Early obesity leads to increases in hepatic arginase I and related systemic changes in nitric oxide and l-arginine metabolism in mice

Obesity is a risk factor for vascular endothelial cell dysfunction characterized by low-grade, chronic inflammation. Increased levels of arginase I and concomitant decreases in l-arginine bioavailability are known to play a role in the pathogenesis of vascular endothelial cell dysfunction. In the present study, we focused on changes in the systemic expression of arginase I as well as l-arginine metabolism in the pre-disease state of early obesity prior to the onset of atherosclerosis. C57BL/6 mice were fed a control diet (CD; 10% fat) or high-fat diet (HFD; 60% fat) for 8 weeks. The mRNA expression of arginase I in the liver, adipose tissue, aorta, and muscle; protein expression of arginase I in the liver and plasma; and systemic levels of l-arginine bioavailability and NO2 − were assessed. HFD-fed mice showed early obesity without severe disease symptoms. Arginase I mRNA and protein expression levels in the liver were significantly higher in HFD-fed obese mice than in CD-fed mice. Arginase I levels were slightly increased, whereas l-arginine levels were significantly reduced, and these changes were followed by reductions in NO2 − levels. Furthermore, hepatic arginase I levels positively correlated with plasma arginase I levels and negatively correlated with l-arginine bioavailability in plasma. These results suggested that increases in the expression of hepatic arginase I and reductions in plasma l-arginine and NO2 − levels might lead to vascular endothelial dysfunction in the pre-disease state of early obesity

Células mieloides supresoras: potencial vínculo entre la enfermedad pulmonar obstructiva crónica y el cáncer de pulmón / Myeloid-Derived Suppressor Cells: Possible Link Between Chronic Obstrucive Pulmonary Disease and Lung Cancer

La enfermedad pulmonar obstructiva crónica (EPOC) y el cáncer de pulmón (CP) son enfermedades prevalentes y representan causas principales de morbimortalidad a nivel global. Existe firme evidencia que demuestra que la EPOC es un factor de riesgo independiente de CP. La inflamación crónica juega un rol patogénico significativo en el desarrollo de las comorbilidades en la EPOC, y en particular en el CP. Diferentes mediadores inflamatorios celulares y moleculares promueven la tumorigénesis e inhiben la capacidad del sistema inmunitario de reconocer y eliminar células premalignas y malignas, proceso conocido como inmunovigilancia tumoral. Esta alteración de la inmunidad antitumoral se debe en parte a la expansión de las células mieloides supresoras (myeloid derived suppressor cells [MDSC]), que se caracterizan por suprimir la función efectora antitumoral de linfocitosT mediante la reducción de la expresión del T-cell receptor ζ (TCRζ) a través del catabolismo de la L-arginina. Los pacientes con EPOC y CP comparten un patrón similar de aumento y activación de las MDSC circulantes asociado a la reducción de la expresión del TCRζ y a la alteración de la función de los linfocitosT periféricos. Los objetivos de este artículo son revisar la evidencia sobre la asociación entre EPOC y CP, y analizar cómo la acumulación de MDSC podría alterar la inmunovigilancia tumoral en la EPOC y favorecer el desarrollo de CP

Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are prevalent diseases and are a leading cause of morbidity and mortality worldwide. There is strong evidence to show that COPD is an independent risk factor for LC. Chronic inflammation plays a significant pathogenic role in COPD comorbidities, particularly in LC. On the one hand, cellular and molecular inflammatory mediators promote carcinogenesis and, on the other, chronic inflammation impairs the capacity of the immune system to identify and destroy pre-malignant and malignant cells, a process known as tumor immune surveillance. This altered antitumor immunity is due in part to the expansion of myeloid-derived suppressor cells (MDSC), which are characterized by an ability to suppress the antitumor activity of T-cells by down-regulation of the T-cell receptor ζ chain (TCRζ) through the catabolism of L-arginine. COPD and LC patients share a common pattern of expansion and activation of circulating MDSC associated with TCRζ downregulation and impaired peripheral T-cell function. The objectives of this study were to review the evidence on the association between COPD and LC and to analyze how MDSC accumulation may alter tumor immune surveillance in COPD, and therefore, promote LC development

