RESUMO
Activated effector T cells (Teff) and/or compromised regulatory T cells (Treg) underlie many chronic inflammatory diseases. We discovered a novel pathway to regulate survival and expansion of Teff without compromising Treg survival and a potential therapeutic to treat these diseases. We found dimethylguanidino valeric acid (DMGV) as a rheostat for Teff survival: while cell-intrinsic DMGV generated by Alanine-Glyoxylate Aminotransferase 2 (AGXT2) is essential for survival and expansion by inducing mitochondrial ROS and regulation of glycolysis, an excessive (or exogenous) DMGV level inhibits activated Teff survival, thereby the AGXT2-DMGV-ROS axis functioning as a switch to turn on and off Teff expansion. DMGV-induced ROS is essential for glycolysis in Teff, and paradoxically DMGV induces ROS only when glycolysis is active. Mechanistically, DMGV rapidly activates mitochondrial calcium uniporter (MCU), causing a surge in mitochondrial Ca2+ without provoking calcium influx to the cytosol. The mitochondrial Ca2+ surge in turn triggers the mitochondrial Na+/Ca2+ exchanger (NCLX) and the subsequent mitochondrial Na+ import induces ROS by uncoupling the Coenzyme Q cycle in Complex III of the electron transport chain. In preclinical studies, DMGV administration significantly diminished the number of inflammatory T cells, effectively suppressing chronic inflammation in mouse models of colitis and rheumatoid arthritis. DMGV also suppressed expansion of cancer cells in vitro and in a mouse T cell leukemic model by the same mechanism. Our data provide a new pathway regulating T cell survival and a novel mode to treat autoimmune diseases and cancers.
Assuntos
Guanidinas , Inflamação , Cetoácidos , Neoplasias , Linfócitos T , Transaminases , Animais , Cálcio/metabolismo , Sobrevivência Celular/genética , Guanidinas/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/genética , Cetoácidos/uso terapêutico , Camundongos , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Espécies Reativas de Oxigênio/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Linfócitos T/fisiologia , Transaminases/genéticaRESUMO
INTRODUCTION: Essential amino acid α-keto acid analogs are used in the treatment of chronic kidney disease to delay the symptoms of uremia. However, it is unknown whether essential amino acid α-keto acid analogs affect the oxidative stress and the inflammation in acute renal injury such as those produced by ischemia-reperfusion. OBJECTIVE: To evaluate the effect of essential amino acid α-keto acid analogs on renal ischemia-reperfusion injury in Wistar rats. MATERIALS AND METHODS: Rats were divided into 11 groups (n=6/group): Two groups received physiological saline with or without ischemia-reperfusion injury (45 min/24 h), six groups received essential amino acid α-keto acid analogs (400, 800, or 1,200 mg/kg/24 h/7d) with or without ischemia-reperfusion injury (essential amino acid α-keto acid analogs + ischemia-reperfusion), and two groups received allopurinol (50 mg/kg/24 h/7d) with or without ischemia-reperfusion injury. Biochemical markers included creatinine and blood urea nitrogen (BUN), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), renal damage markers (cystatin C, KIM-1, and NGAL), and markers of oxidative stress such as malondialdehyde (MDA) and total antioxidant activity. RESULTS: The essential amino acid α-keto acid analog- and allopurinol-treated groups had lower levels of creatinine, BUN, renal damage markers, proinflammatory cytokines, and MDA than their corresponding ischemia-reperfusion groups. These changes were related to the essential amino acid α-keto acid analogs dosage. Total antioxidant activity was lower in essential amino acid α-keto acid analog- and allopurinol-treated groups than in the corresponding ischemia-reperfusion groups. CONCLUSIONS: This is a new report on the nephroprotective effects of essential amino acid α-keto acid analogs against ischemia-reperfusion injury. Essential amino acid α-keto acid analogs decreased the levels of biochemical markers, kidney injury markers, proinflammatory cytokines, and MDA while minimizing total antioxidant consumption.
