NO-cGMP-K+ Channels Pathways Participate in the Antihypertensive Effects of Attalea phalerata Martius ex Spreng Oil-Loaded Nanocapsules.

Attalea phalerata Martius ex Spreng is a palm tree that is widely distributed in the Central-West region of Brazil. In this study, we investigated whether the oil-loaded nanocapsules of A. phalerata (APON) have acute and long-lasting antihypertensive effects in male spontaneously hypertensive rats (SHR), as well as explored the underlying molecular mechanisms. APON was prepared using the interfacial polymer deposition method. The particle size, polydispersity index, and zeta potential were investigated using dynamic and electrophoretic light scattering. The antihypertensive effects of APON (administered at doses of 1, 3, and 10 mg/kg) were evaluated after acute intraduodenal administration and after 7 days of oral treatment. To investigate the molecular pathways involved, we used pharmacological antagonists and inhibitors that target prostaglandin/cyclic adenosine monophosphate, nitric oxide/cyclic guanosine monophosphate, and potassium channels. Both acute and prolonged administration of APON (at doses of 3 and 10 mg/kg) resulted in a significant reduction in systolic, diastolic, and mean arterial pressure. Prior treatment with a non-selective nitric oxide synthase inhibitor (Nω-nitro-L-arginine methyl ester), guanylyl cyclase inhibitor (methylene blue), or non-selective calcium-sensitive K+ channel blocker (tetraethylammonium) abolished the antihypertensive effects of APON. Our study showed that A. phalerata oil-loaded nanocapsules have a significant antihypertensive effect in SHR after both short-term and long-term (7-day) use. This effect seems to rely on the vascular endothelium function and involves the NO-cGMP-K+ channel pathway. This research suggests a new direction for future studies to definitively prove the therapeutic benefits of APON in treating cardiovascular disease.

Cardioprotective Effects of Aloysia polystachya Essential Oil on a Rat Model with Multiple Cardiovascular Risk Factors.

Traditional medicine is a frequently utilized method to treat cardiovascular disease and its primary risk factors, including hypertension and dyslipidemia. Aloysia polystachya is a species that is commonly employed to treat various pathological conditions, and it has already been identified as having some cardioprotective effects. This study aimed to investigate the protective effects of the essential oil extracted from the leaves of A. polystachya in a rat model that simulates multiple cardiovascular risk factors. We evaluate the acute toxicity, as well as the cardioprotective effects, by giving different doses of A. polystachya essential oil (1.47 mg/kg, 4.40 mg/kg, and 13.20 mg/kg) over a period of 42 days. The control group was treated with rosuvastatin (5 mg/kg). At the end of the treatments, the renal function, electrocardiography, blood pressure, vascular reactivity, serum biochemical profile, and organ histopathology were evaluated. The main compounds identified in the essential oil of A. polystachya using gas chromatography coupled with mass spectrometry were beta-myrcene (1.08%), limonene (40.13%), and carvone (56.47%). The essential oil of A. polystachya not only lacks acute toxicity but also mitigates the reduction in the excretion of sodium, chloride, and creatinine in urine. Furthermore, it reduces electrocardiographic abnormalities and decreases blood pressure levels. Moreover, this treatment prevents an elevation in markers of inflammation and oxidative stress in the bloodstream. Our findings indicate significant cardioprotective effects of the essential oil of A. polystachya against multiple risk factors for cardiovascular diseases in hypertensive rats.

Cytotoxicity, anti-inflammatory effect, and acute oral toxicity of a novel Attalea phalerata kernel oil-loaded nanocapsules.

The kernel oil of the Attalea phalerata Mart. Ex Spreng (Acurí) is traditionally used in several Latin American countries to treat respiratory problems, inflammation, and fever. However, it cannot be found on the literature any attend to use this oil in pharmaceutical formulation. In this paper, it was developed Acurí oil-loaded nanocapsules, and it was evaluated the cytotoxicity against cancer cells, the antinflammatory activity and the oral acute toxicity in rats. Acurí oil contains lauric acid as the predominant saturated fatty acid (433.26 mg/g) and oleic acid as the main unsaturated fatty acid (180.06 mg/g). The Acurí oil-loaded nanocapsules showed a size of 237 nm, a polydispersity index of 0.260, and a high ζ-potential of -78.75 mV. It was obtained an encapsulation efficiency of 88.77%, and the nanocapsules remain stable on the shelf for 180 days. The nanocapsules showed a rapid release profile (98.25% in 40 minutes). Nanocapsules at a dose of 10 mg/kg exhibit an anti-inflammatory effect similar to indomethacin at the same dose. The nanocapsules showed excellent antiproliferative effect and selectivity index against prostate tumor cells (IC50 2.09 µg/mL, SI=119.61) and kidney tumor cells (IC50 3.03 µg/mL, SI=82.50). Both Acurí oil and Acurí oil-loaded nanocapsules are nontoxic at a dose of 2000 mg/kg. Additionally, they reduce serum triglyceride and total cholesterol levels in rat and could find application in nutraceutical formulations. The Acurí oil-loaded nanocapsules emerge as a promising candidate for new antitumor therapies.

