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1.
PLoS Negl Trop Dis ; 14(3): e0008125, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214337

RESUMO

BACKGROUND: The disturbance of host metabolic pathways by Leishmania parasites has crucial consequences for the activation status of immune cells and the outcome of infection. Glutamine has been described as an immunomodulatory amino acid, yet its role during Leishmania infection is still unknown. METHODS: We performed transcriptomics in uninfected and L. donovani-infected macrophages 6 hours post-infection. Glutamine quantification by HPLC was assessed in the supernatant of macrophages throughout the infection course. For experimental L. donovani infections, mice were infected with 1.0 x 108 stationary L. donovani promastigotes. Glutaminase (GLS) chemical inhibition was performed using BPTES and glutamine was administered throughout infection. For combined therapy experiment, a daily administration of miltefosine and glutamine was performed by oral gavage. Parasite burden was determined using a Taqman-based assay. Immune cell phenotyping and cytotoxicity were performed in splenic cells using flow cytometry. FINDINGS: We show that glutamine is essential for the control of L. donovani infection. Transcriptomic analysis of L. donovani-infected macrophages demonstrated an upregulation of genes involved in glutamine metabolism. Pharmacological inhibition of glutaminolysis significantly increased the susceptibility to infection, accompanied by an increased recruitment of anti-inflammatory myeloid cells and impaired T cell responses. Remarkably, the supplementation of glutamine to mice infected with L. donovani during miltefosine treatment potentiates parasite clearance through the development of a more effective anti-Leishmania adaptive immune response. CONCLUSIONS: Our data indicates that dietary glutamine supplementation may act as a promising adjuvant for the treatment of visceral leishmaniasis.


Assuntos
Antiprotozoários/administração & dosagem , Suplementos Nutricionais , Glutamina/administração & dosagem , Fatores Imunológicos/administração & dosagem , Leishmaniose Visceral/terapia , Fosforilcolina/análogos & derivados , Animais , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Carga Parasitária , Fosforilcolina/administração & dosagem , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento
2.
Oxid Med Cell Longev ; 2019: 4363672, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281575

RESUMO

The present study was conducted to investigate the effect and potential mechanism of hypoxia-inducible factor-1α (HIF-1α) genetic inhibition plus glutamine (Gln) supplementation on necrosis-apoptosis imbalance during acute pancreatitis (AP), with a specific focus on the regulations of intracellular energy metabolism status. Wistar rats and AR42J cells were used to establish AP models. When indicated, a HIF-1α knockdown with or without a Gln supplementation was administered. In vivo, local and systemic inflammatory injuries were assessed by serum cytokine measurement, H&E staining, and transmission electron microscope (TEM) observation of pancreatic tissue. In vitro, intracellular energy metabolism status was evaluated by measuring the intracellular adenosine triphosphate (ATP), lactic acid, and Ca2+ concentrations and the mitochondrial potential. In addition, changes in the apoptotic activity were analyzed using TUNEL staining in vivo and an apoptosis assay in vitro. HIF-1α knockdown alleviated AP-related inflammatory injury as indicated by the measurements of serum cytokines and examinations of TEM and H&E staining of pancreatic tissues. HIF-1α knockdown played an antioxidative role against AP-related injuries by preventing the increase in the intracellular Ca2+ concentration and the decrease in the mitochondrial membrane potential and subsequently by suppressing the glycolysis pathway and increasing energy anabolism in AR42J cells after AP induction. Apoptosis was significantly upregulated when HIF-1α was knocked down before AP induction due to an attenuation of the translocation of nuclear factor-kappa B to the nuclei. Furthermore, these merits of HIF-1α knockdown in the relief of the metabolic stress and upregulation of apoptosis were more significant when Gln was administered concomitantly. In conclusion, Gln-supplemented HIF-1α knockdown might be promising for the future management of AP by relieving the intracellular energy stress, thereby attenuating the predominance of necrosis over apoptosis.


Assuntos
Glutamina/administração & dosagem , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pancreatite/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Técnicas de Silenciamento de Genes , Glutamina/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Necrose , Pancreatite/genética , Pancreatite/patologia , Ratos , Ratos Wistar
3.
Support Care Cancer ; 27(10): 3997-4010, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31286229

