RESUMO
The metabolic dependencies of cancer cells have substantial potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is identified as a urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high CR levels in patients with cancer as well as their implications for the treatment of these aggressive cancers remain unclear. By integrating multiomics data on lung and liver cancer, we have shown that CR is a cancer cell-derived metabolite. Global metabolomics and gene expression analysis of human tumors and matched liquid biopsies, together with functional studies, revealed that dysregulation of the mitochondrial urea cycle and a nucleotide imbalance were associated with high CR levels and indicators of a poor prognosis. This metabolic phenotype was associated with reduced immune infiltration and supported rapid cancer cell proliferation that drove aggressive tumor growth. CRhi cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of CR not only as a poor-prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve survival for patients with cancer.
Assuntos
Neoplasias Hepáticas , Ribonucleosídeos , Arginina/metabolismo , Creatina/análogos & derivados , Creatina/urina , Humanos , Ribonucleosídeos/urinaRESUMO
Chronic kidney disease (CKD) is defined by decreased glomerular filtration rate (GFR) or increased albumin excretion leading to renal injury. However, exercise training is an important non-pharmacological intervention that ameliorates and protects against Diabetes Mellitus, cardiovascular disease, and CKD. AIM: Our aim was to evaluate the capability of resistance exercise training (RET) to improve CKD outcomes and the contribution of the renal and muscular Akt/mTOR signaling pathway for RET beneficial effects on a CKD model. MAIN METHODS: Male Wistar rats were subjected to RET, followed for 10 weeks, and randomly divided into 5 groups: Sham: Sham-operated; sedentary and nephrectomy (5/6Nx) (SNS); exercising post-5/6Nx (SNE); exercising pre-5/6Nx (ENS); exercising pre- and post-5/6Nx (ENE). The systolic blood pressure (BP) was measured. Creatinine, proteinuria, and blood urea nitrogen (BUN) were evaluated. After euthanasia Renal and muscular Akt/mTOR signaling pathways were analyzed. KEY FINDING: Our study showed that the SNS presented renal injury, hypertension, weight and muscular mass loss and a higher mortality rate. SNS group also decreased renal IL-10 and increased TNF-alfa and TGF-Beta. Renal AKT, mTOR, and rpS6 pathway were increased, PTEN was decreased on SNS. And muscular Akt and mTOR were decreased on SNS. SIGNIFICANCE: The RET before and after the 5/6Nx ameliorates all these parameters mentioned above, suggesting that RET is a good non-pharmacological approach to diminish complications frequently found in CKD. We also suggest that the AKT-m-TOR pathway can play an important role in these beneficial outcomes of RET on the CKD animal model.
Assuntos
Insuficiência Renal Crônica/terapia , Treinamento Resistido , Animais , Creatina/análogos & derivados , Creatina/sangue , Creatina/urina , Modelos Animais de Doenças , Masculino , Nefrectomia , Ratos , Ratos WistarRESUMO
Post-viral fatigue syndrome (PVFS) is a widespread chronic neurological disease with no definite etiological factor(s), no actual diagnostic test, and no approved pharmacological treatment, therapy, or cure. Among other features, PVFS could be accompanied by various irregularities in creatine metabolism, perturbing either tissue levels of creatine in the brain, the rates of phosphocreatine resynthesis in the skeletal muscle, or the concentrations of the enzyme creatine kinase in the blood. Furthermore, supplemental creatine and related guanidino compounds appear to impact both patient- and clinician-reported outcomes in syndromes and maladies with chronic fatigue. This paper critically overviews the most common disturbances in creatine metabolism in various PVFS populations, summarizes human trials on dietary creatine and creatine analogs in the syndrome, and discusses new frontiers and open questions for using creatine in a post-COVID-19 world.
Assuntos
Creatina/administração & dosagem , Creatina/metabolismo , Síndrome de Fadiga Crônica/dietoterapia , Síndrome de Fadiga Crônica/metabolismo , Biomarcadores/metabolismo , Encéfalo/metabolismo , COVID-19/complicações , Creatina/análogos & derivados , Suplementos Nutricionais , Síndrome de Fadiga Crônica/diagnóstico , Humanos , Músculo Esquelético/metabolismo , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Creatine riboside (CR) is a novel metabolite of cancer metabolism. It is a urinary diagnostic biomarker of lung and liver cancer risk and prognosis. The level of CR is highly positive correlated in tumor and urine indicating that it is derived from human lung and liver cancers. A precise and sensitive ultra-pressure liquid chromatography-tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and validated for simultaneous quantification of the noninvasive biomarker CR, along with creatinine riboside (CNR), and their precursors creatine and creatinine, utilizing the labeled internal standard creatine riboside-13C,15N2 (CR-13C,15N2). Chromatography was carried out on a hydrophilic interaction chromatography column under a gradient mobile phase condition. MRM transitions were monitored for CR (264.1 > 132.1, m/z), CNR (246.1 > 113.9, m/z), creatine (132.0 > 72.0, m/z), creatinine (114.0 > 85.8, m/z) and CR-13C,15N2 (267.1 > 134.9, m/z) with a 11.0 min run time in the positive mode ionization. The calibration plot of the method was linear over the concentration range of 4.50-10,000 nM. Method validation was performed according to regulatory guidelines established for sensitivity, selectivity, calibration curve, stability at different storage conditions, reinjection reproducibility, ruggedness with acceptable accuracy, and precision. This assay was applied for the quantification of CR along with CNR, creatine and creatinine in a subset of urine and serum samples from the National Cancer Institute - Maryland (NCI-MD) cohort population controls and lung cancer cases. It can be standardized and used in multiple laboratories for cancer diagnosis and determining the efficacy of cancer therapy and monitoring cancer recurrence.
