The Mas agonist CGEN-856S prevents Ang II induced cardiomyocyte hypertrophy via nitric oxide production.

With the previous knowledge of the cardioprotective effects of the Angiotensin-(1-7) axis, a agonist of Mas receptor has been described, the CGEN-856S. This peptide is more stable than Ang-(1-7), and has a low binding affinity to Angiotensin II receptors. Although the cardioprotective effects of CGEN-856S were previously shown in vivo, the mechanisms behind its effects are still unknown. Here, we employed a combination of molecular biology, confocal microscopy, and genetically modified mouse with Mas deletion to investigate the CGEN-856S protective signaling in cardiomyocytes. In isolated adult ventricular myocytes, CGEN-856S induced an increase in nitric oxide (NO) production which was absent in cells from Mas knockout mice. Using western blot, we observed a significant increase in phosphorylation of AKT after treatment with CGEN-856S. In addition, CGEN-856S prevented the Ang II induced hypertrophy and the nuclear translocation of GRK5 in a culture model of rat neonatal cardiomyocytes. Blockage of Mas receptor and inhibition of the NO synthase abolished the effects of CGEN-856S on Ang II treated cardiomyocytes. In conclusion, we show that CGEN-856S acting via receptor Mas induces NO raise to block Ang II induced cardiomyocyte hypertrophy. These results indicate that CGEN-856S acts very similarly to Ang-(1-7) in cardiac myocytes, highlighting its therapeutic potential for treating cardiovascular diseases.

Effects of oral HPΒCD-angiotensin-(1-7) supplementation on recreational mountain bike athletes: a crossover study.

BACKGROUND: Supplementation with Angiotensin-(1-7) [(Ang-1-7)] has received considerable attention due to its possible ergogenic effects on physical performance. The effects of a single dose of Ang-(1-7) on the performance of mountain bike (MTB) athletes during progressive load tests performed until the onset of voluntary fatigue have previously been demonstrated. This study tested the effects of Ang-(1-7) in two different exercise protocols with different metabolic demands: aerobic (time trial) and anaerobic (repeated sprint). METHODS: Twenty one male recreational athletes were given capsules containing an oral formulation of HPßCD-Ang-(1-7) (0.8 mg) and HPßCD-placebo (only HPßCD) over a 7-day interval; a double-blind randomized crossover design was used. Physical performance was examined using two protocols: a 20-km cycling time trial or 4 × 30-s repeated all-out sprints on a leg cycle ergometer. Data were collected before and after physical tests to assess fatigue parameters, and included lactate levels, and muscle activation during the sprint protocol as evaluated by electromyography (EMG); cardiovascular parameters: diastolic and systolic blood pressure and heart rate; and performance parameters, time to complete (time trial), maximum power and mean power (repeated sprint). RESULTS: Supplementation with an oral formulation of HPßCD-Ang-(1-7) reduced basal plasma lactate levels and promoted the maintenance of plasma glucose levels after repeated sprints. Supplementation with HPßCD-Ang-(1-7) also increased baseline plasma nitrite levels and reduced resting diastolic blood pressure in a time trial protocol. HPßCD-Ang-(1-7) had no effect on the time trial or repeat sprint performance, or on the EMG recordings of the vastus lateralis and vastus medialis. CONCLUSIONS: Supplementation with HPßCD-Ang-(1-7) did not improve physical performance in time trial or in repeated sprints; however, it promoted the maintenance of plasma glucose and lactate levels after the sprint protocol and at rest, respectively. In addition, HPßCD-Ang-(1-7) also increased resting plasma nitrite levels and reduced diastolic blood pressure in the time trial protocol. TRIAL REGISTRATION: RBR-2nbmpbc, registered January 6th, 2023. The study was prospectively registered.

Accessing the Health Risk of Ingestion of Surface Water from Lucrécia and Parelhas Dams in Northeast Brazil Using the Sentinel Organism Drosophila melanogaster.

