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Angiotensin converting enzyme 2 (ACE2) presents pleiotropic actions. It hydrolyzes angiotensin I (AngI) and angiotensin II (AngII) into angiotensin-(1-9) (Ang-(1-9)) and angiotensin-(1-7) (Ang-(1-7)), respectively, as well as participates in tryptophan uptake in the gut and in COVID-19 infection. Our aim was to investigate the metabolic effect of ACE2 deletion in young adults and elderly mice under conditions of high calorie intake. Male C57Bl/6 (WT) and ACE2-deficient (ACE2 -/y ) mice were analyzed at the age of 6 and 12 months under standard diet (StD) and high-fat diet (HFD). Under StD, ACE2 -/y showed lower body weight and fat depots, improved glucose tolerance, enhanced insulin sensitivity, higher adiponectin, and lower leptin levels compared to WT. This difference was even more pronounced after HFD in 6-month-old mice, but, interestingly, it was blunted at the age of 12 months. ACE2 -/y presented a decrease in adipocyte diameter and lipolysis, which reflected in the upregulation of lipid metabolism in white adipose tissue through the increased expression of genes involved in lipid regulation. Under HFD, both food intake and total energy expenditure were decreased in 6-month-old ACE2 -/y mice, accompanied by an increase in liquid intake, compared to WT mice, fed either StD or HFD. Thus, ACE2 -/y mice are less susceptible to HFD-induced obesity in an age-dependent manner, as well as represent an excellent animal model of human lipodystrophy and a tool to investigate new treatments.

Obesity is an epidemic disease worldwide, associated with oxidative stress and the development of several other diseases. Bauhinia rufa (Bong.) Steud. is a native Brazilian Cerrado medicinal plant popularly used for the treatment of obesity. In this context, we investigated the chemical composition of the methanolic extract of B. rufa leaves (MEBr) and evaluated the antioxidant activity and its impact on the prevention and treatment of obesity in mice fed a high-fat diet (HFD 60%). Additionally, the acute oral toxicity of MEBr was evaluated. In MEBr, 17 glycosylated compounds were identified, including myricetin, quercetin, kaempferol, coumaroyl, cyanoglucoside, and megastigmane. In vitro , MEBr showed antioxidant activity in different methods: DPPH • , ABTS •+ , FRAP, iron-reducing power, inhibition of β -carotene bleaching, and inhibition of DNA fragmentation. In human erythrocytes, MEBr increased the activities of antioxidant enzymes, superoxide dismutase, and catalase. Under oxidative stress, MEBr reduced oxidative hemolysis, and the malondialdehyde (MDA) levels generated in erythrocytes. Mice treated acutely with MEBr (2000 mg/kg) showed no signs of toxicity. During 90 days, the mice received water or MEBr simultaneously with HFD for induction of obesity. At this stage, MEBr was able to reduce the gain of subcutaneous white adipose tissue (WAT) and prevent the increase of MDA in the heart and brain. After 180 days of HFD for obesity induction, mice that received MEBr simultaneously with HFD (HFD-MEBr) in the last 60 days of treatment (120-180 days) showed a reduction of retroperitoneal and mesenteric WAT deposits and MDA levels in the heart, liver, kidney, and brain, compared to the HFD-Control group. These effects of MEBr were similar to mice treated with sibutramine (HFD-Sibutramine, 2 mg/kg). Combined, the results show that compounds from the leaves of B. rufa affect controlling oxidative stress and actions in the prevention and treatment of obesity. Thus, associated oxidative stress reduction and body composition modulation, in obese people, can contribute to the prevention of obesity-related comorbidities and improve quality of life., Competing Interests: The authors declare no conflict of interest in this study., (Copyright © 2022 Paola dos Santos da Rocha et al.)

