Evaluation of the Efficacy of Lactobacillus acidophilus in the Treatment of Cyclophosphamide-induced Hemorrhagic Cystitis in Wistar Rats.

BACKGROUND: Hemorrhagic cystitis is an inflammatory complication that can be caused by the administration of cyclophosphamide, which is widely used as an antineoplastic agent. In the search for new therapeutic alternatives, probiotics can suppress the inflammatory process and, therefore, can be used to prevent this disease. OBJECTIVE: Thus, this study aimed to evaluate the effects of using Lactobacillus acidophilus NCFM in the treatment of cyclophosphamide-induced hemorrhagic cystitis in Wistar rats. METHODS: Lactobacillus acidophilus NCFM (2x108 CFU) was used in the treatment of cyclophosphamide- induced hemorrhagic cystitis (200 mg/kg, intraperitoneal) in 77 female Wistar rats. Rats were distributed into experimental groups (n = 9): control group (GC), zero control group (GCZ), inflammation group (GI), 24-hour acute treatment groups: 24-hour lactobacilli treatment group (GL24H) and mesna group (GM), and 30-day chronic treatment groups: lactobacilli treatment group (GTL) and mesna+lactobacilli group (GM+L). After treatment, animals were euthanized and biological materials were collected for blood count, biochemical analyses, examination of abnormal sediment elements (EAS), and histopathological analysis. RESULTS: GI results showed development of edema, macroscopic alterations, and signs of bleeding in the bladder; in addition, lesions in the urothelium and hemorrhage were also found. GL24H and GM presented intact urothelium, without inflammatory reaction and hematological or biochemical urine alterations. CONCLUSION: Therefore, this study demonstrated that L. acidophilus presented uroprotective effect against the action of cyclophosphamide in both the short and long term.

Bioactive peptides from beans with the potential to decrease the risk of developing noncommunicable chronic diseases.

Several studies have demonstrated that peptides obtained from the proteins of different bean species have the potential to act on therapeutic targets of noncommunicable chronic diseases or NCDs. However, peptides with great structural diversity can be obtained from the hydrolysis of proteins present in foods. Therefore, the present review had the objective of identifying, in silico, the possibility of obtaining peptides with potential biological activity from the storage globulin proteins of the bean species Phaseolus vulgaris (L.), Vigna angularis (Willd.), Vigna radiata (L.) and Vigna unguiculata (L.) Walp., using the UniProtKB, BIOPEP and PeptideRanker databases, as well as reviewing available research reports that showed evidence bioactive properties of peptides obtained from beans via in vitro assays. For all the species studied, the highest frequency of the occurrence of bioactive fragments was found for the inhibition of dipeptidyl peptidase-IV, followed by the inhibition of the angiotensin-converting enzyme and by antioxidant activity. The inhibition of the two enzymes is the therapeutic target of drugs used for type 2 diabetes mellitus (T2DM) and for hypertension, respectively, while the antioxidant activity can prevent the development of several chronic diseases related to oxidative stress.

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.

Value of speckle-tracking echocardiography changes in monitoring myocardial dysfunction during treatment of sepsis: potential prognostic implications.

Speckle-tracking echocardiography (STE) has been increasingly used for detection of sepsis-related myocardial dysfunction. However, the impact of strain changes during sepsis treatment has not been defined. This study assessed STE at admission and during the treatment of patients with sepsis to evaluate its changes as a potential factor for predicting in-hospital outcome. This study included 26 patients with sepsis who underwent STE echocardiography on day 1 and 7 during treatment. Myocardial deformation of both ventricles was assessed using global longitudinal strain. The endpoint was in-hospital mortality. The mean age was 51.4 ± 18.3 years, and 54% were female. The average SOFA score at T0 was 8.6 ± 3.8 points and at day 7 was 4.9 ± 4.7 points. The left ventricular (LV) ejection fraction at baseline was 65.6 ± 9.1%, without changes in echocardiographic parameters during treatment. LV and RV longitudinal strain increased significantly in the patients who survived (- 18.8 ± 3.6 at D1 vs - 20.8 ± 2.5 at D7; p = 0.003; and - 21.3 ± 4.9 at D1 vs - 24.3 ± 5.8 at D7; p = 0.035, respectively), whereas strain values remained unchanged in those who died. After adjustment for the SOFA score, RV longitudinal strain at admission was associated with in-hospital mortality [adjusted odds ratio (OR) 0.760; 95% confidence interval (CI) 0.591-0.977; p - 0.033]. STE improved significantly after the first week of treatment in patients with sepsis who survived compared with those patients who died during hospitalization. RV strain at admission predicted in-hospital mortality. An improvement in STE during sepsis treatment appears to be a useful tool for predicting in-hospital outcome.