This study investigated the genotoxic risk of chronic exposure of hemolymph's cells of Drosophila melanogaster (Insecta, Diptera) to water samples from Boqueirão de Parelhas Dam and from Lucrécia Dam in the semiarid region of Brazil. The dams are located over the Pegmatite Province of Borborema, with rocks rich in uranium and thorium. Water samples hydrated a culture medium composed of mashed potatoes, where larvae of D. melanogaster fed for 24 h, before be underwent to the Comet assay. The same water was evaluated for the presence of dissolved Radon gas (222Rn) and concentrations of 11 toxic metals (Ag, Al, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb and Zn). The results indicated a genotoxic effect resulting from exposure to the waters of the Parelhas dam, in the samples of August 2018; and in Lucrécia dam, in January 2019. D. melanogaster stood out for its high sensitivity to monitor the genotoxic effects of compounds dissolved in public dams. And unlike to other essentially aquatic sentinel organisms, this species stood out as a model to concomitant studies of air and water possible contaminated, in a scenario of natural environmental radioactivity present in semiarid of Brazil.

Actual evapotranspiration by machine learning and remote sensing without the thermal spectrum.

The objectives of this study were to use machine learning algorithms to establish a model for estimating the evapotranspiration fraction (ETf) using two data input scenarios from the spectral information of the Sentinel-2 constellation, and to analyze the temporal and spatial applicability of the models to estimate the actual evapotranspiration (ETr) in agricultural crops irrigated by center pivots. The spectral bands of Sentinel 2A and 2B satellite and vegetation indices formed the first scenario. The second scenario was formed by performing the normalized ratio procedure between bands (NRPB) and joining the variables applied in the first scenario. The models were generated to predict the ETf using six regression algorithms and then compared with ETf calculated by the Simple Algorithm For Evapotranspiration Retrieving (SAFER) algorithm, was considered as the standard. The results possible to select the best model, which in both scenarios was Cubist. Subsequently, ETf was estimated only for the center pivots present in the study area and the classification of land use and cover was accessed through the MapBiomas product. Land use was necessary to enable the calculation of ETr in each scenario, in the center pivots with sugarcane and soybean crops. ETr was estimated using two ETo approaches (EToBrazil and Hargreaves-Samani). It was found that the Hargreaves-Samani equation overestimated ETr with higher errors mainly for center pivots with sugarcane, where systematic error (MBE) ranged from 0.89 to 2.02 mm d-1. The EToBrazil product, on the other hand, presented statistical errors with MBE values ranging from 0.00 to 1.26 mm d-1 for both agricultural crops. Based on the results obtained, it is observed that the ETr can be monitored spatially and temporally without the use of the thermal band, which causes the estimation of this parameter to be performed with greater temporal frequency.

Angiotensin-(1-7) mediated calcium signalling by MAS.

The G protein-coupled receptor, MAS, is the receptor of the endogenous ligand, Angiotensin (Ang)-(1-7). It is a promising drug target since the Ang-(1-7)/MAS axis is protective in the cardiovascular system. Therefore, a characterization of MAS signalling is important for developing novel therapeutics for cardiovascular diseases. In this paper, we show that Ang-(1-7) increases intracellular calcium in transiently MAS-transfected HEK293 cells. The calcium influx induced by the activation of MAS is dependent on plasma membrane Ca2+ channels, phospholipase C, and protein kinase C. Specifically, we could demonstrate that MAS employs non-selective, transient receptor potential channels (TRPs) for calcium entry.

Oral Treatment with Angiotensin-(1-7) Attenuates the Kidney Injury Induced by Gentamicin in Wistar Rats.

