Leucine-Rich Diet Improved Muscle Function in Cachectic Walker 256 Tumour-Bearing Wistar Rats.

Skeletal muscle atrophy occurs in several pathological conditions, such as cancer, especially during cancer-induced cachexia. This condition is associated with increased morbidity and poor treatment response, decreased quality of life, and increased mortality in cancer patients. A leucine-rich diet could be used as a coadjutant therapy to prevent muscle atrophy in patients suffering from cancer cachexia. Besides muscle atrophy, muscle function loss is even more important to patient quality of life. Therefore, this study aimed to investigate the potential beneficial effects of leucine supplementation on whole-body functional/movement properties, as well as some markers of muscle breakdown and inflammatory status. Adult Wistar rats were randomly distributed into four experimental groups. Two groups were fed with a control diet (18% protein): Control (C) and Walker 256 tumour-bearing (W), and two other groups were fed with a leucine-rich diet (18% protein + 3% leucine): Leucine Control (L) and Leucine Walker 256 tumour-bearing (LW). A functional analysis (walking, behaviour, and strength tests) was performed before and after tumour inoculation. Cachexia parameters such as body weight loss, muscle and fat mass, pro-inflammatory cytokine profile, and molecular and morphological aspects of skeletal muscle were also determined. As expected, Walker 256 tumour growth led to muscle function decline, cachexia manifestation symptoms, muscle fibre cross-section area reduction, and classical muscle protein degradation pathway activation, with upregulation of FoxO1, MuRF-1, and 20S proteins. On the other hand, despite having no effect on the walking test, inflammation status or muscle oxidative capacity, the leucine-rich diet improved muscle strength and behaviour performance, maintained body weight, fat and muscle mass and decreased some protein degradation markers in Walker 256 tumour-bearing rats. Indeed, a leucine-rich diet alone could not completely revert cachexia but could potentially diminish muscle protein degradation, leading to better muscle functional performance in cancer cachexia.

Does l-glutamine-supplemented diet extenuate NO-mediated damage on myenteric plexus of Walker 256 tumor-bearing rats?

This study was designed to appraise the relationship between enteric neuropathy and oxidative stress in cancer cachexia under l-glutamine-supplemented diet. Total and nitrergic neuronal populations were investigated in jejunum and ileum in four experimental groups: control (C); control l-glutamine-supplemented diet (CG); Walker-256 tumor (TW); and Walker-256 tumor supplemented with l-glutamine (TWG). In addition, local oxidative stress, neuronal nitric oxide synthase (nNOS) enzyme and nitric oxide (NO) levels were evaluated. Neuronal density and somatic area of the total and nitrergic populations were reduced in TW rats, which was accompanied by high oxidative stress, NO and nNOS levels. l-glutamine supplementation prevented neuronal atrophy, changes in pan neuronal density and nNOS overexpression (ileum), and restored total antioxidant capacity. Nevertheless, the oxidative stress was partially mitigated and no effect was observed on the reduction of nitrergic population and NO levels. l-glutamine-supplemented diet extenuates NO-mediated damage on the myenteric plexus although has a small benefit on oxidative stress.

Applicability of the direct parameters of bioelectrical impedance in assessing nutritional status and surgical complications of women with gynecological cancer.

BACKGROUND/OBJECTIVES: Bioelectrical impedance vector analysis (BIVA) has been considered a promising technique in monitoring the nutritional and hydration status of patients with different types of diseases. The aim of this study was to assess the nutritional status provided by direct parameters of bioelectrical impedance analysis (BIA), BIVA and phase angle (PA), in patients with cervical and endometrial cancer undergoing surgical treatment, associating to other parameters of nutritional status and surgical outcomes. SUBJECTS/METHODS: In a prospective cohort, 208 women eligible to surgical treatment, admitted from January to December 2015, were enrolled. Patients were assessed according to the body mass index (BMI), Patient Generated Subjective Global Assessment (PG-SGA) and BIA. The PA was categorized as below and above percentiles 25 and 50 of studied population. RESULTS: According to BMI and PG-SGA, most of them were classified as obese (69%) and well nourished (84%), respectively. PA was significantly lower in patients with endometrial cancer, PG-SGA B or C, and in those who remained longer in hospital. PA below 25th percentile was also associated with surgical complications. Comparison of BIVA detachment of our population with a reference population showed significant impedance vector displacement, characterized by decreased reactance value and increased resistance value in our group of patients. CONCLUSIONS: PA was associated with other parameters of nutritional status and surgical outcomes. BIVA was associated with nutritional status and length of hospital, but did not present significant result for surgical complications.

