EFFECTS OF PTEROSTILBENE ON HEART AND LUNG OXIDATIVE STRESS PARAMETERS IN TWO EXPERIMENTAL MODELS OF CARDIOVASCULAR DISEASE: MYOCARDIAL INFARCTION AND PULMONARY ARTERIAL HYPERTENSION.

Myocardial infarction (MI) and pulmonary artery hypertension (PAH) are two prevalent cardiovascular diseases. In both conditions, oxidative stress is associated with a worse prognosis. Pterostilbene (PTE), an antioxidant compound, has been studied as a possible therapy for cardiovascular diseases. This study aims to evaluate the effect of PTE on oxidative stress in the hearts of animals with myocardial infarction and in the lungs of animals with PAH. Male Wistar rats were used in both models. In the MI model, the experimental groups were sham, MI, and MI+PTE. In PAH model, the experimental groups were control, PAH, and PAH+PTE. Animals were exposed to MI through surgical ligation of the left coronary artery, or to PAH, by administration of monocrotaline (60 mg/kg). Seven days after undergoing cardiac injury, the MI+PTE animals were treated with PTE (100 mg/kg day) for 8 days. After this, the heart was collected for molecular analysis. The PAH+PTE animals were treated with PTE (100 mg/kg day) for 14 days, beginning 7 days after PAH induction. After this, the lungs were collected for biochemical evaluation. We found that PTE administration attenuated the decrease in ejection fraction and improved LV end-systolic volume in infarcted animals. In the PAH model, PTE improved pulmonary artery flow and decreased ROS levels in the lung. PTE administration promoted protective effects in terms of oxidative stress in two experimental models of cardiac diseases: MI and PAH. PTE also improved cardiac function in infarcted rats and pulmonary artery flow in animals with PAH.

Effect of free and nanoemulsified ß-caryophyllene on monocrotaline-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance (PVR), right ventricular (RV) failure and premature death. Compounds with vasodilatory characteristics, such as ß-caryophyllene, could be promising therapeutics for PAH. This study aimed to determine the effects of free and nanoemulsified ß-caryophyllene in lung oxidative stress and heart function in PAH rats. Male Wistar rats (170 g, n = 6/group) were divided into four groups: control (CO), monocrotaline (MCT), monocrotaline + ß-caryophyllene (MCT-Bcar) and monocrotaline + nanoemulsion with ß-caryophyllene (MCT-Nano). PAH was induced by MCT (60 mg/kg i.p.), and 7 days later, treatment with ß-caryophyllene, either free or in a nanoemulsion (by gavage, 176 mg/kg/day) or vehicle was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and after, the RV was collected for morphometry and the lungs for evaluation of oxidative stress, antioxidant enzymes, total sulfhydryl compounds, nitric oxide synthase (NOS) activity and endothelin-1 receptor expression. RV hypertrophy, increased PVR and RV systolic and diastolic pressures (RVSP and RVEDP, respectively) and increased mean pulmonary arterial pressure (mPAP) were observed in the MCT group. Treatment with both free and nanoemulsified ß-caryophyllene reduced RV hypertrophy, mPAP, RVSP and lipid peroxidation. The reduction in RVSP was more pronounced in the MCT-Nano group. Moreover, RVEDP decreased only in the MCT-Nano group. These treatments also increased superoxide dismutase, catalase and NOS activities and decreased endothelin-1 receptors expression. Both ß-caryophyllene formulations improved mPAP, PVR and oxidative stress parameters. However, ß-caryophyllene in a nanoemulsion was more effective in attenuating the effects of PAH.

The challenge of improving pterostilbene (PTS) solubility for solid and semi-solid dosage forms: The obtention of binary and ternary systems.

Pterostilbene (PTS) is a drug candidate with low water solubility and poor bioavailability. On the other hand, drug:cyclodextrins complexes frequently provide bulk powders with low drug concentrations, which is crucial for obtention solid or semi-solid pharmaceutical dosage forms. In order to determine the optimal conditions for enhancing the solubility of PTS:BCD (ß-cyclodextrin) complex, a Box-Behnken design was performed. Although the optimal conditions have been applied, low complexation efficiency (0.127) and the bulk powder remained. A PTS:BCD:HPMC (HPMC, hydroxypropyl methylcellulose) ternary system was developed to overcome this limitation, comparing two media, water and a mixture of ethanol-water. When ethanol was used as a co-solvent, the PTS:BCD:HPMC ternary system (freeze-dried) contained 116.65 ± 1.40 mg/g of PTS. This value was 3.4-fold higher than the PTS content observed when the same ternary system was obtained in aqueous media (34.8 mg/g) and 2.8-fold higher than the PTS content observed for PTS:BCD complex (freeze-dried) obtained using ethanol as a co-solvent. Dissolution tests revealed that after 120 min, in a buffer with a pH value of 1.2, only 43% of PTS dissolved. In contrast, 80% and 90% of PTS were dissolved from the PTS:BCD complex and PTS:BCD:HPMC ternary system, respectively. Moreover, the dissolution was fast in a buffer with a pH value of 6.8. PTS:BCD complex reached the maximum PTS dissolution at 75 min and PTS:BCD:HPMC at 45 min. In summary, the results of this study demonstrated, for the first time, that low-bulk powders with a high content of PTS can be obtained from PTS:BCD:HPMC ternary systems using ethanol as a co-solvent. This new finding offers a valuable alternative for producing solid or semi-solid formulations containing highly soluble PTS.