BACKGROUND: Acute Kidney Injury (AKI), a common disease of the urinary system, can be induced by high doses of gentamicin (GM). The renin-angiotensin system exerts a key role in the progression of the AKI since elevated intrarenal levels of Ang II, and ACE activity is found in this condition. However, it is unknown whether oral administration of angiotensin (Ang)-(1-7), a heptapeptide that evokes opposite effects of Ang II, may attenuate the renal injuries induced by gentamicin. OBJECTIVES: To evaluate the effects of Ang-(1-7) on GM-induced renal dysfunction in rats. METHODS: AKI was induced by subcutaneous administration of GM (80 mg/Kg) for 5 days. Simultaneously, Ang-(1-7) included in hydroxypropyl ß-cyclodextrin (HPßCD) was administered by gavage [46 µg/kg HPßCD + 30 µg/kg Ang-(1-7)]. At the end of the treatment period (sixth day), the rats were housed in metabolic cages for renal function evaluation. Thereafter, blood and kidney samples were collected. RESULTS: Ang-(1-7) attenuated the increase of the plasmatic creatinine and proteinuria caused by GM but did not change the glomerular filtration rate nor tubular necrosis. Ang-(1-7) attenuated the increased urinary flow and the fractional excretion of H2O and potassium observed in GM rats but intensified the elevated excretion of sodium in these animals. Morphological analysis showed that Ang-(1-7) also reduced the tubular vacuolization in kidneys from GM rats. CONCLUSION: Ang-(1-7) promotes selective beneficial effects in renal injuries induced by GM.

Quantifying Renin-Angiotensin-System Alterations in COVID-19.

The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19.

Oral administration of angiotensin-(1-7) decreases muscle damage and prevents the fibrosis in rats after eccentric exercise.

NEW FINDINGS: What is the central question of this study? Eccentric contraction exercises cause damage to muscle fibres and induce inflammatory responses. The exacerbation of this process can induce deposition of fibrous connective tissue, leading to decreased muscle function. The aim of this study was to examine the role of angiotensin-(1-7) in this context. What is the main finding and its importance? Our results show that oral treatment with angiotensin-(1-7) decreases muscle damage induced by eccentric exercise, reducing inflammation and fibrosis in the gastrocnemius and soleus muscles. This study shows a potential effect of angiotensin-(1-7) for the prevention of muscle injuries induced by physical exercise. ABSTRACT: Eccentric contraction exercises cause damage to the muscle fibres and induce an inflammatory reaction. The protective effect of angiotensin-(1-7) [Ang-(1-7)] in skeletal muscle has led us to examine the role of this peptide in modifying processes associated with inflammation and fibrogenesis induced by eccentric exercise. In this study, we sought to investigate the effects of oral administration of Ang-(1-7) formulated in hydroxypropyl ß-cyclodextrin (HPß-CD) in prevention and treatment of muscle damage after downhill running. Male Wistar rats were divided into three groups: control (untreated and not exercised; n = 10); treated/exercised HPß-CD Ang-(1-7) (n = 40); and treated/exercised HPß-CD (n = 40). Exercised groups were subjected to a single eccentric contraction exercise session on a treadmill inclined to -13° at a constant speed of 20 m/min, for 60 min. Oral administration of HPß-CD Ang-(1-7) and HPß-CD was performed 3 h before the exercise protocol and daily as a single dose, until the end of the experiment. Samples were collected 4, 12, 24, 48 and 72 h after the exercise session. The animals treated with the Ang-(1-7) showed lower levels of creatine kinase, lower levels of tumor necrosis factor-α in soleus muscle and increased levels of interleukin-10 cytokines. The inflammatory cells and deposition of fibrous connective tissue in soleus and gastrocnemius muscles were lower in the group treated with Ang-(1-7). The results of this study show that treatment with an oral formulation of Ang-(1-7) enhances the process of repair of muscle injury induced by eccentric exercise.

Angiotensin-(1-7) oral formulation improves physical performance in mountain bike athletes: a double-blinded crossover study.