Aims: The lung is an important target organ damage in intestinal ischemia/reperfusion (II/R), but mechanisms involved in II/R-induced pulmonary artery (PA) dysfunction, as well as its treatment, are not clear. The present study aimed to investigate the mechanisms involved in the II/R-induced PA dysfunction and a possible protective role of acute simvastatin pretreatment., Main Methods: Male Wistar rats were subjected to occlusion of the superior mesenteric artery for 45 min followed by 2 h reperfusion (II/R) or sham-operated surgery (sham). In some rats, simvastatin (20 mg/kg, oral gavage) was administrated 1 h before II/R., Key Findings: II/R reduced acetylcholine-induced relaxation and phenylephrine-induced contraction of PA segments, which were prevented by acute simvastatin pretreatment in vivo or restored by inducible nitric oxide synthase (iNOS) inhibition in situ with 1400 W. Elevated reactive oxygen species (ROS) levels and higher nuclear translocation of nuclear factor kappa B (NFκB) subunit p65 were observed in PA of II/R rats and prevented by simvastatin. Moreover, simvastatin increased superoxide dismutase (SOD) activity and endothelial nitric oxide synthase (eNOS) expression in PA of the II/R group as well as prevented the increased levels of interleukin (IL)-1β and IL-6 in lung explants following II/R., Significance: The study suggests that pretreatment with a single dose of simvastatin prevents the II/R-induced increase of inflammatory factors and oxidative stress, as well as PA endothelial dysfunction and adrenergic hyporreactivity. Therefore, acute simvastatin administration could be therapeutic for pulmonary vascular disease in patients suffering from intestinal ischemic events., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Our aim with this study was to evaluate the consumption, performance, quantitative characteristics of carcasses, biochemical profile, plasma levels of ghrelin and leptin, expression of the receptor for ghrelin (GHS-R1a) in the hypothalamus and duodenum, and the number of goblet cells in the duodenum of calves subjected to milk volume restriction and supplemented with 2-hydroxy-4-(methylthio)butanoic acid (HMTBa). We used 21 Holstein mixed-breed calves, aged between 3 and 15 d with an average weight of 36.8 kg, and housed in pens with troughs for hay, concentrate, and water. The study included two consecutive experimental periods (first period [P1] and second period [P2]) of 21 d each, with 7 d of adaptation to the diet and facilities. The calves were distributed in a completely randomized design in three treatments with seven repetitions. 1) Control: 6 liters of milk/d during P1 and 6 liters of milk/day during P2; 2) RES (milk restriction): 3 liters of milk/day during P1 and 6 liters of milk/day during P2; and 3) RES + HMTBa: 3 liters of milk/day during P1 and 6 liters of milk/day during P2 + 3.3 g of HMTBa/day in both periods. HMTBa was supplied in milk, and the amount of concentrated ration and hay provided and leftovers were recorded daily to estimate dry matter (DM) and crude protein consumption. Mean daily weight gain (DWG), final weight (FW), and feed conversion (FC) were obtained at the beginning and at the end of each 21-d period. Plasma concentrations of ghrelin and leptin, triglycerides, total protein, urea, lactate, creatinine, alkaline phosphatase, and cholesterol were measured for P1 and P2 at the end of each 21-d period. At the end of P2, animals were slaughtered; sections of the duodenum were collected to evaluate the expression of GHS-R1a and quantity of goblet cells; hypothalamus was used to evaluate the expression of GHS-R1a; rumen was used to evaluate the thickness of epithelium and keratin and the density, height, and width of ruminal papillae. In P1, total DM consumption, FW, DWG, glucose, and triglycerides were lower in the RES and RES + HMTBa groups (P < 0.001). In P2, there was an improvement in the FC of the RES + HMTBa group (compared with Control and RES groups) and a lower urea concentration in the RES group (compared with Control and RES + HMTBa groups) (P < 0.001). No differences were observed among groups regarding hormonal concentrations, histological parameters, and GHS-R1a expression in the duodenum and hypothalamus. Therefore, milk restriction combined with HMTBa supplementation promoted greater compensatory gain by a mechanism independent of changes in GHS-R1a expression and hormone levels of ghrelin and leptin., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). Also, among the several mechanisms underlying SUDEP there is the cardiac dysfunction. So, we aimed to evaluate the impact of the number of seizures on heart function and morphology in rats with epilepsy. Rats were randomized into three groups: Sham (without epilepsy), 5 S, and 10 S groups, referred as rats with epilepsy with a total of 5 or 10 GTCS, respectively. Epilepsy was induced by electrical amygdala kindling. The ventricular function was analyzed by the Langendorff technique and challenged by ischemia/reperfusion protocol. Cardiac fibrosis and hypertrophy were analyzed by histology. We also analyzed cardiac metalloproteinases (MMP2 and MMP9), ERK 1/2 and phosphorylated ERK1/2 (P-ERK) by western blot; microRNA-21 and -320 by RT-PCR; and oxidative stress (TBARS, catalase activity and nitrite) by biochemical analysis. Only the 5S group presented decreased values of ventricular function at before ischemia/reperfusion (baseline): intraventricular systolic pressure, developed intraventricular pressure, positive and negative dP/dt. During ischemia/reperfusion protocol, the variation of the ventricular function did not differ among groups. Both 5S and 10S groups had increased cardiomyocyte hypertrophy and fibrosis compared to Sham, but in the 5S group, these alterations were higher than in the 10S group. The 5S group increased in microRNA-21 and decreased in microRNA-320 expression compared to Sham and the 10S group. The 10S group increased in MMP9 and decreased in P-ERK/ERK expression, and increased in nitrite content compared to both Sham and the 5S group. Therefore, seizures impair cardiac function and morphology, probably through microRNA modulation. The continuation of seizures seems to exert a preconditioning-like stimulus that fails to compensate the cardiac tissue alteration., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The present investigation aimed to characterize the effect of a short-time treatment with a new thiazolidinedione (TZD) derivative, GQ-130, on metabolic alterations in rats fed a high-fat diet (HFD). We investigated whether metabolic alterations induced by GQ-130 were mediated though a mechanism that involves PPARβ/δ transactivation. Potential binding and transactivation of PPARα, PPARβ/δ or PPARγ by GQ-130 were examined through cell transactivation, 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence quenching assays and thermal shift assay. For in vivo experiments, male 8-week-old Wistar rats were divided into three groups fed for 6 weeks with: (a) a standard rat chow (14% fat) (control group), (b) a HFD (57.8% fat) alone (HFD group), or (c) a HFD associated with an oral treatment with GQ-130 (10 mg/kg/d) during the last week (HFD-GQ group). In 293T cells, unlike rosiglitazone, GQ-130 did not cause significant transactivation of PPARγ but was able to activate PPARβ/δ by 153.9 folds in comparison with control values (DMSO). Surprisingly, ANS fluorescence quenching assay reveals that GQ-130 does not bind directly to PPARβ/δ binding site, a finding that was further corroborated by thermal shift assay which evaluates the thermal stability of PPARβ/δ in the presence of GQ-130. Compared to the control group, rats of the HFD group showed obesity, increased systolic blood pressure (SBP), insulin resistance, impaired glucose intolerance, hyperglycaemia, and dyslipidaemia. GQ-130 treatment abolished the increased SBP and improved all metabolic dysfunctions observed in the HFD group. Oral treatment with GQ-130 was effective in improving HFD-induced metabolic alterations probably through a mechanism that involves PPARβ/δ activation., (© 2020 John Wiley & Sons Australia, Ltd.)

