Safety assessment of MEFAS: an innovative hybrid salt of mefloquine and artesunate for malaria treatment.

Malaria is a global public health problem that causes approximately 445 000 deaths annually worldwide, especially in underdeveloped countries. Because of the high prevalence and mortality of the disease, new and less toxic therapeutic agents need to be developed, such as MEFAS, a low-cost hybrid salt that consists of artesunate and mefloquine. However, the efficacy of MEFAS has been systematically demonstrated, its safety requires further investigation. This study investigated the acute toxicity of MEFAS and its precursors, artesunate, and mefloquine. A total of 42 female Swiss mice were divided into seven groups (n = 6/group) that were treated orally by gavage with vehicle (filtered water, negative control), MEFAS (50, 500, and 1000 mg/kg), and 1:1 concentrations of artesunate + mefloquine (50, 500, and 1000 mg/kg). Clinical signs of toxicity were observed for 14 d after treatment. On day 15, the animals were weighed, deeply anesthetized with isoflurane, and euthanized for subsequent collection of the liver, spleen, and kidneys. The relative organ weights were determined, followed by histopathological analysis. Artesunate + mefloquine produced toxic effects compared with the negative control group, reflected by changes in clinical signs, relative organ weights, and histopathological alterations. In MEFAS-treated animals, no changes were observed compared with the negative control group. These findings demonstrate that MEFAS is safer than artesunate + mefloquine after acute administration in mice.

Ethnomedicinal Plants Used for the Treatment of Cardiovascular Diseases by Healers in the Southwestern State of Paraná, Brazil, and Their Validation Based on Scientific Pharmacological Data.

Cardiovascular diseases are responsible for high morbidity and mortality rates worldwide. Among treatment options, medicinal plants are frequently used, especially in developing countries, such as Brazil. Despite social development that has been observed in the last decades, the use of medicinal plants is still driven by popular knowledge, especially by healers. The present study sought to identify medicinal species that are used for the treatment of cardiovascular diseases by healers in the microregion of Francisco Beltrão, Paraná, Brazil. The snowball technique was used to select informants, and data were collected through interviews. The research was performed in two stages: (1) a structured interview and (2) the collection and botanical identification of the species that were mentioned by the healers. Medicinal plants were classified into the following categories of cardiovascular agents: hypotensive and antihypertensive agents, lipid-lowering agents, diuretic agents, and cardiotonic agents. To analyze the data, the frequency was determined, Spearman correlations were calculated, and the informant consensus factor (ICF) and use value were obtained. Some characteristics, such as female gender and old age, were associated with knowledge about medicinal plants. Overall, 77 different species and 149 medicinal uses were cited by the healers. With regard to categories of use, the highest number of species was found among lipid-lowering plants, and the highest ICF was found for species that are used as cardiotonics. Moreover, a literature review indicated that among the cited species, several still lack studies that have proven their effects on the cardiovascular system. The traditional use of medicinal plants for the treatment of cardiovascular diseases is broad in the study regions. The present results are important for clarifying popular knowledge in this region and providing a framework for selecting species with potential for the development of new pharmacological studies.

Traditional Plants Used by Remaining Healers from the Region of Grande Dourados, Mato Grosso do Sul, Brazil.

Although the traditional use of medicinal plants is a very widespread practice in Brazil, there are still few studies aimed at native prescribers, known as healers. The aim of this work was to catalog the medicinal species prescribed by remaining healers of the Grande Dourados region, Mato Grosso do Sul, Brazil. Semi-structured interviews were conducted with support of a standardized questionnaire for remaining healers selected using the "snowball" technique. The medicinal species selected were collected, identified, and classified according to the British National Formulary. Remaining healers were identified in seven municipalities in the region of Grande Dourados. Family, divine revelation, and participation of the Catholic Church were the most important sources of knowledge. Seventy-one medicinal species, mainly herbaceous belonging to Asteraceae, Lamiaceae, Amaranthaceae, and Verbenaceae families, were the most prescribed. Most species are used in the treatment of digestive and cardiovascular diseases, in addition to immune and respiratory diseases. Healers from the region of Grande Dourados maintain considerable ethno-knowledge about the medicinal properties of different medicinal species. Sharing this information values their culture and preserves the knowledge for future generations.

