science.gov (United States)

    Feng, Qiaoli; Lu, Chengzhi; Wang, Li; Song, Lijun; Li, Chao; Uppada, Ravi Chandra

    2017-02-17

    This study sought to evaluate the therapeutic effects of renal denervation (RDN) on acute myocardial infarction (MI) in canines and explore its possible mechanisms of action. Eighteen healthy mongrel dogs were randomly assigned to either the control group, the MI group or the MI + RDN group. To assess cardiac function, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD) and fraction shortening (FS) were recorded. Additionally, haemodynamic parameters such as left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and heart rate (HR) were measured. Cardiac oxidative stress levels were evaluated based on the expression of p47 phox mRNA, malondialdehyde (MDA), anti-superoxide anion free radical (ASAFR) and activity of superoxide dismutase (SOD). To measure the local activity of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS), the levels of tyrosine hydroxylase (TH), angiotensin II (AngII), angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7) [Ang(1-7)] and Mas receptor (MasR) in myocardial tissues were recorded. The expression of TH in renal tissue and serum creatinine were used to assess the effectiveness of the RDN procedure and renal function, respectively. We found that MI deteriorated heart function and activated cardiac oxidative stress and the local neurohumoral system, while RDN partially reversed these changes. Compared with the control group, parameters including LVEDD, LVESD, LVEDP and the levels of ASAFR, MDA, p47 phox ,ACE2, Ang(1-7), MasR, AngII and TH-positive nerves were increased (all P < 0.05) in myocardial infracted dogs; meanwhile, LVEF, FS, LVSP and SOD expression were decreased (all P < 0.05). However, after RDN therapy, these changes were significantly improved (P < 0.05), except that there were no significant differences observed in FS or LVSP between the two groups (P = 0

  19. Na+/K+-ATPase: Activity and inhibition

    Science.gov (United States)

    Čolović, M.; Krstić, D.; Krinulović, K.; Momić, T.; Savić, J.; Vujačić, A.; Vasić, V.

    2009-09-01

    The aim of the study was to give an overview of the mechanism of inhibition of Na+/K+-ATPase activity induced by some specific and non specific inhibitors. For this purpose, the effects of some ouabain like compounds (digoxin, gitoxin), noble metals complexes ([PtCl2DMSO2], [AuCl4]-, [PdCl4]2-, [PdCl(dien)]+, [PdCl(Me4dien)]+), transition metal ions (Cu2+, Zn2+, Fe2+, Co2+), and heavy metal ions (Hg2+, Pb2+, Cd2+) on the activity of Na+/K+-ATPase from rat synaptic plasma membranes (SPM), porcine cerebral cortex and human erythrocytes were discussed.

  20. Erythropoietin during hypoglycaemia in type 1 diabetes: relation to basal renin-angiotensin system activity and cognitive function

    DEFF Research Database (Denmark)

    Kristensen, Peter Lommer; Høi-Hansen, Thomas; Olsen, Niels Vidiendal

    2009-01-01

    diabetes with high and nine with low activity in RAS were studied. Hypoglycaemia was induced using a standardized insulin-infusion. RESULTS: Overall, erythropoietin concentrations increased during hypoglycaemia. In the high RAS group erythropoietin rose 29% (p=0.032) whereas no significant response...... was observed in the low RAS group (7% increment; p=0.43). Independently, both hypoglycaemia and high RAS activity were associated with higher levels of erythropoietin (p=0.02 and 0.04, respectively). Low plasma erythropoietin at baseline was associated with poorer cognitive performance during hypoglycaemia...

  1. Local renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy.

    Science.gov (United States)

    Kobori, H; Ichihara, A; Miyashita, Y; Hayashi, M; Saruta, T

    1999-01-01

    We have reported previously that thyroid hormone activates the circulating and tissue renin-angiotensin systems without involving the sympathetic nervous system, which contributes to cardiac hypertrophy in hyperthyroidism. This study examined whether the circulating or tissue renin-angiotensin system plays the principal role in hyperthyroidism-induced cardiac hypertrophy. The circulating renin-angiotensin system in Sprague-Dawley rats was fixed by chronic angiotensin II infusion (40 ng/min, 28 days) via mini-osmotic pumps. Daily i.p. injection of thyroxine (0.1 mg/kg per day, 28 days) was used to mimic hyperthyroidism. Serum free tri-iodothyronine, plasma renin activity, plasma angiotensin II, cardiac renin and cardiac angiotensin II were measured with RIAs. The cardiac expression of renin mRNA was evaluated by semiquantitative reverse transcriptase-polymerase chain reaction. Plasma renin activity and plasma angiotensin II were kept constant in the angiotensin II and angiotensin II+thyroxine groups (0.12+/-0.03 and 0.15+/-0.03 microgram/h per liter, 126+/-5 and 130+/-5 ng/l respectively) (means+/-s.e.m.). Despite stabilization of the circulating renin-angiotensin system, thyroid hormone induced cardiac hypertrophy (5.0+/-0.5 vs 3.5+/-0.1 mg/g) in conjunction with the increases in cardiac expression of renin mRNA, cardiac renin and cardiac angiotensin II (74+/-2 vs 48+/-2%, 6.5+/-0.8 vs 3.8+/-0.4 ng/h per g, 231+/-30 vs 149+/-2 pg/g respectively). These results indicate that the local renin-angiotensin system plays the primary role in the development of hyperthyroidism-induced cardiac hypertrophy.

  2. Theobromine inhibits sensory nerve activation and cough.

    Science.gov (United States)

    Usmani, Omar S; Belvisi, Maria G; Patel, Hema J; Crispino, Natascia; Birrell, Mark A; Korbonits, Márta; Korbonits, Dezso; Barnes, Peter J

    2005-02-01

    Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

  3. Atrial distension, haemodilution, and acute control of renin release during water immersion in humans

    DEFF Research Database (Denmark)

    Gabrielsen, A; Pump, B; Bie, P

    2002-01-01

    immersion. During WI, central venous pressure (CVP) and left atrial diameter (LAD) increased (P ... is not the single pivotal stimulus for the acute suppression of renin release in response to intravascular volume expansion by water immersion in humans. Haemodilution constitutes a significant and conceivably the principal stimulus for the acute immersion-induced suppression of renin-angiotensin system activity....

  4. Kaempferol inhibits thrombosis and platelet activation.

    Science.gov (United States)

    Choi, Jun-Hui; Park, Se-Eun; Kim, Sung-Jun; Kim, Seung

    2015-08-01

    The objectives of the present study were to investigate whether kaempferol affects pro-coagulant proteinase activity, fibrin clot formation, blood clot and thrombin (or collagen/epinephrine)-stimulated platelet activation, thrombosis, and coagulation in ICR (Imprinting Control Region) mice and SD (Sprague-Dawley) rats. Kaempferol significantly inhibited the enzymatic activities of thrombin and FXa by 68 ± 1.6% and 52 ± 2.4%, respectively. Kaempferol also inhibited fibrin polymer formation in turbidity. Microscopic analysis was performed using a fluorescent conjugate. Kaempferol completely attenuated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) 1/2, and phosphoinositide 3-kinase (PI3K)/PKB (AKT) in thrombin-stimulated platelets and delayed aggregation time (clotting) by 34.6% in an assay of collagen/epinephrine-stimulated platelet activation. Moreover, kaempferol protected against thrombosis development in 3 animal models, including collagen/epinephrine- and thrombin-induced acute thromboembolism models and an FeCl3-induced carotid arterial thrombus model. The ex vivo anticoagulant effect of kaempferol was further confirmed in ICR mice. This study demonstrated that kaempferol may be clinically useful due to its ability to reduce or prevent thrombotic challenge. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  5. Studies on renin release in vitro

    DEFF Research Database (Denmark)

    Skøtt, O

    1989-01-01

    1) Measurements of renin secretion from single arterioles at time intervals down to 20 seconds showed that the renin secretion is episodic, the amount of renin released during each episode corresponding to the estimated content of one secretory granule. 2) A decrease in osmolality elicits episodi...

  6. Trace element inhibition of phytase activity.

    Science.gov (United States)

    Santos, T; Connolly, C; Murphy, R

    2015-02-01

    Nowadays, 70 % of global monogastric feeds contains an exogenous phytase. Phytase supplementation has enabled a more efficient utilisation of phytate phosphorous (P) and reduction of P pollution. Trace minerals, such as iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn) are essential for maintaining health and immunity as well as being involved in animal growth, production and reproduction. Exogenous sources of phytase and trace elements are regularly supplemented to monogastric diets and usually combined in a premix. However, the possibility for negative interaction between individual components within the premix is high and is often overlooked. Therefore, this initial study focused on assessing the potential in vitro interaction between inorganic and organic chelated sources of Fe, Zn, Cu and Mn with three commercially available phytase preparations. Additionally, this study has investigated if the degree of enzyme inhibition was dependent of the type of chelated sources. A highly significant relationship between phytase inhibition, trace mineral type as well as mineral source and concentration, p phytases for Fe and Zn, as well as for Cu with E. coli and Aspergillus niger phytases. Different chelate trace mineral sources demonstrated diversifying abilities to inhibit exogenous phytase activity.

  7. Linking algal growth inhibition to chemical activity

    DEFF Research Database (Denmark)

    Schmidt, Stine N.; Mayer, Philipp

    Unitless chemical activity, expressing the energetic level of a compound relative to its energetic level in pure liquid [0-1], has proven useful to quantify the effective exposure to hydrophobic organic compounds through both aerial and aqueous media. Several studies have linked toxicity to chemi......Unitless chemical activity, expressing the energetic level of a compound relative to its energetic level in pure liquid [0-1], has proven useful to quantify the effective exposure to hydrophobic organic compounds through both aerial and aqueous media. Several studies have linked toxicity...... to chemical activity, as opposed to e.g. the total concentration. Baseline toxicity (narcosis) for neutral hydrophobic organic compounds has been shown to initiate in the narrow chemical activity range of 0.01 to 0.1. This presentation focuses on linking algal growth inhibition to chemical activity......-polar liquids were applied to challenge the chemical activity range for baseline toxicity. For each compound, the effective activity (Ea50) was estimated as the ratio of the effective concentration (EC50) and water solubility. Of these ratios, 90% were within the expected chemical activity range of 0.01 to 0...

  8. Early pharmacological inhibition of angiotensin-I converting enzyme activity induces obesity in adulthood

    Directory of Open Access Journals (Sweden)

    Kely ede Picoli Souza

    2015-04-01

    Full Text Available We have investigated early programming of body mass in order to understand the multifactorial etiology of obesity. Considering that the renin-angiotensin system is expressed and functional in the white adipose tissue (WAT and modulates its development, we reasoned whether early transitory inhibition of angiotensin-I converting enzyme activity after birth could modify late body mass development. Therefore, newborn Wistar rats were treated with enalapril (10 mg/kg of body mass or saline, starting at the first day of life until the age of 16 days. Between days 90th and 180th, a group of these animals received high fat diet (HFD. Molecular, biochemical, histological and physiological data were collected. Enalapril treated animals presented hyperphagia, overweight and increased serum level of triglycerides, total cholesterol and leptin, in adult life. Body composition analyses revealed higher fat mass with increased adipocyte size in these animals. Molecular analyses revealed that enalapril treatment increases neuropeptide Y (NPY and cocaine- and amphetamine-regulated transcript (CART gene expression in hypothalamus, fatty acid synthase (FAS and hormone-sensitive lipase (HSL gene expression in retroperitoneal WAT and decreases peroxixome proliferators-activated receptor (PPAR γ, PPARα, uncoupling protein (UCP 2 and UCP3 gene expression in WAT. The results of the current study indicate that enalapril administration during early postnatal development increases body mass, adiposity and serum lipids in adulthood associated with enhanced food intake and decreased metabolic activity in WAT, predisposing to obesity in adulthood.

  9. Brain renin angiotensin system in cardiac hypertrophy and failure

    Directory of Open Access Journals (Sweden)

    Luciana eCampos

    2012-01-01

    Full Text Available Brain renin-angiotensin system (RAS is significantly involved in the roles of the endocrine RAS in cardiovascular regulation. Our studies indicate that the brain RAS participates in the development of cardiac hypertrophy and fibrosis through sympathetic activation. Inhibition of sympathetic hyperactivity after myocardial infarction through suppression of the brain RAS appears beneficial. The brain RAS is involved in the modulation of circadian rhythms of arterial pressure, contributing to nondipping hypertension. We conclude that the brain RAS in pathophysiological states interacts synergistically with the chronically overactive RAS through a positive biofeedback in order to maintain a state of alert diseased conditions, such as cardiac hypertrophy and failure. Therefore, targeting brain RAS with drugs such as angiotensin converting inhibitors or receptor blockers having increased brain penetrability could be of advantage. These RAS-targeting drugs are first-line therapy for all heart failure patients. Since the RAS has both endocrine and local tissue components, RAS drugs are being developed to attain increased tissue penetrability and volume of distribution and consequently an efficient inhibition of both RAS components.

  10. Characterization of the macula densa stimulus for renin secretion

    DEFF Research Database (Denmark)

    Lorenz, J N; Weihprecht, H; Schnermann, J

    1990-01-01

    These studies utilize the isolated perfused rabbit juxtaglomerular apparatus (JGA) to study the macula densa signal for renin secretion in the absence of the confounding influences of intravascular pressure and renal nerve activity. In the first experimental series, JGAs were perfused alternately...... and decreases in macula densa NaCl concentration, and these changes are rapid and largely reversible, 2) the full renin response occurs within the concentration range normally occurring at the macula densa, i.e., below 80 mM Na+ and 61 mM Cl-, and 3) RSR responds with a larger change to alterations in Na...

  11. Bovine ovarian cells have (pro)renin receptors and prorenin induces resumption of meiosis in vitro.

    Science.gov (United States)

    Dau, Andressa Minussi Pereira; da Silva, Eduardo Pradebon; da Rosa, Paulo Roberto Antunes; Bastiani, Felipe Tusi; Gutierrez, Karina; Ilha, Gustavo Freitas; Comim, Fabio Vasconcellos; Gonçalves, Paulo Bayard Dias

    2016-07-01

    The discovery of a receptor that binds prorenin and renin in human endothelial and mesangial cells highlights the possible effect of renin-independent prorenin in the resumption of meiosis in oocytes that was postulated in the 1980s.This study aimed to identify the (pro)renin receptor in the ovary and to assess the effect of prorenin on meiotic resumption. The (pro)renin receptor protein was detected in bovine cumulus-oocyte complexes, theca cells, granulosa cells, and in the corpus luteum. Abundant (pro)renin receptor messenger ribonucleic acid (mRNA) was detected in the oocytes and cumulus cells, while prorenin mRNA was identified in the cumulus cells only. Prorenin at concentrations of 10(-10), 10(-9), and 10(-8)M incubated with oocytes co-cultured with follicular hemisections for 15h caused the resumption of oocyte meiosis. Aliskiren, which inhibits free renin and receptor-bound renin/prorenin, at concentrations of 10(-7), 10(-5), and 10(-3)M blocked this effect (Pmeiosis resumption, cumulus-oocyte complexes and follicular hemisections were treated with prorenin and with angiotensin II or saralasin (angiotensin II antagonist). Prorenin induced the resumption of meiosis independently of angiotensin II. Furthermore, cumulus-oocyte complexes cultured with forskolin (200μM) and treated with prorenin and aliskiren did not exhibit a prorenin-induced resumption of meiosis (Pmeiosis in cattle. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Inhibition of acetylcholinesterase activity by essential oil from Citrus paradisi.

    Science.gov (United States)

    Miyazawa, M; Tougo, H; Ishihara, M

    2001-01-01

    Inhibition of acetylcholinesterase (AChE) activity by essential oils of Citrus paradisi (grapefruit pink in USA) was studied. Inhibition of AChE was measured by the colorimetric method. Nootkatone and auraptene were isolated from C. paradisi oil and showed 17-24% inhibition of AChE activity at the concentration of 1.62 microg/mL.

  13. Nifedipine-sensitive blood pressure component in hypertensive models characterized by high activity of either sympathetic nervous system or renin-angiotensin system

    Czech Academy of Sciences Publication Activity Database

    Zicha, Josef; Dobešová, Zdenka; Behuliak, Michal; Pintérová, Mária; Kuneš, Jaroslav; Vaněčková, Ivana

    2014-01-01

    Roč. 63, č. 1 (2014), s. 13-26 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) 1M0510; GA ČR(CZ) GA305/09/0336; GA ČR(CZ) GAP304/12/0259 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : voltage-gated caclium channels * sympathetic nervous system * renin-angiotensin system * nitric oxide Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.293, year: 2014

  14. Methodologic issues in the measurement of urinary renin

    NARCIS (Netherlands)

    L.C.W. Roksnoer (Lodi); K. Verdonk (Koen); I.M. Garrelds (Ingrid); J.M. van Gool (Jeanette); R. Zietse (Bob); E.J. Hoorn (Ewout); A.H.J. Danser (Jan)

    2014-01-01

    textabstractBackground and objectives Alge et al. recently reported that urinary renin may be a prognostic biomarker for AKI after cardiac surgery. However, their urinary renin levels far exceeded published plasma renin levels, whereas normally, urinary renin is,10%of plasma renin. This result

  15. Renin-aldosterone-sodium profiling in hypertensive Filipinos. Pt. 2

    International Nuclear Information System (INIS)

    Guevara, R.; Torres, J. Jr; Abundo, H.P.; Perez, A.P.; Ochoa, W.K.

    1981-01-01

    Plasma renin activity determination by radioimmunoassay as profiling technique is a useful guide for more rational and precise treatment of hypertension. Statistical nomograms are developed for normals, essential hypertension, diabetic hypertension, renal diseases, renal disease and dialysis, normal pregnancy, toxemic pregnancy and contraceptive pill users with and without hypertension. (orig.) [de

  16. Renin-aldosterone-sodium profiling in hypertensive Filipinos. Pt. 2

    Energy Technology Data Exchange (ETDEWEB)

    Guevara, R.; Torres, J. Jr; Abundo, H.P.; Perez, A.P.; Ochoa, W.K.

    1981-10-01

    Plasma renin activity determination by radioimmunoassay as profiling technique is a useful guide for more rational and precise treatment of hypertension. Statistical nomograms are developed for normals, essential hypertension, diabetic hypertension, renal diseases, renal disease and dialysis, normal pregnancy, toxemic pregnancy and contraceptive pill users with and without hypertension.

  17. Renin-aldosterone-sodium profiling in normal Filipinos. Pt. 1

    International Nuclear Information System (INIS)

    Guevara, R.; Torres, J. Jr.; Abundo, H.P.; Perez, A.P.; Ochoa, W.K.

    1981-01-01

    Plasma renin activity determination by radioimmunoassay is feasible, accurate, reproducible and reliable. This profiling technic is a very useful guide for more rational and precise treatment of the hypertensive state, but even when profiling cannot be done, statistical nomograms can be useful, just as well, as a guide in the treatment of hypertewnsion. (orig.) [de

  18. Effects of Intrarenal and Intravenous Infusion of the Phosphodiesterase 3 Inhibitor Milrinone on Renin Secretion

    Science.gov (United States)

    Kumagai, Kazuhiro; Reid, Ian A.

    1994-01-01

    We have reported that administration of the phosphodiesterase III inhibitor milrinone increases renin secretion in conscious rabbits. The aim of the present study was to determine if the increase in renin secretion results from a direct renal action of milrinone, or from an indirect extrarenal effect of the drug. This was accomplished by comparing the effects of intrarenal and intravenous infusion of graded doses of milrinone on plasma renin activity in unilaterally nephrectomized conscious rabbits. Milrinone was infused into the renal artery in doses of 0.01, 0.1 and 1.0 micro-g/kg/min, and intravenously in the same rabbits in doses of 0.01, 0.1, 1.0 and 10 micro-g/kg/min. Each dose was infused for 15 min. No intrarenal dose of milrinone altered plasma renin activity or arterial pressure, although at the highest dose, there was a small increase in heart rate. Intravenous infusion of milrinone at 1.0 micro-g/kg/min increased plasma renin activity to 176 +/- 55% of the control value (P less than 0.05). Heart rate increased but arterial pressure did not change. Intravenous infusion of milrinone at 1O micro-g/kg/min increased plasma renin activity to 386 +/- 193% of control in association with a decrease in arterial pressure and an increase in heart rate. These results confirm that milrinone increases renin secretion, and indicate that the stimulation is due to an extrarenal effect of the drug.

  19. Radioimmunoassay of renin in human renal tissues

    International Nuclear Information System (INIS)

    Wowra, B.

    1981-01-01

    A method has been developed to quantitatively determine renin in human kidney tissue. The angiotensin I split off angiotensinogs by renin was radioimmunologically determined. The renin-renin substrate reaction rate followed a saturation kinetics, as it increased the larger the substrate content in the incubation medium until it acquired a maximum value; the reaction rate decreased with substrate concentrations over 40 mg/ml incubation medium. The discontinuance of the renin reaction after incubation by adding acid, boiling and neutralizing again, gave highest renin values. The RIA scattering was 8.3% for double determination of the same sample, for the determination in different RIA additions 7.0%. The detection limit was 20 pg angiotensin I. A direct comparison of radioimmunoassay and bioassay exhibited a very significant agreement of both methods, where the radioimmunologically measured renin values were on average four times larger than those obtained using biological technique. The definition of the so-called normal values for absolute and specific renin concentration in human kidney tissue enabled one to assess the renin values in various syndromes. (orig./MG) [de

  20. Hyperoxia Inhibits T Cell Activation in Mice

    Science.gov (United States)

    Hughes-Fulford, M.; Meissler, J.; Aguayo, E. T.; Globus, R.; Aguado, J.; Candelario, T.

    2013-02-01

    , spleens were removed and the splenocytes were isolated and kept as individual biological samples. We have also examined transcription factors (JASPAR) and pathways of the immune system to help us understand the mechanism of regulation. Results: Our recent mouse immunology experiment aboard STS-131 suggests that the early T cell immune response was inhibited in animals that have been exposed to spaceflight, even 24 hours after return to earth. Moreover, recent experiments in hyperoxic mice show that many of the same genes involved in early T cell activation were altered. Specifically, expression of IL-2Rα, Cxcl2, TNFα, FGF2, LTA and BCL2 genes are dysregulated in mice exposed to hyperoxia. Conclusions: If these hyperoxia-induced changes of gene expression in early T cell activation are additive to the changes seen in the microgravity of spaceflight, there could be an increased infection risk to EVA astronauts, which should be addressed prior to conducting a Mars or other long-term mission.

  1. The renin-angiotensin-aldosterone system and calcium-regulatory hormones.

    Science.gov (United States)

    Vaidya, A; Brown, J M; Williams, J S

    2015-09-01

    There is increasing evidence of a clinically relevant interplay between the renin-angiotensin-aldosterone system and calcium-regulatory systems. Classically, the former is considered a key regulator of sodium and volume homeostasis, while the latter is most often associated with skeletal health. However, emerging evidence suggests an overlap in regulatory control. Hyperaldosteronism and hyperparathyroidism represent pathophysiologic conditions that may contribute to or perpetuate each other; aldosterone regulates parathyroid hormone and associates with adverse skeletal complications, and parathyroid hormone regulates aldosterone and associates with adverse cardiovascular complications. As dysregulation in both systems is linked to poor cardiovascular and skeletal health, it is increasingly important to fully characterize how they interact to more precisely understand their impact on human health and potential therapies to modulate these interactions. This review describes the known clinical interactions between these two systems including observational and interventional studies. Specifically, we review studies describing the inhibition of renin activity by calcium and vitamin D, and a potentially bidirectional and stimulatory relationship between aldosterone and parathyroid hormone. Deciphering these relationships might clarify variability in outcomes research, inform the design of future intervention studies and provide insight into the results of prior and ongoing intervention studies. However, before these opportunities can be addressed, more effort must be placed on shifting observational data to the proof of concept phase. This will require reallocation of resources to conduct interventional studies and secure the necessary talent.

  2. Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice

    NARCIS (Netherlands)

    Rosendahl, Alva; Niemann, Gianina; Lange, Sascha; Ahadzadeh, Erfan; Krebs, Christian; Contrepas, Aurelie; van Goor, Harry; Wiech, Thorsten; Bader, Michael; Schwake, Michael; Peters, Judith; Stahl, Rolf; Nguyen, Genevieve; Wenzel, Ulrich

    Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is

  3. Angiogenesis inhibition causes hypertension and placental dysfunction in a rat model of preeclampsia

    DEFF Research Database (Denmark)

    Carlström, Mattias; Wentzel, Parri; Skøtt, Ole

    2009-01-01

    in the mesometrial triangle was smaller in the pregnant Suramin-treated rats group than in the pregnant control rats group. CONCLUSION: The inhibition of uterine angiogenesis increases maternal blood pressure and compromises fetal and placental development. Placental hypoxia and subsequent activation of the renin...

  4. 2C.07: INVOLVEMENT OF THE RENIN-ANGIOTENSIN SYSTEM IN A PREMATURE AGING MOUSE MODEL.

    Science.gov (United States)

    Van Thiel, B S; Ridwan, Y; Garrelds, I M; Vermeij, M; Groningen, M C Clahsen-Van; Danser, A H J; Essers, J; Van Der Pluijm, I

    2015-06-01

    Changes in the renin-angiotensin system (RAS), known for its critical role in the regulation of blood pressure and sodium homeostasis, may contribute to aging and age-related diseases. Here we characterized the RAS and kidney pathology in mice with genomic instability due to a defective nucleotide excision repair gene (Ercc1d/- mice). These mice display premature features of aging, including vascular dysfunction. Studies were performed in male and female Ercc1d/- mice and their wild type controls (Ercc1+/+) at the age of 12 or 18 weeks before and after treatment with losartan. The renin-activatable near-infrared fluorescent probe ReninSense 680™ was applied in vivo to allow non-invasive imaging of renin activity. Plasma renin concentrations (PRC) were additionally measured ex vivo by quantifying Ang I generation in the presence of excess angiotensinogen. Kidneys were harvested and examined for markers of aging, and albumin was determined in urine. Kidneys of 12-week old Ercc1d/- mice showed signs of aging, including tubular anisokaryosis, cell-senescence and increased apoptosis. This was even more pronounced at the age of 18 weeks. Yet, urinary albumin was normal at 12 weeks. The ReninSense 680™ probe showed increased intrarenal renin activity in Ercc1d/- mice versus Ercc1+/+ mice, both at 12 and 18 weeks of age, while PRC in these mice tended to be lower compared to Ercc1+/+ mice. Renin was higher in male than female mice, both in the kidney and in plasma, and losartan increased kidney and plasma renin in both Ercc1d/- and Ercc1+/+ mice. Rapidly aging Ercc1d/- mice display an activated intrarenal RAS, as evidenced by the increased fluorescence detected with the ReninSense 680™ probe. This increased RAS activity may contribute to the disturbed kidney pathology in these mice. The increased intrarenal activity detected with the ReninSense 680™ probe in male vs. female mice, as well as after losartan treatment, are in full agreement with the literature, and

  5. Sodium restriction potentiates the renoprotective effects of combined vitamin D receptor activation and angiotensin-converting enzyme inhibition in established proteinuric nephropathy.

    NARCIS (Netherlands)

    Mirkovic, K.; Frenay, A.S.; Born, J. van den; Goor, H van; Navis, G.; Borst, M.H. de; Bindels, R.J.M.; Hoenderop, J.G.J.; Hillebrands, J.L.

    2017-01-01

    BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) blockade provides renoprotective effects in chronic kidney disease (CKD); yet progressive renal function loss remains common. Dietary sodium restriction potentiates the renoprotective effects of RAAS blockade. Vitamin D receptor activator

  6. Effect of adenosine1-receptor blockade on renin release from rabbit isolated perfused juxtaglomerular apparatus

    DEFF Research Database (Denmark)

    Weihprecht, H; Lorenz, J N; Schnermann, J

    1990-01-01

    Adenosine has been proposed to act within the juxtaglomerular apparatus (JGA) as a mediator of the inhibition of renin secretion produced by a high NaCl concentration at the macula densa. To test this hypothesis, we studied the effects of the adenosine1 (A1)-receptor blocker 8-cyclopentyl-1......,3-dipropylxanthine (CPX) on renin release from single isolated rabbit JGAs with macula densa perfused. The A1-receptor agonist, N6-cyclohexyladenosine (CHA), applied in the bathing solution at 10(-7) M, was found to inhibit renin secretion, an effect that was completely blocked by adding CPX (10(-5) M) to the bath....... Applied to the lumen, 10(-5) M CPX produced a modest stimulation of renin secretion rates suppressed by a high NaCl concentration at the macula densa (P less than 0.05). The effect of changing luminal NaCl concentration on renin secretion rate was examined in the presence of CPX (10(-7) and 10(-5) M...

  7. Radioimmunoassay of renin-angiotensin-aldosterone in patients with adrenal tumors

    International Nuclear Information System (INIS)

    Slavnov, V.N.; Yakovlev, A.A.; Yugrinov, O.G.; Gandzha, T.I.

    1983-01-01

    The results are presented of a study of the renin-angiotensin-aldosterone system in 89 patients with aldosteronoma, corticosteroma, pheochromocytoma and hypertension. Radioimmunoassay was used to measure aldosterone concentration and renin activity in the peripheral blood and blood from vena cava inferior, the renal and adrenal veins, the circadian cycle of their content and the responsiveness of the glomerular zone of the adrenal cortex and the juxtaglomerular renal system under the influence of lasix intake and the change over from a horizontal into vertical position. Patients with adrenal tumors have shown disorders of renin-angiotensin-aldosterone function. Radioimmunoassay of the renin-angiotensin-aldosterone system promotes early detection of adrenal tumors in the general population of patients with hypertension and can be used for control over therapeutic efficacy

  8. Inhibition of PTEN and activation of Akt by menadione

    OpenAIRE

    Yoshikawa, Kyoko; Nigorikawa, Kiyomi; Tsukamoto, Mariko; Tamura, Namiko; Hazeki, Kaoru; Hazeki, Osamu

    2007-01-01

    Menadione (vitamin K3) has been shown to activate Erk in several cell lines. This effect has been shown to be due to the activation of EGF receptors (EGFR) as a result of inhibition of some protein tyrosine phosphatases. In the present study, we examined the effects of menadione on Akt in Chinese hamster ovary cells. The phosphorylation of Akt by menadione was not inhibited by AG1478, an inhibitor of EGFR. Menadione inhibited the lipid phosphatase activity of PTEN in a cell-free system. In an...

  9. The renin-angiotensin-aldosterone system (RAAS – physiology and molecular mechanisms of functioning

    Directory of Open Access Journals (Sweden)

    Monika Chaszczewska-Markowska

    2016-09-01

    Full Text Available Secretion of renin juxtaglomerular cells into bloodstream initiates activation of an enzymatic-hormonal cascade known as the RAAS (renin – angiotensin – aldosterone system. As a result, blood pressure is increased by the means several interrelated mechanisms. Mechanism of Zjednoczoaction of this system has been known for decades, but a few previously unknown components were recently added, such as ACE-2 and Ang(1-7, and their role often seems to be opposite to that of the conventional components. Local tissue systems also have important biological functions. They operate largely independently of the systemic activity, and their activity is observed primarily in the kidney, heart, in blood vessels, adrenal gland and nervous system. Angiotensin-2 (Ang-2, the main RAAS effector, has a wide scope of action, and thus abnormalities in its functioning have many consequences. Excessive activation is accompanied by chronic inflammation, as Ang-2 stimulates inflammatory mediators. As a result, degenerative processes and atherosclerosis are initiated. RAAS imbalance is associated with the most common diseases of civilization, such as cardio-vascular diseases, diabetes, kidney diseases, preeclampsia, osteoporosis and even neurodegenerative diseases. Many of these pathological processes are attributed to the excessive activation of tissue RA system. Therapeutic strategies based on inhibition of the RAAS are commonly used mainly in the treatment of hypertension and other cardiovascular disorders. The benefits of this class of drugs is primarily a decrease in blood pressure, but also the suppression of inflammatory processes and other pathological phenomena resulting from excessive activation of the RAAS. For that reason, some consider to use RAAS inhibitors in other diseases, e.g. Parkinson’s disease. Further studies give hope for the improvement of RAAS inhibitor therapy and the development of new therapeutic strategies

  10. The renin-angiotensin system and aging in the kidney

    OpenAIRE

    Yoon, Hye Eun; Choi, Bum Soon

    2014-01-01

    Aging is associated with progressive functional deterioration and structural changes in the kidney. Changes in the activity or responsiveness of the renin-angiotensin system (RAS) occur with aging. RAS changes predispose the elderly to various fluid and electrolyte imbalances as well as acute kidney injury and chronic kidney disease. Among the multiple pathways involved in renal aging, the RAS plays a central role. This review summarizes the association of the RAS with structural and function...

  11. Mechanisms of renin release from juxtaglomerular cells

    DEFF Research Database (Denmark)

    Skøtt, O; Salomonsson, Max; Sellerup Persson, Anja

    1991-01-01

    In microdissected, nonperfused afferent arterioles changes in intravascular pressure did not affect renin secretion. On the contrary, renin release from isolated afferent arterioles perfused in a free-flow system has been reported to be sensitive to simultaneous changes in luminal pressure and fl....... Hence local blood flow may be involved in the baroreceptor control of renin release. If flow is sensed, the sensor is likely to be located near the endothelial cell layer, where ion channels have been shown to be influenced by variations in shear stress....

  12. Linking algal growth inhibition to chemical activity

    DEFF Research Database (Denmark)

    Schmidt, Stine N.; Mayer, Philipp

    2015-01-01

    for baseline toxicity. First, the reported effective concentrations (EC50) were divided by the respective water solubilities (Swater), since the obtained EC50/Swater ratio essentially equals the effective chemical activity (Ea50). The majority of EC50/Swater ratios were within the expected chemical activity...

  13. Inhibition of PTEN and activation of Akt by menadione.

    Science.gov (United States)

    Yoshikawa, Kyoko; Nigorikawa, Kiyomi; Tsukamoto, Mariko; Tamura, Namiko; Hazeki, Kaoru; Hazeki, Osamu

    2007-04-01

    Menadione (vitamin K(3)) has been shown to activate Erk in several cell lines. This effect has been shown to be due to the activation of EGF receptors (EGFR) as a result of inhibition of some protein tyrosine phosphatases. In the present study, we examined the effects of menadione on Akt in Chinese hamster ovary cells. The phosphorylation of Akt by menadione was not inhibited by AG1478, an inhibitor of EGFR. Menadione inhibited the lipid phosphatase activity of PTEN in a cell-free system. In an intact cell system, menadione inhibited the effect of transfected PTEN on Akt. Thus, one mechanism of its action was considered the accelerated activation of Akt through inhibition of PTEN. This was not the sole mechanism responsible for the EGFR-independent activation of Akt, because menadione attenuated the rate of Akt dephosphorylation even in PTEN-null PC3 cells. The decelerated inactivation of Akt, probably through inhibition of some tyrosine phosphatases, was considered another mechanism of its action.

  14. Different antihypertensive effect of beta-blocking drugs in low and normal-high renin hypertension.

    Science.gov (United States)

    Kralberg, B E; Tolagen, K

    1976-05-31

    The treatment response to beta-adrenoceptor blocking drugs was compared in two groups of patients with primary (essential) hypertension and different renin levels. Each group consisted of 25 patients and was equally distributed regarding age, severity and stage of hypertension. In the first group (group 1), the mean upright plasma renin activity was 0.8 ng ml-1h-1 (range 0.3 to 1.5) and the patients were considered to have low renin hypertension. In the other group (group 2) the patients had a mean plasma renin activity of 2.1 ng ml-1h-1 (range 1.1 to 5.1) and were considered to have normal to high renin hypertension. In both groups the patients were initially treated with beta-blocking drugs; in group 1 with a beta-blocker corresponding to an average dose of 311 mg propranolol a day for at least eight weeks and in group 2 with propranolol 320 mg a day in a fixed dose for eight weeks. The hypotensive response differed significantly between the two groups (p less than 0.001). In group 1 the pretreatment blood pressure was 197/117 mm Hg supine and 198/120 mm Hg standing. During treatment blood pressure decreased only 5/3 mm Hg supine and 9/5 mm Hg standing. The pretreatment blood pressure in group 2 was 187/114 mm Hg supine and 186/117 mm Hg standing. Beta-blocking therapy reduced blood pressure 36/23 and 34/18 mm Hg, respectively (both p less than 0.001). Pulse rates fell significantly in the two groups, both in the lying and standing positions. In 17 patients with low renin hypertension (group 1), a volume-depleting drug was added (spironolactone, 14 patients; thiazides, 3 patients) and this achieved a marked fall in blood pressure levels of 38/16 mm Hg supine and 37/19 mm Hg standing (both p less than 0.001). These results suggest the following: (1) Most patients with normal to high plasma renin activity respond well to moderate doses of propranolol. (2) Propranolol given in the same doses is almost without antihypertensive effect in patients with low renin

  15. Potent radiolabeled human renin inhibitor, [3H]SR42128: enzymatic, kinetic, and binding studies to renin and other aspartic proteases

    International Nuclear Information System (INIS)

    Cumin, F.; Nisato, D.; Gagnol, J.P.; Corvol, P.

    1987-01-01

    The in vitro binding of [ 3 H]SR42128 (Iva-Phe-Nle-Sta-Ala-Sta-Arg), a potent inhibitor of human renin activity, to purified human renin and a number of other aspartic proteases was examined. SR42128 was found to be a competitive inhibitor of human renin, with a K/sub i/ of 0.35 nM at pH 5.7 and 2.0 nM at pH 7.4; it was thus more effective at pH 5.7 than at pH 7.4. Scatchard analysis of the interaction binding of [ 3 H]SR42128 to human renin indicated that binding was reversible and saturable at both pH 5.7 and pH 7.4. There was a single class of binding sites, and the K/sub D/ was 0.9 nM at pH 5.7 and 1 nM at pH 7.4. The association rate was 10 times more rapid at pH 5.7 than at pH 7.4, but there was no difference between the rates of dissociation of the enzyme-inhibitor complex at the two pHs. The effect of pH on the binding of [ 3 H]SR42128 to human renin, cathepsin D, pepsin, and gastricsin was also examined over the pH range 3-8. All the aspartic proteases had a high affinity for the inhibitor at low pH. However, at pH 7.4, [ 3 H]SR42128 was bound only to human renin and to none of the other aspartic proteases. Competitive binding studies with [ 3 H]SR42128 and a number of other inhibitors on human renin or cathepsin D were used to examine the relationships between structure and activity in these systems. The study as a whole indicates that pH plays a major role in the binding of [ 3 H]SR42128 to aspartic proteases and that the nature of the inhibitor residue reacting with the renin S 2 subsites is of critical importance for the specificity of the renin-inhibitor interaction

  16. Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

    Directory of Open Access Journals (Sweden)

    Magdalena Markowicz-Piasecka

    2017-01-01

    Full Text Available The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM may predispose to Alzheimer’s disease (AD. The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition and BuChE (IC50 = 28 nmol/mL, mixed type inhibition, while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL. Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

  17. Complement activation and inhibition: a delicate balance

    DEFF Research Database (Denmark)

    Sjöberg, A P; Trouw, L A; Blom, A M

    2009-01-01

    proteins, pentraxins, amyloid deposits, prions and DNA, all bind the complement activator C1q, but also interact with complement inhibitors C4b-binding protein and factor H. This contrasts to the interaction between C1q and immune complexes, in which case no inhibitors bind, resulting in full complement...

  18. Spironolactone lowers portal hypertension by inhibiting liver fibrosis, ROCK-2 activity and activating NO/PKG pathway in the bile-duct-ligated rat.

    Directory of Open Access Journals (Sweden)

    Wei Luo

    Full Text Available OBJECTIVE: Aldosterone, one of the main peptides in renin angiotensin aldosterone system (RAAS, has been suggested to mediate liver fibrosis and portal hypertension. Spironolactone, an aldosterone antagonist, has beneficial effect on hyperdynamic circulation in clinical practice. However, the mechanisms remain unclear. The present study aimed to investigate the role of spionolactone on liver cirrhosis and portal hypertension. METHODS: Liver cirrhosis was induced by bile duct ligation (BDL. Spironolactone was administered orally (20 mg/kg/d after bile duct ligation was performed. Liver fibrosis was assessed by histology, Masson's trichrome staining, and the measurement of hydroxyproline and type I collagen content. The activation of HSC was determined by analysis of alpha smooth muscle actin (α-SMA expression. Protein expressions and protein phosphorylation were determined by immunohistochemical staining and Western blot analysis, Messenger RNA levels by quantitative real time polymerase chain reaction (Q-PCR. Portal pressure and intrahepatic resistance were examined in vivo. RESULTS: Treatment with spironolactone significantly lowered portal pressure. This was associated with attenuation of liver fibrosis, intrahepatic resistance and inhibition of HSC activation. In BDL rat liver, spironolactone suppressed up-regulation of proinflammatory cytokines (TNFα and IL-6. Additionally, spironolactone significantly decreased ROCK-2 activity without affecting expression of RhoA and Ras. Moreover, spironolactone markedly increased the levels of endothelial nitric oxide synthase (eNOS, phosphorylated eNOS and the activity of NO effector-protein kinase G (PKG in the liver. CONCLUSION: Spironolactone lowers portal hypertension by improvement of liver fibrosis and inhibition of intrahepatic vasoconstriction via down-regulating ROCK-2 activity and activating NO/PKG pathway. Thus, early spironolactone therapy might be the optional therapy in cirrhosis and

  19. Hili Inhibits HIV Replication in Activated T Cells.

    Science.gov (United States)

    Peterlin, B Matija; Liu, Pingyang; Wang, Xiaoyun; Cary, Daniele; Shao, Wei; Leoz, Marie; Hong, Tian; Pan, Tao; Fujinaga, Koh

    2017-06-01

    P-element-induced wimpy-like (Piwil) proteins restrict the replication of mobile genetic elements in the germ line. They are also expressed in many transformed cell lines. In this study, we discovered that the human Piwil 2 (Hili) protein can also inhibit HIV replication, especially in activated CD4 + T cells that are the preferred target cells for this virus in the infected host. Although resting cells did not express Hili, its expression was rapidly induced following T cell activation. In these cells and transformed cell lines, depletion of Hili increased levels of viral proteins and new viral particles. Further studies revealed that Hili binds to tRNA. Some of the tRNAs represent rare tRNA species, whose codons are overrepresented in the viral genome. Targeting tRNA Arg (UCU) with an antisense oligonucleotide replicated effects of Hili and also inhibited HIV replication. Finally, Hili also inhibited the retrotransposition of the endogenous intracysternal A particle (IAP) by a similar mechanism. Thus, Hili joins a list of host proteins that inhibit the replication of HIV and other mobile genetic elements. IMPORTANCE Piwil proteins inhibit the movement of mobile genetic elements in the germ line. In their absence, sperm does not form and male mice are sterile. This inhibition is thought to occur via small Piwi-interacting RNAs (piRNAs). However, in some species and in human somatic cells, Piwil proteins bind primarily to tRNA. In this report, we demonstrate that human Piwil proteins, especially Hili, not only bind to select tRNA species, including rare tRNAs, but also inhibit HIV replication. Importantly, T cell activation induces the expression of Hili in CD4 + T cells. Since Hili also inhibited the movement of an endogenous retrovirus (IAP), our finding shed new light on this intracellular resistance to exogenous and endogenous retroviruses as well as other mobile genetic elements. Copyright © 2017 American Society for Microbiology.

  20. Ammonium inhibition of nitrogenase activity in Herbaspirillum seropedicae

    Energy Technology Data Exchange (ETDEWEB)

    Fu, H.; Burris, R.H. (Univ. of Wisconsin, Madison (USA))

    1989-06-01

    The effect of oxygen, ammonium ion, and amino acids on nitrogenase activity in the root-associated N{sub 2}-fixing bacterium Herbaspirillum seropedicae was investigated in comparison with Azospirillum spp. and Rhodospirillum rubrum. H. seropedicae is microaerophilic, and its optimal dissolved oxygen level is from 0.04 to 0.2 kPa for dinitrogen fixation but higher when it is supplied with fixed nitrogen. No nitrogenase activity was detected when the dissolved O{sub 2} level corresponded to 4.0 kPa. Ammonium, a product of the nitrogenase reaction, reversible inhibited nitrogenase activity when added to derepressed cell cultures. However, the inhibition of nitrogenase activity was only partial even with concentrations of ammonium chloride as high as 20 mM. Amides such as glutamine and asparagine partially inhibited nitrogenase activity, but glutamate did not. Nitrogenase in crude extracts prepared from ammonium-inhibited cells showed activity as high as in extracts from N{sub 2}-fixing cells. The pattern of the dinitrogenase and the dinitrogenase reductase revealed by the immunoblotting technique did not change upon ammonium chloride treatment of cells in vivo. No homologous sequences were detected with the draT-draG probe from Azospirillum lipoferum. There is no clear evidence that ADP-ribosylation of the dinitrogenase reductase is involved in the ammonium inhibition of H. seropedicae. The uncoupler carbonyl cyanide m-chlorophenylhydrazone decreased the intracellular ATP concentration and inhibited the nitrogenase activity of whole cells. The ATP pool was significantly disturbed when cultures were treated with ammonium in vivo.

  1. Cysteine-independent activation/inhibition of heme oxygenase-2

    Directory of Open Access Journals (Sweden)

    Dragic Vukomanovic

    2016-01-01

    Full Text Available Reactive thiols of cysteine (cys residues in proteins play a key role in transforming chemical reactivity into a biological response. The heme oxygenase-2 (HO-2 isozyme contains two cys residues that have been implicated in binding of heme and also the regulation of its activity. In this paper, we address the question of a role for cys residues for the HO-2 inhibitors or activators designed in our laboratory. We tested the activity of full length recombinant human heme oxygenase-2 (FL-hHO-2 and its analog in which cys265 and cys282 were both replaced by alanine to determine the effect on activation by menadione (MD and inhibition by QC-2350. Similar inhibition by QC-2350 and almost identical activation by MD was observed for both recombinant FL-hHO-2s. Our findings are interpreted to mean that thiols of FL-hHO-2s are not involved in HO-2 activation or inhibition by the compounds that have been designed and identified by us. Activation or inhibition of HO-2 by our compounds should be attributed to a mechanism other than altering binding affinity of HO-2 for heme through cys265 and cys282.

  2. Inhibition of existing denitrification enzyme activity by chloramphenicol

    Science.gov (United States)

    Brooks, M.H.; Smith, R.L.; Macalady, D.L.

    1992-01-01

    Chloramphenicol completely inhibited the activity of existing denitrification enzymes in acetylene-block incubations with (i) sediments from a nitrate-contaminated aquifer and (ii) a continuous culture of denitrifying groundwater bacteria. Control flasks with no antibiotic produced significant amounts of nitrous oxide in the same time period. Amendment with chloramphenicol after nitrous oxide production had begun resulted in a significant decrease in the rate of nitrous oxide production. Chloramphenicol also decreased (>50%) the activity of existing denitrification enzymes in pure cultures of Pseudomonas denitrificans that were harvested during log- phase growth and maintained for 2 weeks in a starvation medium lacking electron donor. Short-term time courses of nitrate consumption and nitrous oxide production in the presence of acetylene with P. denitrificans undergoing carbon starvation were performed under optimal conditions designed to mimic denitrification enzyme activity assays used with soils. Time courses were linear for both chloramphenicol and control flasks, and rate estimates for the two treatments were significantly different at the 95% confidence level. Complete or partial inhibition of existing enzyme activity is not consistent with the current understanding of the mode of action of chloramphenicol or current practice, in which the compound is frequently employed to inhibit de novo protein synthesis during the course of microbial activity assays. The results of this study demonstrate that chloramphenicol amendment can inhibit the activity of existing denitrification enzymes and suggest that caution is needed in the design and interpretation of denitrification activity assays in which chloramphenicol is used to prevent new protein synthesis.

  3. Cysteine-independent activation/inhibition of heme oxygenase-2.

    Science.gov (United States)

    Vukomanovic, Dragic; Rahman, Mona N; Maines, Mahin D; Ozolinš, Terence Rs; Szarek, Walter A; Jia, Zongchao; Nakatsu, Kanji

    2016-03-01

    Reactive thiols of cysteine (cys) residues in proteins play a key role in transforming chemical reactivity into a biological response. The heme oxygenase-2 (HO-2) isozyme contains two cys residues that have been implicated in binding of heme and also the regulation of its activity. In this paper, we address the question of a role for cys residues for the HO-2 inhibitors or activators designed in our laboratory. We tested the activity of full length recombinant human heme oxygenase-2 (FL-hHO-2) and its analog in which cys265 and cys282 were both replaced by alanine to determine the effect on activation by menadione (MD) and inhibition by QC-2350. Similar inhibition by QC-2350 and almost identical activation by MD was observed for both recombinant FL-hHO-2s. Our findings are interpreted to mean that thiols of FL-hHO-2s are not involved in HO-2 activation or inhibition by the compounds that have been designed and identified by us. Activation or inhibition of HO-2 by our compounds should be attributed to a mechanism other than altering binding affinity of HO-2 for heme through cys265 and cys282.

  4. Urinary Angiotensinogen and Renin Excretion are Associated with Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Annett Juretzko

    2017-04-01

    Full Text Available Background/Aims: Several studies sought to identify new biomarkers for chronic kidney disease (CKD. As the renal renin-angiotensin system is activated in CKD, urinary angiotensinogen or renin excretion may be suitable candidates. We tested whether urinary angiotensinogen or renin excretion is elevated in CKD and whether these parameters are associated with estimated glomerular filtration rate (eGFR. We further tested whether urinary angiotensinogen or renin excretion may convey additional information beyond that provided by albuminuria. Methods: We measured urinary and plasma angiotensinogen, renin, albumin and creatinine in 177 CKD patients from the Greifswald Approach to Individualized Medicine project and in 283 healthy controls from the Study of Health in Pomerania. The urinary excretion of specific proteins is given as protein-to-creatinine ratio. Receiver operating characteristic (ROC curves, spearman correlation coefficients and linear regression models were calculated. Results: Urinary angiotensinogen [2,511 (196-31,909 vs. 18.6 (8.3-44.0 pmol/g, *P<0.01] and renin excretion [0.311 (0.135-1.155 vs. 0.069 (0.045-0.148 pmol/g, *P<0.01] were significantly higher in CKD patients than in healthy controls. The area under the ROC curve was significantly larger when urinary angiotensinogen, renin and albumin excretion were combined than with urinary albumin excretion alone. Urinary angiotensinogen (ß-coefficient -2.405, standard error 0.117, P<0.01 and renin excretion (ß-coefficient -0.793, standard error 0.061, P<0.01 were inversely associated with eGFR. Adjustment for albuminuria, age, sex, systolic blood pressure and body mass index did not significantly affect the results. Conclusion: Urinary angiotensinogen and renin excretion are elevated in CKD patients. Both parameters are negatively associated with eGFR and these associations are independent of urinary albumin excretion. In CKD patients urinary angiotensinogen and renin excretion may

  5. Urinary Angiotensinogen and Renin Excretion are Associated with Chronic Kidney Disease.

    Science.gov (United States)

    Juretzko, Annett; Steinbach, Antje; Hannemann, Anke; Endlich, Karlhans; Endlich, Nicole; Friedrich, Nele; Lendeckel, Uwe; Stracke, Sylvia; Rettig, Rainer

    2017-01-01

    Several studies sought to identify new biomarkers for chronic kidney disease (CKD). As the renal renin-angiotensin system is activated in CKD, urinary angiotensinogen or renin excretion may be suitable candidates. We tested whether urinary angiotensinogen or renin excretion is elevated in CKD and whether these parameters are associated with estimated glomerular filtration rate (eGFR). We further tested whether urinary angiotensinogen or renin excretion may convey additional information beyond that provided by albuminuria. We measured urinary and plasma angiotensinogen, renin, albumin and creatinine in 177 CKD patients from the Greifswald Approach to Individualized Medicine project and in 283 healthy controls from the Study of Health in Pomerania. The urinary excretion of specific proteins is given as protein-to-creatinine ratio. Receiver operating characteristic (ROC) curves, spearman correlation coefficients and linear regression models were calculated. Urinary angiotensinogen [2,511 (196-31,909) vs. 18.6 (8.3-44.0) pmol/g, *P<0.01] and renin excretion [0.311 (0.135-1.155) vs. 0.069 (0.045-0.148) pmol/g, *P<0.01] were significantly higher in CKD patients than in healthy controls. The area under the ROC curve was significantly larger when urinary angiotensinogen, renin and albumin excretion were combined than with urinary albumin excretion alone. Urinary angiotensinogen (ß-coefficient -2.405, standard error 0.117, P<0.01) and renin excretion (ß-coefficient -0.793, standard error 0.061, P<0.01) were inversely associated with eGFR. Adjustment for albuminuria, age, sex, systolic blood pressure and body mass index did not significantly affect the results. Urinary angiotensinogen and renin excretion are elevated in CKD patients. Both parameters are negatively associated with eGFR and these associations are independent of urinary albumin excretion. In CKD patients urinary angiotensinogen and renin excretion may convey additional information beyond that provided by

  6. Aspergillus ficuum phytase activity is inhibited by cereal grain components.

    Science.gov (United States)

    Bekalu, Zelalem Eshetu; Madsen, Claus Krogh; Dionisio, Giuseppe; Brinch-Pedersen, Henrik

    2017-01-01

    In the current study, we report for the first time that grain components of barley, rice, wheat and maize can inhibit the activity of Aspergillus ficuum phytase. The phytase inhibition is dose dependent and varies significantly between cereal species, between cultivars of barley and cultivars of wheat and between Fusarium graminearum infected and non-infected wheat grains. The highest endpoint level of phytase activity inhibition was 90%, observed with grain protein extracts (GPE) from F. graminearum infected wheat. Wheat GPE from grains infected with F. graminearum inhibits phytase activity significantly more than GPE from non-infected grains. For four barley cultivars studied, the IC50 value ranged from 0.978 ± 0.271 to 3.616 ± 0.087 mg×ml-1. For two non-infected wheat cultivars investigated, the IC50 values were varying from 2.478 ± 0.114 to 3.038 ± 0.097 mg×ml-1. The maize and rice cultivars tested gaveIC50 values on 0.983 ± 0.205 and 1.972 ± 0.019 mg×ml-1, respectively. After purifying the inhibitor from barley grains via Superdex G200, an approximately 30-35 kDa protein was identified. No clear trend for the mechanism of inhibition could be identified via Michaelis-Menten kinetics and Lineweaver-Burk plots. However, testing of the purified phytase inhibitor together with the A. ficuum phytase and the specific protease inhibitors pepstatin A, E64, EDTA and PMSF revealed that pepstatin A repealed the phytase inhibition. This indicates that the observed inhibition of A. ficuum phytase by cereal grain extracts is caused by protease activity of the aspartic proteinase type.

