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1.
Gene ; 760: 145018, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758580

RESUMO

Protein turnover is a process that is regulated by several factors and can lead to muscle hypertrophy or atrophy. The purpose of the present study was to determine the effects of ß-hydroxy-ß-methylbutyrate free acid (HMB-FA) and eccentric resistance exercise on variables related to protein turnover in rats. Thirty-two male rats were randomly assigned into four groups of eight, including control, control-HMB, exercise, and exercise-HMB. Animals in HMB groups received 340 mg/kg/day for two weeks. Animals in the exercise groups performed one session of eccentric resistance exercise consisting of eight repetitions descending from a ladder with a slope of 80 degree, with an extra load of two times body weight (100% 1RM). Twenty-four hours after the exercise session, triceps brachii muscle and serum were collected for further analysis. Exercise and HMB-FA induced lower muscle myostatin and higher muscle Fibronectin type III domain containing 5 (FNDC5), P70-S6 kinase 1 gene expression, as well as higher serum irisin and IGF-1 concentrations. Exercise alone induced higher caspase-3 and caspase-8 gene expression while HMB-FA alone induced lower caspase 3 gene expression. HMB-FA supplement increased the effect of exercise on muscle FNDC5, myostatin, and P70-S6 kinase 1 gene expression. The interaction of exercise and HMBFA resulted in an additive effect, increasing serum irisin and IGF-1 concentrations. In conclusion, a 2-week HMB-FA supplementation paired with acute eccentric resistance exercise can positively affect some genes related to muscle protein turnover.


Assuntos
Proteínas Musculares/efeitos dos fármacos , Valeratos/farmacologia , Animais , Suplementos Nutricionais , Fibronectinas/efeitos dos fármacos , Fibronectinas/metabolismo , Genes Reguladores/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Miostatina/efeitos dos fármacos , Miostatina/metabolismo , Condicionamento Físico Animal/métodos , Ratos , Ratos Sprague-Dawley , Treinamento de Resistência/métodos , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
2.
BMC Vet Res ; 16(1): 171, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32487098

RESUMO

BACKGROUND: A healthy immune system plays a particularly important role in newborns, including in calves that are far more susceptible to infections (viral, bacterial and other) than adult individuals. Therefore, the present study aimed to evaluate the influence of HMB on the chemotactic activity (MIGRATEST® kit), phagocytic activity (PHAGOTEST® kit) and oxidative burst (BURSTTEST® kit) of monocytes and granulocytes in the peripheral blood of calves by flow cytometry. RESULTS: An analysis of granulocyte and monocyte chemotactic activity and phagocytic activity revealed significantly higher levels of phagocytic activity in calves administered HMB than in the control group, expressed in terms of the percentage of phagocytising cells and mean fluorescence intensity (MFI). HMB also had a positive effect on the oxidative metabolism of monocytes and granulocytes stimulated with PMA (4-phorbol-12-ß-myristate-13-acetate) and Escherichia coli bacteria, expressed as MFI values and the percentage of oxidative metabolism. CONCLUSION: HMB stimulates non-specific cell-mediated immunity, which is a very important consideration in newborn calves that are exposed to adverse environmental factors in the first weeks of their life. The supplementation of animal diets with HMB for both preventive and therapeutic purposes can also reduce the use of antibiotics in animal production.


Assuntos
Bovinos/sangue , Granulócitos/fisiologia , Monócitos/fisiologia , Valeratos/farmacologia , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Animais Recém-Nascidos , Bovinos/imunologia , Quimiotaxia/efeitos dos fármacos , Dieta/veterinária , Citometria de Fluxo/veterinária , Granulócitos/citologia , Monócitos/citologia , Fagocitose/efeitos dos fármacos , Explosão Respiratória
3.
J Agric Food Chem ; 68(2): 530-540, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31891490

