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Mendel Tuchman - One of the best experts on this subject based on the ideXlab platform.
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Expression Pattern and Biochemical Properties of Zebrafish N-Acetylglutamate Synthase
PloS one, 2014Co-Authors: Ljubica Caldovic, Mendel Tuchman, Nantaporn Haskins, Amy Mumo, Himani Datta Majumdar, Mary Pinter, Alison KrufkaAbstract:The urea cycle converts ammonia, a waste product of protein catabolism, into urea. Because fish dispose ammonia directly into water, the role of the urea cycle in fish remains unknown. Six enzymes, N-acetylglutamate Synthase (NAGS), carbamylphosphate synthetase III, ornithine transcarbamylase, Argininosuccinate Synthase, Argininosuccinate lyase and arginase 1, and two membrane transporters, ornithine transporter and aralar, comprise the urea cycle. The genes for all six enzymes and both transporters are present in the zebrafish genome. NAGS (EC 2.3.1.1) catalyzes the formation of N-acetylglutamate from glutamate and acetyl coenzyme A and in zebrafish is partially inhibited by L-arginine. NAGS and other urea cycle genes are highly expressed during the first four days of zebrafish development. Sequence alignment of NAGS proteins from six fish species revealed three regions of sequence conservation: the mitochondrial targeting signal (MTS) at the N-terminus, followed by the variable and conserved segments. Removal of the MTS yields mature zebrafish NAGS (zfNAGS-M) while removal of the variable segment from zfNAGS-M results in conserved NAGS (zfNAGS-C). Both zfNAGS-M and zfNAGS-C are tetramers in the absence of L-arginine; addition of L-arginine decreased partition coefficients of both proteins. The zfNAGS-C unfolds over a broader temperature range and has higher specific activity than zfNAGS-M. In the presence of L-arginine the apparent Vmax of zfNAGS-M and zfNAGS-C decreased, their Kmapp for acetyl coenzyme A increased while the Kmapp for glutamate remained unchanged. The expression pattern of NAGS and other urea cycle genes in developing zebrafish suggests that they may have a role in citrulline and/or arginine biosynthesis during the first day of development and in ammonia detoxification thereafter. Biophysical and biochemical properties of zebrafish NAGS suggest that the variable segment may stabilize a tetrameric state of zfNAGS-M and that under physiological conditions zebrafish NAGS catalyzes formation of N-acetylglutamate at the maximal rate.
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clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ
The Journal of Pediatrics, 2013Co-Authors: Mendel Tuchman, Nicholas Ah Mew, Lauren S Krivitzky, Robert Mccarter, Mark L BatshawAbstract:Objective To compare the clinical course and outcome of patients diagnosed with one of 4 neonatal-onset urea cycle disorders (UCDs): deficiency of carbamyl phosphate Synthase 1 (CPSD), ornithine transcarbamylase (OTCD), Argininosuccinate Synthase (ASD), or Argininosuccinate lyase (ALD). Study design Clinical, biochemical, and neuropsychological data from 103 subjects with neonatal-onset UCDs were derived from the Longitudinal Study of Urea Cycle Disorders, an observational protocol of the Urea Cycle Disorders Consortium, one of the Rare Disease Clinical Research Networks. Results Some 88% of the subjects presented clinically by age 7 days. Peak ammonia level was 963 μM in patients with proximal UCDs (CPSD or OTCD), compared with 589 μM in ASD and 573 μM in ALD. Roughly 25% of subjects with CPSD or OTCD, 18% of those with ASD, and 67% of those with ALD had a “honeymoon period,” defined as the time interval from discharge from initial admission to subsequent admission for hyperammonemia, greater than 1 year. The proportion of patients with a poor outcome (IQ/Developmental Quotient Conclusion Neurocognitive outcomes do not differ between patients with proximal UCDs and those with distal UCDs. Factors other than hyperammonemia may contribute to poor neurocognitive outcome in the distal UCDs.
Eduardo F Oliveira - One of the best experts on this subject based on the ideXlab platform.