Endothelium-Dependent Effects of Echinodorus grandiflorus (Cham. & Schltdl.) Micheli Mediated by M3-Muscarinic and B2-Bradykininergic Receptors on Peripheral Vascular Resistance and Its Modulatory Effects on K+ Channels in Mesenteric Vascular Beds.

This work provides the first demonstration that ethanolic extract (EEEG) obtained from Echinodorus grandiflorus leaves (EEEG) and its butanolic fraction (ButFr) has important vasodilatory effects on isolated mesenteric vascular beds (MVBs). First, the EEEG was obtained and a liquid-liquid fractionation was performed. EEEG and its resulting fractions were analyzed by high-performance liquid chromatography. Then, the vasodilatory effects of EEEG and their respective fractions were evaluated. Finally, the molecular mechanisms involved in the vasodilator responses of the EEEG and ButFr were also investigated. EEEG vasodilator response was estimated at ~11 and 18 mm Hg at doses of 0.1 and 0.3 mg, respectively. Moreover, it was found that ButFr was able to induce an expressive dose-dependent vasodilator response in MVBs. The PP reduction values for doses of 0.1 and 0.3 mg were ~10 and 28 mm Hg, respectively. Endothelium removal or inhibition of nitric oxide and prostaglandin synthase (by L-NAME plus indomethacin) inhibited the vasodilatory effects induced by ButFr or EEEG. The peak effect of ButFr and EEEG doses (0.1 and 0.3 mg) was decreased by ~100% (p < 0.001). The association of atropine plus HOE-140 fully inhibited EEEG and ButFr-induced vasodilation (p < 0.001). Moreover, perfusion with nutritive solution containing 40 mM KCl or previous treatment with tetraethylammonium completely blocked vasodilation induced by ButFr (p < 0.001). This study showed that EEEG and its ButFr have important vasodilatory effects by endothelial M3-muscarinic and B2-bradykininergic receptors inducing nitric oxide and prostacyclin release followed by K+ channels activation in the vascular smooth muscle.

Left Ventricular Regional Wall Motion Abnormality is a Strong Predictor of Cardiotoxicity in Breast Cancer Patients Undergoing Chemotherapy.

BACKGROUND: Chemotherapeutic agents of anthracyclines class and humanized monoclonal antibodies are effective treatments for breast cancer, however, they present a potential risk of cardiotoxicity. Several predictors have been recognized as predictors in the development of cardiac toxicity, and the evaluation of left ventricular segmental wall motion abnormalities (LVSWMA) has not been studied. OBJECTIVE: To analyze prospectively the role of LVSWMA among echocardiographic parameters in the prediction of development of cardiotoxicity in breast cancer patients undergoing treatment with chemotherapy. METHODS: Prospective cohort of patients diagnosed with breast cancer and in chemotherapy treatment with potential cardiotoxicity medications including doxorubicin and trastuzumab. Transthoracic echocardiograms including speckle tracking strain echocardiography were performed at standard times before, during and after the treatment to assess the presence (or lack thereof) of cardiotoxicity. Cardiotoxicity was defined by a 10% decrease in the left ventricular ejection fraction, on at least one echocardiogram. Multivariate logistic regression models were used to verify the predictors related to the occurrence of cardiotoxicity over time. RESULTS: Of the 112 patients selected (mean age 51,3 ± 12,9 years), 18 participants (16.1%) had cardiotoxicity. In the multivariate analysis using the logistic regression model, those with LVWMA (OR = 6.25 [CI 95%: 1.03; 37.95], p < 0,05), LV systolic dimension (1.34 [CI 95%: 1.01; 1.79], p < 0,05) and global longitudinal strain by speckle tracking (1.48 [CI 95%: 1.02; 2.12], p < 0,05) were strongly associated with cardiotoxicity. CONCLUSION: In the present study, we showed that LVWMA, in addition to global longitudinal strains, were strong predictors of cardiotoxicity and could be useful in the risk stratification of these patients.