RESUMO

PURPOSE: To update the clinical practice guidelines for the use of natural and miscellaneous agents for the prevention and/or treatment of oral mucositis (OM). METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer / International Society of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. The findings were added to the database used to develop the 2014 MASCC/ISOO clinical practice guidelines. Based on the evidence level, the following guidelines were determined: Recommendation, Suggestion, and No Guideline Possible. RESULTS: A total of 78 papers were identified within the scope of this section, out of which 29 were included in this part, and were analyzed with 27 previously reviewed studies. A new Suggestion was made for oral glutamine for the prevention of OM in head and neck (H&N) cancer patients receiving radiotherapy with concomitant chemotherapy. The previous Recommendation against the use of parenteral glutamine for the prevention of OM in hematopoietic stem cell transplantation (HSCT) patients was re-established. A previous Suggestion for zinc to prevent OM in H&N cancer patients treated with radiotherapy or chemo-radiotherapy was reversed to No Guideline Possible. No guideline was possible for other interventions. CONCLUSIONS: Of the vitamins, minerals, and nutritional supplements studied for the management of OM, the evidence supports a Recommendation against parenteral glutamine in HSCT patients and a Suggestion in favor of oral glutamine in H&N cancer patients for the management of OM.


Assuntos
Glutamina/uso terapêutico , Minerais/uso terapêutico , Mucosite/tratamento farmacológico , Mucosite/prevenção & controle , Estomatite/tratamento farmacológico , Estomatite/prevenção & controle , Vitaminas/uso terapêutico , Suplementos Nutricionais , Glutamina/administração & dosagem , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Neoplasias/tratamento farmacológico
4.
BMC Vet Res ; 15(1): 199, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196135

RESUMO

BACKGROUND: The purpose of the present study was to assess if the exposure to glutamine (Gln), arginine (Arg) or their combination from pregnancy, through the maternal diet, to a post weaning supplemented diet, can stimulate litter performance, gut development and immune function. To this end does and their litters were fed the same basal diet no supplemented (control C), or supplemented with 0.4% Gln, 0.4% Arg, or 0.4 Gln + 0.4 Arg. Rabbits were weaned at 25 d of age and fed the same experimental diet as their mothers for 10 additional days (35 d of age). Bacterial translocation to mesenteric lymph nodes (MLN) at 6 d of age and intestinal histology, enzymatic activity, phenotypical and functional analysis of intraepithelial lymphocytes (IEL) from the appendix were determined at 6, 25 and 35 d of age. RESULTS: No significant differences on animal performance or mortality rates were observed among dietary treatments. However, kits from rabbit does supplemented with Gln tended (P ≤ 0.10) to reduce the translocation of total number of both aerobic and facultative anaerobic bacteria to the MLN. Also, rabbits fed the Gln supplemented diets maintained intestinal villous height at weaning compared to the non-supplemented diets (P < 0.05). The proportions of CD45+CD4+ and CD45+CD8+ IEL in the appendix were not affected by dietary means. However, in rabbits IEL at weaning dietary Gln significantly upregulated IL-2 and downregulated IL-6 expression. CONCLUSIONS: Despite a lack of effect on performance and mortality the inclusion of 0.4% Gln has a positive effect by maintaining intestinal villous height and modulating the cytokine profile at weaning. The supplementation with Arg or Arg + Gln at the selected doses in this study did not exert positive effects on rabbit intestinal health.


Assuntos
Arginina/farmacologia , Dieta/veterinária , Glutamina/farmacologia , Intestinos/efeitos dos fármacos , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Arginina/administração & dosagem , Bactérias , Feminino , Glutamina/administração & dosagem , Intestinos/anatomia & histologia , Intestinos/enzimologia , Intestinos/microbiologia , Linfócitos Intraepiteliais/fisiologia , Linfonodos/microbiologia , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Coelhos , Desmame
5.
J Surg Res ; 243: 281-288, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31254901

RESUMO

BACKGROUND: Sarcopenia is closely related to short-term outcomes of surgery and long-term prognosis. After gastrectomy, a decrease in muscle strength occurs because of insufficient nutrient intake and disturbed digestive function. Branched-chain amino acids (BCAAs) and glutamine (Gln) play vital roles in the signaling pathways regulating protein synthesis and protein degradation. In this study, we investigated the effects of BCAA and Gln supplementation alone or in combination on skeletal muscle atrophy after total gastrectomy in a rat model. METHODS: Male Wistar rats were divided into five groups: (1) sham operation (n = 8); (2) total gastrectomized rats (TG [control group], n = 16); (3) TG with BCAA (TG-B, n = 16); (4) TG with Gln (TG-G, n = 16); and (5) TG with BCAA and Gln (TG-BG, n = 16). In all groups, body weight, muscle weight, and marker for muscle metabolism were examined. RESULTS: Weight gain was significantly greater in the TG-BG group (130.5%) than in the TG group (108.1%) at 15 wk (P < 0.05). The gastrocnemius muscle weight was significantly higher for TG-BG (2.84 g) than for TG (2.44 g) at 15 wk (P < 0.05). Western blotting indicated that atrogin-1 and MuRF1 levels were lower in the TG-BG group than in the TG group but were not suppressed in the TG-B or TG-G group. CONCLUSIONS: In a rodent sarcopenia model induced by TG, the administration of BCAA in combination with Gln more effectively inhibited muscle atrophy than the administration of BCAA or Gln alone.