Pterostilbene Reduces Experimental Myocardial Infarction-Induced Oxidative Stress in Lung and Right Ventricle. / Pterostilbeno Reduz o Estresse Oxidativo no Pulmão e no Ventrículo Direito Induzido por Infarto do Miocárdio Experimental.

BACKGROUND: Pterostilbene (PS), a natural and antioxidant polyphenolic compound emerges as a promising intervention in improving the myocardial infarction (MI) damages. OBJETIVES: This study aimed to evaluate PS actions in promoting redox homeostasis in lungs and right ventricle (RV) of infarcted animals. METHODS: Male Wistar rats (60 day-old) were randomized into three groups: SHAM, MI (infarcted), and MI+PS (MI+pterostilbene). Seven days after MI procedure, rats were treated with PS (100 mg/kg/day) via gavage for eight days. Animals were euthanized and the lungs and RV were harvested for analyses of redox balance (Differences were considered significant when p<0.05). RESULTS: Our results show that MI triggers a redox disruption scenario in RV and lungs, which can contribute to MI-induced damage on these organs. Consistently, PS mitigated oxidative stress and restored antioxidant defenses (GSH in lungs: SHAM= 0.79±0.07; MI=0.67±0.05; MI+PS=0.86±0.14; p<0.05), indicating its protective role in this scenario. CONCLUSIONS: Our work evidences the PS potential use as an adjuvant therapeutic approach after MI focusing on protecting pulmonary and right-sided heart tissues.

FUNDAMENTO: O pterostilbeno (PS), um composto polifenólico natural e antioxidante, surge como uma intervenção promissora para minimizar danos do infarto agudo do miocárdio (IAM). OBJETIVO: Este estudo teve como objetivo avaliar o desempenho do PS na promoção da homeostase redox nos pulmões e no ventrículo direito (VD) de animais infartados. MÉTODOS: Ratos Wistar machos (60 dias de idade) foram randomizados em três grupos: SHAM, IAM (infarto) e IAM+PS (IAM + pterostilbeno). Sete dias após o procedimento de IAM, os ratos foram tratados com PS (100 mg/kg/dia) por gavagem por oito dias. Os animais foram depois sacrificados e os pulmões e VD foram coletados para análise do balanço redox (diferenças foram consideradas significativas quando p<0,05). RESULTADOS: Nossos resultados mostram que o IAM desencadeia a interrupção redox no VD e nos pulmões, o que pode contribuir para danos induzido pelo IAM nesses órgãos. Consistentemente, o PS mitigou o estresse oxidativo e restaurou as defesas antioxidantes (Glutationa ­ GSH nos pulmões: SHAM = 0,79 ± 0,07; IAM = 0,67 ± 0,05; IAM + PS = 0,86 ± 0,14; p<0,05), indicando seu papel protetor neste cenário. CONCLUSÃO: Nosso trabalho evidencia o potencial do uso de PS como abordagem terapêutica adjuvante após IAM para proteção dos tecidos pulmonares e cardíacos direitos.

Pterostilbeno Reduz o Estresse Oxidativo no Pulmão e no Ventrículo Direito Induzido por Infarto do Miocárdio Experimental / Pterostilbene Reduces Experimental Myocardial Infarction-Induced Oxidative Stress in Lung and Right Ventricle

Resumo Fundamento O pterostilbeno (PS), um composto polifenólico natural e antioxidante, surge como uma intervenção promissora para minimizar danos do infarto agudo do miocárdio (IAM). Objetivo Este estudo teve como objetivo avaliar o desempenho do PS na promoção da homeostase redox nos pulmões e no ventrículo direito (VD) de animais infartados. Métodos Ratos Wistar machos (60 dias de idade) foram randomizados em três grupos: SHAM, IAM (infarto) e IAM+PS (IAM + pterostilbeno). Sete dias após o procedimento de IAM, os ratos foram tratados com PS (100 mg/kg/dia) por gavagem por oito dias. Os animais foram depois sacrificados e os pulmões e VD foram coletados para análise do balanço redox (diferenças foram consideradas significativas quando p<0,05). Resultados Nossos resultados mostram que o IAM desencadeia a interrupção redox no VD e nos pulmões, o que pode contribuir para danos induzido pelo IAM nesses órgãos. Consistentemente, o PS mitigou o estresse oxidativo e restaurou as defesas antioxidantes (Glutationa - GSH nos pulmões: SHAM = 0,79 ± 0,07; IAM = 0,67 ± 0,05; IAM + PS = 0,86 ± 0,14; p<0,05), indicando seu papel protetor neste cenário. Conclusão Nosso trabalho evidencia o potencial do uso de PS como abordagem terapêutica adjuvante após IAM para proteção dos tecidos pulmonares e cardíacos direitos.

