EPA/DHA and linseed oil have different effects on liver and adipose tissue in rats fed with a high-fat diet.

The incidence of cardiovascular diseases and metabolic disorders has increased worldwide. Clinical and experimental research has shown that the consumption of ω-3 FAs can be beneficial to metabolism in several ways, as they can act on metabolic pathways. Our objective was to evaluate the effect of treatment with linseed oil, a vegetable oil rich in alpha-linolenic acid, and EPA and DHA in different proportions (3:1 EPA:DHA, and 1:3 EPA:DHA), on the metabolic disorders induced by a high-fat diet (20 % lipids) in rats for 2 weeks, after 18 weeks of consumption of a high-fat diet. In 18 weeks, the high-fat diet increased blood glucose, systolic blood pressure, triglyceride concentration in the liver and adipose tissue, and impaired insulin sensibility without interfering in the weight of the animals. All treatments were effective in reducing the deposition of hepatic type III collagen, the proportion of ω-6/ω-3 in the liver and WAT (white adipose tissue), the proportion of area/number of adipocytes, and the gene expression of the ACC, FAS, and CPT1 enzymes. In addition, treatment with EPA and DHA reduced blood glucose, serum TNF-α concentration, amount of liver fat, degree of microsteatosis and type I collagen deposition in the liver, deposition of type I and III collagen in TA, gene expression of the transcription factor SREBP-1c, and increased hepatic binucleation. EPA in major proportion was more effective in reducing the area of adipocytes, hepatic triglyceride concentration, PPAR-α expression, and WAT fat weight. DHA in a major proportion reduced the concentration of MCP1 in WAT. LO treatment did not have any isolated effects. We concluded that EPA and DHA were more effective in treating metabolic damage than treatment with LO, leading to a more favorable metabolic profile.

Effects of physical exercise combined with captopril or losartan on left ventricular hypertrophy of hypertensive rats.

Background: Left ventricular hypertrophy (LVH) is an endpoint of hypertensive cardiac alterations. Renin-angiotensin-aldosterone system (RAAS) blockers are among the most effective on LVH regression. Physical exercise combined to antihypertensive drug contributes to arterial pressure (AP) control and LVH prevention. We evaluated the effects of physical exercise combined to captopril or losartan during eight weeks for spontaneously hypertensive rats (SHR) on some cardiac parameters.Methods: SHR (n=5-6 per group) were sedentary or trained 5 days a week in treadmill during 8 weeks; and they were treated with daily oral captopril (12.5, 25, or 50mg/kg), losartan (2.5, 5, or 10mg/kg), or vehicle. At the end, it was obtained systolic AP (SAP), electrocardiogram (ECG), and hearts metalloproteinase 2 (MMP-2) activity and histology.Results: Captopril 25 and 50 mg/kg, and losartan 10 mg/kg lowered SAP of sedentary and trained SHR. Losartan 5 mg/kg combined with physical exercise also lowered SAP. Combined with exercise, captopril 50 mg/kg lowered 13.6% of QT interval, 14.2% of QTc interval, and 22.8% of Tpeak-Tend compared to sedentary SHR. Losartan 5 and 10mg/kg lowered QT interval of sedentary and trained SHR. Losartan 2.5, 5 and 10mg/kg combined with physical exercise lowered respectively 25.4%, 24.8%, and 31.8% of MMP-2 activity. Losartan (10mg/kg) combined with exercise reduced cardiomyocyte diameter.Conclusion: These data support the hypothesis of physical exercise combined with RAAS blockers could improve the benefits on hypertensive LVH treatment.

Rapid effects of aldosterone in primary cultures of cardiomyocytes - do they suggest the existence of a membrane-bound receptor?