Background: Obesity is a growing epidemic with limited effective treatments and an important risk factor for several diseases such as metabolic syndrome (MetS). In this study, we aimed to investigate the effect of 3-amino-1,2,4-triazole (ATZ), an inhibitor of catalase and heme synthesis, in a murine model for MetS., Methods: Male C57BL/6 mice with high-fat diet-induced MetS received ATZ (500 mg·kg -1 ·24 h -1 ) for 12 weeks., Results: The HFD group showed increased blood pressure and body weight, enhanced fat deposition accompanied by an increase in adipocyte diameter, and decreased lipolysis in white adipose tissue (WAT). The expression of genes related to inflammation was increased in WAT of the HFD group. Concurrently, these mice exhibited an increase in leptin, nonesterified fatty acid (NEFA), insulin, and glucose in plasma, coupled with glucose intolerance and insulin resistance. Strikingly, ATZ prevented the increase in blood pressure and the HFD-induced obesity as observed by lower body weight, WAT index, triglycerides, NEFA, and leptin in plasma. ATZ treatment also prevented the HFD-induced increase in adipocyte diameter and even induced marked atrophy and the accumulation of macrophages in this tissue. ATZ treatment also improved glucose metabolism by increasing glucose tolerance and insulin sensitivity, GLUT4 mRNA expression in WAT in parallel to decreased insulin levels., Conclusions: In the context of HFD-induced obesity and metabolic syndrome, the fat loss induced by ATZ is probably due to heme synthesis inhibition, which blocks adipogenesis by probably decreased RevErb α activity, leading to apoptosis of adipocytes and the recruitment of macrophages. As a consequence of fat loss, ATZ elicits a beneficial systemic antiobesity effect and improves the metabolic status., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper., (Copyright © 2020 Valéria Nunes-Souza et al.)

Numerous rheumatologic autoimmune diseases, among which rheumatoid arthritis, are chronic inflammatory diseases capable of inducing multiple cumulative articular and extra-articular damage, if not properly treated. Nevertheless, benign conditions may, similarly, exhibit arthritis as their major clinical finding, but with short-term duration instead, and evolve to spontaneous resolution in a few days to weeks, without permanent articular damage. Such distinction- self-limited arthritis with no need of immunosuppressive treatment or chronic arthritis at early stages? -represents one of the greatest challenges in clinical practice, once many metabolic, endocrine, neoplastic, granulomatous, infectious diseases and other autoimmune conditions may mimic rheumatoid arthritis. Indeed, the diagnosis of rheumatoid arthritis at early stages is a crucial step to a more effective mitigation of the disease-related damage. As a prototype of chronic inflammatory autoimmune disease, rheumatoid arthritis has been linked to oxidative stress, a condition in which the pool of reactive oxygen species increases over time, either by their augmented production, the reduction in antioxidant defenses, or the combination of both, ultimately implying compromise in the redox signaling. The exact mechanisms through which oxidative stress may contribute to the initiation and perpetuation of local (in the articular milieu) and systemic inflammation in rheumatoid arthritis, particularly at early stages, still remain to be determined. Furthermore, the role of antioxidants as therapeutic adjuvants in the control of disease activity seems to be overlooked, as a little number of short studies addressing this issue is currently found. Thus, the present review focuses on the binomial rheumatoid arthritis-oxidative stress , bringing insights into their pathophysiological relationships, as well as the implications of potential diagnostic oxidative stress biomarkers and therapeutic interventions directed to the oxidative status in patients with rheumatoid arthritis., Competing Interests: The authors declare that no conflicts of interest exist., (Copyright © 2019 Lucas José Sá da Fonseca et al.)

Diabetes has emerged as one of the largest global epidemics; it is estimated that by 2035, there will be 592 million diabetic people in the world. Brazilian biodiversity and the knowledge of traditional peoples have contributed to the treatment of several diseases, including diabetes. Apis mellifera bee tea is used by indigenous Brazilians to treat diabetes, and this traditional knowledge needs to be recorded and studied.The objective of this study was to record the use and to evaluate the antioxidant, antihyperglycemic, and antidiabetic activity of Apis mellifera bee tea, which is used by the Guarani and Kaiowá indigenous people for the treatment of diabetes. Semi-structured interviews were performed with Guarani and Kaiowá ethnic indigenous people from the State of Mato Grosso do Sul, Brazil, seeking to identify the animal species used for medicinal purposes. For the experimental procedures, tea prepared with macerated Apis mellifera bees was used. In vitro assays were performed to evaluate antioxidant activity; direct free radical scavenging, protection against oxidative hemolysis, lipid peroxidation were evaluated in human erythrocytes and potential in inhibiting the formation of advanced glycation end products (AGEs). In vivo, normoglycemic Swiss male mice treated with Apis mellifera tea (AmT) were subjected to the oral glucose tolerance test and compared with control and metformin-treated groups. Diet-induced diabetic mice were treated for 21 days with AmT and evaluated for glycemia and malondialdehyde levels in the blood, liver, nervous system, and eyes. During interviews, the indigenous people described the use of Apis mellifera bee tea for the treatment of diabetes. In in vitro assays, AmT showed direct antioxidant activity and reduced oxidative hemolysis and malondialdehyde generation in human erythrocytes. The AmT inhibited the formation of AGEs by albumin-fructose pathways and methylglyoxal products. In vivo, after oral glucose overload, normoglycemic mice treated with AmT had reduced hyperglycemia at all times evaluated up to 180 min. AmT also reduced hyperglycemia and malondialdehyde levels in the blood, liver, nervous system, and eyes of diabetic mice to similar levels as those in metformin-treated mice and normoglycemic controls. In summary, Apis mellifera bee tea showed antioxidant, antihyperglycemic, and antidiabetic activity, which provides support for the therapeutic application of Guarani and Kaiowá indigenous knowledge., Competing Interests: The authors have declared that no competing interests exist.