Abstract Background Pterostilbene (PS), a natural and antioxidant polyphenolic compound emerges as a promising intervention in improving the myocardial infarction (MI) damages. Objetives This study aimed to evaluate PS actions in promoting redox homeostasis in lungs and right ventricle (RV) of infarcted animals. Methods Male Wistar rats (60 day-old) were randomized into three groups: SHAM, MI (infarcted), and MI+PS (MI+pterostilbene). Seven days after MI procedure, rats were treated with PS (100 mg/kg/day) via gavage for eight days. Animals were euthanized and the lungs and RV were harvested for analyses of redox balance (Differences were considered significant when p<0.05). Results Our results show that MI triggers a redox disruption scenario in RV and lungs, which can contribute to MI-induced damage on these organs. Consistently, PS mitigated oxidative stress and restored antioxidant defenses (GSH in lungs: SHAM= 0.79±0.07; MI=0.67±0.05; MI+PS=0.86±0.14; p<0.05), indicating its protective role in this scenario. Conclusions Our work evidences the PS potential use as an adjuvant therapeutic approach after MI focusing on protecting pulmonary and right-sided heart tissues.

Efeitos do Óleo de Copaíba em Marcadores Periféricos de Estresse Oxidativo em um Modelo de Cor Pulmonale em Ratos / Effects of Copaiba Oil in Peripheral Markers of Oxidative Stress in a Model of Cor Pulmonale in Rats

Resumo Fundamento Até o presente momento, os efeitos sistêmicos do óleo de copaíba jamais foram documentados no Cor pulmonale induzido por monocrotalina. Objetivos Investigar os efeitos do óleo de copaíba nos marcadores periféricos de stress oxidativo em ratos com Cor pulmonale. Métodos Ratos Wistar machos (170±20g, n=7/grupo) foram divididos em quatro grupos: controle (CO), monocrotalina (MCT), óleo de copaíba (O), e monocrotalina + óleo de copaíba (MCT-O). Foi administrada a MCT (60 mg/kg i.p.) e, depois de uma semana, foi iniciado o tratamento com óleo de copaíba (400 mg/kg/day-gavagem-14 dias). Foi realizado o ecocardiograma e, depois disso, foi coletado sangue do tronco para a realização de avaliações de stress oxidativo. Análise estatística: ANOVA de duas vias com teste Student-Newman-Keuls post hoc. P-valores <0,05 foram considerados significativos. Resultados O óleo de copaíba reduziu a resistência vascular pulmonar e a hipertrofia do ventrículo direito (VD) hipertrofia (Índice de Fulton (mg/mg)): MCT-O= 0,39±0,03; MCT= 0,49±0,01), e função sistólica melhorada (fração de encurtamento do VD, %) no grupo MCT-O (17,8±8,2) em comparação com o grupo de MCT (9,4±3,1; p<0,05). Além disso, no grupo MCT-O, espécies reativas do oxigênio e os níveis de carbonila foram reduzidos, e os parâmetros antioxidantes aumentaram no sangue periférico (p <0,05). Conclusões Os resultados deste estudo sugerem que o óleo de copaíba tem um efeito antioxidante sistêmico interessante, que se reflete na melhoria da função e na morfometria do VD nesse modelo de Cor pulmonale . A atenuação do Cor pulmonale promovida pelo óleo de copaíba coincidiu com uma redução no stress oxidativo sistêmico.

Abstract Background To date, copaiba oil's systemic effects have never documented in Cor pulmonale induced by monocrotaline. Objectives To investigate copaiba oil's effects in peripheral markers of oxidative stress in rats with Cor pulmonale. Methods Male Wistar rats (170±20g, n=7/group) were divided into four groups: control (CO), monocrotaline (MCT), copaiba oil (O), and monocrotaline+copaiba oil (MCT-O). MCT (60 mg/kg i.p.) was administered, and after one week, treatment with copaiba oil (400 mg/kg/day-gavage-14 days) was begun. Echocardiography was performed and, later, trunk blood collection was performed for oxidative stress evaluations. Statistical analysis: two-way ANOVA with Student-Newman-Keuls post-hoc test. P values<0.05 were considered significant. Results Copaiba oil reduced pulmonary vascular resistance and right ventricle (RV) hypertrophy (Fulton index (mg/mg): MCT-O=0.39±0.03; MCT=0.49±0.01), and improved RV systolic function (RV shortening fraction, %) in the MCT-O group (17.8±8.2) as compared to the MCT group (9.4±3.1; p<0.05). Moreover, in the MCT-O group, reactive oxygen species and carbonyl levels were reduced, and antioxidant parameters were increased in the peripheral blood (p<0.05). Conclusions: Our results suggest that copaiba oil has an interesting systemic antioxidant effect, which is reflected in the improvements in function and RV morphometry in this Cor pulmonale model. Cor pulmonale attenuation promoted by copaiba oil coincided with a reduction in systemic oxidative stress.