Assuntos
Neoplasias Pulmonares , Espectrometria de Massas em Tandem , Biomarcadores Tumorais , Cromatografia Líquida de Alta Pressão , Creatina/análogos & derivados , Creatinina , Humanos , Neoplasias Pulmonares/diagnóstico , Maryland , National Cancer Institute (U.S.) , Recidiva Local de Neoplasia , Controle da População , Reprodutibilidade dos Testes , Ribonucleosídeos , Estados UnidosRESUMO
Cyclocreatine (LUM-001), a creatine analog, was evaluated for its nonclinical toxicity in Sprague Dawley (SD) rats. Deionized water as a vehicle control article or cyclocreatine was administered by oral gavage twice daily (approximately 12 ± 1 h apart) at 30, 100 and 300 mg/kg/dose levels in rats up to 26 weeks followed by a 28-day recovery period. Due to an increased incidence of seizures, the 600 mg/kg/day dose group males were dosed only for 16-weeks followed by a 14-week recovery period. Thirteen males and four females from 600 mg/kg/day dose group were sacrificed at interim on Day 113 to study plausible brain lesions and not due to moribundity. There was a dose dependent increase in the number of seizure incidences in ≥60 mg/kg/day males and 600 mg/kg/day females. Microscopically, higher incidences of vacuoles in the brain at 600 mg/kg/day in both sexes, thyroid follicular atrophy and follicular cell hypertrophy at ≥200 mg/kg/day in males and 600 mg/kg/day in females, and seminiferous tubular degeneration and/or interstitial edema in testes at ≥200 mg/kg/day were observed. Mean plasma half-life of cyclocreatine was between 3.5 and 6.5 h. In conclusion, chronic administration of cyclocreatine by oral gavage in Sprague Dawley rats induced the seizures and microscopic lesions in the brain, testes and thyroid. Based on the results of this study the highest tested dose of 600 mg/kg/day (mean Cmax of 151.5 µg/mL; AUC0-24 of 1970 h*µg/mL) was considered the maximum tolerated dose (MTD) in SD rats.
Assuntos
Encéfalo/efeitos dos fármacos , Creatinina/análogos & derivados , Testes de Toxicidade Crônica/métodos , Administração Oral , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Creatina/análogos & derivados , Creatina/sangue , Creatina/toxicidade , Creatinina/administração & dosagem , Creatinina/sangue , Creatinina/toxicidade , Feminino , Masculino , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/fisiologia , Ratos , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Fatores de TempoAssuntos
Acidose/etiologia , Creatina/análogos & derivados , Creatinina/sangue , Suplementos Nutricionais/efeitos adversos , Dispepsia/complicações , Insuficiência Renal/diagnóstico , Acidose/sangue , Adulto , Antiácidos/uso terapêutico , Creatina/administração & dosagem , Creatina/efeitos adversos , Creatinina/metabolismo , Diagnóstico Diferencial , Dispepsia/tratamento farmacológico , Endoscopia do Sistema Digestório , Feminino , Humanos , Recomendações Nutricionais , Eliminação Renal/fisiologia , Insuficiência Renal/sangue , Insuficiência Renal/fisiopatologiaRESUMO
Creatine is pivotal in energy metabolism of the brain. In primary creatine deficiency syndromes, creatine is missing from the brain. Two of them (AGAT and GAMT deficiency) are due to impaired creatine synthesis, and can be treated by creatine supplementation. By contrast, creatine transporter deficiency cannot be treated by such supplementation, since creatine crossing of biological membranes (plasma membrane and blood-brain barrier) is dependent on its transporter. This problem might be overcome by modifying the creatine molecule to allow it to cross biological membranes independently of its transporter. Thus, we designed and synthesized di-acetyl creatine ethyl ester (DAC), a compound that should cross biological membranes independently of the transporter due to its very high lipophilicity. We investigated its ability to increase intracellular creatine levels even after block of creatine transporter, and to counter cell damage induced by transporter block. In our experiments after block of the creatine transporter, DAC was able both to prevent electrophysiological failure and to increase intracellular creatine. Interestingly, it did so in micromolar concentrations, at variance with all the other creatine derivatives that we know of.