Hydrogen sulfide (H 2 S) and NO are important gasotransmitters, but how endogenous H 2 S affects the circulatory system has remained incompletely understood. Here, we show that CTH or CSE (cystathionine γ-lyase)-produced H 2 S scavenges vascular NO and controls its endogenous levels in peripheral arteries, which contribute to blood pressure regulation. Furthermore, eNOS (endothelial NO synthase) and phospho-eNOS protein levels were unaffected, but levels of nitroxyl were low in CTH-deficient arteries, demonstrating reduced direct chemical interaction between H 2 S and NO. Pretreatment of arterial rings from CTH-deficient mice with exogenous H 2 S donor rescued the endothelial vasorelaxant response and decreased tissue NO levels. Our discovery that CTH-produced H 2 S inhibits endogenous endothelial NO bioavailability and vascular tone is novel and fundamentally important for understanding how regulation of vascular tone is tailored for endogenous H 2 S to contribute to systemic blood pressure function., (© 2018 American Heart Association, Inc.)

Doxorubicin is an anticancer drug whose toxic effects on non-cancer cells are associated with increased oxidative stress. This study investigated the chemical composition, antioxidant activity of the methanolic extract of Schinus terebinthifolius Raddi leaves (MESL) as well as effects against doxorubicin-induced toxicity in human erythrocytes, K562 human erythroleukemia cells, and mouse hearts. The chemical composition indicated the presence of phenolic compounds, flavonoids, tannins, and ascorbic acid. MESL showed antioxidant activity by scavenging free radicals and inhibiting hemolysis and lipid peroxidation in human erythrocytes incubated with an oxidizing agent, and was able to increase the enzymatic activity of superoxide dismutase and glutathione peroxidase in human erythrocytes, without influencing the activity of enzyme catalase. The increase of oxidative hemolysis and malondialdehyde levels in erythrocytes incubated with doxorubicin was reduced by treatment with MESL. The cytotoxic activity of doxorubicin in erythroleukemia cells treated with MESL was unmodified. Additionally, the extract protected mice against the doxorubicin-induced cardiotoxicity. In conclusion, the MESL exhibits antioxidant activity, reducing doxorubicin-induced oxidative stress without changing the anticancer action of the drug, and protects against doxorubicin-induced cardiotoxicity. Hence, these findings suggest that these effects are via anti-oxidative by inhibiting free radicals, decreased oxidative stress, and increased antioxidant enzyme activity.

Although acute exercise is apparently pro-inflammatory and increases oxidative stress, it can promote the necessary stress stimulus to train chronic adaptations in patients with chronic heart failure (CHF). This study aimed to compare the effects of exercise intensity and duration on the inflammatory markers soluble tumor necrosis factor receptor (sTNFR1) and interleukin-6 (IL-6), and on oxidative stress [malondialdehyde (MDA) and antioxidant enzymes: catalase (CAT) and superoxide dismutase (SOD)] in individuals with CHF. Eighteen patients performed three exercise sessions: 30 min of moderate-intensity (M30) exercise, 30 min of low-intensity (L30) exercise, and 45 min of low-intensity (L45) exercise. Blood analysis was performed before exercise (baseline), immediately after each session (after), and 1 h after the end of each session (1h after). Thirty min of M30 exercise promoted a larger stressor stimulus, both pro-inflammatory and pro-oxidative, than that promoted by exercises L30 and L45. This was evidenced by increased sTNFR1 and MDA levels after exercise M30. In response to this stressor stimulus, 1 h after exercise, there was an increase in IL-6 and CAT levels, and a return of sTNFR1 to baseline levels. These findings suggest that compared with the duration of exercise, the exercise intensity was an important factor of physiologic adjustments.

Background . Type 2 diabetes mellitus (T2DM) is a serious disease associated with high morbidity and mortality. Scientific findings showed that physical exercise is an option for treatment of these patients. This study's objective is to investigate the effects of supervised aerobic and/or resistance physical training on inflammatory markers in subjects with T2DM. Methods . A systematic review was conducted on four databases, MEDLINE, CENTRAL, LILACS, and Scopus, and manual search from 21 to 30 November 2016. Randomized clinical trials involving individuals diagnosed with T2DM, who have undergone supervised training protocols, were selected in this study. Results . Eleven studies were included. Studies that evaluated control group versus aerobic exercise reported controversial results about the effectiveness of physical training in modifying C-reactive protein (CRP) and cytokine levels. The only variable analyzed by the six studies in comparison to the control group versus resistance exercise was CRP. This protein showed no significant difference between groups. Between the two modes of exercise (aerobic and resistance), only one study demonstrated that aerobic exercise was more effective in reducing CRP. Conclusion . The evidence was insufficient to prove that aerobic or resistance exercise improves systemic levels of inflammatory markers in patients with T2DM.

