767 resultados para MALONYL-COA DECARBOXYLASE


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Statins are widely recognized as hypolipemic drugs, but some studies have observed anti-inflammatory and immunomodulatory effects, known as pleiotropic. The aims of this work was to study possible anti-inflammatory effects of simvastatin in abdominal sepsis. Serum pro-inflammatory cytokines and leukocytes count were determined in an experimental model of abdominal sepsis, using cecal ligation and puncture (CLP) in rats. Methods: Twenty eigth Wistar rats weighing 285±12g were randomly divided in: CLP/Sinvastatin rats (n=7), treated with 10 mg/Kg of oral simvastatin 18 and 2 hs berofe CLP; CLP/Saline group rats (n=7), treated with oral saline; group Sham/Simvastatin (n=7), treated with simvastatin, and group Sham/Saline (n=7), treated with saline. Serum TNF-α, IL-1β and IL-6 by ELISA and total leukocytes, neutrophils, lymphocytes, and eosinophils were determined 24 hs after CLP. ANOVA and Tukey test were used considering significant p<0.05. Results: It was demonstrated that serum TNF-α, IL-1β and IL-6 were respectively 364,8±42pg/mL; 46,3±18pg/mL and 28,4±13pg/mL in CLP/Sinvastatin rats, significantly lower (p<0.05) than in group CLP/Saline (778,5±86pg/ml; 176,9±46pg/ ml; 133,6±21 pg/ml, respectively). The same results were observed in total leukocytes and neutrophils counts. Conclusion: These results clearly demonstrate that simvastatin is an effective agent that reduces cytokines levels and leukocyte count in sepsis, independently of its well-known lipid-lowering effects. Thus, HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory effects in abdominal sepsis in rats

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In Sudanese women with (n = 60) and without (n = 65) pre-eclampsia, circulating lipids, plasma and red cell saturated and monounsaturated fatty (MUFA) acids and dimethyl acetals (DMAs) were investigated. DMAs are an indirect marker of levels of plasmalogens, endogenous antioxidants, which play a critical role in oxidative protection, and cholesterol homeostasis. The pre-eclamptics had higher C18:1n-9 (p < 0.001) and ΣMUFA (p < 0.01) in plasma free fatty acids, C16:1n-7, C18:1n-9, ΣMUFA; 16:0/16:1n-7 (p < 0.01) in erythrocyte choline phosphoglycerides (ePC) and 16:1n-7, 18:1n-7 and 16:0/16:1n-7 (p < 0.01) in erythrocyte ethanolamine phosphoglycerides (ePE). In contrast, the DMAs 18:0, 18:1 and ΣDMAs in ePE, and 16:0, 18:0 and ΣDMAs in ePC were reduced (p < 0.001) in the pre-eclamptic women. This study of pregnant women with high carbohydrate and low fat background diet suggests pre-eclampsia is associated with oxidative stress and enhanced activity of the microsomal enzyme stearyl-CoA desaturase (delta 9 desaturase), as assessed by palmitic/palmitoleic (C16:0/C16:n-1) and stearic/oleic (C18/C18:1n-9) ratios.

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Succinate is a naturally occurring metabolite in organism’s cell and is industrially important chemical with various applications in food and pharmaceutical industry. It is also widely used to produce bio-degradable plastics, surfactants, detergents etc. In last decades, emphasis has been given to bio-based chemical production using industrial biotechnology route rather than fossil-based production considering sustainability and environment friendly economy. In this thesis I am presenting a computational model for silico metabolic engineering of Saccharomyces cerevisiae for large scale production of succinate. For metabolic modelling, I have used OptKnock and OptGene optimization algorithms to identify the reactions to delete from the genome-scale metabolic model of S. cerevisiae to overproduce succinate by coupling with organism’s growth. Both OptKnock and OptGene proposed numerous straightforward and non-intuitive deletion strategies when number of constraints including growth constraint to the model were applied. The most interesting strategy identified by both algorithms was deletion combination of pyruvate decarboxylase and Ubiquinol:ferricytochrome c reductase(respiratory enzyme) reactions thereby also suggesting anaerobic fermentation of the organism in glucose medium. Such strategy was never reported earlier for growth-coupled succinate production in S.cerevisiae.

