Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.380
Filtrar
1.
J Agric Food Chem ; 68(4): 1007-1014, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31914311

RESUMO

Induction of beige adipocytes in white adipose tissue (WAT) is a potential therapeutic target for the treatment of obesity because beige adipocytes release excess energy via uncoupling-protein-1-associated thermogenesis. In this study, we investigated how artepillin C (ArtC) promotes thermogenesis in vivo. We demonstrated that 28 day administration of ArtC (10 mg/kg of body weight) to mice significantly induced thermogenesis in beige adipocytes in inguinal WAT (iWAT) and suppressed reductions in core body temperature induced by cold exposure at 4 °C. Moreover, ArtC-induced thermogenesis in iWAT was significantly inhibited by treatment with a creatine metabolism inhibitor, and ArtC significantly upregulated the expression of creatine-metabolism-related enzymes in the thermogenic pathway. These results indicate that ArtC induces thermogenesis in beige adipocytes in iWAT, and the observed ArtC-induced thermogenesis is associated with the creatine-metabolism-related thermogenic pathway, which is characteristically observed in beige adipocytes.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Creatina/metabolismo , Obesidade/tratamento farmacológico , Fenilpropionatos/administração & dosagem , Própole/análise , Termogênese/efeitos dos fármacos , Adipócitos Bege/efeitos dos fármacos , Adipócitos Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Temperatura Corporal , Brasil , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/fisiopatologia , Própole/administração & dosagem
2.
J Zoo Wildl Med ; 50(4): 891-896, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926520

RESUMO

Clinical assessment of renal function in avian species often involves the measurement of plasma uric acid and blood urea nitrogen, relatively insensitive markers of renal dysfunction and dehydration. In mammals, endogenous creatinine is widely used as an indicator of renal glomerular dysfunction. However, avian species produce primarily creatine. Here, renal creatine, 99mTc99-DTPA (diethylenepentaacetic acid, DTPA) and 99mTc-MAG3 (mercaptoacetyl triglycine, MAG3) renal clearances are characterized in the pigeon avian model by infusing DTPA with inulin and creatine with each tracer and examining the slope of their blood disappearance curves. Clearance curves for inulin and DTPA were parallel, suggesting DTPA is cleared by renal filtration. MAG3 clearance (slope: -2.74 × 105, r2 = 0.97) had a slope almost 10-fold steeper than for DTPA (slope: -6.29 × 104, r2 = 0.90), and orders of magnitude steeper than for creatine (slope: -1.4, r2 = 1.0). These results suggest that DTPA is cleared by glomerular filtration like inulin, while MAG3 is filtered and actively excreted in a manner similar to mammals. In contrast, creatine is filtered and resorbed, has a larger volume of distribution (Vd), or exhibits a greater blood protein binding, making it more complex as a renal marker, when compared with creatinine handling in mammals. The two radiotracers can be readily adapted for use in birds, inviting both qualitative and semiquantitative functional evaluation of avian renal function for research and clinical purposes. The elimination of creatine appears to be more complex requiring further study.


Assuntos
Columbidae/metabolismo , Creatina/metabolismo , Rim/metabolismo , Oligopeptídeos/metabolismo , Ácido Pentético/farmacocinética , Polietilenoimina/análogos & derivados , Animais , Meios de Contraste/farmacocinética , Polietilenoimina/farmacocinética
3.
Immunity ; 51(2): 272-284.e7, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31399282

RESUMO

Macrophage polarization is accompanied by drastic changes in L-arginine metabolism. Two L-arginine catalytic enzymes, iNOS and arginase 1, are well-characterized hallmark molecules of classically and alternatively activated macrophages, respectively. The third metabolic fate of L-arginine is the generation of creatine that acts as a key source of cellular energy reserve, yet little is known about the role of creatine in the immune system. Here, genetic, genomic, metabolic, and immunological analyses revealed that creatine reprogrammed macrophage polarization by suppressing M(interferon-γ [IFN-γ]) yet promoting M(interleukin-4 [IL-4]) effector functions. Mechanistically, creatine inhibited the induction of immune effector molecules, including iNOS, by suppressing IFN-γ-JAK-STAT1 transcription-factor signaling while supporting IL-4-STAT6-activated arginase 1 expression by promoting chromatin remodeling. Depletion of intracellular creatine by ablation of the creatine transporter Slc6a8 altered macrophage-mediated immune responses in vivo. These results uncover a previously uncharacterized role for creatine in macrophage polarization by modulating cellular responses to cytokines such as IFN-γ and IL-4.


