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1.
J Pharmacol Sci ; 142(1): 1-8, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31757742

RESUMO

Ketone bodies, including acetoacetate and ß-hydroxybutyrate (ßOHB), are produced from acetyl coenzyme A in the liver and then secreted into the blood. These molecules are a source of energy for peripheral tissues during exercise or fasting. ßOHB has been reported to inhibit histone deacetylases (HDACs) 1, 3, and 4 in human embryonic kidney 293 cells. Thus, ßOHB may regulate epigenetics by modulating HDACs. There have been several reports that the administration of ßOHB or induction of a physiological state of ketosis has an antitumor effect; however, the mechanism remains unclear. The aim of this study was to investigate whether ßOHB enhances cisplatin-induced apoptosis in hepatocellular carcinoma (HCC) cells by modulating activity and/or expression of HDACs. We found that ßOHB significantly enhanced cisplatin-induced apoptosis and cleavage of caspase-3 and -8 in HCC cells. Further, ßOHB significantly decreased the expression of HDCA 3/5/6 and survivin in liver hepatocellular (HepG2) cells. In HDAC3/6 gene silencing, survivin expression was significantly decreased, and cisplatin-induced cleavage of caspase-3 was significantly enhanced compared with control in HepG2 cells. In conclusion, ßOHB enhanced cisplatin-induced apoptosis via HDAC3/6 inhibition/survivin axis in HepG2 cells, which suggests that ßOHB could be a new adjuvant agent for cisplatin chemotherapy.


Assuntos
Ácido 3-Hidroxibutírico/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Cisplatino/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Ácido 3-Hidroxibutírico/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Nus , Survivina/genética , Survivina/metabolismo
2.
Trials ; 20(1): 61, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30654835

RESUMO

BACKGROUND: Currently available prophylactic migraine treatment options are limited and are associated with many, often intolerable, side-effects. Various lines of research suggest that abnormalities in energy metabolism are likely to be part of migraine pathophysiology. Previously, a ketogenic diet (KD) has been reported to lead to a drastic reduction in migraine frequency. An alternative method to a strict KD is inducing a mild nutritional ketosis (0.4-2 mmol/l) with exogenous ketogenic substances. The aim of this randomised, placebo-controlled, double-blind, crossover, single-centre trial is to demonstrate safety and superiority of beta-hydroxybutyrate (ßHB) in mineral salt form over placebo in migraine prevention. METHODS/DESIGN: Forty-five episodic migraineurs (5-14 migraine days/months), with or without aura, aged between 18 and 65 years, will be recruited at headache clinics in Switzerland, Germany and Austria and via Internet announcements. After a 4-week baseline period, patients will be randomly allocated to one of the two trial arms and receive either the ßHB mineral salt or placebo for 12 weeks. This will be followed by a 4-week wash-out period, a subsequent second baseline period and, finally, another 12-week intervention with the alternative treatment. Co-medication with triptans (10 days per months) or analgesics (14 days per months) is permitted. The primary outcome is the mean change from baseline in the number of migraine days (meeting International Classification of Headache Disorders version 3 criteria) during the last 4 weeks of intervention compared to placebo. Secondary endpoints include mean changes in headache days of any severity, acute migraine medication use, migraine intensity and migraine and headache-related disability. Exploratory outcomes are (in addition to routine laboratory analysis) genetic profiling and expression analysis, oxidative and nitrosative stress, as well as serum cytokine analysis, and blood ßHB and glucose analysis (pharmacokinetics). DISCUSSION: A crossover design was chosen as it greatly improves statistical power and participation rates, without increasing costs. To our knowledge this is the first RCT using ßHB salts worldwide. If proven effective and safe, ßHB might not only offer a new prophylactic treatment option for migraine patients, but might additionally pave the way for clinical trials assessing its use in related diseases. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03132233 . Registered on 27 April 2017.


Assuntos
Ácido 3-Hidroxibutírico/administração & dosagem , Encéfalo/efeitos dos fármacos , Suplementos Nutricionais , Metabolismo Energético/efeitos dos fármacos , Transtornos de Enxaqueca/prevenção & controle , Ácido 3-Hidroxibutírico/efeitos adversos , Ácido 3-Hidroxibutírico/farmacocinética , Adolescente , Adulto , Idoso , Analgésicos/uso terapêutico , Biomarcadores/sangue , Encéfalo/metabolismo , Estudos Cross-Over , Suplementos Nutricionais/efeitos adversos , Avaliação da Deficiência , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/diagnóstico , Medição da Dor , Ensaios Clínicos Controlados Aleatórios como Assunto , Suíça , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
3.
FASEB J ; 33(1): 1062-1073, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085883

