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1.
Anticancer Res ; 40(7): 3831-3837, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620622

RESUMO

BACKGROUND/AIM: The ketogenic diet has recently gained interest as potential adjuvant therapy for cancer. Many researchers have endeavored to support this claim in vitro. One common model utilizes treatment with exogenous acetoacetate in lithium salt form (LiAcAc). We aimed to determine whether the effects of treatment with LiAcAc on cell viability, as reported in the literature, accurately reflect the influence of acetoacetate. MATERIALS AND METHODS: Breast cancer and normal cell lines were treated with acetoacetate, in lithium and sodium salt forms, and cell viability was assessed. RESULTS: The effect of LiAcAc on cells was mediated by Li ions. Our results showed that the cytotoxic effects of LiAcAc treatment were significantly similar to those caused by LiCl, and also treatment with NaAcAc did not cause any significant cytotoxic effect. CONCLUSION: Treatment of cells with LiAcAc is not a convincing in vitro model for studying ketogenic diet. These findings are highly important for interpreting previously published results, and for designing new experiments to study the ketogenic diet in vitro.


Assuntos
Acetoacetatos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Compostos de Lítio/farmacologia , Lítio/farmacologia , Acetoacetatos/química , Trifosfato de Adenosina/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cátions Monovalentes/química , Cátions Monovalentes/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Lítio/química , Cloreto de Lítio/química , Cloreto de Lítio/farmacologia , Compostos de Lítio/química , Células MCF-7
2.
Nat Commun ; 11(1): 1736, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32269227

RESUMO

Carbon-11 (11C) is one of the most ideal positron emitters for labeling bioactive molecules for molecular imaging studies. The lack of convenient and fast incorporation methods to introduce 11C into organic molecules often hampers the use of this radioisotope. Here, a fluoride-mediated desilylation (FMDS) 11C-labeling approach is reported. This method relies on thermodynamically favored Si-F bond formation to generate a carbanion, therefore enabling the highly efficient and speedy incorporation of [11C]CO2 and [11C]CH3I into molecules with diversified structures. It provides facile and rapid access to 11C-labeled compounds with carbon-11 attached at various hybridized carbons as well as oxygen, sulfur and nitrogen atoms with broad functional group tolerance. The exemplified syntheses of several biologically and clinically important radiotracers illustrates the potentials of this methodology.


Assuntos
Radioisótopos de Carbono/química , Fluoretos/química , Compostos de Organossilício/química , Acetoacetatos/química , Metilação , Racloprida/farmacologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
3.
Toxicol Lett ; 323: 19-24, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31962156

RESUMO

Cultured kidney cells maintained in conventional growth media with high glucose levels exhibit increased glycolytic activity compared to the cells in vivo. In contrast, renal proximal tubules utilize substrates such as ketone bodies and rely on mitochondrial oxidative phosphorylation. LLC-PK1 cells maintain many features of the proximal tubule but are exposed to glucose concentrations ranging from 17 to 25 mM. This may impact their reliability in predicting mitochondrial toxicity. This study is designed to test the impact of the ketone body acetoacetate on metabolic characteristics of LLC-PK1 cells. Basal respiration, maximal respiration, spare respiratory capacity and ATP-linked respiration were significantly increased in cells grown in growth medium supplemented with 5 mM acetoacetate. In contrast, glycolytic capacity, as well as glycolytic reserve were significantly reduced in the acetoacetate group. There was an increased expression in biomarkers of mitochondrial biogenesis, and an increase in mitochondrial protein expression. Cells grown in medium complemented with acetoacetate displayed a significantly lower LC50 when treated with clotrimazole and diclofenac. There was a marked increase in uncoupled respiration in the presence of diclofenac, while clotrimazole and ciprofibrate significantly decreased respiration in the acetoacetate. The results indicate that acetoacetate complemented media can alter cellular metabolism and increase sensitization to toxicants.


Assuntos
Acetoacetatos/farmacologia , Rim/efeitos dos fármacos , Animais , Células Cultivadas , Clotrimazol/toxicidade , Diclofenaco/toxicidade , Ácidos Fíbricos/toxicidade , Glicólise/efeitos dos fármacos , Rim/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxirredução , Suínos
4.
Amino Acids ; 51(10-12): 1609-1621, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31712920

RESUMO

The role of pH-dependent ionic structures of L-amino acids in catalysis has been investigated for the two-component Mannich reactions between dimethyl malonate (DMM)/ethyl acetoacetate (EAA) and imines. As catalysts, L-amino acids performed well, even better than corresponding base catalysts and provided the ß-amino carbonyl compounds in very high yields. Density functional calculations were used to gain the mechanistic insight of the reaction. High catalytic efficiency of amino acids was attributed to the facile formation of carbanion intermediate through barrierless transition state TS1 (- 19.43 kcal/mol) and then its stabilization owing to carbanion interaction with protonated amino acid.