Aldosterone acts on its target tissue through a classical mechanism or through the rapid pathway through a putative membrane-bound receptor. Our goal here was to better understand the molecular and biochemical rapid mechanisms responsible for aldosterone-induced cardiomyocyte hypertrophy. We have evaluated the hypertrophic process through the levels of ANP, which was confirmed by the analysis of the superficial area of cardiomyocytes. Aldosterone increased the levels of ANP and the cellular area of the cardiomyocytes; spironolactone reduced the aldosterone-increased ANP level and cellular area of cardiomyocytes. Aldosterone or spironolactone alone did not increase the level of cyclic 3',5'-adenosine monophosphate (cAMP), but aldosterone plus spironolactone led to increased cAMP level; the treatment with aldosterone + spironolactone + BAPTA-AM reduced the levels of cAMP. These data suggest that aldosterone-induced cAMP increase is independent of mineralocorticoid receptor (MR) and dependent on Ca(2+). Next, we have evaluated the role of A-kinase anchor proteins (AKAP) in the aldosterone-induced hypertrophic response. We have found that St-Ht31 (AKAP inhibitor) reduced the increased level of ANP which was induced by aldosterone; in addition, we have found an increase on protein kinase C (PKC) and extracellular signal-regulated kinase 5 (ERK5) activity when cells were treated with aldosterone alone, spironolactone alone and with a combination of both. Our data suggest that PKC could be responsible for ERK5 aldosterone-induced phosphorylation. Our study suggests that the aldosterone through its rapid effects promotes a hypertrophic response in cardiomyocytes that is controlled by an AKAP, being dependent on ERK5 and PKC, but not on cAMP/cAMP-dependent protein kinase signaling pathways. Lastly, we provide evidence that the targeting of AKAPs could be relevant in patients with aldosterone-induced cardiac hypertrophy and heart failure.

Caspofungin Effects on Electrocardiogram of Mice: An Evaluation of Cardiac Safety.

Caspofungin is an echinocandin, exhibiting efficacy against most Candida species invasive infection. Its cardiotoxicity was reported in isolated rat heart and ventricular myocytes, but in vivo and clinical studies are insufficient. Our objective was to evaluate caspofungin in vivo cardiac effects using an efficacious dose against Candida albicans. Female Swiss mice were infected with C. albicans, and treated with caspofungin, 5 or 10 mg/kg, intraperitoneal along 5 days. Survival rate and colony-forming units (CFU) into vital organs were determined. For cardiac effects study, mice were treated with caspofungin 10 mg/kg, and electrocardiogram (ECG) signal was obtained on C. albicans-infected mice, single dose-treated, and uninfected mice treated along 5 days, both groups to measure ECG intervals. Besides, ECG was also obtained by telemetry on uninfected mice to evaluate heart rate variability (HRV) parameters. The MIC for caspofungin on the wild-type C. albicans SC5314 strain was 0.3 µg/ml, indicating the susceptible. Survival rate increased significantly in infected mice treated with caspofungin compared to mice treated with vehicle. None of the survived infected mice presented positive CFU after treatment with 10 mg/kg. C. albicans infection induced prolongation of QRS, QT, and QTc intervals; caspofungin did not alter this effect. Caspofungin induced increase of PR and an additional increase of QRS after 24 h of a single dose in infected mice. No significant alterations occurred in ECG intervals and HRV parameters of uninfected mice, after caspofungin treatment. Caspofungin showed in vivo cardiac relative safety maintaining its antifungal efficacy against C. albicans.

Oral formulation of DPP-4 inhibitor plus Quercetin improves metabolic homeostasis in type 1 diabetic rats.

This study aimed to investigate the potential of an oral formulation (QV formulation) containing Quercetin and a Dipeptidyl Peptidase-4 Inhibitor (DPP-4 inhibitor), Vildagliptin, in improving metabolic homeostasis in type 1 diabetes model. Female albino Fischer rats were divided into four groups: untreated control animals (C), untreated diabetic animals (D), diabetic animals treated with QV formulation (DQV), and diabetic animals treated with insulin (DI). Diabetes was induced by injection of alloxan (135 mg kg body mass)-1 and confirmed by glycemic test. After the 30-day treatment period, biochemical parameters were analyzed in the pancreas, liver, and serum. Histopathological changes in pancreatic tissue were examined by Hematoxyline & Eosin staining and the insulin content in the islet measured by immunohistochemistry with anti-insulin antibody. The glycogen content in the hepatocytes was quantified by Periodic Schiff Acid staining. The QV formulation reduced the glycemia, preserved the pancreatic architecture, increased insulin levels, furthermore ameliorated lipid profile and to promote higher survival rate of animals. Together, our data suggest that the QV formulation treatment was able to normalize metabolic homeostasis in type 1 diabetic rats.