Calcitriol combined with calcium chloride causes apoptosis in undifferentiated adipose tissue-derived human mesenchymal stem cells, but this effect decreases during adipogenic differentiation.

Calcitriol, the bioactive hormone of vitamin D, is currently linked to several diseases, such as obesity and gain of adipose mass, due to its liposolubility and, consequently, its sequestration by adipocytes. As rates of obesity continue to increase, research on the biology of weight gain should be encouraged. This study evaluated the effects of calcitriol combined with CaCl2 on adipose tissue-derived human mesenchymal stem cells. We evaluated the cytotoxicity of the combination by MTT assays, in which undifferentiated cells and cells undergoing adipogenic differentiation were tested for 7 and 14 days. The results demonstrated that the combination of calcitriol at the IC50 and CaCl2 at the IC20 was effective at reducing the viability of mesenchymal stem cells, but with the progression of cell differentiation towards adipocytes, cell resistance to the cytotoxic effects increased. The percentages of dead cells were 88.29, 57.45 and 28.81% for undifferentiated cells and cells exposed to differentiation medium for 7 and 14 days, respectively. Undifferentiated cells were evaluated for apoptosis in response to the same combination using Annexin V assays, and a possible onset of programmed cell death in undifferentiated cells was detected. Additionally, the combination of the compounds altered the membrane permeability of undifferentiated cells by 16 percentage points and induced cell cycle arrest in S phase due to the accumulation of damage. An evaluation of gene expression revealed the overexpression of the GADD45 and ATM genes and the underexpression of the P21, P53, ATR, BCL-2, EIF2 AK3, IGF1R, DNAse-2, ATF, MAP3K4, ENGO-G, CASP3, CASP7 and CASP8 genes. Our results provide valuable insights into the biology of obesity and may contribute to the development of new anti-obesity therapies focusing on the inhibition of adipose tissue mesenchymal stem cell hyperplasia and adipogenic differentiation.

Chemical characterisation of Piper amalago (Piperaceae) essential oil by comprehensive two-dimensional gas chromatography coupled with rapid-scanning quadrupole mass spectrometry (GC×GC/qMS) and their antilithiasic activity and acute toxicity.

INTRODUCTION: Piper amalago has a distribution from Mexico to Brazil; their aerial parts have been used in folk medicine to treat diuretic and kidney diseases. OBJECTIVE: The purpose of this study was to obtain a deeper understanding of the chemical composition of essential oils (EOs) extracted from both the leaves and stems of P. amalago, compare them, and evaluate their antilithiasic activity and acute toxicity. METHODOLOGY: Extraction was performed by hydrodistillation, whereas chemical characterisation by two-dimensional gas chromatography coupled with rapid-scanning quadrupole mass spectrometry (GC×GC/qMS). The antilithiasic activity was evaluated by the effect of the EOs on calcium oxalate crystallisation in vitro. The turbidity index and the number of crystals formed were determined and used as an estimative of the activity. In the acute toxicity assay, the effects of a single oral dose of the EOs in Wistar rats were determined. General behaviour, adverse effects, and mortality were determined. RESULTS: A total of 322 compounds were identified in the EOs. The sesquiterpenes displayed the highest contribution in leaves EOs among which included bicyclogermacrene and δ-cadinene. Sesquiterpenes and oxygenated sesquiterpenes displayed the highest contribution in EOs from stems, among which included bicyclogermacrene and α-cadinol. The EOs demonstrated an excellent action on the crystals growth inhibition, and the oral dose tested did not induce significant changes in the parameters for acute toxicity. CONCLUSION: The oils have a high chemical complexity, and there are differences between their compositions, which could explain the observed differences in antilithiasic activity. The findings support the use of this plant in folk medicine to treat kidney diseases.