Fat-free mass depletion in patients with COPD in Brazil: development of a new cutoff point and its relation with mortality and extrapulmonary manifestations.

BACKGROUND/OBJECTIVES: None of the cutoff points for fat-free mass index (FFMI) were tested for the Brazilian population, and it is unknown whether the available ones are able to discriminate extrapulmonary disease manifestations. This cross-sectional study aims to develop and validate a cutoff point for FFM depletion based on Brazilian patients with chronic obstructive pulmonary disease (COPD) and to verify its association and of previously published cutoffs with extrapulmonary manifestations. SUBJECTS/METHODS: A new cutoff point was obtained from the best FFMI value for discrimination of preserved exercise capacity in a sample of patients (n=57). The discriminative capacity was assessed in another sample (n=96). The new cutoff point and other previously published ones were tested to discriminate low exercise capacity, physical inactivity, sedentary lifestyle and low quality of life. A receiver operation characteristics curve with area under the curve (AUC) value was plotted and each cutoff points' discriminative capacity was calculated. Cox regression and Kaplan-Meier method assessed the association between the cutoff points and mortality. RESULTS: The new cutoff points for FFMI were 14.65 kg/m2 for women (AUC=0.744; sensitivity (Se)=0.88; specificity (Sp)=0.60) and 20.35 kg/m2 for men (AUC=0.565; Se=0.36; Sp=0.81). The new cutoffs were the best to discriminate poor exercise capacity assessed by walked distance in % predicted and quality of life. Only the new cutoff point was associated with mortality (HR=2.123; 95% CI: 1.03-4.33, P=0.039, log rank P=0.035). CONCLUSIONS: Only the new cutoff point was associated with all-cause mortality, and it had the highest discriminating capacity for exercise capacity and quality of life in Brazilian patients with COPD.

Leucine-rich diet alters the 1H-NMR based metabolomic profile without changing the Walker-256 tumour mass in rats.

BACKGROUND: Cachexia is one of the most important causes of cancer-related death. Supplementation with branched-chain amino acids, particularly leucine, has been used to minimise loss of muscle tissue, although few studies have examined the effect of this type of nutritional supplementation on the metabolism of the tumour-bearing host. Therefore, the present study evaluated whether a leucine-rich diet affects metabolomic derangements in serum and tumour tissues in tumour-bearing Walker-256 rats (providing an experimental model of cachexia). METHODS: After 21 days feeding Wistar female rats a leucine-rich diet, distributed in L-leucine and LW-leucine Walker-256 tumour-bearing groups, we examined the metabolomic profile of serum and tumour tissue samples and compared them with samples from tumour-bearing rats fed a normal protein diet (C - control; W - tumour-bearing groups). We utilised 1H-NMR as a means to study the serum and tumour metabolomic profile, tumour proliferation and tumour protein synthesis pathway. RESULTS: Among the 58 serum metabolites examined, we found that 12 were altered in the tumour-bearing group, reflecting an increase in activity of some metabolic pathways related to energy production, which diverted many nutrients toward tumour growth. Despite displaying increased tumour cell activity (i.e., higher Ki-67 and mTOR expression), there were no differences in tumour mass associated with changes in 23 metabolites (resulting from valine, leucine and isoleucine synthesis and degradation, and from the synthesis and degradation of ketone bodies) in the leucine-tumour group. This result suggests that the majority of nutrients were used for host maintenance. CONCLUSION: A leucine rich-diet, largely used to prevent skeletal muscle loss, did not affect Walker 256 tumour growth and led to metabolomic alterations that may partially explain the positive effects of leucine for the whole tumour-bearing host.