Accumulating evidence indicates that angiotensin-converting enzyme 2 (ACE2) plays a critical role in cardiovascular homeostasis, and its altered expression is associated with major cardiac and vascular disorders. The aim of this study was to evaluate the regulation of vascular function and assess the vascular redox balance in ACE2-deficient (ACE2-/y) animals. Experiments were performed in 20-22 week-old C57BL/6 and ACE2-/y male mice. Evaluation of endothelium-dependent and -independent relaxation revealed an impairment of in vitro and in vivo vascular function in ACE2-/y mice. Drastic reduction in eNOS expression at both protein and mRNA levels, and a decrease in •NO concentrations were observed in aortas of ACE2-/y mice in comparison to controls. Consistently, these mice presented a lower plasma and urine nitrite concentration, confirming reduced •NO availability in ACE2-deficient animals. Lipid peroxidation was significantly increased and superoxide dismutase activity was decreased in aorta homogenates of ACE2-/y mice, indicating impaired antioxidant capacity. Taken together, our data indicate, that ACE2 regulates vascular function by modulating nitric oxide release and oxidative stress. In conclusion, we elucidate mechanisms by which ACE2 is involved in the maintenance of vascular homeostasis. Furthermore, these findings provide insights into the role of the renin-angiotensin system in both vascular and systemic redox balance.

Nonalcoholic fatty liver disease (NAFLD) has been considered a novel component of the metabolic syndrome (MetS), with the oxidative stress participating in its progression. This study aimed to evaluate the metabolic profile in young and old mice with MetS, and the effects of apocynin and tempol on glycemic and lipid parameters. Young and old C57BL/6 mice with high fat diet- (HFD-) induced MetS received apocynin and tempol 50 mg·kg(-1)/day in their drinking water for 10 weeks. After HFD, the young group showed elevated fasting glucose, worsened lipid profile in plasma, steatosis, and hepatic lipid peroxidation. Nevertheless, the old group presented significant increase in fasting insulin levels, insulin resistance, plasma and hepatic lipid peroxidation, and pronounced steatosis. The hepatic superoxide dismutase and catalase activity did not differ between the groups. Tempol and apocynin seemed to prevent hepatic lipid deposition in both groups. Furthermore, apocynin improved glucose tolerance and insulin sensitivity in old mice. In summary, old mice are more susceptible to HFD-induced metabolic changes than their young counterparts. Also, the antioxidant therapy improved insulin sensitivity and glucose tolerance, and in addition, apocynin seemed to prevent the HFD-induced hepatic fat deposition, suggesting an important role of oxidative stress in the induction of NAFLD.

Background and Aims . Angiotensin converting enzyme 2 (ACE2) is an important component of the renin-angiotensin system. Since angiotensin peptides have been shown to be involved in hepatic steatosis, we aimed to evaluate the hepatic lipid profile in ACE2-deficient (ACE2 -/y ) mice. Methods . Male C57BL/6 and ACE2 -/y mice were analyzed at the age of 3 and 6 months for alterations in the lipid profiles of plasma, faeces, and liver and for hepatic steatosis. Results . ACE2 -/y mice showed lower body weight and white adipose tissue at all ages investigated. Moreover, these mice had lower levels of cholesterol, triglycerides, and nonesterified fatty acids in plasma. Strikingly, ACE2 -/y mice showed high deposition of lipids in the liver. Expression of CD36, a protein involved in the uptake of triglycerides in liver, was increased in ACE2 -/y mice. Concurrently, these mice exhibited an increase in hepatic oxidative stress, evidenced by increased lipid peroxidation and expression of uncoupling protein 2, and downregulation of sirtuin 1. ACE2 -/y mice also showed impairments in glucose metabolism and insulin signaling in the liver. Conclusions . Deletion of ACE2 causes CD36/sirtuin 1 axis impairment and thereby interferes with lipid homeostasis, leading to lipodystrophy and steatosis., Competing Interests: The authors have declared that no conflict of interests exists.

Lipoic acid (LA) and N -acetylcysteine (NAC) are antioxidant and anti-inflammatory agents that have not yet been tested on mild ulcerative colitis (UC). This study aims to evaluate the action of LA and/or NAC, on oxidative stress and inflammation markers in colonic and hepatic rat tissues with mild UC, induced by dextran sodium sulfate (DSS) (2% w/v). LA and/or NAC (100 mg·kg·day -1 , each) were given, once a day, in the diet, in a pretreatment phase (7 days) and during UC induction (5 days). Colitis induction was confirmed by histological and biochemical analyses (high performance liquid chromatography, spectrophotometry, and Multiplex®). A redox imbalance occurred before an immunological disruption in the colon. NAC led to a decrease in hydrogen peroxide (H 2 O 2 ), malondialdehyde (MDA) levels, and myeloperoxidase activity. In the liver, DSS did not cause damage but treatments with both antioxidants were potentially harmful, with LA increasing MDA and LA + NAC increasing H 2 O 2 , tumor necrosis factor alpha, interferon gamma, and transaminases. In summary, NAC exhibited the highest colonic antioxidant and anti-inflammatory activity, while LA + NAC caused hepatic damage., Competing Interests: The authors confirm that this article's content has no conflict of interests.