Introducción. Los α-cetoanálogos de aminoácidos esenciales se utilizan en el tratamiento de la enfermedad renal crónica para retrasar los síntomas de la uremia. Sin embargo, se desconoce si los α-cetoanálogos de aminoácidos esenciales afectan el estrés oxidativo y la inflamación en la lesión renal aguda tal como en la producida por la isquemia-reperfusión. Objetivo. Evaluar el efecto de las α-cetoanálogos de aminoácidos esenciales sobre la lesión renal por isquemia-reperfusión en ratas Wistar. Materiales y métodos. Se emplearon 11 grupos de ratas (n=6): dos grupos recibieron solución salina fisiológica con lesión isquemia-reperfusión o sin ella (45 min/24 h), seis grupos recibieron α-cetoanálogos de aminoácidos esenciales (400, 800 o 1.200 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella (α-cetoanálogos de aminoácidos esenciales + isquemia-reperfusión), y dos grupos recibieron (50 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella. Los marcadores bioquímicos incluyeron creatinina y nitrógeno ureico en sangre (BUN), citocinas proinflamatorias (IL-1ß, IL-6 y TNF-α), marcadores de daño renal (cistatina C, KIM-1 y NGAL) y marcadores del estrés oxidativo como el malondialdehído (MDA) y la actividad antioxidante total. Resultados. Los grupos tratados con α-cetoanálogos de aminoácidos esenciales y alopurinol tuvieron niveles inferiores de creatinina, BUN, marcadores de daño renal, citocinas proinflamatorias, actividad antioxidante total y MDA que los grupos isquemia-reperfusión correspondientes. Estos cambios se asociaron con la dosis. La actividad antioxidante total fue menor en los grupos tratados con α-cetoanálogos de aminoácidos esenciales que en los grupos isquemia-reperfusión correspondientes. Conclusiones. Este es un nuevo informe de los efectos nefroprotectores de las α-cetoanálogos de aminoácidos esenciales contra la lesión isquemia-reperfusión. Los α-cetoanálogos de aminoácidos esenciales disminuyeron los niveles de los marcadores bioquímicos, de los de lesión renal, de las citocinas proinflamatorias y el MDA, a la vez que minimizaron el consumo total de antioxidantes.
Assuntos
Aminoácidos Essenciais/uso terapêutico , Antioxidantes/uso terapêutico , Cetoácidos/uso terapêutico , Rim/irrigação sanguínea , Traumatismo por Reperfusão/tratamento farmacológico , Alopurinol/uso terapêutico , Aminoácidos Essenciais/administração & dosagem , Animais , Antioxidantes/análise , Biomarcadores , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Cistatina C/sangue , Citocinas/sangue , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Cetoácidos/administração & dosagem , Rim/patologia , Lipocalina-2/sangue , Masculino , Malondialdeído/sangue , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controleRESUMO
BACKGROUND: Keto-analogues administration plays an important role in clinical chronic kidney disease (CKD) adjunctive therapy, however previous studies on their reno-protective effect mainly focused on kidney pathological changes induced by nephrectomy. This study was designed to explore the currently understudied alternative mechanisms by which compound α-ketoacid tablets (KA) influenced ischemia-reperfusion (IR) induced murine renal injury, and to probe the current status of KA administration on staving CKD progression in Chinese CKD patients at different stages. METHODS: In animal experiment, IR surgery was performed to mimic progressive chronic kidney injury, while KA was administrated orally. For clinical research, a retrospective cohort study was conducted to delineate the usage and effects of KA on attenuating CKD exacerbation. End-point CKD event was defined as 50% reduction of initial estimated glomerular filtration rate (eGFR). Kaplan-Meier analysis and COX proportional hazard regression model were adopted to calculate the cumulative probability to reach the end-point and hazard ratio of renal function deterioration. RESULTS: In animal study, KA presented a protective effect on IR induced renal injury and fibrosis by attenuating inflammatory infiltration and apoptosis via inhibition of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. In clinical research, after adjusting basic demographic factors, patients at stages 4 and 5 in KA group presented a much delayed and slower incidence of eGFR decrease compared to those in No-KA group (hazard ratio (HR) = 0.115, 95% confidence interval (CI) 0.021-0.639, p = 0.0134), demonstrating a positive effect of KA on staving CKD progression. CONCLUSION: KA improved IR induced chronic renal injury and fibrosis, and seemed to be a prospective protective factor in end stage renal disease.