Assuntos
Creatina/análogos & derivados , Creatina/deficiência , Guanidinoacetato N-Metiltransferase/deficiência , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Transtornos dos Movimentos/congênito , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encefalopatias Metabólicas Congênitas , Creatina/metabolismo , Creatina/farmacologia , Guanidinoacetato N-Metiltransferase/efeitos dos fármacos , Transtornos do Desenvolvimento da Linguagem , Deficiência Intelectual Ligada ao Cromossomo X , Camundongos , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/farmacologiaRESUMO
Purpose: Adrenal incidentalomas must be differentiated from adrenocortical cancer (ACC). Currently, size, growth, and imaging characteristics determine the potential for malignancy but are imperfect. The aim was to evaluate whether urinary small molecules (<800 Da) are associated with ACC.Experimental Design: Preoperative fasting urine specimens from patients with ACC (n = 19) and benign adrenal tumors (n = 46) were analyzed by unbiased ultraperformance liquid chromatography/mass spectrometry. Creatinine-normalized features were analyzed by Progenesis, SIMCA, and unpaired t test adjusted by FDR. Features with an AUC >0.8 were identified through fragmentation patterns and database searches. All lead features were assessed in an independent set from patients with ACC (n = 11) and benign adrenal tumors (n = 46) and in a subset of tissue samples from patients with ACC (n = 15) and benign adrenal tumors (n = 15) in the training set.Results: Sixty-nine features were discovered and four known metabolites identified. Urinary creatine riboside was elevated 2.1-fold (P = 0.0001) in patients with ACC. L-tryptophan, Nε,Nε,Nε-trimethyl-L-lysine, and 3-methylhistidine were lower 0.33-fold (P < 0.0001), 0.56-fold (P < 0.0001), and 0.33-fold (P = 0.0003) in patients with ACC, respectively. Combined multivariate analysis of the four biomarkers showed an AUC of 0.89 [sensitivity 94.7% (confidence interval {CI}, 73.9%-99.1%), specificity 82.6% (CI, 68.6%-92.2%), PPV 69.2% (CI, 48.2%-85.6%), and NPV 97.4% (CI, 86.5%-99.6%)] for distinguishing ACC from benign tumors. Of the four, creatine riboside and four unknown features were validated. Creatine riboside, Nε,Nε,Nε-trimethyl-L-lysine, and two unknown features were elevated in ACC tumors.Conclusions: There are unique urinary metabolic features in patients with ACC with some metabolites present in patient tumor samples. Urinary creatine riboside can differentiate benign adrenal neoplasms from ACC. Clin Cancer Res; 23(17); 5302-10. ©2017 AACR.
Assuntos
Neoplasias das Glândulas Suprarrenais/urina , Biomarcadores Tumorais/urina , Creatina/análogos & derivados , Neoplasias/urina , Ribonucleosídeos/urina , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Creatina/urina , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
Serum creatinine is a widely used marker in the assessment of renal function. Elevated creatinine levels suggest kidney dysfunction, prompting the need for further investigation. This report describes a case in which the consumption of the bodybuilding supplement creatine ethyl ester resulted in raised serum creatinine in the absence of true underlying kidney pathology. The abnormalities reversed after discontinuation of the supplement. A case of pseudo renal failure was recognised and kidney function was concluded to be normal. This report aims to address the mechanisms by which the ingestion of creatine ethyl ester can mimic the blood results expected in advanced renal failure, and confronts the problems faced when relying on serum creatinine as a diagnostic tool.
Assuntos
Creatina/análogos & derivados , Creatinina/sangue , Suplementos Nutricionais , Rim/efeitos dos fármacos , Insuficiência Renal , Adulto , Creatina/sangue , Creatina/farmacologia , Suplementos Nutricionais/efeitos adversos , Humanos , Rim/fisiologia , Masculino , Insuficiência Renal/fisiopatologia , Treinamento ResistidoRESUMO
Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classifier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis.
