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1.
Nat Cell Biol ; 22(1): 18-25, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31871320

RESUMO

Glycogen has long been considered to have a function in energy metabolism. However, our recent study indicated that glycogen metabolism, directed by cytosolic phosphoenolpyruvate carboxykinase Pck1, controls the formation and maintenance of CD8+ memory T (Tmem) cells by regulating redox homeostasis1. This unusual metabolic program raises the question of how Pck1 is upregulated in CD8+ Tmem cells. Here, we show that mitochondrial acetyl coenzyme A is diverted to the ketogenesis pathway, which indirectly regulates Pck1 expression. Mechanistically, ketogenesis-derived ß-hydroxybutyrate is present in CD8+ Tmem cells; ß-hydroxybutyrate epigenetically modifies Lys 9 of histone H3 (H3K9) of Foxo1 and Ppargc1a (which encodes PGC-1α) with ß-hydroxybutyrylation, upregulating the expression of these genes. As a result, FoxO1 and PGC-1α cooperatively upregulate Pck1 expression, therefore directing the carbon flow along the gluconeogenic pathway to glycogen and the pentose phosphate pathway. These results reveal that ketogenesis acts as an unusual metabolic pathway in CD8+ Tmem cells, linking epigenetic modification required for memory development.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Via de Pentose Fosfato/efeitos dos fármacos , Fosfoenolpiruvato Carboxiquinase (GTP)/efeitos dos fármacos , Animais , Linfócitos T CD8-Positivos/metabolismo , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/genética , Glicogênio/metabolismo , Homeostase/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional/efeitos dos fármacos
2.
Asian Pac J Cancer Prev ; 20(12): 3597-3601, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31870099

RESUMO

BACKGROUND: Altered metabolism is one of the hallmarks of the cancer cells which reciprocally interrelate with epigenetic processes, such as post-translational histone modifications to maintain their desired gene expression profiles. The role of beta-hydroxybutyrate as a ketone body in cancer cell biology and histone modifications are reported. The present study aimed to evaluate the impacts of long-term metabolic reprogramming via glucose restriction and beta-hydroxybutyrate treatment on histone acetylation and butyrylation in MDA-MB231 cells as a model of triple negative stem-like breast cancer. METHODS: For long-term treatment, cells were set up in three groups receiving DMEM with restricted glucose (250 mg/L), DMEM with restricted glucose but enriched with five millimolar beta-hydroxybutyrate and DMEM with standard glucose (1gL) and investigated for a month. Histone modifications, including H3 acetylation and butyrylation, were investigated by immunoblotting after an acid extraction of the histone proteins. RESULTS AND CONCLUSION: Neither beta-hydroxybutyrate enrichment nor glucose restriction elicited a significant effect on the butyrylation or acetylation level of histone H3 upon a long-term treatment. Metabolic plasticity of cancer cells, mainly stem-like triple negative breast cancer cells alleviate or neutralize the impact of long-term metabolic reprogramming via restriction of glucose and histone modifications enrichment. These results shed new light upon the mechanism of controversial efficacy of ketogenic diets in clinical trials.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Glucose/farmacologia , Histonas/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Acetilação , Linhagem Celular Tumoral , Dieta Cetogênica , Epigênese Genética/genética , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
3.
J Biochem Mol Toxicol ; 33(9): e22372, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31332890

RESUMO

ß-Hydroxybutyrate (BHB), one of ketone body, has been traditionally regarded as an alternative carrier of energy, but recent studies found that BHB plays versatile roles in inflammation. It has been previously reported that the level BHB declined in mice with lipopolysaccharide (LPS)/d-galactosamine (d-Gal)-induced liver damage, but the pathological significance remains unclear. In the present study, the pathophysiological roles of BHB in LPS/d-Gal-induced hepatic damage has been investigated. The results indicated pretreatment with BHB further enhanced LPS/d-Gal-induced elevation of aspartate aminotransferase and alanine aminotransferase, exacerbated the histological abnormalities and increased the mortality. Pretreatment with BHB upregulated the level of tumor necrosis factor α and interleukin-6 in plasma, promoted the activities of caspase-3, caspase-8, and caspase-9 and increased the count of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. In addition, post-insult supplement with BHB also potentiated LPS/d-Gal-induced apoptotic liver damage. Therefore, BHB might be a detrimental factor in LPS/d-Gal-induced liver injury via enhancing the inflammation and the apoptosis in the liver.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Apoptose/efeitos dos fármacos , Galactosamina/toxicidade , Hepatócitos/efeitos dos fármacos , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Animais , Caspases/metabolismo , Ativação Enzimática , Hepatócitos/citologia , Hepatócitos/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
4.
Macromol Biosci ; 19(5): e1800432, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30951260