Anti-Inflammatory and Antioxidant Properties of Black Mulberry (Morus nigra L.) in a Model of LPS-Induced Sepsis.

Sepsis is a complex disease and is the cause of many deaths worldwide. Sepsis pathogenesis involves a dysregulated inflammatory response with consequent production of inflammatory mediators and reactive species. The production and excessive release of these substances into the systemic circulation trigger various cellular and metabolic alterations that are observed during the disease evolution. Thus, more studies have been carried out to investigate the therapeutic potential of plants such as Morus nigra L., popularly known as black mulberry. Studies have shown that plants belonging to the Morus genus are rich in secondary metabolites such as flavonoids which are associated with important biological activities as antioxidant and anti-inflammatory actions. Based on this context, the objective of our study was to evaluate the anti-inflammatory and antioxidant properties of Morus nigra L. in a sepsis model induced by LPS. Male C57BL/6 mice were distributed in four groups: control, sepsis, sepsis treated with leaf extract of mulberry, and sepsis treated with mulberry pulp. The animals were treated with 100 µL of their respective treatments for twenty-one days. Sepsis was induced at the 21st day with lipopolysaccharide (LPS) by intraperitoneal injection. The animals were euthanized 24 hours after receiving the LPS injection. The data obtained were analyzed in GraphPad Prism 6.0 software. Our results showed that treatment with either extract significantly decreased the number of leukocytes in the bronchoalveolar lavage fluid and serum levels of TNF in septic animals. Regarding the redox status, the treatments significantly decreased the antioxidant activity of the enzyme glutathione peroxidase. Regarding metalloproteinase type 2, it was observed that the treatment with black mulberry pulp was able to significantly reduce the activity of this enzyme concerning the sepsis group. Finally, these results together promoted an increase in the animal's survival that received the black mulberry leaf or pulp extract.

Baccharis trimera protects against ethanol induced hepatotoxicity in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Baccharis trimera has been traditionally used in Brazil to treat liver diseases. AIM OF THE STUDY: To evaluate the protective effect of Baccharis trimera in an ethanol induced hepatotoxicity model. MATERIALS AND METHODS: The antioxidant capacity was evaluated in vitro by the ability to scavenged the DPPH radical, by the quantification of ROS, NO and the transcription factor Nrf2. Hepatotoxicity was induced in animals by administration of absolute ethanol for 2 days (acute) or with ethanol diluted for 28 days (chronic). The biochemical parameters of hepatic function (ALT and AST), renal function (urea and creatinine) and lipid profile (total cholesterol, triglycerides and HDL) were evaluated. In addition to antioxidant defense (SOD, catalase, glutathione), oxidative damage markers (TBARS and carbonylated protein), MMP-2 activity and liver histology. RESULTS: Baccharis trimera promoted a decrease in ROS and NO, and at low concentrations promoted increased transcription of Nrf2. In the acute experiment it promoted increase of HDL, in the activity of SOD and GPx, besides diminishing TBARS and microesteatosis. Already in the chronic experiment B. trimera improved the hepatic and renal profile, decreased triglycerides and MMP-2 activity, in addition to diminishing microesteatosis. CONCLUSION: We believe that B. trimera action is possibly more associated with direct neutralizing effects or inhibition of reactive species production pathways rather than the modulation of the antioxidant enzymes activity. Thus it is possible to infer that the biological effects triggered by adaptive responses are complex and multifactorial depending on the dose, the time and the compounds used.

Lycopene inhibits reactive oxygen species production in SK-Hep-1 cells and attenuates acetaminophen-induced liver injury in C57BL/6 mice.