Assuntos
Aminoácidos de Cadeia Ramificada/administração & dosagem , Gastrectomia/efeitos adversos , Glutamina/administração & dosagem , Sarcopenia/prevenção & controle , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Masculino , Ratos Wistar , Sarcopenia/etiologia
6.
Arq Bras Cir Dig ; 32(2): e1431, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31038556

RESUMO

BACKGROUND: Sepsis is an important public health issue and is associated with high treatment costs and high mortality rates. Glutamine supplementation has proven to be beneficial to the functions of the immune system, acting beneficially in the evolution of patients in severe catabolic states. AIM: To evaluate the effect of glutamine supplementation via intraperitoneal in rats, induced sepsis, considering the following organs: intestines, liver, kidneys and lungs. METHODS: Male Wistar rats subjected to sepsis by ligature and cecal puncture were divided into two groups: control C (n=6) and glutamine G (n=11), in which were administered dipeptiven 20% at a dose of 2 ml/kg/day (equivalent to 0.4g N(2)-L-alanyl-L-glutamine/kg) intraperitoneally 48 h prior to sepsis induction. After 48 h they were euthanized and intestine, liver, lung and kidney were removed for histological analysis. RESULTS: Intestinal epithelial desquamation of the control group was more intense compared to the glutamine group (p=0.008). In the kidneys, degenerative tubular epithelial changes were less severe in the animals that received glutamine (p=0.029). Regarding to the liver, glutamine group showed lower levels of cell swelling than the control group (p=0.034). In the lung there were no results with statistical significance. CONCLUSION: Prior intraperitoneal supplementation with glutamine in experimental animals is able to reduce the damage to the intestinal mucosa, to the kidneys and liver's histoarchitecture.


Assuntos
Glutamina/administração & dosagem , Sepse/tratamento farmacológico , Animais , Infusões Parenterais , Intestinos/efeitos dos fármacos , Intestinos/patologia , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes , Sepse/patologia , Resultado do Tratamento
7.
J Stroke Cerebrovasc Dis ; 28(7): 1993-2002, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31029568

RESUMO

BACKGROUND: Multiple pathogeneses are involved in Alzheimer's disease (AD), such as amyloid-ß accumulation, neuroinflammation, and oxidative stress. The pathological impact of chronic cerebral hypoperfusion on Alzheimer's disease is still poorly understood. METHODS: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive chronic cerebral hypoperfusion (CCH). The effects of the administration of Twendee X (TwX) were evaluated by behavioral analysis, immunohistochemical analysis, and immunofluorescent histochemistry. RESULTS: In the present study, chronic cerebral hypoperfusion, which is commonly found in aged Alzheimer's disease, significantly exacerbated motor dysfunction of APP23 mice from 5 months and cognitive deficit from 8 months of age, as well as neuronal loss, extracellular amyloid-ß plaque and intracellular oligomer formations, and amyloid angiopathy at 12 months. Severe upregulations of oxidative markers and inflammatory markers were found in the cerebral cortex, hippocampus, and thalamus at 12 months. Twendee X treatment (20 mg/kg/d, from 4.5 to 12 months) substantially rescued the cognitive deficit and reduced the above amyloid-ß pathology and neuronal loss, alleviated neuroinflammation and oxidative stress. CONCLUSIONS: The present findings suggested a potential therapeutic benefit of Twendee X for Alzheimer's disease with chronic cerebral hypoperfusion.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ácido Ascórbico/administração & dosagem , Encéfalo/efeitos dos fármacos , Transtornos Cerebrovasculares/tratamento farmacológico , Cistina/administração & dosagem , Glutamina/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Ascórbico/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cerebrovasculares/patologia , Transtornos Cerebrovasculares/fisiopatologia , Doença Crônica , Cognição/efeitos dos fármacos , Cistina/farmacologia , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Glutamina/farmacologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Mutação , Estresse Oxidativo/efeitos dos fármacos , Placa Amiloide
8.
Nutrients ; 11(4)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999561