RESUMO

In this work, it is first reported that the poly (3-hydroxybutyric acid) (PHB) oligomer with a few degrees of polymerization possesses effective antibacterial and antifungal properties. Two preparation methods for the PHB oligomer are described, namely, one-step ring-opening polymerization of ß-butyrolactone and extraction from the fermented PHB polymer. An appropriate amount of the synthesized PHB oligomer shows no physiological toxicity to the skin and major organs of mice. Topological application of the synthesized PHB oligomer imparts antimicrobial ability to non-antibacterial fabrics with washing resistance. The synthesized PHB oligomer offers effective sterilization and promotes wound healing in infected nude mice. Most importantly, the PHB oligomer is also reactive to drug-resistant bacteria. These results suggest that the PHB oligomer is not only a great candidate for antimicrobial modification but also a promising one for biomedical applications. Finally, the antimicrobial mechanisms of the PHB oligomer are revealed, and these include disruption of biofilm and the bacterial wall/membrane, leakage of the intracellular content, inhibition of protein activity, and change in the transmembrane potential.


Assuntos
Ácido 3-Hidroxibutírico , Antibacterianos , Bactérias/crescimento & desenvolvimento , Fenômenos Fisiológicos Bacterianos/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Poliésteres , Ácido 3-Hidroxibutírico/química , Ácido 3-Hidroxibutírico/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Biofilmes/crescimento & desenvolvimento , Camundongos , Camundongos Nus , Poliésteres/química , Poliésteres/farmacologia
5.
Circulation ; 139(18): 2129-2141, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30884964

RESUMO

BACKGROUND: Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors' aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers. METHODS: Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography. RESULTS: 3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM ( P<0.001). CO rose by 2.0±0.2 L/min ( P<0.001) because of an increase in stroke volume of 20±2 mL ( P<0.001) and heart rate of 7±2 beats per minute (bpm) ( P<0.001). Left ventricular ejection fraction increased 8±1% ( P<0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM ( P<0.001). 3-OHB increased MVO2 without altering MEE. The response to 3-OHB infusion in terms of MEE and CO did not differ between HFrEF patents and age-matched volunteers. CONCLUSIONS: 3-OHB has beneficial hemodynamic effects in HFrEF patients without impairing MEE. These beneficial effects are detectable in the physiological concentration range of circulating 3-OHB levels. The hemodynamic effects of 3-OHB were observed in both HFrEF patients and age-matched volunteers. 3-OHB may potentially constitute a novel treatment principle in HFrEF patients.


Assuntos
Ácido 3-Hidroxibutírico , Insuficiência Cardíaca , Frequência Cardíaca/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Volume Sistólico/efeitos dos fármacos , Ácido 3-Hidroxibutírico/farmacocinética , Ácido 3-Hidroxibutírico/farmacologia , Acetatos/farmacologia , Idoso , Radioisótopos de Carbono/farmacologia , Doença Crônica , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/efeitos dos fármacos
6.
Life Sci ; 222: 125-132, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30851335