Assuntos
Suplementos Nutricionais , Progressão da Doença , Cetoácidos/uso terapêutico , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Animais , Apoptose/efeitos dos fármacos , Dieta com Restrição de Proteínas , Feminino , Humanos , Inflamação/patologia , Cetoácidos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Probabilidade , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Traumatismo por Reperfusão/complicações , Análise de Sobrevida , ComprimidosRESUMO
Intravesical therapy using Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most established cancer immunotherapy for bladder cancer. However, its underlying mechanisms are unknown. Mycolic acid (MA), the most abundant lipid of the BCG cell wall, is suspected to be one of the essential active components of this immunogenicity. Here, we developed cationic liposomes incorporating three subclasses (α, keto, and methoxy) of MA purified separately from BCG, using the dendron-bearing lipid D22. The cationic liposomes using D22 were efficiently taken up by the murine bladder cancer cell line MB49 in vitro, but the non-cationic liposomes were not. Lip-kMA, a cationic liposome containing keto-MA, presented strong antitumor activity in two murine syngeneic graft models using the murine bladder cancer cell lines MB49 and MBT-2 in comparison to both Lip-aMA and Lip-mMA, which contained α-MA and methoxy-MA, respectively. Interestingly, Lip-kMA(D12), which was made of D12 instead of D22, did not exhibit antitumor activity in the murine syngeneic graft model using MB49 cells, although it was successfully taken up by MB49 cells in vitro. Histologically, compared to the number of infiltrating CD4 lymphocytes, the number of CD8 lymphocytes was higher in the tumors treated with Lip-kMA. Antitumor effects of Lip-kMA were not observed in nude mice, whereas weak but significant effects were observed in beige mice with natural killer activity deficiency. Thus, a cationized liposome containing keto-MA derived from BCG induced in vivo antitumor immunity. These findings will provide new insights into lipid immunogenicity and the underlying mechanisms of BCG immunotherapy.
Assuntos
Vacina BCG/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Ácidos Micólicos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia , Animais , Vacina BCG/administração & dosagem , Vacina BCG/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Linhagem Celular Tumoral , Feminino , Humanos , Imunoterapia , Cetoácidos/administração & dosagem , Cetoácidos/isolamento & purificação , Cetoácidos/uso terapêutico , Lipossomos/administração & dosagem , Lipossomos/química , Lipossomos/ultraestrutura , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Nus , Estrutura Molecular , Ácidos Micólicos/administração & dosagem , Ácidos Micólicos/isolamento & purificação , Tamanho da Partícula , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: Renal replacement therapy (RRT) is growing by 10 % per year in Russia, but pre-dialysis care which can retard CKD progression and delay the start of RRT remains limited. We evaluate the effect of Essential Amino Acids and Keto-analogues (EAA/KA) on CKD progression. METHODS: The effect of low protein diet (LPD), supplemented by EAA/KA, on GFR slope changes between first and second treatment period (five sequential visits per period) in 96 patients withs CKD Stage 3B-5 was compared to GFR slope changes in the control group of 96 patients, randomly selected from matched (by gender, age, diagnosis and CKD Stage) cohort of 320 patients from the city Registry. The mean baseline eGFR was 23 ± 9 ml/min/1.73 m2; 29 % had CKD3B, 45 % - CKD4, 26 % - CKD5. RESULTS: The rate of eGFR decline changed from -2.71 ± 2.38 to -2.01 ± 2.26 ml/min/1.73 m2 per year in the treatment group and from -2.18 ± 2.01 to -2.04 ± 2.18 ml/min/1.73 m2 per year in the control group. Only in the treatment group the difference was significant (p = 0.04 and p = 0.6). Standardized effect size for intervention was significant in treatment group: -0.3 (of pooled SD), 95 % CI -0.58 ÷ -0.02 and non-significant in control group: -0.07 (-0.35 ÷ +0.22). The univariate and multivariate analysis of EAA/KA therapy effect demonstrated that it was probably more effective in patients of older age, with higher time-averaged proteinuria (PU), lower phosphate level, in patients with glomerular v. interstitial diseases, and in females. Only the latter factor was significant at pre-specified level (<0.05). CONCLUSIONS: LPD combined with EAA/KA supplementation lead to the decrease of the CKD progression both in well-designed clinical study and in real nephrology practice in wide variety diseases and settings. Registry data can be helpful to reveal patients with optimal chances for beneficial effect of LPD supplemented by EAA/KA. TRIAL REGISTRATION: ISRCTN28190556 06/05/2016.