Assuntos
Arginina/metabolismo , Creatina/metabolismo , Cirrose Hepática/metabolismo , Macrófagos/fisiologia , Proteínas de Membrana Transportadoras/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Reprogramação Celular , Humanos , Imunidade Celular , Interferon gama/metabolismo , Cirrose Hepática/induzido quimicamente , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais , Tetracloroetileno
4.
Eur J Pharm Sci ; 138: 105033, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31382031

RESUMO

This study is to investigate pharmacokinetics (PK) and hemorheology (HR) of exogenous phosphocreatine (PCr), a cardio-protective agent, and its active metabolite creatine (Cr), with particular focus on the PK and PD comparison between PCr and Cr. A specific ion-pair reversed-phase HPLC-UV assay was used to simultaneously measure PCr, Cr and ATP concentrations in plasma and red blood cells (RBC) samples of rabbits. PK and HR parameters were calculated based on concentration-time (C-T) curves and effect-time (E-T) curves, respectively, obtained after i.v. dosing. Meanwhile the apparent pharmacological activity ratio (Rapp) and real pharmacological activity ratio (Rreal) of Cr to PCr were calculated. The PCr disappeared from plasma rapidly and in a biphasic manner; plasma PCr was converted to Cr fast and largely with the elimination rate limited metabolite disposition in vivo (Km < K). The i.v. administration of PCr led to a markedly elevated and long-lasting ATP level in RBC. After i.v. administration of preformed Cr, plasma Cr displayed similar elimination kinetics behaviors to that of Cr generated metabolically after i.v. PCr. The Cr could also raise ATP level in RBC, but to less extent than PCr. Approximately 43% of PCr-derived ATP came from Cr-derived ATP in RBC. PCr could significantly reduce whole blood viscosity and RBC osmotic fragility and Cr could do so, but weakly with estimated Rapp of 0.53-0.68 and Rreal of 0.38-0.48. PCr also inhibited platelet aggregation significantly, as opposed to Cr. The PCr-caused improvement of HR is related to the rise in ATP level in RBC. Cr is likely to partially mediate HR effect of PCr.


Assuntos
Creatina/metabolismo , Creatina/farmacocinética , Hemorreologia/fisiologia , Fosfocreatina/metabolismo , Fosfocreatina/farmacocinética , Trifosfato de Adenosina/metabolismo , Animais , Viscosidade Sanguínea/efeitos dos fármacos , Cinética , Masculino , Agregação Plaquetária/efeitos dos fármacos , Substâncias Protetoras/farmacocinética , Coelhos
5.
Neurology ; 93(8): e758-e765, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31315971

RESUMO

OBJECTIVE: To determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations. METHODS: We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons. RESULTS: Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset. CONCLUSION: Frontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.


Assuntos
Ácido Aspártico/análogos & derivados , Creatina/metabolismo , Demência/metabolismo , Lobo Frontal/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Inositol/metabolismo , Proteínas tau/metabolismo , Adulto , Ácido Aspártico/metabolismo , Doenças Assintomáticas , Biomarcadores/metabolismo , Estudos de Casos e Controles , Demência/complicações , Demência/genética , Feminino , Degeneração Lobar Frontotemporal/complicações , Degeneração Lobar Frontotemporal/diagnóstico , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Espectroscopia de Prótons por Ressonância Magnética , Adulto Jovem , Proteínas tau/genética
6.
Neurology ; 93(1): e52-e58, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31167934

RESUMO

OBJECTIVE: To assess by magnetic resonance spectroscopy (MRS) the N-acetylaspartate, myo-inositol, choline, sum of glutamate and glutamine (Glx), and creatine (Cr) content in the anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) and in the occipital cortex (OCC) (control region) in patients with functional motor symptoms (FMS) and healthy controls, and to determine whether neurochemical limbic changes as estimated by MRS correlate with FMS-related motor symptom severity, alexithymia, anxiety, depression, and quality of life. METHODS: This case-control study enrolled 10 patients with FMS and 10 healthy controls. Participants underwent MRS and were tested with the Mini-Mental State Examination, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, 20-Item Toronto Alexithymia Scale, and EuroQol 5D. RESULTS: In patients with FMS, MRS showed increased Glx/Cr in the ACC/mPFC but normal content in the control OCC. All the other metabolites tested were normal in both regions. The increased Glx/Cr content in the ACC/mPFC correlated with alexithymia, anxiety, and severity of symptoms. CONCLUSIONS: The abnormal limbic Glx increase could have a crucial pathophysiologic role in FMS, possibly by altering limbic-motor interactions, ultimately leading to abnormal movements.