Bridging the Gap: Exploring the Preclinical Potential of Pereskia grandifolia in Metabolic-Associated Fatty Liver Disease.

Metabolic-associated fatty liver disease (MAFLD) is a complex condition characterized by steatosis and metabolic disturbances. Risk factors such as diabetes, cigarette smoking, and dyslipidaemia contribute to its development and progression. Effective and safe therapies for MAFLD are urgently needed. Pereskia grandifolia has shown potential as an alternative treatment, but its effectiveness against liver disease remains unexplored. This research aims to determine the hepatoprotective properties of P. grandifolia using a model of MAFLD. The study was carried out through various phases to assess the safety and efficacy of the ethanol-soluble fraction of P. grandifolia. Initially, an in vitro assay was performed to assess cell viability. This was followed by an acute toxicity test conducted in rats to determine the safety profile of the extract. Subsequently, the anti-inflammatory properties of P. grandifolia were examined in macrophages. For the MAFLD study, diabetic Wistar rats were made diabetic and exposed to a high fat diet and cigarette smoke, for 4 weeks. During the last 2 weeks, the rats were orally given either the vehicle (negative control group; C-), P. grandifolia (30, 100, and 300 mg/kg), or insulin in addition to simvastatin. A basal group of rats not exposed to these risk factors was also assessed. Blood samples were collected to measure cholesterol, triglycerides, glucose, ALT, and AST levels. Liver was assessed for lipid and oxidative markers, and liver histopathology was examined. P. grandifolia showed no signs of toxicity. It demonstrated anti-inflammatory effects by inhibiting phagocytosis and macrophage spreading. The MAFLD model induced liver abnormalities, including increased AST, ALT, disrupted lipid profile, oxidative stress, and significant hepatic damage. However, P. grandifolia effectively reversed these changes, highlighting its potential as a therapeutic agent. These findings emphasize the significance of P. grandifolia in mitigating hepatic consequences associated with various risk factors.

The Protective Effect of Citronellol against Doxorubicin-Induced Cardiotoxicity in Rats.

Citronellol has been reported to have anti-inflammatory, anti-cancer, and antihypertensive activities, but its effect on myocardial ischemia is still unclear. The aim of this study was to investigate the therapeutic effects and pharmacological mechanisms of citronellol on ischemia. Therefore, a rat model of myocardial ischemia was established using the doxorubicin (DOX) model. To induce cardiotoxicity, the rats were given DOX (2.5 mg/kg) intraperitoneally over a 14-day period. Group I served as the control and received tween 80 (0.2%), group II received the vehicle and DOX, group III received the standard drug dexrazoxane and DOX, whereas groups IV, V, and VI were treated orally with citronellol (25, 50, and 100 mg/kg) and DOX, respectively. After treatment, the rats were euthanized, and blood samples were collected to assess the levels of serum cardiac markers, lipid profiles, and tissue antioxidant enzymes. The gene expressions of eNOS, PPAR-g, IL-10, VEGF, and NFkB-1 were also determined using real-time polymerase chain reactions. Simultaneous treatment with DOX and citronellol reduced cardiac antioxidant enzymes and lipid biomarkers in a dose-dependent manner. Citronellol also increased the expression of anti-inflammatory cytokines while reducing the expression of pro-inflammatory cytokines. Therefore, it can be concluded that citronellol may have potential cardioprotective effects in preventing DOX-induced cardiotoxicity.

Chemical Profiles and Cytotoxic Activities of Essential Oils from Six Species of Baccharis Subgenus Coridifoliae (Asteraceae).