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bothrops jararaca peptide with anti hypertensive action normalizes endothelium dysfunction involved in physiopathology of preeclampsia
PLOS ONE, 2011Co-Authors: Juliano R Guerreiro, Eduardo F Oliveira, Katia L. P. Morais, Gabriel Fernando De Souza Benedetti, Mara S Hoshida, Leandro Gustavo De Oliveira, Nelson SassAbstract:Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, is a major cause of fetal and maternal morbidity and mortality especially in developing countries. Bj-PRO-10c, a proline-rich peptide isolated from Bothrops jararaca venom, has been attributed with potent anti-hypertensive effects. Recently, we have shown that Bj-PRO-10c-induced anti-hypertensive actions involved NO production in spontaneous hypertensive rats. Using in vitro studies we now show that Bj-PRO-10c was able to increase NO production in human umbilical vein endothelial cells from hypertensive pregnant women (HUVEC-PE) to levels observed in HUVEC of normotensive women. Moreover, in the presence of the peptide, eNOS expression as well as Argininosuccinate Synthase activity, the key rate-limiting enzyme of the citrulline-NO cycle, were enhanced. In addition, excessive superoxide production due to NO deficiency, one of the major deleterious effects of the disease, was inhibited by Bj-PRO-10c. Bj-PRO-10c induced intracellular calcium fluxes in both, HUVEC-PE and HUVEC, which, however, led to activation of eNOS expression only in HUVEC-PE. Since Bj-PRO-10c promoted biological effects in HUVEC from patients suffering from the disorder and not in normotensive pregnant women, we hypothesize that Bj-PRO-10c induces its anti-hypertensive effect in mothers with preeclampsia. Such properties may initiate the development of novel therapeutics for treating preeclampsia.
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enhancement of the citrulline nitric oxide cycle in astroglioma cells by the proline rich peptide 10c from bothrops jararaca venom
Brain Research, 2010Co-Authors: Eduardo F Oliveira, Claudiana Lameu, Juliano R Guerreiro, Carlos Alberto Silva, Ivo Lebrun, Henning Ulrich, Gabriel Fernando De Souza Benedetti, Antonio C M CamargoAbstract:Abstract The biological activity of the proline-rich decapeptide Bj-PRO-10c, a processing product of the C-type natriuretic peptide precursor protein, expressed in the brain and the venom gland of the pit viper Bothrops jararaca, was originally attributed to the inhibition of the somatic angiotensin-converting enzyme activity with subsequent anti-hypertensive effect. However, recent results suggest broader biological activity may also be involved in the cardiovascular effects of this peptide. Here we show that Bj-PRO-10c enhances and sustains the generation of nitric oxide (NO) by regulating Argininosuccinate Synthase activity and thereby velocity of the citrulline–NO cycle. Bj-PRO-10c-mediated effects not restricted to the cardiovascular system, since NO production was also induced in cells of astroglial origin. Bj-PRO-10c was internalized by C6 astroglioma cells where it induces NO production and upregulation of the citrulline–NO cycle cells in a dose-dependent fashion. In view of that, astroglial cells function as l -arginine pool for NO production in neighboring neurons, we suggest a regulatory function for Bj-PRO-10c on the metabolism of this gaseous neurotransmitter in the CNS. Moreover, proliferation of astroglial cells was reduced in the presence of Bj-PRO-10c; however, cell death was not induced. Since NO donors have been studied for the treatment of solid cancers, Bj-PRO-10c may serve as structural model for developing drugs to improve the effects of cancer therapy based on the peptide's ability to augment NO production.
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brain nitric oxide production by a proline rich decapeptide from bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats
Hypertension Research, 2010Co-Authors: Claudiana Lameu, Vera Pontieri, Juliano R Guerreiro, Eduardo F Oliveira, Carlos Alberto Silva, Joyce M Giglio, Robson L Melo, Ruy R CamposAbstract:Baroreflex sensitivity is disturbed in many people with cardiovascular diseases such as hypertension. Brain deficiency of nitric oxide (NO), which is synthesized by NO Synthase (NOS) in the citrulline–NO cycle (with Argininosuccinate Synthase (ASS) activity being the rate-limiting step), contributes to impaired baroreflex. We recently showed that a decapeptide isolated from Bothrops jararaca snake venom, denoted Bj-PRO-10c, exerts powerful and sustained antihypertensive activity. Bj-PRO-10c promoted vasodilatation dependent on the positive modulation of ASS activity and NO production in the endothelium, and also acted on the central nervous system, inducing the release of GABA and glutamate, two important neurotransmitters in the regulation of autonomic systems. We evaluated baroreflex function using the regression line obtained by the best-fit points of measured heart rate (HR) and mean arterial pressure (MAP) data from spontaneously hypertensive rats (SHRs) treated with Bj-PRO-10c. We also investigated molecular mechanisms involved in this effect, both in vitro and in vivo. Bj-PRO-10c mediated an increase in baroreflex sensitivity and a decrease in MAP and HR. The effects exerted by the peptide include an increase in the gene expression of endothelial NOS and ASS. Bj-PRO-10c-induced NO production depended on intracellular calcium fluxes and the activation of a Gi/o-protein-coupled metabotropic receptor. Bj-PRO-10c induced NO production and the gene expression of ASS and endothelial NOS in the brains of SHRs, thereby improving baroreflex sensitivity. Bj-PRO-10c may reveal novel approaches for treating diseases with impaired baroreflex function.