Heart-Protective Effects of Echinodorus grandiflorus in Rabbits That Are Fed a High-cholesterol Diet.

Excess weight and dyslipidemia are among the most serious health problems in Western societies. These conditions enhance the risk of cardiac disease and have been linked with a higher prevalence of cardiac arrhythmias and sudden death. The present study investigated the cardioprotective effects of Echinodorus grandiflorus on ventricular remodeling in rabbits that were fed a 1% cholesterol-rich diet. We first obtained an ethanol-soluble fraction of E. grandiflorus and performed a detailed phytochemical study by liquid chromatography-DAD/ESI-MS. For 60 days, male rabbits were fed the cholesterol-rich diet or a diet without the addition of cholesterol. After 30 days, different groups of rabbits were treated with the ethanol-soluble fraction of E. grandiflorus (10, 30, and 100 mg/kg, p. o.), simvastatin (2.5 mg/kg), or vehicle once daily for 30 days. At the end of 60 days, the serum lipoprotein ratio, electrocardiographic profile, histopathological alterations, and the cardiac antioxidant defense system were investigated. Echocardiographic analysis showed morphological and functional alterations in cholesterol-rich diet-fed animals, indicating left ventricle hypertrophy. The total cholesterol/high-density lipoprotein ratio and low-density lipoprotein/high-density lipoprotein ratio were significantly higher in cholesterol-rich diet-fed rabbits. Myocardial flaccidity, fatty degeneration, and concentric left ventricular hypertrophy were observed. An increase in lipid peroxidation levels, a decrease in superoxide dismutase activity, and a decrease in reduced glutathione levels were observed in the myocardium of all cholesterol-rich diet-fed rabbits. Treatment with the ethanol-soluble fraction of E. grandiflorus, especially the highest dose, significantly reduced all of these alterations, thus demonstrating the cardioprotective effect of the ethanol-soluble fraction of E. grandiflorus on cardiac changes that are induced by a cholesterol-rich diet.

Bacopa monnieri in Patients with Parkinson's Disease: A Pilot Study.

Bacopa monnieri (L.) Wettst. could be of interest in the control of symptoms of Parkinson's disease, but clinical evidence of its efficacy is lacking. This clinical trial assessed the effects of an extract of B. monnieri on parameters that are related to Parkinson's diseases. Twenty volunteers with Parkinson's disease were recruited for a primary, interventional, controlled, parallel, double-blind clinical study. The volunteers were assigned to treatment with either a commercial B. monnieri extract (225 or 450 mg/day) or placebo. The Parkinson's Disease Quality-of-Life (PDQL) questionnaire was applied, and motor activity was assessed before treatment and 30, 60, and 90 days after treatment with the B. monnieri extract or placebo. Characteristics such as age, body weight, and height were also collected. No differences in parkinsonian and systemic symptoms, emotional function, or social function were observed between. The delta percent (Δ%) showed time-dependent improvements in emotional function with B. monnieri treatment at the daily dose of 450 mg. A strong correlation was found between quality of life and motor outcomes at baseline and 30 days of treatment with B. monnieri, and a moderate correlation for 60 and 90 days of treatment with B. monnieri when compared with baseline time. A moderate correlation was found between motor outcomes and Hoehn and Yahr stages at baseline. Our results suggest that B. monnieri extract can improve emotional function in Parkinson's disease patients, but further clinical trials are needed to confirm this possibility.

Use of propolis for skin wound healing: systematic review and meta-analysis.

Propolis is a natural resin that is produced by bees. It has anti-inflammatory and antibiotic properties, promotes reepithelization, and stimulates skin regeneration. Propolis has great potential for the development of new therapeutic approaches to treat skin ulcers. The present study performed a systematic review and meta-analysis of published studies of the use of propolis for the regeneration of cutaneous wounds and its efficacy as a therapeutic agent. Data were collected from articles in the PubMed, SCOPUS, and Web of Science databases that were published since 1900 by searching the terms "propolis" AND "wound healing." This search yielded 633 articles, of which 43 were included in this systematic review and meta-analysis. The results showed that interest in the therapeutic efficacy of propolis has increased over the years. The studies reported that the propolis was effective for the treatment of skin ulcers by promoting a higher percentage of healing than classically employed interventions. The mode of propolis application has also evolved. An increasing number of studies combined it with other substances and materials to achieve additive or synergistic effects on the skin regeneration process. Propolis appears to be an effective therapeutic alternative for the treatment of skin ulcers.