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Statins are widely recognized as hypolipemic drugs, but some studies have observed anti-inflammatory and immunomodulatory effects, known as pleiotropic. The aims of this work was to study possible anti-inflammatory effects of simvastatin in abdominal sepsis. Serum pro-inflammatory cytokines and leukocytes count were determined in an experimental model of abdominal sepsis, using cecal ligation and puncture (CLP) in rats. Methods: Twenty eigth Wistar rats weighing 285±12g were randomly divided in: CLP/Sinvastatin rats (n=7), treated with 10 mg/Kg of oral simvastatin 18 and 2 hs berofe CLP; CLP/Saline group rats (n=7), treated with oral saline; group Sham/Simvastatin (n=7), treated with simvastatin, and group Sham/Saline (n=7), treated with saline. Serum TNF-α, IL-1β and IL-6 by ELISA and total leukocytes, neutrophils, lymphocytes, and eosinophils were determined 24 hs after CLP. ANOVA and Tukey test were used considering significant p<0.05. Results: It was demonstrated that serum TNF-α, IL-1β and IL-6 were respectively 364,8±42pg/mL; 46,3±18pg/mL and 28,4±13pg/mL in CLP/Sinvastatin rats, significantly lower (p<0.05) than in group CLP/Saline (778,5±86pg/ml; 176,9±46pg/ ml; 133,6±21 pg/ml, respectively). The same results were observed in total leukocytes and neutrophils counts. Conclusion: These results clearly demonstrate that simvastatin is an effective agent that reduces cytokines levels and leukocyte count in sepsis, independently of its well-known lipid-lowering effects. Thus, HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory effects in abdominal sepsis in rats

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Amidas graxas são compostos orgânicos nitrogenados derivados de ácidos carboxílicos, as quais contém em sua estrutura uma longa cadeia carbônica (C16- C24), possuindo ou não insaturações. Estes compostos podem ser encontrados em vegetais terrestres ou aquáticos, microorganismos e animais. Já em meados do século passado, a identificação de duas amidas graxas: a N-araquidonoiletanolamina (AEA, 5) e a cis-oleamida (cOA, 6), membros mais conhecidos e estudados desta família, devido as suas propriedades como indutora do sono fisiológico e canabinomimética respectivamente; levantou o interesse para a investigação das propriedades, identificação, síntese e isolamento de novas amidas graxas. Atualmente as pesquisas acerca das amidas graxas se devem as suas atividades biológicas tais como: aumento da libido sexual, analgesia, inseticida ou agente redutor da fome. Neste contexto, objetivo desse trabalho foi desenvolver metodologias para a síntese de novas amidas graxas. As amidas foram produzidas a partir de ácidos graxos, via cloreto de ácido ou via ésteres metílicos graxos, em rendimentos compreendidos entre 44% e 88%. Todos os compostos sintetizados foram caracterizados por espectroscopia de Infravermelho e RMN de 1H e 13C. Ensaios citotóxicos em células eritroleucêmicas K562 para a série das pirrolidil amidas demonstraram atividade citotóxica e capacidade de inibir proliferação celular em menos de 72 horas na concentração máxima de 1000µg/mL.

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Alopecurus aequalis Sobol. is a common grass weed, which has become increasingly troublesome to control in China wheat fields. One A. aequalis population, collected from Anhui Province China, was suspected to be resistant to fenoxaprop-P-ethyl and mesosulfuron-methyl. This study aimed to establish the cross-resistance pattern using the purified subpopulation and explore the potential targetsite and non-target-site based resistance mechanisms. Sequencing results showed that a single nucleotide change of ATT to AAT was present in acetyl-CoA carboxylase (ACCase) gene of the resistant (R) plants, resulting in an Ile2041Asn amino acid substitution. Besides, another single nucleotide change of CCC to CGC was present in acetolactate synthase (ALS) gene of the R plants, resulting in a Pro197Arg amino acid substitution. The homozygous resistant plants were isolated and the seeds were used in whole-plant herbicide bioassays. Compared with the susceptible (S) population, R population displayed high level resistance to fenoxaprop-P-ethyl and mesosulfuronmethyl. Cross resistance patterns showed that the R population was highly resistant to clodinafop-propargyl, moderately resistant to pyroxsulam and flucarbazoncsodium, lowly resistant to pinoxaden, and susceptible to tralkoxydim, sethoxydim, and isoproturon. The pretreatment of piperonyl butoxide reduced the 50% growth reduction (GR50) value of fenoxaprop-P-ethyl, suggesting that target-site resistance and non-target-site resistance mechanisms were both present in fenoxaprop- P-ethyl-resistance of A. aequalis. This is the first report of ACCase Ile2041Asn and ALS Pro197Arg mutation in A. aequalis.

