RESUMO
Considering a potential exercise-drug interaction, we investigated whether exercise training could improve the efficacy of specific antiparasitic chemotherapy in a rodent model of Chagas disease. Wistar rats were randomized into five groups: sedentary and uninfected (CT); sedentary and infected (SI); sedentary, infected and treated (SIT); trained and infected (TI); trained, infected and treated (TIT). After 9-weeks running training, the animals were infected with T. cruzi and followed up for 4 weeks, receiving 100 mg kg-1 day-1 benznidazole. No evidence of myocarditis was observed in CT animals. TI animals exhibited reduced parasitemia, myocarditis, and reactive tissue damage compared to SI animals, in addition to increased IFN-γ, IL-4, IL-10, heart non-protein antioxidant (NPA) levels and glutathione-s transferase activity (P < 0.05). The CT, SIT and TIT groups presented similar reductions in parasitemia, cytokines (IFN-γ, TNF-α, IL-4, IL-10, IL-17 and MCP-1), inflammatory infiltrate, oxidative heart damage and antioxidant enzymes activity compared to SI and TI animals, as well as reduced heart microstructural remodeling (P < 0.05). By modulating heart inflammation and redox metabolism, exercise training exerts a protective effect against T. cruzi infection in rats. However, the antiparasitic and cardioprotective effects of benznidazole chemotherapy are more pronounced, determining similar endpoints in sedentary and trained T. cruzi-infected rats.
Assuntos
Antiparasitários/uso terapêutico , Cardiotônicos/uso terapêutico , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Condicionamento Físico Animal , Animais , Doença de Chagas/fisiopatologia , Citocinas/imunologia , Modelos Animais de Doenças , Esquema de Medicação , Coração/fisiopatologia , Masculino , Miocardite , Parasitemia/tratamento farmacológico , Ratos , Ratos Wistar , Corrida , Trypanosoma cruzi/efeitos dos fármacosRESUMO
When administered alone, preinfection exercise training and benznidazole-based chemotherapy induce cardioprotection in Chagas disease. However, the effect of concomitant exercise and benznidazole treatment is unknown. We investigated whether exercise and specific chemotherapy could interact to modulate parasitemia, inflammation, redox status and heart damage in a murine model of T. cruzi infection. Wistar rats were randomized into an uninfected control group (CNT) and four groups infected with T. cruzi: sedentary untreated (SUN) and treated (STR), and trained untreated (TUN) and treated (TTR). Running training was administered 5â¯days/week for 4â¯weeks. Treated animals concomitantly received 100â¯mg/kg/day benznidazole. Heart inflammation and reactive damage were not detected in CNT animals. Compared to SUN, TUN animals presented increased levels of parasitemia, myocarditis, nitric oxide, hydrogen peroxide, protein carbonyl, malondialdehyde, cytokines (IFN-γ, TNF-α, IL-4, IL-6, IL-10 and IL-17), catalase, superoxide dismutase and glutathione reductase activity, as well as reduced heart non-protein antioxidant levels (Pâ¯<â¯0.05). TTR animals exhibited higher levels of parasitemia, myocarditis, hydrogen peroxide, malondialdehyde, IFN-γ, TNF-α and IL-6 than STR animals (Pâ¯<â¯0.05), which showed the lowest levels of all analyzed parameters compared to the other groups (Pâ¯<â¯0.05). Our findings indicate that exercise aggravates acute infection. When concomitantly administered with benznidazole, exercise training impaired parasitic control and chemotherapy-induced cardioprotection in T. cruzi-infected rats. Considering that exercise training and T. cruzi infection constitute independent metabolic challenges, the negative effects of concomitant treatment are potentially related to the overlapping oxidative and immunoinflammatory demands of exercise and the infection itself.