Assuntos
Sistema Límbico/diagnóstico por imagem , Sistema Límbico/metabolismo , Espectroscopia de Ressonância Magnética , Transtornos dos Movimentos/diagnóstico por imagem , Transtornos dos Movimentos/metabolismo , Adulto , Sintomas Afetivos/diagnóstico por imagem , Sintomas Afetivos/metabolismo , Ansiedade/diagnóstico por imagem , Ansiedade/metabolismo , Estudos de Casos e Controles , Creatina/metabolismo , Depressão/diagnóstico por imagem , Depressão/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/psicologia , Qualidade de Vida , Índice de Gravidade de Doença
7.
Eur J Radiol ; 116: 55-60, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31153574

RESUMO

OBJECTIVE: To determine the changes in fractional anisotropy (FA) at the proximal spinal cord and in magnetic resonance spectroscopy (MRS) of the precentral gyrus in patients with cervical spondylotic myelopathy (CSM) with respect to clinical symptoms and their duration. MATERIAL AND METHODS: 20 patients with CSM (7 female; mean age 64.6 ± 10.5 years) and 18 age/sex matched healthy controls (9 female; mean age 63.5 ± 6.6 years) were prospectively included. Clinical data (modified Japanese Orthopaedic Association Score (mJOA) and Neck Disability Index (NDI)) and 3T MR measurements including DTI at the spinal cord (level C2/3) with FA and MRS of the left and right precentral gyrus were taken. Clinical correlations and regression analyses were performed. RESULTS: Mean clinical scores of patients were significantly different to controls (mJOA; CSM: 10.2 ± 2.9; controls: 18.0 ± 0.0, p < 0.001; NDI; CSM: 41.4±23.5; controls: 4.4±6.6, p<0.001); FA was significantly lower in patients (CSM: 0.645 ± 0.067; controls: 0.699 ± 0.037, p = 0.005). MRS showed significantly lower metabolite concentrations between both groups: creatine (Cr) (CSM: 46.46±7.64; controls: 51.36±5.76, p = 0.03) and N-acetylaspartate (NAA) (CSM: 93.94±19.22; controls: 107.24±20.20, p = 0.05). Duration of symptoms ≤6 months was associated with increased myo-inositol (Ins) (61.58±17.76; 44.44±10.79; p = 0.02) and Ins/Cr ratio (1.36±0.47; 0.96±0.18; p = 0.014) compared to symptoms >6 months. CONCLUSION: Metabolic profiles of the precentral gyrus and FA in the uppermost spinal cord differ significantly between patients and healthy controls. Ins, thought to be a marker of endogenous neuroinflammatory response, is high in the early course of CSM and normalizes over time.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Córtex Motor/diagnóstico por imagem , Córtex Motor/metabolismo , Doenças da Medula Espinal/patologia , Espondilose/patologia , Idoso , Anisotropia , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Biomarcadores/metabolismo , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/patologia , Creatina/metabolismo , Feminino , Humanos , Inositol/metabolismo , Masculino , Pessoa de Meia-Idade , Córtex Motor/patologia , Doenças da Medula Espinal/metabolismo , Espondilose/metabolismo , Fatores de Tempo
8.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1118-1119: 148-156, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31039544

RESUMO

A simple, rapid and sensitive HPLC-MS/MS method for simultaneous determination of 4 of amino acids, guanidinoacetic acid, S-adenosylmethionine and S-adenosylhomocysteine in human plasma was developed and validated. The method requires no tedious sample preparation, derivatization reagents or ion-pairing reagents. Samples were prepared by combining plasma with a chilled mixture of acetonitrile (ACN) and water, followed by centrifugation and diluting the supernatant with 2 volumes of water. Analytes were detected with multiple reaction monitoring using a positive scan mode with electrospray ionization (ESI). In the assay, all the analytes showed good linearity over the investigated concentration range (r > 0.99). The accuracy expressed in relative error (RE) was between -5.0% and 13.2%, and the precision expressed in coefficient of variation (CV) ranged from 0.6% to 14.7%. In the two spiked levels (low and high), the averaged recoveries of analytes were between 45.0% and 110.9% and the recovery of internal standard was 92.0%. This method was successfully applied to studying the concentration changes of endogenous creatine (Cr) synthesis precursors in the plasma of children with viral myocarditis after intravenous administration of phosphocreatine (PCr).