Assuntos
Aminoácidos/química , Acetoacetatos/química , Catálise , Ácido Glutâmico/química , Concentração de Íons de Hidrogênio , Iminas/química , Malonatos/química , Bases de Mannich/síntese química , Bases de Mannich/química , Estrutura Molecular , Estereoisomerismo
5.
Nutrients ; 11(10)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581549

RESUMO

Diseases involving inflammation and oxidative stress can be exacerbated by high blood glucose levels. Due to tight metabolic regulation, safely reducing blood glucose can prove difficult. The ketogenic diet (KD) reduces absolute glucose and insulin, while increasing fatty acid oxidation, ketogenesis, and circulating levels of ß-hydroxybutyrate (ßHB), acetoacetate (AcAc), and acetone. Compliance to KD can be difficult, so alternative therapies that help reduce glucose levels are needed. Exogenous ketones provide an alternative method to elevate blood ketone levels without strict dietary requirements. In this study, we tested the changes in blood glucose and ketone (ßHB) levels in response to acute, sub-chronic, and chronic administration of various ketogenic compounds in either a post-exercise or rested state. WAG/Rij (WR) rats, a rodent model of human absence epilepsy, GLUT1 deficiency syndrome mice (GLUT1D), and wild type Sprague Dawley rats (SPD) were assessed. Non-pathological animals were also assessed across different age ranges. Experimental groups included KD, standard diet (SD) supplemented with water (Control, C) or with exogenous ketones: 1, 3-butanediol (BD), ßHB mineral salt (KS), KS with medium chain triglyceride/MCT (KSMCT), BD acetoacetate diester (KE), KE with MCT (KEMCT), and KE with KS (KEKS). In rested WR rats, the KE, KS, KSMCT groups had lower blood glucose level after 1 h of treatment, and in KE and KSMCT groups after 24 h. After exercise, the KE, KSMCT, KEKS, and KEMCT groups had lowered glucose levels after 1 h, and in the KEKS and KEMCT groups after 7 days, compared to control. In GLUT1D mice without exercise, only KE resulted in significantly lower glucose levels at week 2 and week 6 during a 10 weeks long chronic feeding study. In 4-month and 1-year-old SPD rats in the post-exercise trials, blood glucose was significantly lower in KD and KE, and in KEMCT groups, respectively. After seven days, the KSMCT group had the most significantly reduced blood glucose levels, compared to control. These results indicate that exogenous ketones were efficacious in reducing blood glucose levels within and outside the context of exercise in various rodent models of different ages, with and without pathology.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Acetoacetatos/farmacologia , Glicemia/efeitos dos fármacos , Butileno Glicóis/farmacologia , Erros Inatos do Metabolismo dos Carboidratos/terapia , Dieta Cetogênica , Suplementos Nutricionais , Epilepsia Tipo Ausência/terapia , Proteínas de Transporte de Monossacarídeos/deficiência , Animais , Biomarcadores , Glicemia/metabolismo , Erros Inatos do Metabolismo dos Carboidratos/sangue , Erros Inatos do Metabolismo dos Carboidratos/genética , Erros Inatos do Metabolismo dos Carboidratos/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Epilepsia Tipo Ausência/sangue , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/fisiopatologia , Transportador de Glucose Tipo 1/deficiência , Transportador de Glucose Tipo 1/genética , Masculino , Camundongos Knockout , Proteínas de Transporte de Monossacarídeos/sangue , Proteínas de Transporte de Monossacarídeos/genética , Esforço Físico , Ratos Sprague-Dawley , Descanso , Fatores de Tempo
6.
Int J Mol Sci ; 20(12)2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31242642