BACKGROUND: The ECA2/Ang-(1-7)/Mas axis is shown to be involved in effects mediated by physical exercise, as it can induce the release of nitric oxide (ON) and bradykinin (BK), which are potent vasodilators. The vasodilating action the NO/BK can contribute to increased metabolic efficiency in muscle tissue and central nervous system. The formulation HPß-CD-Ang-(1-7) through its mechanisms of action can be a promising supplement to aid in the maintenance and improvement of performance and may also favor recovery during competitions. The premise of this study was to investigate the effects of acute oral supplementation HPß-CD-Ang-(1-7) on the performance of mountain bike (MTB) practitioners. METHODS: Fourteen recreational athletes, involved in training programs for at least one year, participated in this crossover design study. Subjects underwent two days of testing with a seven-day interval. HPß-CD-Ang-(1-7) (1.75 mg) and HPßCD-Placebo were provided in capsules three hours prior to tests. To determine the safety of the HPß-CD-Ang-(1-7) formulation associated with physical effort, cardiovascular parameters heart rate (HR) and blood pressure (BP) were analyzed. Physical performance was measured using maximal oxygen uptake (VO2), total exercise time (TET), mechanical work (MW), mechanical efficiency (ME), and rating of perceived exertion (RPE). Respiratory exchange coefficient (REC), lactate and non-esterified fatty acids (NEFAs) were measured. Maximal incremental tests were performed on a progressively loaded leg cycle ergometer. RESULTS: There were no significant differences in terms of HR or BP at rest and maximum effort between the HPß-CD-Ang-(1-7) and placebo groups. The VO2max showed significant differences (p = 0.04). It was higher in the Ang-(1-7)condition (66.15 mlO2.kg- 1.min- 1) compared to the placebo (60.72 mlO2.kg- 1.min- 1). This was also observed for TET (Ang-(1-7) 39.10 min vs. placebo 38.14 min; p = 0.04), MW (Ang-(1-7) 156.7 vs. placebo 148.2; p = 0.04), and at the lowest RPE (Ang-(1-7) vs. placebo; p = 0.009). No significant differences were observed for REC, NEFAs, or Lactate. CONCLUSIONS: These results suggest that HPß-CD-Ang-(1-7) improves the physical performance of MTB recreational athletes and could be a promising supplement. TRIAL REGISTRATION: RBR-2 × 56pw8, registered January 15th, 2021. The study was prospectively registered.

Impact of drought associated with high temperatures on Coffea canephora plantations: a case study in Espírito Santo State, Brazil.

Droughts are major natural disasters that affect many parts of the world all years and recently affected one of the major conilon coffee-producing regions of the world in state of Espírito Santo, which caused a huge crisis in the sector. Therefore, the objective of this study was to conduct an analysis with technical-scientific basis of the real impact of drought associated with high temperatures and irradiances on the conilon coffee (Coffea canephora Pierre ex Froehner) plantations located in the north, northwest, and northeast regions of the state of Espírito Santo, Brazil. Data from 2010 to 2016 of rainfall, air temperature, production, yield, planted area and surface remote sensing were obtained from different sources, statistically analyzed, and correlated. The 2015/2016 season was the most affected by the drought and high temperatures (mean annual above 26 °C) because, in addition to the adverse weather conditions, coffee plants were already damaged by the climatic conditions of the previous season. The increase in air temperature has higher impact (negative) on production than the decrease in annual precipitation. The average annual air temperatures in the two harvest seasons that stood out for the lowest yields (i.e. 2012/2013 and 2015/2016) were approximately 1 °C higher than in the previous seasons. In addition, in the 2015/2016 season, the average annual air temperature was the highest in the entire series. The spatial and temporal distribution of Enhanced Vegetation Index values enabled the detection and perception of droughts in the conilon coffee-producing regions of Espírito Santo. The rainfall volume accumulated in the periods from September to December and from April to August are the ones that most affect coffee yield. The conilon coffee plantations in these regions are susceptible to new climate extremes, as they continue to be managed under irrigation and full sun. The adoption of agroforestry systems and construction of small reservoirs can be useful to alleviate these climate effects, reducing the risk of coffee production losses and contributing to the sustainability of crops in Espírito Santo.