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Desertomycin A is an aminopolyol polyketide containing a macrolactone ring. We have proposed that desertomycin A and similar compounds (marginolactones) are formed by polyketide synthases primed not with gamma-aminobutanoyl-CoA but with 4-guanidinylbutanoyl-CoA, to avoid facile cyclization of the starter unit. This hypothesis requires that there be a final-stage de-amidination of the corresponding guanidino-substituted natural product, but no enzyme for such a process has been described. We have now identified candidate amidinohydrolase genes within the desertomycin and primycin clusters. Deletion of the putative desertomycin amidinohydrolase gene dstH in Streptomyces macronensis led to the accumulation of desertomycin B, the guanidino form of the antibiotic. Also, purified DstH efficiently catalyzed the in vitro conversion of desertomycin B into the A form. Hence this amidinohydrolase furnishes the missing link in this proposed naturally evolved example of protective-group chemistry.

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Coartación Aórtica (CoA) es una cardiopatía congénita frecuente dada por una obstrucción mecánica entre el cayado de la aorta y la porción proximal de la aorta descendente. En nuestro hospital únicamente se practica la cirugía como tratamiento y la morbimortalidad posterior a ella es baja. Objetivo. determinar la sobrevida a tres años postquirúrgico del paciente pediátrico a quien se le realizó corrección quirúrgica de coartación aortica en el Hospital Nacional de Niños Benjamín Bloom en el período comprendido de enero de 2009 a diciembre de 2011, así como conocer las causas de muerte, principales complicaciones, edad, sexo y procedencia. Metodología:se incluyeron 28 pacientes, 25 de ellos se realizaron corrección quirúrgica de CoA, tratándose de un estudio observacional de seguimiento de una cohorte. Se confeccionó un formulario, los datos primarios se procesaron por medio de Excel e IBM SPSS realizándose el análisis de supervivencia de Kaplan Meier. Resultados: el 89.2% de los pacientes diagnosticados se sometieron a cirugía correctiva. Predominó el grupo etáreo entre 1 a 3 meses y el sexo masculino. La principal complicación fue la Recoartación, 2 pacientes fallecieron y la sobrevida a 3 años fue de 91%. El 76% provenían del área rural. Discusión: la sobrevida fue muy similar a estudios internacionales. Fue más frecuente la CoA pura, pero la mayoría de pacientes presentaron malformaciones asociadas como lo demuestran otros estudios. La recoartación como principal complicación conllevó a un fallecido, así como la ICC.

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Picornaviruses are a group of human and animal pathogens capable of inflicting serious public health diseases and economic burdens. Treatments options through vaccines for prevention or antivirals to cure infection are not available for the vast majority of these viruses. These shortcomings, in the development of vaccines or antivirals therapeutic, are linked to the genetic diversity and to an incomplete understanding of the biology of these viruses. Despite the diverse host range, this group of positive-strand RNA viruses shares the same replication mechanisms, including the development of membranous structures (replication organelles) in the cytoplasm of infected cells. The development of these membranous structures, which serve as sites for the replication of the viral RNA genome, has been linked to the hijacking of elements of the cellular membrane metabolism pathways. Here we show that upon picornavirus infection, there is a specific activation of acyl-CoA synthetase enzymes resulting in strong import and accumulation of long chain fatty acids in the cytoplasm of infected cells. We show that the newly imported fatty acids serve as a substrate for the upregulation of phosphatidylcholine synthesis required for the structural development of replication organelles. In this work, we identified that acyl-CoA synthetase long chain 3 (ACSL3) is required for the upregulation of lipids syntheses and the replication of poliovirus. We have shown that the poliovirus protein 2A was required but not sufficient for the activation of import of long chain fatty acids in infected cells. We demonstrated that the fatty acid import is upregulated upon infection by diverse picornaviruses and that such upregulation is not dependent on activation of ER stress response or the autophagy pathways. In this work, we have demonstrated that phosphatidylcholine was required for the structural development of replication organelles. Phosphatidylcholine synthesis was dispensable for the production of infectious particles at high MOI but required at a low MOI for the protection of the replication complexes from the cellular innate immunity mechanisms.

