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.

Repurposing Drugs for the Management of Patients with Confirmed Coronavirus Disease 2019 (COVID-19).

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), termed coronavirus disease 2019 (COVID-19) by the World Health Organization, is a newly emerging zoonotic agent that emerged in China in December 2019. No specific treatment for COVID-19 is currently available. Usual palliative treatment includes maintaining hydration and nutrition and controlling fever and cough. The clinical severity and extent of transmission need to be determined, and therapeutic options need to be developed and optimized. METHODS: The present review discusses the recent repurposing of drugs for COVID-19 treatment. RESULTS: Several compounds, including remdesivir, lopinavir, ritonavir, interferon-ß, ribavirin, chloroquine/ hydroxychloroquine, azithromycin, tocilizumab, and ivermectin, have emerged as promising alternatives. They block the virus from entering host cells, prevent viral replication, and attenuate exacerbation of the host's immune response. CONCLUSION: Although some evidence indicates the positive actions of different classes of compounds for the treatment of COVID-19, few clinical assays have been established to definitively demonstrate their therapeutic value in humans. Multicenter clinical studies are urgently needed to validate and standardize therapeutic regimens that involve these agents. Although science has not yet presented us with a specific drug against COVID-19, the repurposing of drugs appears to be promising in our fight against this devastating disease.

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.

Antimicrobial activity of Asteraceae species against bacterial pathogens isolated from postmenopausal women.

PURPOSE: Investigation of the antibacterial action of aqueous extracts of Bidens sulphurea, Bidens pilosa, and Tanacetum vulgare, species of Asteraceae family that are popularly used for the treatment of genito-urinary infection. METHODS: The minimum inhibitory concentration (MIC) and minimal bacterial concentration (MBC) of the extracts against standard strains of Staphylococcus aureus (ATCC25923), Enterococcus faecalis (ATCC29212), Escherichia coli (ATCC25922), and Pseudomonas aeruginosa (ATCC27853) and against bacteria that were isolated from cultures of vaginal secretions and urine from menopausal women with a diagnosis of recurrent urinary tract infections (rUTI) were determined by broth microdilution. RESULTS: The MIC values of the three extracts against Gram-positive and Gram-negative standard bacterial strains ranged from 7.81 to 125.00 mg ml-1, and the MBC values ranged from 7.81 to 500.00 mg ml-1. However, B. sulphurea was more efficient. In the urine samples, the three extracts inhibited the growth of coagulase-negative Staphylococcus spp., and the B. pilosa was the most active extract against E. coli compared with the other ones. For the vaginal secretion samples, no significant differences in the inhibition of coagulase-positive Staphylococcus spp. and P. mirabilis were found among the extracts. T. vulgare and B. sulphurea were more effective in inhibiting coagulase-negative Staphylococcus spp. compared with B. pilosa. E. coli was more susceptible to the B. sulphurea extract compared with the B. pilosa and T. vulgare extracts. CONCLUSION: The present results suggested the potential medicinal use of Asteraceae species, especially B. sulphurea, as therapeutic agents against rUTI-related bacteria.

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.

Atheroprotective effects of Cuphea carthagenensis (Jacq.) J. F. Macbr. in New Zealand rabbits fed with cholesterol-rich diet.

ETHNOPHARMACOLOGICAL RELEVANCE: Although Cuphea carthagenensis (Jacq.) J. F. Macbr. is used in Brazilian folk medicine in the treatment of atherosclerosis and circulatory disorders, no study evaluating these effects has been conducted. The aim of this study was to evaluate the possible hypolipemiant and antiatherogenic activity of the ethanol soluble fraction obtained from C. carthagenensis (ES-CC) in an experimental atherosclerosis model using New Zealand (NZ) rabbits undergoing cholesterol-rich diet (CRD). MATERIAL AND METHODS: Dyslipidemia and atherogenesis were induced by administration of standard commercial diet increased of 1% cholesterol (CRD) for 8 weeks. ES-CC was orally administered at doses of 10, 30 and 100mg/kg, once daily for four weeks, starting from the 4th week of CRD diet. Body weight measurements were weekly carried out from the beginning of experiments for 8 weeks. Serum levels of triglyceride (TG), total cholesterol (TC) and their fractions (LDL-C, VLDL-C and HDL-C) were measured at the beginning of experiments and at weeks four and eight. After euthanasia of rabbits, aorta segments (aortic arc, thoracic, abdominal and iliac segments) were macroscopically and microscopically evaluated and the intima and media layers of the arteries were measured. Additionally, the antioxidant activity of ES-CC and its influence on the functioning of hepatic antioxidant enzymes were also determined. RESULTS: CRD induced dyslipidemia and major structural changes in the aortic wall. In addition, an increase in lipid peroxidation and a reduction of hepatic glutathione and serum nitrite levels were observed. Treatment with ES-CC was able to prevent the increase in TC, LDL-C, VLDL-C levels and triglycerides and promoted an increase in HDL-C levels in NZ rabbits. These effects were accompanied by a significant reduction in oxidative stress and modulation of the catalase and superoxide dismutase function. Moreover, the intima and media layers of the arterial segments were significantly reduced by ES-CC treatment. CONCLUSIONS: This study demonstrated that ES-CC reduces serum lipids and hepatic oxidative stress when orally administered to NZ rabbits. In addition, it was able to prevent the development of CRD-induced atherosclerosis.