  7. Lactate dehydrogenase activity is inhibited by methylmalonate in vitro.

    Science.gov (United States)

    Saad, Laura O; Mirandola, Sandra R; Maciel, Evelise N; Castilho, Roger F

    2006-04-01

    Methylmalonic acidemia (MMAemia) is an inherited metabolic disorder of branched amino acid and odd-chain fatty acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A. Systemic and neurological manifestations in this disease are thought to be associated with the accumulation of methylmalonate (MMA) in tissues and biological fluids with consequent impairment of energy metabolism and oxidative stress. In the present work we studied the effect of MMA and two other inhibitors of mitochondrial respiratory chain complex II (malonate and 3-nitropropionate) on the activity of lactate dehydrogenase (LDH) in tissue homogenates from adult rats. MMA potently inhibited LDH-catalyzed conversion of lactate to pyruvate in liver and brain homogenates as well as in a purified bovine heart LDH preparation. LDH was about one order of magnitude less sensitive to inhibition by MMA when catalyzing the conversion of pyruvate to lactate. Kinetic studies on the inhibition of brain LDH indicated that MMA inhibits this enzyme competitively with lactate as a substrate (K (i)=3.02+/-0.59 mM). Malonate and 3-nitropropionate also strongly inhibited LDH-catalyzed conversion of lactate to pyruvate in brain homogenates, while no inhibition was observed by succinate or propionate, when present in concentrations of up to 25 mM. We propose that inhibition of the lactate/pyruvate conversion by MMA contributes to lactate accumulation in blood, metabolic acidemia and inhibition of gluconeogenesis observed in patients with MMAemia. Moreover, the inhibition of LDH in the central nervous system may also impair the lactate shuttle between astrocytes and neurons, compromising neuronal energy metabolism.

  8. Recruitment of Perisomatic Inhibition during Spontaneous Hippocampal Activity In Vitro.

    Directory of Open Access Journals (Sweden)

    Anna Beyeler

    Full Text Available It was recently shown that perisomatic GABAergic inhibitory postsynaptic potentials (IPSPs originating from basket and chandelier cells can be recorded as population IPSPs from the hippocampal pyramidal layer using extracellular electrodes (eIPSPs. Taking advantage of this approach, we have investigated the recruitment of perisomatic inhibition during spontaneous hippocampal activity in vitro. Combining intracellular and extracellular recordings from pyramidal cells and interneurons, we confirm that inhibitory signals generated by basket cells can be recorded extracellularly, but our results suggest that, during spontaneous activity, eIPSPs are mostly confined to the CA3 rather than CA1 region. CA3 eIPSPs produced the powerful time-locked inhibition of multi-unit activity expected from perisomatic inhibition. Analysis of the temporal dynamics of spike discharges relative to eIPSPs suggests significant but moderate recruitment of excitatory and inhibitory neurons within the CA3 network on a 10 ms time scale, within which neurons recruit each other through recurrent collaterals and trigger powerful feedback inhibition. Such quantified parameters of neuronal interactions in the hippocampal network may serve as a basis for future characterisation of pathological conditions potentially affecting the interactions between excitation and inhibition in this circuit.

  9. Contribution of the basolateral isoform of the Na-K-2Cl- cotransporter (NKCC1/BSC2) to renin secretion

    DEFF Research Database (Denmark)

    Castrop, Hayo; Lorenz, John N; Hansen, Pernille B

    2005-01-01

    Acute administration of loop diuretics like furosemide leads to a stimulation of renin secretion, an effect thought to result from inhibition of Na-K-2Cl cotransporter (NKCC2)-mediated salt transport at the luminal surface of the macula densa (MD). However, loop diuretics also inhibit NKCC1......, the second isoform of the Na-K-2Cl cotransporter, with similar potency. In the present study, we examined the influence of furosemide on renin secretion in NKCC1-deficient mice to distinguish between effects of the loop diuretic involving NKCC2 and, by implication, the MD pathway, and effects that might...

  10. Thrombomodulin inhibits the activation of eosinophils and mast cells.

    Science.gov (United States)

    Roeen, Ziaurahman; Toda, Masaaki; D'Alessandro-Gabazza, Corina N; Onishi, Masahiro; Kobayashi, Tetsu; Yasuma, Taro; Urawa, Masahito; Taguchi, Osamu; Gabazza, Esteban C

    2015-01-01

    Eosinophils and mast cells play critical roles in the pathogenesis of bronchial asthma. Activation of both cells leads to the release of pro-inflammatory mediators in the airway of asthmatic patients. Recently, we have shown that inhaled thrombomodulin inhibits allergic bronchial asthma in a mouse model. In the present study, we hypothesize that thrombomodulin can inhibit the activation of eosinophils and mast cells. The effect of thrombomodulin on the activation and release of inflammatory mediators from eosinophils and mast cells was evaluated. Thrombomodulin inhibited the eotaxin-induced chemotaxis, upregulation of CD11b and degranulation of eosinophils. Treatment with thrombomodulin also significantly suppressed the degranulation and synthesis of inflammatory cytokines and chemokines in eosinophils and mast cells. Mice treated with a low-dose of inhaled thrombomodulin have decreased number of eosinophils and activated mast cells and Th2 cytokines in the lungs compared to untreated mice. The results of this study suggest that thrombomodulin may modulate allergic responses by inhibiting the activation of both eosinophils and mast cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Radioimmunologic analysis of the state of the renin-angiotensin-aldosterone-system in arterial hypertension

    International Nuclear Information System (INIS)

    Slavnov, V.N.; Yakovlev, A.A.; Gandzha, T.I.; Yugrinov, O.G.

    1985-01-01

    In 110 patients suffering from various forms of arterial hypertension (hypertension, aldosteronoma, phaeochromocytoma, corticosteroma) the parameters of the system renin-angiotensin-aldosterone were measured. Basal values of aldosterone, renin activity in blood as well as their concentration in blood taken from the vena cava inferior, renal and adrenal veins during selective renography were determined. The 24-hours rhythm of the hormones in the blood, the reaction of the glomerular zone of the adrenal cortex and the juxtaglomerular renal system under acute Lasix (furosemide) stress was evaluated. It was found, that the system renin-angiotensin-aldosterone is disturbed in all patients with arterial hypertension. This is indicated by changes of aldosterone concentration, renin activity in peripheral blood and in the blood from the vena cava inferior, renal and adrenal veins, the 24-hours rhythm of their concentrations in serum and the reaction to acute Lasix stress. The radioimmunoassays of quantitative parameters of the renin-angiotensin-aldosterone system are decisive for the differential diagnosis of hypertension and adrenal gland tumors connected with a hypertension syndrome. They facilitate a rational choice of the hypertension therapy and the daily distribution of the medicaments for patients with hypertension. The radioimmunoassays can be used for checking the efficiency of medicaments and surgery. (author)

  12. On the origin of urinary renin: A translational approach

    NARCIS (Netherlands)

    L.C.W. Roksnoer (Lodi); Heijnen, B.F.J. (Bart F.J.); Nakano, D. (Daisuke); Peti-Peterdi, J. (Janos); S.B. Walsh (Stephen); I.M. Garrelds (Ingrid); J.M. van Gool (Jeanette); R. Zietse (Bob); H.A.J. Struijker Boudier (Harry A.); E.J. Hoorn (Ewout); A.H.J. Danser (Jan)

    2016-01-01

    textabstractUrinary angiotensinogen excretion parallels albumin excretion, which is not the case for renin, while renin's precursor, prorenin, is undetectable in urine. We hypothesized that renin and prorenin, given their smaller size, are filtered through the glomerulus in larger amounts than

  13. Inhibition of chrysin on xanthine oxidase activity and its inhibition mechanism.

    Science.gov (United States)

    Lin, Suyun; Zhang, Guowen; Liao, Yijing; Pan, Junhui

    2015-11-01

    Chrysin, a bioactive flavonoid, was investigated for its potential to inhibit the activity of xanthine oxidase (XO), a key enzyme catalyzing xanthine to uric acid and finally causing gout. The kinetic analysis showed that chrysin possessed a strong inhibition on XO ability in a reversible competitive manner with IC50 value of (1.26±0.04)×10(-6)molL(-1). The results of fluorescence titrations indicated that chrysin bound to XO with high affinity, and the interaction was predominately driven by hydrogen bonds and van der Waals forces. Analysis of circular dichroism demonstrated that chrysin induced the conformational change of XO with increases in α-helix and β-sheet and reductions in β-turn and random coil structures. Molecular simulation revealed that chrysin interacted with the amino acid residues Leu648, Phe649, Glu802, Leu873, Ser876, Glu879, Arg880, Phe1009, Thr1010, Val1011 and Phe1013 located within the active cavity of XO. The mechanism of chrysin on XO activity may be the insertion of chrysin into the active site occupying the catalytic center of XO to avoid the entrance of xanthine and causing conformational changes in XO. Furthermore, the interaction assays indicated that chrysin and its structural analog apigenin exhibited an additive effect on inhibition of XO. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. DNA damage protection and 5-lipoxygenase inhibiting activity of ...

    African Journals Online (AJOL)

    DNA damage caused by free radical is associated with mutation-based health impairment. The protective effect on DNA damage mediated by hydroxyl radical and peroxynitrite radical, and the inhibiting activity on 5-lipoxygenase of areca inflorescence extracts were studied in vitro. The results show that the boiling water ...

  15. Irregular activity arises as a natural consequence of synaptic inhibition

    International Nuclear Information System (INIS)

    Terman, D.; Rubin, J. E.; Diekman, C. O.

    2013-01-01

    Irregular neuronal activity is observed in a variety of brain regions and states. This work illustrates a novel mechanism by which irregular activity naturally emerges in two-cell neuronal networks featuring coupling by synaptic inhibition. We introduce a one-dimensional map that captures the irregular activity occurring in our simulations of conductance-based differential equations and mathematically analyze the instability of fixed points corresponding to synchronous and antiphase spiking for this map. We find that the irregular solutions that arise exhibit expansion, contraction, and folding in phase space, as expected in chaotic dynamics. Our analysis shows that these features are produced from the interplay of synaptic inhibition with sodium, potassium, and leak currents in a conductance-based framework and provides precise conditions on parameters that ensure that irregular activity will occur. In particular, the temporal details of spiking dynamics must be present for a model to exhibit this irregularity mechanism and must be considered analytically to capture these effects

  16. Irregular activity arises as a natural consequence of synaptic inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Terman, D., E-mail: terman@math.ohio-state.edu [Department of Mathematics, The Ohio State University, Columbus, Ohio 43210 (United States); Rubin, J. E., E-mail: jonrubin@pitt.edu [Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 (United States); Diekman, C. O., E-mail: diekman@njit.edu [Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, New Jersey 07102 (United States)

    2013-12-15

    Irregular neuronal activity is observed in a variety of brain regions and states. This work illustrates a novel mechanism by which irregular activity naturally emerges in two-cell neuronal networks featuring coupling by synaptic inhibition. We introduce a one-dimensional map that captures the irregular activity occurring in our simulations of conductance-based differential equations and mathematically analyze the instability of fixed points corresponding to synchronous and antiphase spiking for this map. We find that the irregular solutions that arise exhibit expansion, contraction, and folding in phase space, as expected in chaotic dynamics. Our analysis shows that these features are produced from the interplay of synaptic inhibition with sodium, potassium, and leak currents in a conductance-based framework and provides precise conditions on parameters that ensure that irregular activity will occur. In particular, the temporal details of spiking dynamics must be present for a model to exhibit this irregularity mechanism and must be considered analytically to capture these effects.

  17. Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

    Directory of Open Access Journals (Sweden)

    Zhen-Ye Zhang

    2017-09-01

    Full Text Available Large-conductance calcium-activated potassium channels (BK channels belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

  18. Renoprotection by blockade of the renin-angiotensin-aldosterone system in diabetic and non-diabetic chronic kidney disease. Specific involvement of intra-renal angiotensin-converting enzyme activity in therapy resistance?

    NARCIS (Netherlands)

    Vogt, L.; Kocks, M. J. A.; Laverman, G. D.; Navis, G.

    2004-01-01

    Data of numerous clinical trials show that lowering of blood pressure is prerequisite for reducing the rate of renal function loss in chronic renal disease. There is evidence supporting that blood pressure lowering obtained by intervention in the renin-angiotensin-aldosterone system (RAAS) has an

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

    Science.gov (United States)

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

    2015-06-01

    Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomerular filtration. Subcutaneous arteries obtained from patients with preeclampsia displayed an enhanced, AT2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness

  20. The Renal Renin-Angiotensin System

    Science.gov (United States)

    Harrison-Bernard, Lisa M.

    2009-01-01

    The renin-angiotensin system (RAS) is a critical regulator of sodium balance, extracellular fluid volume, vascular resistance, and, ultimately, arterial blood pressure. In the kidney, angiotensin II exerts its effects to conserve salt and water through a combination of the hemodynamic control of renal blood flow and glomerular filtration rate and…

  1. Luteolin, a flavonoid, inhibits AP-1 activation by basophils

    International Nuclear Information System (INIS)

    Hirano, Toru; Higa, Shinji; Arimitsu, Junsuke; Naka, Tetsuji; Ogata, Atsushi; Shima, Yoshihito; Fujimoto, Minoru; Yamadori, Tomoki; Ohkawara, Tomoharu; Kuwabara, Yusuke; Kawai, Mari; Matsuda, Hisashi; Yoshikawa, Masayuki; Maezaki, Naoyoshi; Tanaka, Tetsuaki; Kawase, Ichiro; Tanaka, Toshio

    2006-01-01

    Flavonoids including luteolin, apigenin, and fisetin are inhibitors of IL-4 synthesis and CD40 ligand expression by basophils. This study was done to search for compounds with greater inhibitory activity of IL-4 expression and to clarify the molecular mechanisms through which flavonoids inhibit their expression. Of the 37 flavonoids and related compounds examined, ayanin, luteolin, and apigenin were the strongest inhibitors of IL-4 production by purified basophils in response to anti-IgE antibody plus IL-3. Luteolin did not suppress Syk or Lyn phosphorylation in basophils, nor did suppress p54/46 SAPK/JNK, p38 MAPK, and p44/42 MAPK activation by a basophilic cell line, KU812 cells, stimulated with A23187 and PMA. However, luteolin did inhibit phosphorylation of c-Jun and DNA binding activity of AP-1 in nuclear lysates from stimulated KU812 cells. These results provide a fundamental structure of flavonoids for IL-4 inhibition and demonstrate a novel action of flavonoids that suppresses the activation of AP-1

  2. Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Jose L. Labandeira-Garcia

    2017-05-01

    Full Text Available Microglia can transform into proinflammatory/classically activated (M1 or anti-inflammatory/alternatively activated (M2 phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory to M2 (immunoregulatory phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II, via its type 1 receptor (AT1, is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization

  3. Spillover-mediated feedforward-inhibition functionally segregates interneuron activity

    Science.gov (United States)

    Coddington, Luke T.; Rudolph, Stephanie; Lune, Patrick Vande; Overstreet-Wadiche, Linda; Wadiche, Jacques I.

    2013-01-01

    Summary Neurotransmitter spillover represents a form of neural transmission not restricted to morphologically defined synaptic connections. Communication between climbing fibers (CFs) and molecular layer interneurons (MLIs) in the cerebellum is mediated exclusively by glutamate spillover. Here, we show how CF stimulation functionally segregates MLIs based on their location relative to glutamate release. Excitation of MLIs that reside within the domain of spillover diffusion coordinates inhibition of MLIs outside the diffusion limit. CF excitation of MLIs is dependent on extrasynaptic NMDA receptors that enhance the spatial and temporal spread of CF signaling. Activity mediated by functionally segregated MLIs converges onto neighboring Purkinje cells (PCs) to generate a long-lasting biphasic change in inhibition. These data demonstrate how glutamate release from single CFs modulates excitability of neighboring PCs, thus expanding the influence of CFs on cerebellar cortical activity in a manner not predicted by anatomical connectivity. PMID:23707614

  4. Ginger extract inhibits LPS induced macrophage activation and function

    Directory of Open Access Journals (Sweden)

    Bruch David

    2008-01-01

    Full Text Available Abstract Background Macrophages play a dual role in host defence. They act as the first line of defence by mounting an inflammatory response to antigen exposure and also act as antigen presenting cells and initiate the adaptive immune response. They are also the primary infiltrating cells at the site of inflammation. Inhibition of macrophage activation is one of the possible approaches towards modulating inflammation. Both conventional and alternative approaches are being studied in this regard. Ginger, an herbal product with broad anti inflammatory actions, is used as an alternative medicine in a number of inflammatory conditions like rheumatic disorders. In the present study we examined the effect of ginger extract on macrophage activation in the presence of LPS stimulation. Methods Murine peritoneal macrophages were stimulated by LPS in presence or absence of ginger extract and production of proinflammatory cytokines and chemokines were observed. We also studied the effect of ginger extract on the LPS induced expression of MHC II, B7.1, B7.2 and CD40 molecules. We also studied the antigen presenting function of ginger extract treated macrophages by primary mixed lymphocyte reaction. Results We observed that ginger extract inhibited IL-12, TNF-α, IL-1β (pro inflammatory cytokines and RANTES, MCP-1 (pro inflammatory chemokines production in LPS stimulated macrophages. Ginger extract also down regulated the expression of B7.1, B7.2 and MHC class II molecules. In addition ginger extract negatively affected the antigen presenting function of macrophages and we observed a significant reduction in T cell proliferation in response to allostimulation, when ginger extract treated macrophages were used as APCs. A significant decrease in IFN-γ and IL-2 production by T cells in response to allostimulation was also observed. Conclusion In conclusion ginger extract inhibits macrophage activation and APC function and indirectly inhibits T cell activation.

  5. Artemisinin inhibits chloroplast electron transport activity: mode of action.

    Directory of Open Access Journals (Sweden)

    Adyasha Bharati

    Full Text Available Artemisinin, a secondary metabolite produced in Artemisia plant species, besides having antimalarial properties is also phytotoxic. Although, the phytotoxic activity of the compound has been long recognized, no information is available on the mechanism of action of the compound on photosynthetic activity of the plant. In this report, we have evaluated the effect of artemisinin on photoelectron transport activity of chloroplast thylakoid membrane. The inhibitory effect of the compound, under in vitro condition, was pronounced in loosely and fully coupled thylakoids; being strong in the former. The extent of inhibition was drastically reduced in the presence of uncouplers like ammonium chloride or gramicidin; a characteristic feature described for energy transfer inhibitors. The compound, on the other hand, when applied to plants (in vivo, behaved as a potent inhibitor of photosynthetic electron transport. The major site of its action was identified to be the Q(B; the secondary quinone moiety of photosystemII complex. Analysis of photoreduction kinetics of para-benzoquinone and duroquinone suggest that the inhibition leads to formation of low pool of plastoquinol, which becomes limiting for electron flow through photosystemI. Further it was ascertained that the in vivo inhibitory effect appeared as a consequence of the formation of an unidentified artemisinin-metabolite rather than by the interaction of the compound per se. The putative metabolite of artemisinin is highly reactive in instituting the inhibition of photosynthetic electron flow eventually reducing the plant growth.

  6. Altered renal expression of angiotensin II receptors, renin receptor, and ACE-2 precede the development of renal fibrosis in aging rats.

    Science.gov (United States)

    Schulman, Ivonne Hernandez; Zhou, Ming-Sheng; Treuer, Adriana V; Chadipiralla, Kiranmai; Hare, Joshua M; Raij, Leopoldo

    2010-01-01

    The susceptibility to fibrosis and progression of renal disease is mitigated by inhibition of the renin-angiotensin system (RAS). We hypothesized that activation of the intrarenal RAS predisposes to renal fibrosis in aging. Intrarenal expression of angiotensin II type 1 (AT(1)R), type 2 (AT(2)R), and (pro)renin receptors, ACE and ACE-2, as well as pro- and antioxidant enzymes were measured in 3-month-old (young), 14-month-old (middle-aged), and 24-month-old (old) male Sprague-Dawley rats. Old rats manifested glomerulosclerosis and severe tubulointerstitial fibrosis with increased fibronectin and TGF-β expression (7-fold). AT(1)R /AT(2)R ratios were increased in middle-aged (cortical 1.6-fold, medullary 5-fold) and old rats (cortical 2-fold, medullary 4-fold). Similarly, (pro)renin receptor expression was increased in middle-aged (cortical 2-fold, medullary 3-fold) and old (cortical 5-fold, medullary 3-fold) rats. Cortical ACE was increased (+35%) in old rats, whereas ACE-2 was decreased (-50%) in middle-aged and old rats. NADPH oxidase activity was increased (2-fold), whereas antioxidant capacity and expression of the mitochondrial enzyme manganese superoxide dismutase (cortical -40%, medullary -53%) and medullary endothelial nitric oxide synthase (-48%) were decreased in old rats. Age-related intrarenal activation of the RAS preceded the development of severe renal fibrosis, suggesting that it contributes to the increased susceptibility to renal injury observed in the elderly. Copyright © 2010 S. Karger AG, Basel.

  7. Capturing the dynamics of systemic Renin-Angiotensin-Aldosterone System (RAAS) peptides heightens the understanding of the effect of benazepril in dogs.

    Science.gov (United States)

    Mochel, J P; Peyrou, M; Fink, M; Strehlau, G; Mohamed, R; Giraudel, J M; Ploeger, B; Danhof, M

    2013-04-01

    In dogs, activation of the Renin-Angiotensin-Aldosterone System (RAAS) is an important feature of congestive heart failure (CHF). Long-term increases in angiotensin II (AII) and aldosterone (ALD) lead to the progression of heart failure to its end stage. Angiotensin-converting enzyme inhibitors (ACEIs) are the foremost therapeutic option in the management of CHF. Recent literature has challenged the efficacy of ACEIs, based on modest reduction in urinary aldosterone (UALD) excretion despite marked inhibition of ACE activity. This study was designed to heighten the understanding of the effect of benazepril, a potent ACEI, on the RAAS, using a low-sodium diet as an experimental model of RAAS activation. Time course profiles of RAAS peptides and related areas under the curve (AUC) were used for comparison between benazepril and placebo groups. Results indicated substantial changes in the dynamics of these biomarkers. At presumed benazeprilat steady state, significant differences in AUC of plasma renin activity (+90%), angiotensin I (+43%), and AII (-53%) were found between benazepril and placebo-treated dogs. ALD decreased by 73% in plasma but only by 5% in urine. In conclusion, despite modest reduction in UALD excretion, benazepril markedly influences RAAS dynamics in dogs. © 2012 Blackwell Publishing Ltd.

  8. Emotion potentiates response activation and inhibition in masked priming.

    Science.gov (United States)

    Bocanegra, Bruno R; Zeelenberg, René

    2012-01-01

    Previous studies have shown that emotion can have 2-fold effects on perception. At the object-level, emotional stimuli benefit from a stimulus-specific boost in visual attention at the relative expense of competing stimuli. At the visual feature-level, recent findings indicate that emotion may inhibit the processing of small visual details and facilitate the processing of coarse visual features. In the present study, we investigated whether emotion can boost the activation and inhibition of automatic motor responses that are generated prior to overt perception. To investigate this, we tested whether an emotional cue affects covert motor responses in a masked priming task. We used a masked priming paradigm in which participants responded to target arrows that were preceded by invisible congruent or incongruent prime arrows. In the standard paradigm, participants react faster, and commit fewer errors responding to the directionality of target arrows, when they are preceded by congruent vs. incongruent masked prime arrows (positive congruency effect, PCE). However, as prime-target SOAs increase, this effect reverses (negative congruency effect, NCE). These findings have been explained as evidence for an initial activation and a subsequent inhibition of a partial response elicited by the masked prime arrow. Our results show that the presentation of fearful face cues, compared to neutral face cues, increased the size of both the PCE and NCE, despite the fact that the primes were invisible. This is the first demonstration that emotion prepares an individual's visuomotor system for automatic activation and inhibition of motor responses in the absence of visual awareness.

  9. COBRA1 inhibits AP-1 transcriptional activity in transfected cells

    International Nuclear Information System (INIS)

    Zhong Hongjun; Zhu Jianhua; Zhang Hao; Ding Lihua; Sun Yan; Huang Cuifen; Ye Qinong

    2004-01-01

    Mutations in the breast cancer susceptibility gene (BRCA1) account for a significant proportion of hereditary breast and ovarian cancers. Cofactor of BRCA1 (COBRA1) was isolated as a BRCA1-interacting protein and exhibited a similar chromatin reorganizing activity to that of BRCA1. However, the biological role of COBRA1 remains largely unexplored. Here, we report that ectopic expression of COBRA1 inhibited activator protein 1 (AP-1) transcriptional activity in transfected cells in a dose-dependent manner, whereas reduction of endogenous COBRA1 with a small interfering RNA significantly enhanced AP-1-mediated transcriptional activation. COBRA1 physically interacted with the AP-1 family members, c-Jun and c-Fos, and the middle region of COBRA1 bound to c-Fos. Lack of c-Fos binding site in the COBRA1 completely abolished the COBRA1 inhibition of AP-1 trans-activation. These findings suggest that COBRA1 may directly modulate AP-1 pathway and, therefore, may play important roles in cell proliferation, differentiation, apoptosis, and oncogenesis

  10. MMS 1001 inhibits melanin synthesis via ERK activation.

    Science.gov (United States)

    Lee, Hyun-E; Song, Jiho; Kim, Su Yeon; Park, Kyoung-Chan; Min, Kyung Hoon; Kim, Dong-Seok

    2013-03-01

    Melanin plays major a role in pigmentation of hair, eyes, and skin in mammals. In this study, the inhibitory effects of MMS 1001 on alpha-MSH-stimulated melanogenesis were investigated in B16F10 melanoma cells. MMS 1001 did not show cytotoxic effects up to 10 microM. Melanin content and intracellular tyrosinase activity were inhibited by MMS 1001 treatment in a dose-dependent manner. In Western blot analysis, MITF expression was decreased by MMS 1001. In addition, tyrosinase expressions were also reduced after MMS 1001 treatment. Further results showed that the phosphorylation of ERK was induced by MMS 1001. Moreover, a specific MEK inhibitor, PD98059, abrogated the inhibitory effects of MMS 1001 on melanin production and tyrosinase expression. These results indicate that the hypopigmentary effects of MMS 1001 resulted from the inhibition of MITF and tyrosinase expression via phosphorylation of ERK. Thus, MMS 1001 could be developed as a new effective skin-whitening agent.

  11. Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition.

    Science.gov (United States)

    Harrison, Ian F; Smith, Andrew D; Dexter, David T

    2018-02-14

    Parkinson's disease (PD) is associated with degeneration of nigrostriatal neurons due to intracytoplasmic inclusions composed predominantly of a synaptic protein called α-synuclein. Accumulations of α-synuclein are thought to 'mask' acetylation sites on histone proteins, inhibiting the action of histone acetyltransferase (HAT) enzymes in their equilibrium with histone deacetylases (HDACs), thus deregulating the dynamic control of gene transcription. It is therefore hypothesised that the misbalance in the actions of HATs/HDACs in neurodegeneration can be rectified with the use of HDAC inhibitors, limiting the deregulation of transcription and aiding neuronal homeostasis and neuroprotection in disorders such as PD. Here we quantify histone acetylation in the Substantia Nigra pars compacta (SNpc) in the brains of control, early and late stage PD cases to determine if histone acetylation is a function of disease progression. PD development is associated with Braak-dependent increases in histone acetylation. Concurrently, we show that as expected disease progression is associated with reduced markers of dopaminergic neurons and increased markers of activated microglia. We go on to demonstrate that in vitro, degenerating dopaminergic neurons exhibit histone hypoacetylation whereas activated microglia exhibit histone hyperacetylation. This suggests that the disease-dependent increase in histone acetylation observed in human PD cases is likely a combination of the contributions of both degenerating dopaminergic neurons and infiltrating activated microglia. The HDAC SIRT 2 has become increasingly implicated as a novel target for mediation of neuroprotection in PD: the neuronal and microglial specific effects of its inhibition however remain unclear. We demonstrate that SIRT 2 expression in the SNpc of PD brains remains relatively unchanged from controls and that SIRT 2 inhibition, via AGK2 treatment of neuronal and microglial cultures, results in neuroprotection of

  12. Metformin inhibits glutaminase activity and protects against hepatic encephalopathy.

    Directory of Open Access Journals (Sweden)

    Javier Ampuero

    Full Text Available AIM: To investigate the influence of metformin use on liver dysfunction and hepatic encephalopathy in a retrospective cohort of diabetic cirrhotic patients. To analyze the impact of metformin on glutaminase activity and ammonia production in vitro. METHODS: Eighty-two cirrhotic patients with type 2 diabetes were included. Forty-one patients were classified as insulin sensitizers experienced (metformin and 41 as controls (cirrhotic patients with type 2 diabetes mellitus without metformin treatment. Baseline analysis included: insulin, glucose, glucagon, leptin, adiponectin, TNFr2, AST, ALT. HOMA-IR was calculated. Baseline HE risk was calculated according to minimal hepatic encephalopathy, oral glutamine challenge and mutations in glutaminase gene. We performed an experimental study in vitro including an enzymatic activity assay where glutaminase inhibition was measured according to different metformin concentrations. In Caco2 cells, glutaminase activity inhibition was evaluated by ammonia production at 24, 48 and 72 hours after metformina treatment. RESULTS: Hepatic encephalopathy was diagnosed during follow-up in 23.2% (19/82: 4.9% (2/41 in patients receiving metformin and 41.5% (17/41 in patients without metformin treatment (logRank 9.81; p=0.002. In multivariate analysis, metformin use [H.R.11.4 (95% CI: 1.2-108.8; p=0.034], age at diagnosis [H.R.1.12 (95% CI: 1.04-1.2; p=0.002], female sex [H.R.10.4 (95% CI: 1.5-71.6; p=0.017] and HE risk [H.R.21.3 (95% CI: 2.8-163.4; p=0.003] were found independently associated with hepatic encephalopathy. In the enzymatic assay, glutaminase activity inhibition reached 68% with metformin 100 mM. In Caco2 cells, metformin (20 mM decreased glutaminase activity up to 24% at 72 hours post-treatment (p<0.05. CONCLUSIONS: Metformin was found independently related to overt hepatic encephalopathy in patients with type 2 diabetes mellitus and high risk of hepatic encephalopathy. Metformin inhibits glutaminase

  13. Diethyl 2-(Phenylcarbamoylphenyl Phosphorothioates: Synthesis, Antimycobacterial Activity and Cholinesterase Inhibition

    Directory of Open Access Journals (Sweden)

    Jarmila Vinšová

    2014-05-01

    Full Text Available A new series of 27 diethyl 2-(phenylcarbamoylphenyl phosphorothioates (thiophosphates was synthesized, characterized by NMR, IR and CHN analyses and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium avium and two strains of Mycobacterium kansasii. The best activity against M. tuberculosis was found for O-{4-bromo-2-[(3,4-dichlorophenylcarbamoyl]phenyl} O,O-diethyl phosphorothioate (minimum inhibitory concentration of 4 µM. The highest activity against nontuberculous mycobacteria was exhibited by O-(5-chloro-2-{[4-(trifluoromethylphenyl]carbamoyl}-phenyl O,O-diethyl phosphorothioate with MIC values from 16 µM. Prepared thiophosphates were also evaluated against acetylcholinesterase from electric eel and butyrylcholinesterase from equine serum. Their inhibitory activity was compared to that of the known cholinesterases inhibitors galanthamine and rivastigmine. All tested compounds showed a higher (for AChE inhibition and comparable (for BChE inhibition activity to that of rivastigmine, with IC50s within the 8.04 to 20.2 µM range.

  14. AVS-1357 inhibits melanogenesis via prolonged ERK activation.

    Science.gov (United States)

    Kim, Dong-Seok; Lee, Hyun-Kyung; Park, Seo-Hyoung; Chae, Chong Hak; Park, Kyoung-Chan

    2009-08-01

    In this study, we demonstrated that a derivative of imidazole, AVS-1357, is a novel skin-whitening compound. AVS-1357 was found to significantly inhibit melanin production in a dose-dependent manner; however, it did not directly inhibit tyrosinase. Furthermore, we found that AVS-1357 induced prolonged activation of extracellular signal-regulated kinase (ERK) and Akt, while it downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase. It has been reported that the activation of ERK and/or Akt is involved in melanogenesis. Therefore, we examined the effects of AVS-1357 on melanogenesis in the absence or presence of PD98059 (a specific inhibitor of the ERK pathway) and/or LY294002 (a specific inhibitor of the Akt pathway). PD98059 dramatically increased melanogenesis, whereas LY294002 had no effect. Furthermore, PD98059 attenuated AVS-1357 induced ERK activation, as well as the downregulation of MITF and tyrosinase. These findings suggest that the effects of AVS-1357 occur via downregulation of MITF and tyrosinase, which is caused by AVS-1357-induced prolonged ERK activation. Taken together, our results indicate that AVS-1357 has the potential as a new skin whitening agent.

  15. DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

    International Nuclear Information System (INIS)

    Asmis, Lars; Tanner, Felix C.; Sudano, Isabella; Luescher, Thomas F.; Camici, Giovanni G.

    2010-01-01

    Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents. Methods and results: Human venous blood from healthy volunteers was collected in citrated tubes and platelet activation was studied by cone and platelet analyzer (CPA) and rapid-platelet-function-assay (RPFA). CPA analysis showed that DMSO-treated platelets exhibit a lower adherence in response to shear stress (-15.54 ± 0.9427%, n = 5, P < 0.0001 versus control). Additionally, aggregometry studies revealed that DMSO-treated, arachidonate-stimulated platelets had an increased lag phase (18.0% ± 4.031, n = 9, P = 0.0004 versus control) as well as a decreased maximal aggregation (-6.388 ± 2.212%, n = 6, P = 0.0162 versus control). Inhibitory action of DMSO could be rescued by exogenous thromboxane A2 and was mediated, at least in part, by COX-1 inhibition. Conclusions: Clinically relevant concentrations of DMSO impair platelet activation by a thromboxane A2-dependent, COX-1-mediated effect. This finding may be crucial for the previously reported anti-thrombotic property displayed by DMSO. Our findings support a role for DMSO as a novel drug to prevent not only proliferation, but also thrombotic complications of drug eluting stents.

  16. Hypoxia inhibits colonic ion transport via activation of AMP kinase.

    LENUS (Irish Health Repository)

    Collins, Danielle

    2012-02-01

    BACKGROUND AND AIMS: Mucosal hypoxia is a common endpoint for many pathological processes including ischemic colitis, colonic obstruction and anastomotic failure. Previous studies suggest that hypoxia modulates colonic mucosal function through inhibition of chloride secretion. However, the molecular mechanisms underlying this observation are poorly understood. AMP-activated protein kinase (AMPK) is a metabolic energy regulator found in a wide variety of cells and has been linked to cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride secretion in several different tissues. We hypothesized that AMPK mediates many of the acute effects of hypoxia on human and rat colonic electrolyte transport. METHODS: The fluorescent chloride indicator dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide was used to measure changes in intracellular chloride concentrations in isolated single rat colonic crypts. Ussing chamber experiments in human colonic mucosa were conducted to evaluate net epithelial ion transport. RESULTS: This study demonstrates that acute hypoxia inhibits electrogenic chloride secretion via AMPK mediated inhibition of CFTR. Pre-treatment of tissues with the AMPK inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo [1,5-a] pyrimidine (compound C) in part reversed the effects of acute hypoxia on chloride secretion. CONCLUSION: We therefore suggest that AMPK is a key component of the adaptive cellular response to mucosal hypoxia in the colon. Furthermore, AMPK may represent a potential therapeutic target in diseased states or in prevention of ischemic intestinal injury.

  17. Antioxidant Activity and Acetylcholinesterase Inhibition of Grape Skin Anthocyanin (GSA

    Directory of Open Access Journals (Sweden)

    Mehnaz Pervin

    2014-07-01

    Full Text Available We aimed to investigate the antioxidant and acetylcholinesterase inhibitory activities of the anthocyanin rich extract of grape skin. Grape skin anthocyanin (GSA neutralized free radicals in different test systems, such as 2,-2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS and 2,2-diphenyl-1-picrylhydrazyl (DPPH assays, to form complexes with Fe2+ preventing 2,2'-azobis(2-amidinopropane dihydrochloride (AAPH-induced erythrocyte hemolysis and oxidative DNA damage. Moreover, GSA decreased reactive oxygen species (ROS generation in isolated mitochondria thus inhibiting 2',-7'-dichlorofluorescin (DCFH oxidation. In an in vivo study, female BALB/c mice were administered GSA, at 12.5, 25, and 50 mg per kg per day orally for 30 consecutive days. Herein, we demonstrate that GSA administration significantly elevated the level of antioxidant enzymes in mice sera, livers, and brains. Furthermore, GSA inhibited acetylcholinesterase (AChE in the in vitro assay with an IC50 value of 363.61 µg/mL. Therefore, GSA could be an excellent source of antioxidants and its inhibition of cholinesterase is of interest with regard to neurodegenerative disorders such as Alzheimer’s disease.

  18. Acupuncture inhibits cue-induced heroin craving and brain activation.

    Science.gov (United States)

    Cai, Xinghui; Song, Xiaoge; Li, Chuanfu; Xu, Chunsheng; Li, Xiliang; Lu, Qi

    2012-11-25

    Previous research using functional MRI has shown that specific brain regions associated with drug dependence and cue-elicited heroin craving are activated by environmental cues. Craving is an important trigger of heroin relapse, and acupuncture may inhibit craving. In this study, we performed functional MRI in heroin addicts and control subjects. We compared differences in brain activation between the two groups during heroin cue exposure, heroin cue exposure plus acupuncture at the Zusanli point (ST36) without twirling of the needle, and heroin cue exposure plus acupuncture at the Zusanli point with twirling of the needle. Heroin cue exposure elicited significant activation in craving-related brain regions mainly in the frontal lobes and callosal gyri. Acupuncture without twirling did not significantly affect the range of brain activation induced by heroin cue exposure, but significantly changed the extent of the activation in the heroin addicts group. Acupuncture at the Zusanli point with twirling of the needle significantly decreased both the range and extent of activation induced by heroin cue exposure compared with heroin cue exposure plus acupuncture without twirling of the needle. These experimental findings indicate that presentation of heroin cues can induce activation in craving-related brain regions, which are involved in reward, learning and memory, cognition and emotion. Acupuncture at the Zusanli point can rapidly suppress the activation of specific brain regions related to craving, supporting its potential as an intervention for drug craving.

  19. Hemodynamic, morphometric and autonomic patterns in hypertensive rats - renin-angiotensin system modulation

    Directory of Open Access Journals (Sweden)

    Fernanda S. Zamo

    2010-01-01

    Full Text Available BACKGROUND: Spontaneously hypertensive rats develop left ventricular hypertrophy, increased blood pressure and blood pressure variability, which are important determinants of heart damage, like the activation of renin-angiotensin system. AIMS: To investigate the effects of the time-course of hypertension over 1 hemodynamic and autonomic patterns (blood pressure; blood pressure variability; heart rate; 2 left ventricular hypertrophy; and 3 local and systemic Renin-angiotensin system of the spontaneously hypertensive rats. METHODS: Male spontaneously hypertensive rats were randomized into two groups: young (n=13 and adult (n=12. Hemodynamic signals (blood pressure, heart rate, blood pressure variability (BPV and spectral analysis of the autonomic components of blood pressure were analyzed. LEFT ventricular hypertrophy was measured by the ratio of LV mass to body weight (mg/g, by myocyte diameter (μm and by relative fibrosis area (RFA, %. ACE and ACE2 activities were measured by fluorometry (UF/min, and plasma renin activity (PRA was assessed by a radioimmunoassay (ng/mL/h. Cardiac gene expressions of Agt, Ace and Ace2 were quantified by RT-PCR (AU. RESULTS: The time-course of hypertension in spontaneously hypertensive rats increased BPV and reduced the alpha index in adult spontaneously hypertensive rats. Adult rats showed increases in left ventricular hypertrophy and in RFA. Compared to young spontaneously hypertensive rats, adult spontaneously hypertensive rats had lower cardiac ACE and ACE2 activities, and high levels of PRA. No change was observed in gene expression of Renin-angiotensin system components. CONCLUSIONS: The observed autonomic dysfunction and modulation of Renin-angiotensin system activity are contributing factors to end-organ damage in hypertension and could be interacting. Our findings suggest that the management of hypertensive disease must start before blood pressure reaches the highest stable levels and the consequent

  20. Investigating the Antioxidant and Acetylcholinesterase Inhibition Activities of Gossypium herbaceam

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    Haji Akber Aisa

    2013-01-01

    Full Text Available Our previous research showed that standardized extract from the flowers of the Gossypium herbaceam labeled GHE had been used in clinical trials for its beneficial effects on brain functions, particularly in connection with age-related dementia and Alzheimer’s disease (AD. The aim of this work was to determine the components of this herb and the individual constituents of GHE. In order to better understand this herb for AD treatment, we investigated the acetylcholinesterase (AChE inhibition and antioxidant activity of GHE as well as the protective effects to PC12 cells against cytotoxicity induced by tertiary butyl hydroperoxide (tBHP using in vitro assays. The antioxidant activities were assessed by measuring their capabilities for scavenging 1,1-diphenyl-2-picylhydrazyl (DPPH and 2-2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS free radical as well as in inhibiting lipid peroxidation. Our data showed that GHE exhibited certain activities against AChE and also is an efficient free radical scavenger, which may be helpful in preventing or alleviating patients suffering from AD.

  1. Zeno inhibition of polarization rotation in an optically active medium

    International Nuclear Information System (INIS)

    Gonzalo, Isabel; Luis, Alfredo; Porras, Miguel A

    2015-01-01

    We describe an experiment in which the rotation of the polarization of light propagating in an optically active water solution of D-fructose tends to be inhibited by frequent monitoring whether the polarization remains unchanged. This is an example of the Zeno effect that has remarkable pedagogical interest because of its conceptual simplicity, easy implementation, low cost, and because the same the Zeno effect holds at classical and quantum levels. An added value is the demonstration of the Zeno effect beyond typical idealized assumptions in a practical setting with real polarizers. (paper)

  2. The water channel aquaporin-1 contributes to renin cell recruitment during chronic stimulation of renin production

    DEFF Research Database (Denmark)

    Tinning, Anne Robdrup; Jensen, Boye L; Schweda, Frank

    2014-01-01

    Processing and release of secretory granules involve water movement across granule membranes. It was hypothesized that the water channel aquaporin-1 (AQP-1) contributes directly to recruitment of renin-positive cells in the afferent arteriole. AQP1(-/-) and (+/+) mice were fed a low NaCl diet (LS...... to baseline with no difference between genotypes. Plasma nitrite/nitrate concentration was unaffected by genotype and LS-ACEI. In AQP1(-/-) mice, the number of afferent arterioles with recruitment was significantly lower compared to (+/+) after LS-ACEI. It is concluded that aquaporin-1 is not necessary...... for acutely stimulated renin secretion in vivo and from isolated perfused kidney, whereas recruitment of renin-positive cells in response to chronic stimulation is attenuated or delayed in AQP1(-/-) mice....

  3. Virulent poxviruses inhibit DNA sensing by preventing STING activation.

    Science.gov (United States)

    Georgana, Iliana; Sumner, Rebecca P; Towers, Greg J; Maluquer de Motes, Carlos

    2018-02-28

    Cytosolic recognition of DNA has emerged as a critical cellular mechanism of host immune activation upon pathogen invasion. The central cytosolic DNA sensor cGAS activates STING, which is phosphorylated, dimerises and translocates from the ER to a perinuclear region to mediate IRF-3 activation. Poxviruses are dsDNA viruses replicating in the cytosol and hence likely to trigger cytosolic DNA sensing. Here we investigated the activation of innate immune signalling by 4 different strains of the prototypic poxvirus vaccinia virus (VACV) in a cell line proficient in DNA sensing. Infection with the attenuated VACV strain MVA activated IRF-3 via cGAS and STING, and accordingly STING dimerised and was phosphorylated during MVA infection. Conversely, VACV strains Copenhagen and Western Reserve inhibited STING dimerisation and phosphorylation during infection and in response to transfected DNA and cGAMP, thus efficiently suppressing DNA sensing and IRF-3 activation. A VACV deletion mutant lacking protein C16, thought to be the only viral DNA sensing inhibitor acting upstream of STING, retained the ability to block STING activation. Similar inhibition of DNA-induced STING activation was also observed for cowpox and ectromelia viruses. Our data demonstrate that virulent poxviruses possess mechanisms for targeting DNA sensing at the level of the cGAS-STING axis and that these mechanisms do not operate in replication-defective strains such as MVA. These findings shed light on the role of cellular DNA sensing in poxvirus-host interactions and will open new avenues to determine its impact on VACV immunogenicity and virulence. IMPORTANCE Poxviruses are dsDNA viruses infecting a wide range of vertebrates and include the causative agent of smallpox (variola virus) and its vaccine vaccinia virus (VACV). Despite smallpox eradication VACV remains of interest as a therapeutic. Attenuated strains are popular vaccine candidates, whereas replication-competent strains are emerging as

  4. Fast inhibition of glutamate-activated currents by caffeine.

    Directory of Open Access Journals (Sweden)

    Nicholas P Vyleta

    Full Text Available BACKGROUND: Caffeine stimulates calcium-induced calcium release (CICR in many cell types. In neurons, caffeine stimulates CICR presynaptically and thus modulates neurotransmitter release. METHODOLOGY/PRINCIPAL FINDINGS: Using the whole-cell patch-clamp technique we found that caffeine (20 mM reversibly increased the frequency and decreased the amplitude of miniature excitatory postsynaptic currents (mEPSCs in neocortical neurons. The increase in mEPSC frequency is consistent with a presynaptic mechanism. Caffeine also reduced exogenously applied glutamate-activated currents, confirming a separate postsynaptic action. This inhibition developed in tens of milliseconds, consistent with block of channel currents. Caffeine (20 mM did not reduce currents activated by exogenous NMDA, indicating that caffeine block is specific to non-NMDA type glutamate receptors. CONCLUSIONS/SIGNIFICANCE: Caffeine-induced inhibition of mEPSC amplitude occurs through postsynaptic block of non-NMDA type ionotropic glutamate receptors. Caffeine thus has both pre and postsynaptic sites of action at excitatory synapses.

  5. Angiopoietin1 inhibits mast cell activation and protects against anaphylaxis.

    Directory of Open Access Journals (Sweden)

    Jun-Hua Yao

    Full Text Available Since morbidity and mortality rates of anaphylaxis diseases have been increasing year by year, how to prevent and manage these diseases effectively has become an important issue. Mast cells play a central regulatory role in allergic diseases. Angiopoietin1 (Ang-1 exhibits anti-inflammatory properties by inhibiting vascular permeability, leukocyte migration and cytokine production. However, Ang-1's function in mast cell activation and anaphylaxis diseases is unknown. The results of our study suggest that Ang-1 decreased lipopolysaccharide (LPS-induced pro-inflammatory cytokines production of mast cells by suppressing IκB phosphorylation and NF-κB nuclear translocation. Ang-1 also strongly inhibited compound 48/80 induced and FcεRI-mediated mast cells degranulation by decreasing intracellular calcium levels in vitro. In vivo lentivirus-mediated delivery of Ang-1 in mice exhibited alleviated leakage in IgE-dependent passive cutaneous anaphylaxis (PCA. Furthermore, exogenous Ang-1 intervention treatment prevented mice from compound 48/80-induced mesentery mast cell degranulation, attenuated increases in pro-inflammatory cytokines, relieved lung injury, and improved survival in anaphylaxis shock. The results of our study reveal, for the first time, the important role of Ang-1 in the activation of mast cells, and identify a therapeutic effect of Ang-1 on anaphylaxis diseases.

  6. High maternal sodium intake alters sex-specific renal renin-angiotensin system components in newborn Wistar offspring.

    Science.gov (United States)

    Maia, D R R; Lopes, K L; Heimann, J C; Furukawa, L N S

    2016-01-28

    This study aimed to evaluate the systemic and renal renin-angiotensin-aldosterone system (RAAS) at birth in male and female offspring and in mothers fed a high sodium diet (HSD) before and during gestation. Female Wistar rats were fed a HSD (8.0% NaCl) or a normal sodium diet (1.3% NaCl) from 8 weeks of age until delivery of their first litter. Maternal body weight, tail blood pressure, and food and water intake were evaluated. The litter sizes were assessed, and the body and kidney weights of the offspring were measured. Both mothers and offspring were euthanized immediately following the birth of the pups to evaluate plasma renin activity (PRA), renal renin content (RRC), renal angiotensin-converting enzyme (ACE) activity, renal angiotensin (Ang) II content, serum aldosterone (ALDO) levels, and renal cortical and medullary renin messenger RNA expression. In mothers in the HSD group, water intake and kidney mass were higher, whereas renal ACE activity, Ang II, PRA, ALDO and RRC were decreased. In the offspring of HSD-fed dams, the body and kidney mass were lower in both genders, renal ACE activity was lower in females and renal Ang II was lower in males. PRA, RRC, renin gene expression and ALDO levels did not differ between the groups of offspring. The data presented herein showed that a maternal HSD during pregnancy induces low birth weight and a sex-specific response in the RAAS in offspring.

  7. The Improvement of Hypertension by Probiotics: Effects on Cholesterol, Diabetes, Renin, and Phytoestrogens

    Directory of Open Access Journals (Sweden)

    Huey-Shi Lye

    2009-08-01

    Full Text Available Probiotics are live organisms that are primarily used to improve gastrointestinal disorders such as diarrhea, irritable bowel syndrome, constipation, lactose intolerance, and to inhibit the excessive proliferation of pathogenic intestinal bacteria. However, recent studies have suggested that probiotics could have beneficial effects beyond gastrointestinal health, as they were found to improve certain metabolic disorders such as hypertension. Hypertension is caused by various factors and the predominant causes include an increase in cholesterol levels, incidence of diabetes, inconsistent modulation of renin and imbalanced sexual hormones. This review discusses the antihypertensive roles of probiotics via the improvement and/or treatment of lipid profiles, modulation of insulin resistance and sensitivity, the modulation of renin levels and also the conversion of bioactive phytoestrogens as an alternative replacement of sexual hormones such as estrogen and progesterone.

  8. Modulation of the cardiac sodium/bicarbonate cotransporter by the renin angiotensin aldosterone system: pathophysiological consequences.

    Science.gov (United States)

    De Giusti, Verónica C; Ciancio, María C; Orlowski, Alejandro; Aiello, Ernesto A

    2013-01-01

    The sodium/bicarbonate cotransporter (NBC) is one of the major alkalinizing mechanisms in the cardiomyocytes. It has been demonstrated the existence of at least two functional isoforms, one that promotes the co-influx of 1 molecule of Na(+) per 1 molecule of HCO(-) 3 (electroneutral isoform; NBCn1) and the other one that generates the co-influx of 1 molecule of Na(+) per 2 molecules of HCO(-) 3 (electrogenic isoform; NBCe1). Both isoforms are important to maintain intracellular pH (pH i ) and sodium concentration ([Na(+)] i ). In addition, NBCe1 generates an anionic repolarizing current that modulates the action potential duration (APD). The renin-angiotensin-aldosterone system (RAAS) is implicated in the modulation of almost all physiological cardiac functions and is also involved in the development and progression of cardiac diseases. It was reported that angiotensin II (Ang II) exhibits an opposite effect on NBC isoforms: it activates NBCn1 and inhibits NBCe1. The activation of NBCn1 leads to an increase in pH i and [Na(+)] i , which indirectly, due to the stimulation of reverse mode of the Na(+)/Ca(2+) exchanger (NCX), conduces to an increase in the intracellular Ca(2+) concentration. On the other hand, the inhibition of NBCe1 generates an APD prolongation, potentially representing a risk of arrhythmias. In the last years, the potentially altered NBC function in pathological scenarios, as cardiac hypertrophy and ischemia-reperfusion, has raised increasing interest among investigators. This review attempts to draw the attention on the relevant regulation of NBC activity by RAAS, since it modulates pH i and [Na(+)] i , which are involved in the development of cardiac hypertrophy, the damage produced by ischemia-reperfusion and the generation of arrhythmic events, suggesting a potential role of NBC in cardiac diseases.