Assuntos
Doença de Chagas/tratamento farmacológico , Doença de Chagas/fisiopatologia , Condicionamento Físico Animal/fisiologia , Animais , Antioxidantes/farmacologia , Cardiotônicos/metabolismo , Catalase/metabolismo , Cardiomiopatia Chagásica/fisiopatologia , Cardiomiopatia Chagásica/terapia , Citocinas/metabolismo , Modelos Animais de Doenças , Coração/fisiologia , Inflamação/metabolismo , Interleucina-10/metabolismo , Masculino , Miocardite/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Nitroimidazóis/farmacologia , Parasitemia/parasitologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Trypanosoma cruzi/patogenicidade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
By using an experimental model of dexamethasone-induced osteoporosis we investigated the effects of different therapeutic schemes combining sodium alendronate (SA) and simvastatin on bone mineral and protein composition, microstructural and mechanical remodeling. Wistar rats were randomized into eight groups: G1: non-osteoporotic; G2: osteoporotic; G3, G4, and G5: osteoporotic+SA (0.2, 0.4, and 0.8 mg/kg, respectively); G6, G7, and G8: osteoporotic+SA (0.2, 0.4, and 0.8 mg/kg, respectively)+simvastatin (0.4, 0.6, and 1 mg/kg, respectively). Osteoporosis was induced by dexamethasone (7 mg/kg, i.m.) once a week for 5 weeks. All treatments were administered for 8 weeks. Dexamethasone increased serum levels of alkaline phosphatase, calcium, phosphorus, and urea, especially in non-treated animals, which showed severe osteoporosis. Dexamethasone also induced bone microstructural fragility and reduced mechanical resistance, which were associated with a marked depletion in mineral mass, collagenous and non-collagenous protein levels in cortical and cancellous bone. Although SA has attenuated osteoporosis severity, the effectiveness of drug therapy was enhanced combining alendronate and simvastatin. The restoration in serum parameters, organic and inorganic bone mass, and mechanical behavior showed a dose-dependent effect that was potentially related to the complementary mechanisms by which each drug acts to induce bone anabolism, accelerating tissue repair.
Assuntos
Alendronato/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/prevenção & controle , Osteoporose/tratamento farmacológico , Sinvastatina/uso terapêutico , Fosfatase Alcalina/sangue , Animais , Osso e Ossos/fisiologia , Cálcio/sangue , Dexametasona/toxicidade , Sinergismo Farmacológico , Osteoporose/induzido quimicamente , Fósforo/sangue , Ratos , Ratos Wistar , Ureia/sangueRESUMO
This study investigated the pathological morphofunctional adaptations related to the imbalance of exercise tolerance triggered by paraquat (PQ) exposure in rats. The rats were randomized into four groups with eight animals each: (a) SAL (control): 0.5 ml of 0.9% NaCl solution; (b) PQ10: PQ 10 mg/kg; (c) PQ20: PQ 20 mg/kg; and (d) PQ30: PQ 30 mg/kg. Each group received a single injection of PQ. After 72 hours, the animals were subjected to an incremental aerobic running test until fatigue in order to determine exercise tolerance, blood glucose and lactate levels. After the next 24 h, lung, liver and skeletal muscle were collected for biometric, biochemical and morphological analyses. The animals exposed to PQ exhibited a significant anticipation of anaerobic metabolism during the incremental aerobic running test, a reduction in exercise tolerance and blood glucose levels as well as increased blood lactate levels during exercise compared to control animals. PQ exposure increased serum transaminase levels and reduced the glycogen contents in liver tissue and skeletal muscles. In the lung, the liver and the skeletal muscle, PQ exposure also increased the contents of malondialdehyde, protein carbonyl, 8-hydroxy-2'-deoxyguanosine, superoxide dismutase and catalase, as well as a structural remodelling compared to the control group. All these changes were dose-dependent. Reduced exercise tolerance after PQ exposure was potentially influenced by pathological remodelling of multiple organs, in which glycogen depletion in the liver and skeletal muscle and the imbalance of glucose metabolism coexist with the induction of lipid, protein and DNA oxidation, a destructive process not counteracted by the upregulation of endogenous antioxidant enzymes.