RESUMO

The influence of ß-hydroxy-ß-methylbutyrate (HMB) on proliferation and differentiation of myogenic cells has been well-studied. However, the role of HMB in myofiber specification and potential mechanisms is largely unknown. Thus, the objective of this research was to explore the role of HMB supplementation in myofiber specification. Results showed that HMB treatment significantly increased the fast MyHC protein level (mice: 1.59 ± 0.08, P < 0.01; C2C12: 2.26 ± 0.11, P < 0.001), decreased the slow MyHC protein level (mice: 0.76 ± 0.05, P < 0.05; C2C12: 0.52 ± 0.02, P < 0.001), and increased the miR-199a-3p level (mice: 4.93 ± 0.37, P < 0.001; C2C12: 11.25 ± 0.57, P < 0.001). Besides, we also observed that HMB promoted the activity of glycolysis-related enzymes and reduced the activities of oxidation-related enzymes in mice and C2C12 cells. Overexpression of miR-199a-3p downregulated the slow MyHC protein level (0.71 ± 0.02, P < 0.01) and upregulated the fast MyHC protein level (2.13 ± 0.09, P < 0.001), while repression of miR-199a-3p exhibited the opposite effect. Target identification results verified that miR-199a-3p targets the 3'UTR of the TEA domain family member 1 (TEAD1) to cause its post-transcriptional inhibition (0.41 ± 0.07, P < 0.01). Knockdown of TEAD1 exhibited a similar effect with miR-199a-3p on myofiber specification. Moreover, suppression of miR-199a-3p blocked slow-to-fast myofiber type transition induced by HMB. Together, our finding revealed that miR-199-3p is induced by HMB and contributes to the action of HMB on slow-to-fast myofiber type conversion via targeting TEAD1.


Assuntos
MicroRNAs/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Mioblastos Esqueléticos/efeitos dos fármacos , Valeratos/farmacologia , Regiões 3' não Traduzidas , Animais , Diferenciação Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos , MicroRNAs/genética , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Nutrients ; 12(1)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936727

RESUMO

Creatine monohydrate (CrM) and ß-hydroxy ß-methylbutyrate (HMB) are common ergogenic aids in the field of sports and are frequently used in an isolated way. However, there are a few studies that have investigated the effect of combining both supplements on different variables related to performance, with controversial results. Therefore, the main purpose of this study was to determine the efficacy and the degree of potentiation of 10 weeks of CrM plus HMB supplementation on sports performance, which was measured by an incremental test to exhaustion in elite male traditional rowers. In this placebo-controlled, double-blind trial, 10-week study, participants (n = 28) were randomized to a placebo group (PLG; n = 7), CrM group (0.04 g/kg/day of CrM; n = 7), HMB group (3 g/day of HMB; n = 7) and CrM-HMB group (0.04 g/kg/day of CrM plus 3 g/day of HMB; n = 7). Before and after 10 weeks of different treatments, an incremental test was performed on a rowing ergometer to calculate the power that each rower obtained at the anaerobic threshold (WAT), and at 4 mmol (W4) and 8 mmol (W8) of blood lactate concentration. There were no significant differences in WAT and W4 among groups or in body composition. However, it was observed that the aerobic power achieved at W8 was significantly higher in the CrM-HMB group than in the PLG, CrM and HMB groups (p < 0.001; η2p = 0.766). Likewise, a synergistic effect of combined supplementation was found for the sum of the two supplements separately at WAT (CrM-HMBG = 403.19% vs. CrMG+HMBG = 337.52%), W4 (CrM-HMBG = 2736.17% vs. CrMG+HMBG = 1705.32%) and W8 (CrM-HMBG = 1293.4% vs. CrMG+HMBG = 877.56%). In summary, CrM plus HMB supplementation over 10 weeks showed a synergistic effect on aerobic power (measured as WAT, W4, and W8) during an incremental test but had no influence muscle mass.


Assuntos
Atletas , Desempenho Atlético/normas , Creatina/farmacologia , Suplementos Nutricionais , Valeratos/farmacologia , Adulto , Limiar Anaeróbio , Composição Corporal , Creatina/administração & dosagem , Método Duplo-Cego , Humanos , Masculino , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Resistência Física , Valeratos/administração & dosagem
5.
J Neuroinflammation ; 16(1): 217, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722730