Supplementation with L-glutamine prevents tumor growth and cancer-induced cachexia as well as restores cell proliferation of intestinal mucosa of Walker-256 tumor-bearing rats.

This study aimed to evaluate the intestinal mucosa of the duodenum and jejunum of Walker-256 tumor-bearing rats supplemented with L-glutamine. Thirty-two male 50-day-old Wistar rats (Rattus norvegicus) were randomly divided into four groups: control (C), control supplemented with 2 % L-glutamine (GC), Walker-256 tumor (WT), and Walker-256 tumor supplemented with 2 % L-glutamine (TWG). Walker-256 tumor was induced by inoculation viable tumor cells in the right rear flank. After 10 days, celiotomy was performed and duodenal and jejunal tissues were removed and processed. We evaluated the cachexia index, proliferation index, villus height, crypt depth, total height of the intestinal wall, and number of goblet cells by the technique of periodic acid-Schiff (PAS). Induction of Walker-256 tumor promoted a reduction of metaphase index in the TW group animals, which was accompanied by a reduction in the villous height and crypt depths, resulting in atrophy of the intestinal wall as well as increased PAS-positive goblet cells. Supplementation with L-glutamine reduced the tumor growth and inhibited the development of the cachectic syndrome in animals of the TWG group. Furthermore, amino acid supplementation promoted beneficial effects on the intestinal mucosa in the TWG animals through restoration of the number of PAS-positive goblet cells. Therefore, supplementation with 2 % L-glutamine exhibited a promising role in the prevention of tumor growth and cancer-associated cachexia as well as restoring the intestinal mucosa in the duodenum and jejunum of Walker-256 tumor-bearing rats.

Antitumor and anti-cachectic effects of shark liver oil and fish oil: comparison between independent or associative chronic supplementation in Walker 256 tumor-bearing rats.

BACKGROUND: Shark liver oil (SLOil) and fish oil (FOil), which are respectively rich in alkylglycerols (AKGs) and n-3 polyunsaturated fatty acids (PUFAs), are able to reduce the growth of some tumors and the burden of cachexia. It is known that FOil is able to reduce proliferation rate and increase apoptotic cells and lipid peroxidation of tumor cells efficiently. However, there are few reports revealing the influence of SLOil on these parameters. In the current study, effects of FOil chronic supplementation on tumor growth and cachexia were taken as reference to compare the results obtained with SLOil supplementation. Also, we evaluated if the association of SLOil and FOil was able to promote additive effects. METHODS: Weanling male Wistar rats were divided into 4 groups: fed regular chow (C), supplemented (1 g/kg body weight) with SLOil (CSLO), FOil (CFO) and both (CSLO + FO). After 8 weeks half of each group was inoculated with Walker 256 cells originating new groups (W, WSLO, WFO and WSLO + FO). Biochemical parameters of cachexia, tumor weight, hydroperoxide content, proliferation rate and percentage of apoptotic tumor cells were analysed. Fatty acids and AKG composition of tumor and oils were obtained by high performance liquid chromatography and gas chromatography - mass spectrometry, respectively. Statistical analysis was performed by unpaired t-test and one-way ANOVA followed by a post hoc Tukey test. RESULTS: Fourteen days after inoculation, SLOil was able to restore cachexia parameters to control levels, similarly to FOil. WSLO rats presented significantly lower tumor weight (40%), greater tumor cell apoptosis (~3-fold), decreased tumor cell proliferation (35%), and higher tumor content of lipid hydroperoxides (40%) than observed in W rats, but FOil showed more potent effects. Supplementation with SLOil + FOil did not promote additive effects. Additionally, chromatographic results suggested a potential incorporation competition between the n-3 fatty acids and the AKGs in the tumor cells' membranes. CONCLUSIONS: SLOil is another marine source of lipids with similar FOil anti-cachectic capacity. Furthermore, despite being less potent than FOil, SLOil presented significant in vivo antitumor effects. These results suggest that the chronic supplementation with SLOil may be adjuvant of the anti-cancer therapy.