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.

Regenerative and translational medicine in COPD: hype and hope.

COPD is a common, preventable and usually progressive disease associated with an enhanced chronic inflammatory response in the airways and lung, generally caused by exposure to noxious particles and gases. It is a treatable disease characterised by persistent respiratory symptoms and airflow limitation due to abnormalities in the airways and/or alveoli. COPD is currently the third leading cause of death worldwide, representing a serious public health problem and a high social and economic burden. Despite significant advances, effective clinical treatments have not yet been achieved. In this scenario, cell-based therapies have emerged as potentially promising therapeutic approaches. However, there are only a few published studies of cell-based therapies in human patients with COPD and a small number of ongoing clinical trials registered on clinicaltrials.gov Despite the advances and interesting results, numerous doubts and questions remain about efficacy, mechanisms of action, culture conditions, doses, timing, route of administration and conditions related to homing and engraftment of the infused cells. This article presents the state of the art of cell-based therapy in COPD. Clinical trials that have already been completed and with published results are discussed in detail. We also discuss the questions that remain unanswered about cell-based regenerative and translational medicine for COPD.

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.

Cardioprotective Effects of Solidago microglossa DC. in Nicotine-Treated Hypertensive Rats.

Solidago microglossa DC. (Asteraceae), "arnica brasileira," is a Brazilian species popularly used to treat hypertension or renal ailments. This study investigated the cardioprotective effects of standardized S. microglossa extract (EESM) in nicotine-treated spontaneously hypertensive rats (SHRs). Moreover, the molecular mechanisms involved in the cardiovascular effects were also investigated. The acute toxicity was evaluated in female Wistar rats. Afterwards, six-month-old male spontaneously hypertensive rats received the EESM (14, 28, and 56 mg/kg), hydrochlorothiazide (25 mg/kg), and vehicle (filtered water; 0.1 mL/100 g) once daily for 28 days. All treatments were associated with 1.8 mg/kg of nicotine. At the end of the experimental period, the renal function, electrocardiographic profile, blood pressure, ventricular function, biochemical parameter, and mesenteric vascular bed reactivity were evaluated. Relative organ weights and cardiac morphometry were also investigated. Nicotine treatment in 6-month-old SHRs induced a significant reduction in renal function, with reduced urinary volume and lower renal elimination of sodium and creatinine. In addition, serum markers of the redox state and blood pressure levels remained significantly elevated, contributing to changes in vascular reactivity and left ventricular hypertrophy associated with reduced ventricular function. After 28 days of treatment, we found that the highest dose of EESM could mitigate all renal and cardiovascular changes developed by the nicotine-treated hypertensive rats. This study presented EESM as a possible cardioprotective drug that prevents cardiovascular dysfunctions in nicotine-treated hypertensive rats. Our data suggest EESM as a potential adjuvant therapy when cardioprotective effects are required.

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.

