RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia tirucalli L. is an African plant that grows well in Brazil. Individuals diagnosed with cancer frequently consume latex from E. tirucalli, dissolved in drinking water. In vitro studies confirm the antitumor potential of E. tirucalli latex, but in vivo evaluations are scarce. AIM OF THE STUDY: To evaluate the effect of intake of an aqueous solution of E. tirucalli latex on tumor growth, cachexia, and immune response in Walker 256 tumor-bearing rats. MATERIALS AND METHODS: Latex from E. tirucalli was collected and analyzed by LC-MS. Sixty male Wistar rats (age, 90 days) were randomly divided into four groups: C, control group (without tumor); W, Walker 256 tumor-bearing group; SW1, W animals but treated with 25⯵L latex/mL water; and SW2, W animals but treated with 50⯵L latex/mL water. Animals received 1â¯mL of latex solution once a day by gavage. After 15â¯d, animals were euthanized, tumor mass was determined, and glucose and triacylglycerol serum levels were measured by using commercial kits. Change in the body weight during tumor development was calculated, and proliferation capacity of tumor cells was assessed by the Alamar Blue assay. Phagocytosis and superoxide anion production by peritoneal macrophages and circulating neutrophils were analyzed by enzymatic and colorimetric assays. Data are analyzed by one-way ANOVA followed by Tukey's post-hoc test, with the significance level set at 5%. RESULTS: The analysis of the latex revealed the presence of triterpenes. The ingestion of the latex aqueous solution promoted 40% and 60% reduction of the tumor mass in SW1 and SW2 groups, respectively (pâ¯<â¯0.05). The proliferative capacity of tumor cells from SW2 group was 76% lower than that of cells from W group (pâ¯<â¯0.0001). Animals treated with latex gained, on average, 20â¯g (SW1) and 8â¯g (SW2) weight. Glucose and triacylglycerol serum levels in SW1 and SW2 animals were similar to those in C group rats. Peritoneal macrophages and blood neutrophils from SW1 and SW2 animals produced 30-40% less superoxide anions than those from W group animals (pâ¯<â¯0.05), but neutrophils from SW2 group showed an increased phagocytic capacity (20%, vs. W group). CONCLUSIONS: E. tirucalli latex, administered orally for 15â¯d, efficiently reduced tumor growth and cachexia in Walker 256 tumor-bearing rats. Decreased tumor cell proliferative capacity was one of the mechanisms involved in this effect. Further, the data suggest immunomodulatory properties of E. tirucalli latex. The results agree with folk data on the antitumor effect of latex ingestion, indicating that it may be useful as an adjunct in the treatment of cancer patients. For this, further in vivo studies in animal and human models need to be conducted.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Caquexia/prevención & control , Carcinoma 256 de Walker/tratamiento farmacológico , Euphorbia , Látex/farmacología , Extractos Vegetales/farmacología , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Caquexia/sangre , Caquexia/inmunología , Caquexia/fisiopatología , Carcinoma 256 de Walker/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Euphorbia/química , Látex/aislamiento & purificación , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Extractos Vegetales/aislamiento & purificación , Ratas Wistar , Triglicéridos/sangre , Carga Tumoral/efectos de los fármacos , Pérdida de Peso/efectos de los fármacosRESUMEN
Cancer cachexia is characterised by involuntary weight loss associated with systemic inflammation and metabolic changes. Studies aimed at maintaining lean body mass in cachectic tumour-bearing hosts have made important contributions reducing the number of deaths and improving the quality of life. In recent years, leucine has demonstrated effective action in maintaining lean body mass by decreasing muscle protein degradation. Currently, there is a growing need to understand how leucine stimulates protein synthesis and acts protectively in a cachectic organism. Thus, this study aimed to assess the effects of a leucine-rich diet on protein degradation signalling in muscle over the course of tumour growth. Animals were distributed into four experimental groups, which did or did not receive 2×106 viable Walker-tumour cells. Some were fed a leucine-rich diet, and the groups were subsequently sacrificed at three different time points of tumour evolution (7th, 14th, and 21st days). Protein degradation signals, as indicated by ubiquitin-proteasome subunits (11S, 19S, and 20S) and pro- and anti-inflammatory cytokines, were analysed in all experimental groups. In tumour-bearing animals without nutritional supplementation (W7, W14, and W21 groups), we observed that the tumour growth promoted a concurrent decrease in muscle protein, a sharp increase in pro-inflammatory cytokines (TNFα, IL-6, and IFNγ), and a progressive increase in proteasome subunits (19S and 20S). Thus, the leucine-supplemented tumour-bearing groups showed improvements in muscle mass and protein content, and in this specific situation, the leucine-rich diet led to an increase on the day in cytokine profile and proteasome subunits mainly on the 14th day, which subsequently had a modulating effect on tumour growth on the 21st day. These results indicate that the presence of leucine in the diet may modulate important aspects of the proteasomal pathway in cancer cachexia and may prevent muscle wasting due to the decrease in the cachexia index.