RESUMO

Glutamine is a conditionally essential amino acid widely used in sports nutrition, especially because of its immunomodulatory role. Notwithstanding, glutamine plays several other biological functions, such as cell proliferation, energy production, glycogenesis, ammonia buffering, maintenance of the acid-base balance, among others. Thus, this amino acid began to be investigated in sports nutrition beyond its effect on the immune system, attributing to glutamine various properties, such as an anti-fatigue role. Considering that the ergogenic potential of this amino acid is still not completely known, this review aimed to address the main properties by which glutamine could delay fatigue, as well as the effects of glutamine supplementation, alone or associated with other nutrients, on fatigue markers and performance in the context of physical exercise. PubMed database was selected to examine the literature, using the keywords combination "glutamine" and "fatigue". Fifty-five studies met the inclusion criteria and were evaluated in this integrative literature review. Most of the studies evaluated observed that glutamine supplementation improved some fatigue markers, such as increased glycogen synthesis and reduced ammonia accumulation, but this intervention did not increase physical performance. Thus, despite improving some fatigue parameters, glutamine supplementation seems to have limited effects on performance.


Assuntos
Exercício Físico , Fadiga/prevenção & controle , Glutamina/farmacologia , Ciências da Nutrição e do Esporte , Glutamina/administração & dosagem , Humanos
9.
Poult Sci ; 98(9): 4066-4072, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30843058

RESUMO

An experiment was conducted to investigate the effect of supplemental L-glutamine (L-Gln) and a higher concentration of zinc (Zn) on excreta moisture under nutritionally induced wet droppings via decreased intestinal water reabsorption. A 2 × 2 × 2 factorial arrangement of treatments was used to investigate 3 dietary factors of L-Gln supplementation (0 or 10 g/kg), and added Zn concentration (80 and 160 mg/kg) with or without magnesium chloride (MgCl) (2 g/kg-only in grower diets). A total of 576 male day-old Ross 308 broiler chickens were assigned to the experimental diets. Each diet was replicated 6 times with 12 birds per replicate. Wheat-based diets were formulated to be isocaloric and isonitrogenous. Starter diets were given from day 0 to 9 followed by grower (day 10 to 23) and finisher diets (day 24 to 35). Excreta moisture was measured for all the growth phases. The moisture content of different segments of intestine was assessed for starter and grower phases of feeding. There was no significant effect of any of the 3 main treatments on body weight gain or feed intake of birds during the experiment. Birds fed higher Zn (160 mg/kg) tended (P = 0.09) to have higher weight gain only in the first 9 days of age. Feeding 10 g/kg L-Gln increased the feed conversion ratio of the birds only from hatch until day 9 after which there was no significant effect. No effect of experimental treatments was found on digesta or excreta moisture, except a reduction in ileal moisture at the starter phase resulting from higher Zn concentration in the diets. MgCl at 2 g/kg was not effective in inducing wet droppings in birds fed grower diets. Under the conditions of this study, no positive response was observed in terms of performance or reduction in excreta moisture when birds were fed diets containing 10 g/kg L-Gln or higher concentration of Zn.


Assuntos
Galinhas/fisiologia , Fezes/química , Glutamina/metabolismo , Magnésio/administração & dosagem , Zinco/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Digestão/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glutamina/administração & dosagem , Masculino , Zinco/administração & dosagem
10.
Nutrients ; 11(3)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30832230

RESUMO

In the present study, we aimed to investigate whether chronic oral glutamine (Gln) supplementation may alter metabolic parameters and the inflammatory profile in overweight and obese humans as well as whether Gln may modulate molecular pathways in key tissues linked to the insulin action in rats. Thirty-nine overweight/obese volunteers received 30 g of Gln or alanine (Ala-control) for 14 days. Body weight (BW), waist circumference (WC), hormones, and pro-inflammatory markers were evaluated. To investigate molecular mechanisms, Gln or Ala was given to Wistar rats on a high-fat diet (HFD), and metabolic parameters, euglycemic hyperinsulinemic clamp with tracers, and Western blot were done. Gln reduced WC and serum lipopolysaccharide (LPS) in overweight volunteers. In the obese group, Gln diminished WC and serum insulin. There was a positive correlation between the reduction on WC and LPS. In rats on HFD, Gln reduced adiposity, improved insulin action and signaling, and reversed both defects in glucose metabolism in the liver and muscle. Gln supplementation increased muscle glucose uptake and reversed the increased hepatic glucose production, in parallel with a reduced glucose uptake in adipose tissue. This insulin resistance in AT was accompanied by enhanced IRS1 O-linked-glycosamine association in this tissue, but not in the liver and muscle. These data suggest that Gln supplementation leads to insulin resistance specifically in adipose tissue via the hexosamine pathway and reduces adipose mass, which is associated with improvement in the systemic insulin action. Thus, further investigation with Gln supplementation should be performed for longer periods in humans before prescribing as a beneficial therapeutic approach for individuals who are overweight and obese.