Effects of Copaiba Oil in Peripheral Markers of Oxidative Stress in a Model of Cor Pulmonale in Rats. / Efeitos do Óleo de Copaíba em Marcadores Periféricos de Estresse Oxidativo em um Modelo de Cor Pulmonale em Ratos.

BACKGROUND: To date, copaiba oil's systemic effects have never documented in Cor pulmonale induced by monocrotaline. OBJECTIVES: To investigate copaiba oil's effects in peripheral markers of oxidative stress in rats with Cor pulmonale. METHODS: Male Wistar rats (170±20g, n=7/group) were divided into four groups: control (CO), monocrotaline (MCT), copaiba oil (O), and monocrotaline+copaiba oil (MCT-O). MCT (60 mg/kg i.p.) was administered, and after one week, treatment with copaiba oil (400 mg/kg/day-gavage-14 days) was begun. Echocardiography was performed and, later, trunk blood collection was performed for oxidative stress evaluations. Statistical analysis: two-way ANOVA with Student-Newman-Keuls post-hoc test. P values<0.05 were considered significant. RESULTS: Copaiba oil reduced pulmonary vascular resistance and right ventricle (RV) hypertrophy (Fulton index (mg/mg): MCT-O=0.39±0.03; MCT=0.49±0.01), and improved RV systolic function (RV shortening fraction, %) in the MCT-O group (17.8±8.2) as compared to the MCT group (9.4±3.1; p<0.05). Moreover, in the MCT-O group, reactive oxygen species and carbonyl levels were reduced, and antioxidant parameters were increased in the peripheral blood (p<0.05). Conclusions: Our results suggest that copaiba oil has an interesting systemic antioxidant effect, which is reflected in the improvements in function and RV morphometry in this Cor pulmonale model. Cor pulmonale attenuation promoted by copaiba oil coincided with a reduction in systemic oxidative stress.

FUNDAMENTO: Até o presente momento, os efeitos sistêmicos do óleo de copaíba jamais foram documentados no Cor pulmonale induzido por monocrotalina. OBJETIVOS: Investigar os efeitos do óleo de copaíba nos marcadores periféricos de stress oxidativo em ratos com Cor pulmonale. MÉTODOS: Ratos Wistar machos (170±20g, n=7/grupo) foram divididos em quatro grupos: controle (CO), monocrotalina (MCT), óleo de copaíba (O), e monocrotalina + óleo de copaíba (MCT-O). Foi administrada a MCT (60 mg/kg i.p.) e, depois de uma semana, foi iniciado o tratamento com óleo de copaíba (400 mg/kg/day-gavagem-14 dias). Foi realizado o ecocardiograma e, depois disso, foi coletado sangue do tronco para a realização de avaliações de stress oxidativo. Análise estatística: ANOVA de duas vias com teste Student-Newman-Keuls post hoc. P-valores <0,05 foram considerados significativos. RESULTADOS: O óleo de copaíba reduziu a resistência vascular pulmonar e a hipertrofia do ventrículo direito (VD) hipertrofia (Índice de Fulton (mg/mg)): MCT-O= 0,39±0,03; MCT= 0,49±0,01), e função sistólica melhorada (fração de encurtamento do VD, %) no grupo MCT-O (17,8±8,2) em comparação com o grupo de MCT (9,4±3,1; p<0,05). Além disso, no grupo MCT-O, espécies reativas do oxigênio e os níveis de carbonila foram reduzidos, e os parâmetros antioxidantes aumentaram no sangue periférico (p <0,05). CONCLUSÕES: Os resultados deste estudo sugerem que o óleo de copaíba tem um efeito antioxidante sistêmico interessante, que se reflete na melhoria da função e na morfometria do VD nesse modelo de Cor pulmonale . A atenuação do Cor pulmonale promovida pelo óleo de copaíba coincidiu com uma redução no stress oxidativo sistêmico.

Development and validation of a specific-stability indicating liquid chromatography method for quantitative analysis of pterostilbene: application in food and pharmaceutical products.

Pterostilbene is a natural constituent with numerous preventive and therapeutic properties used for treating a wide range of human diseases. It has been isolated from blueberries in high concentrations. A versatile specific-stability indicating liquid chromatography method for reliable quantitative determination of pterostilbene in blueberry extracts was developed. In the stability-indicating analysis, pterostilbene samples were exposed to stress conditions: temperature, UV light, and oxidative, acid and alkaline media. The robustness of the method was evaluated using a Box-Behnken experimental design. Pterostilbene was stable in acid and alkaline media, but unstable when exposed to oxidation, high temperature, and UV light. Using the proposed method, it was demonstrated that degradation products did not interfere in the analyte analysis. The method revealed to be simple, fast, selective, linear, precise and accurate for the quantitative analysis of pterostilbene in Vaccinium myrtillus extract. Besides being a specific-stability indicating method, it demonstrated to be applicable to quantify pterostilbene in pterostilbene:ß-cyclodextrin complexes and pterostilbene:ß-cyclodextrin:hydrophilic polymer ternary systems. These findings are relevant for the development of food, pharmaceutical or cosmetic products containing pterostilbene or blueberry extracts.