Several Baccharis species are popularly known in traditional medicine as "carquejas", "vassouras", "ervas-santas" and "mio-mios", and are used as anti-inflammatories, digestives, and diuretics. This study aimed to investigate the chemical compositions and cytotoxic activities of essential oils (EOs) of six Baccharis species belonging to subgenus Coridifoliae, namely B. albilanosa, B. coridifolia, B. erigeroides, B. napaea, B. ochracea, and B. pluricapitulata. GC/MS analyses of the EOs showed that the oxygenated sesquiterpenes spathulenol (7.32-38.22 %) and caryophyllene oxide (10.83-16.75 %) were the major components for all the species. The EOs of almost all species were cytotoxic against cancer (BT-549, KB, SK-MEL and SK-OV-3) and normal kidney (VERO and LLC-PK1) cell lines, whereas B. erigeroides EO showed cytotoxicity only against LLC-PK1. This article augments the current knowledge about the chemical-biological properties of Baccharis subgenus Coridifoliae and discusses the therapeutic potentials of these economically unexploited plants.

Natural Products as Modulators of Mitochondrial Dysfunctions Associated with Cardiovascular Diseases: Advances and Opportunities.

The mitochondria have an important role in modulating cell cycle progression, cell survival, and apoptosis. In the adult heart, the cardiac mitochondria have a unique spatial arrangement and occupy nearly one-third the volume of a cardiomyocyte, being highly efficient for converting the products of glucose or fatty acid metabolism into adenosine triphosphate (ATP). In cardiomyocytes, the decline of mitochondrial function reduces ATP generation and increases the production of reactive oxygen species, which generates impaired heart function. This is because mitochondria play a key role in maintaining cytosolic calcium concentration and modulation of muscle contraction, as ATP is required to dissociate actin from myosin. Beyond that, mitochondria have a significant role in cardiomyocyte apoptosis because it is evident that patients who have cardiovascular diseases (CVDs) have increased mitochondrial DNA damage to the heart and aorta. Many studies have shown that natural products have mitochondria-modulating effects in cardiac diseases, determining them as potential candidates for new medicines. This review outlines the leading plant secondary metabolites and natural compounds derived from microorganisms as modulators of mitochondrial dysfunctions associated with CVDs.

A New Approach for the Development of Multiple Cardiovascular Risk Factors in Two Rat Models of Hypertension.

Cardiovascular disease (CVD) is the leading cause of death among non-communicable diseases. There is a lack of valid animal models that mimic associations among multiple cardiovascular risk factors in humans. The present study developed an animal model that uses multiple cardiovascular risk factors-namely, hypertension, hypothyroidism, and a high-fat diet (HFD). Two models of hypertension were used: renovascular hypertension (two-kidney, one clip [2K1C]) and spontaneously hypertensive rats (SHRs). The naive group was composed of normotensive rats. Twelve weeks after surgery to induce renovascular hypertension, rats in the 2K1C and SHR groups underwent thyroidectomy. The HFD was then implemented for 6 weeks. Renal function, serum redox status, biochemical CVD markers, electrocardiographic profile, blood pressure, mesenteric vascular bed reactivity, histopathology, and morphometry were investigated. Both experimental models induced dyslipidemia, renal function impairment, and hepatic steatosis, accompanied by higher levels of different inflammatory markers and serum oxidative stress. These alterations contributed to end-organ damage in all hypertensive rats. Our findings corroborate a viable alternative model that involves multiple cardiovascular risk factors and resembles conditions that are seen in humans. Both models mimicked CVD, but our data show that SHRs exhibit more significant pathophysiological changes.

Croton urucurana Baill. Ameliorates Metabolic Associated Fatty Liver Disease in Rats.

Background: Metabolic associated fatty liver disease (MAFLD) affects a quarter of the worldwide population, but no drug therapies have yet been developed. Croton urucurana Baill. (Euphorbiaceae) is a medicinal species, that is, widely distributed in Brazil. It is used in popular medicine to treat gastrointestinal, cardiovascular, and endocrine system diseases. However, its hepatoprotective and lipid-lowering effects have not yet been scientifically investigated. Aim of the study: The present study investigated the effects of an extract of C. urucurana in a rat model of MAFLD that was associated with multiple risk factors, including hypertension, smoking, and dyslipidemia. Material and Methods: The phytochemical composition of C. urucurana was evaluated by liquid chromatography-mass spectrometry. Spontaneously hypertensive rats received a 0.5% cholesterol-enriched diet and were exposed to cigarette smoke (9 cigarettes/day for 10 weeks). During the last 5 weeks, the animals were orally treated with vehicle (negative control [C-] group), C. urucurana extract (30, 100, and 300 mg/kg), or simvastatin + enalapril (two standard reference drugs that are commonly used to treat dyslipidemia and hypertension, respectively). One group of rats that were not exposed to these risk factors was also evaluated (basal group). Blood was collected for the analysis of cholesterol, triglyceride, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels. The liver and feces were collected for lipid quantification. The liver was also processed for antioxidant and histopathological analysis. Results: The main constituents of the C. urucurana extract were flavonoids, glycosides, and alkaloids. The model successfully induced MAFLD, reflected by increases in AST and ALT levels, and induced oxidative stress in the C- group. Treatment with the C. urucurana extract (300 mg/kg) and simvastatin + enalapril decreased plasma and hepatic lipid levels. In contrast to simvastatin + enalapril treatment, C. urucurana reduced AST and ALT levels. Massive lesions were observed in the liver in the C- group, which were reversed by treatment with the C. urucurana extract (300 mg/kg). Conclusion: C. urucurana extract exerted promising hepatoprotective and lipid-lowering effects in a preclinical rat model of MAFLD.