RESUMO

BACKGROUND: Microglial activation contributes to the development of chronic migraine (CM). The P2Y12 receptor (P2Y12R), a metabolic purinoceptor that is expressed on microglia in the central nervous system (CNS), has been indicated to play a critical role in the pathogenesis of chronic pain. However, whether it contributes to the mechanism of CM remains unknown. Thus, the present study investigated the precise details of microglial P2Y12R involvement in CM. METHODS: Mice subjected to recurrent nitroglycerin (NTG) treatment were used as the CM model. Hyperalgesia were assessed by mechanical withdrawal threshold to electronic von Frey and thermal withdrawal latency to radiant heat. Western blot and immunohistochemical analyses were employed to detect the expression of P2Y12R, Iba-1, RhoA, and ROCK2 in the trigeminal nucleus caudalis (TNC). To confirm the role of P2Y12R and RhoA/ROCK in CM, we systemically administered P2Y12R antagonists (MRS2395 and clopidogrel) and a ROCK2 inhibitor (fasudil) and investigated their effects on microglial activation, c-fos, and calcitonin gene-related peptide (CGRP) expression in the TNC. To further confirm the effect of P2Y12R on microglial activation, we preincubated lipopolysaccharide (LPS)-treated BV-2 microglia with MRS2395 and clopidogrel. ELISA was used to evaluate the levels of inflammatory cytokines. RESULTS: The protein levels of P2Y12R, GTP-RhoA, ROCK2, CGRP, c-fos, and inducible nitric oxide synthase (iNOS) in the TNC were increased after recurrent NTG injection. A double labeling study showed that P2Y12R was restricted to microglia in the TNC. MRS2395 and clopidogrel attenuated the development of tactile allodynia and suppressed the expression of CGRP, c-fos, and GTP-RhoA/ROCK2 in the TNC. Furthermore, fasudil also prevented hyperalgesia and suppressed the expression of CGRP in the TNC. In addition, inhibiting P2Y12R and ROCK2 activities suppressed NTG-induced microglial morphological changes (process retraction) and iNOS production in the TNC. In vitro, a double labeling study showed that P2Y12R was colocalized with BV-2 cells, and the levels of iNOS, IL-1ß, and TNF-α in LPS-stimulated BV-2 microglia were reduced by P2Y12R inhibitors. CONCLUSIONS: These data demonstrate that microglial P2Y12R in the TNC plays a critical role in the pathogenesis of CM by regulating microglial activation in the TNC via RhoA/ROCK pathway.


Assuntos
Microglia/metabolismo , Transtornos de Enxaqueca/metabolismo , Receptores Purinérgicos P2Y12/metabolismo , Núcleos do Trigêmeo/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Clopidogrel/farmacologia , Modelos Animais de Doenças , Camundongos , Microglia/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Núcleos do Trigêmeo/efeitos dos fármacos , Valeratos/farmacologia
6.
Nutrients ; 11(10)2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31635165

RESUMO

Although there are many studies showing the isolated effect of creatine monohydrate (CrM) and ß-hydroxy ß-methylbutyrate (HMB), it is not clear what effect they have when they are combined. The main purpose of this systematic review was to determine the efficacy of mixing CrM plus HMB in comparison with their isolated effects on sports performance, body composition, exercise induced markers of muscle damage, and anabolic-catabolic hormones. This systematic review was carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement guidelines and the PICOS model, for the definition of the inclusion criteria. Studies were found by searching PubMed/MEDLINE, Web of Science (WOS), and Scopus electronic databases from inception to July 3rd 2019. Methodological quality and risk of bias were assessed by two authors independently, and disagreements were resolved by third-party evaluation, in accordance with the Cochrane Collaboration Guidelines samples. The literature was examined regarding the effects of the combination of CrM plus HMB on sport performance using several outcome variables (athletic performance, body composition, markers of muscle damage, and hormone status). This systematic review included six articles that investigated the effects of CrM plus HMB on sport performance (two on strength performance, showing improvements in one of them; three on anaerobic performance, presenting enhancements in two of them; and one on aerobic performance, not presenting improvements), body composition (three on body mass, showing improvements in one of them; two on fat free mass, presenting increases in one of them; and two on fat mass, showing decreases in one of them) and markers of muscle damage and hormone status (four on markers of muscle damage and one on anabolic-catabolic hormones, not showing benefits in any of them). In summary, the combination of 3-10 g/day of CrM plus 3 g/day of HMB for 1-6 weeks could produce potential positive effects on sport performance (strength and anaerobic performance) and for 4 weeks on body composition (increasing fat free mass and decreasing fat mass). However, this combination seems to not show positive effects relating to markers of exercise-induced muscle damage and anabolic-catabolic hormones.


Assuntos
Desempenho Atlético , Composição Corporal/efeitos dos fármacos , Creatina/farmacologia , Doenças Musculares/metabolismo , Valeratos/farmacologia , Creatina/administração & dosagem , Creatina/química , Humanos , Esportes , Valeratos/administração & dosagem , Valeratos/química
7.
Nutrients ; 11(9)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546969