Bioactive compounds with antifungal activity against pathogens isolated from pregnant woman: Gallesia integrifolia (garlic wood) is a promising treatment for vulvovaginal candidiasis.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves, bark, and roots of Gallesia integrifolia are consumed in folk medicine through infusion, decoction, and topical preparation by crushing because of its pharmacological properties in several peripheral system disorders, including microbial infections. The presence of various molecules in different parts of the plant likely confers this species' fungicidal action, but scientific evidence is lacking. Vulvovaginal candidiasis mainly affects women of reproductive age. When left untreated, it can cause pregnancy complications. Currently available antifungals often cause undesirable side effects. New alternative therapeutic strategies based on medicinal plants have been proposed. AIM: To investigate the antifungal activity of G. integrifolia against vulvovaginal candidiasis secretion in pregnant women. MATERIALS AND METHODS: Antifungal activity was determined by the minimum inhibitory concentration (MIC), determined by broth microdilution method using Candida spp (NEWP1210), C. albicans (CCCD-CC001), C. tropicalis (CCCD-CC002) standard and clinical isolates from pregnant women with vulvovaginal candidiasis. Nystatin and fluconazole were used as positive controls. The chemical composition of essential oils that were extracted from leaves, flowers, and fruits of G. integrifolia was determined by gas chromatography coupled to mass spectrometry. Reverse docking was used to suggest a possible target in Candida. Conventional docking was used to identify the most probable compound that inhibits fungal growth. RESULTS: A total of 24 compounds were identified, accounting for ∼99% of volatile constituents in the essential oils. Leaves of G. integrifolia contained 3,5-dithiahexanol-5,5-dioxide (40.93%), flowers contained methionine ethyl ester (46.78%), and fruits contained 2,8-dithianonane (54.01%) as the most abundant compounds. The MICs of essential oils of leaves, flowers, and fruits of G. integrifolia against standard strains of Candida spp, C. albicans, and C. tropicalis ranged from 13.01 to 625.00 µg/mL. The essential oil of flowers more effectively inhibited Candida spp. Essential oils of leaves and flowers were similar to fluconazole against C. albicans. Essential oils of flowers and fruits were similar to fluconazole against C. tropocalis. In Candida yeast species that were isolated from vaginal secretion samples from pregnant patients, the MICs of leaves and flowers ranged from 52.08 to 5000.00 µg/mL. The essential oil of leaves (277.77 µg/mL) was the most active against C. albicans. No significant differences were found between the essential oils of leaves and flowers against C. glabrata. Docking simulations suggested that phytol in leaves and flowers was responsible for the antimicrobial effect. CONCLUSION: The present results suggest the potential therapeutic use of G. integrifolia, especially its leaves and flowers, against Candida and vulvovaginal candidiasis.

Three-Dimensional Cell Cultures as a Research Platform in Lung Diseases and COVID-19.

BACKGROUND: Chronic respiratory diseases (CRD) are a major public health problem worldwide. In the current epidemiological context, CRD have received much interest when considering their correlation with greater susceptibility to SARS-Cov-2 and severe disease (COVID-19). Increasingly more studies have investigated pathophysiological interactions between CRD and COVID-19. AREA COVERED: Animal experimentation has decisively contributed to advancing our knowledge of CRD. Considering the increase in ethical restrictions in animal experimentation, researchers must focus on new experimental alternatives. Two-dimensional (2D) cell cultures have complemented animal models and significantly contributed to advancing research in the life sciences. However, 2D cell cultures have several limitations in studies of cellular interactions. Three-dimensional (3D) cell cultures represent a new and robust platform for studying complex biological processes and are a promising alternative in regenerative and translational medicine. EXPERT OPINION: Three-dimensional cell cultures are obtained by combining several types of cells in integrated and self-organized systems in a 3D structure. These 3D cell culture systems represent an efficient methodological approach in studies of pathophysiology and lung therapy. More recently, complex 3D culture systems, such as lung-on-a-chip, seek to mimic the physiology of a lung in vivo through a microsystem that simulates alveolar-capillary interactions and exposure to air. The present review introduces and discusses 3D lung cultures as robust platforms for studies of the pathophysiology of CRD and COVID-19 and the mechanisms that underlie interactions between CRD and COVID-19.

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.