Involvement of bradykinin B2 and muscarinic receptors in the prolonged diuretic and antihypertensive properties of Echinodorus grandiflorus (Cham. & Schltdl.) Micheli.

BACKGROUND: Although Echinodorus grandiflorus (Cham. & Schltr.) Michel are used in Brazilian folk medicine as a diuretic drug, to date, no study has evaluated the mechanisms involved in this activity after prolonged administration in rats. AIM OF THE STUDY: Evaluate the possible mechanisms involved in the prolonged diuretic activity of ethanol soluble fraction obtained from Echinodorus grandiflorus (ES-EG) and to assess its relationship with hypotensive and antihypertensive activity using normotensive rats and those with renovascular hypertension (2K1C). METHODS: The diuretic effects of ES-EG (30-300 mg/kg; p.o.) were compared with hydrochlorothiazide in a repeated-dose treatment for 7 days. The urinary volume and sodium, potassium, chloride, bicarbonate contents, conductivity, pH and density were estimated in sample collected in 24 h for 7 days. Plasma sodium, potassium, total protein, urea, creatinine, aldosterone, vasopressin, nitrite, acetylcholinesterase concentration and angiotensin converting enzyme (ACE) activity were measured in samples collected at the end of the experimental period (seventh day). Using pharmacological antagonists or inhibitors, the involvement of bradykinin, prostaglandin, acetylcholine and nitric oxide (NO) in ES-EG-induced diuresis was determined. In addition, activities of erythrocytary carbonic anhydrase and renal Na+/K+/ATPase were evaluated in vitro. RESULTS: ES-EG increased diuresis similarly to hydrochlorothiazide and also presented HCO3-sparing effects and increased serum nitrite levels. Moreover, the intraduodenal administration of ES-EG induces significant hypotensive and antihypertensive effects in 2K1C rats. Previous treatment with HOE-140, indometacin and atropine fully avoided the diuretic effect of ES-EG, and including L-NAME pre-administration, it prevented the hypotensive and hypertensive activity induced by ES-EG. In addition, the association between HOE-140 and atropine or indometacin and L-NAME fully inhibited the hypotensive and antihypertensive effects of ES-EG. The 7-day treatment with ES-EG resulted in increased plasma nitrite levels. All other parameters were not affected by treatment with ES-EG. CONCLUSIONS: Our results suggest that the mechanisms through which Echinodorus grandiflorus extracts induce prolonged diuresis and reduce blood pressure in normotensive and 2K1C rats are mainly related to activation of muscarinic and bradykinin receptors with direct effects on prostaglandins and nitric oxide pathways.

Pheromones from male domestic mice influences the sexual function and gonadal steroids levels of female laboratory rats / Feromônios de influências masculinos nos ratos domésticos a função e os níveis de esteróides sexuais dos ratos de laboratório fêmeas / Feromonas de influencias masculinos en ratones domésticos la función y los niveles de esteroides sexuales en ratas hembras de laboratorio

It is well established that the behavior of different mammalians, including rodents, may undergo profound changes in the presence of individuals of other species. Therefore, the aim of this study was to verify if the presence of pheromones from male mice could influence the reproductive parameters of female rats. Twenty Swiss (SW) male mice and 16 Long Evans (LE) female Rats were housed in separate rooms, with communication in the ceiling in its entire length. A continuous flow of air was planned to pass through the room of the mice before the room of the rats and finally be exchanged with the external environment. During 45 days, vaginal smears were collected. Relative weights of reproductive organs, estradiol, progesterone, and dehydroepiandrosterone levels were also measured. The total duration of the estrous cycle and relative organ weight remained unchanged. On the other hand, the proestrus and estrus phases, as well as the estradiol levels were increased, while the diestrus phase was significantly reduced. The results have shown that maintaining LE female rats in the presence of pheromones from male SW mice can significantly change the sexual function and gonadal steroid levels.

É bem conhecido que o comportamento de diferentes mamíferos, incluindo roedores podem sofrer alterações profundas na presença de indivíduos de outras espécies. Portanto, estudamos se a presença de feromônios de camundongos machos poderiam influenciar os parâmetros reprodutivos de ratas. Vinte suíços (SW) ratos do sexo masculino e 16 Long Evans (LE) ratas foram colocadas em locais distintos, com a comunicação no teto em toda a sua extensão. Um fluxo contínuo de ar foi planejado para passar através da sala de ratinhos antes da sala de ratos e, finalmente, ser trocado com o ambiente externo. Durante 45 dias, esfregaços vaginais foram recolhidas. Os pesos relativos dos órgãos reprodutores, o estradiol, progesterona e níveis de dehidroepiandrosterona também foram medidos. A duração total do ciclo estral e peso de órgãos em relação, manteve-se inalterada. Por outro lado, as fases de proestro e estro, bem como os níveis de estradiol foram aumentadas, enquanto que a fase diestro foi reduzida significativamente. Os resultados mostraram que a manutenção de ratas LE na presença de feromônios de camundongos SW do sexo masculino pode alterar significativamente a função sexual e os níveis de esteróides sexuais.