Multiple Risk Factors for Heart Disease: A Challenge to the Ethnopharmacological Use of Croton urucurana Baill.

Croton urucurana Baill. is a native Brazilian tree, popularly known as "sangra-d'água" or "sangue-de-dragão," based on the red resinous sap of the trunk. Its use has been transmitted through generations based on popular tradition that attributes analgesic, anti-inflammatory, and cardioprotective properties to the tree. However, its cardioprotective effects have not yet been scientifically investigated. Thus, the present study investigated the pharmacological response to an ethanol-soluble fraction from the leaves of C. urucurana in Wistar rats exposed to smoking and dyslipidemia, two important cardiovascular risk factors. The extract was evaluated by high-performance liquid chromatography. Wistar rats received a 0.5% cholesterol-enriched diet and were exposed to cigarette smoke (9 cigarettes/day for 10 weeks). During the last 5 weeks, the animals were orally treated with vehicle (negative control group), C. urucurana extract (30, 100, and 300 mg/kg), or simvastatin (2.5 mg/kg) + enalapril (15 mg/kg). One group of rats that was not exposed to these risk factors was also evaluated (basal group). Electrocardiograms and systolic, diastolic, and mean blood pressure were measured. Blood was collected to measure total cholesterol, triglycerides, urea, and creatinine. The heart and kidneys were collected and processed for oxidative status and histopathological evaluation. The phytochemical analysis revealed different classes of flavonoids and condensed tannins. The model induced dyslipidemia and cardiac and renal oxidative stress and increased levels of urea and creatinine in the negative control group. Treatment with the C. urucurana extract (300 mg/kg) and simvastatin + enalapril decreased cholesterol and triglyceride levels. In contrast to simvastatin + enalapril treatment, the C. urucurana extract exerted cardiac and renal antioxidant effects. No alterations of electrocardiograms, blood pressure, or histopathology were observed between groups. These findings indicate that C. urucurana exerts lipid-lowering, renal, and cardioprotective effects against oxidative stress in a preclinical model of multiple risk factors for heart disease.

Prolonged Administration of Rudgea viburnoides (Cham.) Benth. Prevents Impairment of Redox Status, Renal Dysfunction, and Cardiovascular Damage in 2K1C-Hypertensive Rats by Inhibiting ACE Activity and NO-GMPC Pathway Activation.

Rudgea viburnoides is widely found in the Brazilian Cerrado, and commonly used in Brazilian folk medicine. In this study, we evaluated the effects of prolonged administration of the aqueous extract from R. viburnoides leaves (AERV) on impaired redox status, renal dysfunction, and cardiovascular damage in 2K1C hypertensive rats, as well as its chemical composition by LC-DAD-MS. Renal hypertension (two kidney, one-clip model) was surgically induced in male Wistar rats and AERV (30, 100 and 300 mg/kg) was administered orally five weeks after surgery for 28 days. Renal function was assessed and urinary electrolytes, pH, and density were measured. Electrocardiography, blood pressure and heart rate were recorded. Cardiac and mesenteric vascular beds were isolated for cardiac morphometry and evaluation of vascular reactivity, and aortic rings were also isolated for measurement of cyclic guanosine monophosphate levels, and the redox status was assessed. Prolonged treatment with AERV preserved urine excretion and electrolyte levels (Na+, K+, Ca2+ and Cl-), reversed electrocardiographic changes, left ventricular hypertrophy and changes in vascular reactivity induced by hypertension, and reduced blood pressure and heart rate. This effect was associated with a positive modulation of tissue redox state, activation of the NO/cGMP pathway, and inhibition of the angiotensin-converting enzyme. Glycosylated iridoids, chlorogenic acids, glycosylated triterpenes, O-glycosylated flavonols, and triterpenoid saponins were annotated. AERV showed no acute toxicity in female Wistar rats. Therefore, AERV treatment reduced the progression of cardiorenal disease in 2K1C hypertensive rats, which can be involved with an important attenuation of oxidative stress, angiotensin-converting enzyme inhibition, and activation of the NO/cGMP pathway.