Assuntos
Aminoácidos/uso terapêutico , Dieta com Restrição de Proteínas , Cetoácidos/uso terapêutico , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Adulto , Fatores Etários , Idoso , Instituições de Assistência Ambulatorial , Estudos de Casos e Controles , Cidades , Suplementos Nutricionais , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Terapia de Substituição Renal , Federação Russa , Fatores SexuaisRESUMO
Ketoacids (KA) are known to preserve muscle mass among patients with chronic kidney disease (CKD) on a low-protein diet (LPD). The present study was to compare the effects of KA supplemented diet therapy in autophagy and inflammation in CKD rats' skeletal muscle. Rats with 5/6 nephrectomy were randomly divided into three groups and fed with either 11 g/kg/day protein [normal-protein diet (NPD)], 3 g/kg/day protein (LPD) or 3 g/kg/day protein which including 5% protein plus 1% KA (LPD + KA) for 24 weeks. Sham-operated rats with NPD intake were used as control. LPD could improve body weight, gastrocnemius muscle mass, as well as gastrocnemius muscle cross-sectional area, with the effect being more obvious in the LPD + KA group. The autophagy marker LC3 (microtubule-associated protein 1 light chain 3), p62, Parkin and PTEN induced putative kinase 1 (PINK1) were significantly attenuate in LPD + KA group than LPD group. LPD + KA group had the lower total mtDNA (mitochondiral DNA) and cytosol mtDNA, NACHT-PYD-containing protein 3 (NALP3) inflammasome than LPD group, but its reactive oxygen species (ROS), caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC) level was higher. Immunoblotting showed IL-1ß (interleukin-1-beta) was lower in LPD and LPD + KA group than the NPD group, but IL-18 showed no significant difference among control and CKD group; toll-like receptor signalling-dependent IL-6 was higher in LPD + KA group than LPD group, but tumor necrosis factor-α (TNF-α) was not significantly changed between LPD + KA and LPD group. Systematic changes of the four cytokines were different from that of the tissue. Although LPD + KA could further ameliorate-activated autophagy than LPD, its effect on the activated inflammation state in CKD was not distinctly. Further study is still required to explore the method of ameliorating inflammation to provide new therapeutic approaches for CKD protein energy wasting (PEW).
Assuntos
Autofagia , Dieta com Restrição de Proteínas , Inflamação/complicações , Inflamação/dietoterapia , Cetoácidos/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/dietoterapia , Animais , Suplementos Nutricionais/análise , Inflamação/imunologia , Inflamação/patologia , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Atrofia Muscular/dietoterapia , Atrofia Muscular/etiologia , Atrofia Muscular/imunologia , Atrofia Muscular/patologia , Nefrectomia , Ratos , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/patologiaRESUMO
Ketoacids (KA) are known to improve muscle mass among patients with chronic kidney disease (CKD) on a low-protein diet (CKD-LPD), but the mechanism of its preventive effects on muscle atrophy still remains unclear. Since muscle atrophy in CKD may be attributable to the down-regulation of the Wnt7a/Akt/p70S6K pathway and the activation of the ubiquitin-proteasome system (UPS) and the apoptotic signalling pathway, a hypothesis can readily be drawn that KA supplementation improves muscle mass by up-regulating the Wnt7a/Akt/p70S6K pathway and counteracting the activation of the UPS and caspase-3-dependent apoptosis in the muscle of CKD-LPD rats. Rats with 5/6 nephrectomy were randomly divided into three groups, and fed with either 22 % protein (normal-protein diet; NPD), 6 % protein (LPD) or 5 % protein plus 1 % KA for 24 weeks. Sham-operated rats with NPD intake were used as the control. The results demonstrated that KA supplementation improved protein synthesis and increased related mediators such as Wnt7a, phosphorylated Akt and p70S6K in the muscle of CKD-LPD rats. It also inhibited protein degradation, withheld the increase in ubiquitin and its ligases MAFbx (muscle atrophy F-box) and MuRF1 (muscle ring finger-1) as well as attenuated proteasome activity in the muscle of CKD-LPD rats. Moreover, KA supplementation gave rise to a reduction in DNA fragment, cleaved caspase-3 and 14 kDa actin fragment via the down-regulation of the Bax:Bcl-2 ratio in the muscle of CKD-LPD rats. The beneficial effects unveiled herein further consolidate that KA may be a better therapeutic strategy for muscle atrophy in CKD-LPD.