Beneficial effects of arginase inhibition and inhaled l -arginine administration on airway histology in a murine model of chronic asthma

BACKGROUND: Increased arginase activity in the airways induces reduced bioavailability of l -arginine and cause deficiency of bronchodilatating and anti-inflammatory nitric oxide (NO). Therefore, arginine and arginase inhibitors may have therapeutic potential in the treatment of asthma. Using a murine model of asthma, we aimed to investigate the effects of inhaled l -arginine and arginase inhibitor Nω-hydroxy-nor- l -arginine (nor-NOHA) and co-treatment on airway histology of asthmatic lung tissue. METHODS: Forty-two BALB/c mice were divided into six groups: I (control), II (placebo), III, IV, V and VI. All mice except for control group were sensitised by an intraperitoneal injection of ovalbumin with alum adjuvant and then challenged with an aerosol of ovalbumin on three days of the week for eight weeks beginning from the 21st day of the study. Lung histology and bronchoalveolar lavage cell (BAL) counts were evaluated after treatment with inhaled l -arginine, nor-NOHA, l -arginine-nor-NOHA combination, budesonide and placebo. Interleukin (IL)-4 and IL-5 levels are determined in lung homogenates with ELISA. RESULTS: l -Arginine group was similar to budesonide group in lowering all histological parameters. Results of groups treated with nor-NOHA were also similar to budesonide group except for epithelial thickness. The number of eosinophils in BAL decreased significantly in groups receiving study drugs. Decrease was only noted in IL-4 levels in group receiving nor-NOHA. CONCLUSION: We demonstrated that inhaled l -arginine administration alleviated all histological parameters similar to budesonide and treatment with arginase inhibitor improved not all but some of the pathological changes in chronic asthma. Combination therapy had no additive effect on either treatment

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Relación entre la actividad arginasa y el tiempo de conservación de los concentrados de hematíes / Relationship between arginase activity and the storage time of packed red blood cells

Objetivos. Dada la creciente evidencia a favor de una relación entre el tiempo de conservación de los concentrados de hematíes y las complicaciones postransfusionales, nos planteamos analizar la relación existente entre los niveles de enzima arginasa, parámetros bioquímicos y de hemólisis, con el tiempo de conservación de concentrados de hematíes transfundidos. Material y métodos. Diseñamos un estudio prospectivo que incluyó 24 unidades de concentrado de hematíes, que habían sido transfundidos consecutivamente a pacientes de nuestro hospital. Luego de registrar el tiempo de conservación de cada bolsa, se extrajeron 15ml de sangre para determinar la actividad arginasa, los datos bioquímicos y de hemólisis. Se realizó un análisis univariante de todos los parámetros registrados y se incluyeron aquellos que resultaron significativos en un modelo de regresión múltiple (p<0,05). Resultados. El tiempo promedio de conservación fue de 18,6±6,1 días (rango: 6-31 días), con un hematocrito de 59,8%±0,05%, una hemoglobina 20,3±1,8g/dl, un pH de 6,5±0,1 y una actividad arginasa de 140,1±124,0 mU/ml. Se observó una relación lineal en el análisis univariante entre el tiempo de conservación y el pH (p=0,001), el HCO3act (p=0,001), el índice hemolítico (p=0,035) y la SpO2 (p=0,01). Una vez ajustados las variables de confusión procedentes del modelo univariante, se observó una relación lineal entre la actividad arginasa y el tiempo de conservación (p=0,031). Conclusiones. Nuestro trabajo muestra una relación lineal directamente proporcional entre el tiempo de conservación de los concentrados de hematíes y la actividad arginasa presente en los mismos. Sugerimos que estos hallazgos podrían estar relacionados con la elevada incidencia de complicaciones tras la transfusión que puede ser directamente proporcional a su tiempo de conservación(AU)