  9. MODULATION OF THE CARDIAC SODIUM/BICARBONATE COTRANSPORTER BY THE RENIN ANGIOTENSIN ALDOSTERONE SYSTEM: PATHOPHYSIOLOGICAL CONSEQUENCES.

    Directory of Open Access Journals (Sweden)

    Verónica Celeste De Giusti

    2014-01-01

    Full Text Available The sodium/bicarbonate cotransporter (NBC is one of the major alkalinizing mechanisms in the cardiomyocytes. It has been demonstrated the existence of at least two functional isoforms, one that promotes the co-influx of 1 molecule of Na+ per 1 molecule of HCO3- (electroneutral isoform; NBCn1 and the other one that generates the co-influx of 1 molecule of Na+ per 2 molecules of HCO3- (electrogenic isoform; NBCe1. Both isoforms are important to maintain intracellular pH (pHi and sodium concentration ([Na+]i. In addition, NBCe1 generates an anionic repolarizing current that modulates the action potential duration (APD. The renin-angiotensin-aldosterone system (RAAS is implicated in the modulation of almost all physiological cardiac functions and is also involved in the development and progression of cardiac diseases. It was reported that angiotensin II (Ang II exhibits an opposite effect on NBC isoforms: it activates NBCn1 and inhibits NBCe1. The activation of NBCn1 leads to an increase in pHi and [Na+]i, which indirectly, due to the stimulation of reverse mode of the Na+/Ca2+ exchanger (NCX, conduces to an increase in the intracellular Ca2+ concentration. On the other hand, the inhibition of NBCe1 generates an APD prolongation, potentially representing a risk of arrhythmias. In the last years, the potentially altered NBC function in pathological scenarios, as cardiac hypertrophy and ischemia-reperfusion, has raised increasing interest among investigators. This review attempts to draw the attention on the relevant regulation of NBC activity by RAAS, since it modulates pHi and [Na+]i, which are involved in the development of cardiac hypertrophy, the damage produced by ischemia-reperfusion and the generation of arrhythmic events, suggesting a potential role of NBC in cardiac diseases.

  10. Dietary Sodium Suppresses Digestive Efficiency via the Renin-Angiotensin System.

    Science.gov (United States)

    Weidemann, Benjamin J; Voong, Susan; Morales-Santiago, Fabiola I; Kahn, Michael Z; Ni, Jonathan; Littlejohn, Nicole K; Claflin, Kristin E; Burnett, Colin M L; Pearson, Nicole A; Lutter, Michael L; Grobe, Justin L

    2015-06-11

    Dietary fats and sodium are both palatable and are hypothesized to synergistically contribute to ingestive behavior and thereby obesity. Contrary to this hypothesis, C57BL/6J mice fed a 45% high fat diet exhibited weight gain that was inhibited by increased dietary sodium content. This suppressive effect of dietary sodium upon weight gain was mediated specifically through a reduction in digestive efficiency, with no effects on food intake behavior, physical activity, or resting metabolism. Replacement of circulating angiotensin II levels reversed the effects of high dietary sodium to suppress digestive efficiency. While the AT1 receptor antagonist losartan had no effect in mice fed low sodium, the AT2 receptor antagonist PD-123,319 suppressed digestive efficiency. Correspondingly, genetic deletion of the AT2 receptor in FVB/NCrl mice resulted in suppressed digestive efficiency even on a standard chow diet. Together these data underscore the importance of digestive efficiency in the pathogenesis of obesity, and implicate dietary sodium, the renin-angiotensin system, and the AT2 receptor in the control of digestive efficiency regardless of mouse strain or macronutrient composition of the diet. These findings highlight the need for greater understanding of nutrient absorption control physiology, and prompt more uniform assessment of digestive efficiency in animal studies of energy balance.

  11. Sulindac metabolites inhibit epidermal growth factor receptor activation and expression

    Directory of Open Access Journals (Sweden)

    Ahnen Dennis

    2005-01-01

    Full Text Available Abstract Background Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs is associated with a decreased mortality from colorectal cancer (CRC. NSAIDs induce apoptotic cell death in colon cancer cells in vitro and inhibit growth of neoplastic colonic mucosa in vivo however, the biochemical mechanisms required for these growth inhibitory effects are not well defined. We previously reported that metabolites of the NSAID sulindac downregulate extracellular-signal regulated kinase 1/2 (ERK1/2 signaling and that this effect is both necessary and sufficient for the apoptotic effects of these drugs. The goal of this project was to specifically test the hypothesis that sulindac metabolites block activation and/or expression of the epidermal growth factor (EGF receptor (EGFR. Methods HT29 human colon cancer cells were treated with EGF, alone, or in the presence of sulindac sulfide or sulindac sulfone. Cells lysates were assayed by immunoblotting for phosphorylated EGFR (pEGFR, pY1068, total EGFR, phosphorylated ERK1/2 (pERK1/2, total ERK1/2, activated caspase-3, and α-tubulin. Results EGF treatment rapidly induced phosphorylation of both EGFR and ERK1/2 in HT29 colon cancer cells. Pretreatment with sulindac metabolites for 24 h blocked EGF-induced phosphorylation of both EGFR and ERK1/2 and decreased total EGFR protein expression. Under basal conditions, downregulation of pEGFR and total EGFR was detected as early as 12 h following sulindac sulfide treatment and persisted through at least 48 h. Sulindac sulfone induced downregulation of pEGFR and total EGFR was detected as early as 1 h and 24 h, respectively, following drug treatment, and persisted through at least 72 h. EGFR downregulation by sulindac metabolites was observed in three different CRC cell lines, occurred prior to the observed downregulation of pERK1/2 and induction of apoptosis by these drugs, and was not dependent of caspase activation. Conclusion These results suggest that

  12. Inhibition of myeloperoxidase and antioxidative activity of Gentiana lutea extracts.

    Science.gov (United States)

    Nastasijević, Branislav; Lazarević-Pašti, Tamara; Dimitrijević-Branković, Suzana; Pašti, Igor; Vujačić, Ana; Joksić, Gordana; Vasić, Vesna

    2012-07-01

    The aim of this study was to investigate the inhibitory activity of Gentiana lutea extracts on the enzyme myeloperoxidase (MPO), as well as the antioxidant activity of these extracts and their correlation with the total polyphenol content. Extracts were prepared using methanol (100%), water and ethanol aqueous solutions (96, 75, 50 and 25%v/v) as solvents for extraction. Also, isovitexin, amarogentin and gentiopicroside, pharmacologically active constituents of G. lutea were tested as potential inhibitors of MPO. Antioxidant activity of extracts was determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging test and also using cyclic voltammetry (CV). Among all extracts, the antioxidant capacity of 50% ethanol aqueous extract was the highest, both when measured using the DPPH test, with IC(50)=20.6 μg/ml, and when using CV. Also, 50% ethanol extract, showed the best inhibition of MPO activity in comparison with other extracts. In the group of the selected G. lutea constituents, gentiopicroside has proved to be the strongest inhibitor of MPO, with IC(50)=0.8 μg/ml. Also, the concentration of G. lutea constituents were determined in all extracts, using Ultra Performance Liquid Chromatography (UPLC). Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Activated AMPK inhibits PPAR-{alpha} and PPAR-{gamma} transcriptional activity in hepatoma cells.

    Science.gov (United States)

    Sozio, Margaret S; Lu, Changyue; Zeng, Yan; Liangpunsakul, Suthat; Crabb, David W

    2011-10-01

    AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPAR-α) are critical regulators of short-term and long-term fatty acid oxidation, respectively. We examined whether the activities of these molecules were coordinately regulated. H4IIEC3 cells were transfected with PPAR-α and PPAR-γ expression plasmids and a peroxisome-proliferator-response element (PPRE) luciferase reporter plasmid. The cells were treated with PPAR agonists (WY-14,643 and rosiglitazone), AMPK activators 5-aminoimidazole-4-carboxamide riboside (AICAR) and metformin, and the AMPK inhibitor compound C. Both AICAR and metformin decreased basal and WY-14,643-stimulated PPAR-α activity; compound C increased agonist-stimulated reporter activity and partially reversed the effect of the AMPK activators. Similar effects on PPAR-γ were seen, with both AICAR and metformin inhibiting PPRE reporter activity. Compound C increased basal PPAR-γ activity and rosiglitazone-stimulated activity. In contrast, retinoic acid receptor-α (RAR-α), another nuclear receptor that dimerizes with retinoid X receptor (RXR), was largely unaffected by the AMPK activators. Compound C modestly increased AM580 (an RAR agonist)-stimulated activity. The AMPK activators did not affect PPAR-α binding to DNA, and there was no consistent correlation between effects of the AMPK activators and inhibitor on PPAR and the nuclear localization of AMPK-α subunits. Expression of either a constitutively active or dominant negative AMPK-α inhibited basal and WY-14,643-stimulated PPAR-α activity and basal and rosiglitazone-stimulated PPAR-γ activity. We concluded that the AMPK activators AICAR and metformin inhibited transcriptional activities of PPAR-α and PPAR-γ, whereas inhibition of AMPK with compound C activated both PPARs. The effects of AMPK do not appear to be mediated through effects on RXR or on PPAR/RXR binding to DNA. These effects are independent of kinase activity and instead appear to

  14. Activation of TRPV1 channels inhibits mechanosensitive Piezo channel activity by depleting membrane phosphoinositides

    Science.gov (United States)

    Borbiro, Istvan; Badheka, Doreen; Rohacs, Tibor

    2015-01-01

    Capsaicin is an activator of the heat-sensitive TRPV1 (transient receptor potential vanilloid 1) ion channels and has been used as a local analgesic. We found that activation of TRPV1 channels with capsaicin either in dorsal root ganglion neurons or in a heterologous expression system inhibited the mechanosensitive Piezo1 and Piezo2 channels by depleting phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and its precursor PI(4)P from the plasma membrane through Ca2+-induced phospholipase Cδ (PLCδ) activation. Experiments with chemically inducible phosphoinositide phosphatases and receptor-induced activation of PLCβ indicated that inhibition of Piezo channels required depletion of both PI(4)P and PI(4,5)P2. The mechanically activated current amplitudes decreased substantially in the excised inside-out configuration, where the membrane patch containing Piezo1 channels is removed from the cell. PI(4,5)P2 and PI(4)P applied to these excised patches inhibited this decrease. Thus, we concluded that Piezo channel activity requires the presence of phosphoinositides, and the combined depletion of PI(4,5)P2 or PI(4)P reduces channel activity. In addition to revealing a role for distinct membrane lipids in mechanosensitive ion channel regulation, these data suggest that inhibition of Piezo2 channels may contribute to the analgesic effect of capsaicin. PMID:25670203

  15. Radioimmunoassay for determination of blood aldosterone and renin in the diagnosis of some forms of arterial hypertension

    International Nuclear Information System (INIS)

    Khamidov, R.I.; Khalmuratova, R.A.; Sattarova, F.K.

    1987-01-01

    Aldosterone concentration and renin activity in the blood from the ulnar, inferior cava veins at the level of the 12th thoracic vertebra, the left and right renal veins were studied in 60 patients with arterial hypertension by means of a radioimmunoassay kits (France). The patients were divided into 4 groups: with primary and idiopathic hyperaldosteronism, renal-parenchymatous and essential arterial hypertension. The diagnosis of primary and idiopathic hyperaldosteronism was also confirmed by low blood renin activity. Renin activity in the peripheral venous blood was considerably elevated in renal-parenchymatous arterial hypertension and was normal in essential hypertension. Aldosterone concentration in the blood from the vena cava inferior and renal veins was 1.6-2-fold as high on the affected side as on the contralateral one

  16. Dextromethorphan Inhibits Activations and Functions in Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Der-Yuan Chen

    2013-01-01

    Full Text Available Dendritic cells (DCs play an important role in connecting innate and adaptive immunity. Thus, DCs have been regarded as a major target for the development of immunomodulators. In this study, we examined the effect of dextromethorphan (DXM, a common cough suppressant with a high safety profile, on the activation and function of DCs. In the presence of DXM, the LPS-induced expression of the costimulatory molecules in murine bone marrow-derived dendritic cells (BMDCs was significantly suppressed. In addition, DXM treatment reduced the production of reactive oxygen species (ROS, proinflammatory cytokines, and chemokines in maturing BMDCs that were activated by LPS. Therefore, DXM abrogated the ability of LPS-stimulated DCs to induce Ag-specific T-cell activation, as determined by their decreased proliferation and IFN-γ secretion in mixed leukocyte cultures. Moreover, the inhibition of LPS-induced MAPK activation and NF-κB translocation may contribute to the suppressive effect of DXM on BMDCs. Remarkably, DXM decreased the LPS-induced surface expression of CD80, CD83, and HLA-DR and the secretion of IL-6 and IL-12 in human monocyte-derived dendritic cells (MDDCs. These findings provide a new insight into the impact of DXM treatment on DCs and suggest that DXM has the potential to be used in treating DC-related acute and chronic diseases.

  17. Combination therapy with renin-angiotensin-aldosterone system inhibitor telmisartan and serine protease inhibitor camostat mesilate provides further renoprotection in a rat chronic kidney disease model

    Directory of Open Access Journals (Sweden)

    Yuki Narita

    2016-02-01

    Full Text Available We previously reported that camostat mesilate (CM had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE, a renin-angiotensin-aldosterone system (RAS inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day and/or TE (10 mg/kg/day on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA and plasma aldosterone concentration (PAC was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.

  18. The aldo-keto reductase AKR1B7 coexpresses with renin without influencing renin production and secretion.

    Science.gov (United States)

    Machura, Katharina; Iankilevitch, Elina; Neubauer, Björn; Theuring, Franz; Kurtz, Armin

    2013-03-01

    On the basis of evidence that within the adult kidney, the aldo-keto reductase AKR1B7 (aldo-keto reductase family 1, member 7, also known as mouse vas deferens protein, MVDP) is selectively expressed in renin-producing cells, we aimed to define a possible role of AKR1B7 for the regulation and function of renin cells in the kidney. We could confirm colocalization and corecruitment of renin and of AKR1B7 in wild-type kidneys. Renin cells in AKR1B7-deficient kidneys showed normal morphology, numbers, and intrarenal distribution. Plasma renin concentration (PRC) and renin mRNA levels of AKR1B7-deficient mice were normal at standard chow and were lowered by a high-salt diet directly comparable to wild-type mice. Treatment with a low-salt diet in combination with an angiotensin-converting enzyme inhibitor strongly increased PRC and renin mRNA in a similar fashion both in AKR1B7-deficient and wild-type mice. Under this condition, we also observed a strong retrograde recruitment of renin-expressing cell along the preglomerular vessels, however, without a difference between AKR1B7-deficient and wild-type mice. The isolated perfused mouse kidney model was used to study the acute regulation of renin secretion by ANG II and by perfusion pressure. Regarding these parameters, no differences were observed between AKR1B7-deficient and wild-type kidneys. In summary, our data suggest that AKR1B7 is not of major relevance for the regulation of renin production and secretion in spite of its striking coregulation with renin expression.

  19. Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis.

    Science.gov (United States)

    Kenny, Hilary A; Leonhardt, Payton; Ladanyi, Andras; Yamada, S Diane; Montag, Anthony; Im, Hae Kyung; Jagadeeswaran, Sujatha; Shaw, David E; Mazar, Andrew P; Lengyel, Ernst

    2011-02-01

    To understand the functional and preclinical efficacy of targeting the urokinase plasminogen activator receptor (u-PAR) in ovarian cancer. Expression of u-PAR was studied in 162 epithelial ovarian cancers, including 77 pairs of corresponding primary and metastatic tumors. The effect of an antibody against u-PAR (ATN-658) on proliferation, adhesion, invasion, apoptosis, and migration was assessed in 3 (SKOV3ip1, HeyA8, and CaOV3) ovarian cancer cell lines. The impact of the u-PAR antibody on tumor weight, number, and survival was examined in corresponding ovarian cancer xenograft models and the mechanism by which ATN-658 blocks metastasis was explored. Only 8% of all ovarian tumors were negative for u-PAR expression. Treatment of SKOV3ip1, HeyA8, and CaOV3 ovarian cancer cell lines with the u-PAR antibody inhibited cell invasion, migration, and adhesion. In vivo, anti-u-PAR treatment reduced the number of tumors and tumor weight in CaOV3 and SKOV3ip1 xenografts and reduced tumor weight and increased survival in HeyA8 xenografts. Immunostaining of CaOV3 xenograft tumors and ovarian cancer cell lines showed an increase in active-caspase 3 and TUNEL staining. Treatment with u-PAR antibody inhibited α(5)-integrin and u-PAR colocalization on primary human omental extracellular matrix. Anti-u-PAR treatment also decreased the expression of urokinase, u-PAR, β(3)-integrin, and fibroblast growth factor receptor-1 both in vitro and in vivo. This study shows that an antibody against u-PAR reduces metastasis, induces apoptosis, and reduces the interaction between u-PAR and α(5)-integrin. This provides a rationale for targeting the u-PAR pathway in patients with ovarian cancer and for further testing of ATN-658 in this indication. ©2010 AACR.

  20. Renin-sodium profile and renal prostaglandins in the pathogenesis ...

    African Journals Online (AJOL)

    the patients having normal-renin hypertension. At basal level the ... finding was in keeping with their low-renin hypertension. ... pathological factor in the development of hypertension in blacks. ... Subjects and methods .... zero sphygmomanometer. ..... Part 11. Biochemistry and endocrine. Hypertension 1990; 15(6): 681-685.

  1. Activation of ice recrystallization inhibition activity of poly(vinyl alcohol) using a supramolecular trigger

    OpenAIRE

    Phillips, Daniel J.; Congdon, Thomas; Gibson, Matthew I.

    2016-01-01

    Antifreeze (glyco)proteins (AF(G)Ps) have potent ice recrystallisation inhibition (IRI) activity – a desirable phenomenon in applications such as cryopreservation, frozen food and more. In Nature AF(G)P activity is regulated by protein expression levels in response to an environmental stimulus; temperature. However, this level of regulation is not possible in synthetic systems. Here, a synthetic macromolecular mimic is introduced, using supramolecular assembly to regulate activity. Catechol-t...

  2. Studies on renin stimulation in normal controls and in patients with essential hypertension

    International Nuclear Information System (INIS)

    Koh, C.S.; Choe, K.W.; Lee, H.K.; Lee, J.S.

    1978-01-01

    To find out a convenient and reliable method of detecting low renin status, we employed intravenous furosemine injection as a stimulatory maneuver. The results thus obtained were compared with those from the postural stimuli and basal plasma renin activity (PRA) in relation to sodium excretion. Intravenous furosemide test was performed in 66 control subjects and 44 patients with essential hypertension. The results were as follow; 1) Mean PRA in control subjects rose from 2.5+-1.95 ng/ml/hr (basal) to 4.5+-2.51, 5.2+-2.49 and 4.2+-2.44 ng/ml/hr at 1, 2 and 3hrs after IV injection. One-hour response is more convenient in clinical practice. 2) Postural stimuli by assuming an upright posture for 3hrs gave rise to considerable increase in PRA (4.0+-2.92 from 2.4+-1.85), but we found it less convenient than stimulation with furosemide. 3) The increase in PRA was much less marked in patients with essential hypertension as a whole (2.9+-2.75). Hyporesponsiveness to furosemide stimuli was found in 34.1%. Of these hyporesponders, a third had a normal basal PRA, indicating the need for this kind stimulatory procedure. 4) Younger age group showed greater renin responsiveness than older age group after furosemide stimuli. Likewise mean age of low renin patients (52.9+-5.38 years old) was significantly higher than that of high and normal renin patients (44.1+-13.78 years old). (author)

  3. Studies on Renin Stimulation in Normal Controls and in Patients with Essential Hypertension

    Energy Technology Data Exchange (ETDEWEB)

    Koh, Chang Soon; Choe, Kang Won; Lee, Hong Kyu; Lee, Jung Sang [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1978-03-15

    To find out a convenient and reliable method of detecting low renin status, we employed intravenous furosemide injection as a stimulatory maneuver. The results thus obtained were compared with those from the postural stimuli and basal plasma renin activity (PRA) in relation to sodium excretion. Intravenous furosemide test was performed in 66 control subjects and 44 patients with essential hypertension. The results were as follow; 1) Mean PRA in control subjects rose from 2.5+-1.95 ng/ml/hr (basal) to 4.5+-2.51, 5.2+-2.49 and 4.2+-2.44 ng/ml/hr at 1, 2 and 3 hrs after IV injection. One-hour response is more convenient in clinical practice. 2) Postural stimuli by assuming an upright posture for 3 hrs gave rise to considerable increase in PRA (4.0+-2.92 from 2.4+-1.85), but we found it less convenient than stimulation with furosemide. 3) The increase in PRA was much less marked in patients with essential hypertension as a whole (2.9+-2.75). Hyporesponsiveness to furosemide stimuli was found in 34.1%. Of these hyporesponders, a third had a normal basal PRA, indicating the need for this kind stimulatory procedure. 4) Younger age group showed greater renin responsiveness than older age group after furosemide stimuli. Likewise mean age of low renin patients (52.9+-5.38 years old) was significantly higher than that of high and normal renin patients (44.1+-13.78 years old).

  4. Studies on Renin Stimulation in Normal Controls and in Patients with Essential Hypertension

    International Nuclear Information System (INIS)

    Koh, Chang Soon; Choe, Kang Won; Lee, Hong Kyu; Lee, Jung Sang

    1978-01-01

    To find out a convenient and reliable method of detecting low renin status, we employed intravenous furosemide injection as a stimulatory maneuver. The results thus obtained were compared with those from the postural stimuli and basal plasma renin activity (PRA) in relation to sodium excretion. Intravenous furosemide test was performed in 66 control subjects and 44 patients with essential hypertension. The results were as follow; 1) Mean PRA in control subjects rose from 2.5±1.95 ng/ml/hr (basal) to 4.5±2.51, 5.2±2.49 and 4.2±2.44 ng/ml/hr at 1, 2 and 3 hrs after IV injection. One-hour response is more convenient in clinical practice. 2) Postural stimuli by assuming an upright posture for 3 hrs gave rise to considerable increase in PRA (4.0±2.92 from 2.4±1.85), but we found it less convenient than stimulation with furosemide. 3) The increase in PRA was much less marked in patients with essential hypertension as a whole (2.9±2.75). Hyporesponsiveness to furosemide stimuli was found in 34.1%. Of these hyporesponders, a third had a normal basal PRA, indicating the need for this kind stimulatory procedure. 4) Younger age group showed greater renin responsiveness than older age group after furosemide stimuli. Likewise mean age of low renin patients (52.9±5.38 years old) was significantly higher than that of high and normal renin patients (44.1±13.78 years old).

  5. Inhibition of pectin methyl esterase activity by green tea catechins.

    Science.gov (United States)

    Lewis, Kristin C; Selzer, Tzvia; Shahar, Chen; Udi, Yael; Tworowski, Dmitry; Sagi, Irit

    2008-10-01

    Pectin methyl esterases (PMEs) and their endogenous inhibitors are involved in the regulation of many processes in plant physiology, ranging from tissue growth and fruit ripening to parasitic plant haustorial formation and host invasion. Thus, control of PME activity is critical for enhancing our understanding of plant physiological processes and regulation. Here, we report on the identification of epigallocatechin gallate (EGCG), a green tea component, as a natural inhibitor for pectin methyl esterases. In a gel assay for PME activity, EGCG blocked esterase activity of pure PME as well as PME extracts from citrus and from parasitic plants. Fluorometric tests were used to determine the IC50 for a synthetic substrate. Molecular docking analysis of PME and EGCG suggests close interaction of EGCG with the catalytic cleft of PME. Inhibition of PME by the green tea compound, EGCG, provides the means to study the diverse roles of PMEs in cell wall metabolism and plant development. In addition, this study introduces the use of EGCG as natural product to be used in the food industry and agriculture.

  6. Activating and inhibiting connections in biological network dynamics

    Directory of Open Access Journals (Sweden)

    Knight Rob

    2008-12-01

    Full Text Available Abstract Background Many studies of biochemical networks have analyzed network topology. Such work has suggested that specific types of network wiring may increase network robustness and therefore confer a selective advantage. However, knowledge of network topology does not allow one to predict network dynamical behavior – for example, whether deleting a protein from a signaling network would maintain the network's dynamical behavior, or induce oscillations or chaos. Results Here we report that the balance between activating and inhibiting connections is important in determining whether network dynamics reach steady state or oscillate. We use a simple dynamical model of a network of interacting genes or proteins. Using the model, we study random networks, networks selected for robust dynamics, and examples of biological network topologies. The fraction of activating connections influences whether the network dynamics reach steady state or oscillate. Conclusion The activating fraction may predispose a network to oscillate or reach steady state, and neutral evolution or selection of this parameter may affect the behavior of biological networks. This principle may unify the dynamics of a wide range of cellular networks. Reviewers Reviewed by Sergei Maslov, Eugene Koonin, and Yu (Brandon Xia (nominated by Mark Gerstein. For the full reviews, please go to the Reviewers' comments section.

  7. The Protective Arm of the Renin Angiotensin System (RAS)

    DEFF Research Database (Denmark)

    understanding of the protective side of the Renin Angiotensin System (RAS) involving angiotensin AT2 receptor, ACE2, and Ang(1-7)/Mas receptor Combines the knowledge of editors who pioneered research on the protective renin angiotensin system including; Dr. Thomas Unger, one of the founders of AT2 receptor......The Protective Arm of the Renin Angiotensin System: Functional Aspects and Therapeutic Implications is the first comprehensive publication to signal the protective role of a distinct part of the renin-angiotensin system (RAS), providing readers with early insight into a complex system which...... will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1-7) peptide with its receptor...

  8. The renin-angiotensin system and aging in the kidney.

    Science.gov (United States)

    Yoon, Hye Eun; Choi, Bum Soon

    2014-05-01

    Aging is associated with progressive functional deterioration and structural changes in the kidney. Changes in the activity or responsiveness of the renin-angiotensin system (RAS) occur with aging. RAS changes predispose the elderly to various fluid and electrolyte imbalances as well as acute kidney injury and chronic kidney disease. Among the multiple pathways involved in renal aging, the RAS plays a central role. This review summarizes the association of the RAS with structural and functional changes in the aging kidney and age-related renal injury, and describes the underlying mechanisms of RAS-related renal aging. An improved understanding of the renal aging process may lead to better individualized care of the elderly and improved renal survival in age-related diseases.

  9. Inhibition of 5-Lipoxygenase Pathway Attenuates Acute Liver Failure by Inhibiting Macrophage Activation

    Directory of Open Access Journals (Sweden)

    Lu Li

    2014-01-01

    Full Text Available This study aimed to investigate the role of 5-lipoxygenase (5-LO in acute liver failure (ALF and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN/lipopolysaccharide (LPS. Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor, 24 hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT, aspartate transaminase (AST, total bilirubin (Tbil, and tumor necrosis factor- (TNF-α. Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8 hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF-α was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition.

  10. Total renin after gonadotropin stimulation in polycystic ovarian disease.

    Science.gov (United States)

    Matinlauri, I; Anttila, L; Jaatinen, T A; Koskinen, P; Aalto, M; Irjala, K; Nikkanen, V

    1995-02-01

    To examine the influence of polycystic ovarian disease (PCOD) on the levels of total renin in plasma and follicular fluid (FF) after stimulation with hMG. Comparative study of the plasma and FF concentrations of total renin in women with and without PCOD after stimulation with hMG. In vitro fertilization-embryo transfer program at the Department of Obstetrics and Gynecology, the University Central Hospital of Turku, Finland. Thirty-six women undergoing IVF-ET for infertility with (n = 10) or without (n = 26) ultrasonographically diagnosed PCOD. Of the latter group, 15 women had tubal infertility, and the rest suffered from an anovulatory infertility and reacted with PCO-like ovarian response to stimulation. The concentrations of total renin in plasma and FF, serum E2, and protein in FF. The concentrations of plasma total renin after the gonadotropin stimulation were significantly higher in the PCOD and PCO-like groups when compared with the tubal group. The concentration of total renin in FF and the ratio of total renin per protein in FF were higher in the PCOD and PCO-like groups than in the tubal group, but the differences did not reach statistical significance. Positive correlations were found between the plasma total renin and serum E2 concentrations in the PCO-like and in the tubal group and between plasma total renin concentrations and the number of mature follicles in all groups. Follicular fluid total renin did not correlate with FF protein in any group. All findings were independent of the total hMG dosage used and the body mass index of the patients. In the present study the concentrations of total renin in plasma were enhanced markedly after gonadotropin stimulation in women with PCOD compared with women having tubal infertility. The pattern of the hormonal secretions revealed a group of infertile patients reacting biochemically like women with PCOD.

  11. Curcumin inhibits activation of TRPM2 channels in rat hepatocytes

    Directory of Open Access Journals (Sweden)

    E. Kheradpezhouh

    2016-04-01

    Full Text Available Oxidative stress is a hallmark of many liver diseases including viral and drug-induced hepatitis, ischemia-reperfusion injury, and non-alcoholic steatohepatitis. One of the consequences of oxidative stress in the liver is deregulation of Ca2+ homeostasis, resulting in a sustained elevation of the free cytosolic Ca2+ concentration ([Ca2+]c in hepatocytes, which leads to irreversible cellular damage. Recently it has been shown that liver damage induced by paracetamol and subsequent oxidative stress is, in large part, mediated by Ca2+ entry through Transient Receptor Potential Melastatin 2 (TRPM2 channels. Involvement of TRPM2 channels in hepatocellular damage induced by oxidative stress makes TRPM2 a potential therapeutic target for treatment of a range of oxidative stress-related liver diseases. We report here the identification of curcumin ((1E,6E-1,7-bis(4-hydroxy-3-methoxyphenyl-1,6-heptadiene-3,5-dione, a natural plant-derived polyphenol in turmeric spice, as a novel inhibitor of TRPM2 channel. Presence of 5 µM curcumin in the incubation medium prevented the H2O2- and paracetamol-induced [Ca2+]c rise in rat hepatocytes. Furthermore, in patch clamping experiments incubation of hepatocytes with curcumin inhibited activation of TRPM2 current by intracellular ADPR with IC50 of approximately 50 nM. These findings enhance understanding of the actions of curcumin and suggest that the known hepatoprotective properties of curcumin are, at least in part, mediated through inhibition of TRPM2 channels.

  12. A novel interaction between sympathetic overactivity and aberrant regulation of renin by miR-181a in BPH/2J genetically hypertensive mice.

    Science.gov (United States)

    Jackson, Kristy L; Marques, Francine Z; Watson, Anna M D; Palma-Rigo, Kesia; Nguyen-Huu, Thu-Phuc; Morris, Brian J; Charchar, Fadi J; Davern, Pamela J; Head, Geoffrey A

    2013-10-01

    Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg i.p.) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg i.p.) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin-angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin-angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.

  13. Normotensive sodium loading in normal man: Regulation of renin secretion during beta-receptor blockade

    DEFF Research Database (Denmark)

    Mølstrøm, Simon; Larsen, Nils Heden; Simonsen, Jane Angel

    2008-01-01

    and renal excretion during slow saline loading at constant plasma sodium con-centration (Na-loading: 12 micromol Na(+) kg(-1) min(-1) for 4 h). Normal subjects were studied on low-sodium intake with and without beta1-adrenergic blockade by metoprolol. Metoprolol per se reduced RAAS activity as expected. Na......Saline administration may change renin system (RAAS) activity and sodium excretion at constant mean arterial pressure (MAP). We hypothesized that such responses are elicited mainly by renal sympathetic nerve activity by beta1-receptors (beta1-RSNA), and tested the hypothesis by studying RAAS......-loading decreased plasma renin (PRC) by 1/3, AngII by 1/2, and aldosterone (pAldo) by 2/3, (all psodium excretion increased indistinguishably with and without metoprolol (16+/-2 to 71...

  14. Inhibition of endothelial lipase activity by sphingomyelin in the lipoproteins.

    Science.gov (United States)

    Yang, Peng; Belikova, Natalia A; Billheimer, Jeff; Rader, Daniel J; Hill, John S; Subbaiah, Papasani V

    2014-10-01

    Endothelial lipase (EL) is a major determinant of plasma HDL concentration, its activity being inversely proportional to HDL levels. Although it is known that it preferentially acts on HDL compared to LDL and VLDL, the basis for this specificity is not known. Here we tested the hypothesis that sphingomyelin, a major phospholipid in lipoproteins is a physiological inhibitor of EL, and that the preference of the enzyme for HDL may be due to low sphingomyelin/phosphatidylcholine (PtdCho) ratio in HDL, compared to other lipoproteins. Using recombinant human EL, we showed that sphingomyelin inhibits the hydrolysis of PtdCho in the liposomes in a concentration-dependent manner. While the enzyme showed lower hydrolysis of LDL PtdCho, compared to HDL PtdCho, this difference disappeared after the degradation of lipoprotein sphingomyelin by bacterial sphingomyelinase. Analysis of molecular species of PtdCho hydrolyzed by EL in the lipoproteins showed that the enzyme preferentially hydrolyzed PtdCho containing polyunsaturated fatty acids (PUFA) such as 22:6, 20:5, 20:4 at the sn-2 position, generating the corresponding PUFA-lyso PtdCho. This specificity for PUFA-PtdCho species was not observed after depletion of sphingomyelin by sphingomyelinase. These results show that sphingomyelin not only plays a role in regulating EL activity, but also influences its specificity towards PtdCho species.

  15. Activation of Ice Recrystallization Inhibition Activity of Poly(vinyl alcohol) using a Supramolecular Trigger†

    OpenAIRE

    Phillips, Daniel J.; Congdon, Thomas R.; Gibson, Matthew I.

    2016-01-01

    Antifreeze (glyco)proteins (AF(G)Ps) have potent ice recrystallisation inhibition (IRI) activity – a desirable phenomenon in applications such as cryopreservation, frozen food and more. In Nature AF(G)P activity is regulated by protein expression levels in response to an environmental stimulus; temperature. However, this level of regulation is not possible in synthetic systems. Here, a synthetic macromolecular mimic is introduced, using supramolecular assembly to regulate ac...

  16. DAX-1 Inhibits Hepatocellular Carcinoma Proliferation by Inhibiting β-Catenin Transcriptional Activity

    Directory of Open Access Journals (Sweden)

    Hong-Lei Jiang

    2014-08-01

    Full Text Available Background/Aims: Hepatocellular carcinoma (HCC represents the most common type of liver cancer. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1, an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains, has been known for its fundamental roles in the development, especially in the sex determination and steroidogenesis. Previous studies also showed that DAX-1 played a critical role in endocrine and sex steroid-dependent neoplasms such as adrenocortical, pituitary, endometrial, and ovarian tumors. However, its biological roles in the development of HCC remain largely unexplored. Methods: Real-time PCR and Western blot were used to detect the expression of DAX-1 in HCC tissues and cell lines. Immunoprecipitation (IP assay was used to show the interaction between DAX-1 and β-Catenin. Small interfering RNA (siRNA was used to silence the expression of DAX-1. BrdU incorporation and Cell-cycle assays were used to detect the role of DAX-1 in HCC cells proliferation. Migration and invasion assays were carried out to test the metastasis ability of DAX-1 in HCC cells. Results: In the present study, we found that mRNA and protein levels of DAX-1 were down-regulated in HCC tissues and cell lines. Furthermore, overexpression of DAX-1 could inhibit while its knockdown using small interfering RNA promoted cell proliferation in several HCC cell lines. At the molecular level, we demonstrated that DAX-1 could interact with β-Catenin and attenuate its transcriptional activity. Conclusion: Therefore, our results suggest a previously unknown DAX-1/β-Catenin molecular network controlling HCC development.

  17. Effect of furosemide and dietary sodium on kidney and plasma big and small renin

    International Nuclear Information System (INIS)

    Iwao, H.; Michelakis, A.M.

    1981-01-01

    Renin was found in mouse plasma in high-molecular-weight forms (big big renin, big renin) and a low-molecular-weight form (small renin). They were measuerd by a radioimmunoassay procedure for the direct measurement of renin. In the kidney, 89% of total renin was small renin and the rest was big big and big renin. This distribution pattern of renins was not changed when the kideny tissue was homogenized in the presence of protease inhibitors. Low-sodium or high-sodium diets changed renal renin content, but not the distribution pattern of renins in the kidney. Acute stimulation of renin release by furosemide increased small renin but not big big and big renin in plasma. However, dietary sodium depletion for 2 weeks significantly increased big big, big, and small renin in plasma of mice with or without submaxillary glands. In contrast, high-sodium intake significantly decreased big big, big, and small renin in plasma of mice with or without submaxillary glands

  18. Regulation of the renin-angiotensin-aldosterone system in fibromyalgia.

    Science.gov (United States)

    Maliszewski, Anne M; Goldenberg, Don L; Hurwitz, Shelley; Adler, Gail K

    2002-07-01

    To assess the function of the renin-angiotensin-aldosterone (RAA) system in women with fibromyalgia (FM) compared to healthy women. Women with FM [n = 14, age 41.0+/-7.2 yrs, body mass index (BMI) 26.4+/-5.4 kg/m2] and healthy women (n = 13, age 40.0+/-7.7 yrs, BMI 25.0+/-5.0 kg/m2) were placed on a low sodium diet (10 mEq sodium/day) for 5 days. After being supine and fasting overnight, subjects received an intravenous infusion of angiotensin II at successive doses of 1, 3, and 10 ng/kg/min for 45 min per dose. Blood pressure (BP), plasma renin activity (PRA), aldosterone, and cortisol were measured at baseline and after each dose of angiotensin II. Prior to sodium restriction, women with FM completed the Hopkins Symptom Checklist-90, which included a question grading the extent of dizziness/faintness on a scale of 0 (none) to 4 (extremely). After dietary sodium restriction, baseline PRA, aldosterone, and supine BP were similar in healthy women and women with FM. Aldosterone and BP rose in response to infused angiotensin II; these responses did not differ significantly between healthy women and women with FM. In women with FM, symptoms of dizziness correlated inversely with BMI (r = -0.81, p < 0.001) and the systolic BP response to 10 ng/kg/min angiotensin II (r = -0.81, p < 0.001). The functioning of the RAA system, including the vascular response to angiotensin II, was intact in women with FM compared to healthy women. However, women with FM who complained of dizziness had a blunted vascular response to angiotensin II. This blunted vascular response may indicate intravascular volume depletion in women with symptoms of dizziness.

  19. A rhodanine derivative CCR-11 inhibits bacterial proliferation by inhibiting the assembly and GTPase activity of FtsZ.

    Science.gov (United States)

    Singh, Parminder; Jindal, Bhavya; Surolia, Avadhesha; Panda, Dulal

    2012-07-10

    A perturbation of FtsZ assembly dynamics has been shown to inhibit bacterial cytokinesis. In this study, the antibacterial activity of 151 rhodanine compounds was assayed using Bacillus subtilis cells. Of 151 compounds, eight strongly inhibited bacterial proliferation at 2 μM. Subsequently, we used the elongation of B. subtilis cells as a secondary screen to identify potential FtsZ-targeted antibacterial agents. We found that three compounds significantly increased bacterial cell length. One of the three compounds, namely, CCR-11 [(E)-2-thioxo-5-({[3-(trifluoromethyl)phenyl]furan-2-yl}methylene)thiazolidin-4-one], inhibited the assembly and GTPase activity of FtsZ in vitro. CCR-11 bound to FtsZ with a dissociation constant of 1.5 ± 0.3 μM. A docking analysis indicated that CCR-11 may bind to FtsZ in a cavity adjacent to the T7 loop and that short halogen-oxygen, H-bonding, and hydrophobic interactions might be important for the binding of CCR-11 with FtsZ. CCR-11 inhibited the proliferation of B. subtilis cells with a half-maximal inhibitory concentration (IC(50)) of 1.2 ± 0.2 μM and a minimal inhibitory concentration of 3 μM. It also potently inhibited proliferation of Mycobacterium smegmatis cells. Further, CCR-11 perturbed Z-ring formation in B. subtilis cells; however, it neither visibly affected nucleoid segregation nor altered the membrane integrity of the cells. CCR-11 inhibited HeLa cell proliferation with an IC(50) value of 18.1 ± 0.2 μM (∼15 × IC(50) of B. subtilis cell proliferation). The results suggested that CCR-11 inhibits bacterial cytokinesis by inhibiting FtsZ assembly, and it can be used as a lead molecule to develop FtsZ-targeted antibacterial agents.

  20. Expressions of renin, angiotensin II and aldosterone in patients with viral hepatitis or hepatic cirrhosis

    International Nuclear Information System (INIS)

    Huo Ying; Zhu Yalin; Liu Yun

    2008-01-01

    Objective: To explore the changes of renin, angiotensin and aldosterone system in patients with hepatic disorders. Methods: Plasma renin activity (PRA), AT-II and Ald levels were measured with RIA in 31 patients with viral hepatitis, 35 patients with hepatic cirrhosis and 38 controls. Results: The levels of PRA, AT-II and Ald in patients with viral hepatitis were slightly but non-significantly higher than those in controls (P>0.05). The levels of PRA, AT-II and Ald in patients with cirrhosis were significantly higher than those in controls (P<0.01). Conclusion: RAAS was activated during progression of hepatic disorders and participated in the development of hepatic fibrosis. (authors)

  1. Phlorotannins from Alaskan Seaweed Inhibit Carbolytic Enzyme Activity

    Directory of Open Access Journals (Sweden)

    Joshua Kellogg

    2014-10-01

    Full Text Available Global incidence of type 2 diabetes has escalated over the past few decades, necessitating a continued search for natural sources of enzyme inhibitors to offset postprandial hyperglycemia. The objective of this study was to evaluate coastal Alaskan seaweed inhibition of α-glucosidase and α-amylase, two carbolytic enzymes involved in serum glucose regulation. Of the six species initially screened, the brown seaweeds Fucus distichus and Alaria marginata possessed the strongest inhibitory effects. F. distichus fractions were potent mixed-mode inhibitors of α-glucosidase and α-amylase, with IC50 values of 0.89 and 13.9 μg/mL, respectively; significantly more efficacious than the pharmaceutical acarbose (IC50 of 112.0 and 137.8 μg/mL, respectively. The activity of F. distichus fractions was associated with phlorotannin oligomers. Normal-phase liquid chromatography-mass spectrometry (NPLC-MS was employed to characterize individual oligomers. Accurate masses and fragmentation patterns confirmed the presence of fucophloroethol structures with degrees of polymerization from 3 to 18 monomer units. These findings suggest that coastal Alaskan seaweeds are sources of α-glucosidase and α-amylase inhibitory phlorotannins, and thus have potential to limit the release of sugar from carbohydrates and thus alleviate postprandial hyperglycemia.

  2. Phlorotannins from Alaskan Seaweed Inhibit Carbolytic Enzyme Activity

    Science.gov (United States)

    Kellogg, Joshua; Grace, Mary H.; Lila, Mary Ann

    2014-01-01

    Global incidence of type 2 diabetes has escalated over the past few decades, necessitating a continued search for natural sources of enzyme inhibitors to offset postprandial hyperglycemia. The objective of this study was to evaluate coastal Alaskan seaweed inhibition of α-glucosidase and α-amylase, two carbolytic enzymes involved in serum glucose regulation. Of the six species initially screened, the brown seaweeds Fucus distichus and Alaria marginata possessed the strongest inhibitory effects. F. distichus fractions were potent mixed-mode inhibitors of α-glucosidase and α-amylase, with IC50 values of 0.89 and 13.9 μg/mL, respectively; significantly more efficacious than the pharmaceutical acarbose (IC50 of 112.0 and 137.8 μg/mL, respectively). The activity of F. distichus fractions was associated with phlorotannin oligomers. Normal-phase liquid chromatography-mass spectrometry (NPLC-MS) was employed to characterize individual oligomers. Accurate masses and fragmentation patterns confirmed the presence of fucophloroethol structures with degrees of polymerization from 3 to 18 monomer units. These findings suggest that coastal Alaskan seaweeds are sources of α-glucosidase and α-amylase inhibitory phlorotannins, and thus have potential to limit the release of sugar from carbohydrates and thus alleviate postprandial hyperglycemia. PMID:25341030

  3. Severe hypoglycaemia in type 1 diabetes: impact of the renin-angiotensin system and other risk factors

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik

    2009-01-01

    this thesis was conducted to assess the significance of severe hypoglycaemia as a clinical problem in the type 1 diabetic population, to evaluate the impact of known risk factors on occurrence of severe hypoglycaemia, and to identify new markers that could contribute to improved prediction of, and inspire...... targets and thereby open for prevention of severe hypoglycaemia. Furthermore, subjects with elevated renin-angiotensin system activity and a high rate of severe hypoglycaemia might benefit from pharmacological blockade of the renin-angiotensin system by ACE inhibitors or angiotensin II receptor blockers...

  4. Prediction of response to medical therapy by serum soluble (pro)renin receptor levels in Graves' disease.

    Science.gov (United States)

    Mizuguchi, Yuki; Morimoto, Satoshi; Kimura, Shihori; Takano, Noriyoshi; Yamashita, Kaoru; Seki, Yasufumi; Bokuda, Kanako; Yatabe, Midori; Yatabe, Junichi; Watanabe, Daisuke; Ando, Takashi; Ichihara, Atsuhiro

    2018-01-01

    Antithyroid drugs are generally selected as the first-line treatment for Graves' Disease (GD); however, the existence of patients showing resistance or severe side effects to these drugs is an important issue to be solved. The (pro)renin receptor [(P)RR] is a multi-functional protein that activates the tissue renin-angiotensin system and is an essential constituent of vacuolar H+-ATPase, necessary for the autophagy-lysosome pathway. (P)RR is cleaved to soluble (s)(P)RR, which reflects the status of (P)RR expression. In this retrospective study, we aimed to investigate whether serum s(P)RR concentration can be used as a biomarker to predict the outcome of antithyroid drug treatment in GD patients. Serum s(P)RR levels were measured in 54 untreated GD patients and 47 control participants. Effects of medical treatment with antithyroid drugs on these levels were investigated in GD patients. Serum s(P)RR levels were significantly higher in patients with Graves' disease than in control subjects (PGraves' disease. High serum s(P)RR levels were associated with resistance to antithyroid drug treatment, suggesting that serum s(P)RR concentration can be used as a useful biomarker to predict the outcome of antithyroid drug treatment in these patients. Patients with Graves' disease with low body mass index showed higher levels of serum soluble (pro)renin receptor levels than those with high body mass index. In addition, in patients with Graves' disease, serum triglyceride levels were negatively correlated with serum soluble (pro)renin receptor levels. All these data indicated an association between low nutrient condition due to hyperthyroidism and increased (pro)renin receptor expression in these patients, suggesting that (pro)renin receptor expression could be increased in the process of stimulating intracellular energy production via activating autophagy function to compensate energy loss.

  5. Prediction of response to medical therapy by serum soluble (pro)renin receptor levels in Graves’ disease

    Science.gov (United States)

    Kimura, Shihori; Takano, Noriyoshi; Yamashita, Kaoru; Seki, Yasufumi; Bokuda, Kanako; Yatabe, Midori; Yatabe, Junichi; Watanabe, Daisuke; Ando, Takashi

    2018-01-01

    Antithyroid drugs are generally selected as the first-line treatment for Graves’ Disease (GD); however, the existence of patients showing resistance or severe side effects to these drugs is an important issue to be solved. The (pro)renin receptor [(P)RR] is a multi-functional protein that activates the tissue renin-angiotensin system and is an essential constituent of vacuolar H+-ATPase, necessary for the autophagy-lysosome pathway. (P)RR is cleaved to soluble (s)(P)RR, which reflects the status of (P)RR expression. In this retrospective study, we aimed to investigate whether serum s(P)RR concentration can be used as a biomarker to predict the outcome of antithyroid drug treatment in GD patients. Serum s(P)RR levels were measured in 54 untreated GD patients and 47 control participants. Effects of medical treatment with antithyroid drugs on these levels were investigated in GD patients. Serum s(P)RR levels were significantly higher in patients with Graves’ disease than in control subjects (Pantithyroid drug treatment, suggesting that serum s(P)RR concentration can be used as a useful biomarker to predict the outcome of antithyroid drug treatment in these patients. Patients with Graves’ disease with low body mass index showed higher levels of serum soluble (pro)renin receptor levels than those with high body mass index. In addition, in patients with Graves’ disease, serum triglyceride levels were negatively correlated with serum soluble (pro)renin receptor levels. All these data indicated an association between low nutrient condition due to hyperthyroidism and increased (pro)renin receptor expression in these patients, suggesting that (pro)renin receptor expression could be increased in the process of stimulating intracellular energy production via activating autophagy function to compensate energy loss. PMID:29621332

  6. The role of renin angiotensin system intervention in stage B heart failure.

    LENUS (Irish Health Repository)

    Collier, Patrick

    2012-04-01

    This article outlines the link between the renin angiotensin aldosterone system (RAAS) and various forms of cardiomyopathy, and also reviews the understanding of the effectiveness of RAAS intervention in this phase of ventricular dysfunction. The authors focus their discussion predominantly on patients who have had previous myocardial infarction or those who have left ventricular hypertrophy and also briefly discuss the role of RAAS activation and intervention in patients with alcoholic cardiomyopathy.

  7. Inhibition of calmodulin - regulated calcium pump activity in rat brain by toxaphene

    International Nuclear Information System (INIS)

    Trottman, C.H.; Moorthy, K.S.

    1986-01-01

    In vivo effects of toxaphene on calcium pump activity in rat brain synaptosomes was studied. Male Sprague-Dawley rats were dosed with toxaphene at 0,25,50, and 100 mg/kg/day for 3 days and sacrificed 24 h after last dose. Ca 2+ -ATPase activity and 45 Ca uptake were determined in brain P 2 fraction. Toxaphene inhibited both Ca 2+ -ATPase activity and 45 Ca 2+ uptake and the inhibition was dose dependent. Both substrate and Ca 2+ activation kinetics of Ca 2+ -ATPase indicated non-competitive type of inhibition as evidenced by decreased catalytic velocity but not enzyme-substrate affinity. The inhibited Ca 2+ -ATPase activity and Ca 2+ uptake were restored to normal level by exogenously added calmodulin which increased both velocity and affinity. The inhibition of Ca 2+ -ATPase activity and Ca 2+ uptake and restoration by calmodulin suggests that toxaphene may impair active calcium transport mechanisms by decreasing regulator protein calmodulin levels

  8. Renin-Angiotensin System in Diabetes.

    Science.gov (United States)

    Rein, Johannes; Bader, Michael

    2017-11-17

    The renin-angiotensin system (RAS) has two different axes, the classical one with the effector peptide angiotensin II and the new one with the effector peptide angiotensin (1-7). Both peptides have been shown to be involved in the pathogenesis of diabetes mellitus and its consequences, nephropathy, retinopathy and cardiomyopathy in animal models and patients. In diabetes, angiotensin II acts mostly deleterious and angiotensin (1-7) protective. In this review we summarize the knowledge about the role of the different RAS axes in diabetes mellitus and the use of drugs interfering with the RAS in the therapy of the disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Melanogenesis inhibition activity of floralginsenoside A from Panax ginseng berry

    Directory of Open Access Journals (Sweden)

    Dae Young Lee

    2017-10-01

    Conclusion: FGA showed the most potent inhibition of melanogenesis in both in vitro and in vivo studies. This study suggests that FGA purified from P. ginseng may be an effective melanogenesis inhibitor.

  10. Inhibition of glutathione S-transferases (GSTs) activity from cowpea ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-10-19

    Oct 19, 2009 ... Inhibition effect of the plant extracts on the GST was studied by spectrophotometric method. The ... of assuring food security in developing countries like ..... studies on African cat fish (Clarias gariepinus) liver glutathione s-.

  11. Novel approach of fragment-based lead discovery applied to renin inhibitors.

    Science.gov (United States)

    Tawada, Michiko; Suzuki, Shinkichi; Imaeda, Yasuhiro; Oki, Hideyuki; Snell, Gyorgy; Behnke, Craig A; Kondo, Mitsuyo; Tarui, Naoki; Tanaka, Toshimasa; Kuroita, Takanobu; Tomimoto, Masaki

    2016-11-15

    A novel approach was conducted for fragment-based lead discovery and applied to renin inhibitors. The biochemical screening of a fragment library against renin provided the hit fragment which showed a characteristic interaction pattern with the target protein. The hit fragment bound only to the S1, S3, and S3 SP (S3 subpocket) sites without any interactions with the catalytic aspartate residues (Asp32 and Asp215 (pepsin numbering)). Prior to making chemical modifications to the hit fragment, we first identified its essential binding sites by utilizing the hit fragment's substructures. Second, we created a new and smaller scaffold, which better occupied the identified essential S3 and S3 SP sites, by utilizing library synthesis with high-throughput chemistry. We then revisited the S1 site and efficiently explored a good building block attaching to the scaffold with library synthesis. In the library syntheses, the binding modes of each pivotal compound were determined and confirmed by X-ray crystallography and the library was strategically designed by structure-based computational approach not only to obtain a more active compound but also to obtain informative Structure Activity Relationship (SAR). As a result, we obtained a lead compound offering synthetic accessibility as well as the improved in vitro ADMET profiles. The fragments and compounds possessing a characteristic interaction pattern provided new structural insights into renin's active site and the potential to create a new generation of renin inhibitors. In addition, we demonstrated our FBDD strategy integrating highly sensitive biochemical assay, X-ray crystallography, and high-throughput synthesis and in silico library design aimed at fragment morphing at the initial stage was effective to elucidate a pocket profile and a promising lead compound. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Buprofezin inhibits acetylcholinesterase activity in B-biotype Bemisia tabaci.