Assuntos
Tolerância ao Exercício/efeitos dos fármacos , Herbicidas/administração & dosagem , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Paraquat/administração & dosagem , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Relação Dose-Resposta a Droga , Tolerância ao Exercício/fisiologia , Herbicidas/toxicidade , Ácido Láctico/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Insuficiência de Múltiplos Órgãos/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Estresse Oxidativo/fisiologia , Paraquat/toxicidade , Distribuição Aleatória , Ratos WistarRESUMO
The aim of this study was to investigate the effect of Naringin on pre-neoplastic colorectal lesions induced by chemical carcinogen in rats. Female Wistar rats weighing 130.8±27.1 g received weekly one subcutaneous injection of 1,2-dimethylhydrazine (DMH, 20 mg/kg) for 10 weeks. The animals were divided into 5 groups with 6 animals in each group. Group 1: 0.9% saline; Group 2: DMH+0.9% saline; Group 3: DMH+Naringin (10 mg/kg); Group 4: DMH+Naringin (100 mg/kg); Group 5: DMH+Naringin (200 mg/kg). G2 and G3 showed a significant increase in ACF number, AgNOR/nucleus and mitosis compared to G1. G4 and G5 presented a significant reduction in these parameters compared to G2. The number of cells producing acidic and neutral mucins, red blood cells and the level of antioxidant minerals, such as copper, magnesium, selenium and zinc, were significantly reduced in G2 and G3, but similar in G4 and G5 compared to G1. Naringin, especially at 200 mg/kg, was effective in reducing the number of pre-neoplastic lesions in rats exposed to DMH. Some of these effects may be due to reduction in cellular proliferation and tissue levels of iron together with the recovery of antioxidant mineral levels induced by this flavonoid.
Assuntos
Neoplasias Colorretais/prevenção & controle , Flavanonas/farmacologia , Lesões Pré-Cancerosas/prevenção & controle , 1,2-Dimetilidrazina/toxicidade , Animais , Carcinógenos/toxicidade , Neoplasias Colorretais/induzido quimicamente , Feminino , Camundongos , Microscopia Eletrônica de Varredura , Lesões Pré-Cancerosas/induzido quimicamente , Ratos , Ratos WistarRESUMO
Diabetic cardiomyopathy is associated with cardiac muscle remodeling, resulting in myocardial dysfunction, whereas exercise training (ET) is a useful nonpharmacological strategy for the therapy of cardiac diseases. This study tested the effects of low-intensity swimming-training on the structural remodeling of the left ventricle (LV) in growing rats with unmanaged experimental diabetes. Thirty-day-old male Wistar rats were divided into four groups (n=5/group): sedentary-control (SC), exercised-control (EC), sedentary-diabetic (SD), and exercised-diabetic (ED). Swimming-training rats exercised 5 days/week, 90min/day, with a load of 5% BW during 8 weeks. Sections of LV were stained with Periodic acid-Schiff, Sirius Red, and Gomori's reticulin. Seven days and 8 weeks after streptozotocin (STZ) induction (60mgkg(-1) BW), blood glucose (BG) in the diabetic groups (SD=581.40±40.48; ED=558.00±48.89) was greater (p<0.05) than in their controls (SC=88.80±21.70; EC=85.60±11.55). Swimming-training reduced BG by 23mg/dL in the diabetics (p>0.05). The LV of diabetic rats had increased interstitial collagen and reticular fibers on the extracellular matrix and presented glycogen accumulation. More importantly, all these adverse tissue changes induced by STZ were attenuated by ET. Together, these findings support the idea of a beneficial role of exercise in the LV remodeling in rats with unmanaged type-1 diabetes mellitus.