Assuntos
Suplementos Nutricionais , Modelos Animais de Doenças , Cetoácidos/uso terapêutico , Músculo Esquelético/metabolismo , Atrofia Muscular/prevenção & controle , Proteínas Proto-Oncogênicas/agonistas , Insuficiência Renal Crônica/dietoterapia , Proteínas Wnt/agonistas , Animais , Apoptose , Dieta com Restrição de Proteínas/efeitos adversos , Regulação para Baixo , Masculino , Proteínas Musculares/biossíntese , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Nefrectomia/efeitos adversos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteínas Proto-Oncogênicas/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Transdução de Sinais , Ubiquitinação , Regulação para Cima , Proteínas Wnt/metabolismoRESUMO
OBJECTIVE: To investigate the effects of the combination of alpha-keto acid and low-protein diet on the levels of serum cytokines in patients performing continuous ambulatory peritoneal dialysis (CAPD) and to explore the relationship between inflammation and malnutrition in CAPD patients. METHODS: Eighty-nine CAPD patients were randomized into three groups, and 78 cases completed a one-year follow-up and with complete data. There were 31 cases in low-protein diet plus alpha-keto acid group, 26 cases in low-protein diet group and 21 cases in routine-protein diet group. The levels of serum albumin (Alb), prealbumin (PA), retinol-binding protein (RBP), transferrin (TRF), cholesterol (TC), triglycerides (TG), leptin, and triceps skinfold thickness (TSF), mid-arm muscle circumference (MAMC), body mass index (BMI) were measured. The changes of serum interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP) were also detected. RESULTS: Compared with low-protein diet group, serum levels of PA, RBP and TRF were significantly increased both in low-protein diet plus alpha-keto acid and routine-protein diet groups ( P<0.01), however, there was no significant difference in the levels of PA, RBP and TRF between low-protein diet plus alpha-keto acid group and routine-protein diet group. There was an increased tendency in the content of Alb, TC, TG, BMI, TSF and MAMC, but there were no significant differences. The plasma levels of IL-1alpha, IL-6 and TNF-alpha in low-protein diet plus alpha-keto acid group were decreased as compared with the routine-protein diet group, but there were no significant differences. The plasma level of CRP in low-protein diet plus alpha-keto acid group was lower than that in the routine-protein diet group ( P<0.01). CONCLUSION: The combination of alpha-keto acid and low-protein diet can ameliorate malnutrition and micro-inflammation in CAPD patients.
Assuntos
Dieta com Restrição de Proteínas , Cetoácidos/uso terapêutico , Falência Renal Crônica/terapia , Estado Nutricional , Diálise Peritoneal Ambulatorial Contínua , Idoso , Idoso de 80 Anos ou mais , Citocinas/sangue , Feminino , Humanos , Inflamação/terapia , Masculino , Desnutrição/prevenção & controle , Pessoa de Meia-IdadeRESUMO
Supplement with keto acids/amino acids (KA) and erythropoietin can independently improve the metabolic sequels of chronic renal insufficiency. Our study was designed to establish whether a supplementation with keto acids/amino acids (KA) exerts additional beneficial metabolic effects in patients with chronic renal insufficiency (CRF) treated with a low-protein diet (LPD) and recombinant human erythropoietin (EPO). In a prospective randomized controlled trial over a period of 12 months, we evaluated a total of 38 patients (20 M/18 F) aged 32-68 years with a creatinine clearance (CCr) of 20-36 ml/min. All patients were receiving EPO (40 U/kg twice a week s.c.) and a low-protein diet (0.6 g protein/kg/day and 145 kJ/kg/day). The diet of 20 patients (Group I) was supplemented with KA at a dosage of 100 mg/kg/day while 18 patients (Group II) received no supplementation. During the study period, the glomerular filtration rate slightly decreased (CCr from 28.2 +/- 3.4 to 26.4 +/- 4.1 ml/min and 29.6 +/- 4.8 to 23.4 +/- 4.4 ml/min in groups I and II, respectively and Cin); this however was more marked in Group II (Group I vs. Group II, p < 0.01). The serum levels of urea also declined (p < 0.01), more pronouncedly in Group I (p < 0.025). In Group I, there was a significant rise in the levels of leucine (p < 0.01), isoleucine (p < 0.01), valine (p < 0.02) and albumin (p < 0.01) and a decrease in protein-uria (p < 0.01). Analysis of the lipid spectrum revealed a mild yet significant decrease in total cholesterol and LDL-cholesterol (p < 0.02), more pronounced in Group I. In Group I, there was a decrease in plasma triglycerides (from 4.2 +/- 0.8 down to values a low as 2.2 +/- 0.6 mmol/L; p < 0.01) whereas HDL-cholesterol levels increased (from 0.9 +/- 0.1 to 1.2 +/- 0.1 mmol/L, p < 0.01). A further remarkable finding was a reduction in the serum concentration of free radicals (p < 0.01). We conclude that a KA supplementation in patients with CRF receiving LPD and EPO potentiates the beneficial effects on metabolism of proteins, amino acids and surprisingly, also lipids. Long-term co-administration of KA, EPO and LPD was also associated with a delay in progression of renal insufficiency and a reduction in proteinuria. Thus, concomitant administration of KA and EPO during a low-protein diet presents an effective treatment modality in the conservative management of CRF.