Evaluation of the toxicokinetics and apoptotic potential of ethanol extract from Echinodorus macrophyllus leaves in vivo.

This study evaluates the toxicological, genotoxic, mutagenic and apoptotic potential of an in vivo assay from Echinodorus macrophyllus extract (EEM). The acute toxicity test used 02 groups (n = 5) of female Wistar rats: negative control group (saline) and experimental group (2000 mg/kg b.w. EEM), both orally administered (gavage) at single doses and monitored for 14 days. To assess the genotoxic, mutagenic and apoptotic potential, 50 male Swiss mice were divided into 5 groups (n = 10): Group I: negative control (saline solution 0.1 ml/10 g b.w.); Group II: positive control (cyclophosphamide 100 mg/kg b.w.) intraperitoneally administered; groups III-V received EEM at 500, 1000 and 2000 mg/kg b.w., respectively. Groups I, III-V received oral administrations (gavage). The results showed that there was no acute lethality or any signs of acute toxicity, indicating that LD50 is greater than 2000 mg/kg b.w. The groups treated with EEM showed no genotoxic or mutagenic activity and did not induce apoptosis in the liver and kidney. Therefore, EEM showed no acute toxicity and at doses of 500, 1000 and 2000 mg/kg b.w. absence of genotoxicity, mutagenicity and no apoptotic events were observed.

Early detection of left ventricular contractility abnormalities by two-dimensional speckle tracking strain in Chagas' disease.

BACKGROUND: Chagas' disease is an important cause of heart failure, and early identification of cardiac involvement may help to identify patients at risk for disease progression. Two-dimensional (2D) speckle tracking (ST) strain seems to be a useful tool to detect incipient ventricular dysfunction. This study aims to analyze if 2D strain can detect contractility abnormalities in asymptomatic patients with Chagas' disease. METHODS: Seventy-eight asymptomatic Chagas' disease patients (46% male; age 44.7 ± 8.6 years) with normal cardiovascular exams and a control group of 38 healthy subjects (58% male; age 44.1 ± 9.2 years) were included in the study. Using 2D strain software, left ventricular (LV) end-systolic longitudinal, radial, and circumferential strain were measured. Global right ventricular (RV) longitudinal strain was also assessed. RESULTS: Echocardiographic parameters of LV systolic and diastolic function were similar between patients and controls. 2D longitudinal strain in the basal inferior, and inferoseptal walls, as well as apical segment of the inferolateral wall were lower in patients compared with controls. 2D radial strain was reduced in several segments of the LV walls as well as the global radial strain. 2D circumferential strain at the basal segment of the anterior wall showed a lower value in patients compared with controls, whereas global circumferential strain was similar between patients and controls. 2D RV strain did not differ between groups. CONCLUSION: In a subgroup of asymptomatic patients with Chagas' disease without evident cardiac involvement, 2D strain was reduced compared with healthy individuals, suggesting incipient LV dysfunction in these patients. 2D ST strain has the potential for detecting early myocardial impairment in the setting of Chagas' disease.

Diuretic and antilithiasic activities of ethanolic extract from Piper amalago (Piperaceae).

OBJECTIVE: Piper amalago is used in Brazilian folk medicine as diuretic and for the treatment of urinary calculus disease, although no scientific data have been described to support these effects. Thus, this study aims to evaluate the diuretic effects and antilithiatic activity of the ethanolic extract of P. amalago (EEPam). MATERIALS AND METHODS: Ethanolic extracts of P. amalago (125, 250 and 500mg/kg) were orally administered in male Wistar rats (n=5) and urinary excretion was measured at intervals of up to 24h after administration. The antilithiasic effect of EEPam on calcium oxalate urolithiasis crystallization was examined in a turbidimetric model. RESULTS: The oral administration of all doses of EEPam significantly increased urine output after 24h when compared to control group. Moreover, the application of EEPam, induced an inhibitory effect on calcium oxalate crystallization. CONCLUSIONS: According to results, P. amalago extracts showed diuretic and natriuretic activity and antilithiasic effects.