Cardioprotective effects of Talinum paniculatum (Jacq.) Gaertn. in doxorubicin-induced cardiotoxicity in hypertensive rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Talinum paniculatum (Jacq.) Gaertn. (Talinaceae) is a medicinal species that is widely distributed throughout Brazil. Popularly known as "major-gomes," the species is used in folk medicine for the treatment of cardiovascular disorders. AIM OF THE STUDY: To evaluate the effect of an ethanolic extract of T. paniculatum (EETP) in rats with renovascular hypertension and heart failure and determine its chemical composition. MATERIALS AND METHODS: First, EETP was obtained, and its chemical profile was analyzed by LC-DAD-MS. The acute toxicity was evaluated in female Wistar rats. The model of renovascular hypertension was established in male Wistar rats by combining the Goldblatt 2K1C method and intraperitoneal doxorubicin administration for 6 weeks. The animals were then treated daily with EETP (30, 100, and 300 mg/kg) or metoprolol (25 mg/kg) by gavage for 28 days. The negative control group was treated with vehicle (filtered water). The sham group consisted of animals that were not subjected to 2K1C or cardiotoxicity and were treated with vehicle. Renal function was evaluated on days 1, 14, and 28. At the end of treatment, the electrocardiographic profile, blood pressure, and mesenteric vascular reactivity were investigated. Serum urea, creatinine, angiotensin converting enzyme, nitrotyrosine, malondialdehyde, nitrite, aldosterone, and sodium and potassium levels were measured. The heart, aorta artery, liver, and right kidney were collected, weighed, and processed for histopathological analysis. Cardiac chambers also underwent morphometric analysis. RESULTS: No signs of toxicity were observed in female Wistar rats. Thirty-two compounds were annotated from EETP, including flavonoids, chlorogenic acids, and saponins. EETP treatment resulted in a significant cardiorenal-protective response, normalizing electrocardiographic and hemodynamic alterations, and preventing ventricle remodeling. These effects were associated with serum antioxidant activity and angiotensin-converting enzyme (ACE) inhibition. CONCLUSION: The present study demonstrated that EETP may exert cardioprotective effects through serum antioxidant activity and ACE inhibition, preventing alterations of hemodynamic and endothelial function, and reducing damage to cardiac structure. Thus, EETP, especially at the 100 and 300 mg/kg doses, may be useful for preventing doxorubicin-induced cardiotoxicity in hypertensive patients.

Hepato- and cardioprotective effects of Baccharis trimera (Less.) DC. against multiple risk factors for chronic noncommunicable diseases.

Cardiovascular diseases are associated with high morbidity and mortality worldwide and have several risk factors, including dyslipidemia, smoking, and hypertension. Studies have evaluated isolated risk factors in experimental models of cardiovascular disease, but few preclinical studies have assessed associations between multiple risk factors. In the present study, hypertensive Wistar rats (Goldblatt 2K1C model) received a 0.5% cholesterol diet and were exposed to tobacco smoke for 8 weeks. During the last 4 weeks, the animals were treated with vehicle, an ethanol-soluble fraction of B. trimera (30, 100, and 300 mg/kg), or simvastatin + enalapril. A group of normotensive, non-dyslipidemic, and non-smoking rats was treated with vehicle. The levels of aspartate aminotransferase, alanine aminotransferase, urea, creatinine, and hepatic and fecal lipids, blood pressure, and mesenteric arterial bed reactivity were evaluated. Cardiac, hepatic, and renal histopathology and tecidual redox state were also investigated. Untreated animals exhibited significant changes in blood pressure, lipid profile, and biomarkers of heart, liver, and kidney damage. Treatment with B. trimera reversed these changes, with effects that were similar to simvastatin + enalapril. These findings suggest that B. trimera may be promising for the treatment of cardiovascular and hepatic disorders, especially disorders that are associated with multiple risk factors.

Nephroprotective and antilithiatic activities of Costus spicatus (Jacq.) Sw.: Ethnopharmacological investigation of a species from the Dourados region, Mato Grosso do Sul State, Brazil.