RESUMO

The mechanisms underlying neuropathic pain are poorly understood. Here we show the unexplored role of the hydroxyl carboxylic acid receptor type 2 (HCAR2) in 2 models of neuropathic pain. We used an oral treatment with dimethyl fumarate and the HCAR2 endogenous ligand ß-hydroxybutyrate (BHB) in wild-type (WT) and HCAR2-null mice. We found an up-regulation of the HCAR2 in the sciatic nerve and the dorsal root ganglia in neuropathic mice. Accordingly, acute and chronic treatment with dimethylfumarate (DMF) and BHB reduced the tactile allodynia. This effect was completely lost in the HCAR2-null mice after a 2-d starvation protocol, in which the BHB reached the concentration able to activate the HCAR2-reduced tactile allodynia in female WT mice, but not in the HCAR2-null mice. Finally, we showed that chronic treatment with DMF reduced the firing of the ON cells (cells responding with an excitation after noxious stimulation) of the rostral ventromedial medulla. Our results pave the way for investigating the mechanisms by which HCAR2 regulates neuropathic pain plasticity.-Boccella, S., Guida, F., De Logu, F., De Gregorio, D., Mazzitelli, M., Belardo, C., Iannotta, M., Serra, N., Nassini, R., de Novellis, V., Geppetti, P., Maione, S., Luongo, L. Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain.


Assuntos
Cetonas/metabolismo , Neuralgia/fisiopatologia , Receptores Acoplados a Proteínas-G/fisiologia , Ácido 3-Hidroxibutírico/administração & dosagem , Ácido 3-Hidroxibutírico/metabolismo , Potenciais de Ação , Animais , Glicemia/metabolismo , Fumarato de Dimetilo/administração & dosagem , Feminino , Imunofluorescência , Gânglios Espinais/fisiopatologia , Cetonas/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Neuralgia/metabolismo , Receptores Acoplados a Proteínas-G/administração & dosagem , Receptores Acoplados a Proteínas-G/genética , Inanição , Regulação para Cima
4.
J Diet Suppl ; 16(4): 463-469, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29953297

RESUMO

This study investigates the effect of a supplementary ketone, ß-hydroxybutyrate (BHB), on walking economy and ratings of perceived exertion in apparently healthy individuals. In a repeated-measures, crossover design, ten non-aerobically trained participants (three males; seven females) performed two stages of a duration-modified Bruce treadmill protocol. Participants blindly consumed either 1 ounce of an exogenous BHB solution (KETO) or a noncaloric placebo (CON) 30 minutes prior to exercise testing. Blood ketone and glucose concentrations were measured prior to supplementation (baseline), immediately before exercise, and after exercise. Oxygen consumption (VO2), respiratory exchange ratio (RER), energy expenditure (EE), and rating of perceived exertion (RPE) were recorded during the last two minutes of each stage. Blood BHB concentrations were significantly elevated at the pre-exercise and postexercise time points as compared to the CON condition (p < .001), and blood glucose was significantly elevated postexercise in both conditions as compared to baseline levels (p < .001). No significant between-trial differences (p > .05) were found for VO2, RER, EE, or RPE. The intervention of this study did not produce evidence of an ergogenic benefit from BHB supplementation in a healthy subject pool.


Assuntos
Ácido 3-Hidroxibutírico/administração & dosagem , Esforço Físico/efeitos dos fármacos , Esforço Físico/fisiologia , Caminhada/fisiologia , Ácido 3-Hidroxibutírico/sangue , Adulto , Glicemia/análise , Estudos Cross-Over , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Percepção , Placebos , Testes de Função Respiratória
5.
Cell Rep ; 25(3): 677-689.e4, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332647

RESUMO

Dietary salt reduction and exercise are lifestyle modifications for salt-sensitive hypertensives. While exercise has prominent metabolic effects, salt has an adverse effect on metabolic syndrome, of which hypertension is a hallmark. We hypothesized that dietary salt impacts metabolism in a salt-sensitive model of hypertension. An untargeted metabolomic approach demonstrates lower circulating levels of the ketone body, beta-hydroxybutyrate (ßOHB), in high salt-fed hypertensive rats. Despite the high salt intake, specific rescue of ßOHB levels by nutritional supplementation of its precursor, 1,3-butanediol, attenuates hypertension and protects kidney function. This beneficial effect of ßOHB was likely independent of gut-microbiotal and Th17-mediated effects of salt and instead facilitated by ßOHB inhibiting the renal Nlrp3 inflammasome. The juxtaposed effects of dietary salt and exercise on salt-sensitive hypertension, which decrease and increase ßOHB respectively, indicate that nutritional supplementation of a precursor of ßOHB provides a similar benefit to salt-sensitive hypertension as exercise.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hipertensão/prevenção & controle , Inflamassomos/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Cloreto de Sódio na Dieta/toxicidade , Ácido 3-Hidroxibutírico/administração & dosagem , Animais , Pressão Sanguínea , Aromatizantes/toxicidade , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Inflamassomos/imunologia , Inflamassomos/metabolismo , Masculino , Ratos , Ratos Endogâmicos Dahl
6.
Int J Pharm ; 548(1): 104-112, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-29936200