    Science.gov (United States)

    Cottage, Emma L A; Gunning, Robin V

    2006-01-01

    B-biotype Bemisia tabaci is a severe insect pest worldwide in many ornamental, agricultural, and horticultural industries. Control of this insect is hampered by resistance to many acetylcholinesterase (AChE)-inhibiting insecticides, such as organophosphates and carbamates. Consequently, insect growth regulators such as buprofezin, which act by inhibiting chitin synthesis, are being investigated for use against B-biotype B. tabaci in Australia. This study discusses the effects of buprofezin on B. tabaciAChE.

  13. Behavioral inhibition and activation systems in traumatic brain injury.

    Science.gov (United States)

    Wong, Christina G; Rapport, Lisa J; Meachen, Sarah-Jane; Hanks, Robin A; Lumley, Mark A

    2016-11-01

    Personality has been linked to cognitive appraisal and health outcomes; however, research specific to traumatic brain injury (TBI) has been sparse. Gray's theory of behavioral inhibition system and behavioral activation system (BIS/BAS) offers a neurobiologic view of personality that may be especially relevant to neurobehavioral change associated with TBI. The present study examined theoretical and psychometric issues of using the BIS/BAS scale among adults with TBI as well as BIS/BAS personality correlates of TBI. Research Method/Design: Eighty-one adults with complicated-mild to severe TBI and 76 of their significant others (SOs) participated. Measures included the BIS/BAS scale, Positive and Negative Affect Schedule, and Awareness Questionnaire. Among adults with TBI, BIS/BAS internal consistency reliabilities were similar to those found in normative samples of adults without TBI. The TBI group endorsed significantly higher BAS than did the SO group, and injury severity was positively correlated to BAS. The SO group showed expected patterns of correlation between personality and affect; positive affect was associated with BAS, and negative affect with BIS. In contrast, in the TBI group, BAS was positively correlated to both positive and negative affect. Impaired awareness of abilities moderated the intensity of relationships between BIS/BAS and affect. TBI was associated with relatively intensified BAS (approach behavior) but not BIS (avoidance behavior). The observed pattern is consistent with the neurobiology of TBI-related personality change and with theory regarding the independence of the BIS and BAS systems. The BIS/BAS scale shows promise as a personality measure in TBI. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  14. Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases.

    Science.gov (United States)

    Tan, Wan Shun Daniel; Liao, Wupeng; Zhou, Shuo; Mei, Dan; Wong, Wai-Shiu Fred

    2017-12-27

    The renin-angiotensin system (RAS) plays a major role in regulating electrolyte balance and blood pressure. RAS has also been implicated in the regulation of inflammation, proliferation and fibrosis in pulmonary diseases such as asthma, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Current therapeutics suffer from some drawbacks like steroid resistance, limited efficacies and side effects. Novel intervention is definitely needed to offer optimal therapeutic strategy and clinical outcome. This review compiles and analyses recent investigations targeting RAS for the treatment of inflammatory lung diseases. Inhibition of the upstream angiotensin (Ang) I/Ang II/angiotensin receptor type 1 (AT 1 R) pathway and activation of the downstream angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor pathway are two feasible strategies demonstrating efficacies in various pulmonary disease models. More recent studies favor the development of targeting the downstream ACE2/Ang (1-7)/Mas receptor pathway, in which diminazene aceturate, an ACE2 activator, GSK2586881, a recombinant ACE2, and AV0991, a Mas receptor agonist, showed much potential for further development. As the pathogenesis of pulmonary diseases is so complex that RAS modulation may be used alone or in combination with existing drugs like corticosteroids, pirfenidone/nintedanib or endothelin receptor antagonists for different pulmonary diseases. Personalized medicine through genetic screening and phenotyping for angiotensinogen or ACE would aid treatment especially for non-responsive patients. This review serves to provide an update on the latest development in the field of RAS targeting for pulmonary diseases, and offer some insights into future direction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system

    DEFF Research Database (Denmark)

    Aachmann-Andersen, Niels J.; Christensen, Soren J.; Lisbjerg, Kristian

    2018-01-01

    The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt...... that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect...... of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system....

  16. The Low-Renin Hypertension Phenotype: Genetics and the Role of the Mineralocorticoid Receptor

    Directory of Open Access Journals (Sweden)

    Rene Baudrand

    2018-02-01

    Full Text Available A substantial proportion of patients with hypertension have a low or suppressed renin. This phenotype of low-renin hypertension (LRH may be the manifestation of inherited genetic syndromes, acquired somatic mutations, or environmental exposures. Activation of the mineralocorticoid receptor is a common final mechanism for the development of LRH. Classically, the individual causes of LRH have been considered to be rare diseases; however, recent advances suggest that there are milder and “non-classical” variants of many LRH-inducing conditions. In this regard, our understanding of the underlying genetics and mechanisms accounting for LRH, and therefore, potentially the pathogenesis of a large subset of essential hypertension, is evolving. This review will discuss the potential causes of LRH, with a focus on implicated genetic mechanisms, the expanding recognition of non-classical variants of conditions that induce LRH, and the role of the mineralocorticoid receptor in determining this phenotype.

  17. Targeting renin-angiotensin system in malignant hypertension in atypical hemolytic uremic syndrome

    Directory of Open Access Journals (Sweden)

    V Raghunathan

    2017-01-01

    Full Text Available Hypertension is common in hemolytic uremic syndrome (HUS and often difficult to control. Local renin-angiotensin activation is believed to be an important part of thrombotic microangiopathy, leading to a vicious cycle of progressive renal injury and intractable hypertension. This has been demonstrated in vitro via enhanced tissue factor expression on glomerular endothelial cells which is enhanced by angiotensin II. We report two pediatric cases of atypical HUS with severe refractory malignant hypertension, in which we targeted the renin-angiotensin system by using intravenous (IV enalaprilat, oral aliskiren, and oral enalapril with quick and dramatic response of blood pressure. Both drugs, aliskiren and IV enalaprilat, were effective in controlling hypertension refractory to multiple antihypertensive medications. These appear to be promising alternatives in the treatment of severe atypical HUS-induced hypertension and hypertensive emergency.

  18. Aliskiren, a Direct Renin Inhibitor, Improves Vascular Endothelial Function in Patients on Hemodialysis Independent of Antihypertensive Effect ∼ a Pilot Study∼

    Directory of Open Access Journals (Sweden)

    Hidekazu Moriya

    2013-05-01

    Full Text Available Aims: Aliskiren inhibits the first step in the renin-angiotensin system (RAS and recently has been shown to modulate vascular diseases via RAS-dependent and independent pathways. This study aimed to determine the effect of aliskiren-associated direct renin inhibition on endothelial function in patients on hemodialysis via flow-mediated dilatation (FMD and platelet-derived microparticles (PDMP, as biomarkers of atherosclerosis. Methods: A 12-week prospective study was performed with 24 patients on hemodialysis who were administered 150 mg orally aliskiren once daily for 12 weeks. Results: No significant difference were observed between pre-dialysis, home, and weekly averaged blood pressure at baseline and at 12 weeks (151.5 ± 8.5/80.9 ± 12.9 mmHg vs 150.3 ± 15.3/78.9 ± 21.2 mmHg, 151.4 ± 9.7/82.3 ± 14.7 mmHg vs 151.2 ± 17.7/81.4 ± 10.6 mmHg, and 156.0 ± 18.3/81.9 ± 9.4 mmHg vs 152.5 ± 18.9/81.7 ± 12.3 mmHg, respectively. FMD significantly increased from 2.54% ± 1.45% at baseline to 3.11% ± 1.37% at 12 weeks (P = 0.0267, and PDMP significantly decreased from 13.9 ± 5.8 U/mL at baseline to 10.9 ± 4.5 U/mL at 12 weeks (P = 0.0002. Conclusion: Aliskiren improved vascular endothelial function and platelet-endothelium activation in patients on hemodialysis independent of antihypertensive effect.

  19. The satiety signaling neuropeptide perisulfakinin inhibits the activity of central neurons promoting general activity

    Directory of Open Access Journals (Sweden)

    Dieter Wicher

    2007-12-01

    Full Text Available The metabolic state is one of the determinants of the general activity level. Satiety is related to resting or sleep whereas hunger correlates to wakefulness and activity. The counterpart to the mammalian satiety signal cholecystokinin (CCK in insects are the sulfakinins. The aim of this study was to resolve the mechanism by which the antifeedant activity of perisulfakinin (PSK in Periplaneta americana is mediated. We identified the sources of PSK which is used both as hormone and as paracrine messenger. PSK is found in the neurohemal organ of the brain and in nerve endings throughout the central nervous system. To correlate the distributions of PSK and its receptor (PSKR, we cloned the gene coding for PSKR and provide evidence for its expression within the nervous system. It occurs only in a few neurons, among them are the dorsal unpaired median (DUM neurons which release octopamine thereby regulating the general level of activity. Application of PSK to DUM neurons attenuated the spiking frequency (EC50=11pM due to reduction of a pacemaker Ca2+ current through cAMP-inhibited pTRPγ channels. PSK increased the intracellular cAMP level while decreasing the intracellular Ca2+ concentration in DUM neurons. Thus, the satiety signal conferred by PSK acts antagonistically to the hunger signal, provided by the adipokinetic hormone (AKH: PSK depresses the electrical activity of DUM neurons by inhibiting the pTRPγ channel that is activated by AKH under conditions of food shortage.

  20. Radioimmunologic analysis of the state of the renin-angiotensin-aldosterone system in arterial hypertension

    International Nuclear Information System (INIS)

    Slavnov, V.N.; Yakovlev, A.A.; Gandzha, T.I.; Yugrinov, O.G.

    1986-01-01

    For 110 patients having various forms of arterial hypertension (hypertension, aldersteronoma, phaeochromocytoma, corticosteroma) the parameters of the system renin-angiotensin-aldosterone (RAA) were measured. Basal values of aldosterone and renin activity in blood were determined as well as their concentration in blood taken from the vena cava inferior, renal and adrenal veins during selective renography. The 24-hours rhythm of the hormones in the blood, the reaction of the glomerular zone of the adrenal cortex and the juxtaglomerular renal system under acute lasix stress was evaluated. It was found, that the system RAA is disturbed in all patients with arterial hypertension. This is indicated by changes of aldosterone concentration, renin activity in peripheral blood and in the blood from the vena cava inferior, renal and adrenal veins, the 24-hour rhythm of their concentrations in serum and the reaction to acute lasix stress. The radioimmunoassays of quantitative parameters of the RAA system are decisive for the differential diagnostics of hypertension and suprarenomas connected with a hypertension syndrome. They facilitate a rational choice of the hypertension therapy and the daily distribution of the medicaments for patients with hypertension. The radioimmunoassays can be used for checking the efficiency of medicaments and surgery. (author)

  1. Antitumor and antimicrobial activities and inhibition of in-vitro lipid ...

    African Journals Online (AJOL)

    The antitumor activity was measured in DLA cell line induced mice. Inhibition of in vitro lipid peroxidation activity of the D. nobile in both liver homogenate and RBC ghosts was also carried out. The aqueous extracts of stem and flower of D. nobile showed better zone of bacterial inhibition than that of ethanol and chloroform

  2. Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease

    NARCIS (Netherlands)

    Hommes, Daan; van den Blink, Bernt; Plasse, Terry; Bartelsman, Joep; Xu, Cuiping; Macpherson, Bret; Tytgat, Guido; Peppelenbosch, Mailkel; van Deventer, Sander

    2002-01-01

    Background & Aims: We investigated if inhibition of mitogen-activated protein kinases (MAPKs) was beneficial in Crohn's disease. Methods: Inhibition of JNK and p38 MAPK activation with CNI-1493, a guanylhydrazone, was tested in vitro. Twelve patients with severe Crohn's disease (mean baseline, CDAI

  3. Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition.

    Science.gov (United States)

    Meng, Fanying; Bhupathi, Deepthi; Sun, Jessica D; Liu, Qian; Ahluwalia, Dharmendra; Wang, Yan; Matteucci, Mark D; Hart, Charles P

    2015-05-21

    The hypoxia-activated prodrug TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Here, we have explored the effect of Chk1 inhibition on TH-302-mediated pharmacological activities. We employed in vitro cell viability, DNA damage, cellular signaling assays and the in vivo HT29 human tumor xenograft model to study the effect of Chk1inhibition on TH-302 antitumor activities. TH-302 cytotoxicity is greatly enhanced by Chk1 inhibition in p53-deficient but not in p53-proficient human cancer cell lines. Chk1 inhibitors reduced TH-302-induced cell cycle arrest via blocking TH-302-induced decrease of phosphorylation of histone H3 and increasing Cdc2-Y15 phosphorylation. Employing the single-cell gel electrophoresis (comet) assay, we observed a potentiation of the TH-302 dependent tail moment. TH-302 induced γH2AX and apoptosis were also increased upon the addition of Chk1 inhibitor. Potentiation of TH-302 cytotoxicity by Chk1 inhibitor was only observed in cell lines proficient in, but not deficient in homology-directed DNA repair. We also show that combination treatment led to lowering of Rad51 expression levels as compared to either agent alone. In vivo data demonstrate that Chk1 inhibitor enhances TH-302 anti-tumor activity in p53 mutant HT-29 human tumor xenografts, supporting the hypothesis that these in vitro results can translate to enhanced in vivo efficacy of the combination. TH-302-mediated in vitro and in vivo anti-tumor activities were greatly enhanced by the addition of Chk1 inhibitors. The preclinical data presented in this study support a new approach for the treatment of p53-deficient hypoxic cancers by combining Chk1 inhibitors with the hypoxia-activated prodrug TH-302.

  4. Upregulation of cyclooxygenase-2 expression in porcine macula densa with chronic nitric oxide synthase inhibition.

    Science.gov (United States)

    Kommareddy, M; McAllister, R M; Ganjam, V K; Turk, J R; Laughlin, M Harold

    2011-11-01

    The objective of this study was to investigate the effects of chronic inhibition of nitric oxide synthase (NOS) on cyclooxygenase-2 (COX-2) expression in the macula densa (MD) of swine, as well as the effects on expression of related proteins. Adult female Yucatan swine were given either tap water (control, n = 6) or water with N (G)-nitro-L-arginine methyl ester (L-NAME, 100 mg/liter, n = 5) for a minimum of 30 days. Duplicate samples of kidney were fixed or snap frozen. There was a significant (P = .0082) upregulation of COX-2 mRNA expression in the MD of L-NAME, as well as an apparent increase in COX-2 protein. Plasma renin activity also increased with L-NAME treatment (control, 0.34 ± 0.08 ng/ml; L-NAME, 1.26 ± 0.03 ng/ml; P = .00000003). There were no differences between groups in expression of either inducible NOS or renin protein or in serum electrolyte concentrations. In conclusion, with chronic inhibition of NOS, COX-2 in MD is upregulated, perhaps to compensate for loss of nitric oxide. Increases in COX-2 products may counteract renal arteriolar constriction and sustain renin release.

  5. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro

    DEFF Research Database (Denmark)

    Vinggaard, A.M.; Hnida, C.; Breinholt, V.

    2000-01-01

    than 50 mu M. The positive control 4-hydroxyandrostendione (1 mu M) caused an inhibition of aromatase activity by 74%. The compounds, which did not affect the aromatase activity, were bromopropylate, chlorfenvinphos. chlorobenzilate, chlorpyrifos, diuron, heptachlor, iprodion, linuron, pentachlorphenol...

  6. Dasatinib inhibits both osteoclast activation and prostate cancer PC-3-cell-induced osteoclast formation.

    Science.gov (United States)

    Araujo, John C; Poblenz, Ann; Corn, Paul; Parikh, Nila U; Starbuck, Michael W; Thompson, Jerry T; Lee, Francis; Logothetis, Christopher J; Darnay, Bryant G

    2009-11-01

    Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation. Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC(50) of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts, and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release. We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases. Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases.

  7. Immune-suppressive activity of punicalagin via inhibition of NFAT activation

    International Nuclear Information System (INIS)

    Lee, Sang-Ik; Kim, Byoung-Soo; Kim, Kyoung-Shin; Lee, Samkeun; Shin, Kwang-Soo; Lim, Jong-Soon

    2008-01-01

    Since T cell activation is central to the development of autoimmune diseases, we screened a natural product library comprising 1400 samples of medicinal herbal extracts, to identify compounds that suppress T cell activity. Punicalagin (PCG) isolated from the fruit of Punica granatum was identified as a potent immune suppressant, based on its inhibitory action on the activation of the nuclear factor of activated T cells (NFAT). PCG downregulated the mRNA and soluble protein expression of interleukin-2 from anti-CD3/anti-CD28-stimulated murine splenic CD4+ T cells and suppressed mixed leukocytes reaction (MLR) without exhibiting cytotoxicity to the cells. In vivo, the PCG treatment inhibited phorbol 12-myristate 13-acetate (PMA)-induced chronic ear edema in mice and decreased CD3+ T cell infiltration of the inflamed tissue. These results suggest that PCG could be a potential candidate for the therapeutics of various immune pathologies

  8. Zinc ions bind to and inhibit activated protein C

    DEFF Research Database (Denmark)

    Zhu, Tianqing; Ubhayasekera, Wimal; Nickolaus, Noëlle

    2010-01-01

    fold enhanced, presumably due to the Ca2+-induced conformational change affecting the conformation of the Zn2+-binding site. The inhibition mechanism was non-competitive both in the absence and presence of Ca2+. Comparisons of sequences and structures suggested several possible sites for zinc binding...

  9. Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis

    NARCIS (Netherlands)

    Levi, M. [=Marcel M.; Biemond, B. J.; van Zonneveld, A. J.; ten Cate, J. W.; Pannekoek, H.

    1992-01-01

    We investigated the effect of inhibition of plasminogen activator inhibitor-1 (PAI-1) activity by a murine monoclonal anti-human PAI-1 antibody (MAI-12) on in vitro thrombolysis and on in vivo thrombolysis and thrombus extension in an experimental animal model for thrombosis. Thrombolysis, mediated

  10. High-salt diets during pregnancy affected fetal and offspring renal renin-angiotensin system.

    Science.gov (United States)

    Mao, Caiping; Liu, Rong; Bo, Le; Chen, Ningjing; Li, Shigang; Xia, Shuixiu; Chen, Jie; Li, Dawei; Zhang, Lubo; Xu, Zhice

    2013-07-01

    Intrauterine environments are related to fetal renal development and postnatal health. Influence of salty diets during pregnancy on renal functions and renin-angiotensin system (RAS) was determined in the ovine fetuses and offspring. Pregnant ewes were fed high-salt diet (HSD) or normal-salt diet (NSD) for 2 months during middle-to-late gestation. Fetal renal functions, plasma hormones, and mRNA and protein expressions of the key elements of renal RAS were measured in the fetuses and offspring. Fetal renal excretion of sodium was increased while urine volume decreased in the HSD group. Fetal blood urea nitrogen was increased, while kidney weight:body weight ratio decreased in the HSD group. The altered ratio was also observed in the offspring aged 15 and 90 days. Maternal and fetal plasma antidiuretic hormone was elevated without changes in plasma renin activity and Ang I levels, while plasma Ang II was decreased. The key elements of local renal RAS, including angiotensinogen, angiotensin converting enzyme (ACE), ACE2, AT1, and AT2 receptor expression in both mRNA and protein, except renin, were altered following maternal high salt intake. The results suggest that high intake of salt during pregnancy affected fetal renal development associated with an altered expression of the renal key elements of RAS, some alterations of fetal origins remained after birth as possible risks in developing renal or cardiovascular diseases.

  11. Fundamental and clinical study of direct immunoradiometric assay in human renin concentration

    International Nuclear Information System (INIS)

    Kurimoto, Fumihiko; Horiuchi, Junko; Sakurai, Hyoichiro; Suzuki, Hiromichi; Takita, Takashi; Saruta, Takao.

    1988-01-01

    'Renin RIA Pasteur' kit for directly measuring renin concentration in human plasma (PRC) was fundamentally and clinically evaluated. A standard curve for PRC was linear in the range of 10 - 640 pg/ml. Reproducibility, recovery, and stability were satisfactory. There was a significantly positive correlation between direct PRC and conventional plasma renin activity (PRA) and indirect PRC. PRC was directly measured in 119 healthy volunteers and 15 patients with primary aldosteronism (4), Cushing's syndrome (6), or non-functioning tumor (5). The basal PRC was 32.4 +- 18.8 pg/ml for men and 37.9 +- 22.6 pg/ml for women. PRC for primary aldosteronism was below detectable levels, and remained unchanged even after the administratin of ACTH. In the case of Cushing's syndrome, mean PRC and PRA were 19 pg/ml and 1.2 ng/ml/hr, and did not respond to ACTH. Although the administration of ATCH was significantly associated with a decreased PRC, there was only tendency toward the decreased PRA in the case of non-functioning tumors. The results indicate the usefulness of the present kit in terms of its ability to directly measure PRC without any complicated procedures. (Namekawa, K.)

  12. A Study on Renin-Angiotensin System and Total Exchangeable Sodium in Hypertension

    International Nuclear Information System (INIS)

    Choe, Kang Won; Park, Jung Sik; Lee, Jung Sang; Koh, Chang Soon

    1976-01-01

    The etiologic role of renin-angiotensin system and sodium-volume status in the pathophysiology of various forms of hypertension was investigated. Plasma renin activity (PRA) was measured by radioimmunoassay, while sodium-volume status was evaluated by the determination of total exchangeable sodium(NaE) using isotope dilution method. The subjects consisted of 25 controls, 24 patients with essential hypertension, 22 patients with chronic renal failure (13 with hypertension, 9 without hypertension) and 14 patients with malignant hypertension. The results were as follows: 1) An inverse correlation between NaE and PRA was noted in control subjects (r=-0.598, p 0.1) 3) Absolute value of PRA was not deviated significantly from control group (2.53±1.416 ng/ml/hr) except in malignant hypertension (6.09±2.042, p 0.1). It is suggested that renin-angiotensin system plays a predominant role in the pathogenesis of malignant hypertension and in hypertension of chronic renal failure, though sodium retention is also contributing factor. PRA variation in essential hypertension does not appear to be associated with any consistent change in Na-volume status, suggesting the existence of another mechanism in the genesis of hypertension and PRA variation.

  13. IN VITRO ANTIOXIDANT AND α-AMYLASE INHIBITION ACTIVITIES OF PANCHSAKAR CHURNA

    Directory of Open Access Journals (Sweden)

    Ashok Kumar B.S.

    2013-12-01

    Full Text Available Panchsakar Churna is the composition of Cassia angustifolia, Terminalia chebula, Zingiber officinale, Foeniculum vulgare and Saindhava lavana. Aqueous extract of churna was used to investigate antioxidant activity by ferrous ion chelating assay and ferric reducing power and alpha amylase inhibition activity by dinitrosalicylic acid method (DNSA. Aqueous extract of churna showed maximum ferrous chelating activity - 42.01 and ferric reducing power - 1.5 and 83.33 % of inhibition protein denaturation at 1000 µg/ml. Panchsakar churna showed significant antioxidant and alpha amylase inhibition activities.

  14. Cyanide does more to inhibit heme enzymes, than merely serving as an active-site ligand

    Energy Technology Data Exchange (ETDEWEB)

    Parashar, Abhinav [Center for Biomedical Research, VIT University, Vellore, Tamil Nadu, 632014 India (India); Venkatachalam, Avanthika [REDOx Lab, PSG Institute of Advanced Studies, Avinashi Road, Peelamedu, Coimbatore, Tamil Nadu, 641004 (India); Gideon, Daniel Andrew [Center for Biomedical Research, VIT University, Vellore, Tamil Nadu, 632014 India (India); Manoj, Kelath Murali, E-mail: satyamjayatu@yahoo.com [REDOx Lab, PSG Institute of Advanced Studies, Avinashi Road, Peelamedu, Coimbatore, Tamil Nadu, 641004 (India)

    2014-12-12

    Highlights: • Cyanide (CN) is a well-studied toxic principle, known to inhibit heme-enzymes. • Inhibition is supposed to result from CN binding at the active site as a ligand. • Diverse heme enzymes’ CN inhibition profiles challenge prevailing mechanism. • Poor binding efficiency of CN at low enzyme concentrations and ligand pressures. • CN-based diffusible radicals cause ‘non-productive electron transfers’ (inhibition). - Abstract: The toxicity of cyanide is hitherto attributed to its ability to bind to heme proteins’ active site and thereby inhibit their activity. It is shown herein that the long-held interpretation is inadequate to explain several observations in heme-enzyme reaction systems. Generation of cyanide-based diffusible radicals in heme-enzyme reaction milieu could shunt electron transfers (by non-active site processes), and thus be detrimental to the efficiency of oxidative outcomes.

  15. Reversal of androgen inhibition of estrogen-activated sexual behavior by cholinergic agents.

    Science.gov (United States)

    Dohanich, G P; Cada, D A

    1989-12-01

    Androgens have been found to inhibit lordosis activated by estrogen treatment of ovariectomized female rats. In the present experiments, dihydrotestosterone propionate (200 micrograms for 3 days) inhibited the incidence of lordosis in ovariectomized females treated with estradiol benzoate (1 microgram for 3 days). This inhibition of lordosis was reversed 15 min after bilateral intraventricular infusion of physostigmine (10 micrograms/cannula), an acetylcholinesterase inhibitor, or carbachol (0.5 microgram/cannula), a cholinergic receptor agonist. This reversal of inhibition appears to be mediated by cholinergic muscarinic receptors since pretreatment with scopolamine (4 mg/kg, ip), a muscarinic receptor blocker, prevented the reversal of androgen inhibition by physostigmine. These results indicate that androgens may inhibit estrogen-activated lordosis through interference with central cholinergic muscarinic mechanisms.

  16. There is no free won't: antecedent brain activity predicts decisions to inhibit.

    Directory of Open Access Journals (Sweden)

    Elisa Filevich

    Full Text Available Inhibition of prepotent action is an important aspect of self-control, particularly in social contexts. Action inhibition and its neural bases have been extensively studied. However, the neural precursors of free decisions to inhibit have hardly been studied. We asked participants to freely choose to either make a rapid key press in response to a visual cue, or to transiently inhibit action, and briefly delay responding. The task required a behavioural response on each trial, so trials involving inhibition could be distinguished from those without inhibition as those showing slower reaction times. We used this criterion to classify free-choice trials as either rapid or inhibited/delayed. For 13 participants, we measured the mean amplitude of the ERP activity at electrode Cz in three subsequent 50 ms time windows prior to the onset of the signal that either instructed to respond or inhibit, or gave participants a free choice. In two of these 50 ms time windows (-150 to -100, and -100 to -50 ms relative to action onset, the amplitude of prestimulus ERP differed between trials where participants "freely" chose whether to inhibit or to respond rapidly. Larger prestimulus ERP amplitudes were associated with trials in which participants decided to act rapidly as compared to trials in which they decided to delay their responses. Last-moment decisions to inhibit or delay may depend on unconscious preparatory neural activity.

  17. Inhibition of Rac1 Activity in the Hippocampus Impairs the Forgetting of Contextual Fear Memory.

    Science.gov (United States)

    Jiang, Lizhu; Mao, Rongrong; Zhou, Qixin; Yang, Yuexiong; Cao, Jun; Ding, Yuqiang; Yang, Yuan; Zhang, Xia; Li, Lingjiang; Xu, Lin

    2016-03-01

    Fear is crucial for survival, whereas hypermnesia of fear can be detrimental. Inhibition of the Rac GTPase is recently reported to impair the forgetting of initially acquired memory in Drosophila. Here, we investigated whether inhibition of Rac1 activity in rat hippocampus could contribute to the hypermnesia of contextual fear. We found that spaced but not massed training of contextual fear conditioning caused inhibition of Rac1 activity in the hippocampus and heightened contextual fear. Furthermore, intrahippocampal injection of the Rac1 inhibitor NSC23766 heightened contextual fear in massed training, while Rac1 activator CN04-A weakened contextual fear in spaced training rats. Our study firstly demonstrates that contextual fear memory in rats is actively regulated by Rac1 activity in the hippocampus, which suggests that the forgetting impairment of traumatic events in posttraumatic stress disorder may be contributed to the pathological inhibition of Rac1 activity in the hippocampus.

  18. Synthesis of tritium labeled renin inhibitor ditekiren

    International Nuclear Information System (INIS)

    Hsi, R.S.P.; Stolle, W.T.; Bundy, G.L.

    1994-01-01

    In the search for a radioactive form of the peptidomimetic renin inhibitor, ditekiren, with a metabolically suitable radiolabel for conducting drug disposition studies, we prepared [ 3 H]ditekiren with tritium labels in the N-methyl-histidine moiety and in the leu-val alcohol transition-state insert. [His- 3 H]ditekiren was obtained by first introducing two iodine substituents into the N-methyl-histidine moiety of the parent drug, followed by catalytic hydrodehalogenation with tritium gas. Administration of this labeled drug to monkeys, however, resulted in prolonged retention of radioactivity in the test animals, even though little or no tritiated water was detected in urine. The results, together with similar earlier findings after administration of [ 3 H]ditekiren labeled in the proline moiety of the drug, led us to synthesize [ 3 H]ditekiren labeled in the ''unnatural'' leu-val alcohol (LVA) portion of the molecule. The tritium label in [LVA- 3 H]ditekiren was found to be metabolically suitable for conducting drug disposition studies, with no liability for tritiated water production or prolonged retention of radioactivity in tissues of test animals. (author)

  19. Mechanisms of Rose Bengal inhibition on SecA ATPase and ion channel activities.

    Science.gov (United States)

    Hsieh, Ying-Hsin; Huang, Ying-Ju; Jin, Jin-Shan; Yu, Liyan; Yang, Hsiuchin; Jiang, Chun; Wang, Binghe; Tai, Phang C

    2014-11-14

    SecA is an essential protein possessing ATPase activity in bacterial protein translocation for which Rose Bengal (RB) is the first reported sub-micromolar inhibitor in ATPase activity and protein translocation. Here, we examined the mechanisms of inhibition on various forms of SecA ATPase by conventional enzymatic assays, and by monitoring the SecA-dependent channel activity in the semi-physiological system in cells. We build on the previous observation that SecA with liposomes form active protein-conducting channels in the oocytes. Such ion channel activity is enhanced by purified Escherichia coli SecYEG-SecDF·YajC liposome complexes. Inhibition by RB could be monitored, providing correlation of in vitro activity and intact cell functionality. In this work, we found the intrinsic SecA ATPase is inhibited by RB competitively at low ATP concentration, and non-competitively at high ATP concentrations while the translocation ATPase with precursors and SecYEG is inhibited non-competitively by RB. The Inhibition by RB on SecA channel activity in the oocytes with exogenous ATP-Mg(2+), mimicking translocation ATPase activity, is also non-competitive. The non-competitive inhibition on channel activity has also been observed with SecA from other bacteria which otherwise would be difficult to examine without the cognate precursors and membranes. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Resveratrol promotes regression of renal carcinoma cells via a renin-angiotensin system suppression-dependent mechanism.

    Science.gov (United States)

    Li, Jianchang; Qiu, Mingning; Chen, Lieqian; Liu, Lei; Tan, Guobin; Liu, Jianjun

    2017-02-01

    The aim of the present study was to investigate the effect of resveratrol on renal carcinoma cells and explore possible renin-angiotensin system-associated mechanisms. Subsequent to resveratrol treatment, the cell viability, apoptosis rate, cytotoxicity levels, caspase 3/7 activity and the levels of angiotensin II (AngII), AngII type 1 receptor (AT1R), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) were evaluated in renal carcinoma cells. The effects of AngII, AT1R, VEGF and COX-2 on resveratrol-induced cell growth inhibition and apoptosis were also examined. The results indicated that resveratrol treatment may suppress growth, induce apoptosis, and decrease AngII, AT1R, VEGF and COX-2 levels in renal carcinoma ACHN and A498 cells. In addition, resveratrol-induced cell growth suppression and apoptosis were reversed when co-culturing with AT1R or VEGF. Thus, resveratrol may suppress renal carcinoma cell proliferation and induce apoptosis via an AT1R/VEGF pathway.

  1. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels

    Directory of Open Access Journals (Sweden)

    M. Ryan Smith

    2016-08-01

    Full Text Available Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP, decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231 breast adenocarcinoma cells up to 6 days after an initial 24 h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10 µM of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC protein levels, although other protein levels were

  2. Inhibition of total oxygen uptake by silica nanoparticles in activated sludge

    Energy Technology Data Exchange (ETDEWEB)

    Sibag, Mark [Department of Environment and Energy, Sejong University, 98 Gunja-Dong, Gwangjin-Gu, Seoul 143-747 (Korea, Republic of); Choi, Byeong-Gyu [School of Civil, Environmental and Architectural Engineering, Korea University, 145, Anam-ro, Sungbuk-ku, Seoul 136-701 (Korea, Republic of); Suh, Changwon [Energy Lab, Environment Group, Samsung Advanced Institute of Technology, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do 443-803 (Korea, Republic of); Lee, Kwan Hyung; Lee, Jae Woo [Department of Environmental Engineering and Program in Environmental Technology and Policy, Korea University, Sejong 339-700 (Korea, Republic of); Maeng, Sung Kyu [Department of Civil and Environmental Engineering, Sejong University, 98 Gunja-Dong, Gwangjin-Gu, Seoul 143-747 (Korea, Republic of); Cho, Jinwoo, E-mail: jinwoocho@sejong.edu [Department of Environment and Energy, Sejong University, 98 Gunja-Dong, Gwangjin-Gu, Seoul 143-747 (Korea, Republic of)

    2015-02-11

    Highlights: • Silica nanoparticles (SNP) inhibit total oxygen uptake in activated sludge. • Relatively smaller SNP are inhibitorier than larger SNP. • SNP alters C15:0, C16:0 and C18:0 in activated sludge fatty acid methyl ester profile. - Abstract: Nanoparticle toxicity to biological activities in activated sludge is largely unknown. Among the widely used nanoparticles, silica nanoparticles (SNP) have a limited number of studies associated with inhibition to the activated sludge process (ASP). We demonstrated SNP inhibition of activated sludge respiration through oxygen uptake rate (OUR) measurement. Based on the percentage inhibition of total oxygen consumption (I{sub T}), we observed that smaller SNPs (12 nm, I{sub T} = 33 ± 3%; 151 nm, I{sub T} = 23 ± 2%) were stronger inhibitors than larger SNPs (442 and 683 nm, I{sub T} = 5 ± 1%). Transmission electron micrographs showed that some of the SNPs were adsorbed on and/or apparently embedded somewhere in the microbial cell membrane. Whether SNPs are directly associated with the inhibition of total oxygen uptake warrants further studies. However, it is clear that SNPs statistically significantly altered the composition of microbial membrane lipids, which was more clearly described by principal component analysis and weighted Euclidian distance (PCA-ED) of the fatty acid methyl ester (FAME) data. This study suggests that SNPs potentially affect the biological activity in activated sludge through the inhibition of total oxygen uptake.

  3. Monoamine Oxidase-A Inhibition and Associated Antioxidant Activity in Plant Extracts with Potential Antidepressant Actions

    Directory of Open Access Journals (Sweden)

    Tomás Herraiz

    2018-01-01

    Full Text Available Monoamine oxidase (MAO catalyzes the oxidative deamination of amines and neurotransmitters and is involved in mood disorders, depression, oxidative stress, and adverse pharmacological reactions. This work studies the inhibition of human MAO-A by Hypericum perforatum, Peganum harmala, and Lepidium meyenii, which are reported to improve and affect mood and mental conditions. Subsequently, the antioxidant activity associated with the inhibition of MAO is determined in plant extracts for the first time. H. perforatum inhibited human MAO-A, and extracts from flowers gave the highest inhibition (IC50 of 63.6 μg/mL. Plant extracts were analyzed by HPLC-DAD-MS and contained pseudohypericin, hypericin, hyperforin, adhyperforin, hyperfirin, and flavonoids. Hyperforin did not inhibit human MAO-A and hypericin was a poor inhibitor of this isoenzyme. Quercetin and flavonoids significantly contributed to MAO-A inhibition. P. harmala seed extracts highly inhibited MAO-A (IC50 of 49.9 μg/L, being a thousand times more potent than H. perforatum extracts owing to its content of β-carboline alkaloids (harmaline and harmine. L. meyenii root (maca extracts did not inhibit MAO-A. These plants may exert protective actions related to antioxidant effects. Results in this work show that P. harmala and H. perforatum extracts exhibit antioxidant activity associated with the inhibition of MAO (i.e., lower production of H2O2.

  4. ACE inhibition and antioxidant activity of different part of Channa striata prepared by various cooking method

    Science.gov (United States)

    Chasanah, E.; Budiari, S.; Thenawijaya, M.; Palupi, N. S.

    2018-03-01

    Channa striata (snakehead) extract has been known possessing positive activity, one of which is the ability to inhibit Angiotensin Converting Enzyme (ACE) activity in vitro. Aims of this study were to determine the effect of cooking and parts of C. striata, i.e. meat/fillet, gonad, skin, gill against the ACE inhibition activity and antioxidant activity in vitro. Heat processing methods used were direct boiling and indirect boiling and steamed at 100 °C for 10 min. ACE inhibition activity was analyzed using hippuryl-L-histidyl-L-leucine (HHL) as substrate and antioxidant activity was analyzed using DPPH method. The result shows that the higher the concentration of the extract (5 %, 20 %, 35 % and 50 %), the higher the antioxidant activity. The highest antioxidant activity was shown by gonad followed by meat extract, skin, and gill. Cooking treatment affected antioxidant activity, being the detrimental treatment were steam and direct boiling. The egg/gonad of C. striata showed the highest capability to inhibit ACE activity followed by meat/fillet, gill and skin. In concentration of 10 mg, extract of C. striata gonad was comparable to captopril, a commercial hypertension drug. While uncooked fillet showed the highest ACE inhibition activity followed by indirect boiling, direct boiling and steaming.

  5. GSK621 activates AMPK signaling to inhibit LPS-induced TNFα production

    International Nuclear Information System (INIS)

    Wu, Yong-hong; Li, Quan; Li, Ping; Liu, Bei

    2016-01-01

    LPS stimulation in macrophages/monocytes induces TNFα production. We here tested the potential effect of GSK621, a novel AMP-activated protein kinase (AMPK) activator, against the process. In RAW264.7 macrophages, murine bone marrow-derived macrophages (BMDMs), and chronic obstructive pulmonary disease (COPD) patients' monocytes, GSK621 significantly inhibited LPS-induced TNFα protein secretion and mRNA synthesis. Inhibition of AMPK, through AMPKα shRNA knockdown or dominant negative mutation (T172A), almost abolished GSK621's suppression on TNFα in RAW264.7 cells. Reversely, forced-expression of a constitutively-active AMPKα (T172D) mimicked GSK621 actions and reduced LPS-induced TNFα production. Molecularly, GSK621 suppressed LPS-induced reactive oxygen species (ROS) production and nuclear factor kappa B (NFκB) activation. In vivo, GSK621 oral administration inhibited LPS-induced TNFα production and endotoxin shock in mice. In summary, GSK621 activates AMPK signaling to inhibit LPS-induced TNFα production in macrophages/monocytes. - Highlights: • GSK621 inhibits LPS-induced TNFα production/expression in RAW264.7 cells and BMDMs. • GSK621 inhibits LPS-induced TNFα production/expression in COPD patients' PBMCs. • GSK621's inhibition on TNFα production by LPS requires AMPK activation. • GSK621 inhibits LPS-induced ROS production and NFκB activation, dependent on AMPK. • GSK621 oral administration inhibits LPS-induced TNFα production and endotoxin shock in mice.

  6. KATP channels are not essential for pressure-dependent control of renin secretion

    DEFF Research Database (Denmark)

    Jensen, B L; Gambaryan, S; Scholz, H

    1998-01-01

    (IPRK). Cromakalim (0.1-10 muM) stimulated basal renin secretion up to threefold and caused vasorelaxation in the IPRK. Both effects of cromakalim were attenuated by glibenclamide. Cromakalim stimulated renin secretion from isolated juxtaglomerular (JG) cells and from microdissected afferent arterioles......This study aimed to investigate the functional role of ATP-sensitive K+ (KATP) channels in the control of renin secretion by renal perfusion pressure. We studied the effect of openers and blockers of KATP-channels on basal- and low-pressure-induced renin secretion from isolated perfused rat kidneys......, all of which suggests that KATP channel openers stimulate renin secretion at the level of JG cells. A decrease in the perfusion pressure from 13.3 to 9.33 kPa (100 mmHg to 70 mmHg) increased renin secretion twofold, and cromakalim further increased renin secretion. At 5.33 kPa (40 mmHg) renin...

  7. Ramiprilate inhibits functional matrix metalloproteinase activity in Crohn's disease fistulas

    DEFF Research Database (Denmark)

    Efsen, Eva; Saermark, Torben; Hansen, Alastair

    2011-01-01

    from six controls were also included. Total functional MMP activity was measured by a high-pressure liquid chromatography (HPLC)-based, fluorogenic MMP-substrate cleavage assay, and the specific activity of MMP-2, -3 and -9 by the MMP Biotrak Activity Assay. The MMP inhibitors comprised ethylene...

  8. Ramiprilate inhibits functional matrix metalloproteinase activity in Crohn's disease fistulas

    DEFF Research Database (Denmark)

    Efsen, Eva; Saermark, Torben; Hansen, Alastair

    2011-01-01

    Increased expression of matrix metalloproteinase (MMP)-2, -3 and -9 has been demonstrated in Crohn's disease fistulas, but it is unknown whether these enzymes are biologically active and represent a therapeutic target. Therefore, we investigated the proteolytic activity of MMPs in fistula tissue...... from six controls were also included. Total functional MMP activity was measured by a high-pressure liquid chromatography (HPLC)-based, fluorogenic MMP-substrate cleavage assay, and the specific activity of MMP-2, -3 and -9 by the MMP Biotrak Activity Assay. The MMP inhibitors comprised ethylene......-9.83) compared with non-Crohn's fistulas, [0.32 ng/ml, range 0-2.66, (p MMP-9 activity [0.64 ng/ml, range 0-5.66 and 0.17 ng/ml, range 0-1.1, respectively (p MMP activity level by 42% and suppressed the specific MMP-3...

  9. Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels

    NARCIS (Netherlands)

    Asselbergs, Folkert W.; Williams, Scott M.; Hebert, Patricia R.; Coffey, Christopher S.; Hillege, Hans L.; Navis, Gerjan; Vaughan, Douglas E.; van Gilst, Wiek H.; Moore, Jason H.

    Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II

  10. Adenovirus DNA binding protein inhibits SrCap-activated CBP and CREB-mediated transcription

    International Nuclear Information System (INIS)

    Xu Xiequn; Tarakanova, Vera; Chrivia, John; Yaciuk, Peter

    2003-01-01

    The SNF2-related CBP activator protein (SrCap) is a potent activator of transcription mediated by CBP and CREB. We have previously demonstrated that the Adenovirus 2 DNA Binding Protein (DBP) binds to SrCap and inhibits the transcription mediated by the carboxyl-terminal region of SrCap (amino acids 1275-2971). We report here that DBP inhibits the ability of full-length SrCap (1-2971) to activate transcription mediated by Gal-CREB and Gal-CBP. In addition, DBP also inhibits the ability of SrCap to enhance Protein Kinase A (PKA) activated transcription of the enkaphalin promoter. DBP was found to dramatically inhibit transcription of a mammalian two-hybrid system that was dependent on the interaction of SrCap and CBP binding domains. We also found that DBP has no effect on transcription mediated by a transcriptional activator that is not related to SrCap, indicating that our reported transcriptional inhibition is specific for SrCap and not due to nonspecific effects of DBP's DNA binding activity on the CAT reporter plasmid. Taken together, these results suggest a model in which DBP inhibits cellular transcription mediated by the interaction between SrCap and CBP

  11. The role of factor inhibiting HIF (FIH-1 in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Enfeng Wang

    Full Text Available Glioblastoma multiforme (GBM accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1, which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis.

  12. Dasatinib inhibits both osteoclast activation and prostate cancer PC-3 cell-induced osteoclast formation

    Science.gov (United States)

    Araujo, John C.; Poblenz, Ann; Corn, Paul G.; Parikh, Nila U.; Starbuck, Michael W.; Thompson, Jerry T.; Lee, Francis; Logothetis, Christopher J.; Darnay, Bryant G.

    2013-01-01

    Purpose Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation. Results Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC50 of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release. Experimental design We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases. Conclusion Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases. PMID:19855158

  13. Differential Regulation of Telomerase Reverse Transcriptase Promoter Activation and Protein Degradation by Histone Deacetylase Inhibition.

    Science.gov (United States)

    Qing, Hua; Aono, Jun; Findeisen, Hannes M; Jones, Karrie L; Heywood, Elizabeth B; Bruemmer, Dennis

    2016-06-01

    Telomerase reverse transcriptase (TERT) maintains telomeres and is rate limiting for replicative life span. While most somatic tissues silence TERT transcription resulting in telomere shortening, cells derived from cancer or cardiovascular diseases express TERT and activate telomerase. In the present study, we demonstrate that histone deacetylase (HDAC) inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Finally, we demonstrate that HDAC inhibition decreases TERT expression during vascular remodeling in vivo. These data illustrate a differential regulation of TERT transcription and protein stability by HDAC inhibition and suggest that TERT may constitute an important target for the anti-proliferative efficacy of HDAC inhibitors. © 2015 Wiley Periodicals, Inc.

  14. Inhibition of transcriptional activity of c-JUN by SIRT1

    International Nuclear Information System (INIS)

    Gao Zhanguo; Ye Jianping

    2008-01-01

    c-JUN is a major component of heterodimer transcription factor AP-1 (Activator Protein-1) that activates gene transcription in cell proliferation, inflammation and stress responses. SIRT1 (Sirtuin 1) is a histone deacetylase that controls gene transcription through modification of chromatin structure. However, it is not clear if SIRT1 regulates c-JUN activity in the control of gene transcription. Here, we show that SIRT1 associated with c-JUN in co-immunoprecipitation of whole cell lysate, and inhibited the transcriptional activity of c-JUN in the mammalian two hybridization system. SIRT1 was found in the AP-1 response element in the matrix metalloproteinase-9 (MMP9) promoter DNA leading to inhibition of histone 3 acetylation as shown in a ChIP assay. The SIRT1 signal was reduced by the AP-1 activator PMA, and induced by the SIRT1 activator Resveratrol in the promoter DNA. SIRT1-mediaetd inhibition of AP-1 was demonstrated in the MMP9 gene expression at the gene promoter, mRNA and protein levels. In mouse embryonic fibroblast (MEF) with SIRT1 deficiency (SIRT1 -/- ), mRNA and protein of MMP9 were increased in the basal condition, and the inhibitory activity of Resveratrol was significantly attenuated. Glucose-induced MMP9 expression was also inhibited by SIRT1 in response to Resveratrol. These data consistently suggest that SIRT1 directly inhibits the transcriptional activity of AP-1 by targeting c-JUN

  15. Human renin 5'-flanking DNA to nucleotide-2750.

    Science.gov (United States)

    Smith, D L; Jeyapalan, S; Lang, J A; Guo, X H; Sigmund, C D; Morris, B J

    1995-01-01

    Renin is one of the most important factors in blood pressure and electrolyte regulation in mammals and the renin locus has been implicated in hypertension. To assist studies of promoter control we therefore determined the 5'-flanking sequence of the human gene (REN) to residue -2750 relative to the transcription start site (+1). Sites of homology to consensus sequences for binding of trans-acting factors involved in transcriptional control of other genes were identified, and functionality for two of these (a CRE and Pit-1 site) have so far been demonstrated.

  16. Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling.

    Science.gov (United States)

    Mutoh, Shingo; Sobhany, Mack; Moore, Rick; Perera, Lalith; Pedersen, Lee; Sueyoshi, Tatsuya; Negishi, Masahiko

    2013-05-07

    Phenobarbital is a central nervous system depressant that also indirectly activates nuclear receptor constitutive active androstane receptor (CAR), which promotes drug and energy metabolism, as well as cell growth (and death), in the liver. We found that phenobarbital activated CAR by inhibiting epidermal growth factor receptor (EGFR) signaling. Phenobarbital bound to EGFR and potently inhibited the binding of EGF, which prevented the activation of EGFR. This abrogation of EGFR signaling induced the dephosphorylation of receptor for activated C kinase 1 (RACK1) at Tyr(52), which then promoted the dephosphorylation of CAR at Thr(38) by the catalytic core subunit of protein phosphatase 2A. The findings demonstrated that the phenobarbital-induced mechanism of CAR dephosphorylation and activation is mediated through its direct interaction with and inhibition of EGFR.

  17. The PGE(2)-EP4 receptor is necessary for stimulation of the renin-angiotensin-aldosterone system in response to low dietary salt intake in vivo

    DEFF Research Database (Denmark)

    Pöschke, Antje; Kern, Niklas; Maruyama, Takayuki

    2012-01-01

    , creatinine clearance, and plasma antidiuretic hormone (ADH) concentration. Following salt restriction, plasma renin and aldosterone concentrations and kidney renin mRNA level rose significantly in EP4(+/+) but not in EP4(-/-) and in wild-type mice treated with EP4 antagonist ONO-AE3-208. In the latter two...... groups, the low-salt diet caused a significantly greater rise in PGE(2) excretion. Furthermore, mRNA expression for COX-2 and PGE(2) synthetic activity was significantly greater in EP4(-/-) than in EP4(+/+) mice. We conclude that low dietary salt intake induces expression of COX-2 followed by enhanced...... renal PGE(2) synthesis, which stimulates the renin-angiotensin-aldosterone system by activation of EP4 receptor. Most likely, defects at the step of EP4 receptor block negative feedback mechanisms on the renal COX system, leading to persistently high PGE(2) levels, diuresis, and K(+) loss....

  18. Mercuric ions inhibit mitogen-activated protein kinase dephosphorylation by inducing reactive oxygen species

    International Nuclear Information System (INIS)

    Haase, Hajo; Engelhardt, Gabriela; Hebel, Silke; Rink, Lothar

    2011-01-01

    Mercury intoxication profoundly affects the immune system, in particular, signal transduction of immune cells. However, the mechanism of the interaction of mercury with cellular signaling pathways, such as mitogen activated protein kinases (MAPK), remains elusive. Therefore, the objective of this study is to investigate three potential ways in which Hg 2+ ions could inhibit MAPK dephosphorylation in the human T-cell line Jurkat: (1) by direct binding to phosphatases; (2) by releasing cellular zinc (Zn 2+ ); and (3) by inducing reactive oxygen species (ROS). Hg 2+ causes production of ROS, measured by dihydrorhodamine 123, and triggers ROS-mediated Zn 2+ release, detected with FluoZin-3. Yet, phosphatase-inhibition is not mediated by binding of Zn 2+ or Hg 2+ . Rather, phosphatases are inactivated by at least two forms of thiol oxidation; initial inhibition is reversible with reducing agents such as Tris(2-carboxyethyl)phosphine. Prolonged inhibition leads to non-reversible phosphatase oxidation, presumably oxidizing the cysteine thiol to sulfinic- or sulfonic acid. Notably, phosphatases are a particularly sensitive target for Hg 2+ -induced oxidation, because phosphatase activity is inhibited at concentrations of Hg 2+ that have only minor impact on over all thiol oxidation. This phosphatase inhibition results in augmented, ROS-dependent MAPK phosphorylation. MAPK are important regulators of T-cell function, and MAPK-activation by inhibition of phosphatases seems to be one of the molecular mechanisms by which mercury affects the immune system.

  19. Effect of mitochondrial complex I inhibition on Fe-S cluster protein activity

    Energy Technology Data Exchange (ETDEWEB)

    Mena, Natalia P. [Department of Biology, Faculty of Sciences, Universidad de Chile, Las Palmeras 3425, Santiago (Chile); Millennium Institute of Cell Dynamics and Biotechnology, Santiago (Chile); Bulteau, Anne Laure [UPMC Univ Paris 06, UMRS 975 - UMR 7725, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Hopital de la Salpetriere, F-75005 Paris (France); Inserm, U 975, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Hopital de la Salpetriere, F-75005 Paris (France); CNRS, UMR 7225, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Hopital de la Salpetriere, F-75005 Paris (France); ICM, Therapeutique Experimentale de la Neurodegenerescence, Hopital de la Salpetriere, Paris 75013 (France); Salazar, Julio [Millennium Institute of Cell Dynamics and Biotechnology, Santiago (Chile); Hirsch, Etienne C. [UPMC Univ Paris 06, UMRS 975 - UMR 7725, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Hopital de la Salpetriere, F-75005 Paris (France); Inserm, U 975, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Hopital de la Salpetriere, F-75005 Paris (France); CNRS, UMR 7225, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Hopital de la Salpetriere, F-75005 Paris (France); ICM, Therapeutique Experimentale de la Neurodegenerescence, Hopital de la Salpetriere, Paris 75013 (France); Nunez, Marco T., E-mail: mnunez@uchile.cl [Department of Biology, Faculty of Sciences, Universidad de Chile, Las Palmeras 3425, Santiago (Chile); Millennium Institute of Cell Dynamics and Biotechnology, Santiago (Chile)

    2011-06-03

    Highlights: {yields} Mitochondrial complex I inhibition resulted in decreased activity of Fe-S containing enzymes mitochondrial aconitase and cytoplasmic aconitase and xanthine oxidase. {yields} Complex I inhibition resulted in the loss of Fe-S clusters in cytoplasmic aconitase and of glutamine phosphoribosyl pyrophosphate amidotransferase. {yields} Consistent with loss of cytoplasmic aconitase activity, an increase in iron regulatory protein 1 activity was found. {yields} Complex I inhibition resulted in an increase in the labile cytoplasmic iron pool. -- Abstract: Iron-sulfur (Fe-S) clusters are small inorganic cofactors formed by tetrahedral coordination of iron atoms with sulfur groups. Present in numerous proteins, these clusters are involved in key biological processes such as electron transfer, metabolic and regulatory processes, DNA synthesis and repair and protein structure stabilization. Fe-S clusters are synthesized mainly in the mitochondrion, where they are directly incorporated into mitochondrial Fe-S cluster-containing proteins or exported for cytoplasmic and nuclear cluster-protein assembly. In this study, we tested the hypothesis that inhibition of mitochondrial complex I by rotenone decreases Fe-S cluster synthesis and cluster content and activity of Fe-S cluster-containing enzymes. Inhibition of complex I resulted in decreased activity of three Fe-S cluster-containing enzymes: mitochondrial and cytosolic aconitases and xanthine oxidase. In addition, the Fe-S cluster content of glutamine phosphoribosyl pyrophosphate amidotransferase and mitochondrial aconitase was dramatically decreased. The reduction in cytosolic aconitase activity was associated with an increase in iron regulatory protein (IRP) mRNA binding activity and with an increase in the cytoplasmic labile iron pool. Since IRP activity post-transcriptionally regulates the expression of iron import proteins, Fe-S cluster inhibition may result in a false iron deficiency signal. Given that

  20. Effect of mitochondrial complex I inhibition on Fe-S cluster protein activity

    International Nuclear Information System (INIS)

    Mena, Natalia P.; Bulteau, Anne Laure; Salazar, Julio; Hirsch, Etienne C.; Nunez, Marco T.