ETHNOPHARMACOLOGICAL RELEVANCE: Costus spicatus (Jacq.) Sw., also known as "cana-do-brejo," is a species that is widely used in Brazilian traditional medicine for the treatment of kidney diseases. However, no studies have evaluated its nephroprotective and antilithiatic effects. AIM: To investigate nephroprotective and antilithiatic effects of C. spicatus in a preclinical model of acute kidney injury (AKI) and in vitro nephrolithiasis. MATERIALS AND METHODS: C. spicatus leaves were collected directly from the natural environment in the Dourados region, Mato Grosso do Sul State, Brazil. The ethanol-soluble fraction of C. spicatus (ESCS) was obtained by infusion. Phytochemical characterization was performed by liquid chromatography coupled to diode array detector and mass spectrometer (LC-DAD-MS). We assessed whether ESCS has acute or prolonged diuretic activity. The nephroprotective effects of ESCS were evaluated in a model of AKI that was induced by glycerol (10 ml/kg, intramuscularly) in Wistar rats. Different doses of ESCS (30, 100, and 300 mg/kg) were administered orally for 5 days before the induction of AKI. Urinary parameters were measured on days 1, 3, 5, and 7. Twenty-four hours after the last urine collection, blood samples were obtained for the biochemical analysis. Blood pressure levels, renal vascular reactivity, renal tissue redox status, and histopathological changes were measured. Antilithiatic effects were evaluated by in vitro crystallization. Calcium oxalate precipitation was induced by sodium oxalate in urine samples with ESCS at 0.05, 0.5, and 5 mg/ml. RESULTS: From LC-DAD-MS analyses, flavonoids, saponins and other phenolic compounds were determined in the composition of ESCS. Significant reductions of the excretion of urinary total protein, creatinine, sodium, and potassium were observed in the AKI group, with significant histopathological damage (swelling, vacuolization, necrosis, and inflammatory infiltration) in the proximal convoluted tubule. Treatment with ESCS exerted a significant nephroprotective effect by increasing the urinary excretion of total protein, urea, creatinine, sodium, potassium, calcium, and chloride. All of the groups that were treated with ESCS exhibited a reduction of histopathological lesions and significant modulation of the tissue redox state. We also observed a concentration-dependent effect of ESCS on the crystallization of urinary crystals, with reductions of the size and proportion of monohydrated crystals. CONCLUSION: The data suggest that C. spicatus has nephroprotective and antilithiatic effects, suggesting possible effectiveness in its traditional use.

A Randomized Crossover Intervention Study on the Effect a Standardized Maté Extract (Ilex paraguariensis A. St.-Hil.) in Men Predisposed to Cardiovascular Risk.

(1) Background: Due to its richness in chlorogenic acids (CGAs), Maté (Ilex paraguariensis A. St.-Hil.) could be of interest in the prevention of cardiometabolic diseases, however clinical evidence are lacking. This trial aimed to evaluate the impact of maté CGAs, consumed in a daily dose achievable through traditional maté beverages, on parameters related to cardiometabolic risk. (2) Design: Thirty-four male volunteers aged 45-65 years and with at most one criteria of metabolic syndrome, were recruited for a randomized, double-blind, placebo-controlled, and crossover study. The volunteers were assigned to consume an encapsulated dry maté extract for four-weeks, providing 580 mg of caffeoyl quinic acid derivatives (CQAs) daily, or a placebo, with a two weeks washout between intervention periods. Anthropometric variables, blood pressure, plasma glucose, lipids, endothelial, and inflammatory biomarkers were measured in overnight-fasted subjects and after a glucose load. (3) Results: We found no significant effects of treatment on these parameters and the response to the glucose load was also similar between the two interventions. However, a significant decrease in fasting glucose was observed between day 0 and day 28 for the maté group only (-0.57 ± 0.11 mmol/L, p < 0.0002). In subjects with an intermediate to high Framingham risk score, consumption of maté extract induced a 10% increase of high-density lipoprotein (HDL)-c from baseline. In a subgroup representative of the study population, significant decreases in the C-reactive protein (CRP) (-50%) and interleukin-6 (IL-6) (-19%) levels were observed. (4) Conclusions: These clinical observations suggest that maté, naturally rich in CGAs, could improve some cardiometabolic markers in subjects with a higher predisposition to metabolic syndrome, even if that remains to be confirmed in new trials specifically targeting this population.

Nitric oxide and Ca2+-activated high-conductance K+ channels mediate nothofagin-induced endothelium-dependent vasodilation in the perfused rat kidney.