Asunto(s)
Carcinoma 256 de Walker/inmunología , Citocinas/sangre , Suplementos Dietéticos , Leucina/administración & dosificación , Músculo Esquelético/metabolismo , Proteínas/metabolismo , Animales , Composición Corporal , Caquexia/sangre , Caquexia/inmunología , Carcinoma 256 de Walker/metabolismo , Citocinas/biosíntesis , Citocinas/inmunología , Dieta , Inflamación , Interleucina-4/sangre , Interleucina-6/sangre , Músculo Esquelético/química , Biosíntesis de Proteínas , Calidad de Vida , Ratas , Ratas WistarRESUMEN
The aim of this study was to investigate the effects of resistance exercise training (RET) on oxidative stress, systemic inflammatory markers, and muscle wasting in Walker-256 tumor-bearing rats. Male (Wistar) rats were divided into 4 groups: sedentary controls (n = 9), tumor-bearing (n = 9), exercised (n = 9), and tumor-bearing exercised (n = 10). Exercised and tumor-bearing exercised rats were exposed to resistance exercise of climbing a ladder apparatus with weights tied to their tails for 6 weeks. The physical activity of control and tumor-bearing rats was confined to the space of the cage. After this period, tumor-bearing and tumor-bearing exercised animals were inoculated subcutaneously with Walker-256 tumor cells (11.0 × 107 cells in 0.5 mL of phosphate-buffered saline) while control and exercised rats were injected with vehicle. Following inoculation, rats maintained resistance exercise training (exercised and tumor-bearing exercised) or sedentary behavior (control and tumor-bearing) for 12 more days, after which they were euthanized. Results showed muscle wasting in the tumor-bearing group, with body weight loss, increased systemic leukocytes, and inflammatory interleukins as well as muscular oxidative stress and reduced mTOR signaling. In contrast, RET in the tumor-bearing exercised group was able to mitigate the reduced body weight and muscle wasting with the attenuation of muscle oxidative stress and systemic inflammatory markers. RET also prevented loss of muscle strength associated with tumor development. RET, however, did not prevent the muscle proteolysis signaling via FBXO32 gene messenger RNA expression in the tumor-bearing group. In conclusion, RET performed prior tumor implantation prevents cachexia development by attenuating tumor-induced systemic pro-inflammatory condition with muscle oxidative stress and muscle damage.
Asunto(s)
Caquexia/prevención & control , Carcinoma 256 de Walker/terapia , Leucocitosis/prevención & control , Debilidad Muscular/prevención & control , Músculo Esquelético/fisiopatología , Estrés Oxidativo , Condicionamiento Físico Animal , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Caquexia/etiología , Caquexia/inmunología , Carcinoma 256 de Walker/metabolismo , Carcinoma 256 de Walker/patología , Carcinoma 256 de Walker/fisiopatología , Citocinas/sangre , Regulación Neoplásica de la Expresión Génica , Mediadores de Inflamación/sangre , Leucocitosis/etiología , Leucocitosis/inmunología , Masculino , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Debilidad Muscular/etiología , Debilidad Muscular/inmunología , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distribución Aleatoria , Ratas Wistar , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Carga Tumoral , Aumento de Peso , Pérdida de PesoRESUMEN
White adipose tissue (WAT) is no longer considered a tissue whose main function is the storage of TAG. Since the discovery of leptin in 1994, several studies have elucidated the important role of WAT as an endocrine organ, the source of the adipokines. The low-grade inflammation observed in obese and cancer cachexia patients is explained, at least partially, by the exacerbated release of proinflammatory adipokines. Despite of the recent progress in the characterization of the various adipokines and lipokines produced by WAT, little is known about the mechanisms regulating the secretion of these molecules in different physiological and pathological circumstances. Chronic exercise is a nonpharmacological therapy employed in several chronic diseases and shows an anti-inflammatory effect through the regulation of the cytokine network. In this review, we address the potential mechanisms by which the aerobic physical exercise modulate the production and release of inflammatory adipokines, as well as the inflammation-lipolysis axis in WAT, with special focus in the therapeutic role of exercise in obesity-associated insulin resistance and cancer cachexia.