Assuntos
Dieta com Restrição de Proteínas/métodos , Eritropoetina/uso terapêutico , Cetoácidos/uso terapêutico , Falência Renal Crônica/dietoterapia , Adulto , Idoso , Aminoácidos/uso terapêutico , Aminoácidos de Cadeia Ramificada/sangue , Aminoácidos Essenciais/uso terapêutico , Feminino , Alimentos Formulados , Radicais Livres/sangue , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/metabolismo , Falência Renal Crônica/urina , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas/metabolismo , Proteinúria/etiologia , Proteínas Recombinantes , Resultado do TratamentoRESUMO
Sepsis was induced in rats by cecal ligation and puncture. A nutrient mixture was infused that also contained either (A) sodium 2-ketoisocaproate (NaKIC) or (B) NaHCO3, at 18.75 mmol kg/day. In group A, 34 of 43 rats (79%) survived, while only 24 of 44 rats (55%) in group B survived (P < 0.02). In a second experiment, cecal ligation and puncture were performed 1 week after bilateral adrenalectomy or sham adrenalectomy. All adrenalectomized rats died within 2 days of CLP, whether corticosterone replacement level was low, normal, or high. Four of eight sham-adrenalectomized rats receiving NaHCO3 died, but none of seven receiving NaKIC died. Combining both experiments by ANOVA, the effect of KIC on survival in adrenal-intact animals is highly significant (P = 0.002). In NaKIC-infused rats, blood level of pyruvate was higher on day 5 (P < 0.01), and plasma as well as blood levels of oxidized glutathione and ratio of oxidized/reduced glutathione were significantly lower. We conclude that KIC infusion improves survival of septic rats by an antioxidant mechanism, probably involving reaction with hydrogen peroxide.
Assuntos
Antioxidantes/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Cetoácidos/uso terapêutico , Adrenalectomia , Aminoácidos/sangue , Animais , Infecções Bacterianas/mortalidade , Corticosterona/sangue , Glutationa/sangue , Masculino , Piruvatos/sangue , Ácido Pirúvico , Ratos , Ratos Sprague-Dawley , Taxa de SobrevidaRESUMO
The effect of nutritional supplementation with branched chain amino acids or the ketoacid alpha-ketoisocaproate on protein metabolism after surgery was studied in 24 patients with gastrointestinal cancer. They were randomized to receive one of three nutritional regimens. All patients received a balanced amino acid solution and group 1 (n = 8) received no further supplements, group 2 (n = 8) received supplementation with alpha-ketoisocaproate (17 g day-1) and group 3 (n = 8) received a branched chain solution including leucine, isoleucine and valine, corresponding to 3.3 g nitrogen day-1. Plasma albumin, prealbumin, fibronectin and serum urea concentrations, nitrogen balance and 3-methylhistidine release from the leg and its excretion in the urine were measured. Albumin and prealbumin concentrations fell after surgery in all groups, and fibronectin levels fell in group 2 (P less than 0.001). In group 2 there was also a significant increase in serum urea concentration after operation (P less than 0.05). Cumulative nitrogen balance after 3 days was -5.6 g (group 1), -3.8 g (group 2) and -1.7 g (group 3). The release of 3-methylhistidine (nmol 100 g-1 min-1) from the leg after operation, following an overnight fast, was -0.42 (group 1), -0.51 (group 2) and -0.66 (group 3). During infusion the release was -0.56, -0.99 and -0.81, respectively. A balanced amino acid solution with an adequate energy supply has an optimal nitrogen-sparing effect. Branched chain amino acids or alpha-ketoisocaproate did not improve nitrogen balance or reduce protein degradation.
Assuntos
Aminoácidos de Cadeia Ramificada/uso terapêutico , Caproatos/uso terapêutico , Neoplasias Gastrointestinais/cirurgia , Cetoácidos/uso terapêutico , Proteínas/metabolismo , Feminino , Humanos , Masculino , Metilistidinas/metabolismo , Pessoa de Meia-Idade , Nitrogênio/metabolismo , Nutrição Parenteral Total , Período Pós-OperatórioRESUMO
We have investigated the protective effects of the inhaled cysteinyl leukotriene antagonist, L-648,051, on allergen-induced early asthmatic response (EAR) and late asthmatic response (LAR) and the subsequent changes in bronchial responsiveness to methacholine. Ten atopic men with asthma participated in a double-blind, crossover, placebo-controlled trial. All subjects had documented EAR and LAR to house dust-mite extract. Responsiveness to methacholine was measured the day before and the day after a standardized allergen-challenge test. L-648,051 was inhaled in two doses of 12 mg 20 minutes before and 3 hours after the allergen challenge. The response was obtained from FEV1 and flows from maximal (V40m) and partial (V40p) expiratory flow-volume curves. All subjects had an EAR and LAR during placebo therapy, but only a minority demonstrated an increase in methacholine responsiveness of more than one doubling dose. The ratio of V40m to V40p during methacholine challenge was higher than during both EAR and LAR (p less than 0.05). There was no difference between drug- and placebo-therapy periods in baseline function, EAR, LAR, ratio of V40m to V40p, and the allergen-induced hyperresponsiveness (p greater than 0.1). These results indicate that an effective aerosolized leukotriene antagonist in man does not protect against allergen-induced airflow obstruction, despite the evidence of an inflammatory response to allergen challenge. This suggests that either the potency or duration of activity of L-648,051 is limited or that leukotrienes C4 and D4 do not play a causative role in human allergic asthma.