Different reactive species modulate the hypotensive effect triggered by angiotensins at CVLM of 2K1C hypertensive rats.

Hypertension is associated with increased central activity of the renin-angiotensin system (RAS) and oxidative stress. Here, we evaluated whether reactive species and neurotransmitters could contribute to the hypotensive effect induced by angiotensin (Ang) II and Ang-(1-7) at the caudal ventrolateral medulla (CVLM) in renovascular hypertensive rats (2K1C). Therefore, we investigated the effect of Ang II, Ang-(1-7), and the Ang-(1-7) antagonist A-779 microinjected before and after CVLM microinjection of the nitric oxide (NO)-synthase inhibitor, (L-NAME), vitamin C (Vit C), bicuculline, or kynurenic acid in 2K1C and SHAM rats. Baseline values of the mean arterial pressure (MAP) in 2K1C rats were higher than in SHAM rats. CVLM microinjection of Ang II, Ang-(1-7), l-NAME, or bicuculline induced decreases in the MAP in SHAM and 2K1C rats. In addition, Vit C and A-779 produced decreases in the MAP only in 2K1C rats. Kynurenic acid increased the MAP in both SHAM and 2K1C rats. Only the Ang-(1-7) effect was increased by l-NAME and reduced by bicuculline in SHAM rats. L-NAME also reduced the A-779 effect in 2K1C rats. Only the Ang II effect was abolished by CVLM Vit C and enhanced by CVLM kynurenic acid in SHAM and 2K1C rats. Overall, the superoxide anion and glutamate participated in the hypotensive effect of Ang II, while NO and GABA participated in the hypotensive effect of Ang-(1-7) in CVLM. The higher hypotensive response of A-779 in the CVLM of 2K1C rats suggests that Ang-(1-7) contributes to renovascular hypertension.

The Novel Angiotensin-(1-7) Analog, A-1317, Improves Insulin Resistance by Restoring Pancreatic ß-Cell Functionality in Rats With Metabolic Syndrome.

In previous studies we have shown that oral Ang-(1-7) has a beneficial therapeutic effect on cardiometabolic disturbances present in metabolic syndrome (MetS). Based on the fact that Ang-(1-7) acts through release of nitric oxide (NO), a new peptide, A-1317 was engineered adding the amino acid L-Arginine, the NO precursor, to the N-terminal portion of the Ang-(1-7). Therefore, in a single molecule the substrate and the activator of NO are combined. In the present study, we evaluated the effect of A-1317 oral treatment on liver-glucose metabolism in MetS induced by high fat (HF) diet in rats. Rats were subjected to control (AIN-93M, CT) or HF diets for 15 weeks to induce MetS and treated with A-1317, Ang-(1-7) included into hydroxypropyl-ß-cyclodextrin (HPßCD) or empty HPßCD (E), in the last 7 weeks. At the end of 15 weeks, hemodynamic, biometric, and biochemical parameters, redox process, and qRT-PCR gene expression of NO synthase and RAS components were evaluated in the liver. HF/E rats increased body mass gain, adiposity index, despite the reduction in food intake, increased plasma leptin, total cholesterol, triglycerides, ALT, fasting blood glucose, OGTT and insulin, HOMA-IR and MAP and HR. Furthermore, the MetS rats presented increased in liver angiotensinogen, AT1R, ACE mRNA gene expression and concentration of MDA and carbonylated protein. Both Ang-(1-7) and A-1317 oral treatment in MetS rats reverted most of these alterations. However, A-1317 was more efficient in reducing body mass gain, ALT, AST, total cholesterol, insulin, fasting blood glucose, ameliorating ß cell capacity by increasing HOMA-ß and QUICKI, whereas Ang-(1-7) reduced HOMA-ß and QUICKI. In addition, Ang-(1-7) increased Mas and AKT liver mRNA gene expression, while A-1317 increased both Mas and MRGD and AMPK liver mRNA gene expression, suggesting a distinct pathway of action of Ang-(1-7) and A-1317 in MetS rats. Taken together, our data showed that treatment with A-1317 was able to ameliorate MetS disorders and suggested that this effect was mainly via MRGD via activation of AMPK and increasing ß cell function.