RESUMO

Sarcopenia is a frequent complication in liver transplant (LT) recipients. ß-hydroxy-ß-methyl-butyrate (HMB) has the potential to increase muscle-performance and tropism. Our study aims at evaluating the effect on muscle mass and functioning, and the safety of 12 weeks of HMB supplementation in patients after LT. This is a pilot, randomized study. Male patients undergoing LT were randomly assigned to the HMB or control group. A diet interview, anthropometry and body composition by dual energy X-ray absorptiometry (DEXA) were performed at enrollment (T0), after 12 weeks (T1) and after 12 months (T12). Twenty-two liver transplant male patients were enrolled in the study: 12 in the HMB group and 10 as the control group. At enrollment, demographic, clinical and nutritional data were similar. According to the appendicular skeletal muscle index, sarcopenia was present in 50% of patients. The appendix skeletal muscle mass index (ASMI) showed a significant increase at T1 and T12 in HMB patients, but not in controls. The mid-arm muscle-circumference and hand grip strength also increased at T1 and T12 versus T0 only in the HMB group. No side effects were reported in either group. The study showed a positive effect of HMB in the recovery of muscle mass and strength after LT. HMB supplement in patients after LT was safe and well tolerated.


Assuntos
Transplante de Fígado , Valeratos/farmacologia , Idoso , Suplementos Nutricionais , Humanos , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Projetos Piloto , Cuidados Pós-Operatórios , Sarcopenia/prevenção & controle , Valeratos/administração & dosagem
8.
Nutrients ; 11(9)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484462

RESUMO

Both regular exercise training and beta-hydroxy-beta-methylbutyrate (HMB) supplementation are shown as effective treatments to delay or reverse frailty and reduce cognitive impairment in older people. However, there is very little evidence on the true benefits of combining both strategies. The aim of this meta-analysis was to quantify the effects of exercise in addition to HMB supplementation, on physical and cognitive health in older adults. Data from 10 randomized controlled trials (RCTs) investigating the effect of HMB supplementation and physical function in adults aged 50 years or older were analyzed, involving 384 participants. Results showed that HMB supplementation in addition to physical exercise has no or fairly low impact in improving body composition, muscle strength, or physical performance in adults aged 50 to 80 years, compared to exercise alone. There is a gap of knowledge on the beneficial effects of HMB combined with exercise to preserve cognitive functions in aging and age-related neurodegenerative diseases. Future RCTs are needed to refine treatment choices combining HMB and exercises for older people in particular populations, ages, and health status. Specifically, interventions in older adults aged 80 years or older, with cognitive impairment, frailty, or limited mobility are required.


Assuntos
Envelhecimento , Suplementos Nutricionais , Exercício Físico/fisiologia , Valeratos/farmacologia , Humanos , Valeratos/administração & dosagem
9.
Int J Exp Pathol ; 100(3): 175-183, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31321841

RESUMO

Beta-hydroxy-beta-methylbutyrate (HMB) is a leucine metabolite with protein anabolic effects. We examined the effects of an HMB-enriched diet in healthy rats and rats with liver cirrhosis induced by multiple doses of carbon tetrachloride (CCl4). HMB increased branched-chain amino acids (BCAAs; valine, leucine and isoleucine) in blood and BCAA and ATP in muscles of healthy animals. The effect on muscle mass and protein content was insignificant. In CCl4-treated animals alterations characteristic of liver cirrhosis were found with decreased ratio of the BCAA to aromatic amino acids in blood and lower muscle mass and ATP content when compared with controls. In CCl4-treated animals consuming HMB, we observed higher mortality, lower body weight, higher BCAA levels in blood plasma, higher ATP content in muscles, and lower ATP content and higher cathepsin B and L activities in the liver when compared with CCl4-treated animals without HMB. We conclude that (1) HMB supplementation has a positive effect on muscle mitochondrial function and enhances BCAA concentrations in healthy animals and (2) the effects of HMB on the course of liver cirrhosis in CCl4-treated rats are detrimental. Further studies examining the effects of HMB in other models of hepatic injury are needed to determine pros and cons of HMB in the treatment of subjects with liver cirrhosis.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Valeratos/farmacologia , Animais , Tetracloreto de Carbono/metabolismo , Suplementos Nutricionais , Leucina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Ratos Wistar
10.
FASEB J ; 33(9): 10019-10033, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31167080