RESUMO

AIMS: ß-Hydroxybutyrate (ßOHB) is a metabolic intermediate that constitutes about 70% of ketone bodies produced in liver from oxidation of fatty acids released from adipose tissue. A recent study showed that ßOHB inhibits HDAC1, 3 and 4 (classes I and IIa) in human embryonic kidney 293 (HEK293) cells. Therefore, ßOHB could regulate epigenetics via modulating HDACs. However, little is known about the protective effect of ßOHB on renal cells through epigenetics. The aim of this study is to investigate whether ßOHB reduces cisplatin-induced nephrotoxicity in human renal cortical epithelial (HRCE) cells by modulating HDACs. MAIN METHODS: In this study, we used human renal cortical epithelial (HRCE) cells. The anti-apoptotic effect of ßOHB was evaluated using flow cytometry analysis. The expression of apoptosis-related proteins and HDACs was evaluated by western immunoblot. KEY FINDINGS: The results showed that ßOHB significantly reduced cisplatin-induced apoptosis in HRCE cells. Furthermore, ßOHB significantly reduced cisplatin-induced cleavage of caspase-3, acetylation of histone H3, and phosphorylation of AMP-activated kinase. This anti-apoptotic effect of ßOHB was markedly attenuated by an inhibitor of HDAC4/5, and ßOHB-mediated suppression of cleavage of caspase3 was significantly blocked by siRNA-induced gene silencing of HDAC5. SIGNIFICANCE: ßOHB attenuates cisplatin-induced apoptosis by activation of HDAC5 in HRCE cells, suggesting that ßOHB may be a new therapeutic agent for cisplatin nephropathy.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Cisplatino/toxicidade , Células Epiteliais/metabolismo , Histona Desacetilases/metabolismo , Corpos Cetônicos/farmacologia , Córtex Renal/metabolismo , Animais , Antineoplásicos/toxicidade , Células Cultivadas , Cisplatino/antagonistas & inibidores , Citotoxinas/antagonistas & inibidores , Citotoxinas/toxicidade , Células Epiteliais/efeitos dos fármacos , Humanos , Córtex Renal/citologia , Córtex Renal/efeitos dos fármacos , Masculino , Camundongos
7.
BMC Ophthalmol ; 19(1): 42, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30717701

RESUMO

BACKGROUND: To compare the protective effects of the histone deacetylase inhibitors (HDACis) ß-hydroxybutyrate (ßOHB), trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA) on human lens epithelial cells(HLECs) following ultraviolet-B (UVB) exposure. METHODS: HLECs were divided into subgroups: four HDACi groups, a control group, a UVB-treated group and a DMSO group (cells treated with DMSO and UVB irradiation). In the HDACi groups, HLECs were cultured with different concentrations of HDACis 12 h prior to UVB irradiation. The protective effects of the HDACis were evaluated by assessing apoptosis rates, cell activity and expression levels of genes associated with apotosis (caspase-3, Bcl-2, BAX, SOD1, FOXO3A and MT2). The levels of superoxide dismutase (SOD), reactive oxygen species (ROS), malondialdehyde (MDA) and total antioxidant capacity (T-AOC) were detected in order to evaluate oxidative stress. RESULTS: The results showed that SAHA (1 µmol/L, 2 µmol/L) and TSA (0.2 µmol/L) had mild protective effects on cell viability. ßOHB (4 mmol/L) and TSA (0.2 mol/L) demonstrated protective effects on BCL-2 expression. TSA (0.2 mol/L) showed protective effects on SOD1 expression. TSA (0.2 mol/L) and SAHA (1 µmol/L) suppressed BAX and caspase-3 expression. TSA (0.2 mol/L, 0.8 mol/L) and SAHA (1 µmol/L, 2 µmol/L) suppressed the expression of FOXO3A and MT2. SOD levels were increased after treatment with ßOHB (4 mmol/L), SAHA (8 µmol/L) and TSA (0.1 mol/L, 0.2 mol/L). T-AOC levels were increased in UVB-treated HLECs after treatment with SAHA (2 µmol/L). MDA levels decreased in UVB-treated HLECs following treatment with TSA (0.2 mol/L, 0.8 mol/L). ROS levels decreased in UVB-treated HLECs following treatment with ßOHB (4 mmol/L), SAHA (1 µmol/L, 2 µmol/L) and TSA (0.2 mol/L). Western blotting results demonstrated that SOD1 levels significantly increased in the ßOHB (4 mmol/L), SAHA (1 µmol/L, 2 µmol/L), TSA (0.1 mol/L, 0.2 mol/L) and VPA (5 mmol/L) groups. Only SAHA (1 µmol/L) had an anti-apoptotic effect on UVB-treated HLECs. CONCLUSIONS: Our findings indicate that low concentrations of HDACis (1 µmol/L of SAHA) mildly inhibit oxidative stress, thus protecting HLECs from oxidation. These results may suggest that there is a possibility to explore the clinical applications of HDACis for treatment and prevention of cataracts.