Assuntos
Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Condicionamento Físico Animal/fisiologia , Natação , Remodelação Ventricular/fisiologia , Animais , Cardiomiopatias Diabéticas/patologia , Eletrocardiografia , Imuno-Histoquímica , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND: This study investigates morphofunctional adaptations of the heart stroma and parenchyma in rats that are chronically infected with Trypanosoma cruzi. METHODS: Four-month-old male Wistar rats were randomized into control (n=14) and infected (n=14) groups. Infected animals were inoculated with T. cruzi Y strain. After 9 weeks, the animals were euthanized, and the right atrium (RA) and left ventricle (LV) were removed for biochemical, stereological, and cardiomyocyte mechanical analyses. RESULTS: Infected animals presented cardiomyocyte atrophy and myocardial fibrosis. For these animals, the total volume, length, surface area, and cross-sectional area of cardiomyocytes were significantly reduced, and the total interstitial and collagen volumes were significantly increased in the RA and LV compared to the controls. The total volume and length of blood vessels were significantly increased in the LV, and the total blood vessel surface area was significantly higher in the RA of infected animals. RA and LV cardiomyocytes from infected animals exhibited a significant reduction in cell shortening (43.02% and 24.98%, respectively), prolongation of the time to the peak of contraction (17.09%) and the time to half relaxation (23.68%) compared to non-infected animals. Lipid hydroperoxides, but not mineral concentrations, were significantly increased in the RA and LV from infected animals, showing an inverse correlation with cell shortening. CONCLUSIONS: T. cruzi infection induces global structural remodeling of the RA and LV in rats. This remodeling coexists with cardiomyocyte contractility dysfunction, which is possibly related to the abnormal organization of the myocardial stroma and increased cellular lipid peroxidation.
Assuntos
Forma Celular , Cardiomiopatia Chagásica/patologia , Miócitos Cardíacos/patologia , Células Estromais/patologia , Trypanosoma cruzi/patogenicidade , Remodelação Ventricular , Animais , Atrofia , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/fisiopatologia , Cardiomiopatia Chagásica/virologia , Vasos Coronários/patologia , Vasos Coronários/virologia , Modelos Animais de Doenças , Fibrose , Átrios do Coração/patologia , Átrios do Coração/virologia , Ventrículos do Coração/patologia , Ventrículos do Coração/virologia , Peroxidação de Lipídeos , Masculino , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/virologia , Ratos , Ratos Wistar , Células Estromais/metabolismo , Células Estromais/virologia , Fatores de Tempo , VirulênciaAssuntos
Cardiomiopatia Chagásica/metabolismo , Metais/análise , Minerais/análise , Miocárdio/química , Trypanosoma cruzi , Animais , Cálcio , Cardiomiopatia Chagásica/parasitologia , Cobre , Magnésio , Masculino , Microscopia Eletrônica de Varredura , Miocárdio/metabolismo , Potássio , Ratos , Ratos Wistar , Selênio , Sódio , Espectrometria por Raios X , ZincoRESUMO
Phenolic compounds are naturally occurring, bioactive substances with marked antioxidant and anti-inflammatory potential. The flavonoid chrysin, found in high levels in honey bee propolis, inhibits the activity of enzymes involved in carcinogenesis. We have investigated the effect of chrysin on pre-neoplastic colorectal lesions (ACF, aberrant crypt foci) in a rat model of chemical carcinogenesis induced by 1,2-dimethylhydrazine (DMH). Female Wistar rats weighing 137.2 ± 24.3 g received weekly one subcutaneous injection of DMH (20 mg/kg) for 10 weeks. The animals were divided into five groups each with seven animals: Group 1, 0.9% saline; Group 2, DMH+0.9% saline; Group 3, DMH+chrysin (10 mg/kg); Group 4, DMH+chrysin (100 mg/kg); Group 5, DMH+chrysin (200 mg/kg). Groups 2 and 3 showed a significant increase in ACF number, nucleolus organizer regions per enterocyte nucleus and nitrite/nitrate serum levels compared with Group 1. Groups 4 and 5 presented a significant reduction in all these parameters compared with Group 2. The levels of antioxidant minerals (copper, magnesium, selenium, zinc) and the number of enteroendocrine and mucin-producing cells were significantly reduced in Groups 2 and 3 but were similar in Groups 4 and 5 compared with Group 1. Chrysin, at 100 mg/kg and 200 mg/kg, was effective in attenuating pathological colorectal remodeling, reducing the number of pre-neoplastic lesions in rats exposed to DMH. Some of these effects might be attributable to the recovery of antioxidant mineral levels, a reduction in systemic nitrosative stress and an inhibition of the cellular proliferation induced by this flavonoid.