RESUMO

The ketogenic diet (KD), a high-fat/low-carbohydrate/adequate-protein diet, has been proposed as a treatment for a variety of diseases, including cancer. KD leads to generation of ketone bodies (KBs), predominantly acetoacetate (AcAc) and 3-hydroxy-butyrate, as a result of fatty acid oxidation. Several studies investigated the antiproliferative effects of lithium acetoacetate (LiAcAc) and sodium 3-hydroxybutyrate on cancer cells in vitro. However, a critical point missed in some studies using LiAcAc is that Li ions have pleiotropic effects on cell growth and cell signaling. Thus, we tested whether Li ions per se contribute to the antiproliferative effects of LiAcAc in vitro. Cell proliferation was analyzed on neuroblastoma, renal cell carcinoma, and human embryonic kidney cell lines. Cells were treated for 5 days with 2.5, 5, and 10 mM LiAcAc and with equimolar concentrations of lithium chloride (LiCl) or sodium chloride (NaCl). LiAcAc affected the growth of all cell lines, either negatively or positively. However, the effects of LiAcAc were always similar to those of LiCl. In contrast, NaCl showed no effects, indicating that the Li ion impacts cell proliferation. As Li ions have significant effects on cell growth, it is important for future studies to include sources of Li ions as a control.


Assuntos
Acetoacetatos/farmacologia , Lítio/farmacologia , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cloretos/farmacologia , Expressão Gênica , Humanos , Cloreto de Lítio/farmacologia
8.
Am J Clin Nutr ; 109(5): 1239-1250, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31051508

RESUMO

BACKGROUND: Replacing dietary saturated fatty acids (SFAs) with polyunsaturated fatty acids (PUFA) reduces the plasma low-density lipoprotein (LDL) cholesterol and subsequently the risk of cardiovascular disease. However, beyond changes in LDL cholesterol, we lack a complete understanding of the physiologic alterations that occur when improving dietary fat quality. OBJECTIVES: The aim of this study was to gain knowledge of metabolic alterations paralleling improvements in the fat quality of the diet. METHODS: We recently conducted an 8-wk, double-blind, randomized controlled trial replacing SFAs with PUFAs in healthy subjects with moderate hypercholesterolemia (n = 99). In the present substudy, we performed comprehensive metabolic profiling with multiple platforms (both nuclear magnetic resonance- and mass spectrometry-based technology) (n = 99), and analyzed peripheral blood mononuclear cell gene expression (n = 95) by quantitative real-time polymerase chain reaction. RESULTS: A large number of lipoprotein subclasses, myristoylcarnitine and palmitoylcarnitine, and kynurenine were reduced when SFAs were replaced with PUFAs. In contrast, bile acids, proprotein convertase subtilisin/kexin type 9, acetate, and acetoacetate were increased by the intervention. Some amino acids were also altered by the intervention. The mRNA levels of LXRA and LDLR were increased, in addition to several liver X receptor α target genes and genes involved in inflammation, whereas the mRNA levels of UCP2 and PPARD were decreased in peripheral blood mononuclear cells after replacing SFAs with PUFAs. Partial least squares-discriminant analysis showed that the 30 most important variables that contributed to class separation spanned all classes of biomarkers, and was in accordance with the univariate analysis. CONCLUSIONS: Applying metabolomics in randomized controlled dietary intervention trials has the potential to extend our knowledge of the biological and molecular effects of dietary fat quality. This study was registered at clinicaltrials.gov as NCT01679496.


Assuntos
Dieta , Gorduras na Dieta/farmacologia , Ácidos Graxos Insaturados/farmacologia , Comportamento Alimentar , Hipercolesterolemia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas/sangue , Ácido Acético/sangue , Acetoacetatos/sangue , Aminoácidos/sangue , Ácidos e Sais Biliares/sangue , LDL-Colesterol/sangue , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/sangue , Método Duplo-Cego , Ácidos Graxos/administração & dosagem , Ácidos Graxos/sangue , Ácidos Graxos/farmacologia , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos Insaturados/sangue , Ácidos Graxos Insaturados/uso terapêutico , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Hipercolesterolemia/dietoterapia , Hipercolesterolemia/genética , Masculino , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Pessoa de Meia-Idade , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo
9.
NMR Biomed ; 32(6): e4091, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30968985