Assuntos
Antioxidantes/farmacologia , Células Epiteliais/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Raios Ultravioleta/efeitos adversos , Ácido 3-Hidroxibutírico/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos da radiação , Humanos , Ácidos Hidroxâmicos/farmacologia , Cristalino/citologia , Ácido Valproico/farmacologia , Vorinostat/farmacologia
8.
J Dairy Res ; 86(1): 68-72, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30732670

RESUMO

Dairy cows with ketosis display severe oxidative stress as well as high blood concentrations of non-esterified fatty acids (NEFA) and ß-hydroxybutyrate (BHB). Cytochrome P4502E1 (CYP2E1) plays an important role in the induction of oxidative stress. The aim of this study was to investigate CYP2E1 expression and activity in the liver of clinically ketotic cows (in vivo) and the effects of NEFA and BHB on CYP2E1 expression and activity in hepatocytes (in vitro). Dairy cows with clinical ketosis exhibited a low blood concentration of glucose but high concentrations of NEFA and BHB. Hepatic mRNA, protein expression, and activity of CYP2E1 were significantly higher in cows with clinical ketosis than in control cows. In vitro, both NEFA and BHB treatment markedly up-regulated the mRNA and protein expressions as well as activity of CYP2E1 in cow hepatocytes. Taken together, these results indicate that high levels of NEFA and BHB significantly up-regulate the expression and activity of hepatic CYP2E1, and may be influential in the induction of oxidative stress in cows with clinical ketosis.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Doenças dos Bovinos/enzimologia , Citocromo P-450 CYP2E1/efeitos dos fármacos , Ácidos Graxos não Esterificados/farmacologia , Cetose/enzimologia , Fígado/enzimologia , Ácido 3-Hidroxibutírico/sangue , Animais , Bovinos , Doenças dos Bovinos/sangue , China , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Indústria de Laticínios , Ácidos Graxos não Esterificados/sangue , Feminino , Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Cetose/sangue , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/análise , Regulação para Cima/efeitos dos fármacos
9.
Arch Biochem Biophys ; 663: 220-227, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30664838

RESUMO

ß-hydroxybutyrate (BHB), a major ketone body in mammals, is produced from fatty acids through mitochondrial fatty acid oxidation in hepatocytes. To elucidate the role of BHB in the hepatic endoplasmic reticulum (ER), we examined the effects of BHB on hepatic ER stress induced by tunicamycin. In mouse hepatoma Hepa1c1c7 cells, BHB treatment suppressed the protein expression of ER stress responsive genes and increased cell viability, while reducing the protein expression of apoptosis inducible genes, without causing any alterations in the protein expression of sirtuin 1 (SIRT1) or the phosphorylation of AMP-activated protein kinase. The intraperitoneal administration of BHB also reduced the protein expression of ER stress responsive genes in mouse livers. In human hepatoma HepG2 cells, the protein expression levels of ER stress responsive genes were increased by the partial inhibition of BHB production with siRNA targeting endogenous 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lyase, whereas they were decreased by promoting BHB production with fenofibrate. These findings revealed that BHB helps to suppress hepatic ER stress via a SIRT1-independent pathway, and it might be possible to manipulate ER stress by regulating BHB production genetically or pharmacologically.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Sirtuína 1/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular Tumoral , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Camundongos , Fosforilação , Tunicamicina/farmacologia
10.
Macromol Biosci ; 19(4): e1800466, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30694604

RESUMO

Poly([R]-3-hydroxybutyrate) (PHB), a natural biodegradable polyester, has attracted much attention as a new biomaterial because of its sustainability and good biocompatibility. In this study, it is discovered that PHB can be conveniently functionalized to obtain a number of platform chain architectures that may provide a wide range of functional copolymers. In a transesterification reaction, linear (di-hydroxylated) and star shaped (tri- and tetra-hydroxylated) PHB oligomers are synthesized, followed by copolymerization with 2-(dimethylamino)ethyl methacrylate and quaternization with benzyl bromide to afford antimicrobial properties. The antimicrobial activities of the quaternary salts against clinically relevant pathogens on the interactions with outer and cytoplasmic membranes, lethal mechanisms, multipassage resistance, and synergy effect with antibiotics are investigated. Cationic PHB copolymers show effectiveness as antimicrobial agents, with minimum inhibitory concentration values 0.24-0.65 µm (or µmol dm-3 ) (or 32-128 µg mL-1 ) against Gram-positive and Gram-negative bacteria. Modifying the copolymer architectures into star shapes results in enhanced effectiveness to disrupt the membrane integrity. Synergistic effects are attained for all the quaternized PHB derivatives when they are used together with tobramycin. Multipassage resistance does not occur in both the linear and star derivatives against Gram-negative bacteria after 20 passages.