Mapping within­field variability of soybean evapotranspiration and crop coefficient using the Earth Engine Evaporation Flux (EEFlux) application.

Accurate information about the spatiotemporal variability of actual crop evapotranspiration (ETa), crop coefficient (Kc) and water productivity (WP) is crucial for water efficient management in the agriculture. The Earth Engine Evapotranspiration Flux (EEFlux) application has become a popular approach for providing spatiotemporal information on ETa and Kc worldwide. The aim of this study was to quantify the variability of water consumption (ETa) and the Kc for an irrigated commercial planting of soybeans based on the EEFlux application in the western region of the state of Bahia, Brazil. The water productivity (WP) for the fields was also obtained. Six cloud-free images from Landsat 7 and 8 satellites, acquired during the 2016/17 soybean growing season were used and processed on the EEFlux platform. The ETa from EEFlux was compared to that of the modified FAO (MFAO) approach using the following statistical metrics: Willmot's index of agreement (d-index), root mean square error (RMSE), mean absolute error (MAE) and mean bias error (MBE). The Kc from EEFlux was compared to the Kc used in the soybean field (Kc FAO-based) and to the Kc values obtained in different scientific studies using the d-index. A similar procedure was performed for WP. Our results reveal that EEFlux is able to provide accurate information about the variability of ETa and the Kc of soybean fields. The comparison between ETa EEFlux and ETa MFAO showed good agreement based on the d-index, with values of 0.85, 0.83 and 0.89 for central pivots 1, 2 and 3, respectively. However, EEFlux tends to slightly underestimate ETa. The Kc EEFlux showed good accordance with the Kc values considered in this study, except in phase II, where a larger difference was observed; the average WP of the three fields (1.14 kg m-3) was higher than that in the majority of the previous studies, which is a strong indicator of the efficient use of water in the studied soybean fields. The study showed that EEFlux, an innovative and free tool for access spatiotemporal variability of ETa and Kc at global scale is very efficient to estimate the ETa and Kc on different growth stages of soybean crop.

Scientific literature on Inga (Fabaceae) from Santa Catarina state, Southern Brazil (1983-2017)

The genus Inga Mill. belongs to the mimosoid clade (Fabaceae, Caesalpinioideae) that includes 131 species in Brazil. It is the most important genus of Fabaceae. In this sense, this study aimed to perform a bibliometric analysis on Inga from Santa Catarina state. A survey of the published literature was conducted using the electronic databases of the Web of Science, Scopus and Scielo with the accepted names of Inga species and its synonyms. Papers were distributed in four subject categories: C1 (Ecological), C2 (morphology, anatomy, taxonomy, histology, physiology and genetics), C3 (production and use) and C4 (biochemical and nutritional properties). We registered 232 papers for 13 species of Inga. C1 was the most studied subject category, mainly in topics such as nutrient supply, shade and nitrogen fixing capacity. We also noticed that the subjects diversified over the years, with registered papers in all categories. Inga edulis, I. vera and I. marginata were the most registered species in our survey. Our results showed an increase in the number of articles on Inga over time, especially in the last 13 years. However, some important gaps need to be addressed, such as the relatively small number and/or lack of studies conducted for some species.

