Identification of host antioxidant effectors as thioridazine targets: Impact on cardiomyocytes infection and Trypanosoma cruzi-induced acute myocarditis.

Phenothiazines inhibit antioxidant enzymes in trypanosomatids. However, potential interferences with host cell antioxidant defenses are central concerns in using these drugs to treat Trypanosoma cruzi-induced infectious myocarditis. Thus, the interaction of thioridazine (TDZ) with T. cruzi and cardiomyocytes antioxidant enzymes, and its impact on cardiomyocytes and cardiac infection was investigated in vitro and in vivo. Cardiomyocytes and trypomastigotes in culture, and mice treated with TDZ and benznidazole (Bz, reference antiparasitic drug) were submitted to microstructural, biochemical and molecular analyses. TDZ was more cytotoxic and less selective against T. cruzi than Bz in vitro. TDZ-pretreated cardiomyocytes developed increased infection rate, reactive oxygen species (ROS) production, lipid and protein oxidation; similar catalase (CAT) and superoxide dismutase (SOD) activity, and reduced glutathione's (peroxidase - GPx, S-transferase - GST, and reductase - GR) activity than infected untreated cells. TDZ attenuated trypanothione reductase activity in T. cruzi, and protein antioxidant capacity in cardiomyocytes, making these cells more susceptible to H2O2-based oxidative challenge. In vivo, TDZ potentiated heart parasitism, total ROS production, myocarditis, lipid and protein oxidation; as well as reduced GPx, GR, and GST activities compared to untreated mice. Benznidazole decreased heart parasitism, total ROS production, heart inflammation, lipid and protein oxidation in T. cruzi-infected mice. Our findings indicate that TDZ simultaneously interact with enzymatic antioxidant targets in cardiomyocytes and T. cruzi, potentiating the infection by inducing antioxidant fragility and increasing cardiomyocytes and heart susceptibility to parasitism, inflammation and oxidative damage.

The role of IL-10 in regulating inflammation and gut microbiome in mice consuming milk kefir and orally challenged with S. Typhimurium.

Kefir has been suggested as a possible bacterial prophylaxis against Salmonella and IL-10 production seems to be crucial in the pathogenesis of salmonellosis in mice. This study evaluated the role of IL-10 in the inflammation and gut microbiome in mice consuming milk kefir and orally challenged with Salmonella enterica serovar Typhimurium. C57BL wild type (WT) (n = 40) and C57BL IL-10-/- (KO) (n = 40) mice were subdivided into eight experimental groups either treated or not with kefir. In the first 15 days, the water groups received filtered water (0.1 mL) while the kefir groups received milk kefir (10% w/v) orally by gavage. Then, two groups of each strain received a single dose (0.1 mL) of the inoculum of S. Typhimurium (ATCC 14028, dose: 106 CFU mL-1). After four weeks, the animals were euthanized to remove the colon for further analysis. Kefir prevented systemic infections only in IL-10-/- mice, which were able to survive, regulate cytokines, and control colon inflammation. The abundance in Lachnospiraceae and Roseburia, and also the higher SCFA production in the pre-infection, showed that kefir has a role in intestinal health and protection, colonizing and offering competition for nutrients with the pathogen as well as acting in the regulation of salmonella infectivity only in the absence of IL-10. These results demonstrate the role of IL-10 in the prognosis of salmonellosis and how milk kefir can be used in acute infections.

Monotherapy and combination chemotherapy for Chagas disease treatment: a systematic review of clinical efficacy and safety based on randomized controlled trials.

From a systematic review framework, we analysed the clinical evidence on the effectiveness and safety of monotherapy and combination chemotherapy for Chagas disease (ChD) treatment. The research protocol was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and patient, intervention, comparison and outcome strategy. Only randomized controlled trials (RCT) were retrieved from Embase, Medline, Scopus and Web of Science databases. Diagnostic tools, treatment protocols, seroconversion rates and adverse events were investigated. Fifteen RCT mainly concentrated in endemic countries were identified. ChD diagnosis was mainly based on haemagglutination, immunofluorescence, enzyme-linked immunosorbent assay and polymerase chain reaction. Benznidazole (BNZ), nifurtimox, fosravuconazole, posaconazole, allopurinol and thioctic acid were the identified drugs. The best negative seroconversion results (100, 96, 94 and 91.3%) were, respectively, based on BNZ (5 mg kg day−1, 200 mg day−1, 150 mg day−1 and 2.5 mg kg−1) administration for 60 days. Negative seroconversion was not achieved with allopurinol (300 mg day−1 for 60 days). Adverse reactions ranged from 5 to 73% in patients receiving antiparasitic chemotherapy. Treatment discontinuation (1.5­57%) was mainly associated with gastrointestinal, cutaneous and neurological manifestations. Current RCT-based evidence indicates that BNZ is the most viable option for ChD treatment. However, new protocols need to be developed to mitigate side effects and increase patient adherence to antiparasitic chemotherapy. Therefore, shorter regimens, lower concentrations and treatments combining BNZ with posaconazole, fosravuconazole or ravuconazole may be viable to ensure comparable efficacy to BZN-based monotherapy, contributing to reduce dose- and time-dependent toxicity reactions.