Assuntos
Ácido 3-Hidroxibutírico , Antibacterianos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/crescimento & desenvolvimento , Poliésteres , Tobramicina , Ácido 3-Hidroxibutírico/química , Ácido 3-Hidroxibutírico/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Poliésteres/química , Poliésteres/farmacologia , Tobramicina/química , Tobramicina/farmacologia
11.
Molecules ; 24(3)2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678309

RESUMO

Metabolic diseases, such as ketosis, are closely associated with decreased reproductive performance (such as delayed estrus and decreased pregnancy rate) in dairy cows. The change of ß-hydroxybutyrate (BHBA) concentration in dairy cattle is an important mechanism leading to ketosis, and its blood concentration in ketotic cows is always significantly higher than in nonketotic cows. Many studies indicated that BHBA can induce oxidative damage in liver and other organs. Proanthocyanidins (PCs) have gained substantial attention in the last decade as strong antioxidative substances. This study aimed to demonstrate a protective effect of PCs against BHBA-induced oxidative stress damage in bovine endometrial (BEND) cells by activating the nuclear erythroid2-related factor2 (Nrf2) signaling pathway. Our research show that PCs could significantly increase activities of catalase (CAT) and glutathione peroxidase (GSH-PX), glutathione (GSH) content, and antioxidant capacity (T-AOC), while significantly decreasing malondialdehyde (MDA) content in BEND cells. Both mRNA and protein expression levels of Nrf2 were significantly increased in BEND cells, and glutamate⁻cysteine ligase catalytic subunit (GCLC), heme oxygenase 1 (HO-1), manganese superoxide dismutase (Mn-SOD), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were also significantly increased. These results indicate that PCs can antagonize BHBA-induced oxidative damage by activating the Nrf2 signaling pathway to exert an antioxidant effect.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Endométrio/citologia , Endométrio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proantocianidinas/farmacologia , Substâncias Protetoras/farmacologia , Animais , Antioxidantes , Biomarcadores , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Biomacromolecules ; 20(2): 618-624, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30180551

RESUMO

Poly( R-3-hydroxybutyrate- co- R-3-hydroxyhexanoate) (PHBHHx), a family member of microbial polyhydroxyalkanoates (PHA), is a biodegradable and biocompatible material with some hydrophobicity and reasonable strength for packaging and tissue engineering applications. In this study, superhydrophobic PHBHHx is fabricated via a simple nonsolvent-assisted process. The material can absorb all tested hydrophobic solvents and oil up to 6-fold of the material weights from water, permitting applications for cleaning environmental oil or solvent pollutions with convenience of disposal after the usage due to its biodegradability. With an excellent combination of biodegradability and biocompatibility, superhydrophobic PHBHHx films are evaluated for antibioadhesion properities to exploit possible implant usages. Up to 100% reductions for platelet adhesions on the superhydrophobic PHBHHx surfaces are observed compared with that on the control material surfaces. Superhydrophobic biodegradable and biocompatible PHBHHx films demonstrate promising low value and high volume or high value and low volume applications.


Assuntos
Ácido 3-Hidroxibutírico/química , Materiais Biocompatíveis/química , Plásticos Biodegradáveis/química , Caproatos/química , Adesão Celular , Interações Hidrofóbicas e Hidrofílicas , Ácido 3-Hidroxibutírico/farmacologia , Aderência Bacteriana , Materiais Biocompatíveis/farmacologia , Plásticos Biodegradáveis/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/fisiologia , Caproatos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Adesividade Plaquetária , Solventes/química
13.
Neuropharmacology ; 148: 21-30, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30562540