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Os cogumelos comestíveis são uma fonte rica de moléculas bioativas que lhes conferem importantes atividades biológicas. Moléculas como os Polissacáridos, terpenóides e os compostos fenólicos têm sido descritos como os componentes mais importantes no que respeita á atividade anti-inflamatória dos cogumelos (1). No presente trabalho, os extratos etanólicos de cogumelos comestíveis foram obtidos por maceração e caracterizados quimicamente em termos de ácidos fenólicos por técnicas de HPLC-DAD. Além disso, derivados metilados e glucuronados dos ácidos fenólicos identificados foram também sintetizados com o objetivo de mimetizar reações de metabolização no organismo e estudar a capacidade destas moléculas de manter a bioatividade exibida inicialmente. Os extratos obtidos, os ácidos fenólicos e compostos sintetizados foram avaliados pela sua atividade anti-inflamatória. De entre as amostras analisadas, B. impolitus revelou o mais elevado conteúdo em ácidos fenólicos (675 ± 23 μg/g), seguido de C. cibarius > A. caesaria > L. deliciosus > B. aereus > M. esculenta > B. edulis; devido à contribuição do ácido cinâmico que foi encontrada em maior quantidade nesta amostra (505 ± 12 μg/g). Mais ainda, B. impolitus apresentou também maior inibição da produção de NO (EC50=166 ± 10 μg/mL) seguido das amostras A. caesaria > C. cibarius > L. deliciosus > M. esculenta > B. aereus > B. edulis. No que respeita aos compostos individuais, o ácido cinâmico (CA) revelou a atividade mais forte (EC50 = 182 ± 16 μM), seguido pelos ácidos p-hidroxibenzóico (HA) (239 ± 29 μM) e p-Cumárico (CoA) (442± 33 μM), o que realça a importância destas moléculas para a atividade anti-inflamatória dos cogumelos. Comparando a atividade exibida pelos ácidos fenólicos com os respetivos derivados, é possível verificar a seguinte ordem de atividades: ácido p-hidroxibenzóico: HA > HA-M3 > HA-M2 > HA-M1 > HA-G; ácido p-cumárico : CoA-M1 > CoA-G > CoA-M2 > CoA-M3 > CoA e ácido cinâmico: CA-G > CA > CA-M1. Perante os resultados obtidos é de realçar a importância dos ácidos fenólicos na contribuição para a bioatividade exibida pelos cogumelos em estudo. Mais ainda, foi possível concluir que as alterações das moléculas pelas reações de conjugação no organismo têm influência na bioativade das moléculas iniciais, sendo que muitas vezes esta atividade é aumentada.