Es bien sabido que el comportamiento de diferentes mamíferos incluyendo roedores pueden sufrir cambios profundos en la presencia de individuos de otras especies. Por lo tanto, se estudió si la presencia de feromonas de ratones machos podrían influir en los parámetros reproductivos de las ratas hembra. Veinte suizos (SW) ratones machos y 16 Long Evans (LE) ratas hembras, fueron alojados en habitaciones separadas, con la comunicación en el techo en toda su extensión. Se planificó un flujo continuo de aire para pasar a través de la habitación de los ratones antes de la habitación de las ratas y, finalmente, ser intercambiado con el ambiente externo. Durante 45 días se recogieron frotes vaginales. También se midieron los pesos relativos de los órganos reproductivos, estradiol, progesterona, y los niveles de dehidroepiandrosterona. La duración total del ciclo estral y el peso relativo de órganos se mantuvo sin cambios. Por otro lado, las fases de proestro y de estro, así como los niveles de estradiol aumentaron, mientras que la fase de diestro redujo significativamente. Los resultados han demostrado que el mantenimiento de LE en ratas hembras, con presencia de feromonas de ratones SW macho puede cambiar significativamente la función sexual y los niveles de esteroides sexuales.

Ethnopharmacological investigation of the diuretic and hemodynamic properties of native species of the Brazilian biodiversity.

ETHNOPHARMACOLOGICAL RELEVANCE: Although Echinodorus grandiflorus, Cuphea carthagenensis, and Phyllanthus tenellus infusions are used in Brazilian folk medicine due to their possible diuretic effect, none of these species was critically investigated as a diuretic drug. So, the aim of this study was to evaluate the possible acute diuretic activity of ethanol soluble fractions (ES) obtained from these species and assess the relationship between renal cortical blood flow and their antioxidant and hypotensive activity using normotensive Wistar rats. MATERIAL AND METHODS: The preparation obtained from E. grandiflorus (ES-EG), C. carthagenensis (ES-CC), and P. tenellus (ES-PT) infusions was orally administered in a single dose to rats. Urine excretion rate, pH, density, conductivity and Na(+), K(+), Cl(-) and HCO3(-) contents were measured in the urine of saline-loaded animals. Concentration of electrolytes, total protein, urea, creatinine, and angiotensin converting enzyme (ACE) activity were evaluated in collected serum. The involvement of the renal cortical blood flow and antioxidative activity in the hypotensive and diuretic effects was also determined. RESULTS: Water and Na(+), Cl(-) and Na(+) excretion rates were significantly increased by ES-EG, while urinary bicarbonate excretion was reduced. Moreover, ES obtained from E. grandiflorus was able to significantly increase renal blood flow and reduce mean arterial pressure and oxidative stress in "in vitro" and "in vivo" models. All other parameters evaluated were not affected by any treatment. CONCLUSION: The results presented here shown that the ES-EG obtained from E. grandiflorus leaves shown a significant diuretic and hypotensive activity and suggest that these effects could be related with an important renal and systemic vasodilator effect. In addition, it was shown for the first time that the pharmacological effects of ES obtained from P. tenellus and C. carthagenensis do not support its popular use as a diuretic agent.

Prolonged Diuretic Activity and Calcium-Sparing Effect of Tropaeolum majus: Evidence in the Prevention of Osteoporosis.

Although several studies indicate high effectiveness in the use of the hydroethanolic extract from Tropaeolum majus (HETM) as a diuretic, the impact of its prolonged use in the presence of low estrogen levels remains unclear. Thus, the aim of this study was to investigate the diuretic effects of prolonged administration of HETM in ovariectomized rats and their interrelationship between calcium excretion and bone turnover. Forty-two female Wistar rats were ovariectomized (OVX) and treated orally with different doses of HETM (3, 30, and 300 mg/kg) for 4 weeks. On the first day of treatment and at weekly intervals for four weeks the diuretic activity was evaluated. Electrolyte concentrations and creatinine levels were estimated from urine sample of each rat. The serum lipids, urea, creatinine, and osteocalcin were also measured at the end of the experiment. The data revealed that the HETM was able to sustain its diuretic effect after prolonged treatment. Moreover, its use has not affected the urinary calcium or potassium excretion, reduces lipid levels, and maintains osteocalcin levels similarly to untreated rats. These findings support the potential of HETM as a candidate to be used in clinical conditions in which the renal loss of calcium is not desired.