Protective effects of whey protein concentrate admixtured of curcumin on metabolic control, inflammation and oxidative stress in Wistar rats submitted to exhaustive exercise.

This work aimed to evaluate the effects of whey protein concentrate (WPC) admixtured of curcumin on metabolic control, inflammation and oxidative stress in Wistar rats submitted to exhaustive exercise. A total of forty-eight male rats were divided into six experimental groups (n 8): standard diet group (AIN-93M), standard diet submitted to exhaustion test group (AIN-93M ET), WPC admixtured of curcumin group (WPC + CCM), WPC + CCM submitted to exhaustion test group (WPC + CCM ET), CCM group and CCM subjected to exhaustion test group (CCM ET). The swimming exhaustion test was performed after 4 weeks of experiment. The consumption of WPC + CCM as well as isolated CCM did not alter the biometric measurements, the animals' food consumption and the hepatic and kidney function, as well as the protein balance of the animals (P > 0·05), but reduced the glycaemia and the gene expression of TNF-α and IL-6 and increased the expression of IL-10 (P < 0·05). The animals that were submitted to the exhaustion test (AIN-93M ET) showed higher aspartate aminotransferase values when compared to the animals that did not perform the exercise (AIN-93 M) (P < 0·05). WPC + CCM reduced the concentration of nitric oxide, carbonylated protein and increased the concentration of catalase (P < 0·05). Both (WPC + CCM and CCM) were able to increase the concentrations of superoxide dismutase (P < 0·05). We concluded that the WPC admixtured of CCM represents a strategy capable of decreasing blood glucose and oxidative and inflammatory damage caused by exhaustive physical exercise in swimming.

Depletion of enteroendocrine and mucus-secreting cells is associated with colorectal carcinogenesis severity and impaired intestinal motility in rats.

This study investigated the relationship between enteroendocrine and mucus-secreting cells distribution, the severity of colonic mucosal injury and intestinal motility in experimental colorectal carcinogenesis. Using a standardized murine model of colorectal carcinogenesis, eight-weeks-old female Wistar rats weighting 147.30 ± 29.15g were randomized into two groups receiving a subcutaneous injection of 0.9% saline (control) or the chemical carcinogen 1,2-dimethylhydrazine (DMH) at 20 mg/kg per week during 10 weeks. Aberrant crypt foci (ACF) were more frequent in DMH group compared to control group (P < 0.001). The number of enteroendocrine and mucus-secreting cells, and intestinal motility was reduced in DMH animals (P < 0.05). The distribution of enteric neurons was similar in both groups. In DMH animals there was a direct correlation between colonic motility and distribution of enteroendocrine (R(2) = 0.68, P < 0.05) and mucus-secreting cells (R(2) = 0.77, P < 0.05). Inverse correlation between the number of ACF, mucus-secreting cells (R(2) = -0.57, P < 0.05), and enteroendocrine cells (R(2) = -0.74, P < 0.05) was also observed. There was inverse correlation between the severity of the mucosal lesion, the number of mucus-secreting cells (R(2) = -0.83, P < 0.05) and enteroendocrine cells (R(2) = -0.96, P < 0.05). There was a direct correlation between nucleolar organizer regions (AgNOR) and ACF number (R(2) = 0.62; P < 0.01). Inverse correlation was also found between AgNOR, the number of mucus-secreting cells (R(2) = -0.76; P < 0.001), and enteroendocrine cells (R(2) = -0.86; P < 0.001). Taken together, the results indicated that colonic malignant transformation is related to depletion of mucus-secreting and enteroendocrine cells, which was a useful indicator of the evolutionary status of intestinal neoplasm, partially explaining the intestinal motility disorders in the early stages of colorectal carcinogenesis.

CHEMICAL COMPOSITION, CHARACTERIZATION OF ANTHOCYANINS AND ANTIOXIDANT POTENTIAL OF EUTERPE EDULIS FRUITS: APPLICABILITY ON GENETIC DYSLIPIDEMIA AND HEPATIC STEATOSIS IN MICE.