RESUMO

Obesity increases the risk of developing insulin resistance and diabetes and is a major public health concern. Our previous study shows that dietary ß-hydroxy-ß-methylbutyrate (HMB) improves lipid metabolism in a pig model. However, it remains unclear whether HMB blocks obesity through gut microbiota. In this study, we found that HMB reduced body weight, alleviated the whitening of brown adipose tissue, and improved insulin resistance in mice fed a high-fat diet (HFD). High-throughput pyrosequencing of the 16S rRNA demonstrated that HMB administration significantly reversed the gut microbiota dysbiosis in HFD-fed mice, including the diversity of gut microbiota and relative abundances of Bacteroidetes and Firmicutes. Moreover, microbiota transplantation from HMB-treated mice attenuated HFD-induced lipid metabolic disorders. Furthermore, HFD-fed mice showed lower short-chain fatty acids, whereas administration of HMB increased the propionic acid production. Correlation analysis identified a significant correlation between propionic acid production and the relative Bacteroidetes abundance. Sodium propionate treatment also attenuated HFD-induced lipid metabolic disorders. Collectively, our results indicated that HMB might be used as a probiotic agent to reverse HFD-induced obesity, and the potential mechanism was associated with reprogramming gut microbiota and metabolism, especially Bacteroidetes-mediated propionic acid production. In future studies, more efforts should be made to confirm and expand the beneficial effects of HMB to human models.-Duan, Y., Zhong, Y., Xiao, H., Zheng, C., Song, B., Wang, W., Guo, Q., Li, Y., Han, H., Gao, J., Xu, K., Li, T., Yin, Y., Li, F., Yin, J., Kong, X. Gut microbiota mediates the protective effects of dietary ß-hydroxy-ß-methylbutyrate (HMB) against obesity induced by high-fat diets.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Disbiose/metabolismo , Microbioma Gastrointestinal/fisiologia , Obesidade/prevenção & controle , Valeratos/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Bacteroidetes/isolamento & purificação , Disbiose/etiologia , Disbiose/microbiologia , Ácidos Graxos Voláteis/metabolismo , Transplante de Microbiota Fecal , Firmicutes/isolamento & purificação , Perfilação da Expressão Gênica , Resistência à Insulina , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Obesidade/etiologia , Obesidade/microbiologia , Propionatos/metabolismo , Propionatos/farmacologia , RNA Mensageiro/biossíntese , Distribuição Aleatória , Valeratos/uso terapêutico
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 222: 117271, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31226619

RESUMO

Structural changes in the enamel surface subjected to induced demineralization and assessment of the influence of prenatal administration of ß-hydroxy ß-methylbutyrate (HMB) on enamel resistance were investigated. The examination was conducted on five sets of teeth from one-day-old spiny mice (Acomys cahirinus), one from the control and four from the experimental groups. Surface structure, molecular arrangement and crystalline organization of offspring's enamel both before and after etching were studied. Obtained results revealed that the physical and molecular arrangements of enamel were altered after the prenatal supplementation, and significantly affected its final structure and resistance against acid action. The enamel of incisors from the offspring which mothers were supplemented with HMB in a high dose (0.2 g/kgbw) and in the late period of gestation (26th-39th day) showed the highest endurance against acid treatment demonstrating only vestigial changes in their surface structure after acid action. Comparing to the remaining experimental groups, it was characterized by a reduced roughness and fractal dimension, significantly lower degree of demineralization and simultaneous lack of notable differences in the Raman spectra before and after acid etching. The results suggest that an increased enamel resiliency was the effect of a relatively high degree of mineralization and higher organization of the surface.


Assuntos
Esmalte Dentário/efeitos dos fármacos , Valeratos/farmacologia , Ácidos/química , Animais , Animais Recém-Nascidos , Esmalte Dentário/embriologia , Esmalte Dentário/ultraestrutura , Suplementos Nutricionais , Feminino , Camundongos , Modelos Moleculares , Gravidez , Cuidado Pré-Natal , Propriedades de Superfície/efeitos dos fármacos , Valeratos/administração & dosagem
12.
Pol J Vet Sci ; 22(1): 17-24, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30997767

RESUMO

The study was conducted on 26 male, 30 days-old goats, separated from their mothers, divided into two equal groups: I - control and II - experimental, consisting of 13 animals each. All animals were fed with milk replacer, experimental group received additionally 50 g/kg body weight, additive of HMB, for 60 days. The following features were analyzed: body weight, daily increases of body weight, as well as hematological and biochemical blood features. Differences in body weight were found, between experimental and control group, after 60 days of experiment 0.57 kg (p≤0.01). The daily weight gain of experimental animals was higher in comparison with control group. Significant differences were also noted in results of hematological and biochemical blood parameters. Experimental animals showed a higher level of red blood cells as well as number of lymphocytes in comparison with the control group, (p≤0.01).Significant changes were also observed in the level of triglycerides, inorganic phosphorus and protein between both groups. The acid-base balance parameters and ionogram, showed a higher pH level (p≤0.05) HCO - act., HCO - std., BE, ctCO , O sat, K+, Cl- (p≤0.01), while the anion gap (AG) and Na+ were significantly lower in control group (p≤0.01).