Claudiana Lameu - One of the best experts on this subject based on the ideXlab platform.
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enhancement of the citrulline nitric oxide cycle in astroglioma cells by the proline rich peptide 10c from bothrops jararaca venom
Brain Research, 2010Co-Authors: Eduardo F Oliveira, Claudiana Lameu, Juliano R Guerreiro, Carlos Alberto Silva, Ivo Lebrun, Henning Ulrich, Gabriel Fernando De Souza Benedetti, Antonio C M CamargoAbstract:Abstract The biological activity of the proline-rich decapeptide Bj-PRO-10c, a processing product of the C-type natriuretic peptide precursor protein, expressed in the brain and the venom gland of the pit viper Bothrops jararaca, was originally attributed to the inhibition of the somatic angiotensin-converting enzyme activity with subsequent anti-hypertensive effect. However, recent results suggest broader biological activity may also be involved in the cardiovascular effects of this peptide. Here we show that Bj-PRO-10c enhances and sustains the generation of nitric oxide (NO) by regulating Argininosuccinate Synthase activity and thereby velocity of the citrulline–NO cycle. Bj-PRO-10c-mediated effects not restricted to the cardiovascular system, since NO production was also induced in cells of astroglial origin. Bj-PRO-10c was internalized by C6 astroglioma cells where it induces NO production and upregulation of the citrulline–NO cycle cells in a dose-dependent fashion. In view of that, astroglial cells function as l -arginine pool for NO production in neighboring neurons, we suggest a regulatory function for Bj-PRO-10c on the metabolism of this gaseous neurotransmitter in the CNS. Moreover, proliferation of astroglial cells was reduced in the presence of Bj-PRO-10c; however, cell death was not induced. Since NO donors have been studied for the treatment of solid cancers, Bj-PRO-10c may serve as structural model for developing drugs to improve the effects of cancer therapy based on the peptide's ability to augment NO production.
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brain nitric oxide production by a proline rich decapeptide from bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats
Hypertension Research, 2010Co-Authors: Claudiana Lameu, Vera Pontieri, Juliano R Guerreiro, Eduardo F Oliveira, Carlos Alberto Silva, Joyce M Giglio, Robson L Melo, Ruy R CamposAbstract:Baroreflex sensitivity is disturbed in many people with cardiovascular diseases such as hypertension. Brain deficiency of nitric oxide (NO), which is synthesized by NO Synthase (NOS) in the citrulline–NO cycle (with Argininosuccinate Synthase (ASS) activity being the rate-limiting step), contributes to impaired baroreflex. We recently showed that a decapeptide isolated from Bothrops jararaca snake venom, denoted Bj-PRO-10c, exerts powerful and sustained antihypertensive activity. Bj-PRO-10c promoted vasodilatation dependent on the positive modulation of ASS activity and NO production in the endothelium, and also acted on the central nervous system, inducing the release of GABA and glutamate, two important neurotransmitters in the regulation of autonomic systems. We evaluated baroreflex function using the regression line obtained by the best-fit points of measured heart rate (HR) and mean arterial pressure (MAP) data from spontaneously hypertensive rats (SHRs) treated with Bj-PRO-10c. We also investigated molecular mechanisms involved in this effect, both in vitro and in vivo. Bj-PRO-10c mediated an increase in baroreflex sensitivity and a decrease in MAP and HR. The effects exerted by the peptide include an increase in the gene expression of endothelial NOS and ASS. Bj-PRO-10c-induced NO production depended on intracellular calcium fluxes and the activation of a Gi/o-protein-coupled metabotropic receptor. Bj-PRO-10c induced NO production and the gene expression of ASS and endothelial NOS in the brains of SHRs, thereby improving baroreflex sensitivity. Bj-PRO-10c may reveal novel approaches for treating diseases with impaired baroreflex function.
Nicholas Ah Mew - One of the best experts on this subject based on the ideXlab platform.