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Creatina/sangue , Miocardite/sangue , Espectrometria de Massas em Tandem/métodos , Viroses/sangue , Aminoácidos/sangue , Aminoácidos/química , Aminoácidos/metabolismo , Criança , Creatina/química , Creatina/metabolismo , Humanos , Modelos Lineares , Miocardite/diagnóstico , Miocardite/virologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Viroses/diagnóstico , Viroses/virologia
9.
Nutrients ; 11(5)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083291

RESUMO

To accommodate the loss of the plethora of functions of the kidneys, patients with chronic kidney disease require many dietary adjustments, including restrictions on the intake of protein, phosphorus, sodium and potassium. Plant-based foods are increasingly recommended as these foods contain smaller amounts of saturated fatty acids, protein and absorbable phosphorus than meat, generate less acid and are rich in fibers, polyunsaturated fatty acids, magnesium and potassium. Unfortunately, these dietary recommendations cannot prevent the occurrence of many symptoms, which typically include fatigue, impaired cognition, myalgia, muscle weakness, and muscle wasting. One threat coming with the recommendation of low-protein diets in patients with non-dialysis-dependent chronic kidney disease (CKD) and with high-protein diets in patients with dialysis-dependent CKD, particularly with current recommendations towards proteins coming from plant-based sources, is that of creatine deficiency. Creatine is an essential contributor in cellular energy homeostasis, yet on a daily basis 1.6-1.7% of the total creatine pool is degraded. As the average omnivorous diet cannot fully compensate for these losses, the endogenous synthesis of creatine is required for continuous replenishment. Endogenous creatine synthesis involves two enzymatic steps, of which the first step is a metabolic function of the kidney facilitated by the enzyme arginine:glycine amidinotransferase (AGAT). Recent findings strongly suggest that the capacity of renal AGAT, and thus endogenous creatine production, progressively decreases with the increasing degree of CKD, to become absent or virtually absent in dialysis patients. We hypothesize that with increasing degree of CKD, creatine coming from meat and dairy in food increasingly becomes an essential nutrient. This phenomenon will likely be present in patients with CKD stages 3, 4 and 5, but will likely be most pronouncedly present in patients with dialysis-dependent CKD, because of the combination of lowest endogenous production of creatine and unopposed losses of creatine into the dialysate. It is likely that these increased demands for dietary creatine are not sufficiently met. The result of which, may be a creatine deficiency with important contributions to the sarcopenia, fatigue, impaired quality of life, impaired cognition, and premature mortality seen in CKD.


Assuntos
Creatina/metabolismo , Insuficiência Renal Crônica/metabolismo , Dieta , Humanos , Nutrientes
10.
Neurotox Res ; 36(2): 411-423, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069754

RESUMO

Creatine is a nitrogenous organic acid that plays a central role as an energy buffer in high energy demanding systems, including the muscular and the central nervous system. It can be acquired from diet or synthesized endogenously, and its main destination is the system creatine/phosphocreatine that strengthens cellular energetics via a temporal and spatial energy buffer that can restore cellular ATP without a reliance on oxygen. This compound has been proposed to possess secondary roles, such as direct and indirect antioxidant, immunomodulatory agent, and possible neuromodulator. However, these effects may be associated with its bioenergetic role in the mitochondria. Given the fundamental roles that creatine plays in the CNS, several preclinical and clinical studies have tested the potential that creatine has to treat degenerative disorders. However, although in vitro and in vivo animal models are highly encouraging, most clinical trials fail to reproduce positive results suggesting that the prophylactic use for neuroprotection in at-risk populations or patients is the most promising field. Nonetheless, the only clearly positive data of the creatine supplementation in human beings are related to the (rare) creatine deficiency syndromes. It seems critical that future studies must establish the best dosage regime to increase brain creatine in a way that can relate to animal studies, provide new ways for creatine to reach the brain, and seek larger experimental groups with biomarkers for prediction of efficacy.


Assuntos
Encéfalo/metabolismo , Creatina/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/metabolismo , Animais , Encéfalo/patologia , Creatina/uso terapêutico , Metabolismo Energético/fisiologia , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fármacos Neuroprotetores/uso terapêutico
11.
J Anim Physiol Anim Nutr (Berl) ; 103(3): 766-773, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30941826

RESUMO

The objective of this study was to assess the effects of guanidinoacetic acid (GAA) on growth performance, creatine deposition and blood amino acid (AA) profile on broiler chickens. In Exp. 1, a total of 540 one-day-old Arbor Acres male broilers (average initial body weight, 45.23 ± 0.35 g) were divided randomly into five treatments with six replicates of 18 chicks each. Broilers were fed corn-soybean meal-basal diets supplemented with 0, 600, 800, 1,000 or 1,200 mg/kg GAA for 42 days respectively. Results showed that dietary GAA inclusion increased average daily gain (ADG) and improved gain-to-feed ratio (G:F) from 1 to 42 days (p < 0.01). However, average daily feed intake was unaffected by dietary supplementation of GAA. As GAA inclusion increased, the contents of creatine in plasma and kidney were increased (linear, p < 0.01), while the contents of GAA and creatine in liver were decreased (linear, p < 0.01). Similarly, GAA supplementation was inversely related to concentrations of most essential AA in plasma. In Exp. 2, a total of 432 one-day-old Arbor Acres male broilers (average initial body weight, 39.78 ± 0.58 g) were divided randomly into four treatments with six replicates of 18 chicks each. Birds were fed a corn-soybean meal-basal diet supplemented with 0, 200, 400 or 600 mg/kg GAA for 42 days respectively. Dietary inclusion of 600 mg/kg GAA significantly increased ADG and G:F of broilers (p < 0.05). In conclusion, dietary supplementation of 600-1,200 mg/kg GAA can effectively improve the growth performance in broiler chickens by affecting creatine metabolism and utilization efficiency of essential AA, and 600 mg/kg GAA is the minimum dose for improving performance.