Assuntos
Envelhecimento , Cabras/crescimento & desenvolvimento , Valeratos/farmacologia , Desmame , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Dieta/veterinária , Cabras/sangue , Masculino , Substitutos do Leite
13.
J Physiol Biochem ; 75(3): 263-273, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30919256

RESUMO

Various amino acid (AA) metabolites are used as supplements to facilitate metabolic control and enhance responsiveness of insulin-sensitive tissues. ß-hydroxy-ß-methylbutyrate (HMB) is a leucine metabolite proposed to prevent muscle wasting and to mitigate insulin resistance. Taurine, commonly added to energizing drinks, is a metabolite of methionine and cysteine present in bile juice, and proposed to be involved in lipid digestion and to be pro-lipolytic in adipocytes. N-methyltyramine (NMT) is a phenylalanine metabolite found in orange juices at 0.1-3 ppm while its effects on lipid mobilization remain controversial. Here, the putative lipolytic effects of these AA metabolites were studied and it was tested whether they could enhance insulin antilipolytic response in adipocytes. Release of glycerol and non-esterified fatty acids (NEFAs) was measured after a 2-h incubation of adipocytes obtained from control and diet-induced obese mice or from obese patients. In mouse, none of the tested AA derivatives was lipolytic from 1 µM to 1 mM. These compounds did not improve insulin antilipolytic effect or isoprenaline lipolytic action, except for 1 mM NMT that impaired triacylglycerol breakdown in obese mice. In human adipocytes, HMB and taurine were not lipolytic, while NMT weakly activated glycerol and NEFA release at 1 mM. However, 100 µM NMT impaired isoprenaline-stimulated lipolysis in a manner that was hardly added to insulin antilipolytic effect. Since none of these AA derivatives acutely helped or replaced insulin antilipolytic effect in adipocytes, the present in vitro observations do not support their proposed insulin-sensitizing properties. Moreover, NMT, HMB, and taurine were not notably lipolytic.


Assuntos
Adipócitos , Insulina/metabolismo , Lipólise/efeitos dos fármacos , Taurina/farmacologia , Tiramina/análogos & derivados , Valeratos/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Adulto , Animais , Feminino , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Obesidade/metabolismo , Tiramina/farmacologia
14.
J Anim Physiol Anim Nutr (Berl) ; 103(3): 846-857, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30775808

RESUMO

OBJECTIVES: This study aims to investigate the effects and roles of excess leucine (Leu) versus its metabolites α-ketoisocaproate (KIC) and ß-hydroxy-ß-methyl butyrate (HMB) on fatty acid composition and lipid metabolism in skeletal muscle of growing pigs. METHODS AND RESULTS: Thirty-two pigs with a similar initial weight (9.55 ± 0.19 kg) were fed one of the four diets (basal diet, L-Leu, KIC-Ca and HMB-Ca) for 45 days. Results indicated that dietary treatments did not affect the intramuscular fat (IMF) content (p > 0.05), but differently influenced the fatty acid composition of longissimus dorsi muscle (LM) and soleus muscle (SM). In particular, the proportion of N3 PUFA specifically in LM was significantly decreased in the Leu group and increased in both KIC and HMB group relative to the basal diet group (p < 0.05). Furthermore, pigs fed KIC-supplemented diets exhibited decreased expression of FATP-1, ACC, ATGL, C/EBPα, PPARγ and SREBP-1c in LM and increased expression of FATP-1, FAT/CD36, ATGL and M-CPT-1 in SM relative to the basal diet control (p < 0.05). CONCLUSIONS: These findings indicated that doubling dietary Leu content decreased the percentage of N3 PUFA mainly in glycolytic skeletal muscle, whereas KIC and HMB improved muscular fatty acid composition and altered lipid metabolism in skeletal muscle of growing pigs. The mechanism of action of KIC might be related to the TFs, and the mechanism of action of HMB might be associated with the AMPK-mTOR signalling pathway.


Assuntos
Ácidos Graxos/metabolismo , Cetoácidos/farmacologia , Leucina/farmacologia , Músculo Esquelético/efeitos dos fármacos , Suínos/crescimento & desenvolvimento , Valeratos/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Dieta/veterinária , Regulação da Expressão Gênica/efeitos dos fármacos , Cetoácidos/metabolismo , Leucina/administração & dosagem , Leucina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , RNA Mensageiro , Distribuição Aleatória , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição , Valeratos/metabolismo
15.
Nat Commun ; 10(1): 760, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770822