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clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ
The Journal of Pediatrics, 2013Co-Authors: Mendel Tuchman, Nicholas Ah Mew, Lauren S Krivitzky, Robert Mccarter, Mark L BatshawAbstract:Objective To compare the clinical course and outcome of patients diagnosed with one of 4 neonatal-onset urea cycle disorders (UCDs): deficiency of carbamyl phosphate Synthase 1 (CPSD), ornithine transcarbamylase (OTCD), Argininosuccinate Synthase (ASD), or Argininosuccinate lyase (ALD). Study design Clinical, biochemical, and neuropsychological data from 103 subjects with neonatal-onset UCDs were derived from the Longitudinal Study of Urea Cycle Disorders, an observational protocol of the Urea Cycle Disorders Consortium, one of the Rare Disease Clinical Research Networks. Results Some 88% of the subjects presented clinically by age 7 days. Peak ammonia level was 963 μM in patients with proximal UCDs (CPSD or OTCD), compared with 589 μM in ASD and 573 μM in ALD. Roughly 25% of subjects with CPSD or OTCD, 18% of those with ASD, and 67% of those with ALD had a “honeymoon period,” defined as the time interval from discharge from initial admission to subsequent admission for hyperammonemia, greater than 1 year. The proportion of patients with a poor outcome (IQ/Developmental Quotient Conclusion Neurocognitive outcomes do not differ between patients with proximal UCDs and those with distal UCDs. Factors other than hyperammonemia may contribute to poor neurocognitive outcome in the distal UCDs.
Gabriel Fernando De Souza Benedetti - One of the best experts on this subject based on the ideXlab platform.
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bothrops jararaca peptide with anti hypertensive action normalizes endothelium dysfunction involved in physiopathology of preeclampsia
PLOS ONE, 2011Co-Authors: Juliano R Guerreiro, Eduardo F Oliveira, Katia L. P. Morais, Gabriel Fernando De Souza Benedetti, Mara S Hoshida, Leandro Gustavo De Oliveira, Nelson SassAbstract:Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, is a major cause of fetal and maternal morbidity and mortality especially in developing countries. Bj-PRO-10c, a proline-rich peptide isolated from Bothrops jararaca venom, has been attributed with potent anti-hypertensive effects. Recently, we have shown that Bj-PRO-10c-induced anti-hypertensive actions involved NO production in spontaneous hypertensive rats. Using in vitro studies we now show that Bj-PRO-10c was able to increase NO production in human umbilical vein endothelial cells from hypertensive pregnant women (HUVEC-PE) to levels observed in HUVEC of normotensive women. Moreover, in the presence of the peptide, eNOS expression as well as Argininosuccinate Synthase activity, the key rate-limiting enzyme of the citrulline-NO cycle, were enhanced. In addition, excessive superoxide production due to NO deficiency, one of the major deleterious effects of the disease, was inhibited by Bj-PRO-10c. Bj-PRO-10c induced intracellular calcium fluxes in both, HUVEC-PE and HUVEC, which, however, led to activation of eNOS expression only in HUVEC-PE. Since Bj-PRO-10c promoted biological effects in HUVEC from patients suffering from the disorder and not in normotensive pregnant women, we hypothesize that Bj-PRO-10c induces its anti-hypertensive effect in mothers with preeclampsia. Such properties may initiate the development of novel therapeutics for treating preeclampsia.
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enhancement of the citrulline nitric oxide cycle in astroglioma cells by the proline rich peptide 10c from bothrops jararaca venom
Brain Research, 2010Co-Authors: Eduardo F Oliveira, Claudiana Lameu, Juliano R Guerreiro, Carlos Alberto Silva, Ivo Lebrun, Henning Ulrich, Gabriel Fernando De Souza Benedetti, Antonio C M CamargoAbstract:Abstract The biological activity of the proline-rich decapeptide Bj-PRO-10c, a processing product of the C-type natriuretic peptide precursor protein, expressed in the brain and the venom gland of the pit viper Bothrops jararaca, was originally attributed to the inhibition of the somatic angiotensin-converting enzyme activity with subsequent anti-hypertensive effect. However, recent results suggest broader biological activity may also be involved in the cardiovascular effects of this peptide. Here we show that Bj-PRO-10c enhances and sustains the generation of nitric oxide (NO) by regulating Argininosuccinate Synthase activity and thereby velocity of the citrulline–NO cycle. Bj-PRO-10c-mediated effects not restricted to the cardiovascular system, since NO production was also induced in cells of astroglial origin. Bj-PRO-10c was internalized by C6 astroglioma cells where it induces NO production and upregulation of the citrulline–NO cycle cells in a dose-dependent fashion. In view of that, astroglial cells function as l -arginine pool for NO production in neighboring neurons, we suggest a regulatory function for Bj-PRO-10c on the metabolism of this gaseous neurotransmitter in the CNS. Moreover, proliferation of astroglial cells was reduced in the presence of Bj-PRO-10c; however, cell death was not induced. Since NO donors have been studied for the treatment of solid cancers, Bj-PRO-10c may serve as structural model for developing drugs to improve the effects of cancer therapy based on the peptide's ability to augment NO production.