RESUMO

Ketogenesis is a metabolic process wherein ketone bodies are produced from the breakdown of fatty acids. In humans, fatty acid catabolism results in the production of acetyl-CoA which can then be used to synthesize three ketone bodies: acetoacetate, acetone, and ß-hydroxybutyrate. Ketogenesis occurs at a higher rate in situations of low blood glucose, such as during fasting, heavy alcohol consumption, and in situations of low insulin, as well as in individuals who follow a 'ketogenic diet' consisting of low carbohydrate and high fat intake. This diet has various therapeutic indications, including reduction of seizure likelihood in epileptic patients and alcohol withdrawal syndrome. However, the mechanisms underlying these therapeutic benefits are still unclear, with studies suggesting various mechanisms such as a shift in energy production in the brain, effects on neurotransmitter production, or effects on various protein targets. Two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes was used to investigate the actions of ketone bodies on three ionotropic receptors: GABAA, glycine, and NMDA receptors. While physiologically-relevant concentrations of acetone have little effect on inhibitory GABA or glycine receptors, ß-hydroxybutyrate inhibits the effects of agonists of these receptors at concentrations achieved in vivo. Additionally, both acetone and ß-hydroxybutyrate act as inhibitors of glutamate at the excitatory NMDA receptor. Due to the role of hyperexcitability in the pathogenesis of epilepsy and alcohol withdrawal, the inhibitory actions of acetone and ß-hydroxybutyrate at NMDA receptors may underlie the therapeutic benefit of a ketogenic diet for these disorders.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Acetona/farmacologia , Corpos Cetônicos/metabolismo , Receptores de GABA-A/efeitos dos fármacos , Receptores da Glicina/agonistas , Receptores da Glicina/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Interações Medicamentosas , Agonistas de Receptores de GABA-A/farmacologia , Oócitos/fisiologia , Receptores de N-Metil-D-Aspartato/agonistas , Xenopus
14.
Asian Pac J Cancer Prev ; 19(11): 3287-3294, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30486639

RESUMO

Background: Beta-hydroxybutyrate (BHB) as a ketone body is the metabolic fuel in oxidative phosphorylation pathway. So far the effects of BHB on the biology of tumor cells is contradictory. Therefore, we investigated the effect of BHB on viability, metabolism, proliferation and migration of 5FU treated SW480 colon cancer cell line. Methods: we treated the SW480 cells with IC50 dose of 5-fluorouracil (5FU) for 72 h to isolate a subpopulation of 5FU treated cells that were resistant to it. Effects of BHB on cell viability was investigated by MTT assay. Measurement of oxygen consumption rate (OCR) in parallel with extracellular acidification rate (ECAR) upon BHB treatment was used for determination of metabolic profile of these cells. Investigating the relationship between metabolic phenotype and the status of differentiation and stemness was done by analyzing the expression of PGC-1α, c-MYC, NANOG, ALPi and KRT20 genes by qRT-PCR. Clonogenic and scratch assay were performed to determine the proliferation and migration abilities of incubated with BHB compared to untreated cells. Results: BHB increased cell viability in SW480 and 5FU treated SW480 cells. The results showed a significantly decreased ECAR and increased OCR in both cell types following BHB treatment reflecting the superiority of oxidative phosphorylation profile compared to glycolysis in both cell types. Also, treatment with BHB increases the expression of genes normally associated with stemness and mitochondrial biogenesis and decreases the expression of genes related to glycolytic program and differentiation in 5FU treated cells. Self-renewal and migration potential of BHB treated cells increased significantly. Conclusion: These findings suggest that BHB utilization via oxidative mitochondrial metabolism can fuel proliferation, migration and stemness in 5FU treated SW480 colon cancer cells.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fluoruracila/farmacologia , Células-Tronco Neoplásicas/patologia , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicólise , Humanos , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Fosforilação Oxidativa , Células Tumorais Cultivadas
15.
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
16.
Stroke ; 49(9): 2173-2181, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30354983

RESUMO

Background and Purpose- Recent evidence suggests great potential of metabolically targeted interventions for treating neurological disorders. We investigated the use of the endogenous ketone body ß-hydroxybutyrate (BHB) as an alternate metabolic substrate for the brain in the acute phase of ischemia because postischemic hyperglycemia and brain glucose metabolism elevation compromise functional recovery. Methods- We delivered BHB (or vehicle) 1 hour after ischemic insult induced by cortical microinjection of endothelin-1 in sensorimotor cortex of rats. Two days after ischemic insult, the rats underwent multimodal characterization of the BHB effects. We examined glucose uptake on 2-Deoxy-d-glucose chemical exchange saturation transfer magnetic resonance imaging, cerebral hemodynamics on continuous arterial spin labeling magnetic resonance imaging, resting-state field potentials by intracerebral multielectrode arrays, Neurological Deficit Score, reactive oxygen species production, and astrogliosis and neuronal death. Results- When compared with vehicle-administered animals, BHB-treated cohort showed decreased peri-infarct neuronal glucose uptake which was associated with reduced oxidative stress, diminished astrogliosis and neuronal death. Functional examination revealed ameliorated neuronal functioning, normalized perilesional resting perfusion, and ameliorated cerebrovascular reactivity to hypercapnia, suggesting improved functioning. Cellular and functional recovery of the neurogliovascular unit in the BHB-treated animals was associated with improved performance on the withdrawal test. Conclusions- We characterize the effects of the ketone body BHB administration at cellular and system levels after focal cortical stroke. The results demonstrate that BHB curbs the peri-infarct glucose-metabolism driven production of reactive oxygen species and astrogliosis, culminating in improved neurogliovascular and functional recovery.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Astrócitos/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Encéfalo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ácido 3-Hidroxibutírico/metabolismo , Acetoacetatos/metabolismo , Animais , Astrócitos/patologia , Glicemia/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Morte Celular/efeitos dos fármacos , Circulação Cerebrovascular , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos , Endotelina-1 , Hemodinâmica , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Microinjeções , Neurônios/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Córtex Sensório-Motor
17.
Mol Cell ; 71(6): 1064-1078.e5, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30197300