Assuntos
Suplementos Nutricionais , Glutamina/administração & dosagem , Obesidade/terapia , Sobrepeso/terapia , Adulto , Animais , Biomarcadores/metabolismo , Peso Corporal/fisiologia , Dieta Hiperlipídica/efeitos adversos , Método Duplo-Cego , Feminino , Técnica Clamp de Glucose , Humanos , Mediadores da Inflamação/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Obesidade/etiologia , Obesidade/fisiopatologia , Sobrepeso/etiologia , Sobrepeso/fisiopatologia , Ratos , Ratos Wistar , Circunferência da Cintura/fisiologia
11.
Nutr Hosp ; 36(1): 5-12, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30829529

RESUMO

Introduction: Background and objective: malnutrition during cancer treatment is common in patients; therefore, nutritional intervention has an important role in cancer prognosis. Total parenteral nutrition is indicated for patients subjected to a major surgery with gastrointestinal complications. Nutritional support could be improved with glutamine (Gln). Therefore, in this work, the effect of parenteral glutamine in patients with gastrointestinal cancer undergoing surgery was studied. Material and methods: patients were classifi ed into two groups: non-supplemented and supplemented (Gln; 0.4 g/kg/day). Both groups received parenteral nutrition. One and seven days after surgery the nutritional status was evaluated. Hematic cytometry, protein metabolism and biochemical data were analyzed. A questionnaire was also applied to assess gastrointestinal function. Results: after the intervention, the nutritional status in both groups improved. However, the nutritional condition improved signifi cantly better (p = 0.008) in the supplemented group. According to the gastrointestinal function evaluation, the supplemented group changed from severe to mild dysfunction (p = 0.0001). The non-supplemented group progressed from moderate to severe dysfunction, but no changes in blood cell markers were observed. The supplemented group improved its concentration of lymphocytes (p = 0.014). The plasma albumin concentration did not change in groups, but prealbumin improved signifi cantly (p = 0.012) in the group that was supplemented with Gln. Conclusions: intravenous nutritional support supplemented with glutamine can improve gastrointestinal function, improving the absorption of nutrients, which leads to a better state of nutrition. It also has positive effects on plasma concentration of lymphocytes, monocytes and prealbumin.


Assuntos
Neoplasias Gastrointestinais/terapia , Glutamina/administração & dosagem , Glutamina/uso terapêutico , Nutrição Parenteral , Adulto , Idoso , Contagem de Células Sanguíneas , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/cirurgia , Trato Gastrointestinal/fisiopatologia , Humanos , Tempo de Internação , Estudos Longitudinais , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Pré-Albumina/análise , Estudos Prospectivos
12.
Medicine (Baltimore) ; 98(8): e14463, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813149

RESUMO

BACKGROUND: Complications related to concurrent chemoradiotherapy (CCRT) such as acute radiation-induced esophagitis (ARIE) may cause significant morbidity and unplanned treatment delays in patients with advanced non-small cell lung cancer (NSCLC). We designed a prospective randomized study to assess the impact of glutamine (GLN) supplementation in preventing CCRT-induced toxicities of advanced NSCLC patients. METHODS: From September 2014 to September 2015, 60 patients diagnosed with NSCLC were included to the study. Thirty patients (50%) received prophylactic powdered GLN orally at a dose of 10 g/8 h. The prescribed radiation dose to the planning target volume was 30 Gy in 2-Gy fractions. The endpoints were radiation-induced esophagitis, mucositis, body weight loss, overall survival and progression-free survival. RESULTS: The 60 patients with NSCLC included 42 men and 18 women with a mean age ±â€Šstandard deviation of 60.3 years ±â€Š18.2 (range, 44-78 years).At a median follow-up of 26.4 months (range 10.4-32.2), all patients tolerated GLN well. A administration of GLN was associated with a decrease in the incidence of grade 2 or 3 ARIE (6.7% vs 53.4% for Gln+ vs Gln-; P = .004). GLN supplementation appeared to significantly delay ARIE onset for 5.8 days (18.2 days vs 12.4 days; P = .027) and reduced incidence of weight loss (20% vs 73.3%; P = .01). DISCUSSION: Our study suggests a beneficial effect of oral glutamine supplementation for the prevention from radiation-induced injury and body weight loss in advanced NSCLC patients who receiving CCRT.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Esofagite/prevenção & controle , Glutamina/administração & dosagem , Neoplasias Pulmonares/terapia , Lesões por Radiação/prevenção & controle , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Quimiorradioterapia/efeitos adversos , Suplementos Nutricionais , Esofagite/epidemiologia , Esofagite/etiologia , Feminino , Humanos , Incidência , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Lesões por Radiação/epidemiologia , Dosagem Radioterapêutica , Análise de Sobrevida
13.
Am J Clin Nutr ; 109(3): 606-614, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753262