RESUMO

d-ß-hydroxybutyrate and melatonin (BHB/MLT) infusion improves survival in hemorrhagic shock models. The original BHB/MLT formulation contains dimethyl sulfoxide (DMSO) to increase melatonin solubility. We formulated BHB/MLT solutions wherein DMSO was replaced either with 10% polyvinylpyrrolidone (BHB/MLT/PVP) or with 5% hydroxypropyl-ß-cyclodextrin/2.5% PVP/2.5% polyethylene glycol 400 (BHB/MLT/CD). Safety and efficacy of the new and the original BHB/MLT solution were tested in a lethal rat hemorrhagic shock model, with seven groups: 1) sham, 2) shock, untreated, 3) shock, lactated Ringer's solution (LR), 4) shock, 4 M BHB/MLT/DMSO, 5) shock, 2 M BHB/MLT/DMSO, 6) shock, BHB/MLT/PVP and 7) shock, BHB/MLT/CD. BHB/MLT/DMSO was given at full strength and 1:1 dilution to match the concentration of the novel formulations. Rats were anesthetized, instrumented, and 40% of the total blood volume was withdrawn in three steps, followed by four-hour long shock. Treatment boluses were infused half-way throughout hemorrhage. Survival was highest in BHB/MLT/CD-treated rats (8/10), followed by the BHB/MLT/PVP (6/10), 4 M BHB/MLT/DMSO (5/10) or 2 M BHB/MLT/DMSO (5/10), LR (3/10) and the untreated group (0/11). Survival did not differ significantly between BHB/MLT groups (p > 0.05), but was significantly higher in BHB/MLT/CD than in LR-treated animals (p = 0.018). BHB/MLT/PVP and BHB/MLT/CD constitute promising candidates for clinical hemorrhagic shock treatment.


Assuntos
Ácido 3-Hidroxibutírico/administração & dosagem , Melatonina/administração & dosagem , Choque Hemorrágico/tratamento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina/administração & dosagem , 2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/farmacocinética , Ácido 3-Hidroxibutírico/química , Ácido 3-Hidroxibutírico/farmacocinética , Animais , Dimetil Sulfóxido/administração & dosagem , Dimetil Sulfóxido/química , Dimetil Sulfóxido/farmacocinética , Modelos Animais de Doenças , Masculino , Melatonina/química , Melatonina/farmacocinética , Povidona/administração & dosagem , Povidona/química , Povidona/farmacocinética , Ratos Sprague-Dawley , Choque Hemorrágico/sangue , Choque Hemorrágico/fisiopatologia
7.
Physiol Genomics ; 50(6): 468-477, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29625019

RESUMO

To identify molecular pathways that couple metabolic imbalances and reproduction, we randomly assigned 10 castrated male sheep to be centrally injected into the lateral ventricle through intracerebroventricular cannulas with 1 ml of ß-hydroxybutyric acid sodium salt solution (BHB; 12,800 µmol/l) or saline solution (CON; 0.9% NaCl). Approximately 2 h postinjection, sheep were humanely euthanized, and hypothalamus and pituitary tissues were harvested for transcriptome characterization by RNA sequencing. RNA was extracted from the hypothalamus and pituitary and sequenced at a high depth (hypothalamus: 468,912,732 reads; pituitary: 515,106,092 reads) with the Illumina Hi-Seq 2500 platform and aligned to Bos taurus and Ovis aries genomes. Of the total raw reads, 87% (hypothalamus) and 90.5% (pituitary) mapped to the reference O. aries genome. Within these read sets, ~56% in hypothalamus and 69% in pituitary mapped to either known or putative protein coding genes. Fragments per kilobase of transcripts per million normalized counts were averaged and ranked to identify the transcript expression level. Gene Ontology analysis (DAVID Bioinformatics Resources) was utilized to identify biological process functions related to genes shared between tissues, as well as functional categories with tissue-specific enrichment. Between CON- and BHB-treated sheep, 11 and 44 genes were differentially expressed (adj. P < 0.05) within the pituitary and hypothalamus, respectively. Functional enrichment analyses revealed BHB altered expression of genes in pathways related to stimulus perception, inflammation, and cell cycle control. The set of genes altered by BHB creates a foundation from which to identify the signaling pathways that impact reproduction during metabolic imbalances.


Assuntos
Ácido 3-Hidroxibutírico/administração & dosagem , Ácido 3-Hidroxibutírico/farmacologia , Castração , Perfilação da Expressão Gênica , Hipotálamo/metabolismo , Hipófise/metabolismo , Reprodução/efeitos dos fármacos , Ovinos/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Hipotálamo/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Metaboloma/efeitos dos fármacos , Metabolômica , Hipófise/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Análise de Sequência de RNA
8.
PLoS One ; 13(2): e0190556, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29489818

RESUMO

Ketone bodies are neuroprotective in neurological disorders such as epilepsy. We randomly studied nine healthy human subjects twice-with and without continuous infusion of 3-hydroxybutyrate-to define potential underlying mechanisms, assessed regionally (parietal, occipital, temporal, cortical grey, and frontal) by PET scan. During 3-hydroxybutyrate infusions concentrations increased to 5.5±0.4 mmol/l and cerebral glucose utilisation decreased 14%, oxygen consumption remained unchanged, and cerebral blood flow increased 30%. We conclude that acute 3-hydroxybutyrate infusion reduces cerebral glucose uptake and increases cerebral blood flow in all measured brain regions, without detectable effects on cerebral oxygen uptake though oxygen extraction decreased. Increased oxygen supply concomitant with unchanged oxygen utilisation may contribute to the neuroprotective effects of ketone bodies.