Asunto(s)
Caquexia/fisiopatología , Ejercicio Físico , Inflamación , Neoplasias/fisiopatología , Obesidad/fisiopatología , Tejido Adiposo Blanco/inmunología , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/fisiopatología , Caquexia/etiología , Caquexia/inmunología , Caquexia/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Humanos , Neoplasias/complicaciones , Neoplasias/inmunología , Neoplasias/metabolismo , Obesidad/inmunología , Obesidad/metabolismoRESUMEN
Wasting is a prominent feature in tuberculosis (TB), but its underlying mechanisms are incompletely understood. Immunoendocrine disturbances may be linked to the consumption state of TB patients, since hormones and cytokines can affect energy expenditure and metabolism. To approach this possibility, we have determined leptin, IL-18, and adrenal steroid plasma levels and body mass index (BMI) in newly diagnosed patients with mild, moderate and severe pulmonary TB, household contacts (HHC), and healthy controls (HCO). HHC displayed higher levels of leptin than HCO and TB patients. TB patients showed a gradual decrease in BMI and leptin concentrations with increasing disease severity, whereas a positive correlation between this hormone and BMI was found in the HCO group. Cortisol concentrations tended to be higher in TB patients. DHEA levels were decreased in TB patients and to a lesser extent in HHC, whereas IL-18 concentration was significantly increased in patients with severe disease. Since HHC are known to cause a latent subclinical infection, it seems clear that controlled tuberculous infection and manifested TB disease are accompanied by a dissimilar profile of immunoendocrine markers.
Asunto(s)
Caquexia/inmunología , Neuroinmunomodulación/fisiología , Sistemas Neurosecretores/inmunología , Tuberculosis/complicaciones , Tuberculosis/inmunología , Adulto , Biomarcadores/análisis , Biomarcadores/sangre , Índice de Masa Corporal , Caquexia/microbiología , Caquexia/fisiopatología , Femenino , Humanos , Hidrocortisona/análisis , Hidrocortisona/sangre , Interleucina-18/análisis , Interleucina-18/sangre , Leptina/análisis , Leptina/sangre , Masculino , Sistemas Neurosecretores/fisiopatología , Esteroides/análisis , Esteroides/sangre , Tuberculosis/fisiopatologíaRESUMEN
The yeast Candida albicans belongs to the microflora of healthy individuals, although it can infect a variety of tissues ensuing changes in the host's immune status. To evaluate the effect of neuroendocrine input on the early immune response during the fungal infection, we use a 3-day paradigm of chronic varied stress in Wistar rats infected with C. albicans. We find that stress mediators contribute to the spread of the fungus and downregulate critical functions of phagocytic cells at the infection site. Phenotypic and functional alterations of effector cells account for the decreased resistance to candidiasis and condition the development of the adaptive response. Stressed hosts exhibit a higher fungal burden in kidneys and livers associated with hyphal forms. The hepatic inflammatory reaction is compromised with severe steatosis, increment of functional enzymes, marked lipid peroxidation and hepatocyte apoptosis. Moreover, infection-related sickness symptoms are significantly increased by exposure to stress with anorexia, weight loss, lack of leptin and depletion of glycogen depots. Food deprivation exacerbates the liver injury. Stress mediators perturb the complex immune and metabolic program that operates early during fungal spread and promotes severe tissue damage.