Impaired coronary flow reserve in patients with indeterminate form of Chagas' disease.

BACKGROUND: Previous studies suggest that microvascular abnormalities may contribute to the pathogenesis of Chagas' heart disease. Coronary flow reserve (CFR) expressed by the maximum achievable flow relative to baseline flow in the coronary microcirculation, may be useful in identifying patients who may be developing cardiac manifestations of the disease. This study aims to assess the CFR in patients with indeterminate form of Chagas' disease, and also to identify the determinants of CFR. METHODS: Sixty-four asymptomatic patients (37% male; age 49.9 ± 11.5 years) with normal cardiovascular exams classified as in indeterminate form of Chagas' disease underwent transthoracic dipyridamole (0.84 mg/kg in 6 min) stress echocardiography, and were compared with a control group of healthy patients. Coronary flow reserve was assessed on left anterior descending artery using pulsed Doppler as the ratio of maximal peak vasodilation (dipyridamole) to rest diastolic flow velocity. A treadmill exercise test was performed to rule out ischemia. RESULTS: All patients had good functional capacity assessed by exercise testing with peak oxygen consumption (VO2 ) of 28 ± 11 mL/kg per minute, similar to the controls. There were no differences in the echocardiographic parameters of diastolic and systolic left ventricular function and right ventricular function between the patients and controls. Coronary flow reserve was significantly lower in Chagas' disease patients than those in healthy individuals (1.9 ± 0.4 vs. 2.6 ± 0.5; P < 0.001). Several factors were correlated with the CFR, including age, ejection fraction, left ventricular diastolic function, heart rate recovery, and the presence of Chagas' disease. In a multivariate analysis, age and positive serology for Chagas' disease were independent factors associated with the CFR. CONCLUSIONS: Coronary flow reserve was impaired in Chagas' disease patients in the indeterminate form compared with healthy individuals with similar clinical features. Among all variables tested, age and positive serology for Chagas' disease were independent factors associated with the CFR.

Hospital nuclear pharmacy survey: preliminary aspects in Brazil.

Radiopharmaceuticals are special drugs that in the composition preserve one or more radionuclides which can be used as diagnostic or therapeutic tools in Nuclear Medicine Units. This study evaluated hospitals and clinics which have nuclear medicines services at the city of Rio de Janeiro from August to November 2010. The data were obtained through a longitudinal research. The results showed that most of the hospitals (>80%) did not have pharmacist and all them (100%) considered that a pharmacist in the nuclear pharmacy is not required.

Functional capacity and right ventricular function in patients with Chagas heart disease.

AIMS: Right ventricular (RV) dysfunction is an important factor on effort tolerance in cardiopulmonary diseases. Nevertheless, the role of RV function in predicting exercise capacity in patients with Chagas disease has not been reported. This study aims to evaluate whether RV function assessed by tissue Doppler can predict functional capacity in patients with Chagas heart disease. METHODS AND RESULTS: We evaluated 65 patients (48.6 +/- 9.1 years, 60% men) with Chagas heart disease. Standard and tissue Doppler echocardiography were performed before maximal exercise testing. Tissue Doppler imaging (TDI) was used to measure RV peak annular systolic and diastolic velocities. Exercise testing was performed using a standard Bruce protocol. Linear regression analysis was used to determine multivariate peak oxygen consumption (VO(2)) predictors. All patients were in NYHA functional class I or II. Mean peak VO(2) was 32.4 +/- 10.2 mL/kg/min and mean LV ejection fraction was 43 +/- 11%. There was correlation between TDI RV peak systolic velocity and LV ejection fraction (r = 0.5; P < 0.001). In a multivariate analysis, after adjustment for age and gender, RV function emerged as an independent predictor of functional capacity, as demonstrated in the model: peak VO(2) (r = 0.71) was: 42.22-(9.77 x female gender)-(0.29 x age) + (1.54 x RV systolic velocity). CONCLUSION: In this cross-sectional study, RV function was an important, independent determinant of exercise capacity in patients with Chagas heart disease. TDI RV systolic annular velocity was most closely associated with peak VO(2), regardless of the influence of age, gender, and other echocardiographic parameters.