Assuntos
Ácido 3-Hidroxibutírico/administração & dosagem , Circulação Cerebrovascular/efeitos dos fármacos , Corpos Cetônicos/administração & dosagem , Ácido 3-Hidroxibutírico/sangue , Idoso , Transporte Biológico Ativo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estudos Cross-Over , Feminino , Glucose/metabolismo , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Corpos Cetônicos/sangue , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Consumo de Oxigênio/efeitos dos fármacos , Tomografia por Emissão de Pósitrons
9.
Appl Physiol Nutr Metab ; 43(7): 711-717, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29451991

RESUMO

This study examined the effects of a d-ß-hydroxybutyrate (ßHB) containing beverage on cognitive and performance measures during a bout of repeated Wingates. Fifteen healthy, college-aged males (mean ± SD; age: 23.1 ± 2.4 years, height: 165.4 ± 2.0 cm, mass: 81.4 ± 9.2 kg) volunteered for the present study. Trial 1 consisted of baseline measures and familiarization for the protocol. During trials 2 and 3, subjects reported to the laboratory, after a 10-h fast, and ingested 11.38 g of ßHB or a placebo (PLA) beverage 30 min before exercise. Participants then completed a cognitive challenge (CC), consisting of a 5-min FitLight response task while cycling. At the cessation of the test, participants then completed four 15-s repeated Wingates with 4 min of rest between, followed by another 5-min CC response task. Blood ketones, glucose, and lactate were measured pre-CC and post-Wingates. ßHB levels were significantly higher compared with PLA (0.53 vs. 0.21 mmol/L), respectively. A significant order effect was observed across trials 2 and 3 for total FitLight misses and hits, regardless of treatment. Further, there were no significant differences among Wingate power output between treatments, although fatigue index was higher in the ßHB group compared with PLA (32.3 vs. 29.4 W/s), respectively. In conclusion, ßHB did not improve high-intensity cycling or cognitive performance measures; however, these findings might be partially explained by the absolute dosing protocol used for ßHB in the present study as opposed to a relative (g/kg) dosing protocol used in previous research.


Assuntos
Ácido 3-Hidroxibutírico/administração & dosagem , Cognição/efeitos dos fármacos , Exercício Físico , Ácido 3-Hidroxibutírico/sangue , Adulto , Bebidas , Glicemia/metabolismo , Aptidão Cardiorrespiratória , Estudos Cross-Over , Método Duplo-Cego , Humanos , Ácido Láctico/sangue , Masculino , Resistência Física/efeitos dos fármacos , Adulto Jovem
10.
Eur J Sport Sci ; 18(3): 376-386, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29338584

RESUMO

Acute ingestion of ketone salts induces nutritional ketosis by elevating ß-hydroxybutyrate (ßHB), but few studies have examined the metabolic effects of ingestion prior to exercise. Nineteen trained cyclists (12 male, 7 female) undertook graded exercise (8 min each at ∼30%, 40%, 50%, 60%, 70%, and 80% VO2peak) on a cycle ergometer on two occasions separated by either 7 or 14 days. Trials included ingestion of boluses of either (i) plain water (3.8 mL kg body mass-1) (CON) or (ii) ßHB salts (0.38 g kg body mass-1) in plain water (3.8 mL kg body mass-1) (KET), at both 60 min and 15 min prior to exercise. During KET, plasma [ßHB] increased to 0.33 ± 0.16 mM prior to exercise and 0.44 ± 0.15 mM at the end of exercise (both p < .05). Plasma glucose was 0.44 ± 0.27 mM lower (p < .01) 30 min after ingestion of KET and remained ∼0.2 mM lower throughout exercise compared to CON (p < .001). Respiratory exchange ratio (RER) was higher during KET compared to CON (p < .001) and 0.03-0.04 higher from 30%VO2peak to 60%VO2peak (all p < .05). No differences in plasma lactate, rate of perceived exertion, or gross or delta efficiency were observed between trials. Gastrointestinal symptoms were reported in 13 out of 19 participants during KET. Acute ingestion of ßHB salts induces nutritional ketosis and alters the metabolic response to exercise in trained cyclists. Elevated RER during KET may be indicative of increased ketone body oxidation during exercise, but at the plasma ßHB concentrations achieved, ingestion of ßHB salts does not affect lactate appearance, perceived exertion, or muscular efficiency.