RESUMO

ß-hydroxybutyrate (ß-HB) elevation during fasting or caloric restriction is believed to induce anti-aging effects and alleviate aging-related neurodegeneration. However, whether ß-HB alters the senescence pathway in vascular cells remains unknown. Here we report that ß-HB promotes vascular cell quiescence, which significantly inhibits both stress-induced premature senescence and replicative senescence through p53-independent mechanisms. Further, we identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a direct binding target of ß-HB. ß-HB binding to hnRNP A1 markedly enhances hnRNP A1 binding with Octamer-binding transcriptional factor (Oct) 4 mRNA, which stabilizes Oct4 mRNA and Oct4 expression. Oct4 increases Lamin B1, a key factor against DNA damage-induced senescence. Finally, fasting and intraperitoneal injection of ß-HB upregulate Oct4 and Lamin B1 in both vascular smooth muscle and endothelial cells in mice in vivo. We conclude that ß-HB exerts anti-aging effects in vascular cells by upregulating an hnRNP A1-induced Oct4-mediated Lamin B1 pathway.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Senescência Celular/efeitos dos fármacos , Animais , Células Cultivadas , Regulação da Expressão Gênica , Ribonucleoproteína Nuclear Heterogênea A1/efeitos dos fármacos , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fator 3 de Transcrição de Octâmero/efeitos dos fármacos , Fator 3 de Transcrição de Octâmero/metabolismo , RNA Mensageiro , Ativação Transcricional , Regulação para Cima
18.
Am J Clin Nutr ; 108(4): 857-867, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30239561

RESUMO

Background: Acute inflammation, and subsequent release of bacterial products (e.g. LPS), inflammatory cytokines, and stress hormones, is catabolic, and the loss of lean body mass predicts morbidity and mortality. Lipid intermediates may reduce protein loss, but the roles of free fatty acids (FFAs) and ketone bodies during acute inflammation are unclear. Objective: We aimed to test whether infusions of 3-hydroxybutyrate (3OHB), FFAs, and saline reduce protein catabolism during exposure to LPS and Acipimox (to restrict and control endogenous lipolysis). Design: A total of 10 healthy male subjects were randomly tested 3 times, with: 1) LPS, Acipimox (Olbetam) and saline, 2) LPS, Acipimox, and nonesterified fatty acids (Intralipid), and 3) LPS, Acipimox, and 3OHB, during a 5-h basal period and a 2-h hyperinsulinemic, euglycemic clamp. Labeled phenylalanine, tyrosine, and urea tracers were used to estimate protein kinetics, and muscle biopsies were taken for Western blot analysis of protein metabolic signaling. Results: 3OHB infusion increased 3OHB concentrations (P < 0.0005) to 3.5 mM and decreased whole-body phenylalanine-to-tyrosine degradation. Basal and insulin-stimulated net forearm phenylalanine release decreased by >70% (P < 0.005), with both appearance and phenylalanine disappearance being profoundly decreased. Phosphorylation of eukaryotic initiation factor 2α at Ser51 was increased in skeletal muscle, and S6 kinase phosphorylation at Ser235/236 tended (P = 0.074) to be decreased with 3OHB infusion (suggesting inhibition of protein synthesis), whereas no detectable effects were seen on markers of protein breakdown. Lipid infusion did not affect phenylalanine kinetics, and insulin sensitivity was unaffected by interventions. Conclusion: During acute inflammation, 3OHB has potent anticatabolic actions in muscle and at the whole-body level; in muscle, reduction of protein breakdown overrides inhibition of synthesis. This trial was registered at clinicaltrials.gov as NCT01752348.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Ácidos Graxos não Esterificados/farmacologia , Inflamação/metabolismo , Corpos Cetônicos/metabolismo , Proteínas Musculares/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Ácido 3-Hidroxibutírico/metabolismo , Adulto , Biomarcadores/metabolismo , Western Blotting , Ácidos Graxos não Esterificados/metabolismo , Técnica Clamp de Glucose , Humanos , Hipolipemiantes/farmacologia , Resistência à Insulina , Cinética , Lipopolissacarídeos , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Fosforilação , Biossíntese de Proteínas , Proteólise , Pirazinas/farmacologia , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais , Adulto Jovem
19.
Sci Rep ; 8(1): 13766, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30214009