Pterostilbene improves cardiac function in a rat model of right heart failure through modulation of calcium handling proteins and oxidative stress.

This study explored the effect of pterostilbene (PTS) complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) on right heart function, glutathione and glutaredoxin systems, and the expression of redox-sensitive proteins involved with regulation calcium levels in the experimental model of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). After 7 days of PAH induction, rats received daily doses of the PTS:HPßCD complex (corresponding to 25, 50, or 100 mg·kg-1 of PTS) or vehicle (control group, CTR0) (an aqueous solution containing HPßCD; CTR0 and MCT0 (MCT group that did not receive PTS treatment)) via oral administration for 2 weeks. The results showed that the PTS:HPßCD complex increased the content of reduced glutathione and the activity of glutathione-S-transferase and glutaredoxin in the right ventricle (RV) of MCT-treated rats in a dose-dependent manner. Additionally, at higher doses, it also prevented the reduction of stroke volume and cardiac output, prevented myocardial performance index (MPI) increase, reduced lipoperoxidation, reduced total phospholamban, and increased the expression of sarcoplasmic reticulum calcium ATPase in the RV of MCT-treated rats. These results demonstrate that the PTS:HPßCD complex has a dose-dependent antioxidant mechanism that results in improved cardiac function in experimental right heart failure. Our results open a field of possibilities to PTS administration as new therapeutic approach to conventional therapy for right ventricular dysfunction. Novelty Pterostilbene complexed with hydroxypropyl-ß-cyclodextrin could be a new therapeutic approach. Pterostilbene complexed with hydroxypropyl-ß-cyclodextrin reestablishes redox homeostasis through glutathione metabolism modulation, leading to an improved MPI in pulmonary arterial hypertension-provoked right heart failure.

Blueberry extract decreases oxidative stress and improves functional parameters in lungs from rats with pulmonary arterial hypertension.

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a condition characterized by an increased resistance of pulmonary vasculature, culminating in an increase in pulmonary pressure. This process involves disturbances in lung redox homeostasis, causing progressive right heart failure. In this context, the use of natural antioxidants, such as those found in blueberries, may represent a therapeutic approach. The aim of this study was to evaluate the effect of blueberry extract (BB) on functional parameters and oxidative stress levels in rat lungs with induced PAH. METHODS: Forty-eight male Wistar rats (weighing 200 ± 20 g) were randomized into five groups: control, monocrotaline, monocrotaline + BB 50, monocrotaline + BB 100, and monocrotaline + BB 200. PAH was induced by the administration of monocrotaline (60 mg/kg, intraperitoneal). Rats were treated with BB at doses of 50, 100, and 200 mg/kg via gavage for 5 wk (2 wk before monocrotaline and 3 wk after monocrotaline injection). At day 35, rats were submitted to echocardiography and catheterization. They were then sacrificed and lungs were harvested for biochemical analyses. RESULTS: BB increased the E/A ratio of blood flow across the tricuspid valve and tricuspid annular phase systolic excursion, as wells as decreased the mean pulmonary artery pressure of animals compared with the PAH group. Moreover, BB decreased total reactive species concentration and lipid oxidation, reduced activity of nicotinamide adenine dinucleotide phosphate oxidase and expression of xanthine oxidase, increased the activity of superoxide dismutase and restored sulfhydryl content in the animal lungs compared with those in the PAH group. Additionally, BB restored expression of the antioxidant transcriptional factor Nrf2 in the lungs of the animal subjects. Finally, BB normalized the endothelin receptor (ETA/ETB) expression ratio in the animal lungs, which were increased in the PAH group. CONCLUSION: Intervention with BB mitigated functional PAH outcomes through improvement of the pulmonary redox state. Our results provide a basis for future research on natural antioxidant interventions as a novel treatment strategy in PAH.

Carvedilol and thyroid hormones co-administration mitigates oxidative stress and improves cardiac function after acute myocardial infarction.