Arginase is a metalloenzyme which hydrolyzes L-arginine to L-ornithine and urea. Since its discovery, in the early 1900s, this enzyme has gained increasing attention, as literature reports have progressively pointed to its critical participation in regulating nitric oxide bioavailability. Indeed, accumulating evidence in the following years would picture arginase as a key player in vascular health. Recent studies have highlighted the arginase regulatory role in the progression of atherosclerosis, the latter an essentially prooxidant state. Apart from the fact that arginase has been proven to impair different metabolic pathways, and also as a consequence of this, the repercussions of the actions of such enzyme go further than first thought. In fact, such metalloenzyme exhibits direct implications in multiple cardiometabolic diseases, among which are hypertension, type 2 diabetes, and hypercholesterolemia. Considering the epidemiological repercussions of these clinical conditions, arginase is currently seen under the spotlights of the search for developing specific inhibitors, in order to mitigate its deleterious effects. That said, the present review focuses on the role of arginase in endothelial function and its participation in the establishment of atherosclerotic lesions, discussing the main regulatory mechanisms of the enzyme, also highlighting the potential development of pharmacological strategies in related cardiovascular diseases.

Background and Purpose: Leaves of Jacaranda decurrens are used in traditional Brazilian medicine to treat metabolic diseases related to increased reactive oxygen species. The present study evaluated the antioxidant and cytotoxic potential of hydroethanolic extract from the leaves of Jacaranda decurrens subsp. symmetrifoliolata., Experimental Approach: Phenolic compounds, flavonoids and saponins were evaluated in an ethanol:water (80:20, v/v) extract from the leaves of Jacaranda decurrens subsp. symmetrifoliolata (E-Jds). The antioxidant activity of E-Jds was investigated by assessing the following: 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity; protection against 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH)-induced hemolysis of erythrocytes; in vitro and in vivo malondialdehyde dosage; and the ability to activate antioxidant enzymes. K562 leukemia cells were used for the cytotoxic evaluation of E-Jds and for the assessment of the cell death profile through flow cytometry., Key Results: Phenolic and flavonoid compounds were quantified as 14.38% and 2.15%, respectively, of E-Jds. These phenolic and flavonoid compounds proved to be able to scavenge DPPH free radicals with an IC50 of 9.3 ± 3.3 µg/mL, to protect up to 50% of erythrocytes against AAPH-induced hemolysis and to reduce in vitro and in vivo malondialdehyde levels up to 84% and 22%, respectively. E-Jds also increased glutathione peroxidase enzyme activity, with a concomitant decrease in superoxide dismutase and catalase activity, and exhibited dose-dependent cytotoxic activity on K562 erythroleukemia cells with cell death occurring via both late apoptosis and necrosis., Conclusions: E-Jds exhibits in vitro and in vivo antioxidant potential, which may be the mechanism mediating the metabolic activities reported in folk medicine. Furthermore, the cytotoxic activity identified in this study contributes with the knowledge of antiproliferative activities that have been described in the literature for the genus Jacaranda.

Background: Teaching physiology, a complex and constantly evolving subject, is not a simple task. A considerable body of knowledge about cognitive processes and teaching and learning methods has accumulated over the years, helping teachers to determine the most efficient way to teach, and highlighting student's active participation as a means to improve learning outcomes. In this context, this paper describes and qualitatively analyzes an experience of a student-centered teaching-learning methodology based on the construction of physiological-physical models, focusing on their possible application in the practice of teaching physiology., Methods: After having Physiology classes and revising the literature, students, divided in small groups, built physiological-physical models predominantly using low-cost materials, for studying different topics in Physiology. Groups were followed by monitors and guided by teachers during the whole process, finally presenting the results in a Symposium on Integrative Physiology., Results: Along the proposed activities, students were capable of efficiently creating physiological-physical models (118 in total) highly representative of different physiological processes. The implementation of the proposal indicated that students successfully achieved active learning and meaningful learning in Physiology while addressing multiple learning styles., Conclusion: The proposed method has proved to be an attractive, accessible and relatively simple approach to facilitate the physiology teaching-learning process, while facing difficulties imposed by recent requirements, especially those relating to the use of experimental animals and professional training guidelines. Finally, students' active participation in the production of knowledge may result in a holistic education, and possibly, better professional practices.

The present study evaluated the cardiometabolic and redox balance profiles in patients with Metabolic Syndrome compared to apparently healthy individuals, and the participation of the myeloperoxidase/hydrogen peroxide axis in systemic lipid peroxidation. Twenty-four patients with Metabolic Syndrome and eighteen controls underwent a full clinical assessment. Venous blood samples were collected for general biochemical dosages, as well as for the oxidative stress analyses (superoxide dismutase, catalase, and arginase activities; and lipid peroxidation, myeloperoxidase activity, nitrite, and hydrogen peroxide concentrations in plasma). Arterial stiffness was assessed by radial artery applanation tonometry. Plasma lipid peroxidation, erythrocyte superoxide dismutase activity, myeloperoxidase activity, and hydrogen peroxide concentrations were shown to be increased in Metabolic Syndrome patients, without significant differences for the other enzymes, plasma nitrite concentrations, and arterial stiffness. Linear regression analysis revealed a positive and significant correlation between lipid peroxidation and myeloperoxidase and also between this enzyme and hydrogen peroxide. In contrast, such correlation was not observed between lipid peroxidation and hydrogen peroxide. In summary, Metabolic Syndrome patients exhibited evident systemic redox imbalance compared to controls, with the possible participation of the myeloperoxidase/hydrogen peroxide axis as a contributor in lipid peroxidation.