Suplementação de ácidos graxos ômega-3, estado nutricional e qualidade de vida de pacientes com câncer gastrintestinal: estudo duplo-cego, randomizado e placebo controlado / Omega-3 fatty acid supplementation, nutritional statusand quality of life in patients with gastrointestinal cancer:double-blind, placebo-controlled, randomized study

Introdução: a caquexia do câncer é caracterizada pela perda ponderal, imunossupressão e está associada a pior prognóstico e qualidade de vida. Objetivos: avaliar o efeito da suplementação de ω-3 sobre o estado nutricional, capacidade funcional e qualidade de vida de pacientes com câncer gastrintestinal. Métodos: o grupo placebo (P) (n=10) recebeusete cápsulas de 1.000 mg de óleo de soja e o grupo suplemento (S) (n=11) sete cápsulas de 1.000 mg de óleo de peixe e linhaça contendo 214,3 mg de ácido eicosapentaenoico e 113,5 mg de docosahexaenoico, diariamente, por 14 dias. Foram avaliados peso, composição corporal, marcadores inflamatórios e imunológicos, capacidade funcional e qualidade de vida. Resultados: a média de variação de peso do grupo P antes e depois do tratamento foi de -0,44 ± 2,7 kg e do grupo S foi de 0,07 ± 1,4 kg, sem diferença estatística. A média de IMC da amostra foi de 20,5 ± 3,4 kg/m2. Houve significativa redução dos níveis séricos de proteínas totais (p=0,005) e albumina (p=0,011) para o grupo P; aumento dos níveis de proteína C reativa (PCR) (p=0,005) e redução da contagem total de linfócitos (p=0,037). Verificou-se aumento dos níveis séricos da transferrina do grupo S (p=0,010), bem como redução dos níveis de PCR (p=0,033) e da cortisolemia (p=0,020). Encontrou-se aumento para a Escala de Performance de Karnofsky (p=0,020) no grupo S. Não foram encontradas diferenças para status funcional, sintomas e saúde global. Conclusões: o presente estudo encontrou resultados que dão suporte à suplementação de ω-3 em Oncologia. No entanto, são necessárias mais investigações associando os ω-3 a outras estratégias terapêuticas.

Introduction: Cancer cachexia is characterized by weight loss, immunosuppression and is associated with worse prognosis and quality of life. Objectives: To evaluate the effect of ω-3 supplementation on nutritional status, functional capacity and quality of life of patients withgastrointestinal cancer. Methods: the placebo group (P) (n = 10) received seven 1,000 mg capsules of soybean oil and the supplement group (S) (n = 11) seven 1,000 mg capsules of fish oil and flaxseed containing 214.3 mg of eicosapentaenoic acid and 113.5 mg of docosahexaenoicacid daily for 14 days. We evaluated weight, body composition, inflammatory and immunological markers, functional capacity and quality of life. Results: The average weight variation of the P group before and after treatment was -0.44 ± 2.7 kg and of S group was 0.07 ± 1.4 kg, with no statistical difference. The average BMI of the sample was 20.5 ± 3.4 kg / m 2. There was a significant reduction of total serum protein (p = 0.005) and albumin (p = 0.011) in the P group; and an increase in levels of C-reactive protein (CRP) (p = 0.005) and decrease in total lymphocyte count (p = 0.037). An increase in serum transferdiagnósrin (p = 0.010) as well as a reduction in levels of CRP (p = 0.033) and cortisol (p = 0.020) were found in the S group. We found an increase for the Karnofsky Performance Scale (p = 0.020) in group S. No differences were foundfor functional status, symptoms, and overall health. Conclusions: The present study supports the supplementation of ω-3 in Oncology. However, more research is needed involving ω-3 and other therapeutic strategies.

Light aerobic physical exercise in combination with leucine and/or glutamine-rich diet can improve the body composition and muscle protein metabolism in young tumor-bearing rats.