RESUMO

Mitochondrial dysfunction is considered to be an important component of many metabolic diseases yet there is no reliable imaging biomarker for monitoring mitochondrial damage in vivo. A large prior literature on inter-conversion of ß-hydroxybutyrate and acetoacetate indicates that the process is mitochondrial and that the ratio reflects a specifically mitochondrial redox state. Therefore, the conversion of [1,3-13 C]acetoacetate to [1,3-13 C]ß-hydroxybutyrate is expected to be sensitive to the abnormal redox state present in dysfunctional mitochondria. In this study, we examined the conversion of hyperpolarized (HP) 13 C-acetoacetate (AcAc) to 13 C-ß-hydroxybutyrate (ß-HB) as a potential imaging biomarker for mitochondrial redox and dysfunction in perfused rat hearts. Conversion of HP-AcAc to ß-HB was investigated using 13 C magnetic resonance spectroscopy in Langendorff-perfused rat hearts in four groups: control, global ischemic reperfusion, low-flow ischemic, and rotenone (mitochondrial complex-I inhibitor)-treated hearts. We observed that more ß-HB was produced from AcAc in ischemic hearts and the hearts exposed to complex I inhibitor rotenone compared with controls, consistent with the accumulation of excess mitochondrial NADH. The increase in ß-HB, as detected by 13 C MRS, was validated by a direct measure of tissue ß-HB by 1 H nuclear magnetic resonance in tissue extracts. The redox ratio, NAD+ /NADH, measured by enzyme assays of homogenized tissue, also paralleled production of ß-HB from AcAc. Transmission electron microscopy of tissues provided direct evidence for abnormal mitochondrial structure in each ischemic tissue model. The results suggest that conversion of HP-AcAc to HP-ß-HB detected by 13 C-MRS may serve as a useful diagnostic marker of mitochondrial redox and dysfunction in heart tissue in vivo.


Assuntos
Ácido 3-Hidroxibutírico/metabolismo , Acetoacetatos/metabolismo , Isótopos de Carbono/metabolismo , Coração/fisiopatologia , Espectroscopia de Ressonância Magnética , Mitocôndrias/metabolismo , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Congelamento , Hemodinâmica , Masculino , Mitocôndrias/ultraestrutura , Miocárdio/metabolismo , Miocárdio/ultraestrutura , NAD/metabolismo , Oxirredução , Perfusão , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley
10.
Carbohydr Polym ; 211: 173-180, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30824077

RESUMO

Herein, the acetoacetyl group was directly anchored on the surface of cotton fabric (Cotton-acac) via heterogeneous transesterification. This surface modification strategy was systematically characterized by Fourier transform infrared spectroscopy, solid-state 13C nuclear magnetic resonance spectroscopy, X-ray diffraction, and thermogravimetric analysis, which confirmed it was a mild and efficient process. Besides, Cotton-acac was used as the versatile intermediate post-modified with gentamicin (Gen) and octadecyl amine (ODA) molecules to impart cotton fabric dual functions with hydrophobic and antibacterial properties. The resulting cotton fabric showed dual and outstanding hydrophobic and antibacterial performance against E. coli and S. aureus, with the bactericidal rates of over 99.99% and the water contact angle of 145°even after 10 cycles of standard washing. Therefore, the heterogeneous modification provided a benign and versatile method for regulating the interfacial properties of the cellulosic materials, with the possibility of post modification for various applications through the acetoacetyl chemistry.


Assuntos
Aminas/química , Antibacterianos/química , Fibra de Algodão , Gentamicinas/química , Têxteis , Acetoacetatos/química , Escherichia coli/crescimento & desenvolvimento , Interações Hidrofóbicas e Hidrofílicas , Staphylococcus aureus/crescimento & desenvolvimento
13.
Trends Endocrinol Metab ; 30(4): 227-229, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30712977

RESUMO

The ketone bodies acetoacetate (AcAc) and ß-hydroxybutyrate (ßHB) are the subject of renewed interest given recently established pleiotropic effects regulating inflammation, oxidative stress, and gene expression. Anticatabolic effects of ß-hydroxybutyrate have recently been demonstrated in human skeletal muscle under inflammatory insult, thereby expanding upon the wide-ranging therapeutic applications of nutritional ketosis.


Assuntos
Ácido 3-Hidroxibutírico , Acetoacetatos , Dieta Cetogênica , Inflamação/metabolismo , Corpos Cetônicos , Cetose/metabolismo , Músculo Esquelético/metabolismo , Humanos
14.
Cell Metab ; 29(2): 383-398.e7, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30449686

RESUMO

Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[13C]ß-hydroxybutyrate (D-ßOHB) labeled almost none. [13C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-ßOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-ßOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.