UNLABELLED: The significance of polyphenol intake for the prevention of chronic diseases is controversial. OBJECTIVE: this study investigated the chemical composition and antioxidant potential of an anthocyanin-rich extract from Euterpe edulis fruits (LPEF) and its effects on liver steatosis in dyslipidemic apoE-/- knockout mice. MATERIALS AND METHODS: mice were divided into G1 (C57BL/6) standard diet; G2 (apoE-/-) standard diet, G3 (apoE-/-) 2% LPEF, G4 (apoE-/-) 6% LPEF, G5 (apoE-/-) 10% LPEF, G6 (apoE-/-) 2% α-tocopherol acetate. After 75 days of treatment, the animals were euthanized. The LPEF contained a high level of monomeric anthocyanins (301.4 mg/100g) and marked antioxidant activity. RESULTS: Catalase activity was reduced in G3, G4, G5 and G6 compared to G2. Superoxide dismutase was reduced only in G4. The animals in G4, G5, and G6 showed low HDL and triglycerides levels compared to G2. The proportion of lipid droplets in liver tissue was reduced in G4 and G5 compared to G2, G3, and G6. CONCLUSION: The results indicated that E. edulis pulp is rich in anthocyanins and the LPEF dietary consumption can reduce the severity of liver steatosis in apoE-/- mice, an effect that is potentially mediated by the antioxidant activity of this extract and modulation of triglyceride serum levels.

El papel de los polifenoles en la prevención de enfermedades crónicas es controvertido. Objetivo: este estudio investigó la composición química y el potencial antioxidante de un extracto del fruto de Euterpe edulis rico en antocianinas (LPEF) y sus efectos en la esteatosis hepática en ratones apoE-/- knockout con dislipidemia. Material y métodos: los ratones fueron divididos en los siguientes grupos; G1 (C57BL/6) con una dieta estándar; G2 (apoE-/-) con dieta estándar; G3 G3 (apoE-/-) con 2% de LPEF; G4 (apoE-/-) con 6% de LPEF; G5 (apoE-/-) con 10% de LPEF y G6 (apoE-/-) con 2% acetato α-tocoferol (α-tocopherol acetate). Después de 75 días de tratamiento, los animales fueron eutanizados. El LPEF contenía un alto nivel de antocianinas monoméricas (301,4 mg/100 g) con notable actividad antioxidante. Resultados: la actividad catalasa fue reducida en los grupos G3, G4, G5 y G6 comparada con G2. La superoxidasa dismutasa solo se redujo en el grupo G4. Los animales de G4, G5 y G6 mostraron bajos niveles de HDL triglicéridos, comparados con G2. La proporción de lípidos en el tejido hepático fue reducida en G4 y G5, comparado con G2, G3 y G6. Conclusión: los resultados indicaron que la pulpa de E. edulis es rica en antocianinas, y que el consumo de LPEF en la dieta puede reducir la severidad de la esteatosis hepática en ratones apoE-/-, un efecto que es potencialmente mediado por la actividad antioxidante de este extracto y la modulación en los niveles séricos de triglicéridos.

The promoting effect of carbamide peroxide teeth bleaching gel in a preclinical model of head and neck cancer in hamster buccal pouch.

OBJECTIVES: The aim of this study was to verify the promoting effect of carbamide peroxide on dimethylbenzanthracene (DMBA)-induced carcinogenesis in the hamster buccal pouch, in order to reduce the period of latency for tumor formation. METHODS: Sixteen hamsters were randomized into two groups of eight animals each. The hamsters of the group I had their right buccal pouches treated with 0.5% DMBA and 10% carbamide peroxide teeth bleaching gel for 55 days. The animals of the group II had their right pouches treated only with DMBA. After, six animals of each group had their pouches prepared for light microscopy. Histomorphometry was performed to assess the presence of keratinization, nuclear polymorphism, pattern of invasion, number of blood vessels, and inflammatory infiltrate in the tumor front. Furthermore, the newly formed lesions were graded according the Bryne's grading system. The remaining animals had the vascular system of the pouches casted by Mercox and qualitatively analyzed by scanning electron microscopy. RESULTS: Histopathological analysis of the buccal pouches treated with DMBA and carbamide peroxide exhibited formation of squamous cell carcinoma well-differentiated with a high degree of malignancy in all pouches. The development of this neoplasm was associated with a significant increase in the number of blood vessels, presence of keratin pearls, and inflammatory infiltrate. The pouches of the group II showed inflammation, epithelial hyperplasia, dysplasia, and squamous cell carcinoma in only three right pouches. The analysis of the electron micrographs of the pouches chemically inducted with DBMA and carbamide peroxide reveled formation of a new vascular network characteristic of squamous cell carcinoma. CONCLUSION: The protocol presented here, using DMBA associated with carbamide peroxide, shortens the period of latency to produce squamous cell carcinoma in the hamster buccal pouch, decreasing the time and costs of the experiments.