Assuntos
Colo/efeitos dos fármacos , Neoplasias Colorretais/prevenção & controle , Flavonoides/farmacologia , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/tratamento farmacológico , Reto/efeitos dos fármacos , 1,2-Dimetilidrazina , Animais , Carcinógenos , Colo/enzimologia , Colo/patologia , Neoplasias Colorretais/induzido quimicamente , Feminino , Lesões Pré-Cancerosas/patologia , Ratos , Ratos Wistar , Reto/enzimologia , Reto/patologiaRESUMO
This study investigated the effects of Trypanosoma cruzi infection on pancreatic morphology and glucose metabolism at rest and during exercise. Wistar rats were randomized into control (CG=10) and infected (IG=10) groups. The IG animals were inoculated with T. cruzi Y strain (300,000 trypomastigotes/50 g). After 9 weeks, the animals were subjected to glucose (OGTT) and insulin (ITT) tolerance tests and a treadmill running protocol. Blood glucose, lactate and time to fatigue were determined. After euthanasia, the pancreases were removed for morphological and biochemical analyses. The IG presented abnormal glucose kinetics in OGTT and a similar glucose curve in ITT compared to the CG. During the exercise test, the IG showed anticipation of time to fatigue. At the point of fatigue, no difference was found in blood glucose and lactate between the groups. There was a significant correlation between lactate levels and the time to fatigue. The IG presented marked pancreatic inflammation, fibrosis and protein oxidation. The number of ß cells in the IG animals was not reduced. T. cruzi infection impaired pancreas morphology and glucose metabolism at rest and during exercise in rats, which could constitute an additional mechanism in the induction of exercise intolerance in Chagas' disease.
Assuntos
Glicemia/metabolismo , Doença de Chagas/sangue , Ilhotas Pancreáticas/patologia , Doenças Parasitárias em Animais/sangue , Condicionamento Físico Animal/fisiologia , Trypanosoma cruzi/fisiologia , Animais , Doença de Chagas/parasitologia , Modelos Animais de Doenças , Teste de Esforço , Fibrose/patologia , Teste de Tolerância a Glucose , Ilhotas Pancreáticas/metabolismo , Masculino , Estresse Oxidativo , Doenças Parasitárias em Animais/parasitologia , Carbonilação Proteica/fisiologia , Ratos , Ratos Wistar , Descanso/fisiologiaRESUMO
3,4-Dihydroxycinnamic acid (3,4-DA) is a natural compound with high antioxidant potential found in various foods. This study found that animals administered with 3,4-DA had higher exercise tolerance, reduced blood lactate, and markers of hepatic oxidation. Blood glucose and antioxidant enzymes were not affected by this treatment. 3,4-DA may have applicability in reducing the fatigue associated with exercise.
Assuntos
Antioxidantes/administração & dosagem , Ácidos Cafeicos/administração & dosagem , Tolerância ao Exercício/efeitos dos fármacos , Fadiga/prevenção & controle , Administração Oral , Animais , Glicemia/análise , Tolerância ao Exercício/fisiologia , Fadiga/metabolismo , Lactatos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Condicionamento Físico Animal , Ratos , Ratos WistarRESUMO
The aim of this study was to investigate the effects of Trypanosoma cruzi (T. cruzi) infection on myocardial morphology, single cardiomyocyte contractile function and exercise tolerance in rats. Adult Wistar rats were randomized into control (n = 14) and infected (n = 14) groups. Infected animals were inoculated with T. cruzi Y strain (300,000 trypomastigotes/50 g body weight). After 9 weeks, the animals were subjected to a treadmill running protocol. Then, the right atrium (RA) and left ventricle (LV) were removed for morphological and cell contractile evaluation. The infected animals exhibited a significant reduction in distance travelled, total time to fatigue and workload. In addition, these animals had hypertrophy, increased myocardial cellularity, and an increase in the proportion of collagen and blood vessels. RA and LV myocytes from infected animals showed marked contractile dysfunction under basal conditions and a reduced contractile response to ß-adrenergic stimulation. The workload of infected animals was correlated closely with the amplitude of cell shortening of RA and LV myocytes. T. cruzi infection influenced the myocardial morphology and the mechanical properties of RA and LV single myocytes negatively and reduced exercise tolerance. Single cardiomyocyte contractile dysfunction could constitute an additional mechanism of cardiac impairment and reduced exercise tolerance in this infection.