Assuntos
Aminoácidos/sangue , Galinhas/crescimento & desenvolvimento , Creatina/metabolismo , Glicina/análogos & derivados , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Galinhas/sangue , Dieta/veterinária , Suplementos Nutricionais , Glicina/administração & dosagem , Glicina/farmacologia , Masculino , Distribuição Aleatória
12.
Kidney Blood Press Res ; 44(2): 149-157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30939483

RESUMO

Three randomized control trials (Canagliflozin Cardiovascular Assessment Study, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME], and Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 [DECLARE-TIMI 58]) showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally developed as glucose-lowering drugs, are associated with a lower rate of adverse renal outcomes, such as need for renal replacement therapy, doubling of serum creatinine, and loss of glomerular filtration rate (GFR) compared to those in placebo groups. Besides, canagliflozin and empagliflozin also showed a lower risk of progression to macroalbuminuria. The EMPA-REG OUTCOME trial and DECLARE-TIMI 58 trial also indicated that these SGLT2 inhibitors might have beneficial effects on the prevention of acute kidney injury. The United States Food and Drug Administration (FDA) warned of the risk of acute kidney injury for canagliflozin and dapagliflozin. We compared canagliflozin, empagliflozin, and dapagliflozin with respect to chemical structure and pharmacological properties, to explain the observed differences in preventing acute kidney injury, and put forward the hypotheses of the potential mechanisms of different effects of SGLT2 inhibitors on acute kidney injury. Given the raising clinical use of SGLT2 inhibitors, our review should stimulate further basic science and clinical studies in order to definitively understand the role of SGLT2 inhibitors in acute kidney injury. A weakness of the clinical data obtained so far is the fact that the statements concerning acute kidney injury are just based on safety data - mainly creatine measurements. However, given the mode of action of SGLT2 blockers, initiation of a therapy with a SGLT2 blocker will cause an increase of creatine because of its effects on the tubuloglomerular feedback mechanisms/glomerular hemodynamics like RAAS blocking agents do. To really understand the potential effects of SGLT2 inhibitors, we need preclinical and clinical SGLT2 inhibitor studies focusing on all aspects of acute kidney injury - not just changes in GFR biomarkers.


Assuntos
Lesão Renal Aguda/prevenção & controle , Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Lesão Renal Aguda/induzido quimicamente , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/farmacologia , Canagliflozina/efeitos adversos , Canagliflozina/uso terapêutico , Creatina/efeitos dos fármacos , Creatina/metabolismo , Glucosídeos/efeitos adversos , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes , Estrutura Molecular , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Relação Estrutura-Atividade
13.
Poult Sci ; 98(7): 2896-2905, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30850832

RESUMO

Two studies were conducted to test the efficacy of guanidinoacetic acid (GAA) to spare Arg and serve as a precursor of creatine (Cr) by evaluating growth performance and muscle cellular energy homeostasis in broiler chicks. In both studies, 12 replicate pens of 6 chicks received dietary treatments beginning at day 2 post-hatch. At conclusion of each study, muscle biopsy samples were collected within 60 s of euthanasia for analysis of Cr-related energy metabolites. In study 1, Arg-deficient starter and grower basal diets were supplemented with 0 (negative control, NC), 0.06, 0.12, or 0.18% GAA, or supplemental Arg (positive control, PC; 0.37 and 0.32% L-Arg in starter and grower phases, respectively). Dietary GAA elicited graded improvements, with final BW, overall BW gain, and overall G:F being increased (P < 0.05) by 0.12% GAA compared with the NC diet with no difference to PC diet. Increases (P < 0.001) of phosphocreatine (PCr), total Cr (tCr), and glycogen concentrations, as well as the PCr-to-adenosine triphosphate (ATP) and glycogen:ATP ratios, were observed with supplementation of 0.12% GAA compared with the NC diet, even exceeding responses to the PC diet. In study 2, Arg-adequate starter and grower basal diets were supplemented with 0 (negative control, NC), 0.06, or 0.12% GAA, 0.12% Cr monohydrate (PC1), or salmon protein (PC2; containing total Arg concentrations equal to those of the NC diet in each phase and containing similar Cr as in PC1). Overall G:F was increased (P < 0.05) by PC1, but not by PC2, compared with the NC, while GAA supplementation elicited a response intermediate to NC and PC1 diets. However, GAA supplementation increased (P < 0.01) concentrations of tCr and glycogen, as well as the PCr:ATP and glycogen:ATP ratios, when compared with the NC (Arg-adequate) diet. Collectively, these data indicate that GAA can be used to replace Arg in practical, Arg-deficient diets and improve muscle energy homeostasis in broiler chicks receiving either Arg-deficient or Arg-adequate practical diets.