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Aunque hace más de 50 años que se describió que la glutamato descarboxilasa (GAD) lleva a cabo la descarboxilación del glutamato para producir GABA, y en animales ha sido muy estudiada debido al papel del GABA como neurotransmisor, la información disponible sobre las GADs de plantas es aún limitada, conociéndose sólo algunos aspectos de la regulación por calcio de su actividad enzimática o de expresión de algunos de los genes de su familia génica. El GABA es un metabolito que tradicionalmente se ha asociado a estrés, pero su papel en plantas todavía no está claro. En las últimas dos décadas los resultados experimentales obtenidos sobre la GAD y el GABA, destacando las alteraciones fenotípicas mostradas por plantas tratadas con GABA y por plantas transgénicas para GAD, han generado preguntas interesantes sobre el posible papel de este metabolito y la enzima en señalización en plantas. En plantas, son varios los papeles que se han propuesto para el metabolismo del GABA tales como su participación como componente del metabolismo del carbono y del nitrógeno (Fait y col., 2008), protección frente especies reactivas de oxigeno (Liu y col., 2011), regulación de la expresión génica incluyendo la regulación de genes implicados en la síntesis de hormonas (Khatiresan y col., 1997; Shi y col., 2010; Lancien y Roberts, 2006) y señalización a larga distancia (Beuve y col., 2004) y en gradiente guiando el crecimiento del tubo polínico (Palanivelu y col., 2013). Nuestro grupo de investigación ha sugerido un papel novedoso para la producción de GABA durante la xilogénesis en pino (Molina-Rueda y col., 2010, 2015). En base a estos antecedentes, los objetivos planteados para este trabajo han sido: la asignación de posibles funciones a las GADs de Populus en condiciones normales de crecimiento y en estrés abióticos, estudiar la adquisición del dominio de unión a calmodulina (CaMBD) de las GADs de plantas vasculares y analizar el efecto del GABA y del glutamato en las raíces de Populus. Las conclusiones que se derivan de los resultados de este trabajo se detallan a continuación. El dominio de unión a calmodulina de la GAD de plantas esta conservado en GADs de plantas consideradas ancestros de plantas vasculares y ausente en plantas no vasculares, lo que sitúa juntos en la evolución los eventos de adquisición del dominio de unión a CaM y el desarrollo del tejido vascular de plantas. Los resultados similares de la localización de GABA en xilema y una expresión GAD asociada a la formación de madera de reacción tanto en pino como en chopo apuntan a un papel relevante de la producción de GABA durante la xilogénesis en leñosas. La familia génica GAD posee seis genes codificando todos ellos para proteínas aparentemente funcionales y susceptibles de ser reguladas por calcio. Esta familia génica ha sufrido duplicaciones y eventos de especialización durante la evolución de Populus. Este trabajo ha posibilitado la asociación entre papeles específicos y los diferentes genes de esta familia. Beuvé N, Rispail N, Laine P, Cliquet J-B, Ourry A, Deunff F (2004) Putative role of Υ-aminobutyric acid as a long-distance signal in up-regulation of nitrate uptake in Brassica napus L. Plant Cell Environ. 27: 1035-1046 Fait A, Fromm H, Walter D, Galili G, Fernie AR (2008) Highway or byway: the metabolic role of the GABA shunt in plants. Trends in plant science 13: 14-19 Kathiresan A, Tung P, Chinnappa CC, Reid DM (1997) gamma-Aminobutyric acid stimulates ethylene biosynthesis in sunflower. Plant Physiol. 115: 129-135 Lancien M, Roberts MR (2006) Regulation of Arabidopsis thaliana 14-3-3 gene expression by ϒ-aminobutyric acid. Plant Cell Environ. 29: 1430-1436 Liu C, Zhao L, Yu G (2011) The dominant glutamic acid metabolic flux to produce gamma-amino butyric acid over proline in Nicotiana tabacum leaves under water stress relates to its significant role in antioxidant activity. Journal of integrative plant biology 53: 608-618 Molina-Rueda JJ, Pascual MB, Canovas FM, Gallardo F (2010) Characterization and developmental expression of a glutamate decarboxylase from maritime pine. Planta 232: 1471-1483 Molina-Rueda, J.J. y col., 2015. A putative role for γ-aminobutyric acid (GABA) in vascular development in pine seedlings. Planta 241: 257-267 Palanivelu R, Brass L, Edlund AF, D P (2003) Pollen tube growth and guidance is regulated by POP2, an Arabidopsis gene that controls GABA levels. Cell 114: 47-59 Shi SQ, Shi Z, Jiang ZP, Qi LW, Sun XM, Li CX, Liu JF, Xiao WF, Zhang SG (2010) Effects of exogenous GABA on gene expression of Caragana intermedia roots under NaCl stress: regulatory roles for H2O2 and ethylene production. Plant, cell & environment 33: 149-162

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Purpose: To investigate the pathogenesis of high fat diet (HFD)-induced hyperlipidemia (HLP) in mice, rats and hamsters and to comparatively evaluate their sensitivity to HFD. Methods: Mice, rats and hamsters were fed with high-fat diet formulation (HFD, n = 8) or a control diet (control, n = 8) for 4 weeks. Changes in body weight, relative liver weight, serum lipid profile, expressions of hepatic marker gene of lipid metabolism and liver morphology were observed in three hyperlipidemic models. Results: Elevated total cholesterol (TC), triglyceride, low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C) levels and body weight were observed in all hyperlipidemic animals (p < 0.05), while hepatic steatosis was manifested in rat and hamster HLP models, and increased hepatic TC level was only seen (p < 0.05) in hamster HLP model. Suppression of HMG-CoA reductase and up-regulation of lipoproteinlipase were observed in all HFD groups. Hepatic gene expression of LDLR, CYP7A1, LCAT, SR-B1, and ApoA I, which are a response to reverse cholesterol transport (RCT), were inhibited by HFD in the three models. Among these models, simultaneous suppression of HMG-CR, LCAT, LDLR and SR-BI and elevated LPL were features of the hamster model. Conclusion: As the results show, impaired RCT and excessive fat accumulation are major contributors to pathogenesis of HFD-induced murine HLP. Thus, the hamster model is more appropriate for hyperlipidemia research.