Autologous Infusion of Bone Marrow and Mesenchymal Stromal Cells in Patients with Chronic Obstructive Pulmonary Disease: Phase I Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is characterized by the destruction of alveolar walls, chronic inflammation and persistent respiratory symptoms. There is no curative clinical treatment for COPD. In this context, cell-based therapy is a promising therapeutic alternative for COPD. Thus, in this open, controlled and randomized Phase I Clinical Trial, we aimed to assess the safety of the infusion of autologous bone marrow mononuclear cells (BMMC), adipose-derived mesenchymal stromal cells (ADSC) and, especially, the safety of concomitant infusion (co-infusion) of BMMC and ADSC as a new therapeutic alternative for COPD. The rationale for co-infusion of BMMC and ADSC is based on the hypothesis of an additive or synergistic therapeutic effect resulting from this association. METHODS: To achieve the proposed objectives, twenty patients with moderate-to-severe COPD were randomly divided into four groups: control group - patients receiving conventional treatment; BMMC group - patients receiving only BMMC; ADSC group - patients receiving only ADSC, and co-infusion group - patients receiving the concomitant infusion of BMMC and ADSC. Patients were assessed for pulmonary function, biochemical profile, and quality of life over a 12 months follow-up. RESULTS: No adverse events were detected immediately after the infusion of BMMC, ADSC or co-infusion. In the 12-month follow-up, no causal relationship was established between adverse events and cell therapy procedures. Regarding the efficacy, the BMMC group showed an increase in forced expiratory volume (FEV1) and diffusing capacity for carbon monoxide (DLCO). Co-infusion group showed a DLCO, and gas exchange improvement and a better quality of life. CONCLUSION: The results obtained allow us to conclude that cell-based therapy with co-infusion of BMMC and ADSC is a safe procedure and a promising therapeutic for COPD. However, additional studies with a greater number of patients are needed before randomized and controlled Phase III clinical trials can be implemented.

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.

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.

Non-genetic rats models for atherosclerosis research: from past to present.

Atherosclerosis is an inflammatory, progressive, and chronic illness that involves several molecular and epigenetic factors. Despite treatment limitations, clinical and therapeutic approaches have undeniably changed radically in recent decades through better knowledge of the pathophysiological basis of the disease, which has considerably improved patients' survival and quality of life. Some of these advances are attributable to basic biomedical research that provides insights into a better understanding and identification of new molecular and cellular targets for atherosclerosis treatment. Although rodent models have contributed substantially to a better understanding of the development of atherosclerosis, the accuracy of these models remains controversial. Research that utilizes genetic rodent models is well established, but the use of specific diets that are associated with other risk factors (e.g., hypertension, hormone deprivation, and pharmacological tools) is still debatable. The present review provides an update on non-genetic rat models of atherosclerosis and an overview of the main methodologies that are currently available.

Plinia cauliflora (Mart.) Kausel: A comprehensive ethnopharmacological review of a genuinely Brazilian species.

ETHNOPHARMACOLOGICAL RELEVANCE: Plinia cauliflora (Mart.) Kausel is widespread in alluvial plains and open forests in Brazil, Argentina, and Paraguay. The fruits of P. cauliflora are used as food, and almost all parts of this species have long been used as a traditional Brazilian medicine for the treatment of skin irritations, flu, diarrhea, labyrinthitis, genito-urinary problems, and asthma. THE AIM OF THE REVIEW: This review provides comprehensive and up-to-date information on P. cauliflora with regard to its ethnopharmacological uses, constituents, biological activities, and toxicology, all of which are useful for future research and the development of new drugs. MATERIALS AND METHODS: The information and data on P. cauliflora were collected from ethnobotanical textbooks and scientific databases, such as PubMed, Scopus, EBSCO, Science Direct, Google, and Google Scholar. RESULTS: The main chemical constituents in P. cauliflora preparations were depsides, flavonoids, and hydrolysable tannins. The main medicinal use of the species in Brazil is for the treatment of diarrhea. Although antimicrobial potential of this species has been demonstrated, data on gastrointestinal motility are still incipient and need further investigation. Studies that indicate the efficacy of its traditional use for sore throat, pelvic hemorrhage, uterine wounds, vaginal discharge, and flu are nonexistent. The scientific literature does not describe any toxic effects of its popular use. However, the available data do not allow us to conclude that the ethnomedicinal use of this species is safe, with a lack of well-designed preclinical tests and randomized clinical trials. CONCLUSION: This review summarizes research on the traditional use, phytochemistry, biological activities, and toxicology of P. cauliflora. Although P. cauliflora possesses significant biological activities, much of its ethnomedicinal use has not been scientifically evaluated. Well-designed pharmacological and toxicological assays and randomized clinical trials are still needed to validate its ethnopharmacological use as an herbal medicine.