RESUMO

The rapid decline in fertility that has been occurring to high-producing dairy cows in the past 50 years seems to be associated with metabolic disturbances such as ketosis, supporting the need for research to improve our understanding of the relations among the diet, metabolism and embryonic development. Recently, the ketone body ß-hydroxybutyrate (BOHB) was demonstrated to be a potent inhibitor of histone deacetylases (HDACs). Herein, we performed a series of experiments aiming to investigate the epigenetic effects of BOHB on histone acetylation in somatic cells, cumulus-oocyte complexes (COCs) and somatic cell nuclear transfer (SCNT) embryos. Treatment with BOHB does not increase histone acetylation in cells but stimulates genes associated with ketolysis and master regulators of metabolism. We further demonstrated that maturing COCs with high levels of BOHB does not affect their maturation rate or histone acetylation but increases the expression of PPARA in cumulus cells. Treatment of somatic cell nuclear transfer zygotes with BOHB causes hyperacetylation, which is maintained until the blastocyst stage, causing enhanced FOXO3A expression and blastocyst production. Our data shed light on the epigenetic mechanisms caused by BOHB in bovine cells and embryos and provide a better understanding of the connection between nutrition and reproduction.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Embrião de Mamíferos/citologia , Desenvolvimento Embrionário/efeitos dos fármacos , Fertilidade/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Oócitos/metabolismo , Ácido 3-Hidroxibutírico/biossíntese , Ácido 3-Hidroxibutírico/genética , Acetilação , Animais , Blastocisto/citologia , Bovinos , Linhagem Celular , Células do Cúmulo/metabolismo , Feminino , Proteína Forkhead Box O3/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Técnicas de Transferência Nuclear , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/biossíntese , Gravidez
20.
Cell Mol Neurobiol ; 38(8): 1479-1489, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30218403

RESUMO

Activation of inflammasome leads to the formation of an inflammatory microenvironment which plays an important role in the process of cancer development. Beta-hydroxybutyrate (BHB) is a ketone body that has recently been reported to exert anti-inflammatory effects via inhibition of NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. Here, we investigated the potential influence of BHB on the in vitro migration of C6 glioma cells and the activation of NLRP3 inflammasome. Our results indicated that administration of BHB suppressed C6 cells migration and NLRP3 inflammasome activation, reducing the levels of activated cysteinyl aspartate-specific proteinase 1 (caspase-1) and mature Interleukin 1ß (IL-1ß). Fully activation of NLRP3 inflammasome was induced by lipopolysaccharide (LPS) prime plus adenosine triphosphate (ATP) stimulation in C6 cells, which promoted in vitro migration of C6 cell. BHB also counteracted the LPS/ATP-promoted cell migration by suppressing the activation of caspase-1 and the maturation of IL-1ß. The enhancement of phospho-signal transducer and activator of transcription 3 (p-STAT3), degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) as well as the overexpression of fibroblast growth factor 2 (FGF2) resulting from LPS/ATP treatment, and subsequent IL-1ß maturation could also be compensated by BHB. Our results suggested that BHB inhibits the activation of NLRP3 inflammasome in C6 glioma cells and consequently suppressed the C6 cell migration. These findings also implicated that by inhibiting NLRP3 inflammasome, BHB reduced the inflammatory microenvironment which provided ancillary therapeutic benefits for the intervention of glioma.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Movimento Celular/efeitos dos fármacos , Glioma/metabolismo , Glioma/patologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Toxina Pertussis/farmacologia , Ratos
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