Assuntos
Ração Animal/análise , Arginina/deficiência , Galinhas/crescimento & desenvolvimento , Glicina/análogos & derivados , Fenômenos Fisiológicos da Nutrição Animal , Animais , Galinhas/fisiologia , Creatina/metabolismo , Dieta/veterinária , Metabolismo Energético , Glicina/farmacologia , Homeostase , Masculino , Músculos/metabolismo
14.
Bipolar Disord ; 21(4): 330-341, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30864200

RESUMO

OBJECTIVES: To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode. METHODS: Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n = 117) and matched healthy controls (HC group, n = 61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4 months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr + Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects. RESULTS: There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr + Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P = 0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects. CONCLUSIONS: We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr + Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation.


Assuntos
Sintomas Afetivos , Transtorno Bipolar , Filho de Pais Incapacitados/psicologia , Creatina/análise , Giro do Cíngulo/metabolismo , Fosfocreatina/análise , Córtex Pré-Frontal/metabolismo , Medição de Risco , Adolescente , Adulto , Sintomas Afetivos/diagnóstico , Sintomas Afetivos/metabolismo , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/metabolismo , Criança , Creatina/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Espectroscopia de Prótons por Ressonância Magnética/métodos , Medição de Risco/métodos
15.
Poult Sci ; 98(8): 3223-3232, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30789221

RESUMO

This study evaluated the effects of dietary guanidinoacetic acid (GAA) supplementation on growth performance, plasma variables, muscle energy status, glycolytic potential, and meat quality of broilers experiencing transport stress during the summer. A total of 320 28-day-old male Arbor Acres broilers were randomly allotted to 3 dietary treatments, including a GAA-free basal control diet (160 birds) and basal diet supplementation with 600 (80 birds) or 1,200 mg/kg (80 birds) GAA for 14 D. On the morning of day 42, after an 8-h fast, the birds fed basal diets were divided into 2 equal groups, and all birds in the 4 groups of 80 birds were transported according to the following protocols: 1) a 0.5-h transport of birds on basal diets (as a lower-stress control group), 2) a 3-h transport of birds on basal diets, and a 3-h transport of birds on basal diets supplemented with either 3) 600 or 4) 1,200 mg/kg GAA. The results revealed that dietary supplementation with GAA at 600 and 1,200 mg/kg for 14 D prior to slaughter did not affect growth performance, carcass traits, and most textural characteristics and chemical composition of the pectoralis major (PM) muscle (P > 0.05). In the GAA-free group, a 3-h transport increased the broiler live weight loss, elevated the plasma corticosterone concentration, decreased the plasma glucose concentration, muscle concentrations of ATP, creatine and energy charge value, increased the muscle AMP concentration and AMP/ATP ratio, and accelerated glycolysis metabolism, which resulted in inferior meat quality (lower pH and higher drip loss, P < 0.05). However, dietary addition of GAA at 1,200 mg/kg increased the mRNA expression of S-adenosyl-l-methionine: N-guanidino-acetate methyltransferase in the liver and creatine transporter in both the liver and PM muscle. It also elevated muscle concentrations of creatine and phosphocreatine (P < 0.05), which helps improve meat quality by ameliorating the 3-h transport-induced muscle energy expenditure and delaying anaerobic glycolysis of broilers.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Glicina/análogos & derivados , Glicólise/efeitos dos fármacos , Carne/análise , Ração Animal/análise , Animais , Glicemia/efeitos dos fármacos , Galinhas , Corticosterona/sangue , Creatina/metabolismo , Dieta/veterinária , Glicina/farmacologia , Masculino , Músculos Peitorais/metabolismo , Distribuição Aleatória , Estresse Fisiológico , Transportes
16.
Neurosci Biobehav Rev ; 98: 306-319, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30625337

RESUMO

Magnetic resonance spectroscopy (MRS) holds promise for understanding neurochemical mechanisms associated with human cognitive aging in vivo. Recent advances in magnetic field strength and methods provide the opportunity to examine neurometabolites with greater accuracy and detail. The current review summarizes recent literature on age-associated neurometabolite changes as measured by proton MRS, and the associations with cognition in non-clinical populations. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 179 studies were screened for review, of these, 42 were eligible. When a subset of studies were assessed based on voxel placement, magnetic field strength and sample size, N acetyl aspartate (NAA) concentration was consistently reduced with age predominantly in the frontal lobe and Myo-inositol (mI) concentration increased with age consistently in the posterior cingulate cortex (PCC). These findings are of particular interest as these NAA and mI changes mirror neurometabolite changes often seen in Alzheimer disease. The findings of this review provide further evidence of the potential for 1H-MRS to track age-related neurometabolite changes.