Nutritional supplementation with some amino acids may influence host's responses and also certain mechanism involved in tumor progression. It is known that exercise influences body weight and muscle composition. Previous findings from our group have shown that leucine has beneficial effects on protein composition in cachectic rat model as the Walker 256 tumor. The main purpose of this study was to analyze the effects of light exercise and leucine and/or glutamine-rich diet in body composition and skeletal muscle protein synthesis and degradation in young tumor-bearing rats. Walker tumor-bearing rats were subjected to light aerobic exercise (swimming 30 min/day) and fed a leucine-rich (3%) and/or glutamine-rich (4%) diet for 10 days and compared to healthy young rats. The carcasses were analyzed as total water and fat body content and lean body mass. The gastrocnemious muscles were isolated and used for determination of total protein synthesis and degradation. The chemical body composition changed with tumor growth, increasing body water and reducing body fat content and total body nitrogen. After tumor growth, the muscle protein metabolism was impaired, showing that the muscle protein synthesis was also reduced and the protein degradation process was increased in the gastrocnemius muscle of exercised rats. Although short-term exercise (10 days) alone did not produce beneficial effects that would reduce tumor damage, host protein metabolism was improved when exercise was combined with a leucine-rich diet. Only total carcass nitrogen and protein were recovered by a glutamine-rich diet. Exercise, in combination with an amino acid-rich diet, in particular, leucine, had effects beyond reducing tumoral weight such as improving protein turnover and carcass nitrogen content in the tumor-bearing host.

L-Carnitine induces recovery of liver lipid metabolism in cancer cachexia.

Cancer cachexia causes metabolic alterations with a marked effect on hepatic lipid metabolism. L-Carnitine modulates lipid metabolism and its supplementation has been proposed as a therapeutic strategy in many diseases. In the present study, the effects of L-carnitine supplementation on gene expression and on liver lipid metabolism-related proteins was investigated in cachectic tumour-bearing rats. Wistar rats were assigned to receive 1 g/kg of L-carnitine or saline. After 14 days, supplemented and control animals were assigned to a control (N), control supplemented with L-carnitine (CN), tumour-bearing Walker 256 carcinosarcoma (TB) and tumour-bearing supplemented with L-carnitine (CTB) group. The mRNA expression of carnitine palmitoyltransferase I and II (CPT I and II), microsomal triglyceride transfer protein (MTP), liver fatty acid-binding protein (L-FABP), fatty acid translocase (FAT/CD36), peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and organic cation transporter 2 (OCTN2) was assessed, and the maximal activity of CPT I and II in the liver measured, along with plasma and liver triacylglycerol content. The gene expression of MTP, and CPT I catalytic activity were reduced in TB, who also showed increased liver (150%) and plasma (3.3-fold) triacylglycerol content. L-Carnitine supplementation was able to restore these parameters back to control values (p<0.05). These data show that L-carnitine preserves hepatic lipid metabolism in tumour-bearing animals, suggesting its supplementation to be of potential interest in cachexia.

Ratio of n6 to n-3 fatty acids in the diet affects tumor growth and cachexia in Walker 256 tumor-bearing rats.

In this study we investigate the impact of the dietary ratio of n-6 to n-3 fatty acids (FAs) from postweaning until adult age upon tumor growth, lipid peroxidation in tumor tissue, and metabolic indicators of cancer cachexia in Walker 256 tumor-bearing rats. Weanling male Wistar rats received a normal low-fat (40 g/kg diet) chow diet or high-fat diets (300 g/kg) that included fish oil (FO) or sunflower oil or blends of FO and sunflower oil to yield n-6 to n-3 FA ratios of approximately 6:1, 30:1, and 60:1 ad libitum. After 8 wk, half of each group was inoculated with 1 ml of 2 x 10(7) Walker 256 cells. At the 14th day after tumor inoculation, the animals were killed, and tumors and blood were removed. The different diets did not modify the blood parameters in the absence of tumor bearing, except the high-FO diet, which decreased serum cholesterol and triacylglycerol concentrations. Tumor weight in chow-fed rats was 19 g, and these rats displayed cancer cachexia, characterized by hypoglycemia, hyperlacticidemia, hypertriacylglycerolemia, loss of body weight, and food intake reduction. Tumor weight in FO-fed rats was 7.7 g, and these animals gained body weight (14.6 g) and maintained blood metabolic parameters similar to non-tumor-bearing animals. Tumor weight in rats fed the diet with an n-6 to n-3 FA ratio of 6:1 was similar to tumor-bearing, chow-fed rats, but they gained 2 g in the body weight and blood metabolic parameters were similar to those in non-tumor-bearing rats. However, a further increase in the n-6 FA content of the diet did not change the cachectic state associated with tumor bearing. In this experimental model, a dietary n-6 to n-3 FA ratio of 6:1 was able to increase food intake and body weight, restore the biochemical blood parameters of cachexia, and prevent the development of cancer cachexia.