El género Inga Mill. pertenece al clado mimosoide (Fabaceae, Caesalpinioideae) con 131 especies en Brasil. Es el género más importante de las Fabáceas. En este sentido, el objetivo de este estudio fue realizar un análisis bibliométrico de Inga en el Estado de Santa Catarina. Se condujo un estudio de la literatura publicada utilizando las bases de datos electrónicas de la Web of Science, Scopus y SciELO con los nombres aceptados de las especies Inga y sus sinónimos. Los trabajos se distribuyeron en cuatro categorías temáticas: C1 (ecológico), C2 (morfología, anatomía, taxonomía, histología, fisiología y genética), C3 (producción y uso) y C4 (propiedades bioquímicas y nutricionales). Se registraron 232 trabajos para 13 especies de Inga, donde se exhibió un notable incremento de publicaciones. C1 fue la categoría temática más estudiada, principalmente en temas tales como: suministro de nutrientes, sombra y capacidad de fijación de nitrógeno. Inga edulis, I. vera e I. marginata fueron las especies más registradas en nuestro estudio. Nuestros resultados mostraron un aumento en el número de artículos sobre Inga con el tiempo, especialmente en los últimos 13 años. Sin embargo, es necesario abordar algunos vacíos importantes como el número relativamente pequeño y/o la falta de estudios realizados para algunas especies.

Antioxidant Effects of Oral Ang-(1-7) Restore Insulin Pathway and RAS Components Ameliorating Cardiometabolic Disturbances in Rats.

In prevention studies of metabolic syndrome (MetS), Ang-(1-7) has shown to improve the insulin signaling. We evaluated the HPßCD/Ang-(1-7) treatment on lipid metabolism, renin-angiotensin system (RAS) components, oxidative stress, and insulin pathway in the liver and gastrocnemius muscle and hepatic steatosis in rats with established MetS. After 7 weeks of high-fat (FAT) or control (CT) diets, rats were treated with cyclodextrin (HPßCD) or HPßCD/Ang-(1-7) in the last 6 weeks. FAT-HPßCD/empty rats showed increased adiposity index and body mass, gene expression of ACE/ANG II/AT1R axis, and oxidative stress. These results were accompanied by imbalances in the insulin pathway, worsening of liver function, hyperglycemia, and dyslipidemia. Oral HPßCD/Ang-(1-7) treatment decreased ACE and AT1R, increased ACE2 gene expression in the liver, and restored thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), insulin receptor substrate (Irs-1), glucose transporter type 4 (GLUT4), and serine/threonine kinase 2 (AKT-2) gene expression in the liver and gastrocnemius muscle improving hepatic function, cholesterol levels, and hyperglycemia in MetS rats. Overall, HPßCD/Ang-(1-7) treatment restored the RAS components, oxidative stress, and insulin signaling in the liver and gastrocnemius muscle contributing to the establishment of blood glucose and lipid homeostasis in MetS rats.

Angiotensin-(1-7) and Alamandine Promote Anti-inflammatory Response in Macrophages In Vitro and In Vivo.

The renin-angiotensin system (RAS) peptides play an important role in inflammation. Resolution of inflammation contributes to restore tissue homeostasis, and it is characterized by neutrophil apoptosis and their subsequent removal by macrophages, which are remarkable plastic cells involved in the pathophysiology of diverse inflammatory diseases. However, the effects of RAS peptides on different macrophage phenotypes are still emerging. Here, we evaluated the effects of angiotensin-(1-7) (Ang-(1-7)) and the most novel RAS peptide, alamandine, on resting (M0), proinflammatory M(LPS+IFN-γ), and anti-inflammatory M(IL-4) macrophage phenotypes in vitro, as well as on specific immune cell populations and macrophage subsets into the pleural cavity of LPS-induced pleurisy in mice. Our results showed that Ang-(1-7) and alamandine, through Mas and MrgD receptors, respectively, do not affect M0 macrophages but reduce the proinflammatory TNF-α, CCL2, and IL-1ß transcript expression levels in LPS+IFN-γ-stimulated macrophages. Therapeutic administration of these peptides in LPS-induced inflammation in mice decreased the number of neutrophils and M1 (F4/80lowGr1+CD11bmed) macrophage frequency without affecting the other investigated macrophage subsets. Our data suggested that both Ang-(1-7) and alamandine, through their respective receptors Mas and MrgD, promote an anti-inflammatory reprogramming of M(LPS+IFN-γ)/M1 macrophages under inflammatory circumstances and potentiate the reprogramming induced by IL-4. In conclusion, our work sheds light on the emerging proresolving properties of Ang-(1-7) and alamandine, opening new avenues for the treatment of inflammatory diseases.