Assuntos
Ácido 3-Hidroxibutírico/administração & dosagem , Ácido 3-Hidroxibutírico/sangue , Ciclismo/fisiologia , Cetose , Adulto , Glicemia/metabolismo , Estudos Cross-Over , Ingestão de Alimentos , Ergometria , Feminino , Frequência Cardíaca , Humanos , Ácido Láctico/sangue , Masculino , Oxirredução , Consumo de Oxigênio , Sais/administração & dosagem , Adulto Jovem
11.
BMC Res Notes ; 10(1): 649, 2017 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-29187245

RESUMO

OBJECTIVE: Treatment with a combination of D-ß-hydroxybutyrate (BHB) and melatonin (M) improves survival in hemorrhagic shock models. Our objective was to find the most effective melatonin concentration in combination with 4 molar BHB (4 M BHB). Survival and markers of organ injury were analyzed in pigs exposed to pulmonary contusion, liver crush injury, and hemorrhagic shock and treated with lactated Ringer's solution; 4 M BHB/43 mM M; 4 M BHB/20 mM M; 4 M BHB/10 mM M; 4 M BHB/4.3 mM M; or 4 M BHB/0.43 mM M. This work is an extension of a previously published research study. RESULTS: Survival was highest in pigs receiving 4 M BHB/43 mM M (13/14), followed by lactated Ringer's solution (11/16) and BHB/M with decreased melatonin concentrations (4 M BHB/20 mM M 3/6, 4 M BHB/10 mM M 2/6, 4 M BHB/4.3 mM M 3/6, 4 M BHB/0.43 mM M 1/6, p = 0.011). High mortality was associated with increases in serum lactate, higher liver and muscle injury markers and decreases in PaO2:FiO2 ratios. Our study indicates that treatment with 4 M BHB and melatonin concentrations below 43 mM lack the survival benefit observed from 4 M BHB/43 mM melatonin in pigs experiencing hemorrhagic shock and polytrauma.


Assuntos
Ácido 3-Hidroxibutírico/uso terapêutico , Antioxidantes/uso terapêutico , Melatonina/uso terapêutico , Traumatismo Múltiplo/tratamento farmacológico , Choque Hemorrágico/tratamento farmacológico , Ácido 3-Hidroxibutírico/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Feminino , Masculino , Melatonina/administração & dosagem , Traumatismo Múltiplo/complicações , Choque Hemorrágico/complicações , Suínos
12.
Sci Rep ; 7(1): 7677, 2017 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-28794421

RESUMO

Neuro-inflammation has been shown to play a critical role in the development of depression. Beta-hydroxybutyrate (BHB) is a ketone body and has recently been reported to exert anti-inflammatory effects via inhibition of NLRP3 inflammasome. Here, we investigated the potential antidepressant and anti-inflammatory effects of BHB on rats exposed to acute and chronic stress. We examined the influence of repeated BHB administration on depressive and anxiety behaviors in a rodent model of chronic unpredictable stress (CUS). Additionally, the influence of acute immobilization (IMM) stress and single BHB administration on hippocampal interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) were assessed. Repeated administration of BHB attenuated CUS-induced depressive- and anxiety-related behaviors. IMM stress increased levels of IL-1ß in the hippocampus, while a single pre-administration of BHB attenuated this increase. Although no effect was observed on hippocampal TNF-α levels after 1 h of IMM stress, a single BHB pre-administration reduced hippocampal TNF-α. Our previous report showed that the release of IL-1ß and TNF-α caused by stress is tightly regulated by NLRP3 inflammasome. These findings demonstrate that BHB exerts antidepressant-like effects, possibly by inhibiting NLRP3-induced neuro-inflammation in the hippocampus, and that BHB may be a novel therapeutic candidate for the treatment of stress-related mood disorders.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Inflamação/etiologia , Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Estresse Fisiológico , Estresse Psicológico , Ácido 3-Hidroxibutírico/administração & dosagem , Animais , Ansiedade , Comportamento Animal , Biomarcadores , Citocinas/metabolismo , Depressão , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/psicologia , Masculino , Ratos
13.
J Dairy Sci ; 100(8): 6648-6661, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28601458