Nothofagin is a natural 3'-C-ß-D-glucoside of the polyphenol phloretin that is mainly found in Aspalathus linearis, Nothofagus fusca, and Leandra dasytricha. In recent years, nothofagin has been described as a potential therapeutic agent for renal disorders, but the mechanisms that are involved in its renoprotective effects remain unclear. In the present study, perfused rat kidneys were used to test the hypothesis that nothofagin causes the direct relaxation of renal arteries. The molecular mechanisms that underlie these vascular effects were also investigated. The left kidney from Wistar rats was coupled in a perfusion system and continuously perfused with physiological saline solution (PSS). Initially, preparations with and without the endothelium were contracted with phenylephrine and received injections of 1-300 nmol nothofagin. The preparations were then perfused with PSS that contained phenylephrine plus KCl, indomethacin, l-NAME, tetraethylammonium, glibenclamide, 4-aminopyridine, iberiotoxin, charybdotoxin, and apamin. After 15 min under perfusion, nothofagin was injected again. In preparations with an intact endothelium, nothofagin dose-dependently reduced perfusion pressure. Endothelium removal or the inhibition of nitric oxide synthase by l-NAME prevented the vasodilatory effect of nothofagin at all doses tested. Perfusion with PSS that contained KCl or tetraethylammonium chloride also abolished the vasodilatory effect of nothofagin. Treatment with glibenclamide, 4-aminopyridine, and apamin did not affect the vasodilatory effect of nothofagin. Iberiotoxin (selective Ca2+-activated high-conductance K+ channel [KCa1.1] blocker) and charybdotoxin (selective KCa1.1 and Ca2+-activated intermediate-conductance K+ channel [KCa3.1] blocker) application blocked the vasodilatory effect of nothofagin at all doses tested, pointing to a predominant role for KCa1.1 in the action of nothofagin. However, these data cannot exclude a potential contribution of endothelial KCa3.1 channel in the nothofagin-induced vasodilation. Overall, our findings indicate that nothofagin induces vasodilation in renal arteries, an effect that is mediated by Ca2+ -activated high-conductance K+ channels opening and endothelial nitric oxide production.

Promising therapeutic use of Baccharis trimera (less.) DC. as a natural hepatoprotective agent against hepatic lesions that are caused by multiple risk factors.

ETHNOPHARMACOLOGICAL RELEVANCE: Baccharis trimera (Less.) DC is a perennial subshrub, popularly known as "carqueja," that belongs to the Asteraceae family. Ethnobotanical studies indicate that this species is used for the treatment of diabetes and digestive and liver diseases. However, studies that sought to validate its popular use were conducted using ethanolic extracts of the plant, which does not reflect the ethnomedicinal use of this species in humans. AIM OF THE STUDY: Non-alcoholic fatty liver disease (NAFLD) is characterized by triglyceride accumulation in the liver that can progress to cirrhosis and hepatocellular carcinoma. Because of the severity of this disease, less toxic and more effective therapeutic agents need to be developed. B. trimera may be a promising therapeutic alternative, but its activity against multiple risk factors for liver disease (e.g., smoking, dyslipidemia, and diabetes mellitus) has not been studied. The present study investigated the effects of an ethnomedicinal form of a B. trimera preparation in a rat model of NAFLD that is associated with multiple risk factors. MATERIAL AND METHODS: Phytochemical analysis of the ethanolic soluble fraction of B. trimera extract was performed using ultra-performance liquid chromatography coupled to high-resolution mass spectrometry. Streptozotocin was used to induce diabetes in male Wistar rats. The rats received a 0.5% cholesterol-enriched diet and were exposed to cigarette smoke (9 cigarettes/day, 5 days/week, for 4 weeks). In the last 2 weeks, the animals were orally treated with vehicle (negative control group), B. trimera extract (30, 100, and 300 mg/kg), or insulin + simvastatin. One group of rats that was not exposed to these risk factors was also evaluated. Blood was collected for glucose, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) analysis. The liver and feces were collected for lipid quantification. The liver was additionally processed for histopathological analysis. RESULTS: The model successfully induced NAFLD and increased levels of glucose, AST, and ALT in the negative control group. Treatment with the B. trimera extract (30 and 100 mg/kg) and insulin + simvastatin decreased hepatic and fecal lipids. In contrast to insulin + simvastatin treatment, all three doses of B. trimera effectively reduced AST and ALT levels. CONCLUSION: B. trimera may be promising as a hepatoprotective agent against hepatic lesions that are caused by multiple risk factors.

Baccharis trimera (Less.) DC: An Innovative Cardioprotective Herbal Medicine Against Multiple Risk Factors for Cardiovascular Disease.