Assuntos
Asma/fisiopatologia , Cetoácidos/farmacologia , Sulfonas/farmacologia , Administração por Inalação , Adulto , Asma/tratamento farmacológico , Testes de Provocação Brônquica , Ensaios Clínicos como Assunto , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Consentimento Livre e Esclarecido , Cetoácidos/administração & dosagem , Cetoácidos/uso terapêutico , Compostos de Metacolina/farmacologia , Placebos , Sulfonas/administração & dosagem , Sulfonas/uso terapêuticoRESUMO
The therapeutical effect of keto acids on bone histology was investigated in a prospective randomized controlled study of 40 patients. A marked improvement in osteofibrotic as well as in osteomalacic changes was found in bone biopsies after 12 months of treatment with keto acids.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Cetoácidos/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/dietoterapia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Terapia Combinada , Proteínas Alimentares/administração & dosagem , Humanos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina D/uso terapêuticoRESUMO
Examinations of 137 patients with inflammatory diseases of the maxillofacial area and neck, treated with baliz-2, have shown that this agent is characterized by a manifest antibacterial action on the wound microflora, helps thinning the purulent exudate, and accelerates detachment of the necrotic mass. No cases of local irritation were recorded.
Assuntos
Abscesso/tratamento farmacológico , Anti-Infecciosos Locais/uso terapêutico , Celulite (Flegmão)/tratamento farmacológico , Infecção Focal Dentária/tratamento farmacológico , Cistos Maxilomandibulares/tratamento farmacológico , Doenças Maxilomandibulares/tratamento farmacológico , Cetoácidos/uso terapêutico , Avaliação de Medicamentos , Face , Feminino , Humanos , Masculino , Fatores de TempoRESUMO
KA administration given in addition to a low-protein diet leads to a reduction of PTH secretion followed by diminishing of osteofibrosis. Osteomalacia will also be reduced by a better control of the calcium-phosphate metabolism, an increase of 1,25-(OH)2-D levels, and a lower burden of aluminum. Therapeutic levels of 25-OH-D and calcitonin (caused by simultaneous administration of vitamin D) are probably necessary to achieve this effect. KA are not only the optimum form of substitution in the nutritional treatment of chronic renal failure, but they seem to be very effective in the treatment of renal osteodystrophy.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/prevenção & controle , Cetoácidos/uso terapêutico , Falência Renal Crônica/terapia , Aminoácidos Essenciais/uso terapêutico , Osso e Ossos/metabolismo , Proteínas Alimentares/administração & dosagem , Humanos , Hormônio Paratireóideo/metabolismo , Fósforo/administração & dosagem , Vitamina D/uso terapêuticoRESUMO
Starting from the results of former investigations the influence of the long-term treatment with the KA of the essential amino acids on the renal osteopathy is investigated. For this purpose we compared 27 patients with renal insufficiency (serum creatinine 981 +/- 354 mumol/l), who besides vitamin D had been treated with KA for at least 12 months, to a group of 50 patients (serum creatinine 778 +/- 273 mumol/l), who had received vitamin D over 19 +/- 9 months, and to a control group of 27 patients (serum creatinine 928 +/- mumol/l) without an adequate conservative therapy. While the control group showed the typical constellation in advanced renal insufficiency with hypocalcaemia, hyperphosphataemia, clearly increased PTH levels, clearly increased CT values and normal 25-OH-D concentrations, during the diettherapy and the vitamin D substitution a significant increase of the serum levels of calcium, 25-OH-D and CT as well as a significant decrease of the PTH and the anorganic phosphate in the serum developed. Under the combination therapy with KA and vitamin D despite the reduction of the phosphate binders another significant decrease of the PTH and the anorganic phosphate was observed. The mineral content of the bones was within the normal in the two therapy groups. The percentage of the normal histological findings of the bones was with 40.7% highest despite the advanced renal insufficiency in the simultaneous substitution with KA. While in the vitamin D group during the control biopsy after 12 months in 20.5% of the cases an improvement of the histological findings developed, this effect occurred under additional KA-therapy in 51.9% of the cases. The results allow the conclusion that by means of the long-term treatment with KA a favourable influence on the renal osteopathy develops.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Ergocalciferóis/uso terapêutico , Cetoácidos/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Osso e Ossos/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/dietoterapia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Terapia Combinada , Ergocalciferóis/administração & dosagem , Humanos , Cetoácidos/administração & dosagem , Falência Renal Crônica/dietoterapia , Falência Renal Crônica/patologia , Pessoa de Meia-Idade , ComprimidosRESUMO