RESUMO

The enhanced growth performance of calves fed a higher plane of nutrition pre-weaning is well documented, and the effect of butyrate on the development of the gastrointestinal tract in calves has been evaluated. The aim of this study was to examine the synergistic effects of ad libitum milk replacer (MR) feeding and butyrate supplementation on growth performance and energy metabolism in calves. Sixty-four (32 male, 32 female) Holstein calves were examined from birth until wk 11 of life. Calves received MR either ad libitum (Adl) or restrictively (Res) with (AdlB+, ResB+) or without (AdlB-, ResB-) 0.24% butyrate supplementation. Colostrum and transition milk were fed in predefined amounts (Res or Adl) for the first 3 d postpartum. Ad libitum and restrictive MR feeding with or without butyrate was performed from d 4 until wk 8 of age. From wk 9 to 10, all calves were gradually weaned and were fed 2 L/d until the end of the trial. Concentrate (CON), hay, and water were freely available. Intakes of MR and CON were measured daily. Calves were weighed at birth and weekly thereafter. Blood was drawn on d 1 before the first colostrum intake; on d 2, 4, and 7; and weekly thereafter until the end of the study to measure plasma concentrations of metabolites and hormones. Liver samples were taken at d 50 and at the end of the study to determine gene expression related to glucose metabolism. Milk, MR, and total nutrient intake were greater, but CON intake was lower in Adl than in Res calves, resulting in a greater body weight, but partially lower gain to feed ratio in Adl than in Res. Plasma concentrations of glucose and insulin were higher during the ad libitum milk-feeding period, whereas plasma ß-hydroxybutyrate was lower in Adl than in Res. Plasma concentrations of nonesterified fatty acids, lactate, total bilirubin, and cortisol were lower, but triglyceride and cholesterol concentrations were higher in Adl than in Res at specific time points. Feed intake, growth performance, and metabolic and endocrine changes were insignificantly affected by butyrate, and hepatic gene expression of enzymes related to endogenous glucose production was barely influenced by ad libitum MR feeding and butyrate supplementation. Intensive MR feeding indicated greater stimulation of growth and anabolic metabolism, but butyrate supplementation did not further improve postnatal growth or anabolic processes either in intensive or restrictive MR-fed calves.


Assuntos
Bovinos/crescimento & desenvolvimento , Bovinos/metabolismo , Dieta/veterinária , Substitutos do Leite/administração & dosagem , Desmame , Ácido 3-Hidroxibutírico/administração & dosagem , Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Animais , Animais Recém-Nascidos , Colostro , Ingestão de Energia/fisiologia , Feminino , Masculino , Leite/metabolismo , Substitutos do Leite/metabolismo , Gravidez
14.
Br J Pharmacol ; 174(13): 1961-1971, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28320049

RESUMO

BACKGROUND AND PURPOSE: Spinal cord injury (SCI) leads to severe motor and sensory dysfunction and significantly reduces the quality of life. The aim of the present work was to investigate the effect of administration of exogenous D-ß-hydroxybutyrate (DBHB) on functional recovery and neuropathic pain in spinal cord-injured mice. EXPERIMENTAL APPROACH: Mice were given a moderate-severe thoracic spinal contusion injury at the T9-10 level and treated with exogenous DBHB. KEY RESULTS: Treatment of SCI mice with DBHB markedly improved locomotor function and relieved SCI-induced hypersensitivities to mechanical and thermal stimulation. DBHB treatment partly prevented the SCI-induced loss of motor neurons and suppressed microglial and glial activation. DBHB treatment enhanced histone acetylation and up-regulated expression of the transcription factor FOXO3a, catalase and SOD2 in injured region of SCI mice. DBHB treatment suppressed SCI-induced NLRP3 inflammasome activation and reduced protein expression of IL-1ß and IL-18. In addition, DBHB treatment improved mitochondrial function and abated oxidative stress following SCI. CONCLUSIONS AND IMPLICATIONS: DBHB promoted functional recovery and relieved pain hypersensitivity in mice with SCI, possibly through inhibition of histone deacetylation and NLRP3 inflammasome activation and preservation of mitochondrial function. DBHB could thus be envisaged as a potential use of interventions for SCI but remains to be tested in humans.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Hipersensibilidade/tratamento farmacológico , Dor/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Ácido 3-Hidroxibutírico/administração & dosagem , Animais , Modelos Animais de Doenças , Hipersensibilidade/patologia , Laminectomia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/patologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/cirurgia
15.
Adv Healthc Mater ; 5(20): 2679-2685, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27594657

RESUMO

Injectable thermogel to deliver chemotherapeutics in a minimally invasive manner and to achieve their long term sustained release at tumor sites to minimize side effects is attractive for chemotherapy and precision medicine, but its rational design remains a challenge. In this work, a copolymer with natural biodegradable poly[(R)-3-hydroxybutyrate] (PHB), hydrophilic poly(ethylene glycol), and temperature sensitive poly(propylene glycol) blocks linked by urethane linkages is designed to show thermogelling characteristics which are beneficial for minimally invasive injection and safe degradation. This thermogelling polymer possesses in vitro biocompatibility with very low cyto-toxicity in HEK293 cells. Furthermore, it is able to form the gel to achieve the controllable release of paclitaxel (PTX) and doxorubicin (DOX) by adjusting polymer concentrations. A rodent model of hepatocarcinoma has been performed to demonstrate the in vivo applications of this PHB-based thermogel. The drug-loaded thermogel has been intratumorally injected and both PTX-loaded and DOX-loaded thermogel have significantly slowed down tumor growth. This work represents the first time that injectable PHB thermogels have possessed good controllable release effect of chemotherapeutics against the in vivo model of tumors and will benefit various applications, including on-demand drug delivery and personalized medicine.