    2011-01-01

    Highlights: → Mitochondrial complex I inhibition resulted in decreased activity of Fe-S containing enzymes mitochondrial aconitase and cytoplasmic aconitase and xanthine oxidase. → Complex I inhibition resulted in the loss of Fe-S clusters in cytoplasmic aconitase and of glutamine phosphoribosyl pyrophosphate amidotransferase. → Consistent with loss of cytoplasmic aconitase activity, an increase in iron regulatory protein 1 activity was found. → Complex I inhibition resulted in an increase in the labile cytoplasmic iron pool. -- Abstract: Iron-sulfur (Fe-S) clusters are small inorganic cofactors formed by tetrahedral coordination of iron atoms with sulfur groups. Present in numerous proteins, these clusters are involved in key biological processes such as electron transfer, metabolic and regulatory processes, DNA synthesis and repair and protein structure stabilization. Fe-S clusters are synthesized mainly in the mitochondrion, where they are directly incorporated into mitochondrial Fe-S cluster-containing proteins or exported for cytoplasmic and nuclear cluster-protein assembly. In this study, we tested the hypothesis that inhibition of mitochondrial complex I by rotenone decreases Fe-S cluster synthesis and cluster content and activity of Fe-S cluster-containing enzymes. Inhibition of complex I resulted in decreased activity of three Fe-S cluster-containing enzymes: mitochondrial and cytosolic aconitases and xanthine oxidase. In addition, the Fe-S cluster content of glutamine phosphoribosyl pyrophosphate amidotransferase and mitochondrial aconitase was dramatically decreased. The reduction in cytosolic aconitase activity was associated with an increase in iron regulatory protein (IRP) mRNA binding activity and with an increase in the cytoplasmic labile iron pool. Since IRP activity post-transcriptionally regulates the expression of iron import proteins, Fe-S cluster inhibition may result in a false iron deficiency signal. Given that inhibition of complex

  1. NAC selectively inhibit cancer telomerase activity: A higher redox homeostasis threshold exists in cancer cells

    Directory of Open Access Journals (Sweden)

    Pengying Li

    2016-08-01

    Full Text Available Telomerase activity controls telomere length, and this plays an important role in stem cells, aging and tumors. Antioxidant was shown to protect telomerase activity in normal cells but inhibit that in cancer cells, but the underlying mechanism is elusive. Here we found that 7721 hepatoma cells held a higher redox homeostasis threshold than L02 normal liver cells which caused 7721 cells to have a higher demand for ROS; MnSOD over-expression in 7721 decreased endogenous reactive oxygen species (ROS and inhibited telomerase activity; Akt phosphorylation inhibitor and NAC both inhibited 7721 telomerase activity. The over-elimination of ROS by NAC resulted in the inhibition of Akt pathway. Our results suggest that ROS is involved in the regulation of cancer telomerase activity through Akt pathway. The different intracellular redox homeostasis and antioxidant system in normal cells and tumor cells may be the cause of the opposite effect on telomerase activity in response to NAC treatment. Our results provide a theoretical base of using antioxidants selectively inhibit cancer telomerase activity. Findings of the present study may provide insights into novel approaches for cancer treatment.

  2. (Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy.

    Science.gov (United States)

    Kanda, Atsuhiro; Ishida, Susumu

    2018-03-25

    The renin-angiotensin system (RAS), a crucial regulator of systemic blood pressure (circulatory RAS), plays distinct roles in pathological angiogenesis and inflammation in various organs (tissue RAS), such as diabetic microvascular complications. Using ocular clinical samples and animal disease models, we elucidated molecular mechanisms in which tissue RAS excites the expression of vascular endothelial growth factor (VEGF)-A responsible for retinal inflammation and angiogenesis, the two major pathological events in diabetic retinopathy (DR). Furthermore, we showed the involvement of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction (e.g., extracellular signal-regulated kinase); namely, the (P)RR-induced dual pathogenic bioactivity referred to as the receptor-associated prorenin system. Indeed, neovascular endothelial cells in the fibrovascular tissue collected from eyes with proliferative DR were immunoreactive for the receptor-associated prorenin system components including prorenin, (P)RR, phosphorylated extracellular signal-regulated kinase and VEGF-A. Protein levels of soluble (P)RR increased with its positive correlations with prorenin, renin enzymatic activity and VEGF in the vitreous of proliferative DR eyes, suggesting a close link between (P)RR and VEGF-A-driven angiogenic activity. Furthermore, we revealed an unsuspected, PAPS-independent role of (P)RR in glucose-induced oxidative stress. Recently, we developed an innovative single-strand ribonucleic acid interference molecule selectively targeting human and mouse (P)RR, and confirmed its efficacy in suppressing diabetes-induced retinal inflammation in mice. Our data using clinical samples and animal models suggested the significant implication of (P)RR in the pathogenesis of DR, and the potential usefulness of the ribonucleic acid interference molecule as a therapeutic agent to attenuate ocular inflammation and angiogenesis. © 2018 The Authors

  3. Shaping inhibition: activity dependent structural plasticity of GABAergic synapses

    Directory of Open Access Journals (Sweden)

    Carmen E Flores

    2014-10-01

    Full Text Available Inhibitory transmission through the neurotransmitter Ɣ-aminobutyric acid (GABA shapes network activity in the mammalian cerebral cortex by filtering synaptic incoming information and dictating the activity of principal cells. The incredibly diverse population of cortical neurons that use GABA as neurotransmitter shows an equally diverse range of mechanisms that regulate changes in the strength of GABAergic synaptic transmission and allow them to dynamically follow and command the activity of neuronal ensembles. Similarly to glutamatergic synaptic transmission, activity-dependent functional changes in inhibitory neurotransmission are accompanied by alterations in GABAergic synapse structure that range from morphological reorganization of postsynaptic density to de novo formation and elimination of inhibitory contacts. Here we review several aspects of structural plasticity of inhibitory synapses, including its induction by different forms of neuronal activity, behavioral and sensory experience and the molecular mechanisms and signaling pathways involved. We discuss the functional consequences of GABAergic synapse structural plasticity for information processing and memory formation in view of the heterogenous nature of the structural plasticity phenomena affecting inhibitory synapses impinging on somatic and dendritic compartments of cortical and hippocampal neurons.

  4. RKIP Inhibits Local Breast Cancer Invasion by Antagonizing the Transcriptional Activation of MMP13.

    Directory of Open Access Journals (Sweden)

    Ila Datar

    Full Text Available Raf Kinase Inhibitory Protein or RKIP was initially identified as a Raf-1 binding protein using the yeast 2-hybrid screen. RKIP inhibits the activation phosphorylation of MEK by Raf-1 by competitively inhibiting the binding of MEK to Raf-1 and thus exerting an inhibitory effect on the Raf-MEK-Erk pathway. RKIP has been identified as a metastasis suppressor gene. Expression of RKIP is low in cancer metastases. Although primary tumor growth remains unaffected, re- expression of RKIP inhibits cancer metastasis. Mechanistically, RKIP constrains metastasis by inhibiting angiogenesis, local invasion, intravasation, and colonization. The molecular mechanism of how RKIP inhibits these individual steps remains undefined. In our present study, using an unbiased PCR based screening and by analyzing DNA microarray expression datasets we observe that the expression of multiple metalloproteases (MMPs including MMP1, MMP3, MMP10 and MMP13 are negatively correlated with RKIP expression in breast cancer cell lines and clinical samples. Since expression of MMPs by cancer cells is important for cancer metastasis, we hypothesize that RKIP may mediate suppression of breast cancer metastasis by inhibiting multiple MMPs. We show that the expression signature of RKIP and MMPs is better at predicting high metastatic risk than the individual gene. Using a combination of loss- and gain-of-function approaches, we find that MMP13 is the cause of RKIP-mediated inhibition of local cancer invasion. Interestingly expression of MMP13 alone is not sufficient to reverse the inhibition of breast cancer cell metastasis to the lung due to the expression of RKIP. We find that RKIP negatively regulates MMP13 through the Erk2 signaling pathway and the repression of MMP13 by RKIP is transcription factor AP-1 independent. Together, our findings indicate that RKIP inhibits cancer cell invasion, in part, via MMP13 inhibition. These data also implicate RKIP in the regulation of MMP

  5. Sprouty regulates cell migration by inhibiting the activation of Rac1 GTPase

    International Nuclear Information System (INIS)

    Poppleton, Helen M.; Edwin, Francis; Jaggar, Laura; Ray, Ramesh; Johnson, Leonard R.; Patel, Tarun B.

    2004-01-01

    Sprouty (SPRY) protein negatively modulates fibroblast growth factor and epidermal growth factor actions. We showed that human SPRY2 inhibits cell growth and migration in response to serum and several growth factors. Using rat intestinal epithelial (IEC-6) cells, we investigated the involvement of the Rho family of GTPases, RhoA, Rac1, and cdc42 in SPRY2-mediated inhibition of cell migration and proliferation. The ability of TAT-tagged SPRY2 to inhibit proliferation and migration of IEC-6 cells transfected with constitutively active mutants of RhoA(G14V), Rac1(G12V), and cdc42 (F28L) was determined. Constitutively active RhoA(G14V), Rac1(G12V), or cdc42(F28L) did not protect cells from the anti-proliferative actions of TAT-SPRY2. The ability of TAT-hSPRY2 to inhibit migration was not altered by of RhoA(G14V) and cdc42(F28L). However, Rac1(G12V) obliterated the ability of SPRY2 to inhibit cell autonomous or serum-induced migration. Also, the activation of endogenous Rac1 was attenuated by TAT-SPRY2. Thus, SPRY2 mediates its anti-migratory actions by inhibiting Rac1 activation

  6. Comparable cortical activation with inferior performance in women during a novel cognitive inhibition task.

    Science.gov (United States)

    Halari, R; Kumari, V

    2005-03-07

    Men are hypothesised to perform better than women at tasks requiring cognitive inhibition. The present study applied whole-brain functional magnetic resonance imaging to investigate the neural correlates of cognitive inhibition using a novel task, requiring detection of numbers decreasing in numerical order, in relation to sex. The study involved 19 young healthy subjects (9 men, 10 women). Behavioural sex differences favouring men were found on the inhibition, but not on the automatization (i.e. detection of numbers increasing in numerical order), condition of the task. Significant areas of activation associated with cognitive inhibition included the right inferior prefrontal and bilateral dorsolateral prefrontal cortices, left inferior and superior parietal lobes, and bilateral temporal regions across men and women. No brain region was significantly differently activated in men and women. Our findings demonstrate that (a) cognitive inhibition is dependent on intact processes within frontal and parietal regions, and (b) women show inferior cognitive inhibition despite of comparable activation to men in relevant regions. Equated behavioural performance may elicit sex differences in brain activation.

  7. Inhibition of micturition reflex by activation of somatic afferents in posterior femoral cutaneous nerve.

    Science.gov (United States)

    Tai, Changfeng; Shen, Bing; Mally, Abhijith D; Zhang, Fan; Zhao, Shouguo; Wang, Jicheng; Roppolo, James R; de Groat, William C

    2012-10-01

    This study determined if activation of somatic afferents in posterior femoral cutaneous nerve (PFCN) could modulate the micturition reflex recorded under isovolumetric conditions in α-chloralose anaesthetized cats. PFCN stimulation inhibited reflex bladder activity and significantly (P acid (AA). The optimal frequency for PFCN stimulation-induced bladder inhibition was between 3 and 10 Hz, and a minimal stimulation intensity of half of the threshold for inducing anal twitching was required. Bilateral pudendal nerve transection eliminated PFCN stimulation-induced anal twitching but did not change the stimulation-induced bladder inhibition, excluding the involvement of pudendal afferent or efferent axons in PFCN afferent inhibition.Mechanical or electrical stimulation on the skin surface in the PFCN dermatome also inhibited bladder activity. Prolonged (2 × 30 min) PFCN stimulation induced a post-stimulation inhibition that persists for at least 2 h. This study revealed a new cutaneous-bladder reflex activated by PFCN afferents. Although the mechanisms and physiological functions of this cutaneous-bladder reflex need to be further studied, our data raise the possibility that stimulation of PFCN afferents might be useful clinically for the treatment of overactive bladder symptoms.

  8. Reactive oxygen species inhibit catalytic activity of peptidylarginine deiminase

    DEFF Research Database (Denmark)

    Damgaard, Dres; Bjørn, Mads Emil; Jensen, Peter Østrup

    2017-01-01

    on calcium and reducing conditions. However, reactive oxygen species (ROS) have been shown to induce citrullination of histones in granulocytes. Here we examine the ability of H2O2 and leukocyte-derived ROS to regulate PAD activity using citrullination of fibrinogen as read-out. H2O2 at concentrations above...... from stimulated leukocytes was unaffected by exogenously added H2O2 at concentrations up to 1000 µM. The role of ROS in regulating PAD activity may play an important part in preventing hypercitrullination of proteins....

  9. Inhibition of class IIa histone deacetylase activity by gallic acid, sulforaphane, TMP269, and panobinostat.

    Science.gov (United States)

    Choi, Sin Young; Kee, Hae Jin; Jin, Li; Ryu, Yuhee; Sun, Simei; Kim, Gwi Ran; Jeong, Myung Ho

    2018-05-01

    Histone deacetylase (HDAC) inhibitors are gaining increasing attention as potential therapeutics for cardiovascular diseases as well as cancer. We recently reported that the class II HDAC inhibitor, MC1568, and the phytochemical, gallic acid, lowered high blood pressure in mouse models of hypertension. We hypothesized that class II HDACs may be involved in the regulation of hypertension. The aim of this study was to determine and compare the effects of well-known HDAC inhibitors (TMP269, panobinostat, and MC1568), phytochemicals (gallic acid, sulforaphane, and piceatannol), and anti-hypertensive drugs (losartan, carvedilol, and furosemide) on activities of class IIa HDACs (HDAC4, 5, 7, and 9). The selective class IIa HDAC inhibitor, TMP269, and the pan-HDAC inhibitor, panobinostat, but not MC1568, clearly inhibited class IIa HDAC activities. Among the three phytochemicals, gallic acid showed remarkable inhibition, whereas sulforaphane presented mild inhibition of class IIa HDACs. Piceatannol inhibited only HDAC7 activity. As expected, the anti-hypertensive drugs losartan, carvedilol, and furosemide did not affect the activity of any class IIa HDAC. In addition, we evaluated the inhibitory effect of several compounds on the activity of class l HDACs (HDAC1, 2, 3, and 8) and class IIb HDAC (HDAC6). MC1568 did not affect the activities of HDAC1, HDAC2, and HDAC3, but it reduced the activity of HDAC8 at concentrations of 1 and 10 μM. Gallic acid weakly inhibited HDAC1 and HDAC6 activities, but strongly inhibited HDAC8 activity with effectiveness comparable to that of trichostatin A. Inhibition of HDAC2 activity by sulforaphane was stronger than that by piceatnnaol. These results indicated that gallic acid is a powerful dietary inhibitor of HDAC8 and class IIa/b HDAC activities. Sulforaphane may also be used as a dietary inhibitor of HDAC2 and class IIa HDAC. Our findings suggest that the class II HDAC inhibitor, MC1568, does not inhibit class IIa HDAC, but inhibits

  10. Inhibition of parathyroid hormone release by maitotoxin, a calcium channel activator

    International Nuclear Information System (INIS)

    Fitzpatrick, L.A.; Yasumoto, T.; Aurbach, G.D.

    1989-01-01

    Maitotoxin, a toxin derived from a marine dinoflagellate, is a potent activator of voltage-sensitive calcium channels. To further test the hypothesis that inhibition of PTH secretion by calcium is mediated via a calcium channel we studied the effect of maitotoxin on dispersed bovine parathyroid cells. Maitotoxin inhibited PTH release in a dose-dependent fashion, and inhibition was maximal at 1 ng/ml. Chelation of extracellular calcium by EGTA blocked the inhibition of PTH by maitotoxin. Maitotoxin enhanced the effects of the dihydropyridine calcium channel agonist (+)202-791 and increased the rate of radiocalcium uptake in parathyroid cells. Pertussis toxin, which ADP-ribosylates and inactivates a guanine nucleotide regulatory protein that interacts with calcium channels in the parathyroid cell, did not affect the inhibition of PTH secretion by maitotoxin. Maitotoxin, by its action on calcium channels allows entry of extracellular calcium and inhibits PTH release. Our results suggest that calcium channels are involved in the release of PTH. Inhibition of PTH release by maitotoxin is not sensitive to pertussis toxin, suggesting that maitotoxin may act distal to the site interacting with a guanine nucleotide regulatory protein, or maitotoxin could interact with other ions or second messengers to inhibit PTH release

  11. Renin angiotensin system and gender differences in dopaminergic degeneration

    Directory of Open Access Journals (Sweden)

    Rodriguez-Perez Ana I

    2011-08-01

    Full Text Available Abstract Background There are sex differences in dopaminergic degeneration. Men are approximately two times as likely as premenopausal women of the same age to develop Parkinson's disease (PD. It has been shown that the local renin angiotensin system (RAS plays a prominent role in sex differences in the development of chronic renal and cardiovascular diseases, and there is a local RAS in the substantia nigra and dopaminergic cell loss is enhanced by angiotensin via type 1 (AT1 receptors. Results In the present study, we observed that intrastriatal injection of 6-hydroxydopamine induced a marked loss of dopaminergic neurons in the substantia nigra of male rats, which was significantly higher than the loss induced in ovariectomized female rats given estrogen implants (i.e. rats with estrogen. However, the loss of dopaminergic neurons was significantly lower in male rats treated with the AT1 antagonist candesartan, and similar to that observed in female rats with estrogen. The involvement of the RAS in gender differences in dopaminergic degeneration was confirmed with AT1a-null mice lesioned with the dopaminergic neurotoxin MPTP. Significantly higher expression of AT1 receptors, angiotensin converting enzyme activity, and NADPH-oxidase complex activity, and much lower levels of AT2 receptors were observed in male rats than in female rats with estrogen. Conclusions The results suggest that brain RAS plays a major role in the increased risk of developing PD in men, and that manipulation of brain RAS may be an efficient approach for neuroprotective treatment of PD in men, without the feminizing effects of estrogen.

  12. Relative Atrial Natriuretic Peptide Deficiency and Inadequate Renin and Angiotensin II Suppression in Obese Hypertensive Men

    DEFF Research Database (Denmark)

    Asferg, Camilla L; Nielsen, Søren J; Andersen, Ulrik B

    2013-01-01

    Obesity is a strong risk factor for hypertension, but the mechanisms by which obesity leads to hypertension are incompletely understood. On this background, we assessed dietary sodium intake, serum levels of natriuretic peptides (NPs), and the activity of the renin-angiotensin system in 63 obese...... hypertensive men (obeseHT: body mass index, ≥30.0 kg/m(2); 24-hour ambulatory blood pressure, ≥130/80 mm Hg), in 40 obese normotensive men (obeseNT: body mass index, ≥30.0 kg/m(2); 24-hour ambulatory blood pressure,...

  13. Dexamethasone-responsive hypertension in young women with suppressed renin and aldosterone

    International Nuclear Information System (INIS)

    Hoefnagels, W.H.L.; Hofman, J.A.; Smals, A.G.H.; Drayer, J.I.M.; Kloppenborg, P.W.C.; Benraad, T.J.

    1978-01-01

    Pronounced hypoaldosteronism was found in three young women with hypertension and symptoms of mineralocorticoid overproduction - i.e., hyporeninaemia, hypokalaemia, and a fall in blood-pressure after diuretic therapy. Plasma 11-deoxycorticosterone and 18-hydroxy-11-deoxycorticosterone concentrations were normal. Treatment with dexamethasone induced a return to normal of blood-pressure and plasma-potassium and an increase in plasma-renin activity and urinary aldosterone excretion. The data suggest that hypertension in these patients is maintained by overproduction of an unknown adrenocorticotropin-dependent mineralocortocoid. (author)

  14. CYTOTOXIC, α-CHYMOTRYPSIN AND UREASE INHIBITION ACTIVITIES OF THE PLANT Heliotropium dasycarpum L.

    Science.gov (United States)

    Ghaffari, Muhammad Abuzar; Chaudhary, Bashir Ahmed; Uzair, Muhammad; Ashfaq, Khuram

    2016-01-01

    The aim of this study was to investigate Cytotoxic, α-Chymotrypsin and Urease inhibition activities of the plant Heliotropium dasycarpum . Dichloromethane and methanol extracts of the plant were evaluated for cytotoxic, α-Chymotrypsin and Urease inhibition by using in vivo Brine Shrimp lethality bioassay and in vitro enzymatic inhibition assays respectively. The methanol extract of the plant exhibited significant cytotoxic activity. Out of 30 brine shrimp larvae, 2 (6%), 26 (86%) and 28 (93%) larvae were survived at concentration of 1000μg/ml, 100μg/ml and 10μg/ml respectively with LD50; 215.837. Similarly 21 (70%), 25 (83%), 29 (96%) larvae were survived of dichloromethane plant extract with LD50; 6170.64. The methanol and dichloromethane extract exhibited 10.50±0.18% and 41.51±0.15% α-chymotrypsin enzyme inhibition respectively with IC 50 values of greater than 500 μmol. The methanol extract showed 24.39±0.21% Urease enzyme inhibition with IC 50 values of greater than 400 μmol While dichloromethane extract has 11.46±0.09% enzyme inhibition with IC 50 values of greater than 500 μmol. The results clearly indicated that Heliotropium dasycarpum has cytotoxic potential and enzyme inhibition properties. Further study is needed to screen out antitumor and anti-ulcerative agents.

  15. Characterization and Antioxidant Properties of Six Algerian Propolis Extracts: Ethyl Acetate Extracts Inhibit Myeloperoxidase Activity

    Directory of Open Access Journals (Sweden)

    Yasmina Mokhtaria Boufadi

    2014-02-01

    Full Text Available Because propolis contains many types of antioxidant compounds such as polyphenols and flavonoids, it can be useful in preventing oxidative damages. Ethyl acetate extracts of propolis from several Algerian regions show high activity by scavenging free radicals, preventing lipid peroxidation and inhibiting myeloperoxidase (MPO. By fractioning and assaying ethyl acetate extracts, it was observed that both polyphenols and flavonoids contribute to these activities. A correlation was observed between the polyphenol content and the MPO inhibition. However, it seems that kaempferol, a flavonoid, contributes mainly to the MPO inhibition. This molecule is in a high amount in the ethyl acetate extract and demonstrates the best efficiency towards the enzyme with an inhibiting concentration at 50% of 4 ± 2 µM.

  16. Disposition, Metabolism and Histone Deacetylase and Acetyltransferase Inhibition Activity of Tetrahydrocurcumin and Other Curcuminoids

    Directory of Open Access Journals (Sweden)

    Júlia T. Novaes

    2017-10-01

    Full Text Available Tetrahydrocurcumin (THC, curcumin and calebin-A are curcuminoids found in turmeric (Curcuma longa. Curcuminoids have been established to have a variety of pharmacological activities and are used as natural health supplements. The purpose of this study was to identify the metabolism, excretion, antioxidant, anti-inflammatory and anticancer properties of these curcuminoids and to determine disposition of THC in rats after oral administration. We developed a UHPLC–MS/MS assay for THC in rat serum and urine. THC shows multiple redistribution phases with corresponding increases in urinary excretion rate. In-vitro antioxidant activity, histone deacetylase (HDAC activity, histone acetyltransferase (HAT activity and anti-inflammatory inhibitory activity were examined using commercial assay kits. Anticancer activity was determined in Sup-T1 lymphoma cells. Our results indicate THC was poorly absorbed after oral administration and primarily excreted via non-renal routes. All curcuminoids exhibited multiple pharmacological effects in vitro, including potent antioxidant activity as well as inhibition of CYP2C9, CYP3A4 and lipoxygenase activity without affecting the release of TNF-α. Unlike curcumin and calebin-A, THC did not inhibit HDAC1 and PCAF and displayed a weaker growth inhibition activity against Sup-T1 cells. We show evidence for the first time that curcumin and calebin-A inhibit HAT and PCAF, possibly through a Michael-addition mechanism.

  17. Investigating the association of vitamin D with blood pressure and the renin-angiotensin-aldosterone system in hypertensive subjects: a cross-sectional prospective study.

    Science.gov (United States)

    Cremer, Antoine; Tambosco, Chloé; Corcuff, Jean-Benoît; Boulestreau, Romain; Gaillard, Prune; Lainé, Marion; Papaioannou, Georgios; Gosse, Philippe

    2018-02-01

    The hypothesis that vitamin D (25(OH)D) insufficiency plays a role in occurring of various disease has led to a rise in requests of dosages and to an increase of health-care costs. 25(OH)D insufficiency is associated with increased risk of cardiovascular disease and hypertension in many studies. Animal studies demonstrated that 25(OH)D insufficiency activates renin angiotensin system but corresponding humans data are limited. The aim of the study was to document relationship between 25(OH)D, blood pressure, and renin angiotensin system in hypertensive subjects. In all, 248 hypertensive individuals, 46.8 years (±14), were hospitalized for an etiological assessment of hypertension in this cross-sectional study over two calendar years. 25(OH)D, plasma renin activity, and aldosterone were determined in stringent conditions and blood pressure was measure. Statistical analyses were carried out to analyze the association between 25(OH)D, blood pressure, and renin angiotensin system using linear and logistic regressions with adjustments on relevant variables. In all, 80% of the studied population had a 25(OH)D insufficiency. There were no significant association between 25(OH)D and levels of systolic or diastolic blood pressure, plasma renin activity, and aldosterone whatever the statiscal method used after adjustment. 25(OH)D is not associated with blood pressure and renin angiontensin component in hypertensive subjects. These results corroborate the interventional studies which are for a large majority negatives. A new definition of the 25(OH)D insufficiency in general population is necessary.

  18. Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation

    OpenAIRE

    Wang, Gene-Jack; Volkow, Nora D.; Telang, Frank; Jayne, Millard; Ma, Yeming; Pradhan, Kith; Zhu, Wei; Wong, Christopher T.; Thanos, Panayotis K.; Geliebter, Allan; Biegon, Anat; Fowler, Joanna S.

    2009-01-01

    Although impaired inhibitory control is linked to a broad spectrum of health problems, including obesity, the brain mechanism(s) underlying voluntary control of hunger are not well understood. We assessed the brain circuits involved in voluntary inhibition of hunger during food stimulation in 23 fasted men and women using PET and 2-deoxy-2[18F]fluoro-D-glucose (18FDG). In men, but not in women, food stimulation with inhibition significantly decreased activation in amygdala, hippocampus, insul...

  19. Inhibition by AA861 of prostaglandin E2 production by activated peritoneal macrophages of rat

    Energy Technology Data Exchange (ETDEWEB)

    Ohuchi, K; Watanabe, M; Taniguchi, J; Tsurufuji, S; Levine, L

    1983-10-01

    Prostaglandin E2 production by rat peritoneal activated macrophages was inhibited by AA861 which had been reported as a selective inhibitor of 5-lipoxygenase from guinea pig peritoneal leukocytes. At a dose of 3.06 microM, prostaglandin E2 production was decreased to 27% of control. No inhibition of the release of (3H)arachidonic acid from the prelabeled macrophages was observed at the dose.

  20. Inhibition by nucleosides of glucose-transport activity in human erythrocytes.

    OpenAIRE

    Jarvis, S M

    1988-01-01

    The interaction of nucleosides with the glucose carrier of human erythrocytes was examined by studying the effect of nucleosides on reversible cytochalasin B-binding activity and glucose transport. Adenosine, inosine and thymidine were more potent inhibitors of cytochalasin B binding to human erythrocyte membranes than was D-glucose [IC50 (concentration causing 50% inhibition) values of 10, 24, 28 and 38 mM respectively]. Moreover, low concentrations of thymidine and adenosine inhibited D-glu...

  1. Activation of protein kinase C inhibits synthesis and release of decidual prolactin

    International Nuclear Information System (INIS)

    Harman, I.; Costello, A.; Ganong, B.; Bell, R.M.; Handwerger, S.

    1986-01-01

    Activation of calcium-activated, phospholipid-dependent protein kinase C by diacylglycerol and phorbol esters has been shown to mediate release of hormones in many systems. To determine whether protein kinase C activation is also involved in the regulation of prolactin release from human decidual, the authors have examined the effects of various acylglycerols and phorbol esters on the synthesis and release of prolactin from cultured human decidual cells. sn-1,2-Dioctanolyglycerol (diC 8 ), which is known to stimulate protein kinase C in other systems, inhibited prolactin release in a dose-dependent manner with maximal inhibition of 53.1% at 100 μM. Diolein (100 μM), which also stimulates protein kinase C activity in some systems, inhibited prolactin release by 21.3%. Phorbol 12-myristate 13-acetate (PMA), phorbol 12,13-didecanoate, and 4β-phorbol 12,13-dibutyrate, which activate protein kinase C in other systems, also inhibited the release of prolactin, which the protein kinase C inactivate 4α-phorbol-12,13-didecanoate was without effect. The inhibition of prolactin release was secondary to a decrease in prolactin synthesis. Although diC 8 and PMA inhibited the synthesis and release of prolactin, these agents had no effect on the synthesis or release of trichloroacetic acid-precipitable [ 35 S]methionine-labeled decidual proteins and did not cause the release of the cytosolic enzymes lactic dehydrogenase and alkaline phosphatase. DiC 8 and PMA stimulates the specific activity of protein kinase C in decidual tissue by 14.6 and 14.0-fold, respectively. The inhibition of the synthesis and release of prolactin by diC 8 and phorbol esters strongly implicates protein kinase C in the regulation of the production and release of prolactin from the decidua

  2. Inhibition of Pectin Methyl Esterase Activity By Green Tea Catechins

    OpenAIRE

    Sagi, Irit; Lewis, Kristin; Tworowski, Dmitry; Shahar, Chen; Selzer, Tzvia

    2008-01-01

    Pectin methyl esterases (PMEs) and their endogenous inhibitors are involved in the regulation of many processes in plant physiology, ranging from tissue growth and fruit ripening to parasitic plant haustorial formation and host invasion. Thus, control of PME activity is critical for enhancing our understanding of plant physiological processes and regulation. Here we report on the identification of epigallocatechin gallate (EGCG), a green tea component, as a natural inhibitor for pectin ...

  3. BLM and RMI1 alleviate RPA inhibition of TopoIIIα decatenase activity.

    Science.gov (United States)

    Yang, Jay; Bachrati, Csanad Z; Hickson, Ian D; Brown, Grant W

    2012-01-01

    RPA is a single-stranded DNA binding protein that physically associates with the BLM complex. RPA stimulates BLM helicase activity as well as the double Holliday junction dissolution activity of the BLM-topoisomerase IIIα complex. We investigated the effect of RPA on the ssDNA decatenase activity of topoisomerase IIIα. We found that RPA and other ssDNA binding proteins inhibit decatenation by topoisomerase IIIα. Complex formation between BLM, TopoIIIα, and RMI1 ablates inhibition of decatenation by ssDNA binding proteins. Together, these data indicate that inhibition by RPA does not involve species-specific interactions between RPA and BLM-TopoIIIα-RMI1, which contrasts with RPA modulation of double Holliday junction dissolution. We propose that topoisomerase IIIα and RPA compete to bind to single-stranded regions of catenanes. Interactions with BLM and RMI1 enhance toposiomerase IIIα activity, promoting decatenation in the presence of RPA.

  4. BLM and RMI1 Alleviate RPA Inhibition of TopoIIIa Decatenase Activity

    DEFF Research Database (Denmark)

    Yang, Jay; Bachrati, Csanad Z; Hickson, Ian D

    2012-01-01

    RPA is a single-stranded DNA binding protein that physically associates with the BLM complex. RPA stimulates BLM helicase activity as well as the double Holliday junction dissolution activity of the BLM-topoisomerase IIIa complex. We investigated the effect of RPA on the ssDNA decatenase activity...... of topoisomerase IIIa. We found that RPA and other ssDNA binding proteins inhibit decatenation by topoisomerase IIIa. Complex formation between BLM, TopoIIIa, and RMI1 ablates inhibition of decatenation by ssDNA binding proteins. Together, these data indicate that inhibition by RPA does not involve species......-specific interactions between RPA and BLM-TopoIIIa-RMI1, which contrasts with RPA modulation of double Holliday junction dissolution. We propose that topoisomerase IIIa and RPA compete to bind to single-stranded regions of catenanes. Interactions with BLM and RMI1 enhance toposiomerase IIIa activity, promoting...

  5. Renin secretion and total body sodium: Pathways of integrative control

    DEFF Research Database (Denmark)

    Bie, Peter; Damkjaer, Mads

    2009-01-01

    to a spring/shock absorber set-up: Non-adaptive RAAS functions determine the new steady state position while TGF controls the rate of change. Recruitment of renin-secreting cells during sustained stimulation may be essential for chronic adaptation, although details of this afferent arteriolar cell plasticity...

  6. Osmotically sensitive renin release from permeabilized juxtaglomerular cells

    DEFF Research Database (Denmark)

    Jensen, B L; Skøtt, O

    1993-01-01

    Renin secretion from juxtaglomerular (JG) cells is sensitive to external osmolality in a way that has been suggested to depend either on cellular volume or on effects on secretory granules. To distinguish between these possibilities, a technique for permeabilization of JG cell membranes was devel...

  7. Direct demonstration of macula densa-mediated renin secretion

    DEFF Research Database (Denmark)

    Skøtt, O; Briggs, J P

    1987-01-01

    An in vitro method has been used to examine whether secretion of renin from the juxtaglomerular apparatus is affected by changes in the sodium chloride concentration of the tubular fluid at the macula densa. Single juxtaglomerular apparatuses were microdissected from rabbits and the tubule segmen...

  8. Effect of Dual Blockade of Renin-Angiotensin Aldosterone System ...

    African Journals Online (AJOL)

    Methods: Patients with diabetes of > 5 years duration, proteinuria at a ... nephropathy, Azotemia, Proteinuria, Aldosterone, Renin, Blood pressure ... Hypertension is a risk factor that exacerbates all ... Arterial tension values of the patients were measured with an. ERKA sleeve .... receiving treatment remained within normal.

  9. Platycodin D inhibits tumor growth by antiangiogenic activity via blocking VEGFR2-mediated signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Luan, Xin; Gao, Yun-Ge; Guan, Ying-Yun; Xu, Jian-Rong; Lu, Qin [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Zhao, Mei [Department of Pharmacy, Shanghai Institute of Health Sciences and Health School Attached to SJTU-SM, 279 Zhouzhu Road, Shanghai 201318 (China); Liu, Ya-Rong; Liu, Hai-Jun [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Fang, Chao, E-mail: fangchao100@hotmail.com [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Chen, Hong-Zhuan, E-mail: hongzhuan_chen@hotmail.com [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China)

    2014-11-15

    Platycodin D (PD) is an active component mainly isolated from the root of Platycodon grandiflorum. Recent studies proved that PD exhibited inhibitory effect on proliferation, migration, invasion and xenograft growth of diverse cancer cell lines. However, whether PD is suppressive for angiogenesis, an important hallmark in cancer development, remains unknown. Here, we found that PD could dose-dependently inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration and tube formation. PD also significantly inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM). Moreover, the antiangiogenic activity of PD contributed to its in vivo anticancer potency shown in the decreased microvessel density and delayed growth of HCT-15 xenograft in mice with no overt toxicity. Western blot analysis indicated that PD inhibited the phosphorylation of VEGFR2 and its downstream protein kinase including PLCγ1, JAK2, FAK, Src, and Akt in endothelial cells. Molecular docking simulation showed that PD formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic activity and the underlying molecular basis of PD, suggesting that PD may be a potential antiangiogenic agent for angiogenesis-related diseases. - Highlights: • Platycodin D inhibits HUVEC proliferation, motility, migration and tube formation. • Platycodin D inhibits the angiogenesis in chick embryo chorioallantoic membrane. • Platycodin D suppresses the angiogenesis and growth of HCT-15 xenograft in mice. • Platycodin D inhibits the phosphorylation of VEGFR2 and downstream kinases in HUVEC.

  10. Platycodin D inhibits tumor growth by antiangiogenic activity via blocking VEGFR2-mediated signaling pathway

    International Nuclear Information System (INIS)

    Luan, Xin; Gao, Yun-Ge; Guan, Ying-Yun; Xu, Jian-Rong; Lu, Qin; Zhao, Mei; Liu, Ya-Rong; Liu, Hai-Jun; Fang, Chao; Chen, Hong-Zhuan

    2014-01-01

    Platycodin D (PD) is an active component mainly isolated from the root of Platycodon grandiflorum. Recent studies proved that PD exhibited inhibitory effect on proliferation, migration, invasion and xenograft growth of diverse cancer cell lines. However, whether PD is suppressive for angiogenesis, an important hallmark in cancer development, remains unknown. Here, we found that PD could dose-dependently inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration and tube formation. PD also significantly inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM). Moreover, the antiangiogenic activity of PD contributed to its in vivo anticancer potency shown in the decreased microvessel density and delayed growth of HCT-15 xenograft in mice with no overt toxicity. Western blot analysis indicated that PD inhibited the phosphorylation of VEGFR2 and its downstream protein kinase including PLCγ1, JAK2, FAK, Src, and Akt in endothelial cells. Molecular docking simulation showed that PD formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic activity and the underlying molecular basis of PD, suggesting that PD may be a potential antiangiogenic agent for angiogenesis-related diseases. - Highlights: • Platycodin D inhibits HUVEC proliferation, motility, migration and tube formation. • Platycodin D inhibits the angiogenesis in chick embryo chorioallantoic membrane. • Platycodin D suppresses the angiogenesis and growth of HCT-15 xenograft in mice. • Platycodin D inhibits the phosphorylation of VEGFR2 and downstream kinases in HUVEC

  11. Salinity Inhibits Rice Seed Germination by Reducing α-Amylase Activity via Decreased Bioactive Gibberellin Content

    Directory of Open Access Journals (Sweden)

    Li Liu

    2018-03-01

    Full Text Available Seed germination plays important roles in the establishment of seedlings and their subsequent growth; however, seed germination is inhibited by salinity, and the inhibitory mechanism remains elusive. Our results indicate that NaCl treatment inhibits rice seed germination by decreasing the contents of bioactive gibberellins (GAs, such as GA1 and GA4, and that this inhibition can be rescued by exogenous bioactive GA application. To explore the mechanism of bioactive GA deficiency, the effect of NaCl on GA metabolic gene expression was investigated, revealing that expression of both GA biosynthetic genes and GA-inactivated genes was up-regulated by NaCl treatment. These results suggest that NaCl-induced bioactive GA deficiency is caused by up-regulated expression of GA-inactivated genes, and the up-regulated expression of GA biosynthetic genes might be a consequence of negative feedback regulation of the bioactive GA deficiency. Moreover, we provide evidence that NaCl-induced bioactive GA deficiency inhibits rice seed germination by decreasing α-amylase activity via down-regulation of α-amylase gene expression. Additionally, exogenous bioactive GA rescues NaCl-inhibited seed germination by enhancing α-amylase activity. Thus, NaCl treatment reduces bioactive GA content through promotion of bioactive GA inactivation, which in turn inhibits rice seed germination by decreasing α-amylase activity via down-regulation of α-amylase gene expression.

  12. δ-Tocopherol inhibits receptor tyrosine kinase-induced AKT activation in prostate cancer cells.

    Science.gov (United States)

    Wang, Hong; Hong, Jungil; Yang, Chung S

    2016-11-01

    The cancer preventive activity of vitamin E is suggested by epidemiological studies and supported by animal studies with vitamin E forms, γ-tocopherol and δ-tocopherol (δ-T). Several recent large-scale cancer prevention trials with high dose of α-tocopherol, however, yielded disappointing results. Whether vitamin E prevents or promotes cancer is a serious concern. A better understanding of the molecular mechanisms of action of the different forms of tocopherols would enhance our understanding of this topic. In this study, we demonstrated that δ-T was the most effective tocopherol form in inhibiting prostate cancer cell growth, by inducing cell cycle arrest and apoptosis. By profiling the effects of δ-T on the cell signaling using the phospho-kinase array, we found that the most inhibited target was the phosphorylation of AKT on T308. Further study on the activation of AKT by EGFR and IGFR revealed that δ-T attenuated the EGF/IGF-induced activation of AKT (via the phosphorylation of AKT on T308 induced by the activation of PIK3). Expression of dominant active PIK3 and AKT in prostate cancer cell line DU145 in which PIK3, AKT, and PTEN are wild type caused the cells to be reflectory to the inhibition of δ-T, supporting that δ-T inhibits the PIK3-mediated activation of AKT. Our data also suggest that δ-T interferes with the EGF-induced EGFR internalization, which leads to the inhibition of the receptor tyrosine kinase-dependent activation of AKT. In summary, our results revealed a novel mechanism of δ-T in inhibiting prostate cancer cell growth, supporting the cancer preventive activity δ-T. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  13. ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo.

    Science.gov (United States)

    Yin, Gang; Fan, Jin; Zhou, Wei; Ding, Qingfeng; Zhang, Jun; Wu, Xuan; Tang, Pengyu; Zhou, Hao; Wan, Bowen; Yin, Guoyong

    2017-10-10

    mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415. ERK inhibition (by MEK162/U0126) or knockdown (by targeted ERK1/2 shRNAs) dramatically sensitized CZ415-induced osteosarcoma cell apoptosis. In vivo , CZ415 oral administration efficiently inhibited U2OS tumor growth in mice. Its activity was further potentiated with co-administration of MEK162. Collectively, we demonstrate that ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo . CZ415 could be further tested as a promising anti-osteosarcoma agent, alone or in combination of ERK inhibition.

  14. Dimerization inhibits the activity of receptor-like protein-tyrosine phosphatase-alpha

    DEFF Research Database (Denmark)

    Jiang, G; den Hertog, J; Su, J

    1999-01-01

    that dimerization can negatively regulate activity, through the interaction of an inhibitory 'wedge' on one monomer with the catalytic cleft of domain 1 in the other monomer. Here we show that dimerization inhibits the activity of a full-length RPTP in vivo. We generated stable disulphide-bonded full...

  15. Oral glucose intake inhibits hypothalamic neuronal activity more effectively than glucose infusion

    NARCIS (Netherlands)

    Smeets, P.A.M.; Vidarsdottir, S.; Graaf, de C.; Stafleu, A.; Osch, M.J.P.; Viergever, M.A.; Pijl, H.; Grond, van der J.

    2007-01-01

    Oral glucose intake inhibits hypothalamic neuronal activity more effectively than glucose infusion. Am J Physiol Endocrinol Metab 293: E754-E758, 2007. First published June 12, 2007; doi:10.1152/ajpendo.00231.2007. - We previously showed that hypothalamic neuronal activity, as measured by the blood

  16. Impairment of GABA transporter GAT-1 terminates cortical recurrent network activity via enhanced phasic inhibition

    Directory of Open Access Journals (Sweden)

    Daniel Simon Razik

    2013-09-01

    Full Text Available In the central nervous system, GABA transporters (GATs very efficiently clear synaptically released GABA from the extracellular space, and thus exert a tight control on GABAergic inhibition. In neocortex, GABAergic inhibition is heavily recruited during recurrent phases of spontaneous action potential activity which alternate with neuronally quiet periods. Therefore, such activity should be quite sensitive to minute alterations of GAT function. Here, we explored the effects of a gradual impairment of GAT-1 and GAT-2/3 on spontaneous recurrent network activity – termed network bursts and silent periods – in organotypic slice cultures of rat neocortex. The GAT-1 specific antagonist NO-711 depressed activity already at nanomolar concentrations (IC50 for depression of spontaneous multiunit firing rate of 42 nM, reaching a level of 80% at 500-1000 nM. By contrast, the GAT-2/3 preferring antagonist SNAP-5114 had weaker and less consistent effects. Several lines of evidence pointed towards an enhancement of phasic GABAergic inhibition as the dominant activity-depressing mechanism: network bursts were drastically shortened, phasic GABAergic currents decayed slower, and neuronal excitability during ongoing activity was diminished. In silent periods, NO-711 had little effect on neuronal excitability or membrane resistance, quite in contrast to the effects of muscimol, a GABA mimetic which activates GABAA receptors tonically. Our results suggest that an enhancement of phasic GABAergic inhibition efficiently curtails cortical recurrent activity and may mediate antiepileptic effects of therapeutically relevant concentrations of GAT-1 antagonists.

  17. [Changes in the renin-angiotensin-aldosterone system and water-salt exchange in mining workers in coal mines].

    Science.gov (United States)

    Rebrov, B A

    1996-01-01

    Blood and urine content of electrolytes and creatinine was determined in 76 essentially healthy miners before and after work shift, as was activity of plasma renin, blood plasma level of aldosterone and its urinary excretion, with the aid of radioimmunoassay. The greatest activity of the renin-angiotensine-aldosterone system (RAAS) occurred in those individuals engaged in hard physical labour under most harsh conditions of underground workings, this being recordable not only is response to the load but also from the very start. Controls and miners doing jobs of medium-level strenuousness demonstrated changes in the correlations between RAAS and water-salt balance after the work shift as compared with those before the work shift, while in those miners engaged in hard work correlations RAAS-water-salt exchange remained practically the same throughout the study.

  18. Toxoplasma gondii Actively Inhibits Neuronal Function in Chronically Infected Mice

    Science.gov (United States)

    Haroon, Fahad; Händel, Ulrike; Angenstein, Frank; Goldschmidt, Jürgen; Kreutzmann, Peter; Lison, Holger; Fischer, Klaus-Dieter; Scheich, Henning; Wetzel, Wolfram; Schlüter, Dirk; Budinger, Eike

    2012-01-01

    Upon infection with the obligate intracellular parasite Toxoplasma gondii, fast replicating tachyzoites infect a broad spectrum of host cells including neurons. Under the pressure of the immune response, tachyzoites convert into slow-replicating bradyzoites, which persist as cysts in neurons. Currently, it is unclear whether T. gondii alters the functional activity of neurons, which may contribute to altered behaviour of T. gondii–infected mice and men. In the present study we demonstrate that upon oral infection with T. gondii cysts, chronically infected BALB/c mice lost over time their natural fear against cat urine which was paralleled by the persistence of the parasite in brain regions affecting behaviour and odor perception. Detailed immunohistochemistry showed that in infected neurons not only parasitic cysts but also the host cell cytoplasm and some axons stained positive for Toxoplasma antigen suggesting that parasitic proteins might directly interfere with neuronal function. In fact, in vitro live cell calcium (Ca2+) imaging studies revealed that tachyzoites actively manipulated Ca2+ signalling upon glutamate stimulation leading either to hyper- or hypo-responsive neurons. Experiments with the endoplasmatic reticulum Ca2+ uptake inhibitor thapsigargin indicate that tachyzoites deplete Ca2+ stores in the endoplasmatic reticulum. Furthermore in vivo studies revealed that the activity-dependent uptake of the potassium analogue thallium was reduced in cyst harbouring neurons indicating their functional impairment. The percentage of non-functional neurons increased over time In conclusion, both bradyzoites and tachyzoites functionally silence infected neurons, which may significantly contribute to the altered behaviour of the host. PMID:22530040

  19. Toxoplasma gondii actively inhibits neuronal function in chronically infected mice.

    Directory of Open Access Journals (Sweden)

    Fahad Haroon

    Full Text Available Upon infection with the obligate intracellular parasite Toxoplasma gondii, fast replicating tachyzoites infect a broad spectrum of host cells including neurons. Under the pressure of the immune response, tachyzoites convert into slow-replicating bradyzoites, which persist as cysts in neurons. Currently, it is unclear whether T. gondii alters the functional activity of neurons, which may contribute to altered behaviour of T. gondii-infected mice and men. In the present study we demonstrate that upon oral infection with T. gondii cysts, chronically infected BALB/c mice lost over time their natural fear against cat urine which was paralleled by the persistence of the parasite in brain regions affecting behaviour and odor perception. Detailed immunohistochemistry showed that in infected neurons not only parasitic cysts but also the host cell cytoplasm and some axons stained positive for Toxoplasma antigen suggesting that parasitic proteins might directly interfere with neuronal function. In fact, in vitro live cell calcium (Ca(2+ imaging studies revealed that tachyzoites actively manipulated Ca(2+ signalling upon glutamate stimulation leading either to hyper- or hypo-responsive neurons. Experiments with the endoplasmatic reticulum Ca(2+ uptake inhibitor thapsigargin indicate that tachyzoites deplete Ca(2+ stores in the endoplasmatic reticulum. Furthermore in vivo studies revealed that the activity-dependent uptake of the potassium analogue thallium was reduced in cyst harbouring neurons indicating their functional impairment. The percentage of non-functional neurons increased over time In conclusion, both bradyzoites and tachyzoites functionally silence infected neurons, which may significantly contribute to the altered behaviour of the host.

  20. General Anesthesia Inhibits the Activity of the "Glymphatic System".

    Science.gov (United States)

    Gakuba, Clement; Gaberel, Thomas; Goursaud, Suzanne; Bourges, Jennifer; Di Palma, Camille; Quenault, Aurélien; de Lizarrondo, Sara Martinez; Vivien, Denis; Gauberti, Maxime

    2018-01-01

    INTRODUCTION: According to the "glymphatic system" hypothesis, brain waste clearance is mediated by a continuous replacement of the interstitial milieu by a bulk flow of cerebrospinal fluid (CSF). Previous reports suggested that this cerebral CSF circulation is only active during general anesthesia or sleep, an effect mediated by the dilatation of the extracellular space. Given the controversies regarding the plausibility of this phenomenon and the limitations of currently available methods to image the glymphatic system, we developed original whole-brain in vivo imaging methods to investigate the effects of general anesthesia on the brain CSF circulation. METHODS: We used magnetic resonance imaging (MRI) and near-infrared fluorescence imaging (NIRF) after injection of a paramagnetic contrast agent or a fluorescent dye in the cisterna magna, in order to investigate the impact of general anesthesia (isoflurane, ketamine or ketamine/xylazine) on the intracranial CSF circulation in mice. RESULTS: In vivo imaging allowed us to image CSF flow in awake and anesthetized mice and confirmed the existence of a brain-wide CSF circulation. Contrary to what was initially thought, we demonstrated that the parenchymal CSF circulation is mainly active during wakefulness and significantly impaired during general anesthesia. This effect was especially significant when high doses of anesthetic agent were used (3% isoflurane). These results were consistent across the different anesthesia regimens and imaging modalities. Moreover, we failed to detect a significant change in the brain extracellular water volume using diffusion weighted imaging in awake and anesthetized mice. CONCLUSION: The parenchymal diffusion of small molecular weight compounds from the CSF is active during wakefulness. General anesthesia has a negative impact on the intracranial CSF circulation, especially when using a high dose of anesthetic agent.