RESUMO

BACKGROUND: Glutamine is the primary fuel for the gastrointestinal epithelium and maintains the mucosal structure. Oncologists frequently encounter oral mucositis, which can cause unplanned breaks in radiotherapy (RT). OBJECTIVES: The aim of this study was to explore the association between oral glutamine and acute toxicities in patients with head and neck cancer undergoing RT. METHODS: This was a parallel, double-blind, randomized, placebo-controlled Phase III trial conducted in a university hospital. A central randomization center used computer-generated tables to allocate interventions to 71 patients with stages I-IV head and neck cancers. The patients, care providers, and investigators were blinded to the group assignment. Eligible patients received either oral glutamine (5 g glutamine and 10 g maltodextrin) or placebo (15 g maltodextrin) 3 times daily from 7 d before RT to 14 d after RT. The primary and secondary endpoints were radiation-induced oral mucositis and neck dermatitis, respectively. These were documented in agreement with the National Cancer Institute Common Terminology Criteria for Adverse Events version 3. RESULTS: The study included 64 patients (placebo n = 33; glutamine n = 31) who completed RT for the completers' analysis. Based on multivariate analysis, glutamine had no significant effect on the severity of oral mucositis (OR: 0.3; 95% CI: 0.05, 1.67; P = 0.169). Only the change in body mass index (BMI) was significant in both multivariate completers (OR: 0.41; 95% CI: 0.20, 0.84; P = 0.015) and per-protocol analysis (OR: 0.40; 95% CI: 0.20, 0.83; P = 0.014). No difference was found in the incidence and severity of neck dermatitis between the two arms. CONCLUSIONS: The decrease in BMI was strongly related to the severity of oral mucositis in the head and neck cancer patients under RT, but not to the use of glutamine. This trial was registered at clinicaltrials.gov as NCT03015077.


Assuntos
Dermatite/tratamento farmacológico , Glutamina/administração & dosagem , Neoplasias de Cabeça e Pescoço/radioterapia , Lesões por Radiação/tratamento farmacológico , Radioterapia/efeitos adversos , Estomatite/tratamento farmacológico , Adulto , Idoso , Dermatite/etiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/lesões , Mucosa Bucal/efeitos da radiação , Lesões por Radiação/etiologia , Estomatite/etiologia
14.
J Diet Suppl ; 16(5): 576-591, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29969326

RESUMO

We aimed to evaluate effects of ß-hydroxy-ß-methylbutyrate, L-glutamine, and L-arginine (HMB/GLN/ARG) on radiation-induced acute intestinal toxicity. Forty rats were divided into four groups: group (G) 1 was defined as control group, and G2 was radiation therapy (RT) control group. G3 and G4 were HMB/GLN/ARG control and RT plus HMB/GLN/ARG groups, respectively. HMB/GLN/ARG started from day of RT and continued until the animals were sacrificed 10 days after RT. The extent of surface epithelium smoothing, villous atrophy, lamina propria inflammation, cryptitis, crypt distortion, regenerative atypia, vascular dilatation and congestion, and fibrosis were quantified on histological sections of intestinal mucosa. Statistical analyses were performed using the analysis of variance (ANOVA) test. There were significant differences between study groups regarding extent of surface epithelium smoothing, villous atrophy, lamina propria inflammation, cryptitis and crypt distortion, regenerative atypia, vascular dilatation and congestion, and fibrosis (p values were 0.019 for fibrosis, <.001 for the others). Pair-wise comparisons revealed significant differences regarding surface epithelium smoothing, villous atrophy, lamina propria inflammation, cryptitis, vascular dilatation, and congestion between G2 and G4 (p values were <.001, .033, <.001, .007, and <.001, respectively). Fibrosis score was significantly different only between G1 and G2 (p = .015). Immunohistochemical TGF-ß score of G2 was significantly higher than G1 and G3 (p values were .006 and .017, respectively). There was no difference between TGF-ß staining scores of G2 and G4. Concomitant use of HMB/GLN/ARG appears to ameliorate radiation-induced acute intestinal toxicity; however, this finding should be clarified with further studies.