Assuntos
Ácido 3-Hidroxibutírico/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Géis/administração & dosagem , Géis/química , Neoplasias/tratamento farmacológico , Ácido 3-Hidroxibutírico/administração & dosagem , Animais , Linhagem Celular , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Paclitaxel/administração & dosagem , Paclitaxel/química , Poliésteres/administração & dosagem , Poliésteres/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polímeros/química , Temperatura
16.
J Anim Physiol Anim Nutr (Berl) ; 100(2): 331-6, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26283277

RESUMO

ß-Hydroxybutyricacid (BHBA) is an important metabolite that involved in the development of ketosis and fatty liver in dairy cows. Dairy cows with fatty liver displayed high blood concentration of BHBA and very low-density lipoprotein (VLDL) assembly. The effects of BHBA on VLDL synthesis and assembly in hepatocytes of cows were unclear. In this study, bovine hepatocytes were cultured and treated with different concentrations of BHBA. We found that BHBA treatment upregulated the mRNA and protein levels of apolipoprotein B100 (ApoB 100), apolipoprotein E (ApoE) and microsomal triglyceride transfer protein (MTTP) and showed in a firstly increased and then decreased trend. Meanwhile, the mRNA and protein levels of LDLR showed in a reverse trend. Consequently, VLDL content was significantly increased in medium-dose BHBA treatment group, while decreased in high-dose group. These results indicate that the effects of BHBA on the VLDL synthesis showed in a dose-dependent manner that low levels of BHBA increase VLDL synthesis and high levels of BHBA decrease VLDL synthesis.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Bovinos/fisiologia , VLDL-Colesterol/biossíntese , Hepatócitos/efeitos dos fármacos , Ácido 3-Hidroxibutírico/administração & dosagem , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Hepatócitos/metabolismo
17.
PLoS One ; 10(3): e0122818, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25816337

RESUMO

Circulating redox state changes, determined by the ratio of reduced/oxidized pairs of different metabolites, have been associated with metabolic diseases. However, the pathogenic contribution of these changes and whether they modulate normal tissue function is unclear. As alterations in hepatic gluconeogenesis and glycogen metabolism are hallmarks that characterize insulin resistance and type 2 diabetes, we tested whether imposed changes in the extracellular redox state could modulate these processes. Thus, primary hepatocytes were treated with different ratios of the following physiological extracellular redox couples: ß-hydroxybutyrate (ßOHB)/acetoacetate (Acoc), reduced glutathione (GSH)/oxidized glutathione (GSSG), and cysteine/cystine. Exposure to a more oxidized ratio via extracellular ßOHB/Acoc, GSH/GSSG, and cysteine/cystine in hepatocytes from fed mice increased intracellular hydrogen peroxide without causing oxidative damage. On the other hand, addition of more reduced ratios of extracellular ßOHB/Acoc led to increased NAD(P)H and maximal mitochondrial respiratory capacity in hepatocytes. Greater ßOHB/Acoc ratios were also associated with decreased ß-oxidation, as expected with enhanced lipogenesis. In hepatocytes from fasted mice, a more extracellular reduced state of ßOHB/Acoc led to increased alanine-stimulated gluconeogenesis and enhanced glycogen synthesis capacity from added glucose. Thus, we demonstrated for the first time that the extracellular redox state regulates the major metabolic functions of the liver and involves changes in intracellular NADH, hydrogen peroxide, and mitochondrial respiration. Because redox state in the blood can be communicated to all metabolically sensitive tissues, this work confirms the hypothesis that circulating redox state may be an important regulator of whole body metabolism and contribute to alterations associated with metabolic diseases.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/genética , Mitocôndrias/metabolismo , Oxirredução/efeitos dos fármacos , Ácido 3-Hidroxibutírico/administração & dosagem , Acetoacetatos/administração & dosagem , Animais , Cisteína/administração & dosagem , Cistina/administração & dosagem , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Gluconeogênese/efeitos dos fármacos , Glutationa/administração & dosagem , Dissulfeto de Glutationa/administração & dosagem , Glicogênio/biossíntese , Hepatócitos/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , NAD/biossíntese , Respiração/efeitos dos fármacos
18.
Pediatrics ; 134(4): e1224-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25246622

RESUMO

Multiple acyl coenzyme A dehydrogenase deficiency (MADD) is a severe inborn error of metabolism. Experiences with sodium-D,L-3-hydroxybutyrate (3-HB) treatment are limited although positive; however, the general view on outcome of severely affected patients with MADD is relatively pessimistic. Here we present an infant with MADD in whom the previously reported dose of 3-HB did not prevent the acute, severe, metabolic decompensation or progressive cardiomyopathy in the subsequent months. Only after a physiologic dose of 2600 mg/kg of 3-HB per day were ketone bodies detected in blood associated with improvement of the clinical course, N-terminal prohormone of brain natriuretic peptide and echocardiographic parameters. Long-term studies are warranted on 3-HB treatment in patients with MADD.