  1. Cocoa Procyanidins Suppress Transformation by Inhibiting Mitogen-activated Protein Kinase Kinase*S⃞

    Science.gov (United States)

    Kang, Nam Joo; Lee, Ki Won; Lee, Dong Eun; Rogozin, Evgeny A.; Bode, Ann M.; Lee, Hyong Joo; Dong, Zigang

    2008-01-01

    Cocoa was shown to inhibit chemically induced carcinogenesis in animals and exert antioxidant activity in humans. However, the molecular mechanisms of the chemopreventive potential of cocoa and its active ingredient(s) remain unknown. Here we report that cocoa procyanidins inhibit neoplastic cell transformation by suppressing the kinase activity of mitogen-activated protein kinase kinase (MEK). A cocoa procyanidin fraction (CPF) and procyanidin B2 at 5 μg/ml and 40 μm, respectively, inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ mouse epidermal (JB6 P+) cells by 47 and 93%, respectively. The TPA-induced promoter activity and expression of cyclooxygenase-2, which is involved in tumor promotion and inflammation, were dose-dependently inhibited by CPF or procyanidin B2. The activation of activator protein-1 and nuclear factor-κB induced by TPA was also attenuated by CPF or procyanidin B2. The TPA-induced phosphorylation of MEK, extracellular signal-regulated kinase, and p90 ribosomal s6 kinase was suppressed by CPF or procyanidin B2. In vitro and ex vivo kinase assay data demonstrated that CPF or procyanidin B2 inhibited the kinase activity of MEK1 and directly bound with MEK1. CPF or procyanidin B2 suppressed JB6 P+ cell transformation induced by epidermal growth factor or H-Ras, both of which are known to be involved in MEK/ERK signal activation. In contrast, theobromine (up to 80 μm) had no effect on TPA-induced transformation, cyclooxygenase-2 expression, the transactivation of activator protein-1 or nuclear factor-κB, or MEK. Notably, procyanidin B2 exerted stronger inhibitory effects compared with PD098059 (a well known pharmacological inhibitor of MEK) on MEK1 activity and neoplastic cell transformation. PMID:18519570

  2. Monoubiquitination Inhibits the Actin Bundling Activity of Fascin.

    Science.gov (United States)

    Lin, Shengchen; Lu, Shuang; Mulaj, Mentor; Fang, Bin; Keeley, Tyler; Wan, Lixin; Hao, Jihui; Muschol, Martin; Sun, Jianwei; Yang, Shengyu

    2016-12-30

    Fascin is an actin bundling protein that cross-links individual actin filaments into straight, compact, and stiff bundles, which are crucial for the formation of filopodia, stereocillia, and other finger-like membrane protrusions. The dysregulation of fascin has been implicated in cancer metastasis, hearing loss, and blindness. Here we identified monoubiquitination as a novel mechanism that regulates fascin bundling activity and dynamics. The monoubiquitination sites were identified to be Lys 247 and Lys 250 , two residues located in a positive charge patch at the actin binding site 2 of fascin. Using a chemical ubiquitination method, we synthesized chemically monoubiquitinated fascin and determined the effects of monoubiquitination on fascin bundling activity and dynamics. Our data demonstrated that monoubiquitination decreased the fascin bundling EC 50 , delayed the initiation of bundle assembly, and accelerated the disassembly of existing bundles. By analyzing the electrostatic properties on the solvent-accessible surface of fascin, we proposed that monoubiquitination introduced steric hindrance to interfere with the interaction between actin filaments and the positively charged patch at actin binding site 2. We also identified Smurf1 as a E3 ligase regulating the monoubiquitination of fascin. Our findings revealed a previously unidentified regulatory mechanism for fascin, which will have important implications for the understanding of actin bundle regulation under physiological and pathological conditions. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Monoubiquitination Inhibits the Actin Bundling Activity of Fascin*

    Science.gov (United States)

    Lin, Shengchen; Lu, Shuang; Mulaj, Mentor; Fang, Bin; Keeley, Tyler; Wan, Lixin; Hao, Jihui; Muschol, Martin; Sun, Jianwei; Yang, Shengyu

    2016-01-01

    Fascin is an actin bundling protein that cross-links individual actin filaments into straight, compact, and stiff bundles, which are crucial for the formation of filopodia, stereocillia, and other finger-like membrane protrusions. The dysregulation of fascin has been implicated in cancer metastasis, hearing loss, and blindness. Here we identified monoubiquitination as a novel mechanism that regulates fascin bundling activity and dynamics. The monoubiquitination sites were identified to be Lys247 and Lys250, two residues located in a positive charge patch at the actin binding site 2 of fascin. Using a chemical ubiquitination method, we synthesized chemically monoubiquitinated fascin and determined the effects of monoubiquitination on fascin bundling activity and dynamics. Our data demonstrated that monoubiquitination decreased the fascin bundling EC50, delayed the initiation of bundle assembly, and accelerated the disassembly of existing bundles. By analyzing the electrostatic properties on the solvent-accessible surface of fascin, we proposed that monoubiquitination introduced steric hindrance to interfere with the interaction between actin filaments and the positively charged patch at actin binding site 2. We also identified Smurf1 as a E3 ligase regulating the monoubiquitination of fascin. Our findings revealed a previously unidentified regulatory mechanism for fascin, which will have important implications for the understanding of actin bundle regulation under physiological and pathological conditions. PMID:27879315

  4. Antimycobacterial and Photosynthetic Electron Transport Inhibiting Activity of Ring-Substituted 4-Arylamino-7-Chloroquinolinium Chlorides

    Directory of Open Access Journals (Sweden)

    Alois Cizek

    2013-09-01

    Full Text Available In this study, a series of twenty-five ring-substituted 4-arylamino-7-chloroquinolinium chlorides were prepared and characterized. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET in spinach (Spinacia oleracea L. chloroplasts and also primary in vitro screening of the synthesized compounds was performed against mycobacterial species. 4-[(2-Bromophenylamino]-7-chloroquinolinium chloride showed high biological activity against M. marinum, M. kansasii, M. smegmatis and 7-chloro-4-[(2-methylphenylamino]quinolinium chloride demonstrated noteworthy biological activity against M. smegmatis and M. avium subsp. paratuberculosis. The most effective compounds demonstrated quite low toxicity (LD50 > 20 μmol/L against the human monocytic leukemia THP-1 cell line within preliminary in vitro cytotoxicity screening. The tested compounds were found to inhibit PET in photosystem II. The PET-inhibiting activity expressed by IC50 value of the most active compound 7-chloro-4-[(3-trifluoromethylphenylamino]quinolinium chloride was 27 μmol/L and PET-inhibiting activity of ortho-substituted compounds was significantly lower than this of meta- and para-substituted ones. The structure-activity relationships are discussed for all compounds.

  5. Genistein inhibited ammonia induced astrocyte swelling by inhibiting NF-κB activation-mediated nitric oxide formation.

    Science.gov (United States)

    Dai, Hongliang; Jia, Guizhi; Wang, Wei; Liang, Chunguang; Han, Siyu; Chu, Minghui; Mei, Xifan

    2017-06-01

    Our previous study has indicated the involvement of epidermal growth factor receptor (EGFR) transactivation in ammonia-induced astrocyte swelling, which represents a major pathogenesis of brain edema in hepatic encephalopathy. In this study, we examined the effect of genistein, a naturally occurred broad-spectrum protein tyrosine kinase (PTK) inhibitor, on ammonia-induced cell swelling. We found that genistein pretreatment significantly prevented ammonia-induced astrocyte swelling. Mechanistically, ammonia triggered EGFR/extracellular signal-regulated kinase (ERK) association and subsequent ERK phosphorylation were alleviated by genistein pretreatment. Moreover, ammonia-induced NF-κB nuclear location, iNOS expression, and consequent NO production were all prevented by AG1478 and genistein pretreatment. This study suggested that genistein could alleviate ammonia-induced astrocyte swelling, which may be, at least partly, related to its PTK-inhibiting activity and repression of NF-κB mediated iNOS-derived NO accumulation.

  6. Triterpenoids from Ganoderma lucidum inhibit the activation of EBV antigens as telomerase inhibitors.

    Science.gov (United States)

    Zheng, Dong-Shu; Chen, Liang-Shu

    2017-10-01

    Nasopharyngeal carcinoma (NPC) is a malignant disease that threatens the health of humans. To find effective agents for the inhibition of Epstein-Barr virus (EBV) infection, which is associated with NPC, a phytochemical investigation of Ganoderma lucidum was carried out in the present study. Five triterpenoids were identified, including ganoderic acid A (compound 1), ganoderic acid B (compound 2), ganoderol B (compound 3), ganodermanontriol (compound 4), and ganodermanondiol (compound 5), on the basis of spectroscopic analysis. An inhibition of EBV antigens activation assay was implemented to elucidate the triterpenoids from G. lucidum and potentially prevent NPC. All the triterpenoids showed significant inhibitory effects on both EBV EA and CA activation at 16 nmol. At 3.2 nmol, all the compounds moderately inhibited the activation of the two antigens. The activity of telomerase was inhibited by these triterpenoids at 10 µM. Molecular docking demonstrated that compound 1 was able to inhibit telomerase as a ligand. In addition, the physicochemical properties of these compounds were calculated to elucidate their drug-like properties. These results provided evidence for the application of these triterpenoids and whole G. lucidum in the treatment of NPC.

  7. Concurrent inhibition of kit- and FcepsilonRI-mediated signaling: coordinated suppression of mast cell activation

    DEFF Research Database (Denmark)

    Jensen, Bettina M; Beaven, Michael A; Iwaki, Shoko

    2008-01-01

    Although primarily required for the growth, differentiation, and survival of mast cells, Kit ligand (stem cell factor) is also required for optimal antigen-mediated mast cell activation. Therefore, concurrent inhibition of Kit- and FcepsilonRI-mediated signaling would be an attractive approach...... characterized Kit inhibitor imatinib mesylate (imatinib). In contrast to imatinib, however, hypothemycin also effectively inhibited FcepsilonRI-mediated degranulation and cytokine production in addition to the potentiation of these responses via Kit. The effect of hypothemycin on Kit-mediated responses could...... be explained by its inhibition of Kit kinase activity, whereas the inhibitory effects on FcepsilonRI-dependent signaling were at the level of Btk activation. Because hypothemycin also significantly reduced the mouse passive cutaneous anaphylaxis response in vivo, these data provide proof of principle...

  8. Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system.

    Science.gov (United States)

    Aachmann-Andersen, Niels J; Christensen, Soren J; Lisbjerg, Kristian; Oturai, Peter; Johansson, Pär I; Holstein-Rathlou, Niels-Henrik; Olsen, Niels V

    2018-03-01

    The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  9. TRANSCRIPTIONAL INHIBITION OF INTERLEUKIN-12 PROMOTER ACTIVITY IN LEISHMANIA SPP.-INFECTED MACROPHAGES

    Science.gov (United States)

    Jayakumar, Asha; Widenmaier, Robyn; Ma, Xiaojing; McDowell, Mary Ann

    2009-01-01

    To establish and persist within a host, Leishmania spp. parasites delay the onset of cell-mediated immunity by suppressing interleukin-12 (IL-12) production from host macrophages. Although it is established that Leishmania spp.-infected macrophages have impaired IL-12 production, the mechanisms that account for this suppression remain to be completely elucidated. Using a luciferase reporter assay assessing IL-12 transcription, we report here that Leishmania major, Leishmania donovani, and Leishmania chagasi inhibit IL-12 transcription in response to interferon-gamma, lipopolysaccharide, and CD40 ligand and that Leishmania spp. lipophosphoglycan, phosphoglycans, and major surface protein are not necessary for inhibition. In addition, all the Leishmania spp. strains and life-cycle stages tested inhibited IL-12 promoter activity. Our data further reveal that autocrine-acting host factors play no role in the inhibitory response and that phagocytosis signaling is necessary for inhibition of IL-12. PMID:18372625

  10. Lithium potentiates GSK-3β activity by inhibiting phosphoinositide 3-kinase-mediated Akt phosphorylation

    International Nuclear Information System (INIS)

    Tian, Nie; Kanno, Takeshi; Jin, Yu; Nishizaki, Tomoyuki

    2014-01-01

    Highlights: • Lithium suppresses Akt activity by reducing PI3K-mediated Akt phosphorylation. • Lithium enhances GSK-3β activity by reducing Akt-mediated GSK-3β phosphorylation. • Lithium suppresses GSK-3β activity through its direct inhibition. - Abstract: Accumulating evidence has pointed to the direct inhibitory action of lithium, an anti-depressant, on GSK-3β. The present study investigated further insight into lithium signaling pathways. In the cell-free assay Li 2 CO 3 significantly inhibited phosphoinositide 3-kinase (PI3K)-mediated phosphorylation of Akt1 at Ser473, but Li 2 CO 3 did not affect PI3K-mediated PI(3,4,5)P 3 production and 3-phosphoinositide-dependent protein kinase 1 (PDK1)-mediated phosphorylation of Akt1 at Thr308. This indicates that lithium could enhance GSK-3β activity by suppressing Akt-mediated Ser9 phosphorylation of GSK-3β in association with inhibition of PI3K-mediated Akt activation. There was no direct effect of Li 2 CO 3 on Akt1-induced phosphorylation of GSK-3β at Ser9, but otherwise Li 2 CO 3 significantly reduced GSK-3β-mediated phosphorylation of β-catenin at Ser33/37 and Thr41. This indicates that lithium directly inhibits GSK-3β in an Akt-independent manner. In rat hippocampal slices Li 2 CO 3 significantly inhibited phosphorylation of Akt1/2 at Ser473/474, GSK-3β at Ser9, and β-catenin at Ser33/37 and Thr41. Taken together, these results indicate that lithium exerts its potentiating and inhibiting bidirectional actions on GSK-3β activity

  11. Anthrarobin and its derivatives: evaluation of antibacterial and lipoxygenase inhibition activities

    International Nuclear Information System (INIS)

    Lateef, M.; Iqbal, S.

    2013-01-01

    The antibacterial activity of anthrarobin and its synthesized derivatives 1, 10-dihydoxyanthracen-2-0-acetate (1) and anthracen-1, 2-10-tri-O-acetate (2) is determined against two Gram-negative bacteria (Escherichia coli, Pseudomonas aerogenosa) and two Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis) along with the lipoxygenase inhibition activity. Gentamycin (0.3 %) was used as standard antibiotic for antibacterial assay. The minimum inhibitory concentration (MIC) was determined by agar well diffusion method. Anthrarobin showed highest antibacterial activity against all the tested bacteria while anthracen-1, 2-10-tri-0-acetate (2) exhibited 97 % activity against Gram-positive bacteria, Staphylococcus aureus, and; 36 % activity against Gram-negative bacteria Escherichia coli. On the other hand, 1, 10-dihydoxyanthracen-2-0-acetate (1) remained non-significant against all the bacteria tested. When anthrarobin and its derivatives were analyzed for lipoxygenase inhibition studies, only anthrarobin showed weak inhibition activity with IC 5 0 value of 65.2 μM. It is concluded that anthrarobin has significant potential for antibacterial activity as compared to its synthesized derivatives. Structure-activity relationship suggests that numbers of hydroxyl group in anthrarobin may be responsible for antimicrobial activity and the activity decreases with the substitution of acyl groups in synthesized derivatives. (author)

  12. Tanshinone IIA attenuates neuropathic pain via inhibiting glial activation and immune response.

    Science.gov (United States)

    Cao, Fa-Le; Xu, Min; Wang, Yan; Gong, Ke-Rui; Zhang, Jin-Tao

    2015-01-01

    Neuropathic pain, characterized by spontaneous pain, hyperalgesia and allodynia, is a devastating neurological disease that seriously affects patients' quality of life. We have previously shown that tanshinone IIA (TIIA), an important lipophilic component of Danshen, had significant anti-nociceptive effect in somatic and visceral pain, it is surprisingly noted that few pharmacological studies have been carried out to explore the possible analgesic action of TIIA on neuropathic pain and the underlying mechanisms. Therefore, in the present study, by using spinal nerve ligation (SNL) pain model, the antinociceptive and antihyperalgesic effects of TIIA on neuropathic pain were evaluated by intraperitoneal administration in rats. The results indicated that TIIA dose-dependently inhibited SNL-induced mechanical hyperalgesia. As revealed by OX42 levels, TIIA effectively repressed the activation of spinal microglial activation in SNL-induced neuropathic pain. Meanwhile, TIIA also decreased the expressions of inflammatory cytokines TNF-α and IL-1β in the spinal cord. Furthermore, TIIA inhibited oxidative stress by significantly rescuing the superoxide dismutase (SOD) activity and decreasing the malondialdehyde (MDA). Moreover, TIIA depressed SNL-induced MAPKs activation in spinal cord. Taken together, our study provides evidence that TIIA inhibited SNL-induced neuropathic pain through depressing microglial activation and immune response by the inhibition of mitogen-activated protein kinases (MAPKs) pathways. Our findings suggest that TIIA might be a promising agent in the treatment of neuropathic pain. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Punigratane, a novel pyrrolidine alkaloid from Punica granatum rind with putative efflux inhibition activity.

    Science.gov (United States)

    Rafiq, Zumaana; Narasimhan, Sreevidya; Vennila, Rosy; Vaidyanathan, Rama

    2016-02-25

    A new pyrrolidine alkaloid named Punigratane was isolated from the rind of Punica granatum. This is the first report of a pyrrolidine-like structure from the rind. The activity of this compound was tested in a representative MDR Klebsiella pneumoniae strain which exhibited high efflux pump activity. At a concentration of 6 mg, this compound Punigratane was found to have efflux inhibition activity.

  14. Fluoxetine Prevents Oligodendrocyte Cell Death by Inhibiting Microglia Activation after Spinal Cord Injury

    Science.gov (United States)

    Lee, Jee Y.; Kang, So R.

    2015-01-01

    Abstract Oligodendrocyte cell death and axon demyelination after spinal cord injury (SCI) are known to be important secondary injuries contributing to permanent neurological disability. Thus, blocking oligodendrocyte cell death should be considered for therapeutic intervention after SCI. Here, we demonstrated that fluoxetine, an antidepressant drug, alleviates oligodendrocyte cell death by inhibiting microglia activation after SCI. After injury at the T9 level with a Precision Systems and Instrumentation (Lexington, KY) device, fluoxetine (10 mg/kg, intraperitoneal) was administered once a day for the indicated time points. Immunostaining with CD11b (OX-42) antibody and quantification analysis showed that microglia activation was significantly inhibited by fluoxetine at 5 days after injury. Fluoxetine also significantly inhibited activation of p38 mitogen-activated protein kinase (p38-MAPK) and expression of pro-nerve growth factor (pro-NGF), which is known to mediate oligodendrocyte cell death through the p75 neurotrophin receptor after SCI. In addition, fluoxetine attenuated activation of Ras homolog gene family member A and decreased the level of phosphorylated c-Jun and, ultimately, alleviated caspase-3 activation and significantly reduced cell death of oligodendrocytes at 5 days after SCI. Further, the decrease of myelin basic protein, myelin loss, and axon loss in white matter was also significantly blocked by fluoxetine, as compared to vehicle control. These results suggest that fluoxetine inhibits oligodendrocyte cell death by inhibiting microglia activation and p38-MAPK activation, followed by pro-NGF production after SCI, and provide a potential usage of fluoxetine for a therapeutic agent after acute SCI in humans. PMID:25366938

  15. Liver δ-Aminolevulinate Dehydratase Activity is Inhibited by Neonicotinoids and Restored by Antioxidant Agents

    Directory of Open Access Journals (Sweden)

    Elisa Sauer

    2014-11-01

    Full Text Available Neonicotinoids represent the most used class of insecticides worldwide, and their precursor, imidacloprid, is the most widely marketed. The aim of this study was to evaluate the effect of imidacloprid on the activity of hepatic δ-aminolevulinate dehydratase (δ-ALA-D, protective effect of potential antioxidants against this potential effect and presence of chemical elements in the constitution of this pesticide. We observed that δ-ALA-D activity was significantly inhibited by imidacloprid at all concentrations tested in a dose-dependent manner. The IC50 value was obtained and used to evaluate the restoration of the enzymatic activity. δ-ALA-D inhibition was completely restored by addition of dithiotreitol (DTT and partly by ZnCl2, demonstrating that the inhibition occurs by oxidation of thiol groups and by displacement of the Zn (II, which can be explained by the presence of chemical elements found in the constitution of pesticides. Reduced glutathione (GSH had the best antioxidant effect against to δ-ALA-D inhibition caused by imidacloprid, followed by curcumin and resveratrol. It is well known that inhibition of the enzyme δ-ALA-D may result in accumulation of its neurotoxic substrate (δ-ALA, in this line, our results suggest that further studies are needed to investigate the possible neurotoxicity induced by neonicotinoids and the involvement of antioxidants in cases of poisoning by neonicotinoids.

  16. Potent inhibition of human neutrophil activations by bractelactone, a novel chalcone from Fissistigma bracteolatum

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Yang-Chang [Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan (China); Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan (China); Sureshbabu, Munisamy; Fang, Yao-Ching; Wu, Yi-Hsiu [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan (China); Lan, Yu-Hsuan [School of Pharmacy, China Medical University, Taichung 404, Taiwan (China); Chang, Fang-Rong [Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan (China); Chang, Ya-Wen [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan (China); Hwang, Tsong-Long, E-mail: htl@mail.cgu.edu.tw [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan (China); Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan 333, Taiwan (China)

    2013-02-01

    Fissistigma bracteolatum is widely used in traditional medicine to treat inflammatory diseases. However, its active components and mechanisms of action remain unclear. In this study, (3Z)-6,7-dihydroxy-4-methoxy-3-(phenylmethylidene)-5-(3-phenylpropanoyl) -1-benzofuran-2(3H) (bractelactone), a novel chalcone from F. bracteolatum, showed potent inhibitory effects against superoxide anion (O{sub 2}{sup ·−}) production, elastase release, and CD11b expression in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-induced human neutrophils. However, bractelactone showed only weak inhibition of phorbol myristate acetate-caused O{sub 2}{sup ·−} production. The peak cytosolic calcium concentration ([Ca{sup 2+}]{sub i}) was unaltered by bractelactone in FMLP-induced neutrophils, but the decay time of [Ca{sup 2+}]{sub i} was significantly shortened. In a calcium-free solution, changes in [Ca{sup 2+}]{sub i} caused by the addition of extracellular Ca{sup 2+} were inhibited by bractelactone in FMLP-activated cells. In addition, bractelactone did not alter the phosphorylation of p38 MAPK, ERK, JNK, or AKT or the concentration of cAMP. These results suggest that bractelactone selectively inhibits store-operated calcium entry (SOCE). In agreement with this concept, bractelactone suppressed sustained [Ca{sup 2+}]{sub i} changes in thapsigargin-activated neutrophils. Furthermore, bractelactone did not alter FMLP-induced formation of inositol 1,4,5-triphosphate. Taken together, our results demonstrate that the anti-inflammatory effects of bractelactone, an active ingredient of F. bracteolatum, in human neutrophils are through the selective inhibition of SOCE. Highlights: ► Bractelactone isolated from Fissistigma bracteolatum. ► Bractelactone inhibited FMLP-induced human neutrophil activations. ► Bractelactone had no effect on IP3 formation. ► Bractelactone did not alter MAPKs, AKT, and cAMP pathways. ► Bractelactone inhibited store-operated calcium entry.

  17. Glaucocalyxin A inhibits platelet activation and thrombus formation preferentially via GPVI signaling pathway.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available Platelets play a pivotal role in atherothrombosis and the antiplatelet agents have been proved to be useful in preventing onset of acute clinical events including myocardial infarction and stroke. Increasing number of natural compounds has been identified to be potential antiplatelet agents. Here we report the antiplatelet effect of glaucocalyxin A (GLA, an ent-diterpenoid that we isolated and purified from the aerial parts of Rabdosia japonica (Burm. f. var. glaucocalyx (Maxim. Hara, and investigate the molecular mechanisms by which GLA inhibits platelet activation and thrombus formation. The effect of GLA on platelet activation was measured using platelets freshly isolated from peripheral blood of healthy donors. Results showed that pretreatment of human platelets with lower concentrations of GLA (0.01 μg/ml, 0.1 μg/ml significantly inhibited platelet aggregation induced by collagen (P<0.001 and CRP (P<0.01, a synthetic GPVI ligand, but not by ADP and U46619. Accordingly, GLA inhibited collagen-stimulated tyrosine phosphorylation of Syk, LAT, and phospholipase Cγ2, the signaling events in collagen receptor GPⅥ pathway. GLA also inhibited platelet p-selectin secretion and integrin activation by convulxin, a GPVI selective ligand. Additionally, GLA was found to inhibit low-dose thrombin-induced platelet activation. Using a flow chamber device, GLA was found to attenuate platelet adhesion on collagen surfaces in high shear condition. In vivo studies showed that GLA administration increased the time for complete occlusion upon vascular injury in mice, but did not extend tail-bleeding time when mice were administered with relatively lower doses of GLA. Therefore, the present results provide the molecular basis for the inhibition effect of GLA on platelet activation and its in vivo effect on thrombus formation, suggesting that GLA could potentially be developed as an antiplatelet and antithrombotic agent.

  18. Locally formed dopamine inhibits Na+-K+-ATPase activity in rat renal cortical tubule cells

    International Nuclear Information System (INIS)

    Seri, I.; Kone, B.C.; Gullans, S.R.; Aperia, A.; Brenner, B.M.; Ballermann, B.J.

    1988-01-01

    Dopamine, generated locally from L-dopa, inhibits Na + -K + -ATPase in permeabilized rat proximal tubules under maximum transport rate conditions for sodium. To determine whether locally formed dopamine inhibits Na + -K + -ATPase activity in intact cortical tubule cells we studied the effect of L-dopa on ouabain-sensitive oxygen consumption rate (Qo 2 ) and 86 Rb uptake in renal cortical tubule cell suspensions. L-Dopa did not affect ouabain-insensitive Qo 2 or mitochondrial respiration. However, L-dopa inhibited ouabain-sensitive Qo 2 in a concentration-dependent manner, with half-maximal inhibition (K 0.5 ) of 5 x 10 -7 M and a maximal inhibition of 14.1 ± 1.5% at 10 -4 M. L-Dopa also blunted the nystatin-stimulated Qo 2 in a concentration-dependent manner, indicating the L-dopa directly inhibits Na + -K + -ATPase activity and not sodium entry. Ouabain-sensitive 86 Rb uptake was also inhibited by L-dopa. Carbidopa, an inhibitor of the conversion of L-dopa to dopamine, eliminated the effect of L-dopa on ouabain-sensitive Qo 2 and 86 Rb uptake, indicating that dopamine rather than L-dopa was the active agent. The finding that the L-dopa concentration-response curve was shifted to the left by one order of magnitude in the presence of nystatin suggests that the inhibitory effect is enhanced when the intracellular sodium concentration is increased. By studying the effect of L-dopa on ouabain-sensitive Qo 2 at increasing extracellular sodium concentrations in the presence of nystatin, the authors demonstrated that the inhibitory effect of locally formed dopamine on the Na + -K + -ATPase is indeed dependent on the sodium available for the enzyme and occurs in an uncompetitive manner

  19. Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

    Science.gov (United States)

    Sabharwal, Rasna; Chapleau, Mark W

    2014-04-01

    New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of

  20. Heart-specific overexpression of (pro)renin receptor induces atrial fibrillation in mice.

    Science.gov (United States)

    Lian, Hong; Wang, Xiaojian; Wang, Juan; Liu, Ning; Zhang, Li; Lu, Yingdong; Yang, Yanmin; Zhang, Lianfeng

    2015-04-01

    Atrial fibrillation (AF) is the most common cardiac arrhythmia, causing substantial cardiovascular morbidity and mortality. The renin-angiotensin system (RAS) has been shown to be involved in the pathophysiology of AF. The (pro)renin receptor [(p)RR] is the last identified member of RAS. However, the role of (p)RR in AF is still unknown. Circulating levels of (p)RR were determined using an immunosorbent assay in 22 patients with AF (paroxysmal or persistent) and 22 healthy individuals. The plasma levels of (p)RR increased 3.6-fold in AF patients (Patrial flutter since 2 months, then spontaneously converted to atrial fibrillation by 10 months. The atria of the transgenic mice demonstrated significant dilation and fibrosis, and exhibited a high incidence of sudden death. Additionally, the genes of SERCA and HCN4, which are involved in the electrophysiology of AF, were significantly down-regulated and up-regulated respectively in transgenic mice atria. The phosphorylation of Erk1/2 significantly increased in the atria of the transgenic mice, and the activated Erk1/2 was found predominantly in cardiac fibroblasts, suggesting that the transgenic (p)RR gene may induce atrial fibrillation by activation of Erk1/2 in the cardiac fibroblasts of the atria. (p)RR promotes atrial structural and electrical remodeling in vivo, which indicates that (p)RR plays an important role in the pathological development of AF. Copyright © 2015. Published by Elsevier Ireland Ltd.

  1. Effects Of The Direct Renin Inhibitor Aliskiren On Oxidative Stress In Isolated Rat Heart

    Directory of Open Access Journals (Sweden)

    Plecevic Sasa

    2015-09-01

    Full Text Available Increased activity of the renin-angiotensin-aldosterone system (RAAS plays a significant role in the development and progression of various cardio-metabolic diseases, such as hypertension, atherosclerosis and heart failure. Aliskiren is the newest antihypertensive drug and the first orally active direct renin inhibitor to become available for clinical use. This study investigated the acute and direct effects of Aliskiren on different parameters of oxidative stress on isolated rat heart. The hearts of male Wistar albino rats (n = 24, 8 per experimental group, age 8 weeks, body mass 180–200 g, were excised and retrogradely perfused according to the Langendorfftechnique at a gradually increasing perfusion pressure (40-120 cmH2O. Markers of oxidative stress (NO2−, TBARS, H2O2 and O2− were measured spectrophotometrically after perfusion with three different concentrations of Aliskiren (0.1 μM, 1 μM, and 10 μM. The results demonstrated possible dose-dependent cardioprotective properties of Aliskiren, particularly with higher CPP. Lipid peroxidation (TBARS levels decreased with the highest dose of Aliskiren and higher CPP, and the same trend was observed in nitrite (NO2− and hydrogen peroxide (H2O2 levels. These findings indicate that the acute effects of Aliskiren do not likely promote the production of reactive oxygen species upon higher pressure with the highest dose. Aliskiren may exert beneficial effects on oxidative stress biomarkers.

  2. Costunolide inhibits proinflammatory cytokines and iNOS in activated murine BV2 microglia.

    Science.gov (United States)

    Rayan, Nirmala Arul; Baby, Nimmi; Pitchai, Daisy; Indraswari, Fransisca; Ling, Eng-Ang; Lu, Jia; Dheen, Thameem

    2011-06-01

    Costunolide, a sesquiterpene lactone present in Costus speciosus root exerts a variety of pharmacological activity but its effects on neuroinflammation have not been studied. Microglia, the resident phagocytic cells in the central nervous system respond to neuroinflammation and their overwhelming response in turn aggravate brain damage during infection, ischemia and neurodegenerative diseases. In this study, we report the effect of Costunolide on the production of proinflammatory mediators and mechanisms involved in BV2 microglial cells stimulated with LPS. Costunolide attenuated the expression of tumour necrosis factor-alpha, interleukin-1,6, inducible nitric oxide synthase, monocyte chemotactic protein 1 and cyclooxygenase 2 in activated microglia. This Costunolide-mediated inhibition was correspondent with the inhibition of NFkappaB activation. It has been further shown that Costunolide suppressed MAPK pathway activation by inducing MKP-1 production. Collectively our results suggest that Costunolide shows an ability to inhibit expression of multiple neuroinflammatory mediators and this is attributable to the compounds inhibition of NFkappaB and MAPK activation. This novel role of Costunolide upon investigation may aid in developing better therapeutic strategies for treatment of neuroinflammatory diseases.

  3. Regorafenib inhibited gastric cancer cells growth and invasion via CXCR4 activated Wnt pathway.

    Science.gov (United States)

    Lin, Xiao-Lin; Xu, Qi; Tang, Lei; Sun, Li; Han, Ting; Wang, Li-Wei; Xiao, Xiu-Ying

    2017-01-01

    Regorafenib is an oral small-molecule multi kinase inhibitor. Recently, several clinical trials have revealed that regorafenib has an anti-tumor activity in gastric cancer. However, only part of patients benefit from regorafenib, and the mechanisms of regorafenib's anti-tumor effect need further demonstrating. In this study, we would assess the potential anti-tumor effects and the underlying mechanisms of regorafenib in gastric cancer cells, and explore novel biomarkers for patients selecting of regorafenib. The anti-tumor effects of regorafenib on gastric cancer cells were analyzed via cell proliferation and invasion. The underlying mechanisms were demonstrated using molecular biology techniques. We found that regorafenib inhibited cell proliferation and invasion at the concentration of 20μmol/L and in a dose dependent manner. The anti-tumor effects of regorafenib related to the decreased expression of CXCR4, and elevated expression and activation of CXCR4 could reverse the inhibition effect of regorafenib on gastric cancer cells. Further studies revealed that regorafenib reduced the transcriptional activity of Wnt/β-Catenin pathway and led to decreased expression of Wnt pathway target genes, while overexpression and activation of CXCR4 could attenuate the inhibition effect of regorafenib on Wnt/β-Catenin pathway. Our findings demonstrated that regorafenib effectively inhibited cell proliferation and invasion of gastric cancer cells via decreasing the expression of CXCR4 and further reducing the transcriptional activity of Wnt/β-Catenin pathway.

  4. Optimal Fermentation Conditions of Hyaluronidase Inhibition Activity on Asparagus cochinchinensis Merrill by Weissella cibaria.

    Science.gov (United States)

    Kim, Minji; Kim, Won-Baek; Koo, Kyoung Yoon; Kim, Bo Ram; Kim, Doohyun; Lee, Seoyoun; Son, Hong Joo; Hwang, Dae Youn; Kim, Dong Seob; Lee, Chung Yeoul; Lee, Heeseob

    2017-04-28

    This study was conducted to evaluate the hyaluronidase (HAase) inhibition activity of Asparagus cochinchinesis (AC) extracts following fermentation by Weissella cibaria through response surface methodology. To optimize the HAase inhibition activity, a central composite design was introduced based on four variables: the concentration of AC extract ( X 1 : 1-5%), amount of starter culture ( X 2 : 1-5%), pH ( X 3 : 4-8), and fermentation time ( X 4 : 0-10 days). The experimental data were fitted to quadratic regression equations, the accuracy of the equations was analyzed by ANOVA, and the regression coefficients for the surface quadratic model of HAase inhibition activity in the fermented AC extract were estimated by the F test and the corresponding p values. The HAase inhibition activity indicated that fermentation time was most significant among the parameters within the conditions tested. To validate the model, two different conditions among those generated by the Design Expert program were selected. Under both conditions, predicted and experimental data agreed well. Moreover, the content of protodioscin (a well-known compound related to anti-inflammation activity) was elevated after fermentation of the AC extract at the optimized fermentation condition.

  5. Lactobacillus bulgaricus OLL1181 activates the aryl hydrocarbon receptor pathway and inhibits colitis

    Science.gov (United States)

    Takamura, Takeyuki; Harama, Daisuke; Fukumoto, Suguru; Nakamura, Yuki; Shimokawa, Naomi; Ishimaru, Kayoko; Ikegami, Shuji; Makino, Seiya; Kitamura, Masanori; Nakao, Atsuhito

    2011-01-01

    Increasing evidence suggests that the aryl hydrocarbon receptor (AhR) pathway has an important role in the regulation of inflammatory responses. Most recently, we have shown that the activation of the AhR pathway by a potent AhR agonist inhibits the development of dextran sodium sulfate (DSS)-induced colitis, a model of human ulcerative colitis, by the induction of prostaglandin E2 (PGE2) in the large intestine. Because several strains of probiotic lactic acid bacteria have been reported to inhibit DSS-induced colitis by unidentified mechanisms, we hypothesized that particular strains of lactic acid bacterium might have the potential to activate the AhR pathway, thereby inhibiting DSS-induced colitis. This study investigated whether there are specific lactic acid bacterial strains that can activate the AhR pathway, and if so, whether this AhR-activating potential is associated with suppression of DSS-induced colitis. By using AhR signaling reporter cells, we found that Lactobacillus bulgaricus OLL1181 had the potential to activate the AhR pathway. OLL1181 also induced the mRNA expression of cytochrome P450 family 1A1 (CYP1A1), a target gene of the AhR pathway, in human colon cells, which was inhibited by the addition of an AhR antagonist, α-naphthoflavon (αNF). In addition, mice treated orally with OLL1181 showed an increase in CYP1A1 mRNA expression in the large intestine and amelioration of DSS-induced colitis. Thus, OLL1181 can induce activation of the intestinal AhR pathway and inhibit DSS-induced colitis in mice. This strain of lactic acid bacterium has therefore the potential to activate the AhR pathway, which may be able to suppress colitis. PMID:21321579

  6. Chk1 inhibition activates p53 through p38 MAPK in tetraploid cancer cells.

    Science.gov (United States)

    Vitale, Ilio; Senovilla, Laura; Galluzzi, Lorenzo; Criollo, Alfredo; Vivet, Sonia; Castedo, Maria; Kroemer, Guido

    2008-07-01

    We have previously shown that tetraploid cancer cells succumb through a p53-dependent apoptotic pathway when checkpoint kinase 1 (Chk1) is depleted by small interfering RNAs (siRNAs) or inhibited with 7-hydroxystaurosporine (UCN-01). Here, we demonstrate that Chk1 inhibition results in the activating phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Depletion of p38 MAPK by transfection with a siRNA targeting the alpha isoform of p38 MAPK (p38alpha MAPK) abolishes the phosphorylation of p53 on serines 15 and 46 that is induced by Chk1 knockdown. The siRNA-mediated downregulation and pharmacological inhibition of p38alpha MAPK (with SB 203580) also reduces cell death induced by Chk1 knockdown or UCN-01. These results underscore the role of p38 MAPK as a pro-apoptotic kinase in the p53-dependant pathway for the therapeutic elimination of polyploidy cells.

  7. New Frontiers in the Intrarenal Renin-Angiotensin System: A Critical Review of Classical and New Paradigms

    Science.gov (United States)

    Zhuo, Jia L.; Ferrao, Fernanda M.; Zheng, Yun; Li, Xiao C.

    2013-01-01

    The renin-angiotensin system (RAS) is well-recognized as one of the oldest and most important regulators of arterial blood pressure, cardiovascular, and renal function. New frontiers have recently emerged in the RAS research well beyond its classic paradigm as a potent vasoconstrictor, an aldosterone release stimulator, or a sodium-retaining hormone. First, two new members of the RAS have been uncovered, which include the renin/(Pro)renin receptor (PRR) and angiotensin-converting enzyme 2 (ACE2). Recent studies suggest that prorenin may act on the PRR independent of the classical ACE/ANG II/AT1 receptor axis, whereas ACE2 may degrade ANG II to generate ANG (1–7), which activates the Mas receptor. Second, there is increasing evidence that ANG II may function as an intracellular peptide to activate intracellular and/or nuclear receptors. Third, currently there is a debate on the relative contribution of systemic versus intrarenal RAS to the physiological regulation of blood pressure and the development of hypertension. The objectives of this article are to review and discuss the new insights and perspectives derived from recent studies using novel transgenic mice that either overexpress or are deficient of one key enzyme, ANG peptide, or receptor of the RAS. This information may help us better understand how ANG II acts, both independently or through interactions with other members of the system, to regulate the kidney function and blood pressure in health and disease. PMID:24273531

  8. The inhibition of the Human Immunodeficiency Virus type 1 activity by crude and purified human pregnancy plug mucus and mucins in an inhibition assay

    Directory of Open Access Journals (Sweden)

    Schoeman Leann

    2008-05-01

    Full Text Available Abstract Background The female reproductive tract is amongst the main routes for Human Immunodeficiency Virus (HIV transmission. Cervical mucus however is known to protect the female reproductive tract from bacterial invasion and fluid loss and regulates and facilitates sperm transport to the upper reproductive tract. The purpose of this study was to purify and characterize pregnancy plug mucins and determine their anti-HIV-1 activity in an HIV inhibition assay. Methods Pregnancy plug mucins were purified by caesium chloride density-gradient ultra-centrifugation and characterized by Western blotting analysis. The anti-HIV-1 activities of the crude pregnancy plug mucus and purified pregnancy plug mucins was determined by incubating them with HIV-1 prior to infection of the human T lymphoblastoid cell line (CEM SS cells. Results The pregnancy plug mucus had MUC1, MUC2, MUC5AC and MUC5B. The HIV inhibition assay revealed that while the purified pregnancy plug mucins inhibit HIV-1 activity by approximately 97.5%, the crude pregnancy plug mucus failed to inhibit HIV-1 activity. Conclusion Although it is not clear why the crude sample did not inhibit HIV-1 activity, it may be that the amount of mucins in the crude pregnancy plug mucus (which contains water, mucins, lipids, nucleic acids, lactoferrin, lysozyme, immunoglobulins and ions, is insufficient to cause viral inhibition or aggregation.

  9. Inhibition of nitric oxide synthase expression in activated microglia and peroxynitrite scavenging activity by Opuntia ficus indica var. saboten.

    Science.gov (United States)

    Lee, Ming Hong; Kim, Jae Yeon; Yoon, Jeong Hoon; Lim, Hyo Jin; Kim, Tae Hee; Jin, Changbae; Kwak, Wie-Jong; Han, Chang-Kyun; Ryu, Jae-Ha

    2006-09-01

    Activated microglia by neuronal injury or inflammatory stimulation overproduce nitric oxide (NO) by inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) such as superoxide anion, resulting in neurodegenerative diseases. The toxic peroxynitrite (ONOO-), the reaction product of NO and superoxide anion further contributes to oxidative neurotoxicity. A butanol fraction obtained from 50% ethanol extracts of Opuntia ficus indica var. saboten (Cactaceae) stem (SK OFB901) and its hydrolysis product (SK OFB901H) inhibited the production of NO in LPS-activated microglia in a dose dependent manner (IC50 15.9, 4.2 microg/mL, respectively). They also suppressed the expression of protein and mRNA of iNOS in LPS-activated microglial cells at higher than 30 microg/mL as observed by western blot analysis and RT-PCR experiment. They also inhibited the degradation of I-kappaB-alpha in activated microglia. Moreover, they showed strong activity of peroxynitrite scavenging in a cell free bioassay system. These results imply that Opuntia ficus indica may have neuroprotective activity through the inhibition of NO production by activated microglial cells and peroxynitrite scavenging activity. Copyright (c) 2006 John Wiley & Sons, Ltd.

  10. Resveratrol inhibits Cdk5 activity through regulation of p35 expression

    Directory of Open Access Journals (Sweden)

    Kulkarni Ashok B

    2011-07-01

    Full Text Available Abstract Background We have previously reported that cyclin-dependent kinase 5 (Cdk5 participates in the regulation of nociceptive signaling. Through activation of the ERK1/2 pathway, Tumor Necrosis Factor-α (TNF-α induces expression of Egr-1. This results in the sustained and robust expression of p35, a coactivator of Cdk5, in PC12 cells, thereby increasing Cdk5 kinase activity. The aim of our present study was to test whether resveratrol, a polyphenolic compound with known analgesic activity, can regulate Cdk5/p35 activity. Results Here we used a cell-based assay in which a p35 promoter-luciferase construct was stably transfected in PC12 cells. Our studies demonstrate that resveratrol inhibits p35 promoter activity and also blocks the TNF-α mediated increase in Cdk5 activity in PC12 cells. Resveratrol also inhibits p35 expression and blocks the TNF-α mediated increase in Cdk5 activity in DRG neurons. In the presence of resveratrol, the MEK inhibitor decreased p35 promoter activity, whereas the inhibitors of p38 MAPK, JNK and NF-κB increased p35 promoter activity, indicating that these pathways regulate p35 expression differently. The TNF-α-mediated increase in Egr-1 expression was decreased by resveratrol treatment with a concomitant reduction in p35 expression and protein levels, resulting in reduced Cdk5 kinase activity. Conclusions We demonstrate here that resveratrol regulates p35 promoter activity in PC12 cells and DRG neurons. Most importantly, resveratrol blocks the TNF-α-mediated increase in p35 promoter activity, thereby reducing p35 expression and subsequent Cdk5 kinase activity. This new molecular mechanism adds to the known analgesic effects of resveratrol and confirms the need for identifying new analgesics based on their ability to inhibit Cdk5 activity for effective treatment of pain.

  11. Caffeine inhibition of GLUT1 is dependent on the activation state of the transporter.

    Science.gov (United States)

    Gunnink, Leesha K; Busscher, Brianna M; Wodarek, Jeremy A; Rosette, Kylee A; Strohbehn, Lauren E; Looyenga, Brendan D; Louters, Larry L

    2017-06-01

    Caffeine has been shown to be a robust uncompetitive inhibitor of glucose uptake in erythrocytes. It preferentially binds to the nucleotide-binding site on GLUT1 in its tetrameric form and mimics the inhibitory action of ATP. Here we demonstrate that caffeine is also a dose-dependent, uncompetitive inhibitor of 2-deoxyglucose (2DG) uptake in L929 fibroblasts. The inhibitory effect on 2DG uptake in these cells was reversible with a rapid onset and was additive to the competitive inhibitory effects of glucose itself, confirming that caffeine does not interfere with glucose binding. We also report for the first time that caffeine inhibition was additive to inhibition by curcumin, suggesting distinct binding sites for curcumin and caffeine. In contrast, caffeine inhibition was not additive to that of cytochalasin B, consistent with previous data that reported that these two inhibitors have overlapping binding sites. More importantly, we show that the magnitude of maximal caffeine inhibition in L929 cells is much lower than in erythrocytes (35% compared to 90%). Two epithelial cell lines, HCLE and HK2, have both higher concentrations of GLUT1 and increased basal 2DG uptake (3-4 fold) compared to L929 cells, and subsequently display greater maximal inhibition by caffeine (66-70%). Interestingly, activation of 2DG uptake (3-fold) in L929 cells by glucose deprivation shifted the responsiveness of these cells to caffeine inhibition (35%-70%) without a change in total GLUT1 concentration. These data indicate that the inhibition of caffeine is dependent on the activity state of GLUT1, not merely on the concentration. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  12. KSHV inhibits stress granule formation by viral ORF57 blocking PKR activation.

    Directory of Open Access Journals (Sweden)

    Nishi R Sharma

    2017-10-01

    Full Text Available TIA-1 positive stress granules (SG represent the storage sites of stalled mRNAs and are often associated with the cellular antiviral response. In this report, we provide evidence that Kaposi's sarcoma-associated herpesvirus (KSHV overcomes the host antiviral response by inhibition of SG formation via a viral lytic protein ORF57. By immunofluorescence analysis, we found that B lymphocytes with KSHV lytic infection are refractory to SG induction. KSHV ORF57, an essential post-transcriptional regulator of viral gene expression and the production of new viral progeny, inhibits SG formation induced experimentally by arsenite and poly I:C, but not by heat stress. KSHV ORF37 (vSOX bearing intrinsic endoribonuclease activity also inhibits arsenite-induced SG formation, but KSHV RTA, vIRF-2, ORF45, ORF59 and LANA exert no such function. ORF57 binds both PKR-activating protein (PACT and protein kinase R (PKR through their RNA-binding motifs and prevents PACT-PKR interaction in the PKR pathway which inhibits KSHV production. Consistently, knocking down PKR expression significantly promotes KSHV virion production. ORF57 interacts with PKR to inhibit PKR binding dsRNA and its autophosphorylation, leading to inhibition of eIF2α phosphorylation and SG formation. Homologous protein HSV-1 ICP27, but not EBV EB2, resembles KSHV ORF57 in the ability to block the PKR/eIF2α/SG pathway. In addition, KSHV ORF57 inhibits poly I:C-induced TLR3 phosphorylation. Altogether, our data provide the first evidence that KSHV ORF57 plays a role in modulating PKR/eIF2α/SG axis and enhances virus production during virus lytic infection.

  13. Novel dimeric bis(7)-tacrine proton-dependently inhibits NMDA-activated currents

    International Nuclear Information System (INIS)

    Luo, Jialie; Li, Wenming; Liu, Yuwei; Zhang, Wei; Fu, Hongjun; Lee, Nelson T.K.; Yu, Hua; Pang, Yuanping; Huang, Pingbo; Xia, Jun; Li, Zhi-Wang; Li, Chaoying; Han, Yifan

    2007-01-01

    Bis(7)-tacrine has been shown to prevent glutamate-induced neuronal apoptosis by blocking NMDA receptors. However, the characteristics of the inhibition have not been fully elucidated. In this study, we further characterize the features of bis(7)-tacrine inhibition of NMDA-activated current in cultured rat hippocampal neurons. The results show that with the increase of extracellular pH, the inhibitory effect decreases dramatically. At pH 8.0, the concentration-response curve of bis(7)-tacrine is shifted rightwards with the IC 50 value increased from 0.19 ± 0.03 μM to 0.41 ± 0.04 μM. In addition, bis(7)-tacrine shifts the proton inhibition curve rightwards. Furthermore, the inhibitory effect of bis(7)-tacrine is not altered by the presence of the NMDA receptor proton sensor shield spermidine. These results indicate that bis(7)-tacrine inhibits NMDA-activated current in a pH-dependent manner by sensitizing NMDA receptors to proton inhibition, rendering it potentially beneficial therapeutic effects under acidic conditions associated with stroke and ischemia

  14. Lactadherin inhibits secretory phospholipase A2 activity on pre-apoptotic leukemia cells.

    Directory of Open Access Journals (Sweden)

    Steffen Nyegaard

    Full Text Available Secretory phospholipase A2 (sPLA2 is a critical component of insect and snake venoms and is secreted by mammalian leukocytes during inflammation. Elevated secretory PLA2 concentrations are associated with autoimmune diseases and septic shock. Many sPLA2's do not bind to plasma membranes of quiescent cells but bind and digest phospholipids on the membranes of stimulated or apoptotic cells. The capacity of these phospholipases to digest membranes of stimulated or apoptotic cells correlates to the exposure of phosphatidylserine. In the present study, the ability of the phosphatidyl-L-serine-binding protein, lactadherin to inhibit phospholipase enzyme activity has been assessed. Inhibition of human secretory phospholipase A2-V on phospholipid vesicles exceeded 90%, whereas inhibition of Naja mossambica sPLA2 plateaued at 50-60%. Lactadherin inhibited 45% of activity of Naja mossambica sPLA2 and >70% of human secretory phospholipase A2-V on the membranes of human NB4 leukemia cells treated with calcium ionophore A23187. The data indicate that lactadherin may decrease inflammation by inhibiting sPLA2.

  15. Inhibition of APOBEC3G Activity Impedes Double-Strand DNA Repair

    Science.gov (United States)

    Prabhu, Ponnandy; Shandilya, Shivender; Britan-Rosich, Elena; Nagler, Adi; Schiffer, Celia A.; Kotler, Moshe

    2015-01-01

    The cellular cytidine deaminase APOBEC3G (A3G) was first described as an anti-HIV-1 restriction factor by directly deaminating reverse transcripts of the viral genome. HIV-1 Vif neutralizes the activity of A3G, primarily by mediating degradation of A3G to establish effective infection in host target cells. Lymphoma cells, which express high amounts of A3G, can restrict Vif-deficient HIV-1. Interestingly, these cells are more stable in the face of treatments that result in dsDNA damage, such as ionizing irradiation (IR) and chemotherapies. Previously, we showed that the Vif-derived peptide (Vif25-39) efficiently inhibits A3G deamination, and increases sensitivity of lymphoma cells to IR. In the current study, we show that additional peptides derived from Vif, A3G and A3F, which contain the LYYF motif, inhibit deamination activity. Each residue in the Vif25-39 sequence moderately contributes to the inhibitory effect, while, replacing a single amino acid in the LYYF motif completely abrogate inhibition of deamination. Treatment of A3G-expressing lymphoma cells exposed to ionizing radiation with the new inhibitory peptides reduces double-strand break (DSB) repair after radiation. Incubation of cultured irradiated lymphoma cells with peptides that inhibit DSB repair halts their propagation. These results suggest that A3G may be a potential therapeutic target amenable to peptide and peptidomimetic inhibition. PMID:26460502

  16. Inhibition of APOBEC3G activity impedes double-stranded DNA repair.

    Science.gov (United States)

    Prabhu, Ponnandy; Shandilya, Shivender M D; Britan-Rosich, Elena; Nagler, Adi; Schiffer, Celia A; Kotler, Moshe

    2016-01-01

    The cellular cytidine deaminase APOBEC3G (A3G) was first described as an anti-HIV-1 restriction factor, acting by directly deaminating reverse transcripts of the viral genome. HIV-1 Vif neutralizes the activity of A3G, primarily by mediating degradation of A3G to establish effective infection in host target cells. Lymphoma cells, which express high amounts of A3G, can restrict Vif-deficient HIV-1. Interestingly, these cells are more stable in the face of treatments that result in double-stranded DNA damage, such as ionizing radiation and chemotherapies. Previously, we showed that the Vif-derived peptide (Vif25-39) efficiently inhibits A3G deamination, and increases the sensitivity of lymphoma cells to ionizing radiation. In the current study, we show that additional peptides derived from Vif, A3G, and APOBEC3F, which contain the LYYF motif, inhibit deamination activity. Each residue in the Vif25-39 sequence moderately contributes to the inhibitory effect, whereas replacing a single residue in the LYYF motif completely abrogates inhibition of deamination. Treatment of A3G-expressing lymphoma cells exposed to ionizing radiation with the new inhibitory peptides reduces double-strand break repair after irradiation. Incubation of cultured irradiated lymphoma cells with peptides that inhibit double-strand break repair halts their propagation. These results suggest that A3G may be a potential therapeutic target that is amenable to peptide and peptidomimetic inhibition. © 2015 FEBS.

  17. B7-H4 Treatment of T Cells Inhibits ERK, JNK, p38, and AKT Activation.

    Directory of Open Access Journals (Sweden)

    Xiaojie Wang

    Full Text Available B7-H4 is a newly identified B7 homolog that plays an important role in maintaining T-cell homeostasis by inhibiting T-cell proliferation and lymphokine-secretion. In this study, we investigated the signal transduction pathways inhibited by B7-H4 engagement in mouse T cells. We found that treatment of CD3(+ T cells with a B7-H4.Ig fusion protein inhibits anti-CD3 elicited T-cell receptor (TCR/CD28 signaling events, including phosphorylation of the MAP kinases, ERK, p38, and JNK. B7-H4.Ig treatment also inhibited the phosphorylation of AKT kinase and impaired its kinase activity as assessed by the phosphorylation of its endogenous substrate GSK-3. Expression of IL-2 is also reduced by B7-H4. In contrast, the phosphorylation state of the TCR proximal tyrosine kinases ZAP70 and lymphocyte-specific protein tyrosine kinase (LCK are not affected by B7-H4 ligation. These results indicate that B7-H4 inhibits T-cell proliferation and IL-2 production through interfering with activation of ERK, JNK, and AKT, but not of ZAP70 or LCK.