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Purpose: To investigate the anticonvulsant and sedative effects of Fufang Changniu Pills (FCP) and its probable mechanism of action in mice. Methods: The water decoction of FCP was prepared and the main constituents were determined by high performance liquid chromatography (HPLC). The anticonvulsant activities of FCP were evaluated by maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced seizures in mice. Pentobarbital sodium-induced sleeping time and locomotor activity measurements were performed to evaluate the sedative effects of FCP in mice. Finally, PTZ-induced chronic seizures were established, and expressions of gamma-aminobutyric acid A receptor (GABA-A) and glutamic acid decarboxylase 65 (GAD65) in the brains of the mice were assayed by western blot in order to explore the probable mechanisms of action of the drug. Results: Gallic acid, liquiritin, cinnamyl alcohol, cinnamic acid and glycyrrhizic acid were detected in FCP decoction. FCP (50, 100 and 200 mg/kg) showed significant anticonvulsant and sedative effects on epileptic mice induced by MES (p < 0.05) and PTZ (p < 0.05). Moreover, pentobarbital sodium-induced sleeping time and locomotor activity tests showed that FCP possesses sedative effect (p < 0.05). Western blot data indicate that FCP significantly up-regulated GABA-A and GAD 65 in the brains of chronic epileptic rats (p < 0.05). Conclusion: FCP has significant anticonvulsant and sedative effects, and the mechanism of its action may be related to the up-regulation of GABA-A and GAD 65 in mice brain.

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Changes induced by PA on nucleic acid (NA) conformation and synthesis is proven to be a major reason for PA essentiality (1-3). However, PA interactions with other polyanions, for instance polyanionic membrane lipid bilayers and glyosaminoglycans have received less attention (3-4). The functional importance of these interactions still is an obscure but interesting area of cell and molecular biology, especially in mammalian cells for which specific PA transport systems are not fully characterized (5). In mammals, activity and turnover of the polyamine (PA) synthesis key enzyme is controlled by a set of proteins: Antizymes (OAZ1-3) and antizyme inhibitors (AZIN1 and 2). It is demonstrated that AOZ modulate polyamine uptake (6), and that PA transport to mitochondria is linked to the respiratory chain state and modulates mitochondrial permeability transition (7). Antizyme expression variants have been located in mitochondria, being proposed as a proapoptotic factor (7-8). AZIN 2 is only expressed in a reduced set of tissues that includes mast cells, where it is associated to mast cell granules membrane (9). This fact, together to the abnormalities observed in bone marrow derived mast cell granules when they are differentiated under restricted PA synthesis conditions (10 and unpublished results), point out to important roles of PA and their related proteins in structure and function of mast cell granules. We will also present novel biophysical results on tripartite interactions of PA that remark the interest of the characterization of PA interactions with lipid bilayers for biomedicine and biotechnology. Thus, the information reported in this paper integrates previously reported information with our still unpublished results, all indicating that PA and their related proteins also are important factors for structure and dynamics of biological membranes and their associated functions essential in human physiology; for instance, solute interchange with the environment (uptake and secretion), oxidative metabolism and apoptosis. The importance of these involved processes for human homeostasis claim for further research efforts. 1. Ruiz-Chica J, Medina MA, Sánchez-Jiménez F and Ramírez FJ (2001) Fourier Transform Raman study of the structural specificities on the interaction between DNA and biogenic polyamines. Biophysical J. 80:443-454. 2. Lightfoot HL, Hall J (2014) Endogenous polyamine function--the RNA perspective. Nucleic Acids Res. 42:11275-11290. 3. Igarashi K, Kashiwagi K (2010) Modulation of cellular function by polyamines. Int J Biochem Cell Biol. 42:39-51. 4. Finger S, Schwieger C, Arouri A, Kerth A, Blume A (2014) Interaction of linear polyamines with negatively charged phospholipids: the effect of polyamine charge distance. Biol Chem. 395:769-778. 5. Poulin R, Casero RA, Soulet D. (2012) Recent advances in the molecular biology of metazoan polyamine transport. Amino Acids. 42:711-723. 6. Kahana C (2009) Regulation of cellular polyamine levels and cellular proliferation by antizyme and antizyme inhibitor. Essays Biochem. 4:47-61. 7. Agostinelli E, Marques MP, Calheiros R, Gil FP, Tempera G, Viceconte N, Battaglia V, Grancara S, Toninello A (2010) Polyamines: fundamental characters in chemistry and biology. Amino Acids 38:393-403. 8. Liu GY, Liao YF, Hsu PC, Chang WH, Hsieh MC, Lin CY, Hour TC, Kao MC, Tsay GJ, Hung HC (2006) Antizyme, a natural ornithine decarboxylase inhibitor, induces apoptosis of haematopoietic cells through mitochondrial membrane depolarization and caspases' cascade. Apoptosis 11:1773-1788. 9. Kanerva K, Lappalainen J, Mäkitie LT, Virolainen S, Kovanen PT, Andersson LC (2009). Expression of antizyme inhibitor 2 in mast cells and role of polyamines as selective regulators of serotonin secretion. PLoS One 31:e6858. 10. García-Faroldi G, Rodríguez CE, Urdiales JL, Pérez-Pomares JM, Dávila JC, Pejler G, Sánchez-Jiménez F, Fajardo I (2010) Polyamines are present in mast cell secretory granules and are important for granule homeostasis. PLoS One 30:e15071.