Assuntos
Ácido 3-Hidroxibutírico/administração & dosagem , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico por imagem , Deficiência Múltipla de Acil Coenzima A Desidrogenase/tratamento farmacológico , Índice de Gravidade de Doença , Feminino , Humanos , Recém-Nascido , Resultado do Tratamento , Ultrassonografia
19.
Mol Biol Rep ; 41(6): 3705-13, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24535268

RESUMO

Advanced glycation end products (AGEs), which are the final products of glycation, have a major role in diabetic complication and neurodegenerative disorders. The 3-ß-hydroxybutyrate (3BHB), a ketone body which is produced by the liver, can be detected in increased concentrations in individuals post fasting and prolonged exercises and in diabetic (type I) patients. In this study, the inhibitory effect of 3BHB on AGEs formation by glucose from the human serum albumin (HSA) was studied at physiological conditions after 35 days of incubation, using physical techniques such as circular dichroism and fluorescence spectroscopy, as well as differential scanning calorimetry (DSC). The fluorescence intensity measurements of glycated HSA by glucose (GHSA) in the presence of 3BHB indicate a decrease in AGEs formation. The DSC deconvolution profile results also confirm the protective role of 3BHB on incubated with glucose by preventing the enthalpy reduction of the HSA tail segment, compared with the deconvolution profile seen for incubated with glucose alone. The concentration of 3BHB used in this study is in accordance with the concentration detected in the body of individuals post fasting and prolonged exercises.


Assuntos
Complicações do Diabetes/metabolismo , Glucose/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Albumina Sérica/efeitos dos fármacos , Ácido 3-Hidroxibutírico/administração & dosagem , Varredura Diferencial de Calorimetria , Dicroísmo Circular , Complicações do Diabetes/patologia , Exercício Físico/fisiologia , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Produtos Finais de Glicação Avançada/química , Glicosilação/efeitos dos fármacos , Humanos , Albumina Sérica/metabolismo , Espectrometria de Fluorescência , Termodinâmica
20.
J Dairy Sci ; 96(5): 2960-72, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23498021

RESUMO

Elevation of ketone bodies in dairy cows frequently occurs in early lactation, usually concomitantly with a lack of energy and glucose. The objective of this study was to induce an elevated plasma ß-hydroxybutyrate (BHBA) concentration over 48 h in mid-lactating dairy cows (i.e., during a period of positive energy balance and normal glucose plasma concentrations). Effects of BHBA infusion on feed intake, metabolism, and performance were investigated. Thirteen cows were randomly assigned to 1 of 2 infusion groups, including an intravenous infusion with Na-dl-ß-OH-butyrate (1.7 mol/L) to achieve a plasma concentration of 1.5 to 2.0 mmol/L of BHBA (HyperB; n=5), or an infusion of 0.9% saline solution (control; n=8). Blood was sampled before and hourly during the 48 h of infusion. In the liver, mRNA transcripts related to gluconeogenesis (pyruvate carboxylase, glucose 6-phosphatase, mitochondrial phosphoenolpyruvate carboxykinase), phosphofructokinase, pyruvate dehydrogenase complex, and fatty acid synthesis (acetyl-coenzyme A carboxylase, fatty acid synthase) were measured by real-time PCR. Glyceraldehyde-3-phosphate dehydrogenase and ubiquitin were used as housekeeping genes. Changes (difference between before and after 48-h infusion) during the infusion period were evaluated by ANOVA with treatment as fixed effect, and area under the curve of variables was calculated on the second day of experiment. The plasma BHBA concentration in HyperB cows was 1.74 ± 0.02 mmol/L (mean ± SE) compared with 0.59 ± 0.02 mmol/L for control cows. The change in feed intake, milk yield, and energy corrected milk did not differ between the 2 experimental groups. Infusion of BHBA reduced the plasma glucose concentration (3.47 ± 0.11 mmol/L) in HyperB compared with control cows (4.11 ± 0.08 mmol/L). Plasma glucagon concentration in HyperB was lower than the control group. All other variables measured in plasma were not affected by treatment. In the liver, changes in mRNA abundance for the selected genes were similar between 2 groups. Results demonstrate that intravenous infusion of BHBA decreased plasma glucose concentration in dairy cows, but this decrease could not be explained by alterations in insulin concentrations or key enzymes related to gluconeogenesis. Declined glucose concentration is likely functionally related to decreased plasma glucagon concentration.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Lactação/efeitos dos fármacos , Ácido 3-Hidroxibutírico/administração & dosagem , Ácido 3-Hidroxibutírico/sangue , Ácido 3-Hidroxibutírico/fisiologia , Animais , Glicemia/análise , Bovinos , Ingestão de Alimentos/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Feminino , Infusões Intravenosas/veterinária , Lactação/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo
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