Assuntos
Arginina/administração & dosagem , Glutamina/administração & dosagem , Enteropatias/tratamento farmacológico , Lesões Experimentais por Radiação/tratamento farmacológico , Valeratos/administração & dosagem , Animais , Suplementos Nutricionais , Feminino , Fibrose/patologia , Imuno-Histoquímica , Inflamação/patologia , Enteropatias/etiologia , Enteropatias/patologia , Mucosa Intestinal/química , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos da radiação , Lesões Experimentais por Radiação/etiologia , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta/análise
15.
Amino Acids ; 51(3): 451-462, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30449005

RESUMO

Glutamine (GLN) is the most abundant free amino acid in the body, and is considered as a conditionally essential amino acid under stress conditions, acting as an important modulator of the immune response. We here investigated the role of exogenous GLN treatment on leukocyte migration after the onset of endotoxemia and the intracellular mechanisms of GLN actions on neutrophils. Two in vivo models of endotoxemia caused by lipopolysaccharide of Escherichia coli (LPS) injection were carried out in male outbred Balb/C mice 2-3 months old, as follow: (1) LPS (50 µg/kg) was intravenously injected 1 h prior to intravenous injection of GLN (0.75 mg/kg) and samples were collected 2 h later to investigate the role of GLN on the acute lung inflammation; (2) LPS (1 mg/kg) was intraperitoneally injected 1 h prior to intravenous injection of GLN (0.75 mg/kg) and samples were collected 18 h later to measure the effects of GLN on local and later phases of inflammation in the peritoneum. Results showed that GLN administration reduced the number of neutrophils in the inflamed lungs, partially recovery of the reduced number of leukocytes in the blood; reduced adhesion molecules on lung endothelium and on circulating neutrophils. Moreover, GLN treatment diminished the number of neutrophils, levels of chemotactic cytokine CXCL2 in the inflamed peritoneum, and neutrophils collected from the peritoneum of GLN-treated mice presented lower levels of Rho, Rac, and JNK. Together, our data show novel mechanisms involved in the actions of GLN on neutrophils migration.


Assuntos
Movimento Celular/efeitos dos fármacos , Endotoxemia/tratamento farmacológico , Glutamina/administração & dosagem , Lipopolissacarídeos/toxicidade , Neutrófilos/efeitos dos fármacos , Peritônio/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Endotoxemia/induzido quimicamente , Endotoxemia/metabolismo , Endotoxemia/patologia , Regulação da Expressão Gênica , Glutamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/metabolismo , Peritônio/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/patologia
16.
In Vivo ; 33(1): 155-161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30587616

RESUMO

BACKGROUND/AIM: Sorafenib is standard treatment for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a notorious side-effect of this therapy. This study evaluated prophylactic benefits of an oral nutritional supplement (ONS) on sorafenib-associated HFSR in advanced HCC. PATIENTS AND METHODS: This was a prospective, single-center, open-label trial arm using combined ONS and sorafenib in patients with unresectable HCC from August 2014 to February 2018. Control patients received sorafenib without ONS from 2011 to 2014. From September 2014, prophylactic ONS containing ß-hydroxy-ß-methylbutyrate (HMB), L-arginine, and L-glutamine was given. Sorafenib dosage was 400 mg/day for both groups. RESULTS: Each group comprised 22 men and three women. Age, sex, Child-Pugh score, and clinical stage excluding IV-B did not significantly differ between the groups. HFSR occurred after 2 weeks: 15/25 patients in the control group (60%; HFSR grade 1: 6, grade 2: 7, grade 3: 2) vs. 8/25 in the ONS group (32%; HFSR grade 1: 4, grade 2: 4, grade 3: 0; p=0.047, Pearson's Chi-square test). CONCLUSION: Prophylactic HMB, L-arginine and L-glutamine supplementation effectively prevented sorafenib-associated HFSR in patients with advanced HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Síndrome Mão-Pé/dietoterapia , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Arginina/administração & dosagem , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Feminino , Glutamina/administração & dosagem , Síndrome Mão-Pé/etiologia , Síndrome Mão-Pé/patologia , Síndrome Mão-Pé/prevenção & controle , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pele/efeitos dos fármacos , Pele/patologia , Valeratos/administração & dosagem
17.
Genes Cells ; 23(12): 1043-1055, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30353943