Assuntos
Ácido 3-Hidroxibutírico/metabolismo , Acetoacetatos/metabolismo , Hepatócitos/metabolismo , Cirrose Hepática Experimental/metabolismo , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Animais , Hepatócitos/patologia , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL
15.
FASEB J ; 33(2): 2409-2421, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30303740

RESUMO

The dietary R-3-hydroxybutyrate- R-1,3-butanediol monoester increases resting energy expenditure (REE) and markers of brown and white adipose thermogenesis in lean mice. The purpose of this investigation was to determine whether the ketone ester, R, S-1,3-butanediol diacetoacetate (BD-AcAc2), increases energy expenditure and markers of adipose tissue thermogenesis in the context of high-fat diet (HFD)-induced obesity. Thirty-five-week-old male C57BL/6J mice were placed on an ad libitum HFD (45% kcal) for 10 wk. The mice were then randomized to 1 of 3 groups ( n = 10 per group) for an additional 12 wk: 1) control (Con), continuous HFD, 2) pair-fed (PF) to ketone ester (KE); and 3) KE: HFD+30% energy from BD-AcAc2. Mean energy intake throughout the study was ∼26% lower in the KE compared to the Con group (8.2 ± 0.5 vs. 11.2 ± 0.7 kcal/d; P < 0.05). Final body weight (26.8 ± 3.6 vs. 34.9 ± 4.8 g; P < 0.001) and fat mass (5.2 ± 1.2 vs. 11.3 ± 4.5 g; P < 0.001) of the KE group was significantly lower than PF, despite being matched for energy provisions. Differences in body weight and adiposity were accompanied by higher REE and total energy expenditure in the KE group compared to PF after adjustment for lean body mass and fat-mass ( P = 0.001 and 0.007, respectively). Coupled or uncoupled mitochondrial respiratory rates in skeletal muscle were not different among groups, but markers of mitochondrial uncoupling and thermogenesis (uncoupling protein-1, deiodinase-2, and peroxisome proliferator-activated receptor γ coactivator-1α) were higher in interscapular brown adipose tissue (BAT) of mice receiving the KE diet. The absence of mitochondrial uncoupling in skeletal muscle and increased markers of mitochondrial uncoupling in BAT suggest that BD-AcAc2 initiates a transcriptional signature consistent with BAT thermogenesis in the context of HFD-induced obesity.-Davis, R. A. H., Deemer, S. E., Bergeron, J. M., Little, J. T., Warren, J. L., Fisher, G., Smith, D. L., Jr., Fontaine, K. R., Dickinson, S. L., Allison, D. B., Plaisance, E. P. Dietary R, S-1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet.


Assuntos
Acetoacetatos/administração & dosagem , Adiposidade/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Butileno Glicóis/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Obesidade/prevenção & controle , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Composição Corporal , Ingestão de Energia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/fisiopatologia
16.
Endocr J ; 66(1): 107-114, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30393272

RESUMO

Soft-drink diabetic ketosis, characterized by acute onset ketosis induced by excessive ingestion of sugar-containing drinks, is often seen in obese, young patients, even with undiagnosed type 2 diabetes. We herein report a 15-year-old obese patient with the apolipoprotein E4/2 phenotype, in whom eruptive xanthomas lead to a diagnosis of soft-drink diabetic ketosis. He developed multiple asymptomatic yellowish papules on the auricles, back, buttocks and the extensor surfaces of the elbows and knees. He initially visited a dermatology clinic and his blood triglyceride and HbA1c levels were found to be 6,490 mg/dL and 16.5%, respectively. He was referred to our hospital for treatment of hyperglycemia and hypertyriglyceridemia. On admission, he had ketonuria and increased blood levels of 3-hydroxybutylate and acetoacetate. He habitually drank 1-3 litters of sweet beverages daily to quench his thirst. Therefore, "soft-drink diabetic ketosis" was diagnosed. Severe hypertriglyceridemia was considered to have been a consequence of impaired insulin action and his apolipoprotein E4/2 phenotype. We treated the diabetic ketosis and hypertriglyceridemia with intensive insulin therapy and a fat-restricted diet. At discharge, he no longer required insulin therapy and his blood glucose levels were controlled with metformin and voglibose. Along with amelioration of the hyperglycemia, triglyceride levels decreased to 247 mg/dL without administration of anti-hyperlipidemia agents. The eruptive xanthoma lesions gradually diminished in size and number and eventually disappeared by 12 months. This case provides an instructive example of eruptive xanthomas serving as a sign of severe dysregulation, not only of lipid, but also glucose, metabolism.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Cetoacidose Diabética/diagnóstico , Hipertrigliceridemia/diagnóstico , Xantomatose/diagnóstico , Ácido 3-Hidroxibutírico/sangue , Acetoacetatos/sangue , Adolescente , Apolipoproteína E2 , Apolipoproteína E4 , Bebidas Gaseificadas/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Cetoacidose Diabética/tratamento farmacológico , Cetoacidose Diabética/etiologia , Cetoacidose Diabética/metabolismo , Dieta com Restrição de Gorduras , Hemoglobina A Glicada/metabolismo , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/dietoterapia , Hipertrigliceridemia/metabolismo , Hipoglicemiantes/uso terapêutico , Inositol/análogos & derivados , Inositol/uso terapêutico , Insulina/uso terapêutico , Cetose/diagnóstico , Cetose/etiologia , Masculino , Metformina/uso terapêutico , Obesidade/complicações , Obesidade/metabolismo , Xantomatose/etiologia , Xantomatose/patologia
17.
Diving Hyperb Med ; 48(4): 235-240, 2018 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-30517956