Asunto(s)
Tolerancia Inmunológica/inmunología , Huésped Inmunocomprometido/inmunología , Micosis/inmunología , Sistemas Neurosecretores/inmunología , Inmunidad Adaptativa/inmunología , Animales , Caquexia/inmunología , Caquexia/metabolismo , Caquexia/fisiopatología , Modelos Animales de Enfermedad , Hepatitis/inmunología , Hepatitis/metabolismo , Hepatitis/fisiopatología , Humanos , Inmunidad Innata/inmunología , Inmunocompetencia/fisiología , Micosis/fisiopatología , Ratas , Estrés Psicológico/inmunologíaRESUMEN
Fish oil supplementation has been shown to improve the cachectic state of tumor-bearing animals and humans. Our previous study showed that fish oil supplementation (1 g per kg body weight per day) for 2 generations had anticancer and anticachetic effects in Walker 256 tumor-bearing rats as demonstrated by reduced tumor growth and body weight loss and increased food intake and survival. In this study, the effect of fish oil supplementation for 2 generations on membrane integrity, proliferation capacity, and CD4/CD8 ratio of lymphocytes isolated from mesenteric lymph nodes, spleen, and thymus of Walker 256 tumor-bearing animals was investigated. We also determined fish oil effect on plasma concentration and ex vivo production of cytokines [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-6, and IL-10]. Lymphocytes from thymus of tumor-bearing rats presented lower viability, but this change was abolished by fish oil supplementation. Tumor growth increased proliferation of lymphocytes from all lymphoid organs, and fish oil supplementation abolished this effect. Ex vivo production of TNF-alpha and IL-6 was reduced in supplemented animals, but IL-4 and IL-10 secretion was stimulated in both nontumor and tumor-bearing rats. IL-10 and IFN-gamma plasma levels was also decreased in supplemented animals. These results suggest that the anticachetic effects of fish oil supplementation for a long period of time (2 generations) in Walker 256 tumor-bearing rats may be associated to a decrease in lymphocyte function as demonstrated by reduced viability, proliferation capacity, and cytokine production.
Asunto(s)
Anticarcinógenos/administración & dosificación , Caquexia/prevención & control , Carcinoma 256 de Walker/complicaciones , Carcinoma 256 de Walker/fisiopatología , Aceites de Pescado/administración & dosificación , Activación de Linfocitos , Linfocitos/fisiología , Animales , Caquexia/etiología , Caquexia/inmunología , Carcinoma 256 de Walker/inmunología , Carcinoma 256 de Walker/mortalidad , Membrana Celular/metabolismo , Proliferación Celular , Supervivencia Celular , Citocinas/sangre , Citocinas/metabolismo , Femenino , Ganglios Linfáticos/citología , Activación de Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Trasplante de Neoplasias , Ratas , Ratas Wistar , Bazo/citología , Timo/citología , Timo/metabolismo , Pérdida de PesoRESUMEN
The effect of coconut fat (rich in medium saturated fatty acids) or fish oil (rich in omega-3 polyunsaturated fatty acids) supplementation for 2 generations on tumor growth, cancer cachexia, animal survival and macrophage function was investigated in Walker 256 tumor-bearing rats. Female Wistar rats were supplemented with coconut fat or fish oil prior to mating and then throughout pregnancy and gestation. Both supplementations were daily and orally given at 1 g per kg body weight as a single bolus. Same treatment was performed by the 2 following generations. At 90 days of age, male offspring (50%) from F2 generation were subcutaneously inoculated with 2 x 10(7) Walker 256 tumor cells. At 14 days after tumor implantation, rats not supplemented displayed cancer cachexia characterized by loss of body weight, hypoglycemia, hyperlacticidemia, hypertriglyceridemia, decreased food intake and depletion of glycogen stores in the liver and skeletal muscles. Supplementation with coconut fat did not affect these parameters. However, supplementation with fish oil decreased tumor growth (59%), prevented body weight loss and food intake reduction and attenuated cancer cachexia. In addition, fish oil increased animal survival up to 20 days (from 25% in rats not supplemented to 67% in rats supplemented with fish oil) and improved macrophage function characterized by increased phagocytosis capacity and production of hydrogen peroxide and nitric oxide. These results suggest that fish oil supplementation for 2 generations improves macrophage function in association to reduced tumor growth and attenuated cancer cachexia, maintaining food intake and increasing animal survival.