A male infant who had vomiting and coma in the absence of ketoacidosis was initially thought to have dysautonomia because of abnormal responses to methacholine and histamine, as well as abnormal urinary catecholamine excretion. Following an episode of hyperammonemia, a liver biopsy was performed which revealed a partial deficiency of carbamyl phosphate synthetase activity. The patient was treated with a protein-restricted diet supplemented with a mixture of ketoacid analogues of the essential amino acids, which precipitated ketosis and acidosis. A primary deficiency of propionyl coenzyme A (CoA) carboxylase was subsequently demonstrated. Because disorders of propionate metabolism may not initially present with ketoacidosis, we recommend examination of both plasma and urine for metabolites of this pathway, as well as direct measurement of propionyl CoA carboxylase activity in peripheral blood leukocytes, before performing a liver biopsy to evaluate urea cycle enzyme activities, and particularly before adding keto acid/amino acid mixtures to a protein-restricted diet.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/sangue , Amônia/sangue , Disautonomia Familiar/sangue , Ligases/deficiência , Acil Coenzima A , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Aminoácidos/uso terapêutico , Carbamoil-Fosfato Sintase (Amônia)/sangue , Carbamoil-Fosfato Sintase (Amônia)/deficiência , Diagnóstico Diferencial , Humanos , Lactente , Cetoácidos/uso terapêutico , Leucócitos/enzimologia , Ligases/sangue , Fígado/enzimologia , Masculino , Propionatos/sangueRESUMO
Assay of ornithine transcarbamylase (OTC) activity in multiple small bits of liver (approximately 5 mg) that were obtained from a single surgical biopsy in a patient with OTC deficiency revealed a 10- to 40-fold variation in enzyme activity. Similar studies with control autopsy liver specimens varied 2.5-fold at most. The greater variation in the patient with OTC deficiency probably is due to sampling of clusters of normal or abnormal hepatocytes that resulted from inactivation of either the abnormal or normal X chromosone. Enzyme activity assayed on small liver biopsy specimens may not be representative of the entire liver in female patients with OTC deficiency. The hyperammonemia in individuals heterozygous for OTC deficiency may be due in part to shunting of blood through multiple "metabolic portosystemic shunts." Treatment of a girl who has OTC deficiency with a low-protein diet, a low-protein diet supplemented with oral essential amino acids, and a low-protein diet plus oral ketoacids of essential amino acids, on a separate occasion, a low-protein diet was compared to a low-protein diet plus lactulose. The low-protein diet plus oral ketoacid supplementation resulted in the best metabolic control of the patient's disease. On the other hand, paradoxical transient hyperammonemia was observed after the intarvenous administration of ketoacids to two acutely ill female patients with OTC deficiency.
Assuntos
Amônia/sangue , Doença da Deficiência de Ornitina Carbomoiltransferase , Aminoácidos Essenciais , Criança , Proteínas Alimentares/uso terapêutico , Feminino , Heterozigoto , Humanos , Cetoácidos/uso terapêutico , Lactulose/uso terapêutico , Fígado/enzimologia , Cromossomo XRESUMO
Congenital carbamyl phosphate synthetase deficiency was diagnosed by liver biopsy in a 13-year-old girl, alpha-Keto analogues of essential amino acids have been shown to spare nitrogen by reducing urea formation; hence, they were given to this patient in the hope of reducing hyperammonemia and improving protein tolerance. After intravenous infusion of the keto analogues of valine, leucine, isoleucine, methionine and phenylalanine, the corresponding plasma amino acids, including alloisoleucine and tyrosine, rose sharply. Twenty-four hours later, fasting plasma ammonia had fallen from the preinfusion value of 0.050 to 0.028 mM. Protein intake was kept at 0.5 g per kilogram for two weeks. Addition of keto acids by mouth reduced plasma ammonia and alanine to normal or near normal levels. Seizures and episodes of vomiting and lethargy decreased in frequency. Urinary nitrogen decreased, suggesting that nitrogen balance improved. These data indicate that keto acids may be useful in the treatment of congenital hyperammonemia.