RESUMO

Antibiotics sometimes exert adverse effects on the pathogenesis of colitis due to the dysbiosis resulting from the disruption of gut homeostasis. However, the precise mechanisms underlying colitogenic effects of antibiotic-induced colitis are largely unknown. Here, we show a novel murine fecal occult bleeding model induced by the combinatorial treatment of ampicillin and vancomycin, which is accompanied by an enlarged cecum, upregulation of pro-inflammatory cytokines IL-6 and IL-12, a reduction in Ki-67-positive epithelial cell number and an increase in the apoptotic cell number in the colon. Moreover, gas chromatography-tandem mass analysis showed that various kinds of metabolites, including glutamic acid and butyric acid, were significantly decreased in the cecal contents. In addition, abundance of butyric acid producer Clostridiales was dramatically reduced in the enlarged cecum. Interestingly, supplementation of monosodium glutamate or its precursor glutamine suppressed colonic IL-6 and IL-12, protected from cell apoptosis and prevented fecal occult blood indicating that the reduced level of glutamic acid is a possible mechanism of antibiotic-induced fecal occult bleeding. Our data showed a novel mechanism of antibiotic-induced fecal occult bleeding providing a new insight into the clinical application of glutamic acid for the treatment of antibiotic-induced colitis.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Colo/patologia , Células Epiteliais/patologia , Doenças Metabólicas/complicações , Sangue Oculto , Administração Oral , Ampicilina/administração & dosagem , Ampicilina/farmacologia , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Ácido Butírico/farmacologia , Metabolismo dos Carboidratos/efeitos dos fármacos , Ceco/microbiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Citocinas/metabolismo , Glutamina/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metaboloma/efeitos dos fármacos , Metagenômica , Camundongos , Microbiota/efeitos dos fármacos , Microbiota/genética , Células RAW 264.7 , Regeneração/efeitos dos fármacos , Glutamato de Sódio/administração & dosagem , Especificidade da Espécie , Vancomicina/administração & dosagem , Vancomicina/farmacologia
18.
Nutrients ; 10(11)2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30360490

RESUMO

Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities, and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver, and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to the impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g., ill/critically ill, post-trauma, sepsis, exhausted athletes), it is currently difficult to determine whether glutamine supplementation (oral/enteral or parenteral) should be recommended based on the amino acid plasma/bloodstream concentration (also known as glutaminemia). Although the beneficial immune-based effects of glutamine supplementation are already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review of how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism and action, and important issues related to the effects of glutamine supplementation in catabolic situations.


Assuntos
Suplementos Nutricionais , Glutamina/administração & dosagem , Nutrição Enteral , Glutamina/deficiência , Humanos , Nutrição Parenteral
20.
J Neuroendocrinol ; 30(11): e12642, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30168642

RESUMO

The astrocytic glutamine (Gln)-glutamate (Glu) cycle (GGC) supplies Gln for the regulation of glutamatergic synaptic transmission (GST) in the adult hippocampus. Increased synaptic Glu release in the perinatal ventrolateral ventromedial nucleus of the hypothalamus (vlVMH) modulates sexual differentiation, however, whether GGC regulates GST in the perinatal vlVMH has not been determined. Sex differences in oestradiol (E2 ) levels exist in the neonatal hypothalamus, and E2 increases levels of glutamine synthetase and glutaminase, two key enzymes involved in the GGC. Thus, it is hypothesised that sexually dimorphic phenotypes may exist in glutamatergic synapses associated with the GGC in the vlVMH in perinatal rats. Whole-cell voltage-clamp recordings in vlVMH neurones in brain slices from male and female pups revealed that pharmacological disruption of the GGC by α-(methylamino) isobutyric acid (5 mmol L-1 ), which blocks neuronal Gln uptake; or by l-methionine sulphoximine (1.5 mmol L-1 ), which inhibits astrocytic Gln synthesis, decreased miniature excitatory postsynaptic current (mEPSC) amplitudes in female but not male pups. By contrast, GGC interruptions decreased evoked (e)EPSC amplitudes in both sexes following increased synaptic activity produced by a period of stimulation. In male pups, the decreased eEPSCs were attributable to reduced Glu release, as assessed by paired-pulse stimulations, whereas, in female pups, they were attributable to decreased Glu content in the synaptic vesicles, as measured by strontium-evoked mEPSCs. The l-methionine sulphoximine-mediated decrease in eEPSCs was rapidly rescued by exogenous Gln in female but not male pups. The reductions in mEPSCs and eEPSCs in female pups were accompanied by enhanced blocking effects of the low-affinity Glu AMPA receptor antagonist, γ-d-glutamylglycine, consistent with diminished Glu release. In conclusion, female, but not male pups, rely on constitutive astrocytic Gln for sustained synaptic Glu release in the vlVMH. This glutamatergic synaptic phenotype may be associated with brain and behaviour feminisation and/or defeminisation in rats.


Assuntos
Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Neurônios/fisiologia , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores , Feminino , Glutamina/administração & dosagem , Hipotálamo Médio/efeitos dos fármacos , Hipotálamo Médio/metabolismo , Masculino , Potenciais Pós-Sinápticos em Miniatura , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Caracteres Sexuais , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , beta-Alanina/administração & dosagem , beta-Alanina/análogos & derivados
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