Asunto(s)
Caquexia/inmunología , Caquexia/prevención & control , Carcinoma 256 de Walker/complicaciones , Aceites de Pescado/administración & dosificación , Macrófagos Peritoneales/efectos de los fármacos , Animales , Glucemia/análisis , Peso Corporal/efectos de los fármacos , Caquexia/etiología , Aceite de Coco , Ingestión de Alimentos/efectos de los fármacos , Ácidos Grasos Omega-3/análisis , Femenino , Aceites de Pescado/química , Glucógeno/análisis , Hipertrigliceridemia/prevención & control , Hipoglucemia/prevención & control , Ácido Láctico/sangre , Glucógeno Hepático/análisis , Músculo Esquelético/química , Fagocitosis , Aceites de Plantas/administración & dosificación , Ratas , Ratas WistarRESUMEN
It is commonly accepted that moderate intensity exercise is beneficial to the immune system. We tested the influence of a moderate intensity training protocol (8 weeks) upon immune system function in Wistar tumour-bearing (TB) rats. The metabolism of glucose and glutamine in lymphocytes and macrophages was assessed, together with some functional parameters (hydrogen peroxide production and lymphocyte proliferative response). These substrates were chosen since they represent the most important energetic and synthetic metabolites for these cellular types. The training protocol caused a decrease of 17.4 per cent in the production of H(2)O(2) by macrophages, as well as a decrease in glucose consumption (25 per cent) and lactate production (47.1 per cent), and an increase in the production of labelled CO(2) from the oxidation of [U-(14)C]-glucose, in TB rats. The training protocol was also able to induce changes in the maximal activity of some key enzymes in the metabolism of glucose and glutamine, a reduction of hexokinase (68.8 per cent) activity and an increase in the activity of citrate synthase (10.1 per cent) in TB rats. The training protocol increased the proliferative response of lymphocytes cultivated in the absence of mitogens (75 per cent), of those cultivated in the presence of ConA (38.2 per cent) and in the presence of LPS (45.0 per cent). These cells also showed an increase in the maximal activity of some key enzymes of the glycolytic and glutaminolytic pathways. Our data demonstrated that the training protocol was able to induce an increase in aerobic utilisation of both substrates in lymphocytes and macrophages. The training protocol was also able to prevent several changes in glucose and glutamine metabolism that are normally present in sedentary TB rats. These changes in immune cell metabolism induced by the training protocol were able to increase TB rat survival.
Asunto(s)
Caquexia/inmunología , Carcinoma 256 de Walker/inmunología , Linfocitos/metabolismo , Macrófagos/metabolismo , Condicionamiento Físico Animal , Animales , Caquexia/mortalidad , Caquexia/terapia , Carcinoma 256 de Walker/mortalidad , Carcinoma 256 de Walker/terapia , Glucosa/metabolismo , Glutamina/metabolismo , Peróxido de Hidrógeno/metabolismo , Lactatos/metabolismo , Activación de Linfocitos , Masculino , Fagocitosis , Ratas , Ratas WistarRESUMEN
Parasitic infections and malnutrition coexist in many tropical and subtropical areas. Studies of Leishmania donovani and of experimentally infected Syrian hamsters have provided important insights into the complex interrelationships between malnutrition and this parasitic disease. Malnutrition, which adversely affects cell-mediated immunity, is associated with the development of visceral leishmaniasis (kala-azar) in children living in endemic areas. In turn, L. donovani can cause wasting as well as hepatosplenomegaly, fever, and anemia. Syrian hamsters infected with L. donovani develop a disease that is comparable to that of humans with kala-azar. Weight loss in infected hamsters is associated with splenic macrophage secretion of potentially catabolic cytokines as measured by the D10.G4.1 assay for interleukin-1 and the L929 cytotoxicity assay for tumor necrosis factor/cachectin. Although decreased food intake contributes to wasting in infected hamsters, studies of skeletal muscle function indicate that it is not the sole factor. Leishmania donovani-infected hamsters have also been used to study drugs with the potential to prevent or reverse cachexia.
Asunto(s)
Caquexia/fisiopatología , Leishmaniasis Visceral/fisiopatología , Tejido Adiposo , Animales , Brasil , Caquexia/inmunología , Niño , Trastornos de la Nutrición del Niño/inmunología , Trastornos de la Nutrición del Niño/fisiopatología , Preescolar , Cricetinae , Modelos Animales de Enfermedad , Humanos , Interleucina-1/biosíntesis , Leishmaniasis Visceral/inmunología , Mesocricetus , Trastornos Nutricionales/inmunología , Trastornos Nutricionales/fisiopatología , Desnutrición Proteico-Calórica/inmunología , Desnutrición Proteico-Calórica/fisiopatología , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
1. Newborn anthymic nude rats, innoculated with KB human tumor, normally develop a great level of tumoral taken. With the augmentation in volume of the tumoral mass, animals may enter in a cachetic state that leads them to death. 2. However, proportionally to the total of days of observation, the number of rats that enter in cachexia was significantly greater than in the group that did not develop growth of tumoral mass post-innoculum. 3. This fact may suggest that any factor produced by the organism, in an excessive amount, with the aim to hinder the development of the tumoral mass, ha d a parallel effect strondgly cachetizing. 4. Relevant is the fact that the production of this substance may be thymus-independent, since these animals are congenitally athymic