After acute myocardial infarction (AMI), reactive oxygen species and oxidative stress have important roles in the progression to heart failure. As a therapeutic alternative, thyroid hormones (TH) revealed cardioprotective effects after AMI, including decreasing oxidative stress. Carvedilol beta-blocker, already used in the clinical treatment of AMI, also mitigate cardiac pathological remodelling. This study assessed the effects of post-AMI carvedilol and TH co-administration on oxidative stress and cardiac function as well as whether those effects were synergistic. Male Wistar rats were divided into five groups: sham-operated (SHAM), infarcted (MI), infarcted + TH (MI + TH), infarcted + carvedilol (MI + C) and infarcted + C + TH (MI + C + TH). Two days post-surgery, the SHAM and MI groups received saline, and treated groups received their respective treatments by gavage for 12 days. The animals were submitted to echocardiographic evaluation, ventricular catheterization and euthanized for heart collection to perform oxidative stress analysis. Treated groups improved for ejection fraction compared to the MI group. Carvedilol decreased the positive chronotropic TH effects in the MI + C + TH group. The MI and MI + C groups had increased reactive oxygen species and reduced sulfhydryl levels. Carvedilol and TH co-administration showed synergic effects in the MI + C + TH group, reducing reactive oxygen species levels and improving GSH/GSSG ratio. Moreover, co-treatment attenuated NADPH oxidase activity in the MI group. Therefore, this study showed for the first time that carvedilol and TH co-administration may improve redox balance and cardiac function after AMI. Such co-administration could represent a therapeutic strategy capable of preventing cardiac dysfunction and redox unbalance after AMI.

Copaiba Oil Attenuates Right Ventricular Remodeling by Decreasing Myocardial Apoptotic Signaling in Monocrotaline-Induced Rats.

There is an increase in oxidative stress and apoptosis signaling during the transition from hypertrophy to right ventricular (RV) failure caused by pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). In this study, it was evaluated the action of copaiba oil on the modulation of proteins involved in RV apoptosis signaling in rats with PAH. Male Wistar rats (±170 g, n = 7/group) were divided into 4 groups: control, MCT, copaiba oil, and MCT + copaiba oil. PAH was induced by MCT (60 mg/kg intraperitoneally) and, 7 days later, treatment with copaiba oil (400 mg/kg by gavage) was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and the RV was collected for morphometric evaluations, oxidative stress, apoptosis, and cell survival signaling, and eNOS protein expression. Copaiba oil reduced RV hypertrophy (24%), improved RV systolic function, and reduced RV end-diastolic pressure, increased total sulfhydryl levels and eNOS protein expression, reduced lipid and protein oxidation, and the expression of proteins involved in apoptosis signaling in the RV of MCT + copaiba oil as compared to MCT group. In conclusion, copaiba oil reduced oxidative stress, and apoptosis signaling in RV of rats with PAH, which may be associated with an improvement in cardiac function caused by this compound.

Stilbenoid pterostilbene complexed with cyclodextrin preserves left ventricular function after myocardial infarction in rats: possible involvement of thiol proteins and modulation of phosphorylated GSK-3ß.

Oxidative stress alters signalling pathways for survival and cell death favouring the adverse remodelling of postmyocardial remnant cardiomyocytes, promoting functional impairment. The administration of pterostilbene (PTS), a phytophenol with antioxidant potential, can promote cardioprotection and represents a therapeutic alternative in acute myocardial infarction (AMI). The present study aims to explore the effects of oral administration of PTS complexed with hydroxypropyl-ß-cyclodextrin HPßCD (PTS:HPßCD complex) on the glutathione cycle, thiol protein activities and signalling pathways involving the protein kinase B (AKT) and glycogen synthase kinase-3ß (GSK-3ß) proteins in the left ventricle (LV) of infarcted rats. Animals were submitted to acute myocardial infarction through surgical ligation of the descending anterior branch of the left coronary artery and received over 8 days, by gavage, PTS:HPßCD complex at dose of 100 mg kg-1 day-1 (AMI + PTS group) or vehicle (aqueous solution with HPßCD) divided into Sham-operated (SHAM) and infarcted (AMI) groups. The results showed that the PBS: HPßCD complex decreased lipid peroxidation, prevented the decrease in thioredoxin reductase (TRxR) activity, and increased the activity of glutathione-S-transferase (GST) and glutaredoxin (GRx). Additionally, the expression of nuclear factor-erythroid two (Nrf2) and p-GSK-3ß was increased, whereas the p-GSK-3ß/GSK-3ß ratio was reduced in the LV of the infarcted animals. Overall, the PTS:HPßCD complex modulates activity of thiol-dependent enzymes and induces to the expression of antioxidant proteins, improving systolic function and mitigating the adverse cardiac remodelling post infarction.

Trapidil improves hemodynamic, echocardiographic and redox state parameters of right ventricle in monocrotaline-induced pulmonary arterial hypertension model.