Assuntos
Envelhecimento , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Creatina/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/fisiologia , Colina/metabolismo , Cognição/fisiologia , Humanos
17.
Eur J Radiol ; 111: 41-46, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30691663

RESUMO

PURPOSE: Although brain magnetic resonance spectroscopy (MRS) imaging findings in adult Wilson disease (WD) have been explained in extensive details, a paucity of information currently exists regarding brain MRS imaging findings in pediatric WD. The purpose of this study was to clarify the role of brain MRS in detecting early metabolite abnormalities in children with WD. PATIENT AND METHODS: A case-controlled prospective study included 26 children with WD and 26 healthy controls. All children were subjected to examination on a 1.5 T MRI scanner. The spectra of N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr), as well as the metabolite ratios of NAA/Cho, NAA/Cr, and Cho/Cr, were measured and compared between two groups. RESULTS: Eight patients revealed increased signal intensity in the basal ganglia at T1-weighted images. When compared with healthy controls, WD patients showed a significant decrease (p < 0.05) in NAA (63.8 ± 9.6 vs 97.6 ± 3.8), Cho (46.7 ± 8.9 vs 87.3 ± 4.7), Cr (44 ± 10.1 vs 81.9 ± 4.05), NAA/Cho (1.92 ± 1.2 vs 3.34 ± 0.55), NAA/Cr (1.29 ± 0.7 vs 2.46 ± 0.34), and Cho/Cr (0.78 ± 0.4 vs 2 ± 0.13). Patients complicated with liver cell failure showed a significant decrease in all previous parameters (p < 0.05) than patients without complications. Patients with mixed neurological and hepatic diseases showed a severe reduction in NAA, NAA/Cr, and NAA/Cho compared with patients with hepatic disease only. CONCLUSION: MRS in pediatric WD detects early neurological changes even with normal MRI.


Assuntos
Gânglios da Base/diagnóstico por imagem , Degeneração Hepatolenticular/diagnóstico por imagem , Espectroscopia de Ressonância Magnética , Neuroimagem , Adolescente , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Gânglios da Base/fisiopatologia , Estudos de Casos e Controles , Criança , Colina/metabolismo , Creatina/metabolismo , Diagnóstico Precoce , Feminino , Degeneração Hepatolenticular/fisiopatologia , Humanos , Masculino , Estudos Prospectivos
18.
BMJ Open ; 9(1): e026756, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30647050

RESUMO

INTRODUCTION: The creatine kinase circuit is central to the regulation of high-energy phosphate metabolism and the maintenance of cellular energy turnover. This circuit is fuelled by creatine, an amino acid derivative that can be obtained from a diet containing animal products, and by synthesis in the body de novo. A recent retrospective study conducted in a cohort of 287 pregnant women determined that maternal excreted levels of creatine may be associated with fetal growth. This prospective study aims to overcome some of the limitations associated with the previous study and thoroughly characterise creatine homeostasis throughout gestation in a low-risk pregnant population. METHODS AND ANALYSIS: This study is recruiting women with a singleton low-risk pregnancy who are attending Monash Health, in Melbourne, Australia. Maternal blood and urine samples, along with dietary surveys, are collected at five time points during pregnancy and then at delivery. Cord blood and placenta (including membranes and cord) are collected at birth. A biobank of tissue samples for future research is being established. Primary outcome measures will include creatine, creatine kinase and associated metabolites in antenatal bloods and urine, cord bloods and placenta, along with molecular analysis of the creatine transporter (SLC6A8) and synthesising enzymes L - arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) in placental tissues. Secondary outcome measures include dietary protein intake over pregnancy and any associations with maternal creatine, pregnancy events and birth outcomes. ETHICS AND DISSEMINATION: Ethical approval was granted in August 2015 from Monash Health (Ref: 14140B) and Monash University (Ref: 7785). Study outcomes will be disseminated at international conferences and published in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: ACTRN12618001558213; Pre-results.