  18. Speed-accuracy modulation in case of conflict: The roles of activation and inhibition

    NARCIS (Netherlands)

    Band, G.P.; Ridderinkhof, K.R.; van der Molen, M.W.

    2003-01-01

    This study investigated how the speed-accuracy balance is modulated by changes in the time course of motor activation and inhibition of a primed response. Responses and event-related brain potentials were recorded in a paradigm in which the first stimulus indicated the correct response with 80%

  19. Tiamulin inhibits breast cancer growth and pulmonary metastasis by decreasing the activity of CD73.

    Science.gov (United States)

    Yang, Xu; Pei, Shimin; Wang, Huanan; Jin, Yipeng; Yu, Fang; Zhou, Bin; Zhang, Hong; Zhang, Di; Lin, Degui

    2017-04-11

    Metastasis is the leading cause of death in breast cancer patients. CD73, also known as ecto-5'-nucleotidase, plays a critical role in cancer development including metastasis. The existing researches indicate that overexpression of CD73 promotes growth and metastasis of breast cancer. Therefore, CD73 inhibitor can offer a promising treatment for breast cancer. Here, we determined whether tiamulin, which was found to inhibit CD73, was able to suppress breast cancer development and explored the related mechanisms. We firstly measured the effect of tiamulin hydrogen fumarate (THF) on CD73 using high performance liquid chromatography (HPLC). Then, we investigated cell proliferation, migration and invasion in MDA-MB-231 human breast cancer cell line and 4 T1 mouse breast cancer cell line treated with THF by migration assay, invasion assay and activity assay. Besides, we examined the effect of THF on syngeneic mammary tumors of mice by immunohistochemistry. Our data demonstrated that THF inhibited CD73 by decreasing the activity instead of the expression of CD73. In vitro, THF inhibited the proliferation, migration and invasion of MDA-MB-231 and 4 T1 cells by suppressing CD73 activity. In vivo, animal experiments showed that THF treatment resulted in significant reduction in syngeneic tumor growth, microvascular density and lung metastasis rate. Our results indicate that THF inhibits growth and metastasis of breast cancer by blocking the activity of CD73, which may offer a promising treatment for breast cancer therapy.

  20. Effect of pH, temperature and water activity on the inhibition of ...

    African Journals Online (AJOL)

    WiN 7

    2012-01-31

    Jan 31, 2012 ... Low values of water activity and acid pH were unfavourable for the growth inhibition. ... treatments, such as surface sterilization and high-dose irradiation ..... biological control of grey mould (Botrytis cinerea Pers.:Fr.) on fresh-.

  1. Potassium humate inhibits complement activation and the production of inflammatory cytokines in vitro

    Energy Technology Data Exchange (ETDEWEB)

    van Rensburg, C.E.J.; Naude, P.J. [University of Pretoria, Pretoria (South Africa)

    2009-08-15

    The effects of brown coal derived potassium humate on lymphocyte proliferation, cytokine production and complement activation were investigated in vitro. Potassium humate increased lymphocyte proliferation of phytohaemaglutinin A (PHA) and pokeweed mitogen (PWM) stimulated mononuclear lymphocytes (MNL) in vitro from concentrations of 20 to 80 {mu} g/ml, in a dose dependant manner. On the other hand potassium humate, at 40 {mu} g/ml, significantly inhibited the release of TNF-alpha, IL-1 beta, IL-6 and IL-10 by PHA stimulated MNL. Regarding complement activation it was found that potassium humate inhibits the activation of both the alternative and classical pathways without affecting the stability of the red blood cell membranes. These results indicate that the anti-inflammatory potential of potassium humate could be partially due to the inhibition of pro-inflammatory cytokines responsible for the initiation of these reactions as well as inhibition of complement activation. The increased lymphocyte proliferation observed, might be due to increased IL-2 production as previously been documented.

  2. Behavioral inhibition system (BIS), Behavioral activation system (BAS) and schizophrenia : Relationship with psychopathology and physiology

    NARCIS (Netherlands)

    Scholten, Marion R. M.; van Honk, Jack; Aleman, Andre; Kahn, Rene S.

    2006-01-01

    Objective: The Behavioral Inhibition System (BIS) and the Behavioral Activation System (BAS) have been conceptualized as two neural motivational systems that regulate sensitivity to punishment (BIS) and reward (BAS). Imbalance in BIS and BAS levels has been reported to be related to various forms of

  3. Antimicrobial activity and acetylcholinesterase inhibition by extracts from chromatin modulated fungi

    Directory of Open Access Journals (Sweden)

    Matheus Thomaz Nogueira Silva Lima

    Full Text Available ABSTRACT Major health challenges as the increasing number of cases of infections by antibiotic multiresistant microorganisms and cases of Alzheimer's disease have led to searching new control drugs. The present study aims to verify a new way of obtaining bioactive extracts from filamentous fungi with potential antimicrobial and acetylcholinesterase inhibitory activities, using epigenetic modulation to promote the expression of genes commonly silenced. For such finality, five filamentous fungal species (Talaromyces funiculosus, Talaromyces islandicus, Talaromyces minioluteus, Talaromyces pinophilus, Penicillium janthinellum were grown or not with DNA methyltransferases inhibitors (procainamide or hydralazine and/or a histone deacetylase inhibitor (suberohydroxamic acid. Extracts from T. islandicus cultured or not with hydralazine inhibited Listeria monocytogenes growth in 57.66 ± 5.98% and 15.38 ± 1.99%, respectively. Increment in inhibition of acetylcholinesterase activity was observed for the extract from P. janthinellum grown with procainamide (100%, when compared to the control extract (39.62 ± 3.76%. Similarly, inhibition of acetylcholinesterase activity increased from 20.91 ± 3.90% (control to 92.20 ± 3.72% when the tested extract was obtained from T. pinophilus under a combination of suberohydroxamic acid and procainamide. Concluding, increases in antimicrobial activity and acetylcholinesterase inhibition were observed when fungal extracts in the presence of DNA methyltransferases and/or histone deacetylase modulators were tested.

  4. CCR 20th anniversary commentary: a chimeric antibody, C225, inhibits EGFR activation and tumor growth.

    Science.gov (United States)

    Mendelsohn, John; Prewett, Marie; Rockwell, Patricia; Goldstein, Neil I

    2015-01-15

    Murine mAb 225 was effective against the EGFR tyrosine kinase and inhibited tumor growth in preclinical studies. A phase I trial showed safety, tumor localization, and satisfactory pharmacokinetics. Human:murine chimeric C225 retained biologic activity, which was essential for the conduct of subsequent combination therapy trials and eventual regulatory approval. ©2015 American Association for Cancer Research.

  5. In vitro antioxidant and α-amylase inhibition activities of spiced red ...

    African Journals Online (AJOL)

    Spiced chili paste (green or red), locally known as Datta, is a traditional popular spicy paste consumed in Ethiopia. This study investigated the total phenolic contents (TPC), total flavonoid contents (TFC), in vitro antioxidant, and α-amylase inhibition activities of water, acetone, petroleum ether, methanol, and 80% methanol ...

  6. Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea

    Science.gov (United States)

    Li, Wenyan; Chen, Yan; Zhang, Shasha; Tang, Mingliang; Sun, Shan; Chai, Renjie; Li, Huawei

    2016-01-01

    Hair cell (HC) loss is the main cause of permanent hearing loss in mammals. Previous studies have reported that in neonatal mice cochleae, Wnt activation promotes supporting cell (SC) proliferation and Notch inhibition promotes the trans-differentiation of SCs into HCs. However, Wnt activation alone fails to regenerate significant amounts of new HCs, Notch inhibition alone regenerates the HCs at the cost of exhausting the SC population, which leads to the death of the newly regenerated HCs. Mitotic HC regeneration might preserve the SC number while regenerating the HCs, which could be a better approach for long-term HC regeneration. We present a two-step gene manipulation, Wnt activation followed by Notch inhibition, to accomplish mitotic regeneration of HCs while partially preserving the SC number. We show that Wnt activation followed by Notch inhibition strongly promotes the mitotic regeneration of new HCs in both normal and neomycin-damaged cochleae while partially preserving the SC number. Lineage tracing shows that the majority of the mitotically regenerated HCs are derived specifically from the Lgr5+ progenitors with or without HC damage. Our findings suggest that the co-regulation of Wnt and Notch signaling might provide a better approach to mitotically regenerate HCs from Lgr5+ progenitor cells. PMID:27564256

  7. Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats

    NARCIS (Netherlands)

    van Westerloo, D. J.; Giebelen, I. A. J.; Meijers, J. C. M.; Daalhuisen, J.; de Vos, A. F.; Levi, M. [=Marcel M.; van der Poll, T.

    2006-01-01

    BACKGROUND: Sepsis and endotoxemia are associated with concurrent activation of inflammation and the hemostatic mechanism, which both contribute to organ dysfunction and death. Electrical vagus nerve stimulation (VNS) has been found to inhibit tumor necrosis factor (TNF)-alpha release during

  8. Effects on atrial fibrillation in aged hypertensive rats by Ca(2+)-activated K(+) channel inhibition

    DEFF Research Database (Denmark)

    Diness, Jonas Goldin; Skibsbye, Lasse; Jespersen, Thomas

    2011-01-01

    We have shown previously that inhibition of small conductance Ca(2+)-activated K(+) (SK) channels is antiarrhythmic in models of acutely induced atrial fibrillation (AF). These models, however, do not take into account that AF derives from a wide range of predisposing factors, the most prevalent ...

  9. The dynamical mechanism of auto-inhibition of AMP-activated protein kinase.

    Directory of Open Access Journals (Sweden)

    Cheng Peng

    2011-07-01

    Full Text Available We use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK. A recent X-ray and mutagenesis experiment (Chen, et al Nature 2009, 459, 1146 of the AMPK homolog S. Pombe sucrose non-fermenting 1 (SNF1 has proposed a new conformational switch model involving the movement of the kinase domain (KD between an inactive unphosphorylated open state and an active or semi-active phosphorylated closed state, mediated by the autoinhibitory domain (AID, and a similar mutagenesis study showed that rat AMPK has the same auto-inhibition mechanism. However, there is no direct dynamical evidence to support this model and it is not clear whether other functionally important local structural components are equally inhibited. By using the same SNF1 KD-AID fragment as that used in experiment, we show that AID inhibits the catalytic function by restraining the KD into an unproductive open conformation, thereby limiting local structural rearrangements, while mutations that disrupt the interactions between the KD and AID allow for both the local structural rearrangement and global interlobe conformational transition. Our calculations further show that the AID also greatly impacts the structuring and mobility of the activation loop.

  10. Inhibitory effect of ebselen on cerebral acetylcholinesterase activity in vitro: kinetics and reversibility of inhibition.

    Science.gov (United States)

    Martini, Franciele; Bruning, César Augusto; Soares, Suelen Mendonca; Nogueira, Cristina Wayne; Zeni, Gilson

    2015-01-01

    Ebselen is a synthetic organoselenium compound that has been considered a potential pharmacological agent with low toxicity, showing antioxidant, anti-inflammatory and neuroprotective effects. It is bioavailable, blood-brain barrier permeant and safe based on cellular toxicity and Phase I-III clinical trials. There is evidence that ebselen inhibits acetylcholinesterase (AChE) activity, an enzyme that plays a key role in the cholinergic system by hydrolyzing acetylcholine (ACh), in vitro and ex vivo. This system has a well-known relationship with cognitive process, and AChE inhibitors, such as donepezil and galantamine, have been used to treat cognitive deficits, mainly in the Alzheimer's Disease (AD). However, these drugs have poor bioavailability and a number of side effects, including gastrointestinal upsets and hepatotoxicity. In this way, this study aimed to evaluate the effect of ebselen on cerebral AChE activity in vitro and to determine the kinetic profile and the reversibility of inhibition by dialysis. Ebselen inhibited the cerebral AChE activity with an IC50 of 29 µM, similar to IC50 found with pure AChE from electric eel, demonstrating a mixed and reversible inhibition of AChE, since it increased Km and decreased Vmax. The AChE activity was recovered within 60 min of dialysis. Therefore, the use of ebselen as a therapeutic agent for treatment of AD should be considered, although memory behavior tasks are needed to support such hypothesis.

  11. Testosterone is inversely related to brain activity during emotional inhibition in schizophrenia.

    Directory of Open Access Journals (Sweden)

    Ans Vercammen

    Full Text Available Sex steroids affect cognitive function as well as emotion processing and regulation. They may also play a role in the pathophysiology of schizophrenia. However, the effects of sex steroids on cognition and emotion-related brain activation in schizophrenia are poorly understood. Our aim was to determine the extent to which circulating testosterone relates to brain activation in men with schizophrenia compared to healthy men during cognitive-emotional processing. We assessed brain activation in 18 men with schizophrenia and 22 age-matched healthy men during an emotional go/no-go task using fMRI and measured total serum testosterone levels on the same morning. We performed an ROI analysis to assess the relationship between serum testosterone and brain activation, focusing on cortical regions involved the emotional go/no-go task. Slower RT and reduced accuracy was observed when participants responded to neutral stimuli, while inhibiting responses to negative stimuli. Healthy men showed a robust increase in activation of the middle frontal gyrus when inhibiting responses to negative stimuli, but there was no significant association between activation and serum testosterone level in healthy men. Men with schizophrenia showed a less pronounced increase in activation when inhibiting responses to negative stimuli; however, they did show a strong inverse association between serum testosterone level and activation of the bilateral middle frontal gyrus and left insula. Additionally, increased accuracy during inhibition of response to negative words was associated with both higher serum testosterone levels and decreased activation of the middle frontal gyrus in men with schizophrenia only. We conclude that endogenous hormone levels, even within the normal range, may play an enhanced modulatory role in determining the neural and behavioural response during cognitive-emotional processing in schizophrenia.

  12. 3-Bromopyruvate inhibits calcium uptake by sarcoplasmic reticulum vesicles but not SERCA ATP hydrolysis activity.

    Science.gov (United States)

    Jardim-Messeder, Douglas; Camacho-Pereira, Juliana; Galina, Antonio

    2012-05-01

    3-Bromopyruvate (3BrPA) is an antitumor agent that alkylates the thiol groups of enzymes and has been proposed as a treatment for neoplasias because of its specific reactivity with metabolic energy transducing enzymes in tumor cells. In this study, we show that the sarco/endoplasmic reticulum calcium (Ca(2+)) ATPase (SERCA) type 1 is one of the target enzymes of 3BrPA activity. Sarco/endoplasmic reticulum vesicles (SRV) were incubated in the presence of 1mM 3BrPA, which was unable to inhibit the ATPase activity of SERCA. However, Ca(2+)-uptake activity was significantly inhibited by 80% with 150 μM 3BrPA. These results indicate that 3BrPA has the ability to uncouple the ATP hydrolysis from the calcium transport activities. In addition, we observed that the inclusion of 2mM reduced glutathione (GSH) in the reaction medium with different 3BrPA concentrations promoted an increase in 40% in ATPase activity and protects the inhibition promoted by 3BrPA in calcium uptake activity. This derivatization is accompanied by a decrease of reduced cysteine (Cys), suggesting that GSH and 3BrPA increases SERCA activity and transport by pyruvylation and/or S-glutathiolation mediated by GSH at a critical Cys residues of the SERCA. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Does SGLT2 inhibition with dapagliflozin overcome individual therapy resistance to RAAS inhibition?

    NARCIS (Netherlands)

    Petrykiv, Sergei; Laverman, Gozewijn D.; de Zeeuw, Dick; Heerspink, Hiddo J. L.

    Individual patients show a large variation in their response to renin-angiotensin-aldosteron system (RAAS) inhibition (RAASi), both in surrogates such as albuminuria and in hard renal outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2) have been shown to lower albuminuria and to confer

  14. Inhibition of dehydrogenase activity in petroleum refinery wastewater bacteria by phenolic compounds

    OpenAIRE

    Gideon C. Okpokwasili; Christian Okechukwu Nweke

    2010-01-01

    The toxicity of phenol, 2-nitrophenol, 4-nitrophenol, 2,4-dinitrophenol, 2-chlorophenol, 4-chlorophenol, 4-bromophenol and 3,5-dimethylphenol on Pseudomonas, Bacillus and Escherichia species isolated from petroleum refinery wastewater was assessed via inhibition of dehydrogenase enzyme activity. At low concentrations, 2-nitrophenol, 2-chlorophenol, 4-chlorophenol, 4-bromophenol and 3,5-dimethylphenol stimulated dehydrogenase activity and at sufficient concentrations, phenolic compounds inhibi...

  15. Dehydration-induced modulation of κ-opioid inhibition of vasopressin neurone activity

    Science.gov (United States)

    Scott, Victoria; Bishop, Valerie R; Leng, Gareth; Brown, Colin H

    2009-01-01

    Dehydration increases vasopressin (antidiuretic hormone) secretion from the posterior pituitary gland to reduce water loss in the urine. Vasopressin secretion is determined by action potential firing in vasopressin neurones, which can exhibit continuous, phasic (alternating periods of activity and silence), or irregular activity. Autocrine κ-opioid inhibition contributes to the generation of activity patterning of vasopressin neurones under basal conditions and so we used in vivo extracellular single unit recording to test the hypothesis that changes in autocrine κ-opioid inhibition drive changes in activity patterning of vasopressin neurones during dehydration. Dehydration increased the firing rate of rat vasopressin neurones displaying continuous activity (from 7.1 ± 0.5 to 9.0 ± 0.6 spikes s−1) and phasic activity (from 4.2 ± 0.7 to 7.8 ± 0.9 spikes s−1), but not those displaying irregular activity. The dehydration-induced increase in phasic activity was via an increase in intraburst firing rate. The selective κ-opioid receptor antagonist nor-binaltorphimine increased the firing rate of phasic neurones in non-dehydrated rats (from 3.4 ± 0.8 to 5.3 ± 0.6 spikes s−1) and dehydrated rats (from 6.4 ± 0.5 to 9.1 ± 1.2 spikes s−1), indicating that κ-opioid feedback inhibition of phasic bursts is maintained during dehydration. In a separate series of experiments, prodynorphin mRNA expression was increased in vasopressin neurones of hyperosmotic rats, compared to hypo-osmotic rats. Hence, it appears that dynorphin expression in vasopressin neurones undergoes dynamic changes in proportion to the required secretion of vasopressin so that, even under stimulated conditions, autocrine feedback inhibition of vasopressin neurones prevents over-excitation. PMID:19822541

  16. Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif.

    Directory of Open Access Journals (Sweden)

    Mei Ying Ng

    Full Text Available Cycle inhibiting factors (Cifs are virulence proteins secreted by the type III secretion system of some Gram-negative pathogenic bacteria including Burkholderia pseudomallei. Cif is known to function to deamidate Nedd8, leading to inhibition of Cullin E3 ubiquitin ligases (CRL and consequently induction of cell cycle arrest. Here we show that Cif can function as a potent activator of MAPK/ERK signaling without significant activation of other signaling pathways downstream of receptor tyrosine kinases. Importantly, we found that the ability of Cif to activate ERK is dependent on its deamidase activity, but independent of Cullin E3 ligase inhibition. This suggests that apart from Nedd8, other cellular targets of Cif-dependent deamidation exist. We provide evidence that the mechanism involved in Cif-mediated ERK activation is dependent on recruitment of the Grb2-SOS1 complex to the plasma membrane. Further investigation revealed that Cif appears to modify the phosphorylation status of SOS1 in a region containing the CDC25-H and proline-rich domains. It is known that prolonged Cullin E3 ligase inhibition leads to cellular apoptosis. Therefore, we hypothesize that ERK activation is an important mechanism to counter the pro-apoptotic effects of Cif. Indeed, we show that Cif dependent ERK activation promotes phosphorylation of the proapoptotic protein Bim, thereby potentially conferring a pro-survival signal. In summary, we identified a novel deamidation-dependent mechanism of action of the B. pseudomallei virulence factor Cif/CHBP to activate MAPK/ERK signaling. Our study demonstrates that bacterial proteins such as Cif can serve as useful molecular tools to uncover novel aspects of mammalian signaling pathways.

  17. Some Aspects of the Renin-Angiotensin-System in Hemodialysis Patients

    Directory of Open Access Journals (Sweden)

    Umar Malik

    2015-11-01

    Full Text Available Understanding of the renin-angiotensin system (RAS has changed remarkably over the past decade. Renin, angiotensin converting enzyme (ACE, angiotensin II (Ang II, and Ang II receptors are the main components of the RAS. Recent studies identified the ACE2/Ang 1-7/Mas receptor axis, which counter-regulates the classical RAS. Many studies have examined the effects of the RAS on the progression of cardiovascular disease and chronic kidney disease (CKD. In addition, many studies have documented increased levels of ACE in hemodialysis (HD patients, raising concerns about the negative effects of RAS activation on the progression of renal disease. Elevated ACE increases the level of Ang II, leading to vasoconstriction and cell proliferation. Ang II stimulation of the sympathetic system leads to renal and cardiovascular complications that are secondary to uncontrolled hypertension. This review provides an overview of the RAS, evaluates new research on the role of ACE2 in dialysis, and reviews the evidence for potentially better treatments for patients undergoing HD. Further understanding of the role of ACE and ACE2 in HD patients may aid the development of targeted therapies that slow the progression of CKD and cardiovascular disease.

  18. The role of vascular protein and renin in chronic two-kidney, one clip Goldblatt hypertension

    International Nuclear Information System (INIS)

    Nakada, T.; Yamori, Y.

    1982-01-01

    Chronic hypertension was induced in rats by application of a clip for 17 or 20 weeks to the unilateral renal artery and leaving the contrarenal vessel intact. Some of the rats received antihypertensive treatment with phenoxybenzamine (POB). 3 H-proline was injected into all rats in the 17th experimental week to observe the in vivo incorporation rates of 3 H-proline into vascular non-collagenous protein and vascular collagen. Plasma renin activity (PRA) of decapitated rats was assayed in the terminal stage of the experiment. Significant differences were noted between 2K-1C hypertensive rats and sham-operated normotensive rats, the former rats having significantly higher incorporation rates of 3 H-proline into non-collagenous protein and collagen of testicular or mesenteric artery. These results indicate that increased synthesis of vascular non-collagenous protein as well as collagen, especially of small arteries, plays a major role for the pathogenesis of chronic hypertension in 2K-1C rats, and renin does not contribute to elevation of the blood pressure in the maintenance phase of this type of experimental hypertension

  19. The role of renin angiotensin system in retinal inflammation

    OpenAIRE

    Zhu, Tong

    2017-01-01

    Purpose: Retinopathy of prematurity (ROP) is the main cause of vision loss and blindness in children, and is replicated and intensively studied in rodent models of oxygen-induced retinopathy (OIR). One signature feature of ROP is retinal neovascularization, which is also present in patients with proliferative diabetic retinopathy (PDR). Inflammation is another feature in ROP and PDR. In both diseases, the renin angiotensin system (RAS) is dysregulated, and blockade of RAS via angiotensin II (...

  20. Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade

    Directory of Open Access Journals (Sweden)

    Richa Tyagi

    2015-02-01

    Full Text Available Rheb, a ubiquitous small GTPase, is well known to bind and activate mTOR, which augments protein synthesis. Inhibition of protein synthesis is also physiologically regulated. Thus, with cell stress, the unfolded protein response system leads to phosphorylation of the initiation factor eIF2α and arrest of protein synthesis. We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK. Interplay between the stimulatory and inhibitory roles of Rheb may enable cells to modulate protein synthesis in response to varying environmental stresses.

  1. EGFR Activation Mediates Inhibition of Axon Regeneration by Myelin and Chondroitin Sulfate Proteoglycans

    Science.gov (United States)

    Koprivica, Vuk; Cho, Kin-Sang; Park, Jong Bae; Yiu, Glenn; Atwal, Jasvinder; Gore, Bryan; Kim, Jieun A.; Lin, Estelle; Tessier-Lavigne, Marc; Chen, Dong Feng; He, Zhigang

    2005-10-01

    Inhibitory molecules associated with myelin and the glial scar limit axon regeneration in the adult central nervous system (CNS), but the underlying signaling mechanisms of regeneration inhibition are not fully understood. Here, we show that suppressing the kinase function of the epidermal growth factor receptor (EGFR) blocks the activities of both myelin inhibitors and chondroitin sulfate proteoglycans in inhibiting neurite outgrowth. In addition, regeneration inhibitors trigger the phosphorylation of EGFR in a calcium-dependent manner. Local administration of EGFR inhibitors promotes significant regeneration of injured optic nerve fibers, pointing to a promising therapeutic avenue for enhancing axon regeneration after CNS injury.

  2. Revisiting the mechanistic basis of the French Paradox: red wine inhibits the activity of protein disulfide isomerase in vitro

    Science.gov (United States)

    Galinski, Christine N.; Zwicker, Jeffrey I.; Kennedy, Daniel R.

    2015-01-01

    Introduction Although epidemiologic evidence points to cardioprotective activity of red wine, the mechanistic basis for antithrombotic activity has not been established. Quercetin and related flavonoids are present in high concentrations in red but not white wine. Quercetin-glycosides were recently shown to prevent thrombosis in animal models through the inhibition of extracellular protein disulfide isomerase (PDI). We evaluated whether red or white wine inhibited PDI activity in vitro. Methods Quercetin levels in red and white wines were measured by HPLC analysis. Inhibition of PDI activity by red and white wines was assessed by an insulin reduction turbidity assay at various concentrations of wine. PDI inhibition was confirmed using a reduced peptide that contained a disulfide containing peptide as a substrate. The inhibition of PDI related thiol isomerases ERp5 and ERp57 was also assessed. Results We observed a dose-dependent decrease of PDI activity for a variety of red but not white wines. Red wine diluted to 3% final concentration resulted in over 80% inhibition of PDI activity by insulin reductase assay for all varieties tested. This inhibition was also observed in the peptide based assay. Red grape juice yielded similar results but ethanol alone did not affect PDI activity. Interestingly, red wine also inhibited the PDI related thiol isomerases ERp5 and ERp57, albeit to a lesser degree than PDI. Conclusions PDI activity is inhibited by red wine and grape juice, identifying a potentially novel mechanism underlying the cardiovascular benefits attributed to wine consumption. PMID:26585763

  3. Scoparone exerts anti-tumor activity against DU145 prostate cancer cells via inhibition of STAT3 activity.

    Directory of Open Access Journals (Sweden)

    Jeong-Kook Kim

    Full Text Available Scoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3 contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2 or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.

  4. Selective antibacterial activity of patchouli alcohol against Helicobacter pylori based on inhibition of urease.

    Science.gov (United States)

    Yu, Xiao-Dan; Xie, Jian-Hui; Wang, Yong-Hong; Li, Yu-Cui; Mo, Zhi-Zhun; Zheng, Yi-Feng; Su, Ji-Yan; Liang, Ye-er; Liang, Jin-Zhi; Su, Zi-Ren; Huang, Ping

    2015-01-01

    The aim of this study is to evaluate the antibacterial activity and urease inhibitory effects of patchouli alcohol (PA), the bioactive ingredient isolated from Pogostemonis Herba, which has been widely used for the treatment of gastrointestinal disorders. The activities of PA against selected bacteria and fungi were determined by agar dilution method. It was demonstrated that PA exhibited selective antibacterial activity against Helicobacter pylori, without influencing the major normal gastrointestinal bacteria. Noticeably, the antibacterial activity of PA was superior to that of amoxicillin, with minimal inhibition concentration value of 78 µg/mL. On the other hand, PA inhibited ureases from H.pylori and jack bean in concentration-dependent fashion with IC50 values of 2.67 ± 0.79 mM and 2.99 ± 0.41 mM, respectively. Lineweaver-Burk plots indicated that the type of inhibition was non-competitive against H.pylori urease whereas uncompetitive against jack bean urease. Reactivation of PA-inactivated urease assay showed DL-dithiothreitol, the thiol reagent, synergistically inactivated urease with PA instead of enzymatic activity recovery. In conclusion, the selective H.pylori antibacterial activity along with urease inhibitory potential of PA could make it a possible drug candidate for the treatment of H.pylori infection. Copyright © 2014 John Wiley & Sons, Ltd.

  5. Thiazolidinediones inhibit TNFα induction of PAI-1 independent of PPARγ activation

    International Nuclear Information System (INIS)

    Liu, H.B.; Hu, Y.S.; Medcalf, R.L.; Simpson, R.W.; Dear, A.E.

    2005-01-01

    Increased plasminogen activator inhibitor type 1 (PAI-1) levels are observed in endothelial cells stimulated by tumour necrosis factor α (TNFα). Thiazolidinediones (TZDs) may inhibit elevated endothelial cell PAI-1 accounting, in part, for the putative atheroprotective effects of TZDs. In an endothelial cell line, Rosiglitazone (RG) and Pioglitazone (PG) inhibited induction of PAI-1 by TNFα. The specific peroxisome proliferator-activated receptor γ (PPARγ) inhibitor, SR-202, failed to modulate this effect. RG also inhibited the effect of TNFα on a reporter gene construct harbouring the proximal PAI-1 promoter and PAI-1 mRNA in cells co-transfected with a dominant-negative PPARγ construct. RG and PG attenuated TNFα-mediated induction of trans-acting factor(s) Nur77/Nurr1 and binding of nuclear proteins (NP) to the cis-acting element (NBRE). SR-202 failed to modulate these effects. The observations suggest TZDs inhibit TNFα-mediated PAI-1 induction independent of inducible PPARγ activation and this may involve in the modulation of Nur77/Nurr1 expression and NP binding to the PAI-1 NBRE

  6. Brain activation for response inhibition under gaming cue distraction in internet gaming disorder

    Directory of Open Access Journals (Sweden)

    Gin-Chung Liu

    2014-01-01

    Full Text Available We evaluated neural substrates related to the loss of control in college students with internet gaming disorder (IGD. We hypothesized that deficit in response inhibition under gaming cue distraction was the possible mechanism for the loss of control internet use. Eleven cases of IGD and 11 controls performed Go/NoGo tasks with/without gaming distraction in the functional magnetic resonance imaging scanner. When the gaming picture was shown as background while individuals were performing Go/NoGo tasks, the IGD group committed more commission errors. The control group increased their brain activations more over the right dorsolateral prefrontal cortex (DLPFC and superior parietal lobe under gaming cue distraction in comparison with the IGD group. Furthermore, brain activation of the right DLPFC and superior parietal lobe were negatively associated with performance of response inhibition among the IGD group. The results suggest that the function of response inhibition was impaired under gaming distraction among the IGD group, and individuals with IGD could not activate right DLPFC and superior parietal lobe to keep cognitive control and attention allocation for response inhibition under gaming cue distraction. This mechanism should be addressed in any intervention for IGD.

  7. Effects of protease-activated receptor 1 inhibition on anxiety and fear following status epilepticus.

    Science.gov (United States)

    Bogovyk, Ruslan; Lunko, Oleksii; Fedoriuk, Mihail; Isaev, Dmytro; Krishtal, Oleg; Holmes, Gregory L; Isaeva, Elena

    2017-02-01

    Protease-activated receptor 1 (PAR1) is an important contributor to the pathogenesis of a variety of brain disorders associated with a risk of epilepsy development. Using the lithium-pilocarpine model of temporal lobe epilepsy (TLE), we recently showed that inhibition of this receptor during the first ten days after pilocarpine-induced status epilepticus (SE) results in substantial anti-epileptogenic and neuroprotective effects. As PAR1 is expressed in the central nervous system regions of importance for processing emotional reactions, including amygdala and hippocampus, and TLE is frequently associated with a chronic alteration of the functions of these regions, we tested the hypothesis that PAR1 inhibition could modulate emotionally driven behavioral responses of rats experiencing SE. We showed that SE induces a chronic decrease in the animals' anxiety-related behavior and an increase of locomotor activity. PAR1 inhibition after SE abolished the alteration of the anxiety level but does not affect the increase of locomotor activity in the open field and elevated plus maze tests. Moreover, while PAR1 inhibition produces an impairment of memory recall in the context fear conditioning paradigm in the control group, it substantially improves contextual and cued fear learning in rats experiencing SE. These data suggest that PAR1-dependent signaling is involved in the mechanisms underlying emotional disorders in epilepsy. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Pyridine-substituted thiazolylphenol derivatives: Synthesis, modeling studies, aromatase inhibition, and antiproliferative activity evaluation.

    Science.gov (United States)

    Ertas, Merve; Sahin, Zafer; Berk, Barkin; Yurttas, Leyla; Biltekin, Sevde N; Demirayak, Seref

    2018-04-01

    Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non-steroidal-type inhibitors. Non-steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition. In this study, pyridine-substituted thiazolylphenol derivatives, which are non-steroidal triazole bioisosteres, were synthesized using the Hantzsch method, and physical analysis and structural determination studies were performed. The IC 50 values of the compounds were determined by a fluorescence-based aromatase inhibition assay. Then, their antiproliferative activities on the MCF7 and HEK 293 cell lines were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the crystal structure of human placental aromatase was subjected to a series of docking experiments to identify the possible interactions between the most active structure and the active site. Lastly, an in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules. © 2018 Deutsche Pharmazeutische Gesellschaft.

  9. Survivin inhibits anti-growth effect of p53 activated by aurora B

    International Nuclear Information System (INIS)

    Jung, Ji-Eun; Kim, Tae-Kyung; Lee, Joong-Seob; Oh, Se-Yeong; Kwak, Sungwook; Jin, Xun; Sohn, Jin-Young; Song, Min-Keun; Sohn, Young-Woo; Lee, Soo-Yeon; Pian, Xumin; Lee, Jang-Bo; Chung, Yong Gu; Choi, Young Ki; You, Seungkwon; Kim, Hyunggee

    2005-01-01

    Genomic instability and apoptosis evasion are hallmarks of cancer, but the molecular mechanisms governing these processes remain elusive. Here, we found that survivin, a member of the apoptosis-inhibiting gene family, and aurora B kinase, a chromosomal passenger protein, were co-overexpressed in the various glioblastoma cell lines and tumors. Notably, exogenous introduction of the aurora B in human BJ cells was shown to decrease cell growth and increase the senescence-associated β-galactosidase activity by activation of p53 tumor suppressor. However, aurora B overexpression failed to inhibit cell proliferation in BJ and U87MG cells transduced with dominant-negative p53 as well as in p53 -/- mouse astrocytes. Aurora B was shown to increase centrosome amplification in the p53 -/- astrocytes. Survivin was shown to induce anchorage-independent growth and inhibit anti-proliferation and drug-sensitive apoptosis caused by aurora B. Overexpression of both survivin and aurora B further accelerated the proliferation of BJ cells. Taken together, the present study indicates that survivin should accelerate tumorigenesis by inhibiting the anti-proliferative effect of p53 tumor suppressor that is activated by aurora B in normal and glioblastoma cells containing intact p53

  10. cGMP-Phosphodiesterase Inhibition Prevents Hypoxia-Induced Cell Death Activation in Porcine Retinal Explants.

    Directory of Open Access Journals (Sweden)

    Lorena Olivares-González

    Full Text Available Retinal hypoxia and oxidative stress are involved in several retinal degenerations including diabetic retinopathy, glaucoma, central retinal artery occlusion, or retinopathy of prematurity. The second messenger cyclic guanosine monophosphate (cGMP has been reported to be protective for neuronal cells under several pathological conditions including ischemia/hypoxia. The purpose of this study was to evaluate whether the accumulation of cGMP through the pharmacological inhibition of phosphodiesterase (PDE with Zaprinast prevented retinal degeneration induced by mild hypoxia in cultures of porcine retina. Exposure to mild hypoxia (5% O2 for 24h reduced cGMP content and induced retinal degeneration by caspase dependent and independent (PARP activation mechanisms. Hypoxia also produced a redox imbalance reducing antioxidant response (superoxide dismutase and catalase activities and increasing superoxide free radical release. Zaprinast reduced mild hypoxia-induced cell death through inhibition of caspase-3 or PARP activation depending on the cell layer. PDE inhibition also ameliorated the effects of mild hypoxia on antioxidant response and the release of superoxide radical in the photoreceptor layer. The use of a PKG inhibitor, KT5823, suggested that cGMP-PKG pathway is involved in cell survival and antioxidant response. The inhibition of PDE, therefore, could be useful for reducing retinal degeneration under hypoxic/ischemic conditions.

  11. Cytostatic versus cytocidal activities of chloroquine analogues and inhibition of hemozoin crystal growth.

    Science.gov (United States)

    Gorka, Alexander P; Alumasa, John N; Sherlach, Katy S; Jacobs, Lauren M; Nickley, Katherine B; Brower, Jonathan P; de Dios, Angel C; Roepe, Paul D

    2013-01-01

    We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365-374, 2013).

  12. O-sulfated bacterial polysaccharides with low anticoagulant activity inhibit metastasis.

    Science.gov (United States)

    Borgenström, Marjut; Wärri, Anni; Hiilesvuo, Katri; Käkönen, Rami; Käkönen, Sanna; Nissinen, Liisa; Pihlavisto, Marjo; Marjamäki, Anne; Vlodavsky, Israel; Naggi, Annamaria; Torri, Giangiacomo; Casu, Benito; Veromaa, Timo; Salmivirta, Markku; Elenius, Klaus

    2007-07-01

    Heparin-like polysaccharides possess the capacity to inhibit cancer cell proliferation, angiogenesis, heparanase-mediated cancer cell invasion, and cancer cell adhesion to vascular endothelia via adhesion receptors, such as selectins. The clinical applicability of the antitumor effect of such polysaccharides, however, is compromised by their anticoagulant activity. We have compared the potential of chemically O-sulfated and N,O-sulfated bacterial polysaccharide (capsular polysaccharide from E. COLI K5 [K5PS]) species to inhibit metastasis of mouse B16-BL6 melanoma cells and human MDA-MB-231 breast cancer cells in two in vivo models. We demonstrate that in both settings, O-sulfated K5PS was a potent inhibitor of metastasis. Reducing the molecular weight of the polysaccharide, however, resulted in lower antimetastatic capacity. Furthermore, we show that O-sulfated K5PS efficiently inhibited the invasion of B16-BL6 cells through Matrigel and also inhibited the in vitro activity of heparanase. Moreover, treatment with O-sulfated K5PS lowered the ability of B16-BL6 cells to adhere to endothelial cells, intercellular adhesion molecule-1, and P-selectin, but not to E-selectin. Importantly, O-sulfated K5PSs were largely devoid of anticoagulant activity. These findings indicate that O-sulfated K5PS polysaccharide should be considered as a potential antimetastatic agent.

  13. The importance of the renin-angiotensin system in normal cardiovascular homeostasis

    Science.gov (United States)

    Haber, E.

    1975-01-01

    Studies were carried out on adult mongrel dogs (20 to 30 kilograms) to investigate the importance of the renin-angiotensin system. Results indicate that the renin-angiotensin system plays a major role in the maintenance of circulatory homeostasis when extracellular fluid volume is depleted. It was also found that angiotensin II concentration, in addition to renal perfusion pressure, is a factor in the regulation of renin release.

  14. Neuroprotection of Scutellarin is mediated by inhibition of microglial inflammatory activation.

    Science.gov (United States)

    Wang, S; Wang, H; Guo, H; Kang, L; Gao, X; Hu, L

    2011-06-30

    Inhibition of microglial over-reaction and the inflammatory processes may represent a therapeutic target to alleviate the progression of neurological diseases, such as neurodegenerative diseases and stroke. Scutellarin is the major active component of Erigeron breviscapus (Vant.) Hand-Mazz, a herbal medicine in treatment of cerebrovascular diseases for a long time in the Orient. In this study, we explored the mechanisms of neuroprotection by Scutellarin, particularly its anti-inflammatory effects in microglia. We observed that Scutellarin inhibited lipopolysaccharide (LPS)-induced production of proinflammatory mediators such as nitric oxide (NO), tumor necrosis factor α (TNFα), interleukin-1β (IL-1β) and reactive oxygen species (ROS), suppressed LPS-stimulated inducible nitric oxide synthase (iNOS), TNFα, and IL-1β mRNA expression in rat primary microglia or BV-2 mouse microglial cell line. Scutellarin inhibited LPS-induced nuclear translocation and DNA binding activity of nuclear factor κB (NF-κB). It repressed the LPS-induced c-Jun N-terminal kinase (JNK) and p38 phosphorylation without affecting the activity of extracellular signal regulated kinase (ERK) mitogen-activated protein kinase. Moreover, Scutellarin also inhibited interferon-γ (IFN-γ)-induced NO production, iNOS mRNA expression and transcription factor signal transducer and activator of transcription 1α (STAT1α) activation. Concomitantly, conditioned media from Scutellarin pretreated BV-2 cells significantly reduced neurotoxicity compared with conditioned media from LPS treated alone. Together, the present study reported the anti-inflammatory activity of Scutellarin in microglial cells along with their underlying molecular mechanisms, and suggested Scutellarin might have therapeutic potential for various microglia mediated neuroinflammation. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Hydrogenase activity in Azospirillum brasilense is inhibited by nitrite, nitric oxide, carbon monoxide, and acetylene

    Energy Technology Data Exchange (ETDEWEB)

    Tibelius, K.H.; Knowles, R.

    1984-10-01

    Nitrite, NO, CO, and C/sub 2/H/sub 2/ inhibited O/sub 2/-dependent H/sub 2/ uptake (H/sup 3/H oxidation) in denitrifying Azospirillum brasilense Sp7 grown anaerobically on N/sub 2/O or NO/sub 3//sup -/. The apparent K/sub i/ values for inhibition of O/sub 2/-dependent H/sub 2/ uptake were 20 ..mu..M for NO/sub 2//sup -/, 0.4 ..mu..M for NO, 28 ..mu..M for CO, and 88 ..mu..M for C/sub 2/H/sub 2/. These inhibitors also affected methylene blue-dependent H/sub 2/ uptake, presumably by acting directly on the hydrogenase. Nitrite and NO inhibited H/sub 2/ uptake irreversibly, whereas inhibition due to CO was easily reversed by repeatedly evacuating and backfilling with N/sub 2/. The C/sub 2/H/sub 2/ inhibition was not readily reversed, partly due to difficulty in removing the last traces of this gas from solution. The NO/sub 2//sup -/ inhibition of malate-dependent respiration was readily reversed by repeatedly washing the cells, in contrast to the effect of NO/sub 2//sup -/ on H/sub 2/-dependent respiration. These results suggest that the low hydrogenase activities observed in NO/sub 3//sup -/-grown cultures of A. brasilense may be due to the irreversible inhibition of hydrogenase by NO/sub 2//sup -/ and NO produced by NO/sub 3//sup -/ reduction.

  16. Inhibition of enzyme activity by nanomaterials: potential mechanisms and implications for nanotoxicity testing.

    Science.gov (United States)

    Maccormack, Tyson J; Clark, Rhett J; Dang, Michael K M; Ma, Guibin; Kelly, Joel A; Veinot, Jonathan G C; Goss, Greg G

    2012-08-01

    The objective of this study was to investigate whether nanoparticle-exposure affects enzyme function and to determine the mechanisms responsible. Silicon, Au, and CdSe nanoparticles were synthesized in house and their physicochemical properties were characterized. The activity of purified lactate dehydrogenase (LDH) was inhibited or abolished by all nanoparticles tested. Inhibition was dependent upon particle core and surface-functional group composition. Inhibition of LDH was absent in crude tissue homogenates, in the presence of albumin, and at the isoelectric point of the protein, indicating that nanoparticles bind non-specifically to abundant proteins via a charge interaction. Circular dichroism spectroscopy suggests that the structure of LDH may be altered by nanoparticles in a manner different from that of bulk controls. We present new data on the specific physicochemical properties of nanoparticles that may lead to bioactivity and highlight a number of potentially serious problems with common nanotoxicity testing methods.

  17. Free radical scavenging activity and lipoxygenase inhibition of Mahonia aquifolium extract and isoquinoline alkaloids

    Directory of Open Access Journals (Sweden)

    Kettmann Viktor

    2007-07-01

    Full Text Available Abstract Roots and stem-bark of Mahonia aquifolium (Oregon grape (Berberidaceae are effectively used in the treatment of skin inflammatory conditions. In the present study, the effect of Mahonia aquifolium crude extract and its two representative alkaloid fractions containing protoberberine and bisbenzylisoquinoline (BBIQ alkaloids on activity of 12-lipoxygenase (12-LOX, was studied. The reactivity with 1,1-diphenyl-2-picryl-hydrazyl (DPPH, a free stable radical, was evaluated to elucidate the rate of possible lipid-derived radical scavenging in the mechanism of the enzyme inhibition. The results indicate that although the direct radical scavenging mechanism cannot be ruled out in the lipoxygenase inhibition by Mahonia aquifolium and its constituents, other mechanisms based on specific interaction between enzyme and alkaloids could play the critical role in the lipoxygenase inhibition rather than non-specific reactivity with free radicals.

  18. HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes.

    Directory of Open Access Journals (Sweden)

    Beth S Zha

    Full Text Available HIV protease inhibitors (PI are core components of Highly Active Antiretroviral Therapy (HAART, the most effective treatment for HIV infection currently available. However, HIV PIs have now been linked to lipodystrophy and dyslipidemia, which are major risk factors for cardiovascular disease and metabolic syndrome. Our previous studies have shown that HIV PIs activate endoplasmic reticulum (ER stress and disrupt lipid metabolism in hepatocytes and macrophages. Yet, little is known on how HIV PIs disrupt lipid metabolism in adipocytes, a major cell type involved in the pathogenesis of metabolic syndrome.Cultured and primary mouse adipocytes and human adipocytes were used to examine the effect of frequently used HIV PIs in the clinic, lopinavir/ritonavir, on adipocyte differentiation and further identify the underlying molecular mechanism of HIV PI-induced dysregulation of lipid metabolism in adipocytes. The results indicated that lopinavir alone or in combination with ritonavir, significantly activated the ER stress response, inhibited cell differentiation, and induced cell apoptosis in adipocytes. In addition, HIV PI-induced ER stress was closely linked to inhibition of autophagy activity. We also identified through the use of primary adipocytes of CHOP(-/- mice that CHOP, the major transcriptional factor of the ER stress signaling pathway, is involved in lopinavir/ritonavir-induced inhibition of cell differentiation in adipocytes. In addition, lopinavir/ritonavir-induced ER stress appears to be associated with inhibition of autophagy activity in adipocytes.Activation of ER stress and impairment of autophagy activity are involved in HIV PI-induced dysregulation of lipid metabolism in adipocytes. The key components of ER stress and autophagy signaling pathways are potential therapeutic targets for HIV PI-induced metabolic side effects in HIV patients.

  19. Lipid peroxidation inhibition and antiradical activities of some leaf fractions of Mangifera indica.

    Science.gov (United States)

    Badmus, Jelili A; Adedosu, Temitope O; Fatoki, John O; Adegbite, Victor A; Adaramoye, Oluwatosin A; Odunola, Oyeronke A

    2011-01-01

    This study was undertaken to assess in vitro lipid peroxidation inhibitions and anti-radical activities of methanolic, chloroform, ethyl acetate and water fractions of Mangifera indica leaf. Inhibition of Fe(2+)-induced lipid peroxidation (LPO) in egg, brain, and liver homogenates, 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydroxyl (OH-) radical scavenging activities were evaluated. Total phenol was assessed in all fractions, and the reducing power of methanolic fraction was compared to gallic acid and ascorbic acid. The results showed that Fe2+ induced significant lipid peroxidation (LPO) in all the homogenates. Ethyl acetate fraction showed the highest percentage inhibition of LPO in both egg yolk (68.3%) and brain (66.3%), while the aqueous fraction exerted the highest inhibition in liver homogenate (89.1%) at a concentration of 10 microg/mL. These observed inhibitions of LPO by these fractions were higher than that of ascorbic acid used as a standard. The DPPH radical scavenging ability exhibited by ethyl acetate fraction was found to be the highest with IC50 value of 1.5 microg/mL. The ethyl acetate and methanolic fractions had the highest OH- radical scavenging ability with the same IC50 value of 5 microg/mL. The total phenol content of ethyl acetate fraction was the highest with 0.127 microg/mg gallic acid equivalent (GAE). The reductive potential of methanolic fraction showed a concentration-dependent increase. This study showed that inhibition of LPO and the DPPH and OH- radicals scavenging abilities of Mangifera indica leaf could be related to the presence of phenolic compounds. Therefore, the ethyl acetate fraction of the leaf may be a good source of natural antioxidative agent.

  20. Manuka honey (Leptospermum scoparium) inhibits jack bean urease activity due to methylglyoxal and dihydroxyacetone.

    Science.gov (United States)

    Rückriemen, Jana; Klemm, Oliver; Henle, Thomas

    2017-09-01

    Manuka honey (Leptospermum scoparium) exerts a strong antibacterial effect. Bacterial enzymes are an important target for antibacterial compounds. The enzyme urease produces ammonia and enables bacteria to adapt to an acidic environment. A new enzymatic assay, based on photometric detection of ammonia with ninhydrin, was developed to study urease activity. Methylglyoxal (MGO) and its precursor dihydroxyacetone (DHA), which are naturally present in manuka honey, were identified as jack bean urease inhibitors with IC 50 values of 2.8 and 5.0mM, respectively. Urease inhibition of manuka honey correlates with its MGO and DHA content. Non-manuka honeys, which lack MGO and DHA, showed significantly less urease inhibition. MGO depletion from manuka honey with glyoxalase reduced urease inhibition. Therefore, urease inhibition by manuka honey is mainly due to MGO and DHA. The results obtained with jack bean urease as a model urease, may contribute to the understanding of bacterial inhibition by manuka honey. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Isolation, Identification, and Xanthine Oxidase Inhibition Activity of Alkaloid Compound from Peperomia pellucida

    Science.gov (United States)

    Fachriyah, E.; Ghifari, M. A.; Anam, K.

    2018-04-01

    The research of the isolation and xanthine oxidation inhibition activity of alkaloid compound from Peperomia pellucida has been carried out. Alkaloid extract is isolated by column chromatography and preparative TLC. Alkaloid isolate is identified spectroscopically by UV-Vis spectrophotometer, FT-IR, and LC-MS/MS. Xanthine oxidase inhibition activity is carried out by in vitro assay. The result showed that the alkaloid isolated probably has piperidine basic structure. The alkaloid isolate has N-H, C-H, C = C, C = O, C-N, C-O-C groups and the aromatic ring. The IC50 values of ethanol and alkaloid extract are 71.6658 ppm and 76.3318 ppm, respectively. Alkaloid extract of Peperomia pellucida showed higher activity than ethanol extract.

  2. Inhibition of NF-κB activity in rabbit vascular smooth muscle cells by lovastatin

    International Nuclear Information System (INIS)

    Luan Zhaoxia; Lan Xiaoli

    2003-01-01

    Nuclear factor NF-κB is believed to play an important role in regulating the production of matrix metalloproteinase (MMPs), which induce atherosclerosis, restenosis and plaque rupture. We incubated rabbit vascular smooth muscle cells (RVSMCs) with 5 μmol/L lovastatin in the presence of IL-1-α and PDGF BB (20 μg/L, respectively) to study whether lovastatin inhibited NF-κB binding activity induced by IL-1 and PDGF. The NF-κB activity was detected by electrophoretic mobility shift assay (EMSA); MMP-1 and MMP-3 were measured by western blotting; and MMP-9 was detected by zymography. The result showed that lovastatin strongly reduced NF-κB activity upregulated by IL-1 combined with PDGF, and lovastatin also dose-dependently inhibited the expression of MMP-1, -3 and -9 induced by IL-1 and PDGF. It suggested that the beneficial effects of statins may extend to mechanisms beyond cholesterol reduction

  3. Apigenin Restricts FMDV Infection and Inhibits Viral IRES Driven Translational Activity

    Directory of Open Access Journals (Sweden)

    Suhong Qian

    2015-03-01

    Full Text Available Foot-and-mouth disease (FMD is a highly contagious disease of domestic and wild ruminants that is caused by FMD virus (FMDV. FMD outbreaks have occurred in livestock-containing regions worldwide. Apigenin, which is a flavonoid naturally existing in plant, possesses various pharmacological effects, including anti-inflammatory, anticancer, antioxidant and antiviral activities. Results show that apigenin can inhibit FMDV-mediated cytopathogenic effect and FMDV replication in vitro. Further studies demonstrate the following: (i apigenin inhibits FMDV infection at the viral post-entry stage; (ii apigenin does not exhibit direct extracellular virucidal activity; and (iii apigenin interferes with the translational activity of FMDV driven by internal ribosome entry site. Studies on applying apigein in vivo are required for drug development and further identification of potential drug targets against FDMV infection.

  4. Picomolar-affinity binding and inhibition of adenylate cyclase activity by melatonin in Syrian hamster hypothalamus

    International Nuclear Information System (INIS)

    Niles, L.P.; Hashemi, F.