RESUMO

Short-chain fatty acids (SCFAs) have immunomodulatory effects, but the underlying mechanisms are not well understood. Here we show that pentanoate, a physiologically abundant SCFA, is a potent regulator of immunometabolism. Pentanoate induces IL-10 production in lymphocytes by reprogramming their metabolic activity towards elevated glucose oxidation. Mechanistically, this reprogramming is mediated by supplying additional pentanoate-originated acetyl-CoA for histone acetyltransferases, and by pentanoate-triggered enhancement of mTOR activity. In experimental mouse models of colitis and multiple sclerosis, pentanoate-induced regulatory B cells mediate protection from autoimmune pathology. Additionally, pentanoate shows a potent histone deacetylase-inhibitory activity in CD4+ T cells, thereby reducing their IL-17A production. In germ-free mice mono-colonized with segmented filamentous bacteria (SFB), pentanoate inhibits the generation of small-intestinal Th17 cells and ameliorates SFB-promoted inflammation in the central nervous system. Taken together, by enhancing IL-10 production and suppressing Th17 cells, the SCFA pentanoate might be of therapeutic relevance for inflammatory and autoimmune diseases.


Assuntos
Autoimunidade/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Valeratos/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Colite/tratamento farmacológico , Colite/metabolismo , Ácidos Graxos Voláteis/fisiologia , Ácidos Graxos Voláteis/uso terapêutico , Interleucina-10/metabolismo , Camundongos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Valeratos/uso terapêutico
16.
Theriogenology ; 128: 91-100, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30743108

RESUMO

Beta-hydroxy-beta-methylbutyrate (HMB) is a leucine metabolite with protein anabolic effects. This study was designed to determine whether prenatal HMB treatment has an effect on oogenesis and folliculogenesis in the ovary of newborn piglets. HMB decreased the number of egg nests and primordial follicles and increased the pool of developing follicles compared to the control group. Although the percentage of TUNEL-positive oocytes within the egg nests was higher in HMB-treated group no increase in the Bax/Bcl-2 ratio and active caspase-3 expression was observed. Moreover, the granulosa cell proliferation index and StAR protein expression were higher in HMB-treated group. In contrast to the control group, the expression of E-cadherins was reduced after the HMB treatment. In addition, a significant increase in the serum level of gonadotropins and steroid hormones was detected in HMB-treated piglets. In conclusion, prenatal HMB treatment dysregulates hormonal homeostasis which impairs early folliculogenesis in piglets.


Assuntos
Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , Suínos/crescimento & desenvolvimento , Valeratos/farmacologia , Animais , Caspase 3/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Gonadotropinas/sangue , Homeostase/efeitos dos fármacos , Imuno-Histoquímica/veterinária , Marcação In Situ das Extremidades Cortadas , Folículo Ovariano/crescimento & desenvolvimento , Ovário/crescimento & desenvolvimento , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
17.
In Vivo ; 33(2): 353-358, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30804112

RESUMO

BACKGROUND/AIM: Stress reactions, especially those related to surgery, cause poor convalescence of cancer patients. ß-Hydroxyß-methylbutyrate (HMB) is known to regulate excessive inflammation in the body. The objective of this work was to investigate the capacity of HMB to suppress activation of nuclear factor-kappa B (NF-ĸB) and production of interleukin-6 (IL-6) in a human esophageal squamous cell carcinoma cell line (TE-1). MATERIALS AND METHODS: Cell proliferation was measured using the water-soluble tetrazolium-1 method, while tumor necrosis factor alpha (TNFα)-induced IL-6 production was measured using an enzyme-linked immunosorbent assay (ELISA) assay. Nuclear translocation of NF-ĸB was detected by immunofluorescence staining. RESULTS: HMB did not affect cell proliferation. However, HMB suppressed the TNFα-induced increase in IL-6 production in TE-1 cells by inhibiting NF-ĸB activation. CONCLUSION: HMB did not influence TE-1 cell proliferation, but inhibited activation of NF-ĸB and IL-6 production. This result may be useful for improving excessive stress reactions during and after surgery.


Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Interleucina-6/genética , Valeratos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , NF-kappa B/genética , Fator de Necrose Tumoral alfa/genética
18.
J Anim Physiol Anim Nutr (Berl) ; 103(2): 626-643, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30659706