Physical training improves thermogenesis and insulin pathway, and induces remodeling in white and brown adipose tissues.

Physical training (PT) has been considered as a treatment in metabolic syndrome (MS), since it induces thermogenic activity in brown (BAT) and white (WAT) adipose tissues. We evaluated the therapeutic effect of PT on activity of WAT and BAT in rats with MS induced by high-fat diet (30% lard) for 13 weeks and submitted, for the last 6 weeks, to swimming or kept sedentary (SED) rats. MS-SED rats compared to control diet (CT-SED) rats showed low physical fitness and high levels of glucose, insulin, homeostasis evaluation of insulin resistance (HOMA-IR), homeostasis evaluation of the functional capacity of ß-cells (HOMA-ß), and blood pressure. The gastrocnemius muscle decreased in peroxisome proliferator-activated receptor gamma coactivator 1-alpha and beta (PGC-1α, PGC-1ß), and uncoupled protein 2 and 3 (UCP2 and UCP3) expressions. Both WAT and BAT increased in the adipocyte area and decreased in blood vessels and fibroblast numbers. WAT increased in expression of pro-inflammatory adipokines and decreased in anti-inflammatory adipokine and adiponectin. WAT and gastrocnemius showed impairment in the insulin signaling pathway. In response to PT, MS rats showed increased physical fitness and restoration of certain biometric and biochemical parameters and blood pressure. PT also induced thermogenic modulations in skeletal muscle, WAT and BAT, and also improved the insulin signaling pathway. Collectively, PT was effective in treating MS by inducing improvement in physical fitness and interchangeable effects between skeletal muscle, WAT and BAT, suggesting a development of brown-like adipocyte cells.

Lack of interferon-gamma attenuates foreign body reaction to subcutaneous implants in mice.

Subcutaneous implantation of synthetic materials and biomedical devices often induces abnormal tissue healing - the foreign body reaction-which impairs their function. In particular, Interferon-γ (IFN-γ) is a critical endogenous mediator of inflammation and plays a key role in a wide variety of biological responses including tissue healing. However, the contribution of endogenous IFN-γ on different features of the foreign body response induced by synthetic implants regarding neovascularization, inflammation, and fibrogenesis is not well known. Here, we evaluated inflammatory angiogenesis and fibrogenesis induced by implantation of polyether-polyurethane sponges in mice targeted disrupted of the interferon-γ gene (IFN-γ-/- ) and wild-type (WT). The hemoglobin content, the number of vessels, and blood flow (evaluated by LDPI-laser Doppler perfusion imaging) were decreased in the implants from IFN-γ-/- as compared to WT mice. Likewise, neutrophils and macrophages accumulation (MPO and NAG activities, respectively) was decreased in IFN-γ-/- implants. Interestingly, while the local content of VEGF, TNF-α, CXCL-1/KC, as measured by ELISA, and iNOS expression, as measured by qPCR, were significantly reduced, the content of IL-10 was greatly increased in the implants from IFN-γ-/- mice as compared to WT mice. No alterations were observed in CCL-2/MCP-1 levels. Lastly, the collagen deposition, assessed by Picro-Sirius red-stained histological sections, was also reduced in IFN-γ-/- implants. Altogether, these data suggest that IFN-γ activity contributes to inflammatory angiogenesis and fibrogenesis in synthetic implants and that lack of IFN-γ expression attenuates foreign body reaction to implants in mice. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2243-2250, 2018.