    1990-01-01

    1. The effect of melatonin on forskolin-stimulated adenylate cyclase activity was measured in homogenates of Syrian hamster hypothalamus. In addition, the saturation binding characteristics of the melatonin receptor ligand, [ 125 I]iodomelatonin, was examined using an incubation temperature (30 degree C) similar to that used in enzyme assays. 2. At concentrations ranging from 10 pM to 1 nM, melatonin caused a significant decrease in stimulated adenylate cyclase activity with a maximum inhibition of approximately 22%. 3. Binding experiments utilizing [ 125 I]iodomelatonin in a range of approximately 5-80 pM indicated a single class of high-affinity sites: Kd = 55 +/- 9 pM, Bmax = 1.1 +/- 0.3 fmol/mg protein. 4. The ability of picomolar concentrations of melatonin to inhibit forskolin-stimulated adenylate cyclase activity suggests that this affect is mediated by picomolar-affinity receptor binding sites for this hormone in the hypothalamus

  5. Apigenin restricts FMDV infection and inhibits viral IRES driven translational activity.

    Science.gov (United States)

    Qian, Suhong; Fan, Wenchun; Qian, Ping; Zhang, Dong; Wei, Yurong; Chen, Huanchun; Li, Xiangmin

    2015-03-31

    Foot-and-mouth disease (FMD) is a highly contagious disease of domestic and wild ruminants that is caused by FMD virus (FMDV). FMD outbreaks have occurred in livestock-containing regions worldwide. Apigenin, which is a flavonoid naturally existing in plant, possesses various pharmacological effects, including anti-inflammatory, anticancer, antioxidant and antiviral activities. Results show that apigenin can inhibit FMDV-mediated cytopathogenic effect and FMDV replication in vitro. Further studies demonstrate the following: (i) apigenin inhibits FMDV infection at the viral post-entry stage; (ii) apigenin does not exhibit direct extracellular virucidal activity; and (iii) apigenin interferes with the translational activity of FMDV driven by internal ribosome entry site. Studies on applying apigein in vivo are required for drug development and further identification of potential drug targets against FDMV infection.

  6. Prediction of renovascualar hypertension by captopril-stimulated renal vein renin ratios

    International Nuclear Information System (INIS)

    Roubidoux, M.A.; Dunnick, N.R.; Svetkey, L.; Newmann, G.E.; Cohan, R.H.; Kadir, S.; Klotman, P.

    1989-01-01

    The authors have prospectively studied 114 patients with suspected renovascular hypertension to determine whether captopril-stimulated, selective, renal vein renin ratios could be used to predict renovascular hypertension. As judged by the response to correction of renal artery lesions, 14 patients had renovascular hypertension, and renal vein renin ratios were significant in eight (sensitivity 57%). Overall, the positive predictive value of renal vein renin ratios was 33%, and the negative predictive value was 89%. The authors concluded that, in patients with renal artery stenosis, renal vein renin ratios predict neither the need for conventional arteriography nor potential benefit from the correction of vascular insufficiency

  7. Kynurenic acid inhibits intestinal hypermotility and xanthine oxidase activity during experimental colon obstruction in dogs.

    Science.gov (United States)

    Kaszaki, J; Palásthy, Z; Erczes, D; Rácz, A; Torday, C; Varga, G; Vécsei, L; Boros, M

    2008-01-01

    Kynurenic acid (KynA), an endogenous antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors, protects the central nervous system in excitotoxic neurological diseases. We hypothesized that the inhibition of enteric glutamate receptors by KynA may influence dysmotility in the gastrointestinal tract. Group 1 of healthy dogs served as the sham-operated control, in group 2, the animals were treated with KynA, while in groups 3 and 4 mechanical colon obstruction was maintained for 7 h. Group 4 was treated with KynA at the onset of ileus. Hemodynamics and motility changes were monitored, and the activities of xanthine oxidoreductase (XOR) and myeloperoxidase (MPO) were determined from tissue samples. Colon obstruction induced a hyperdynamic circulatory reaction, significantly elevated the motility index and increased the mucosal leucocyte accumulation and the XOR activity. The KynA treatment augmented the tone of the colon, permanently decreased the motility index of the giant colonic contractions and reduced the increases in XOR and MPO activities. These effects were concomitant with the in vitro inhibition of XOR activity. In conclusion, KynA antagonizes the obstruction-induced motility responses and XOR activation in the colon. Inhibition of enteric NMDA receptors may provide an option to influence intestinal hypermotility and inflammatory changes.

  8. Environmentally persistent free radicals inhibit cytochrome P450 activity in rat liver microsomes

    Energy Technology Data Exchange (ETDEWEB)

    Reed, James R., E-mail: rreed@lsuhsc.edu [Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Science Center, 533 Bolivar St., New Orleans, LA 70112 (United States); The Stanley S. Scott Cancer Center, Louisiana State University Health Science Center, 533 Bolivar St., New Orleans, LA 70112 (United States); Cawley, George F.; Ardoin, Taylor G. [Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Science Center, 533 Bolivar St., New Orleans, LA 70112 (United States); The Stanley S. Scott Cancer Center, Louisiana State University Health Science Center, 533 Bolivar St., New Orleans, LA 70112 (United States); Dellinger, Barry; Lomnicki, Slawomir M.; Hasan, Farhana; Kiruri, Lucy W. [Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803 (United States); Backes, Wayne L. [Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Science Center, 533 Bolivar St., New Orleans, LA 70112 (United States); The Stanley S. Scott Cancer Center, Louisiana State University Health Science Center, 533 Bolivar St., New Orleans, LA 70112 (United States)

    2014-06-01

    Combustion processes generate particulate matter that affects human health. When incineration fuels include components that are highly enriched in aromatic hydrocarbons (especially halogenated varieties) and redox-active metals, ultrafine particulate matter containing air-stable, environmentally persistent free radicals (EPFRs) is generated. The exposure to fine EPFRs (less than 2.5 μm in diameter) has been shown to negatively influence pulmonary and cardiovascular functions in living organisms. The goal of this study was to determine if these EPFRs have a direct effect on cytochrome P450 function. This was accomplished by direct addition of the EPFRs to rat liver microsomal preparations and measurement of several P450 activities using form-selective substrates. The EPFRs used in this study were formed by heating vapors from an organic compound (either monochlorophenol (MCP230) or 1,2-dichlorobenzene (DCB230)) and 5% copper oxide supported on silica (approximately 0.2 μm in diameter) to 230 °C under vacuum. Both types of EPFRs (but not silica, physisorbed silica, or silica impregnated with copper oxide) dramatically inhibited the activities of CYP1A, CYP2B, CYP2E1, CYP2D2 and CYP3A when incubated at concentrations less than 0.1 mg/ml with microsomes and NADPH. Interestingly, at the same concentrations, the EPFRs did not inhibit HO-1 activity or the reduction of cytochrome c by NADPH-cytochrome P450 reductase. CYP2D2-selective metabolism by rat liver microsomes was examined in more detail. The inhibition of CYP2D2-selective metabolism by both DCB230- and MCP230-EPFRs appeared to be largely noncompetitive and was attenuated in the presence of catalase suggesting that reactive oxygen species may be involved in the mechanism of inhibition. - Highlights: • Combustion of organic pollutants generates long-lived particulate radicals (EPFRs). • EPFRs inhibit metabolism by all cytochromes P450 tested in rat liver microsomes. • EPFR-mediated inhibition is related to

  9. Environmentally persistent free radicals inhibit cytochrome P450 activity in rat liver microsomes

    International Nuclear Information System (INIS)

    Reed, James R.; Cawley, George F.; Ardoin, Taylor G.; Dellinger, Barry; Lomnicki, Slawomir M.; Hasan, Farhana; Kiruri, Lucy W.; Backes, Wayne L.

    2014-01-01

    Combustion processes generate particulate matter that affects human health. When incineration fuels include components that are highly enriched in aromatic hydrocarbons (especially halogenated varieties) and redox-active metals, ultrafine particulate matter containing air-stable, environmentally persistent free radicals (EPFRs) is generated. The exposure to fine EPFRs (less than 2.5 μm in diameter) has been shown to negatively influence pulmonary and cardiovascular functions in living organisms. The goal of this study was to determine if these EPFRs have a direct effect on cytochrome P450 function. This was accomplished by direct addition of the EPFRs to rat liver microsomal preparations and measurement of several P450 activities using form-selective substrates. The EPFRs used in this study were formed by heating vapors from an organic compound (either monochlorophenol (MCP230) or 1,2-dichlorobenzene (DCB230)) and 5% copper oxide supported on silica (approximately 0.2 μm in diameter) to 230 °C under vacuum. Both types of EPFRs (but not silica, physisorbed silica, or silica impregnated with copper oxide) dramatically inhibited the activities of CYP1A, CYP2B, CYP2E1, CYP2D2 and CYP3A when incubated at concentrations less than 0.1 mg/ml with microsomes and NADPH. Interestingly, at the same concentrations, the EPFRs did not inhibit HO-1 activity or the reduction of cytochrome c by NADPH-cytochrome P450 reductase. CYP2D2-selective metabolism by rat liver microsomes was examined in more detail. The inhibition of CYP2D2-selective metabolism by both DCB230- and MCP230-EPFRs appeared to be largely noncompetitive and was attenuated in the presence of catalase suggesting that reactive oxygen species may be involved in the mechanism of inhibition. - Highlights: • Combustion of organic pollutants generates long-lived particulate radicals (EPFRs). • EPFRs inhibit metabolism by all cytochromes P450 tested in rat liver microsomes. • EPFR-mediated inhibition is related to

  10. FK866-induced NAMPT inhibition activates AMPK and downregulates mTOR signaling in hepatocarcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Schuster, Susanne, E-mail: Susanne.Schuster@medizin.uni-leipzig.de [Center for Pediatric Research Leipzig, University Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Liebigstr. 21, 04103 Leipzig (Germany); Penke, Melanie; Gorski, Theresa [Center for Pediatric Research Leipzig, University Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Liebigstr. 21, 04103 Leipzig (Germany); Gebhardt, Rolf [Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Johannisallee 30, 04103 Leipzig (Germany); Weiss, Thomas S. [Children' s University Hospital, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg (Germany); Kiess, Wieland; Garten, Antje [Center for Pediatric Research Leipzig, University Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Liebigstr. 21, 04103 Leipzig (Germany)

    2015-03-06

    Background: Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme of the NAD salvage pathway starting from nicotinamide. Cancer cells have an increased demand for NAD due to their high proliferation and DNA repair rate. Consequently, NAMPT is considered as a putative target for anti-cancer therapies. There is evidence that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) become dysregulated during the development of hepatocellular carcinoma (HCC). Here, we investigated the effects of NAMPT inhibition by its specific inhibitor FK866 on the viability of hepatocarcinoma cells and analyzed the effects of FK866 on the nutrient sensor AMPK and mTOR complex1 (mTORC1) signaling. Results: FK866 markedly decreased NAMPT activity and NAD content in hepatocarcinoma cells (Huh7 cells, Hep3B cells) and led to delayed ATP reduction which was associated with increased cell death. These effects could be abrogated by administration of nicotinamide mononucleotide (NMN), the enzyme product of NAMPT. Our results demonstrated a dysregulation of the AMPK/mTOR pathway in hepatocarcinoma cells compared to non-cancerous hepatocytes with a higher expression of mTOR and a lower AMPKα activation in hepatocarcinoma cells. We found that NAMPT inhibition by FK866 significantly activated AMPKα and inhibited the activation of mTOR and its downstream targets p70S6 kinase and 4E-BP1 in hepatocarcinoma cells. Non-cancerous hepatocytes were less sensitive to FK866 and did not show changes in AMPK/mTOR signaling after FK866 treatment. Conclusion: Taken together, these findings reveal an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of hepatocarcinoma cells and suggest NAMPT inhibition as a potential treatment option for HCC. - Highlights: • FK866 increases cell death in p53-deficient hepatocarcinoma cells. • AMPK/mTOR signaling is dysregulated in hepatocarcinoma cells. • FK866-induced NAMPT inhibition activates AMPK

  11. FK866-induced NAMPT inhibition activates AMPK and downregulates mTOR signaling in hepatocarcinoma cells

    International Nuclear Information System (INIS)

    Schuster, Susanne; Penke, Melanie; Gorski, Theresa; Gebhardt, Rolf; Weiss, Thomas S.; Kiess, Wieland; Garten, Antje

    2015-01-01

    Background: Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme of the NAD salvage pathway starting from nicotinamide. Cancer cells have an increased demand for NAD due to their high proliferation and DNA repair rate. Consequently, NAMPT is considered as a putative target for anti-cancer therapies. There is evidence that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) become dysregulated during the development of hepatocellular carcinoma (HCC). Here, we investigated the effects of NAMPT inhibition by its specific inhibitor FK866 on the viability of hepatocarcinoma cells and analyzed the effects of FK866 on the nutrient sensor AMPK and mTOR complex1 (mTORC1) signaling. Results: FK866 markedly decreased NAMPT activity and NAD content in hepatocarcinoma cells (Huh7 cells, Hep3B cells) and led to delayed ATP reduction which was associated with increased cell death. These effects could be abrogated by administration of nicotinamide mononucleotide (NMN), the enzyme product of NAMPT. Our results demonstrated a dysregulation of the AMPK/mTOR pathway in hepatocarcinoma cells compared to non-cancerous hepatocytes with a higher expression of mTOR and a lower AMPKα activation in hepatocarcinoma cells. We found that NAMPT inhibition by FK866 significantly activated AMPKα and inhibited the activation of mTOR and its downstream targets p70S6 kinase and 4E-BP1 in hepatocarcinoma cells. Non-cancerous hepatocytes were less sensitive to FK866 and did not show changes in AMPK/mTOR signaling after FK866 treatment. Conclusion: Taken together, these findings reveal an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of hepatocarcinoma cells and suggest NAMPT inhibition as a potential treatment option for HCC. - Highlights: • FK866 increases cell death in p53-deficient hepatocarcinoma cells. • AMPK/mTOR signaling is dysregulated in hepatocarcinoma cells. • FK866-induced NAMPT inhibition activates AMPK

  12. Crystal structure, phytochemical study and enzyme inhibition activity of Ajaconine and Delectinine

    Science.gov (United States)

    Ahmad, Shujaat; Ahmad, Hanif; Khan, Hidayat Ullah; Shahzad, Adnan; Khan, Ezzat; Ali Shah, Syed Adnan; Ali, Mumtaz; Wadud, Abdul; Ghufran, Mehreen; Naz, Humera; Ahmad, Manzoor

    2016-11-01

    The Crystal structure, comparative DFT study and phytochemical investigation of atisine type C-20 diterpenoid alkaloid ajaconine (1) and lycoctonine type C-19 diterpenoid alkaloid delectinine (2) is reported here. These compounds were isolated from Delphinium chitralense. Both the natural products 1 and 2 crystallize in orthorhombic crystal system with identical space group of P212121. The geometric parameters of both compounds were calculated with the help of DFT using B3LYP/6-31+G (p) basis set and HOMO-LUMO energies, optimized band gaps, global hardness, ionization potential, electron affinity and global electrophilicity are calculated. The compounds 1 and 2 were screened for acetyl cholinesterase and butyryl cholinesterase inhibition activities in a dose dependent manner followed by molecular docking to explore the possible inhibitory mechanism of ajaconine (1) and delectinine (2). The IC50 values of tested compounds against AChE were observed as 12.61 μM (compound 1) and 5.04 μM (compound 2). The same experiments were performed for inhibition of BChE and IC50 was observed to be 10.18 μM (1) and 9.21 μM (2). Promising inhibition activity was shown by both the compounds against AChE and BChE in comparison with standard drugs available in the market such as allanzanthane and galanthamine. The inhibition efficiency of both the natural products was determined in a dose dependent manner.

  13. Inhibition of p53 acetylation by INHAT subunit SET/TAF-Iβ represses p53 activity.

    Science.gov (United States)

    Kim, Ji-Young; Lee, Kyu-Sun; Seol, Jin-Ee; Yu, Kweon; Chakravarti, Debabrata; Seo, Sang-Beom

    2012-01-01

    The tumor suppressor p53 responds to a wide variety of cellular stress signals. Among potential regulatory pathways, post-translational modifications such as acetylation by CBP/p300 and PCAF have been suggested for modulation of p53 activity. However, exactly how p53 acetylation is modulated remains poorly understood. Here, we found that SET/TAF-Iβ inhibited p300- and PCAF-mediated p53 acetylation in an INHAT (inhibitor of histone acetyltransferase) domain-dependent manner. SET/TAF-Iβ interacted with p53 and repressed transcription of p53 target genes. Consequently, SET/TAF-Iβ blocked both p53-mediated cell cycle arrest and apoptosis in response to cellular stress. Using different apoptosis analyses, including FACS, TUNEL and BrdU incorporation assays, we also found that SET/TAF-Iβ induced cellular proliferation via inhibition of p53 acetylation. Furthermore, we observed that apoptotic Drosophila eye phenotype induced by either dp53 overexpression or UV irradiation was rescued by expression of dSet. Inhibition of dp53 acetylation by dSet was observed in both cases. Our findings provide new insights into the regulation of stress-induced p53 activation by HAT-inhibiting histone chaperone SET/TAF-Iβ.

  14. Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation.

    Science.gov (United States)

    Wang, Gene-Jack; Volkow, Nora D; Telang, Frank; Jayne, Millard; Ma, Yeming; Pradhan, Kith; Zhu, Wei; Wong, Christopher T; Thanos, Panayotis K; Geliebter, Allan; Biegon, Anat; Fowler, Joanna S

    2009-01-27

    Although impaired inhibitory control is linked to a broad spectrum of health problems, including obesity, the brain mechanism(s) underlying voluntary control of hunger are not well understood. We assessed the brain circuits involved in voluntary inhibition of hunger during food stimulation in 23 fasted men and women using PET and 2-deoxy-2[(18)F]fluoro-D-glucose ((18)FDG). In men, but not in women, food stimulation with inhibition significantly decreased activation in amygdala, hippocampus, insula, orbitofrontal cortex, and striatum, which are regions involved in emotional regulation, conditioning, and motivation. The suppressed activation of the orbitofrontal cortex with inhibition in men was associated with decreases in self-reports of hunger, which corroborates the involvement of this region in processing the conscious awareness of the drive to eat. This finding suggests a mechanism by which cognitive inhibition decreases the desire for food and implicates lower ability to suppress hunger in women as a contributing factor to gender differences in obesity.

  15. Chinese medicinal formula Fufang Xueshuantong capsule could inhibit the activity of angiotensin converting enzyme

    Science.gov (United States)

    Sheng, Shujing; Wang, Yonggang; Long, Chaofeng; Su, Weiwei; Rong, Xia

    2014-01-01

    Fufang Xueshuantong (FXST) capsule, a Chinese medicinal formula composed of four herbals – Panax notoginseng, Radix Astragali, Radix Salvia Miltiorrhizae and Radix Scrophulariaceae, has been used to treat cardiovascular diseases for many years, but the pharmacological mechanisms underlying its effects has not been clarified. This study investigates if a connection between FXST and angiotensin converting enzyme (ACE) might be an explanation for its pharmacological effects. ACE inhibition assay was performed on FXST capsule, 50% ethanol extracts from the four herbals and three selected saponins most abundant in P. notoginseng (Ginsenoside Rg1, Ginsenoside Rb1 and Notoginsenoside R1) using a biochemical test. Reversed-phase high-performance liquid chromatography of liberated hippuric acid from the ACE assay was conducted to determine the inhibitory effect. As a result, FXST and extracts from P. notoginseng showed a significant and dose-dependent inhibition on ACE activity with the IC50 values of 115 μg/ml and 179 μg/ml, respectively. But extracts from the other three herbals and the three selected saponins had no significant effect on ACE inhibition. Compared to other reported plant extracts, FXST could be considered as an effective ACE inhibitor. The inhibition of ACE activity supports the traditional use of FXST on blood circulation and the inhibitory property of FXST is mainly caused by P. notoginseng. PMID:26019516

  16. Inhibition of nuclear factor-kappa B activation decreases survival of Mycobacterium tuberculosis in human macrophages.

    Directory of Open Access Journals (Sweden)

    Xiyuan Bai

    Full Text Available Nuclear factor-kappa B (NFκB is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NFκB has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NFκB are more likely to succumb to Mycobacterium tuberculosis (MTB. However, the role of NFκB in host defense in humans is not fully understood. We sought to examine the role of NFκB activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NFκB activation using BAY 11-7082 (BAY, an inhibitor of IκBα kinase or an adenovirus construct with a dominant-negative IκBα significantly decreased the number of viable intracellular mycobacteria recovered from THP-1 macrophages four and eight days after infection. The results with BAY were confirmed in primary human monocyte-derived macrophages and alveolar macrophages. NFκB inhibition was associated with increased macrophage apoptosis and autophagy, which are well-established killing mechanisms of intracellular MTB. Inhibition of the executioner protease caspase-3 or of the autophagic pathway significantly abrogated the effects of BAY. We conclude that NFκB inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy.

  17. Propranolol, but not naloxone, enhances spinal reflex bladder activity and reduces pudendal inhibition in cats.

    Science.gov (United States)

    Rogers, Marc J; Xiao, Zhiying; Shen, Bing; Wang, Jicheng; Schwen, Zeyad; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2015-01-01

    This study examined the role of β-adrenergic and opioid receptors in spinal reflex bladder activity and in the inhibition induced by pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS). Spinal reflex bladder contractions were induced by intravesical infusion of 0.25% acetic acid in α-chloralose-anesthetized cats after an acute spinal cord transection (SCT) at the thoracic T9/T10 level. PNS or TNS at 5 Hz was applied to inhibit these spinal reflex contractions at 2 and 4 times the threshold intensity (T) for inducing anal or toe twitch, respectively. During a cystrometrogram (CMG), PNS at 2T and 4T significantly (P reflex bladder contractions. After administering propranolol (3 mg/kg iv, a β₁/β₂-adrenergic receptor antagonist), the effects of 2T and 4T PNS on bladder capacity were significantly (P reflex bladder contractions or PNS inhibition. At the end of experiments, hexamethonium (10 mg/kg iv, a ganglionic blocker) significantly (P reflex bladder contractions. This study indicates an important role of β₁/β₂-adrenergic receptors in pudendal inhibition and spinal reflex bladder activity. Copyright © 2015 the American Physiological Society.

  18. Inhibition of Anaerobic Phosphate Release by Nitric Oxide in Activated Sludge

    Science.gov (United States)

    Van Niel, E. W. J.; Appeldoorn, K. J.; Zehnder, A. J. B.; Kortstee, G. J. J.

    1998-01-01

    Activated sludge not containing significant numbers of denitrifying, polyphosphate [poly(P)]-accumulating bacteria was grown in a fill-and-draw system and exposed to alternating anaerobic and aerobic periods. During the aerobic period, poly(P) accumulated up to 100 mg of P · g of (dry) weight. When portions of the sludge were incubated anaerobically in the presence of acetate, 80 to 90% of the intracellular poly(P) was degraded and released as orthophosphate. Degradation of poly(P) was mainly catalyzed by the concerted action of polyphosphate:AMP phosphotransferase and adenylate kinase, resulting in ATP formation. In the presence of 0.3 mM nitric oxide (NO) in the liquid-phase release of phosphate, uptake of acetate, formation of poly-β-hydroxybutyrate, utilization of glycogen, and formation of ATP were severely inhibited or completely abolished. In cell extracts of the sludge, adenylate kinase activity was completely inhibited by 0.15 mM NO. The nature of this inhibition was probably noncompetitive, similar to that with hog adenylate kinase. Activated sludge polyphosphate glucokinase was also completely inhibited by 0.15 mM NO. It is concluded that the inhibitory effect of NO on acetate-mediated phosphate release by the sludge used in this study is due to the inhibition of adenylate kinase in the phosphate-releasing organisms. The inhibitory effect of nitrate and nitrite on phosphate release is probably due to their conversion to NO. The lack of any inhibitory effect of NO on adenylate kinase of the poly(P)-accumulating Acinetobacter johnsonii 210A suggests that this type of organism is not involved in the enhanced biological phosphate removal by the sludges used. PMID:9687452

  19. Determinants of the renin-angiotensin-aldosterone system in cirrhosis with special emphasis on the central blood volume

    DEFF Research Database (Denmark)

    Møller, Søren; Bendtsen, Flemming; Henriksen, Jens H

    2006-01-01

    OBJECTIVE: Several studies have shown activation of the renin-angiotensin-aldosterone system (RAAS) in cirrhosis. Although the activated RAAS may have several determinants, the system is often considered a surrogate marker of effective hypovolaemia. In this study we investigated the activity...... of the RAAS and its potential determinants with special focus on the central and arterial blood volume (CBV). MATERIAL AND METHODS: Eighty-nine patients (Child class A/B/C: 19/41/29) and 32 controls were included in the study. All were given a haemodynamic examination with measurement of determinants...

  20. Modulation of Olfactory Bulb Network Activity by Serotonin: Synchronous Inhibition of Mitral Cells Mediated by Spatially Localized GABAergic Microcircuits

    Science.gov (United States)

    Schmidt, Loren J.; Strowbridge, Ben W.

    2014-01-01

    Although inhibition has often been proposed as a central mechanism for coordinating activity in the olfactory system, relatively little is known about how activation of different inhibitory local circuit pathways can generate coincident inhibition of principal cells. We used serotonin (5-HT) as a pharmacological tool to induce spiking in ensembles…

  1. Fern extracts potentiate fluconazole activity and inhibit morphological changes in Candida species

    Directory of Open Access Journals (Sweden)

    Maria A. Freitas

    2017-11-01

    Conclusions: The extracts obtained from the fern species L. venustum and P. calomelanos dose not present significant antifungal activity. However, P. calomelanos potentiates the activity of fluconazole and both extracts inhibits the morphological changes in Candida species, indicating that they have potential pharmacological activity as modulators of fungal biology. Therefore, novel studies are required to characterize the interference of these extracts in the virulence and pathogenicity of Candida species as well as the potential of fern species to treat fungal infections.

  2. Synthesis, anticancer activity, and inhibition of tubulin polymerization by conformationally restricted analogues of lavendustin A.

    Science.gov (United States)

    Mu, Fanrong; Hamel, Ernest; Lee, Debbie J; Pryor, Donald E; Cushman, Mark

    2003-04-24

    Compounds in the lavendustin A series have been shown to inhibit both protein-tyrosine kinases (PTKs) and tubulin polymerization. Since certain lavendustin A derivatives can exist in conformations that resemble both the trans-stilbene structure of the PTK inhibitor piceatannol and the cis-stilbene structure of the tubulin polymerization inhibitor combretastatin A-4, the possibility exists that the ratio of the two types of activities of the lavendustins could be influenced through the synthesis of conformationally restricted analogues. Accordingly, the benzylaniline structure of a series of pharmacologically active lavendustin A fragments was replaced by either their cis- or their trans-stilbene relatives, and effects on both inhibition of tubulin polymerization and cytotoxicity in cancer cell cultures were monitored. Both dihydrostilbene and 1,2-diphenylalkyne congeners were also prepared and evaluated biologically. Surprisingly, conformational restriction of the bridge between the two aromatic rings of the lavendustins had no significant effect on biological activity. On the other hand, conversion of the three phenolic hydroxyl groups of the lavendustin A derivatives to their corresponding methyl ethers consistently abolished their ability to inhibit tubulin polymerization and usually decreased cytotoxicity in cancer cell cultures as well, indicating the importance of at least one of the phenolic hydroxyl groups. Further investigation suggested that the phenolic hydroxyl group in the salicylamide ring was required for activity, while the two phenol moieties in the hydroquinone ring could be methylated with retention of activity. Two of the lavendustin A derivatives displayed IC(50) values of 1.4 microM for inhibition of tubulin polymerization, which ranks them among the most potent of the known tubulin polymerization inhibitors.

  3. Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Barros, Francisco W.A. [Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará (Brazil); Bezerra, Daniel P., E-mail: danielpbezerra@gmail.com [Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe (Brazil); Ferreira, Paulo M.P. [Department of Biological Sciences, Federal University of Piauí, Picos, Piauí (Brazil); Cavalcanti, Bruno C. [Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará (Brazil); Silva, Teresinha G.; Pitta, Marina G.R.; Lima, Maria do C.A. de; Galdino, Suely L.; Pitta, Ivan da R. [Department of Antibiotics, Federal, University of Pernambuco, Recife, Pernembuco (Brazil); Costa-Lotufo, Letícia V.; Moraes, Manoel O. [Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará (Brazil); Burbano, Rommel R. [Institute of Biological Sciences, Federal University of Pará, Belém, Pará (Brazil); Guecheva, Temenouga N.; Henriques, João A.P. [Biotechnology Center, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul (Brazil); Pessoa, Cláudia, E-mail: cpessoa@ufc.br [Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará (Brazil)

    2013-04-01

    Thiazacridine derivatives (ATZD) are a novel class of cytotoxic agents that combine an acridine and thiazolidine nucleus. In this study, the cytotoxic action of four ATZD were tested in human colon carcinoma HCT-8 cells: (5Z)-5-acridin-9-ylmethylene-3-(4-methylbenzyl)-thiazolidine-2,4-dione — AC-4; (5ZE)-5-acridin-9-ylmethylene-3-(4-bromo-benzyl)-thiazolidine-2,4-dione — AC-7; (5Z)-5-(acridin-9-ylmethylene)-3-(4-chloro-benzyl) -1,3-thiazolidine-2,4-dione — AC-10; and (5ZE)-5-(acridin-9-ylmethylene)-3-(4-fluoro-benzyl)-1,3-thiazolidine-2, 4-dione — AC-23. All of the ATZD tested reduced the proliferation of HCT-8 cells in a concentration- and time-dependent manner. There were significant increases in internucleosomal DNA fragmentation without affecting membrane integrity. For morphological analyses, hematoxylin–eosin and acridine orange/ethidium bromide were used to stain HCT-8 cells treated with ATZD, which presented the typical hallmarks of apoptosis. ATZD also induced mitochondrial depolarisation and phosphatidylserine exposure and increased the activation of caspases 3/7 in HCT-8 cells, suggesting that this apoptotic cell death was caspase-dependent. In an assay using Saccharomyces cerevisiae mutants with defects in DNA topoisomerases 1 and 3, the ATZD showed enhanced activity, suggesting an interaction between ATZD and DNA topoisomerase enzyme activity. In addition, ATZD inhibited DNA topoisomerase I action in a cell-free system. Interestingly, these ATZD did not cause genotoxicity or inhibit the telomerase activity in human lymphocyte cultures at the experimental levels tested. In conclusion, the ATZD inhibited the DNA topoisomerase I activity and induced tumour cell death through apoptotic pathways. - Highlights: ► Thiazacridine derivatives induce mitochondrial-dependent apoptotic cell death. ► Thiazacridine derivatives inhibit DNA topoisomerase I action. ► Thiazacridine derivatives failed to cause genotoxicity on human lymphocytes.

  4. Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives

    International Nuclear Information System (INIS)

    Barros, Francisco W.A.; Bezerra, Daniel P.; Ferreira, Paulo M.P.; Cavalcanti, Bruno C.; Silva, Teresinha G.; Pitta, Marina G.R.; Lima, Maria do C.A. de; Galdino, Suely L.; Pitta, Ivan da R.; Costa-Lotufo, Letícia V.; Moraes, Manoel O.; Burbano, Rommel R.; Guecheva, Temenouga N.; Henriques, João A.P.; Pessoa, Cláudia

    2013-01-01

    Thiazacridine derivatives (ATZD) are a novel class of cytotoxic agents that combine an acridine and thiazolidine nucleus. In this study, the cytotoxic action of four ATZD were tested in human colon carcinoma HCT-8 cells: (5Z)-5-acridin-9-ylmethylene-3-(4-methylbenzyl)-thiazolidine-2,4-dione — AC-4; (5ZE)-5-acridin-9-ylmethylene-3-(4-bromo-benzyl)-thiazolidine-2,4-dione — AC-7; (5Z)-5-(acridin-9-ylmethylene)-3-(4-chloro-benzyl) -1,3-thiazolidine-2,4-dione — AC-10; and (5ZE)-5-(acridin-9-ylmethylene)-3-(4-fluoro-benzyl)-1,3-thiazolidine-2, 4-dione — AC-23. All of the ATZD tested reduced the proliferation of HCT-8 cells in a concentration- and time-dependent manner. There were significant increases in internucleosomal DNA fragmentation without affecting membrane integrity. For morphological analyses, hematoxylin–eosin and acridine orange/ethidium bromide were used to stain HCT-8 cells treated with ATZD, which presented the typical hallmarks of apoptosis. ATZD also induced mitochondrial depolarisation and phosphatidylserine exposure and increased the activation of caspases 3/7 in HCT-8 cells, suggesting that this apoptotic cell death was caspase-dependent. In an assay using Saccharomyces cerevisiae mutants with defects in DNA topoisomerases 1 and 3, the ATZD showed enhanced activity, suggesting an interaction between ATZD and DNA topoisomerase enzyme activity. In addition, ATZD inhibited DNA topoisomerase I action in a cell-free system. Interestingly, these ATZD did not cause genotoxicity or inhibit the telomerase activity in human lymphocyte cultures at the experimental levels tested. In conclusion, the ATZD inhibited the DNA topoisomerase I activity and induced tumour cell death through apoptotic pathways. - Highlights: ► Thiazacridine derivatives induce mitochondrial-dependent apoptotic cell death. ► Thiazacridine derivatives inhibit DNA topoisomerase I action. ► Thiazacridine derivatives failed to cause genotoxicity on human lymphocytes

  5. Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits myeloperoxidase activity in inflammatory cells.

    Science.gov (United States)

    Mishra, Om P; Popov, Anatoliy V; Pietrofesa, Ralph A; Nakamaru-Ogiso, Eiko; Andrake, Mark; Christofidou-Solomidou, Melpo

    2018-06-01

    Myeloperoxidase (MPO) generates hypochlorous acid (HOCl) during inflammation and infection. We showed that secoisolariciresinol diglucoside (SDG) scavenges radiation-induced HOCl in physiological solutions. However, the action of SDG and its synthetic version, LGM2605, on MPO-catalyzed generation of HOCl is unknown. The present study evaluated the effect of LGM2605 on human MPO, and murine MPO from macrophages and neutrophils. MPO activity was determined fluorometrically using hypochlorite-specific 3'-(p-aminophenyl) fluorescein (APF). The effect of LGM2605 on (a) the peroxidase cycle of MPO was determined using Amplex Red while the effect on (b) the chlorination cycle was determined using a taurine chloramine assay. Using electron paramagnetic resonance (EPR) spectroscopy we determined the effect of LGM2605 on the EPR signals of MPO. Finally, computational docking of SDG was used to identify energetically favorable docking poses to enzyme's active site. LGM2605 inhibited human and murine MPO activity. MPO inhibition was observed in the absence and presence of Cl - . EPR confirmed that LGM2605 suppressed the formation of Compound I, an oxoiron (IV) intermediate [Fe(IV)O] containing a porphyrin π-radical of MPO's catalytic cycle. Computational docking revealed that SDG can act as an inhibitor by binding to the enzyme's active site. We conclude that LGM2605 inhibits MPO activity by suppressing both the peroxidase and chlorination cycles. EPR analysis demonstrated that LGM2605 inhibits MPO by decreasing the formation of the highly oxidative Compound I. This study identifies a novel mechanism of LGM2605 action as an inhibitor of MPO and indicates that LGM2605 may be a promising attenuator of oxidant-dependent inflammatory tissue damage. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Platelet-derived growth factor inhibits platelet activation in heparinized whole blood.

    Science.gov (United States)

    Selheim, F; Holmsen, H; Vassbotn, F S

    1999-08-15

    We previously have demonstrated that human platelets have functionally active platelet-derived growth factor alpha-receptors. Studies with gel-filtered platelets showed that an autocrine inhibition pathway is transduced through this tyrosine kinase receptor during platelet activation. The physiological significance of this inhibitory effect of platelet-derived growth factor on gel-filtered platelets activation is, however, not known. In the present study, we investigated whether platelet-derived growth factor inhibits platelet activation under more physiological conditions in heparinized whole blood, which represents a more physiological condition than gel-filtered platelets. Using flow cytometric assays, we demonstrate here that platelet-derived growth factor inhibits thrombin-, thrombin receptor agonist peptide SFLLRN-, and collagen-induced platelet aggregation and shedding of platelet-derived microparticles from the platelet plasma membrane during platelet aggregation in stirred heparinized whole blood. The inhibitory effect of platelet-derived growth factor was dose dependent. However, under nonaggregating conditions (no stirring), we could not demonstrate any significant effect of platelet-derived growth factor on thrombin- and thrombin receptor agonist peptide-induced platelet surface expression of P-selectin. Our results demonstrate that platelet-derived growth factor appears to be a true antithrombotic agent only under aggregating conditions in heparinized whole blood.

  7. IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity

    Science.gov (United States)

    Liu, Daofeng; Song, Liping; Wei, Jie; Courtney, Amy N.; Gao, Xiuhua; Marinova, Ekaterina; Guo, Linjie; Heczey, Andras; Asgharzadeh, Shahab; Kim, Eugene; Dotti, Gianpietro; Metelitsa, Leonid S.

    2012-01-01

    Vα24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs). Tumor progression therefore requires that TAMs evade NKT cell activity through yet-unknown mechanisms. Here we report that a subset of cells in neuroblastoma (NB) cell lines and primary tumors expresses membrane-bound TNF-α (mbTNF-α). These proinflammatory tumor cells induced production of the chemokine CCL20 from TAMs via activation of the NF-κB signaling pathway, an effect that was amplified in hypoxia. Flow cytometry analyses of human primary NB tumors revealed selective accumulation of CCL20 in TAMs. Neutralization of the chemokine inhibited in vitro migration of NKT cells toward tumor-conditioned hypoxic monocytes and localization of NKT cells to NB grafts in mice. We also found that hypoxia impaired NKT cell viability and function. Thus, CCL20-producing TAMs served as a hypoxic trap for tumor-infiltrating NKT cells. IL-15 protected antigen-activated NKT cells from hypoxia, and transgenic expression of IL-15 in adoptively transferred NKT cells dramatically enhanced their antimetastatic activity in mice. Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15–transduced NKT cells. PMID:22565311

  8. IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity.

    Science.gov (United States)

    Liu, Daofeng; Song, Liping; Wei, Jie; Courtney, Amy N; Gao, Xiuhua; Marinova, Ekaterina; Guo, Linjie; Heczey, Andras; Asgharzadeh, Shahab; Kim, Eugene; Dotti, Gianpietro; Metelitsa, Leonid S

    2012-06-01

    Vα24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs). Tumor progression therefore requires that TAMs evade NKT cell activity through yet-unknown mechanisms. Here we report that a subset of cells in neuroblastoma (NB) cell lines and primary tumors expresses membrane-bound TNF-α (mbTNF-α). These proinflammatory tumor cells induced production of the chemokine CCL20 from TAMs via activation of the NF-κB signaling pathway, an effect that was amplified in hypoxia. Flow cytometry analyses of human primary NB tumors revealed selective accumulation of CCL20 in TAMs. Neutralization of the chemokine inhibited in vitro migration of NKT cells toward tumor-conditioned hypoxic monocytes and localization of NKT cells to NB grafts in mice. We also found that hypoxia impaired NKT cell viability and function. Thus, CCL20-producing TAMs served as a hypoxic trap for tumor-infiltrating NKT cells. IL-15 protected antigen-activated NKT cells from hypoxia, and transgenic expression of IL-15 in adoptively transferred NKT cells dramatically enhanced their antimetastatic activity in mice. Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15-transduced NKT cells.

  9. Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity.

    Science.gov (United States)

    Shirakawa, Kotaro; Wang, Lan; Man, Na; Maksimoska, Jasna; Sorum, Alexander W; Lim, Hyung W; Lee, Intelly S; Shimazu, Tadahiro; Newman, John C; Schröder, Sebastian; Ott, Melanie; Marmorstein, Ronen; Meier, Jordan; Nimer, Stephen; Verdin, Eric

    2016-05-31

    Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms, including the inhibition of cyclo-oxygenases, modulation of NF-κB activity, and direct activation of AMPK. However, the full spectrum of their activities is incompletely understood. Here we show that salicylate specifically inhibits CBP and p300 lysine acetyltransferase activity in vitro by direct competition with acetyl-Coenzyme A at the catalytic site. We used a chemical structure-similarity search to identify another anti-inflammatory drug, diflunisal, that inhibits p300 more potently than salicylate. At concentrations attainable in human plasma after oral administration, both salicylate and diflunisal blocked the acetylation of lysine residues on histone and non-histone proteins in cells. Finally, we found that diflunisal suppressed the growth of p300-dependent leukemia cell lines expressing AML1-ETO fusion protein in vitro and in vivo. These results highlight a novel epigenetic regulatory mechanism of action for salicylate and derivative drugs.

  10. Inhibition of dehydrogenase activity in petroleum refinery wastewater bacteria by phenolic compounds

    Directory of Open Access Journals (Sweden)

    Gideon C. Okpokwasili

    2010-04-01

    Full Text Available The toxicity of phenol, 2-nitrophenol, 4-nitrophenol, 2,4-dinitrophenol, 2-chlorophenol, 4-chlorophenol, 4-bromophenol and 3,5-dimethylphenol on Pseudomonas, Bacillus and Escherichia species isolated from petroleum refinery wastewater was assessed via inhibition of dehydrogenase enzyme activity. At low concentrations, 2-nitrophenol, 2-chlorophenol, 4-chlorophenol, 4-bromophenol and 3,5-dimethylphenol stimulated dehydrogenase activity and at sufficient concentrations, phenolic compounds inhibited dehydrogenase activities. Generally, phenol is less toxic than substituted phenols. Estimations of the degree of inhibition/stimulation of dehydrogenase activities showed significant dose-dependent responses that are describable by logistic functions. The toxicity thresholds varied significantly (P < 0.05 among the bacterial strains and phenolic compounds. The median inhibitory concentrations (IC50s ranged from 4.118 ± 0.097 mg.L-1 for 4-nitrophenol against Pseudomonas sp. DAF1 to 1407.997 ± 7.091 mg.L-1 for phenol against Bacillus sp. DISK1. This study suggested that the organisms have moderate sensitivity to phenols and have the potential to be used as indicators for assessment of chemical toxicity. They could also be used as catalysts for degradation of phenols in effluents.

  11. Inhibition of proteases activity in intestine needs a sustainable acidic environment rather than a transient.

    Science.gov (United States)

    Xing, Chang; Xing, Jin-Feng; Ge, Zhi-Qiang

    2017-10-01

    α-Chymotrypsin (α-CT) and trypsin are important components of the enzymatic barrier. They could degrade the therapeutic proteins and peptides, inhibit their activity consequently, and thereby reduce their oral bioavailability. Acidic agents, as one type of indirect protease inhibitors, have shown proof of concept in clinical trials. We report here the inactivated proteases due to acid influence can be reactivated immediately by environmental pH recovery regardless of how long the inactivation last. To keep the inactivation time of proteases for 4-5 h, we designed and prepared a sustained-release tablet containing citric acid (CA) which can effectively reduce the pH below 5.0 and maintain it for 5 h in the dissolution-reaction medium. The activity of α-CT and trypsin was quantified by analyzing the residual amount of their respective substrates BTEE and TAME. More than 80% of the substrates were survived in 5.0 h of incubation, whereas the common tablet inhibited the proteases activity for only two hours in the same experimental medium. It indicates that the sustained-release tablet loaded with CA can efficiently inhibit the α-CT and trypsin activity longer than the common tablet. The results will be beneficial for designing and formulating the peroral administration of peptide and protein drugs.

  12. Assessment of the degree of oxidative stress injury, renin-angiotensin system activity and podocyte loss after combined treatment of keto acid with low protein diet for patients with diabetic nephropathy

    OpenAIRE

    Yuan-Hua Xu; Mei Wang

    2016-01-01

    Objective: To analyze the degree of oxidative stress injury, RAS activity and podocyte loss after patients with diabetic nephropathy received keto acid combined with low protein diet. Methods: A total of 106 cases of patients with diabetic nephropathy who received hospital treatment in our hospital from September 2012 to July 2015 were selected as research subjects and randomly divided into observation group and control group according to different treatment, each group with 53...

  13. Assessment of the degree of oxidative stress injury, renin-angiotensin system activity and podocyte loss after combined treatment of keto acid with low protein diet for patients with diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Yuan-Hua Xu

    2016-03-01

    Full Text Available Objective: To analyze the degree of oxidative stress injury, RAS activity and podocyte loss after patients with diabetic nephropathy received keto acid combined with low protein diet. Methods: A total of 106 cases of patients with diabetic nephropathy who received hospital treatment in our hospital from September 2012 to July 2015 were selected as research subjects and randomly divided into observation group and control group according to different treatment, each group with 53 cases. Control group received low protein diet treatment alone, observation group received keto acid combined with low protein diet treatment, and then the degree of oxidative stress injury, RAS activity and podocyte loss of two groups were compared. Results: Serum MDA and AOPP levels of observation group after treatment were lower than those of control group, and levels of SOD and T-AOC were higher than those of control group; PRA, Ang栻 and Aldosterone levels of observation group after treatment were lower than those of control group; mRNA expression levels of podocin and synaptopodin in urine sediment of observation group after treatment were lower than those of control group. Conclusion: Keto acid combined with low protein diet treatment for patients with diabetic nephropathy can reduce the degree of oxidative stress injury and RAS activity, decrease podocyte loss and optimize patients’ condition.

  14. Sildenafil Protects against Myocardial Ischemia-Reperfusion Injury Following Cardiac Arrest in a Porcine Model: Possible Role of the Renin-Angiotensin System

    Science.gov (United States)

    Wang, Guoxing; Zhang, Qian; Yuan, Wei; Wu, Junyuan; Li, Chunsheng

    2015-01-01

    Sildenafil, a phosphodiesterase-5 inhibitor sold as Viagra, is a cardioprotector against myocardial ischemia/reperfusion (I/R) injury. Our study explored whether sildenafil protects against I/R-induced damage in a porcine cardiac arrest and resuscitation (CAR) model via modulating the renin-angiotensin system. Male pigs were randomly divided to three groups: Sham group, Saline group, and sildenafil (0.5 mg/kg) group. Thirty min after drug infusion, ventricular fibrillation (8 min) and cardiopulmonary resuscitation (up to 30 min) was conducted in these animals. We found that sildenafil ameliorated the reduced cardiac function and improved the 24-h survival rate in this model. Sildenafil partly attenuated the increases of plasma angiotensin II (Ang II) and Ang (1–7) levels after CAR. Sildenafil also decreased apoptosis and Ang II expression in myocardium. The increases of expression of angiotensin-converting-enzyme (ACE), ACE2, Ang II type 1 receptor (AT1R), and the Ang (1–7) receptor Mas in myocardial tissue were enhanced after CAR. Sildenafil suppressed AT1R up-regulation, but had no effect on ACE, ACE2, and Mas expression. Sildenafilfurther boosted the upregulation of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) and inducible nitric oxide synthase(iNOS). Collectively, our results suggest that cardioprotection of sildenafil in CAR model is accompanied by an inhibition of Ang II-AT1R axis activation. PMID:26569234

  15. Sildenafil Protects against Myocardial Ischemia-Reperfusion Injury Following Cardiac Arrest in a Porcine Model: Possible Role of the Renin-Angiotensin System

    Directory of Open Access Journals (Sweden)

    Guoxing Wang

    2015-11-01

    Full Text Available Sildenafil, a phosphodiesterase-5 inhibitor sold as Viagra, is a cardioprotector against myocardial ischemia/reperfusion (I/R injury. Our study explored whether sildenafil protects against I/R-induced damage in a porcine cardiac arrest and resuscitation (CAR model via modulating the renin-angiotensin system. Male pigs were randomly divided to three groups: Sham group, Saline group, and sildenafil (0.5 mg/kg group. Thirty min after drug infusion, ventricular fibrillation (8 min and cardiopulmonary resuscitation (up to 30 min was conducted in these animals. We found that sildenafil ameliorated the reduced cardiac function and improved the 24-h survival rate in this model. Sildenafil partly attenuated the increases of plasma angiotensin II (Ang II and Ang (1–7 levels after CAR. Sildenafil also decreased apoptosis and Ang II expression in myocardium. The increases of expression of angiotensin-converting-enzyme (ACE, ACE2, Ang II type 1 receptor (AT1R, and the Ang (1–7 receptor Mas in myocardial tissue were enhanced after CAR. Sildenafil suppressed AT1R up-regulation, but had no effect on ACE, ACE2, and Mas expression. Sildenafilfurther boosted the upregulation of endothelial nitric oxide synthase (eNOS, cyclic guanosine monophosphate (cGMP and inducible nitric oxide synthase(iNOS. Collectively, our results suggest that cardioprotection of sildenafil in CAR model is accompanied by an inhibition of Ang II-AT1R axis activation.

  16. Locally formed dopamine inhibits Na sup + -K sup + -ATPase activity in rat renal cortical tubule cells

    Energy Technology Data Exchange (ETDEWEB)

    Seri, I.; Kone, B.C.; Gullans, S.R.; Aperia, A.; Brenner, B.M.; Ballermann, B.J. (Harvard Medical School, Boston, MA (USA) Karolinska Institute, Stockholm (Sweden))

    1988-10-01

    Dopamine, generated locally from L-dopa, inhibits Na{sup +}-K{sup +}-ATPase in permeabilized rat proximal tubules under maximum transport rate conditions for sodium. To determine whether locally formed dopamine inhibits Na{sup +}-K{sup +}-ATPase activity in intact cortical tubule cells we studied the effect of L-dopa on ouabain-sensitive oxygen consumption rate ({dot Q}o{sub 2}) and {sup 86}Rb uptake in renal cortical tubule cell suspensions. L-Dopa did not affect ouabain-insensitive {dot Q}o{sub 2} or mitochondrial respiration. However, L-dopa inhibited ouabain-sensitive {dot Q}o{sub 2} in a concentration-dependent manner, with half-maximal inhibition (K{sub 0.5}) of 5 {times} 10{sup {minus}7} M and a maximal inhibition of 14.1 {plus minus} 1.5% at 10{sup {minus}4}M. L-Dopa also blunted the nystatin-stimulated {dot Q}o{sub 2} in a concentration-dependent manner, indicating the L-dopa directly inhibits Na{sup +}-K{sup +}-ATPase activity and not sodium entry. Ouabain-sensitive {sup 86}Rb uptake was also inhibited by L-dopa. Carbidopa, an inhibitor of the conversion of L-dopa to dopamine, eliminated the effect of L-dopa on ouabain-sensitive {dot Q}o{sub 2} and {sup 86}Rb uptake, indicating that dopamine rather than L-dopa was the active agent. The finding that the L-dopa concentration-response curve was shifted to the left by one order of magnitude in the presence of nystatin suggests that the inhibitory effect is enhanced when the intracellular sodium concentration is increased. By studying the effect of L-dopa on ouabain-sensitive {dot Q}o{sub 2} at increasing extracellular sodium concentrations in the presence of nystatin, the authors demonstrated that the inhibitory effect of locally formed dopamine on the Na{sup +}-K{sup +}-ATPase is indeed dependent on the sodium available for the enzyme and occurs in an uncompetitive manner.

  17. Selective inhibition by harmane of the apurinic apyrimidinic endonuclease activity of phage T4-induced UV endonuclease.

    Science.gov (United States)

    Warner, H R; Persson, M L; Bensen, R J; Mosbaugh, D W; Linn, S

    1981-11-25

    1-Methyl-9H-pyrido-[3,4-b]indole (harmane) inhibits the apurinic/apyrimidinic (AP) endonuclease activity of the UV endonuclease induced by phage T4, whereas it stimulates the pyrimidine dimer-DNA glycosylase activity of that enzyme. E. coli endonuclease IV, E. coli endonuclease VI (the AP endonuclease activity associated with E. coli exonuclease III), and E. coli uracil-DNA glycosylase were not inhibited by harmane. Human fibroblast AP endonucleases I and II also were only slightly inhibited. Therefore, harmane is neither a general inhibitor of AP endonucleases, nor a general inhibitor of Class I AP endonucleases which incise DNA on the 3'-side of AP sites. However, E. coli endonuclease III and its associated dihydroxythymine-DNA glycosylase activity were both inhibited by harmane. This observation suggests that harmane may inhibit only AP endonucleases which have associated glycosylase activities.

  18. Effects of aqueous extract of Hibiscus sabdariffa on the renin-angiotensin-aldosterone system of Nigerians with mild to moderate essential hypertension: A comparative study with lisinopril.

    Science.gov (United States)

    Nwachukwu, Daniel Chukwu; Aneke, Eddy Ikemefuna; Obika, Leonard Fidelis; Nwachukwu, Nkiru Zuada

    2015-01-01

    The present study investigated the effects of aqueous extract of Hibiscus sabdariffa (HS) on the three basic components of renin-angiotensin-aldosterone system: Plasma renin, serum angiotensin-converting enzyme (ACE), and plasma aldosterone (PA) in mild to moderate essential hypertensive Nigerians and compared with that of lisinopril, an ACE inhibitor. A double-blind controlled randomized clinical study was used. Seventy-eight newly diagnosed but untreated mild to moderate hypertensive subjects attending Medical Outpatients Clinic of Enugu State University Teaching Hospital, Enugu were recruited for the study. Those in Group A received placebo (150 mg/kg/day), Group B were given lisinopril (10 mg once daily) while those in Group C received aqueous extract of HS (150 mg/kg/day). After 4 weeks of treatment, the levels of plasma renin, serum ACE, and PA were determined. HS and lisinopril significantly (P < 0.001) reduced PA compared to placebo by 32.06% and 30.01%, respectively. Their effects on serum ACE and plasma renin activity (PRA) were not significant compared to placebo; they reduced ACE by 6.63% and 5.67% but increased plasma PRA by 2.77% and 5.36%, respectively. HS reduced serum ACE and PA in mild to moderate hypertensive Nigerians with equal efficacy as lisinopril. These actions are possibly due to the presence of anthocyanins in the extract.

  19. Heritability of brain activity related to response inhibition: a longitudinal genetic study in adolescent twins

    Science.gov (United States)

    Anokhin, Andrey P.; Golosheykin, Simon; Grant, Julia D.; Heath, Andrew C.

    2017-01-01