RESUMO

It has been demonstrated in animal studies that prenatal administration of ß-hydroxy-ß-methylbutyrate (HMB, metabolite of leucine) influences general growth and mechanical endurance of long bones in newborn offspring in sex-dependent manner. The present experiment was conducted to evaluate the effect of HMB treatment of pregnant sows on bone development in offspring at weaning. From 70th day until the 90th day of gestation, sows received either a basal diet (n = 12) or the same diet supplemented with HMB (n = 12) at the dose of 0.2 g/kg of body weight/day. Femora obtained from six males and females in each group weaned at the age of 35 days were examined. Maternal HMB treatment significantly enhanced body weight and changed bone morphology increasing femur mechanical strength in both sexes. Maternal HMB supplementation also elevated bone micro- and macroelement concentrations and enhanced content of proteoglycans in articular cartilage. Based on the obtained results, it can be concluded that maternal HMB supplementation in the mid-gestation period significantly accelerated bone development in both sexes by upregulation of a multifactorial system including leptin and osteoprotegerin. However, the sex (irrespective of the HMB treatment) was the factor which influenced the collagen structure in cartilages and trabecular bone, as demonstrated both by the Picrosirius red staining and performed analysis of thermal stability of collagenous tissues. The structural differences in collagen between males and females were presumably related to a different collagen maturity. No studies conducted so far provided a detailed morphological analysis of bone, articular cartilage, growth plate and the activities of the somatotropic and pituitary-gonadal axes, as well as leptin/osteoprotegerin system in weaned offspring prenatally treated with HMB. This study showed also the relationship between the maternal HMB treatment and bone osteometric and mechanical traits, hormones, and growth and bone turnover markers such as leptin, osteoprotegerin and insulin-like growth factor-1.


Assuntos
Dieta/veterinária , Suplementos Nutricionais , Cartilagem Hialina/efeitos dos fármacos , Leptina/metabolismo , Suínos , Valeratos/farmacologia , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Fenômenos Biomecânicos , Desenvolvimento Ósseo/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cartilagem Hialina/crescimento & desenvolvimento , Gravidez , Fenômenos Fisiológicos da Nutrição Pré-Natal , Distribuição Aleatória , Valeratos/administração & dosagem
19.
Nutrition ; 60: 217-226, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30677545

RESUMO

OBJECTIVES: Mitochondrial dysfunction in skeletal muscle has emerged as key to the development of obesity and its related metabolic disorders. Leucine (Leu) is an essential amino acid that has been reported to increase mitochondrial biogenesis in muscle cells, as has its metabolite ß-hydroxy-ß-methylbutyrate (HMB). However, two questions-which one is more potent and what is the cellular mechanisms of the action of Leu and HMB-remain to be answered. Therefore we aimed to investigate the effects of Leu and HMB on mitochondrial function in C2 C12 myotubes and analyze the underlying molecular mechanism. METHODS AND RESULTS: The effects of Leu and HMB on mitochondrial mass, mitochondrial respiration capacity, and the expression of genes related to mitochondrial biogenesis were evaluated in C2 C12 myotubes. Differentiated myotubes were treated with Leu (0.5 mM) or HMB (50 µM) with or without PPARß/δ antagonist (GSK3787, 1 µM) and CDK4 antagonist (LY2835219, 1.5 µM), respectively, for 24 h. The results indicated that treatment with Leu or HMB significantly increased mitochondrial mass, mitochondrial respiration capacity, and the messenger RNA expression of genes associated with mitochondrial biogenesis (P < 0.05). In addition, these positive effects of Leu or HMB on these parameters were attenuated by GSK3787 and LY2835219 treatments (P < 0.05). CONCLUSIONS: Our results provide evidence indicating that as with Leu, HMB alone could increase mitochondrial biogenesis and function via regulation of PPARß/δ and CDK4 pathways. Moreover, HMB seems to be more potent than Leu in the positive regulation of mitochondrial biogenesis and function in C2 C12 myotubes because the dosage used for HMB was much lower than that for Leu.


Assuntos
Mitocôndrias/efeitos dos fármacos , Células Musculares/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Valeratos/farmacologia , Animais , Técnicas de Cultura de Células , Quinase 4 Dependente de Ciclina/metabolismo , Humanos , Leucina/farmacologia , PPAR gama/metabolismo , PPAR beta/metabolismo
20.
Mol Divers ; 23(1): 19-33, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29974364

RESUMO

Most of reported steroidal FXR antagonists are restricted due to low potency. We described the design and synthesis of novel nonsteroidal scaffold SIPI-7623 derivatives as FXR antagonists. The most potent compound A-11 (IC50 = 7.8 ± 1.1 µM) showed better activity compared to SIPI-7623 (IC50 = 40.8 ± 1.7 µM) and guggulsterone (IC50 = 45.9 ± 1.1 µM). Docking of A-11 in FXR's ligand-binding domain was also studied.


Assuntos
Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Valeratos/química , Valeratos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Receptores Citoplasmáticos e Nucleares/metabolismo
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