Effects of celecoxib, medroxyprogesterone, and dietary intervention on systemic syndromes in patients with advanced lung adenocarcinoma: a pilot study.

Systemic syndromes characterized by a persistent activity of circulating mediators (cytokines) are frequently present with advanced cancer. We grouped under the general heading of "Systemic Immune-Metabolic Syndrome (SIMS)" a particular variety of distressing systemic syndrome characterized by dysregulation of the psycho-neuro-immune-endocrine homeostasis, with overlapping clinical manifestations. SIMS may include cachexia, anorexia, nausea, early satiety, fatigue, tumor fever, cognitive changes and superinfection. The aim of this study was to ameliorate some of the SIMS symptoms in a homogeneous group of lung adenocarcinoma patients using a multitargeted therapy. Fifteen patients with evidence of SIMS were studied. SIMS was defined as the presence of weight loss, anorexia, fatigue performance status>/=2 and acute-phase protein response. Patients received medroxyprogesterone (MPA) (500 mg twice daily), celecoxib (200 mg twice daily), plus oral food supplementation for 6 weeks. After treatment, 13 patients either had stable weight (+/- 1%) or had gained weight. There were significant differences in improvement of body-weight-change rate, nausea, early satiety, fatigue, appetite and performance status. Patients who had any kind of lung infection showed higher levels of IL-10 compared to non-infected patients (P=0.039). Our results suggest that patients with advanced lung adenocarcinoma, treated with MPA, celecoxib and dietary intervention, might have considerable improvement in certain SIMS outcomes. This multitargeted symptomatic approach deserves further study.

Nutrición en la etiología y tratamiento del cáncer / Nutrition in the etiology and therapy of cancer

La nutrición juega papel importante en la historia natural del cáncer. La dieta está involucrada en la carcinogénesis a través de mecanismos que son cada vez más claros. Se considera que por lo menos el 35 por ciento del total de casos de cáncer se asocian a la dieta y que cáncer y caquexia están entre las causas más comunes de muerte por enfermedad maligna. Esta revisión tiene el propósito de mostrar la relación del cáncer con la nutrición desde sus cuatro perspectivas: 1. La dieta como factor etiológico; 2. Las alteraciones nutricias causadas por la enfermedad; 3. Las alteraciones nutricias causadas por los tratamientos; y La alimentación del paciente con cáncer. Destacado además, la importancia que tiene la terapia nutricia en este especial grupo de pacientes.

Cáncer cachexiaand nutrition support in the cancer patien a clinical review / Nutrición convencional de la caquexia en pacientes con cáncer

La nutrición convencional ha producido exitos limitados en la reducción de la morbilidad y de la mortalidad de los pacientes con cáncer. Un conocimiento mayor de los mecanismos de la caquexia en el cáncer es claramente necesario. Además, se debe desarrollar un enfoque innovativo del manejo metabólico y nutricional de los pacientes con cáncer para invertir los efectos catabólicos progresivos del estado tumoral. Mas, sin embargo, la ciencia básica y la investigación clínica son requeridos en el futuro para desarrollar un planteamiento selectivo y exitoso para el tratamiento de la caquexia por cáncer.