Our aim was to investigate the antioxidant potential of lycopene in different experimental liver models: in vitro, to evaluate the influence of lycopene on reactive oxygen species (ROS) production mediated by the PKC pathway and in vivo, to evaluate the protective effects of lycopene in an experimental model of hepatotoxicity. The in vitro study assessed the lycopene antioxidant potential by the quantification of ROS production in SK-Hep-1 cells unstimulated or stimulated by an activator of the PKC pathway. The role of NADPH oxidase was evaluated by measuring its inhibition potential using an inhibitor of this enzyme. In the in vivo study, male C57BL/6 mice received lycopene (10 or 100 mg/kg by oral gavage) and 1 h later, acetaminophen (APAP) (500 mg/kg) was administrated. Lycopene decreased ROS production in SK-Hep-1 cells through inhibition of NADPH oxidase, brought about in the PKC pathway. Lycopene improved hepatotoxicity acting as an antioxidant, reduced GSSG and regulated tGSH and CAT levels, reduced oxidative damage primarily by decreasing protein carbonylation, promoted the downregulation of MMP-2 and reduced areas of necrosis improving the general appearance of the lesion in C57BL/6 mice. Lycopene is a natural compound that was able to inhibit the production of ROS in vitro and mitigate the damage caused by APAP overdose in vivo.

Morus nigra leaf extract improves glycemic response and redox profile in the liver of diabetic rats.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia and alterations in the carbohydrate, lipid, and protein metabolism. DM is associated with increased oxidative stress and pancreatic beta cell damage, which impair the production of insulin and the maintenance of normoglycemia. Inhibiting oxidative damage and controlling hyperglycemia are two important strategies for the prevention of diabetes. The pulp and leaf extracts of mulberry (Morus nigra L.) have abundant total phenolics and flavonoids, and its antioxidant potential may be an important factor for modulating oxidative stress induced by diabetes. In this study, DM was induced by intraperitoneal injection of alloxan monohydrate (135 mg kg(-1)). Female Fischer rats were divided into four groups: control, diabetic, diabetic pulp, and diabetic leaf extract. Animals in the diabetic pulp and diabetic leaf extract groups were treated for 30 days with M. nigra L. pulp or leaf extracts, respectively. At the end of treatment, animals were euthanized and, liver and blood samples were collected for analysis of biochemical and metabolic parameters. Our study demonstrated that treatment of diabetic rats with leaf extracts decreased the superoxide dismutase (SOD)/catalase (CAT) ratio and carbonylated protein levels by reducing oxidative stress. Moreover, the leaf extract of M. nigra L. decreased the matrix metalloproteinase (MMP)-2 activity, increased insulinemia, and alleviated hyperglycemia-induced diabetes. In conclusion, our study found that the leaf extract of M. nigra L. improved oxidative stress and complications in diabetic rats, suggesting the utility of this herbal remedy in the prevention and treatment of DM.

Baccharis trimera improves the antioxidant defense system and inhibits iNOS and NADPH oxidase expression in a rat model of inflammation.

Acetaminophen is a common analgesic and antipyretic compound which, when administered in high doses, has been associated with significant morbidity and mortality, secondary to hepatic toxicity. Although this may be due to a direct interaction of reactive acetaminophen metabolites with hepatocyte proteins, recent studies have suggested that reactive species produced by neutrophils also contribute to the pathophysiological process. Researches on the chemical composition of B. trimera show that this plant has bioactive compounds such as flavonoids, related to the organism's protection against free radicals. Therefore, in the present study, using Fischer rats, the effect of B. trimera on the antioxidant defense system, the production of nitric oxide (NO) and on the expression of nitric oxide synthase (iNOS), superoxide dismutase (SOD), catalase (CAT) and of the subunits of the NADPH oxidase in neutrophils was evaluated in a model of phagocytosis induced by zimosan (ZC3b) and in a model of inflammation induced by acetaminophen. The results show that the treatment with B. trimera improves the defense system of antioxidant and restores the balance ROS / NO that is altered in the inflammatory process induced by APAP. In conclusion, B. trimera extracts exert antioxidant properties by scavenging ROS and decrease the expression of genes responsible by reactive species production in neutrophils.