Objective: To evaluate the impact of a short-term cardiovascular physical programme on the metabolic, anthropometric and oxidative stress parameters of women with metabolic syndrome., Methods: Thirty sedentary female patients, age range 30-60 years, were invited to participate in a 6-week cardiovascular physical programme. The training consisted of 60-min sessions of aerobic and strength exercises performed 3 times a week; a total of 18 sessions. Anthropometric data, functional exercise capacity, general biochemical profile, serum lipid peroxidation, superoxide dismutase and catalase activity in erythrocytes were evaluated according to standardized protocols. Peripheral vascular function was assessed using applanation tonometry. All assessments were performed before and after the training programme., Results: The physical programme proved effective in improving the distance covered in the 6-min walk test and in reducing arterial pressure levels, pulse pressure and the Augmentation Index, without modifying heart rate. The plasma thiobarbituric acid reactive substances levels, indicators of oxidative stress, were significantly decreased after the programme. Superoxide dismutase activity was increased in erythrocyte lysates, with no significant change in catalase activity. Waist circumference was significantly decreased compared with baseline. The distance covered in the 6-min walk test was significantly greater after the short-term cardiovascular training., Conclusion: These findings indicate that short-term combined aerobic and strength training may represent an important non-pharmacological approach for treating individuals with metabolic syndrome.

The high prevalence of diabetes mellitus and its increasing incidence worldwide, coupled with several complications observed in its carriers, have become a public health issue of great relevance. Chronic hyperglycemia is the main feature of such a disease, being considered the responsible for the establishment of micro and macrovascular complications observed in diabetes. Several efforts have been directed in order to better comprehend the pathophysiological mechanisms involved in the course of this endocrine disease. Recently, numerous authors have suggested that excess generation of highly reactive oxygen and nitrogen species is a key component in the development of complications invoked by hyperglycemia. Overproduction and/or insufficient removal of these reactive species result in vascular dysfunction, damage to cellular proteins, membrane lipids and nucleic acids, leading different research groups to search for biomarkers which would be capable of a proper and accurate measurement of the oxidative stress (OS) in diabetic patients, especially in the presence of chronic complications. In the face of this scenario, the present review briefly addresses the role of hyperglycemia in OS, considering basic mechanisms and their effects in diabetes mellitus, describes some of the more commonly used biomarkers of oxidative/nitrosative damage and includes selected examples of studies which evaluated OS biomarkers in patients with diabetes, pointing to the relevance of such biological components in general oxidative stress status of diabetes mellitus carriers.

This study evaluated the oxidative stress through enzymatic and nonenzymatic biomarkers in diabetic patients with and without hypertension and prediabetics. The SOD and CAT (in erythrocytes) and GPx (in plasma) enzymatic activities, plasma levels of lipid peroxidation, and total thiols were measured in the blood of 55 subjects with type 2 diabetes and 38 subjects without diabetes (9 pre-diabetics and 29 controls) aged 40-86 years. The total SOD activity and the lipid peroxidation were higher in diabetics compared to nondiabetics. In stratified groups, the total SOD activity was different for the hypertensive diabetics compared to the prediabetics and normotensive controls. Lipid peroxidation was significantly higher in both groups of diabetics (hypertensive and normotensive) compared to prediabetic groups and hypertensive and normotensive controls. There was no significant difference in the CAT and GPx activities, as well as in the concentration of total thiols in the groups studied. Present data strongly suggest the involvement of oxidative stress in the pathophysiology of diabetes, revealing that the increased lipid peroxidation has a close relationship with high glucose levels, as observed by the fasting glucose and HbA1c levels. The results evidence the correlation between lipid peroxidation and DM, irrespective of the presence of hypertension.

Background: Recent studies describe the participation of reactive oxygen and nitrogen species in hypertension., Objective: To identify the redox imbalance in the blood of hypertensive., Methods: Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), vitamin C, transferrin, ceruloplasmin, malondialdehyde (MDA) and carbonyl group were quantified in the blood of 20 hypertensives and 21 controls. The individuals had a Body Mass Index of ≥ 18.5 and ≤ 30 kg/m(2), glycemia ≤ 100 mg/dL, serum cholesterol ≤ 200 mg/dL, and were nonsmokers, non-pregnant and non-lactating women, non-users of alopurinol and probucol, with hypertensives on antihypertensive medication. All individuals underwent a preparatory period of 4 weeks without alcohol, vitamin supplements, dexamethasone and paracetamol., Results: Reduced levels of CAT (p 0.013), GSH (p 0.003) and MDA (p 0.014), and high levels of GPx (p 0.001) and ceruloplasmin (p 0.015) were obtained in the hypertensive group compared with controls. A positive correlation between systolic pressure and MDA in hypertensive and diastolic pressure and CAT in controls was obtained., Conclusion: The data obtained suggest that the hypertensives were in redox imbalance, despite the possibly attenuating effect of their antihypertensive medication.