Objectives. Given the increasing evidence regarding a relationship between packed red blood cells storage time and post-transfusion complications, we decided to determine the relationship between the arginase enzyme levels, biochemical parameters and haemolysis, with the storage time of transfused packed red blood cells. Material and methods. We designed a prospective study that included 24 units of packed cells that had been consecutively transfused to patients of our hospital. After recording the storage time of each bag, 15ml of blood was removed to determine arginase activity, biochemical parameters and haemolysis. A univariate analysis was performed on all the recorded parameters, and included those that were significant in the multiple regression model (P<.05). Results. The mean storage time was 18.6±6.1 days (range: 6-31 days), with a haematocrit of 59.8%±0.05%, a haemoglobin of 20.3±1.8g/dl, a pH of 6.5±0.1, and an arginase activity of 140.1±124.0mU/ml. A linear relationship was observed in the univariate analysis between the storage time and the pH (P=.001), the actualHCO3 (P=.001), the haemolysis index (P=.035) and the SpO2 (P=.01). Once adjusted for the confounding variables of the univariate model, a linear relationship was observed between the arginase activity and the storage time (P=.031). Conclusions. Our study shows a directly proportional linear relationship between the storage time of packed red blood cells and their arginase activity. We suggest that these findings could be associated with the high incidence of complications after transfusion that may be directly proportional to their storage time(AU)

Decreased glutamine synthetase, increased citrulline–nitric oxide cycle activities, and oxidative stress in different regions of brain in epilepsy rat model

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To understand their role in epilepsy, the nitric oxide synthetase (NOS), argininosuccinate synthetase (AS), argininosuccinate lyase (AL), glutamine synthetase (GS), and arginase activities, along with the concentration of nitrate/nitrite (NOx), thiobarbituric acid reactive substances (TBARS), and total antioxidant status (TAS), were estimated in different regions of brain in rats subjected to experimental epilepsy induced by subcutaneous administration of kainic acid (KA). The short-term (acute) group animals were killed after 2 h and the long term (chronic) group animals were killed after 5 days of single injection of KA (15 mg/kg body weight). After decapitation of rats, the brain regions were separated and in their homogenates, the concentration of NOx, TBARS and TAS and the activities of NOS, AS, AL, arginase and glutamine synthetase were assayed by colorimetric methods. The results of the study demonstrated the increased activity of NOS and formation of NO in acute and chronic groups epilepsy. The activities of AS and AL were increased and indicate the effective recycling of citrulline to arginine. The activity of glutamine synthetase was decreased in acute and chronic groups of epilepsy compared to control group and indicate the modulation of its activity by NO in epilepsy. The activity of arginase was not changed in acute group; however it was decreased in chronic group and may favor increased production of NO in this condition. The concentration TBARS were increased and TAS decreased in acute and chronic groups of epilepsy and supports the oxidative stress in epilepsy (AU)

Production of nitric oxide and self-nitration of proteins during monocyte differentiation to dendritic cells

Nitric oxide (NO) can stimulate dendritic cells to a more activated state. However,nitric oxide and peroxynitrites production by dendritic cells has been usuallyassociated with pathological situations such as autoimmunity or inflammatory diseases.This study was designed to determine if dendritic cells obtained from healthyvolunteers produce nitric oxide and peroxynitrites, which results in protein nitration.The expression of arginase II, but not arginase I, isoform was detected in monocytesand dendritic cells. There was higher inducible nitric oxide synthase (iNOS) proteinexpression and lower arginase activity both in immature and mature dendritic cells,compared to monocytes. This caused nitric oxide production, and maturation of dendriticcells which provoked a significative increase of nitrites and nitrates comparedto immature dendritic cells. There was also peroxynitrites synthesis during monocytedifferentiation as shown by the nitration of proteins. Immunoblot revealed a patternof nitrated proteins in cell extracts obtained from monocytes and dendritic cells,however there were bands that appeared only in human dendritic cells, in particularan intense 90 kDa band. Nitric oxide production and nitrotyrosine formation couldaffect the antigen presentation and modify the immune response