RESUMO

BACKGROUND: Recent studies indicated that ketone ester R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) may be effective in preventing central nervous system oxygen toxicity (CNS-OT) and concomitant acute lung injury, a serious medical problem to be faced when breathing hyperbaric oxygen (HBO). This study aimed to further investigate the protective effects of BD-AcAc2 against CNS-OT and concomitant acute lung injury (ALI) in mice. METHODS: Mice were treated with BD-AcAc2 in peanut oil vehicle (2.5, 5.0 or 10.0 g·kg⁻² body weight) by gavage 20 minutes before 600 kPa HBO exposure. Control mice received the vehicle only. Seizure latency was recorded. Malondialdehyde content in brain and lung tissues, total protein level in bronchoalveolar lavage fluid (BLF) and lung water content were measured 60 minutes after the hyperbaric exposure. Histopathology of lung tissue was undertaken. RESULTS: Compared with the vehicle alone, BD-AcAc2 prolonged seizure latency in a dose-dependent manner (P < 0.01). The HBO-induced increase in brain malondialdehyde, BLF protein and lung water were significantly reduced by BD-AcAc2 (P < 0.01). CONCLUSION: Oral administration of the ketone ester BD-AcAc2 significantly protected against CNS-OT and concomitant ALI. Alleviation of oxidative stress may be one underlying mechanism providing this effect.


Assuntos
Acetoacetatos/uso terapêutico , Lesão Pulmonar Aguda , Encéfalo/efeitos dos fármacos , Butileno Glicóis/uso terapêutico , Oxigenação Hiperbárica , Acetoacetatos/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Oxigenação Hiperbárica/efeitos adversos , Camundongos , Oxigênio , Ratos Sprague-Dawley , Convulsões/tratamento farmacológico
18.
Biochemistry ; 57(49): 6757-6761, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30472832

RESUMO

The temperature dependence of psychrophilic and mesophilic ( R)-3-hydroxybutyrate dehydrogenase steady-state rates yields nonlinear and linear Eyring plots, respectively. Solvent viscosity effects and multiple- and single-turnover pre-steady-state kinetics demonstrate that while product release is rate-limiting at high temperatures for the psychrophilic enzyme, either interconversion between enzyme-substrate and enzyme-product complexes or a step prior to it limits the rate at low temperatures. Unexpectedly, a similar change in the rate-limiting step is observed with the mesophilic enzyme, where a step prior to chemistry becomes rate-limiting at low temperatures. This observation may have implications for past and future interpretations of temperature-rate profiles.


Assuntos
Hidroxibutirato Desidrogenase/química , Hidroxibutirato Desidrogenase/metabolismo , Acetoacetatos/metabolismo , Acinetobacter baumannii/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Biocatálise , Cinética , Modelos Lineares , Modelos Biológicos , Psychrobacter/enzimologia , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Solventes , Especificidade por Substrato , Temperatura , Valeratos/metabolismo , Viscosidade
19.
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
20.
Bull Environ Contam Toxicol ; 101(5): 672-677, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30298273

RESUMO

A high-performance liquid chromatography method with methyl acetoacetate derivatization via the Hantzsch reaction was developed for the analysis of formaldehyde (HCHO) in several water samples. Under optimized conditions, HCHO was detected within 4 min and was not affected by excessive derivatization reagents. The calibration curve constructed from the peak height of HCHO was linear, with a correlation coefficient of 0.9998. The relative standard deviation of the peak height from ten replicates was 0.29%. The detection and quantitative limits were 0.96 µg/L and 3.16 µg/L, respectively. A recovery test of HCHO was performed to compare the developed method with the official analysis method (DNPH method). The developed method was used to determine the HCHO levels in several water samples (tap water, river water, and waste water).


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Formaldeído/análise , Água/análise , Acetoacetatos/química , Águas Residuárias/análise , Água/química
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