BACKGROUND: Pulmonary arterial hypertension is a disease characterized by increased pulmonary vascular resistance and redox imbalance, leading to failure of right ventricle. Trapidil has been described to improve the redox balance and cardiac conditions. HYPOTHESIS: Trapidil can improve the redox balance and contribute to functional improvements of the RV in PAH. METHODS AND RESULTS: Male, 5week-old Wistar rats were divided into four groups: Control, Control + Trapidil, Monocrotaline and Monocrotaline + Trapidil. PAH was induced by an intraperitoneal injection of monocrotaline 60 mg/kg at day 0. Treatment started at day 7 (5 or 8 mg/kg/day) until day 14, when animals were euthanized after echocardiography and catheterism. Right ventricular systolic pressure and pressure/time derivatives were increased in monocrotaline animals. The increased right ventricular diameters in monocrotaline groups were reduced with trapidil. Monocrotaline groups showed higher lipid peroxidation and glutathione peroxidase activity. Trapidil reduced NADPH oxidases activities and increased the reduced glutathiones/total glutathiones ratio. Protein expression of phospholamban in RV was diminished in monocrotaline groups, whereas expression of RyR and SERCA was enhanced in the groups treated with trapidil. CONCLUSION: Our data suggest that trapidil induces an improvement in RV remodeling in PAH model, mitigating the progression of the disease.

Pterostilbene reduces oxidative stress, prevents hypertrophy and preserves systolic function of right ventricle in cor pulmonale model.

BACKGROUND AND PURPOSE: In cor pulmonale, the increased afterload imposed on the right ventricle (RV) generates a maladaptive response, impairing the contractile cardiac function. Oxidative mechanisms play an important role in the pathophysiology and progression of this disease. The administration of pterostilbene (PTS), a phytophenol with antioxidant potential, may represent a therapeutic option. In the present study, we evaluated the effect of PTS complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) on hypertrophy, contractile function and oxidative parameters in the RV of rats with pulmonary hypertension, induced by the administration of monocrotaline (MCT). EXPERIMENTAL APPROACH: The rats received daily doses of the PTS : HPßCD complex at 25, 50 or 100 mg·kg-1 , p.o., for 14 days. The diastolic function, E/A ratio, and systolic function, shortening fraction, fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE) of the RV were determined by echocardiography. KEY RESULTS: The PTS : HPßCD complex reduced the production of NADPH oxidase-dependent superoxide anions and oxidative stress in the RV of MCT-treated rats in a dose-dependent manner. At higher doses it prevented the reduction in FAC and TAPSE in MCT-treated animals. CONCLUSIONS AND IMPLICATIONS: The PTS : HPßCD complex prevented the maladaptative remodelling and protected systolic function in the RV of rats with pulmonary hypertension. These cardioprotective mechanisms may be related, in part, to the antioxidant potential of PTS, favoured by the increased p.o. bioavailability promoted by the presence of HPßCD in the complex.

Consumo exacerbado de lipídeos provoca dano celular em algumas doenças metabólicas e cardiovasculares / Excessive consumption of fat provokes systemic cellular damage in some metabolic and cardiovascular diseases

OBJECTIVE: To review the deleterious biochemical mechanisms related to changes of oxidative stress and inflammation, provoked by excessive consumption and accumulation of lipids in different tissues, in cardiovascular diseases, diabetes and metabolic syndrome. Data source: This review article was based on papers selected for their relevance from databases such as Science Direct, PubMed and SciELO, published between 1995 and 2014. The search included the following keywords: High-fat diet, obesity, oxidative stress, inflammation. Data synthesis: Evidence suggests that the deleterious effects of lipotoxicity are related to ectopic deposition, activation of lipolysis, formation of lipid metabolites, generation of reactive oxygen species and oxidative stress, as well as to stimulation of inflammatory cascades. In this context, the simultaneous activation of these biochemical mechanisms interferes with intracellular signaling cascades, disrupting homeostasis, leading to systemic cellular damage or even lipoapoptosis. CONCLUSIONS: The identification of the biochemical cellular pathways involved in the process provides an understanding of the molecular mechanisms and, especially, may identify potential therapeutic targets

OBJETIVO: Revisar mecanismos bioquímicos deletérios relacionados com alterações de estresse oxidativo e inflamação ocasionados pelo consumo excessivo e acúmulo de lipídeos em diferentes tecidos, nas doenças cardiovasculares, diabetes e síndrome metabólica. Fonte de dados: Este artigo de revisão baseou-se em artigos científicos, selecionados por sua relevância e provenientes de bases de dados como Science Direct, Scielo e Pubmed, publicados entre 1995 e 2014. A busca contemplou as seguintes palavras-chave: dieta hiperlipídica, obesidade, estresse oxidativo, inflamação. Síntese dos dados: Evidências sugerem que os efeitos deletérios da lipotoxidade estão relacionados com a deposição ectópica, ativação da lipólise, formação de metabólitos lipídicos, geração de espécies reativas e estresse oxidativo, bem como estimulação de cascatas inflamatórias. Nesse contexto, a ativação simultânea desses mecanismos bioquímicos interfere em cascatas de sinalização intracelular, prejudicando a homeostase, levando ao dano celular sistêmico ou até mesmo à lipoapoptose. CONCLUSÕES: A identificação das vias bioquímicas celulares envolvidas proporciona a compreensão dos mecanismos moleculares e, principalmente, pode identificar possíveis alvos terapêuticos

Hepatoprotective and Antioxidant Potential of Organic and Conventional Grape Juices in Rats Fed a High-Fat Diet.