Assuntos
Creatina/metabolismo , Desenvolvimento Fetal , Placenta/metabolismo , Amidinotransferases/metabolismo , Austrália , Metabolismo Energético , Feminino , Guanidinoacetato N-Metiltransferase/metabolismo , Homeostase , Humanos , Proteínas do Tecido Nervoso/metabolismo , Estudos Observacionais como Assunto , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo , Gravidez , Estudos Prospectivos , Projetos de Pesquisa
19.
Neurology ; 92(5): e395-e405, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30610093

RESUMO

OBJECTIVE: To investigate the association between longitudinal changes in proton magnetic resonance spectroscopy (MRS) metabolites and amyloid pathology in individuals without dementia, and to explore the relationship between MRS and cognitive decline. METHODS: In this longitudinal multiple time point study (a subset of the Swedish BioFINDER), we included cognitively healthy participants, individuals with subjective cognitive decline, and individuals with mild cognitive impairment. MRS was acquired serially in 294 participants (670 individual spectra) from the posterior cingulate/precuneus. Using mixed-effects models, we assessed the association between MRS and baseline ß-amyloid (Aß), and between MRS and the longitudinal Mini-Mental State Examination, accounting for APOE, age, and sex. RESULTS: While baseline MRS metabolites were similar in Aß positive (Aß+) and negative (Aß-) individuals, in the Aß+ group, the estimated rate of change was +1.9%/y for myo-inositol (mI)/creatine (Cr) and -2.0%/y for N-acetylaspartate (NAA)/mI. In the Aß- group, mI/Cr and NAA/mI yearly change was -0.05% and +1.2%; however, this was not significant across time points. The mild cognitive impairment Aß+ group showed the steepest MRS changes, with an estimated rate of +2.93%/y (p = 0.07) for mI/Cr and -3.55%/y (p < 0.01) for NAA/mI. Furthermore, in the entire cohort, we found that Aß+ individuals with low baseline NAA/mI had a significantly higher rate of cognitive decline than Aß+ individuals with high baseline NAA/mI. CONCLUSION: We demonstrate that the longitudinal change in mI/Cr and NAA/mI is associated with underlying amyloid pathology. MRS may be a useful noninvasive marker of Aß-related processes over time. In addition, we show that in Aß+ individuals, baseline NAA/mI may predict the rate of future cognitive decline.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Inositol/metabolismo , Idoso , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Creatina/metabolismo , Estudos Transversais , Programas de Triagem Diagnóstica , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Espectroscopia de Prótons por Ressonância Magnética
20.
Acta Radiol ; 60(1): 106-112, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29665708

RESUMO

BACKGROUND: Magnetic resonance (MR) spectroscopy (1H-MRS) has been demonstrated to be useful in grading glioma, but the utility in assessing cellular proliferation activity and prognosis correlated with the expression of minichromosome maintenance protein 2 (MCM2) has not been reported. PURPOSE: To explore the correlation between proton MR spectroscopy parameters (including choline [Cho]/creatine [Cr], N-acetyl aspartate [NAA]/Cr, and Cho/NAA ratios) and the expression of MCM2 and to further evaluate whether 1H-MRS can predict cell proliferative activity and provide prognostic information in high-grade gliomas (HGGs). MATERIAL AND METHODS: Forty-three patients with histopathologically confirmed gliomas were involved in this study. All patients underwent 1H-MRS examination before surgery. Proliferative activity of gliomas was evaluated by MCM2 labeling index (LI). Pearson correlation analysis and empiric receiver operating characteristic (ROC) curves were performed. The Kaplan-Meier method and Cox regression were used for survival analysis. RESULTS: Significant correlation was observed between the Cho/Cr ratio and MCM2 LI ( r = 0.522, P < 0.01); however, there was no correlation between MCM2 LI and the Cho/NAA or NAA/Cr ratios ( r = 0.295, P = 0.55 and r = -0.042, P = 0.788, respectively). According to ROC analysis, MCM2 LI of 50% and Cho/Cr ratio of 2.68 represented the optimized cut-off values, respectively, to distinguish longer or shorter survival than 15 months in HGGs patients. Multivariate analysis revealed that both the Cho/Cr ratio and MCM2 expression were independent prognostic markers. CONCLUSION: Cho/Cr ratio has a potential in predicting the expression of MCM2 and can evaluate cell proliferative activity noninvasively. Both the Cho/Cr ratio and MCM2 expression are independent prognostic markers in patients with HGGs.


Assuntos
Neoplasias Encefálicas/patologia , Proliferação de Células/fisiologia , Colina/metabolismo , Creatina/metabolismo , Glioma/patologia , Espectroscopia de Ressonância Magnética/métodos , Componente 2 do Complexo de Manutenção de Minicromossomo/metabolismo , Adolescente , Adulto , Idoso , Ácido Aspártico/análogos & derivados , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Criança , Feminino , Glioma/genética , Glioma/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Componente 2 do Complexo de Manutenção de Minicromossomo/genética , Gradação de Tumores , Análise de Sobrevida , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA