Melatonin improves nitric oxide bioavailability in isoproterenol induced myocardial injury.

Isoproterenol administration is associated with cardiac inflammation and decreased NO availability. Melatonin has been reported to have cardioprotective effect. The aim of this study was to investigate the effect of melatonin on NO bioavailability and inflammation in myocardial injury induced by isoproterenol. Isoproterenol was administrated in male Wistar rats for 7 days to induce cardiac injury. The animals were divided into 3 groups: Control, Isoproterenol, Isoproterenol + Melatonin. Animals received melatonin for 7 days. Echocardiographic analysis was performed and the hearts were collected for molecular analysis. Animals that received isoproterenol demonstrated a reduction in left ventricle systolic and diastolic diameter, indicating the presence of concentric hypertrophy. Melatonin was able to attenuate this alteration. Melatonin also improved NO bioavailability and decreased NF-κß, TNFα and IL-1ß expression. In conclusion, melatonin exhibited a cardioprotective effect which was associated with improving NO bioavailability and decreasing the pro-inflammatory proteins.

Effects of Pterostilbene on Heart and Lung Oxidative Stress Parameters in 2 Experimental Models of Cardiovascular Disease: Myocardial Infarction and Pulmonary Arterial Hypertension.

ABSTRACT: Myocardial infarction (MI) and pulmonary arterial hypertension (PAH) are 2 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 MI 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 the 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 the 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 left ventricle end-systolic volume in infarcted animals. In the PAH model, PTE improved pulmonary artery flow and decreased reactive oxygen species levels in the lung. PTE administration promoted protective effects in terms of oxidative stress in 2 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.

Gestational purple grape juice consumption does not change fetal ductus arteriosus constriction in Wistar rats.

Grape juice consumption may influence the early occurrence of ductal constriction during pregnancy, since the consumption of foods rich in polyphenols can be linked to the premature constriction of the ductus arteriosus. This study aimed to evaluate the effect of purple grape juice consumption during gestation on fetal ductus arteriosus closure, prostaglandin levels, and oxidative stress markers in Wistar rats. We divided 18 pregnant rats into four groups: a control group (C), a single-dose grape juice group (SDGJ), a two-dose grape juice group (TDGJ) of 7 µl/g body weight per day, and an indomethacin group (I). Blood was collected on gestational day (GD) 0, 14, and 20. Prostaglandin levels were measured, and the livers and hearts were removed from the mothers and fetuses for oxidative stress analysis; histology of the fetal ductus arteriosus was performed. Prostaglandin levels (pg/ml) at GD 20 were (C:1462.10 ± 314.61); (SDGJ:987.66 ± 86.25); (TDGJ:1290.00 ± 221.57), and (I:584.75 ± 46.77). Fetal ductus arteriosus closure occurred only in the indomethacin group. Lipid peroxidation evaluated through thiobarbituric acid reactive substances (nmol/mg protein) in maternal livers was lower in the grape juice groups (C: 4.11 ± 0.76 nmol/mg protein), (SDGJ: 2.34 ± 0.36), (TDGJ: 1.52 ± 0.18), and (I: 4.20 ± 0.76). Sulfhydryls (nmol/mg protein) were lower in the TDGJ group (C:763.59 ± 61.38 nmol/mg protein), (SDGJ:978.88 ± 158.81), (TDGJ:385.32 ± 86.78), and (I:727.72 ± 49.12). Also, superoxide dismutase activity (USOD/mg protein) was higher in fetal hearts in this group: (C:5.29 ± 0.33), (SDGJ:4.48 ± 0.47), (TDGJ:7.35 ± 0.43), and (I:6.00 ± 0.18). We conclude that grape juice consumption in pregnancy does not induce ductus arteriosus closure in the fetus and presented potential antioxidant effects.

Antioxidant system disturbances and mitochondrial dysfunction induced by 3-methyglutaric acid in rat heart are prevented by bezafibrate.

Barth syndrome (BTHS) and dilated cardiomyopathy with ataxia syndrome (DCMA) are biochemically characterized by high levels of 3-methylglutaric acid (MGA) in the urine and plasma of affected patients. Although cardiolipin abnormalities have been observed in these disorders, their pathophysiology is not fully established. We evaluated the effects of MGA administration on redox homeostasis and mitochondrial function in heart, as well as on vascular reactivity in aorta of Wistar rats without cardiolipin genetic deficiency. Potential cardioprotective effects of a pretreatment with bezafibrate (BEZ), a pan-PPAR agonist that induces mitochondrial biogenesis, were also determined. Our findings showed that MGA induced lipid peroxidation, altered enzymatic and non-enzymatic antioxidant defenses and reduced respiratory chain function in rat heart. MGA also increased Drp1 and reduced MFN1 levels, suggesting mitochondrial fission induction. Moreover, MGA altered MAPK and Akt signaling pathways, and had a strong tendency to reduce Sirt1 and PGC-1α, indicative of mitochondrial biogenesis impairment. Aorta vascular reactivity was further altered by MGA. Additionally, BEZ mitigated most alterations on antioxidant defenses and mitochondrial quality control proteins provoked by MGA. However, vascular reactivity disturbances were not prevented. It may be presumed that oxidative stress, mitochondrial bioenergetics and control quality disturbances, and vascular reactivity impairment caused by MGA may be involved in the cardiac failure observed in BTHS and DCMA, and that BEZ should be considered as a pharmacological candidate for the treatment of these disorders.

Blueberry extract attenuates norepinephrine-induced oxidative stress and apoptosis in H9c2 cardiac cells.

Enhanced sympathetic system activation mediated by norepinephrine (NE) contributes to adverse cardiac remodeling leading to oxidative stress and cell death, progressing to heart failure. Natural antioxidants may help maintain redox balance, attenuating NE-mediated cardiac cell damage. In the present study, we evaluated the effect of a blueberry extract (BBE) on H9c2 cardiac cells exposed to NE on cell death, oxidative stress status and its major signaling pathways. H9c2 cells were pre-incubated with 50 µg/ml of BBE for 4 h and maintained in the presence of 100 µM NE for 24 h. NE exposure resulted in increased caspase 3/7 activity. This was associated with reduced protein expression of antioxidants catalase, superoxide dismutase and glutathione peroxidase and increase in 4-hydroxynonenal adduct formation. NE led to increased activity of Protein kinase B (Akt), Forkhead box O3a and AMP-activated protein kinase alpha and decreased activity of Signal transducer and activator of transcription 3. BBE prevented caspases activation and abrogated NE-induced increase in oxidative stress, as well as attenuated the increase in Akt. Based on these findings, it is concluded that BBE promoted cardioprotection of H9c2 cells in an in vitro model of NE-induced oxidative damage, suggesting a cardioprotective role for BBE in response to NE exposure.

Blueberry extract improves redox balance and functional parameters in the right ventricle from rats with pulmonary arterial hypertension.

PURPOSE: Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary vascular resistance and right ventricle (RV) failure. In this context, oxidative stress is an essential element contributing to PAH's pathophysiology. Thus, blueberry (BB), which has a high antioxidant capacity, emerges as a natural therapeutic approach in PAH. This work evaluated the effect of BB extract on redox balance in RV in a PAH's animal model. METHODS: Male Wistar rats (200 ± 20 g) (n = 72) were randomized into eight groups: control (CTR); monocrotaline (MCT); CTR and MCT treated at doses of 50, 100, and 200 mg/kg BB. PAH was induced by administration of MCT (60 mg/kg, intraperitoneal). Rats were treated with BB orally for 5 weeks (2 weeks before monocrotaline and 3 weeks after monocrotaline injection). On day 35, rats were submitted to echocardiography and catheterization, then euthanasia and RV harvesting for biochemical analyses. RESULTS: RV hypertrophy, observed in the MCT groups, was reduced with BB treatment. MCT elevated RV systolic pressure and pressure/time derivatives, while the intervention with BB decreased these parameters. PAH decreased RV output and pulmonary artery outflow acceleration/ejection time ratio, while increased RV diameters, parameters restored by BB treatment. Animals from the MCT group showed elevated lipid peroxidation and NADPH oxidase activity, outcomes attenuated in animals treated with BB, which also led to increased catalase activity. CONCLUSION: Treatment with BB partially mitigated PAH, which could be associated with improvement of RV redox state. Such findings constitute an advance in the investigation of the role of BB extract in chronic progressive cardiovascular diseases that involve the redox balance, such as PAH.

Nicotinamide riboside reduces cardiometabolic risk factors and modulates cardiac oxidative stress in obese Wistar rats under caloric restriction.

AIMS: NAD-based therapeutic strategies are encouraged against obesity and heart disease. Our study, therefore, aimed to investigate the effects of nicotinamide riboside (NR), isolated or combined with caloric restriction (CR), both approaches well-known for stimulating NAD levels, on adiposity parameters, cardiometabolic factors and cardiac oxidative stress in rats submitted to cafeteria diet (CAF). MAIN METHODS: After 42 days of CAF-induced obesity (hypercaloric and ultra-processed foods common to humans), we examined the effects of oral administration of NR (400 mg/kg for 28 days), combined or not with CR (-62% kcal, for 28 days), on anthropometric, metabolic, tissue, and cardiac oxidative stress parameters in obese male Wistar rats. KEY FINDINGS: In obese rats, treatment with NR alone mitigated final body weight gain, reduced adiposity (visceral and subcutaneous), improved insulin resistance, and decreased TG/HDL ratio and heart size. In cardiac OS, treatment with NR increased the antioxidant capacity via glutathione peroxidase and catalase enzymes (in rats under CR) as well as reduced the pro-oxidant complex NADPH oxidase (in obese and lean rats). Hyperglycemia, hypertriglyceridemia and elevated levels of TBARS in the heart were state-dependent adverse effects, induced by treatment with NR. SIGNIFICANCE: This is the first study to report effects of nicotinamide riboside on cardiac oxidative stress in an obesity model. Nicotinamide riboside, a natural dietary compound, presented antiobesity effects and cardiometabolic benefits, in addition to positively modulating oxidative stress in the heart, in a state-dependent manner.

Thyroid hormone treatment improved the response to maximum exercise test and preserved the ventricular geometry in myocardial infarcted rats.

NEW FINDINGS: What is the central question of this study? Does thyroid hormone treatment given after myocardial infarction preserve left ventricular function and treadmill exercise performance, and improve parameters of oxidative stress in the right ventricle and lungs of Wistar rats? What is the main finding and its importance? Thyroid hormone treatment improved the performance of the maximum exercise test in infarcted rats and induced effects in the heart and lungs that were similar to those observed with exercise training. This suggests there is a significant value of thyroid hormones for preserving exercise tolerance after myocardial infarction. ABSTRACT: Left ventricular myocardial infarction (MI) provokes damage in the heart and in other tissues, such as right ventricle and lungs. The present study elucidated whether thyroid hormone treatment (THT) may present positive effects in heart and lungs after MI, and whether or not these effects are similar to those of exercise training (ET). Male Wistar rats were divided into four groups: sham operated (SHAM), infarcted (MI), infarcted + exercise training (MIE), and infarcted + thyroid hormones (MIH). A maximum exercise test, left ventricle echocardiography, pulmonary histology, and oxidative stress in the right ventricle and lung were evaluated. THT and ET both reduced left ventricular dilatation and end-diastolic wall stress indexes to a similar extent. MI accentuated the content of macrophages and inflammatory infiltrate in the lungs, which was partially prevented in the MIH and MIE groups. THT and ET presented similar effects in the heart and lungs, and both improved the performance of the maximum exercise test in infarcted animals.

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.

Bucindolol Modulates Cardiac Remodeling by Attenuating Oxidative Stress in H9c2 Cardiac Cells Exposed to Norepinephrine.

The increased circulation of norepinephrine, found in the diseased heart as a result of sympathetic nervous system overactivation, is responsible for its cardiotoxic effects including pathological hypertrophy, cell death, and oxidative stress. Bucindolol is a third generation adrenergic blocker, which acts on the ß1 and ß2 receptors, and has additional α1 antagonist activity. Thus, the aim of this study was to investigate the action of bucindolol on oxidative stress, hypertrophy, cell survival, and cell death signaling pathways in H9c2 cardiac cells exposed to norepinephrine. H9c2 cells were incubated with 10 µM norepinephrine for 24 h in the presence or absence of bucindolol (10 µM) treatment for 8 h. Western blot was used to determine the expression of proteins for hypertrophy/survival and death signaling pathways. Flow cytometry was used to assess cell death via caspase-3/7 activity and propidium iodide and reactive oxygen species via measuring the fluorescence of CM-H2DCFDA. Norepinephrine exposure resulted in an increase in oxidative stress as well as cell death. This was accompanied by an increased protein expression of LC3B-II/I. The protein kinase B/mammalian target of the rapamycin (Akt/mTOR) pathway which is involved in cardiac remodeling process was activated in response to norepinephrine and was mitigated by bucindolol. In conclusion, bucindolol was able to modulate cardiac remodeling which is mediated by oxidative stress.

Withdrawal effects following repeated ethanol exposure are prevented by N-acetylcysteine in zebrafish.

Alcohol abuse is a highly prevalent condition that substantially contributes to global morbidity and mortality. Most available pharmacological treatments offer little efficacy as relapse rates are high, due in part to the symptoms experienced during abstinence. The roles of oxidative stress and glutamatergic transmission in alcohol withdrawal have been demonstrated in several studies, suggesting that restoration of oxidative status and glutamatergic function may represent a new pharmacological target to prevent the behavioral and biochemical alterations observed during withdrawal. A well-known antioxidant and glutamatergic modulator, N-acetylcysteine (NAC), has shown promise in treating a variety of psychiatric conditions, including substance use disorders, and is a promising molecule in the management of alcohol withdrawal syndrome. Thus, the aim of this study was to investigate whether NAC is able to prevent the expression of behavioral and biochemical alterations induced by ethanol withdrawal in chronically exposed zebrafish. Animals were exposed to ethanol (1% v/v, 20 min) or control water, followed by treatment with NAC (1 mg/L, 10 min) or control water daily for 8 days; 24 h later, experimental animals were submitted to the novel tank test (NTT). Ethanol withdrawal decreased the distance traveled and increased the number of immobile episodes, indicating locomotor deficits; moreover, withdrawal decreased the number of entries and time spent in the top area, while increasing time spent in the bottom area, indicating anxiety-like behavior. Alcohol withdrawal also increased lipid peroxidation (TBARS) and decreased non-protein reduced sulfhydryl (NPSH) and superoxide dismutase (SOD) and catalase (CAT) activities. NAC attenuated these locomotor deficits and prevented the manifestation of anxiety-like behavior as well as the oxidative damage observed following ethanol withdrawal. Given its favorable safety profile, additional clinical and preclinical studies are warranted to unravel the long-term effects of NAC in the context of alcohol abuse and the exact mechanisms involved. Nevertheless, our study adds to the existing body of evidence supporting the clinical evaluation of NAC in substance abuse disorders.

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.

Acetyl-L-carnitine as a putative candidate for the treatment of stress-related psychiatric disorders: Novel evidence from a zebrafish model.

Stress-related psychiatric disorders are mental conditions that affect mood, cognition and behavior and arise because of the impact of prolonged stress on the central nervous system (CNS). Acetyl-L-carnitine (ALC) is an acetyl ester of L-carnitine that easily crosses the blood-brain barrier and was recently found to be decreased in patients with major depressive disorder. ALC plays a role in energy metabolism and is widely consumed as a nutritional supplement to improve physical performance. In this study, our objective was to evaluate the effects of ALC treatment (0.1 mg/L, 10 min) for 7 days on behavior and oxidative stress in zebrafish subjected to unpredictable chronic stress (UCS) protocol. Behavioral outcomes were assessed in the novel tank test, and parameters of oxidative status (lipid peroxidation and antioxidant defenses) were evaluated in the brain using colorimetric methods. According to our previous findings, UCS increased anxiety-like behavior and lipid peroxidation, while it decreased non-protein thiol levels and superoxide dismutase activity. However, ALC reversed the anxiety-like behavior and oxidative damage in stressed animals, while it was devoid of effect in control animals. Although our data reinforce the neuroprotective potential of ALC in the treatment of psychiatric disorders related to stress, further investigations are required to clarify its mechanisms of action and confirm its efficacy.

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.

Sulforaphane effects on oxidative stress parameters in culture of adult cardiomyocytes.

The aim of this study was to analyse the effect of sulforaphane (SFN) in cultures of adult cardiomyocytes, evaluating oxidative stress at different times. Cells were isolated, cultured, and divided into 4 groups: Control, SFN (5µM), H2O2 (5µM), and SFN+H2O2 (5µM both), and subdivided into groups undergoing 1 or 24 h of SFN incubation. After 1 h of incubation, reactive oxygen species production was 40% lower in the SFN group than the Control, and lipid peroxidation was 63% higher in the H2O2 group than the Control, and it was reduced in both of the SFN groups. The SOD activity was 59% higher in groups incubated for 24 h than in those incubated for 1 h. Protein expression of SOD-1 and SOD-2 was higher in the 24-h groups compared to the 1-h groups (55% and 24%, respectively). The Nrf2 protein expression in the 1-h groups was 17% higher than in the 24-h groups, and the SFN + H2O2 group had 40% more Nrf2 than the Control in the 1-h groups. Unlike Nrf2, the PGC-1α expression was 69% higher in the 24-h groups in relation to the 1-h groups. Regarding the 24-h groups, the SFN and SFN+H2O2 groups were higher than the Control (32% and 33%, respectively), and the SFN+H2O2 group was increased (21%) compared to H2O2. SFN had a protective action against oxidative damage, but had no effect on the antioxidant enzymes analyzed. The different responses in the expression of Nrf2 and PGC-1α in relation to the incubation times, draws attention to the importance of establishing a timeline of the action of SFN, since there appears to be a temporal difference in its mechanism in adult cardiomyocytes.

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.

Exercise training versus T3 and T4 hormones treatment: The differential benefits of thyroid hormones on the parasympathetic drive of infarcted rats.

AIMS: This study aimed to investigate whether beneficial effects of thyroid hormones are comparable to those provided by the aerobic exercise training, to verify its applicability as a therapeutic alternative to reverse the pathological cardiac remodeling post-infarction. MATERIALS AND METHODS: Male rats were divided into SHAM-operated (SHAM), myocardial infarction (MI), MI subjected to exercise training (MIE), and MI who received T3 and T4 treatment (MIH) (n = 8/group). MI, MIE and MIH groups underwent an infarction surgery while SHAM was SHAM-operated. One-week post-surgery, MIE and MIH groups started the exercise training protocol (moderate intensity on treadmill), or the T3 (1.2 µg/100 g/day) and T4 (4.8 µg/100 g/day) hormones treatment by gavage, respectively, meanwhile SHAM and MI had no intervention for 9 weeks. The groups were accompanied until 74 days after surgery, when all animals were anesthetized, left ventricle echocardiography and femoral catheterization were performed, followed by euthanasia and left ventricle collection for morphological, oxidative stress, and intracellular kinases expression analysis. KEY FINDINGS: Thyroid hormones treatment was more effective in cardiac dilation and infarction area reduction, while exercise training provided more protection against fibrosis. Thyroid hormones treatment increased the lipoperoxidation and decreased GSHPx activity as compared to MI group, increased the t-Akt2 expression as compared to SHAM group, and increased the vascular parasympathetic drive. SIGNIFICANCE: Thyroid hormones treatment provided differential benefits on the LV function and autonomic modulation as compared to the exercise training. Nevertheless, the redox unbalance induced by thyroid hormones highlights the importance of more studies targeting the ideal duration of this treatment.

Neonatal hyperglycemia induces cell death in the rat brain.

Several studies have examined neonatal diabetes, a rare disease characterized by hyperglycemia and low insulin levels that is usually diagnosed in the first 6 month of life. Recently, the effects of diabetes on the brain have received considerable attention. In addition, hyperglycemia may perturb brain function and might be associated with neuronal death in adult rats. However, few studies have investigated the damaging effects of neonatal hyperglycemia on the rat brain during central nervous system (CNS) development, particularly the mechanisms involved in the disease. Thus, in the present work, we investigated whether neonatal hyperglycemia induced by streptozotocin (STZ) promoted cell death and altered the levels of proteins involved in survival/death pathways in the rat brain. Cell death was assessed using FluoroJade C (FJC) staining and the expression of the p38 mitogen-activated protein kinase (p38), phosphorylated-c-Jun amino-terminal kinase (p-JNK), c-Jun amino-terminal kinase (JNK), protein kinase B (Akt), phosphorylated-protein kinase B (p-Akt), glycogen synthase kinase-3ß (Gsk3ß), B-cell lymphoma 2 (Bcl2) and Bcl2-associated X protein (Bax) protein were measured by Western blotting. The main results of this study showed that the metabolic alterations observed in diabetic rats (hyperglycemia and hypoinsulinemia) increased p38 expression and decreased p-Akt expression, suggesting that cell survival was altered and cell death was induced, which was confirmed by FJC staining. Therefore, the metabolic conditions observed during neonatal hyperglycemia may contribute to the harmful effect of diabetes on the CNS in a crucial phase of postnatal neuronal development.