The objective of this study was to investigate the antioxidant and hepatoprotective effect of the chronic use of conventional (CGJ) or organic (OGJ) grape juice from the Bordeaux variety grape on oxidative stress and cytoarchitecture in the liver of rats supplemented with a high-fat diet (HFD) for three months. The results demonstrated that HFD induced an increase in thiobarbituric acid-reactive substances (TBARS), catalase (CAT) activity and 2',7'-dihydrodichlorofluorescein (DCFH) oxidation and a decrease in sulfhydryl content and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. HFD also induced hepatocellular degeneration and steatosis. These alterations were prevented by CGJ and OGJ, where OGJ was more effective. Therefore, it was concluded that HFD induced oxidative stress and liver damage and that the chronic use of grape juice was able to prevent these alterations.

Effect of chronic treatment with conventional and organic purple grape juices (Vitis labrusca) on rats fed with high-fat diet.

Serra Gaucha is described as the most important wine region of Brazil. Regarding cultivars widespread in the Serra Gaucha, about 90 % of the area is occupied by vines of Vitis labrusca that is the most important specie used in grape juice production. The objective of this study was to investigate the antioxidant and neuroprotective effect of chronic intake of purple grape juice (organic and conventional) from Bordo variety (V. labrusca) on oxidative stress in different brain regions of rats supplemented with high-fat diet (HFD) for 3 months. A total of 40 male rats were randomly divided into 4 groups. Group 1 received a standard diet and water, group 2 HFD and water, group 3 HFD and conventional grape juice (CGJ), and group 4 HFD and organic grape juice (OGJ). All groups had free access to food and drink and after 3 months of treatment the rats were euthanized by decapitation and the cerebral cortex, hippocampus and cerebellum isolated and homogenized on ice for oxidative stress analysis. We observed that the consumption of calories in HFD and control groups, were higher than the groups supplemented with HFD and grape juices and that HFD diet group gain more weight than the other animals. Our results also demonstrated that HDF enhanced lipid peroxidation (TBARS) and protein damage (carbonyl) in cerebral cortex and hippocampus, reduced the non-enzymatic antioxidants defenses (sulfhydryl) in cerebral cortex and cerebellum, reduced catalase and superoxide dismutase activities in all brain tissues and enhanced nitric oxide production in all cerebral tissues. CGJ and OGJ were able to ameliorate these oxidative alterations, being OGJ more effective in this protection. Therefore, grape juices could be useful in the treatment of some neurodegenerative diseases associated with oxidative damage.

Toxicological evaluation of chronic exposure to the organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one in male rats.

The aim of this study was to evaluate the effect of chronic treatment with the organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on some behavioral and biochemical parameters in the brain, liver, kidney and serum of 90-day-old male Wistar rats. The animals received the organoselenium at doses of 125, 250 or 500 µg/kg body weight intraperitoneally once daily for 30 days. Results showed that chronic treatment with this compound induced behavioral changes in animals, such as increasing of rearing at dose of 250 µg/kg and increasing of ambulation in all concentrations tested. On the other hand, we did not observe any alterations in the body weight gain of the animals. Moreover, the activity of the enzyme creatine kinase (CK) decreased in the cerebral cortex, cerebellum and kidney and increased in the liver after the chronic treatment with the organoselenium compound at dose of 500 µg/kg. The compound also increased aspartate aminotransferase (AST) and urea levels in serum of rats at 500 µg/kg. Glucose, cholesterol, triglycerides, creatinine, alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels were not changed by the treatment. Our results thus show that chronic administration of 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one is able to significantly change the activity of CK in Wistar rats, resulting in a change in cellular energy homeostasis in these tissues, liver damage and behavioral changes in the animals studied.

Acute administration of the organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one induces biochemical and hematological disorders in male rats.

Organochalcogens are extensively produced and employed by industry and agriculture, and the risk of occupational and environmental toxicity to them has been poorly understood. Here, we investigated the acute effect of a new organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on biochemical and hematological parameters in male Wistar rats. The animals were treated with a single intraperitoneal injection of the organochalcogen at doses of 125, 250 or 500 µg·kg(-1). After 60 min, the animals were sacrificed by decapitation, and the trunk blood was collected for determination of glucose, triglycerides, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase, lactate dehydrogenase, urea, creatinine, C-reactive protein, red blood cells, hematocrit, hemoglobin and white blood cells (WBC). Our results showed a reduction in cholesterol levels in all treated groups, an increase in ALT activity at doses of 250 and 500 µg·kg(-1), a decrease of hemoglobin and an increase in WBC in animals that received 250 and 500 µg·kg(-1) of the organoselenium. In addition, we observed an increase in neutrophil counts at 125 µg·kg(-1) dose and a decrease at 500 µg·kg(-1) dose. We also verified an increase in lymphocyte counts at the dose of 500 µg·kg(-1). Thus, the present study shows that the acute treatment with this new organochalcogen causes biochemical changes and hematological disorders in male rats.