The renin-angiotensin-aldosterone system (RAAS) is a pivotal regulator of physiological homeostasis and diseases of the cardiovascular system. Recently, new factors have been discovered, such as angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) and Mas. This newly defined ACE2-angiotensin-(1-7)-Mas axis was shown to have a critical role in the vasculature and in the heart, exerting mainly protective effects. One important mechanism of the classic and the new RAAS regulate vascular function is through the regulation of redox signaling. Angiotensin II is a classic prooxidant peptide that increases superoxide production through the activation of NAD(P)H oxidases. This review summarizes the current knowledge about the ACE2-angiotensin-(1-7)-Mas axis and redox signaling in the context of cardiovascular regulation and disease. By interacting with its receptor Mas, angiotensin-(1-7) induces the release of nitric oxide from endothelial cells and thereby counteracts the effects of angiotensin II. ACE2 converts angiotensin II to angiotensin-(1-7) and, thus, is a pivotal regulator of the local effects of the RAAS on the vessel wall. Taken together, the ACE2-angiotensin-(1-7)-Mas axis emerges as a novel therapeutic target in the context of cardiovascular and metabolic diseases.

The Mas gene codes for an angiotensin (1-7) receptor. There is accumulating evidence that Mas is involved in vascular homeostasis. We have recently backcrossed Mas-knockout mice to two different genetic backgrounds, C57Bl/6 and FVB/N. FVB/NMas-deficient mice exhibited elevation in blood pressure (BP) and impaired endothelial function. In the present study, we aimed to address the question whether this phenotype is strain-specific. Therefore, we evaluated endothelial function in C57Bl/6Mas-deficient mice. Similar to FVB/NMas-knockout animals, Mas-deficiency in C57Bl/6 mice leads to endothelial dysfunction evaluated by the acute BP effect of acetylcholine administration. Measurements of nitric oxide (NO) and reactive oxygen species (ROS) and the systems involved in their metabolism revealed an imbalance between these vasoactive factors in C57Bl/6Mas-knockout mice, which may explain the impairment of endothelial function in these animals. However, endothelial dysfunction was less prominent in Mas-deficient mice on a C57Bl/6 background compared to FVB/N. Moreover, C57Bl/6Mas-deficient mice remained normotensive while FVB/N-based animals exhibited elevated BP. The impairment of endothelium-dependent vasodilatory response to acetylcholine in two different mouse strains with Mas deficiency indicates a key role of Mas in endothelial function by its effects on the generation and metabolism of NO and ROS.

Mas codes for a G protein-coupled receptor that is implicated in angiotensin-(1-7) signaling. We studied the cardiovascular phenotype of Mas-deficient mice backcrossed onto the FVB/N genetic background using telemetry and found that they exhibit higher blood pressures compared with controls. These Mas(-/-) mice also had impaired endothelial function, decreased NO production, and lower endothelial NO synthase expression. Reduced nicotinamide-adenine dinucleotide phosphate oxidase catalytic subunit gp91(phox) protein content determined by Western blotting was higher in Mas(-/-) mice than in controls, whereas superoxide dismutase and catalase activities were reduced. The superoxide dismutase mimetic, Tempol, decreased blood pressure in Mas(-/-) mice but had a minimal effect in control mice. Our results show a major cardiovascular phenotype in Mas(-/-) mice. Mas-deletion results in increased blood pressure, endothelial dysfunction, and an imbalance between NO and reactive oxygen species. Our animals represent a promising model to study angiotensin-(1-7)-mediated cardiovascular effects and to evaluate Mas agonistic compounds as novel cardioprotective and antihypertensive agents based on their beneficial effects on endothelial function.

1. In this study, the role of endogenous H(2)O(2) as an endothelium-dependent relaxant factor was characterised in aortas from C57BL/6J and LDL receptor-deficient mice (LDLR(-/-)). 2. Aortic rings from LDLR(-/-) mice showed impaired endothelium-dependent relaxation to acetylcholine (ACh; 0.001-100 micro M) and to the Ca(2+) ionophore A23187 (0.001-3 micro M) compared with aortic rings from control mice. Endothelium-independent relaxation produced by the NO donor, 3-morpholino-sydnonimine (SIN-1) was not different between strains. 3. Pretreatment of vessels with L-NNA (100 micro M) or L-NNA (100 micro M) plus L-NAME (300 micro M) plus haemoglobin (10 micro M) markedly decreased, but did not abolish the relaxation to ACh in control mice. In the aortas from LDLR(-/-) mice treated with L-NNA (100 micro M), ACh induced a contractile effect. Catalase (800 and 2400 U ml(-1)) shifted to the right the endothelium-dependent relaxation to ACh in aortas from control but not from LDLR(-/-) mice. Aminotriazole (50 mM), which inhibits catalase, abolished its effect on control mice. Treatment of vessels with L-NNA and catalase abolished vasorelaxation induced by ACh. Indomethacin (10 micro M) did not modify the concentration-response curve to ACh. Superoxide dismutase (300 U ml(-1)) did not change ACh-induced relaxation in both strains. 4. Exogenous H(2)O(2) produced a concentration-dependent relaxation in endothelium-denuded aortic rings, which was not different between strains. 5. It is concluded that H(2)O(2) greatly contributes to relaxation to ACh in aorta from control mice. Endothelial-dependent relaxation to ACh is impaired in LDLR(-/-) mice. Reduced biosynthesis or increased inactivation of H(2)O(2) is the possible mechanism responsible for endothelial dysfunction in aortas of atherosclerosis-susceptible LDLR(-/-) mice.