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Hypertension, a major risk factor in the cardiovascular system, is characterized by an increase in the arterial blood pressure. High dietary sodium is linked to multiple cardiovascular disorders including hypertension. Salt sensitivity, a measure of how the blood pressure responds to salt intake is observed in more than 50% of the hypertension cases. Nitric Oxide (NO), as an endogenous vasodilator serves many important biological roles in the cardiovascular physiology including blood pressure regulation. The physiological concentrations for NO bioactivity are reported to be in 0-500 nM range. Notably, the vascular response to NO is highly regulated within a small concentration spectrum. Hence, much uncertainty surrounds how NO modulates diverse signaling mechanisms to initiate vascular relaxation and alleviate hypertension. Regulating the availability of NO in the vasculature has demonstrated vasoprotective effects. In addition, modulating the NO release by different means has proved to restore endothelial function. In this study we addressed parameters that regulated NO release in the vasculature, in physiology and pathophysiology such as salt sensitive hypertension. We showed that, in the rat mesenteric arterioles, Ca2+ induced rapid relaxation (time constants 20.8 ± 2.2 sec) followed with a much slower constriction after subsequent removal of the stimulus (time constants 104.8 ± 10.0 sec). An interesting observation was that a fourfold increase in the Ca2+ frequency improved the efficacy of arteriolar relaxation by 61.1%. Our results suggested that, Ca2+ frequency-dependent transient release of NO from the endothelium carried encoded information; which could be translated into different steady state vascular tone. Further, Agmatine, a metabolite of L-arginine, as a ligand, was observed to relax the mesenteric arterioles. These relaxations were NO-dependent and occurred via α-2 receptor activity. The observed potency of agmatine (EC50, 138.7 ± 12.1 µM; n=22), was 40 fold higher than L-arginine itself (EC50, 18.3 ± 1.3 mM; n = 5). This suggested us to propose alternative parallel mechanism for L-arginine mediated vascular relaxation via arginine decarboxylase activity. In addition, the biomechanics of rat mesentery is important in regulation of vascular tone. We developed 2D finite element models that described the vascular mechanics of rat mesentery. With an inverse estimation approach, we identified the elasticity parameters characterizing alterations in normotensive and hypertensive Dahl rats. Our efforts were towards guiding current studies that optimized cardiovascular intervention and assisted in the development of new therapeutic strategies. These observations may have significant implications towards alternatives to present methods for NO delivery as a therapeutic target. Our work shall prove to be beneficial in assisting the delivery of NO in the vasculature thus minimizing the cardiovascular risk in handling abnormalities, such as hypertension.