Cardiovascular disease (CVD) is the leading cause of death worldwide and among its modifiable risk factors are dyslipidemia, diabetes, and smoking. Experimental models evaluated this risk factors singly, however, there is a lack of models that agglomerate these risk factors, resembling real patients and elucidating the pathophysiology of CVD. Moreover, few studies have investigated the cardioprotective effects of Baccharis trimera, a species with lipid-lowering effects. In this study, ethanol-soluble fraction of B. trimera was characterized by liquid chromatography-mass spectrometry. Diabetes was induced by streptozotocin in Wistar rats that also received 0.5% cholesterol-enriched chow and were exposed to the smoke of nine cigarettes, 5 days/week, for 4 weeks. During the last 2 weeks, the animals were treated with vehicle (C-), B. trimera, or simvastatin plus insulin. At the end, cholesterol, triglyceride, urea, and creatinine levels; blood pressure (BP); heart rate (HR); abdominal aortic morphometry; vascular reactivity; renal and cardiac oxidative status; and histopathological changes were evaluated. The agglomerate of risk factors promoted alterations contrary to those described in the literature for the isolated risk factors. The C- group exhibited oxidative stress, increase in biochemical parameters, and thickening of the wall of the abdominal aorta. HR, systolic, diastolic, and mean BP decreased, and vascular reactivity was altered. Cardiac and renal histopathological changes were observed. Treatment with B. trimera reversed these changes and this effect may be partially attributable to lipid-lowering action and to the inhibition of free radical generation. B. trimera has cardioprotective effects in this model, with no toxicity.

Development of a Predictive Model to Induce Atherogenesis and Hepato-Renal Impairment in Female Rats.

Therapeutic approaches for the treatment of dyslipidemia and atherosclerosis have radically changed in recent decades. Part of this advance undeniably stems from basic biomedical research that has provided a better understanding and identification of new therapeutic targets. The aim of this work was to develop a model to induce atherogenesis and hepato-renal impairment in female Wistar rats. The following groups received the respective treatments for 60 days: control animals, non-ovariectomized rats that received an atherogenic diet (NEAD), ovariectomized rats that received an atherogenic diet (NOAD), non-ovariectomized rats that received an atherogenic diet and oral Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME; LEAD), and ovariectomized rats that received an atherogenic diet and oral l-NAME (LOAD). Animals in the NEAD, NOAD, LEAD, and LOAD groups also received methimazole and cholecalciferol daily. Urinary, biochemical, hemodynamic, and electrocardiographic parameters and renal function were assessed. Samples of the liver, heart, kidney, and arteries were collected to investigate redox status and perform histopathological analyses. All of the groups developed dyslipidemia and hepatic steatosis. Only the NEAD group developed arterial lesions that were compatible with fatty streaks. Renal function was significantly impaired in the LEAD and NOAD groups. These results indicate a viable alternative to induce atherogenesis and hepato-renal impairment in female rats.

Antiatherosclerotic Properties of Echinodorus grandiflorus (Cham. & Schltdl.) Micheli: From Antioxidant and Lipid-Lowering Effects to an Anti-Inflammatory Role.

Echinodorus grandiflorus is an important medicinal plant species that is native to South America. Despite extensive popular usage as a hypolipidemic drug, its effects as an atheroprotective agent remain unknown. The aim of this study was to evaluate the effects of an ethanol-soluble fraction that was obtained from E. grandiflorus (ESEG) leaves against the development of atherosclerosis in rabbits. Male rabbits received a diet that was supplemented with 1% cholesterol (cholesterol-rich diet [CRD]) for 60 days. After 30 days of the CRD, the animals were divided into five groups (n = 6) and treated with ESEG (10, 30, and 100 mg/kg), simvastatin (2.5 mg/kg), or vehicle once daily for 30 days. The negative control group was fed a cholesterol-free diet and treated orally with vehicle. At the end of 60 days, serum lipids, oxidized low-density lipoprotein, thiobarbituric acid reactive substances, nitrotyrosine, and serum interleukin 1 beta (IL-1ß), IL-6, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were determined. Samples from the aortic arch and thoracic segment were also collected to investigate the tissue antioxidant defense system and perform histopathological analysis. Oral ESEG administration significantly reduced serum lipid levels in CRD-fed rabbits. This treatment also modulated the arterial antioxidant defense system by reducing lipid and protein oxidation. Similarly, serum IL-1ß, IL-6, sICAM-1, and sVCAM-1 levels significantly decreased, accompanied by a reduction of atherosclerotic lesions in all arterial branches. These findings suggest that ESEG may be a new herbal medicine that can be directly applied for the treatment and prevention of atherosclerotic disease.