Assuntos
Biomarcadores Tumorais/urina , Carcinoma Pulmonar de Células não Pequenas/urina , Creatina/análogos & derivados , Neoplasias Pulmonares/urina , Ácido N-Acetilneuramínico/urina , Ribonucleosídeos/urina , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Casos e Controles , Creatina/urina , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Metaboloma , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Fumar/urinaRESUMO
The creatine/phosphocreatine system carries ATP from production to consumption sites and buffers the intracellular content of ATP at times of energy deprivation. The creatine transporter deficiency syndrome is an X-linked disease caused by a defective creatine transporter into the central nervous system. This disease is presently untreatable because creatine lacking its carrier cannot cross neither the blood-brain barrier nor the cell plasma membranes. Possible strategies to cure this condition are to couple creatine to molecules which have their own carrier, to exploit the latter to cross biological membranes or to modify the creatine molecule to make it more lipophilic, in such a way that it may more easily cross lipid-rich biological membranes. Such molecules could moreover be useful for treatment of stroke or other ischemic brain syndromes of normal (transporter working) tissue. In this paper we tested four molecules in in vitro hippocampal slices experiments to investigate whether or not they had a neuroprotective effect similar to that of creatine. On two of them we also performed biochemical measurements to investigate whether or not they were able to increase the creatine and phosphocreatine content of the hippocampal slices with and without block of the transporter. We found that these molecules increase levels of creatine after block of the transporter, and significantly increased the levels of phosphocreatine. Both significantly increased the total creatine content in both conditions of active and blocked transporter. This shows that these molecules are capable of entering cells through biological membranes without using the creatine transporter. By contrast, neither of them was able to delay synaptic block during anoxia of normal (transporter functioning) tissue. We conclude that these compounds might possibly be useful for therapy of creatine transporter deficiency, but further research is needed to understand their possible role in anoxia/ischemia of normal tissue.
Assuntos
Creatina/análogos & derivados , Proteínas de Membrana Transportadoras/deficiência , Animais , Encefalopatias Metabólicas Congênitas , Creatina/deficiência , Creatina/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X , Camundongos , Fármacos Neuroprotetores/farmacologia , Fosfocreatina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiênciaRESUMO
Reported serum creatinine concentrations can sometimes vary considerably, even when the renal function does less so or even not. This variation is partly due to true changes in actual serum concentration, and partly due to interferences in the measurement technique, thus not reflecting a true change in concentration. Increased or decreased endogenous creatinine production, ingested creatinine sources through meat eating or certain creatine formulations, and interference by either browning of chromogenic substances in Jaffe measurement techniques or promotors and inhibitors of enzymatic reaction methods do play a role. Reliable serum creatinine measurements are needed for renal function estimating equations. In screening circumstances and daily practice, chronic kidney disease staging is based on these estimated glomerular filtration rate values. Given the possible influences on reported serum creatinine concentrations, it is important for health care workers to remain critical when interpreting outcomes of renal function estimating equations and to not see every reported result based on an equation as a true reflection of renal function.
Assuntos
Creatina/análogos & derivados , Creatinina/sangue , Suplementos Nutricionais/efeitos adversos , Taxa de Filtração Glomerular/fisiologia , Insuficiência Renal/etiologia , Feminino , HumanosRESUMO
Creatine ethyl ester hydrochloride (CEE) was synthesized as a prodrug of creatine (CRT) to improve aqueous solubility, gastrointestinal permeability, and ultimately the pharmacodynamics of CRT. We used high-performance liquid chromatography (HPLC) and proton nuclear magnetic resonance (NMR) to characterize the pH-dependent stability of CEE in aqueous solution and compared the permeability of CEE to CRT and creatinine (CRN) across Caco-2 human epithelial cell monolayers and transdermal permeability across porcine skin. CEE was most stable in a strongly acidic condition (half-life = 570 hours at pH 1.0) where it undergoes ester hydrolysis to CRT and ethanol. At pH ≥ 1.0, CEE cyclizes to CRN with the logarithm of the first order rate constant increasing linearly with pH. Above pH 8.0 (half-life = 23 sec) the rate of degradation was too rapid to be determined. The rate of degradation of CEE in cell culture media and simulated intestinal fluid (SIF) was a function of pH and correlated well with the stability in aqueous buffered solutions. The permeability of CEE across Caco-2 monolayers and porcine skin was significantly greater than that of CRT or CRN. The stability of CEE in acidic media together with its improved permeability suggests that CEE has potential for improved oral absorption compared to CRT.
Assuntos
Creatina/análogos & derivados , Creatina/metabolismo , Ácido Gástrico , Mucosa Intestinal/metabolismo , Pró-Fármacos/metabolismo , Pele/metabolismo , Administração Oral , Animais , Células CACO-2 , Química Farmacêutica , Creatina/administração & dosagem , Creatinina/metabolismo , Estabilidade de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Pró-Fármacos/administração & dosagem , SuínosRESUMO
BACKGROUND: Renal function is currently estimated using the Modification of Diet in Renal Disease (MDRD) formula, which is partly based on the serum creatinine level. Patients with impaired renal function are referred to nephrologists in accordance with the Dutch national transmural agreement for 'Chronic renal impairment'. CASE DESCRIPTION: A 54-year-old woman without significant history was referred to analyse a coincidentally found decline in the estimated glomerular filtration rate (eGFR). The patient had no complaints and used no medication except creatine supplements. Additional diagnostic testing showed no abnormalities. After cessation of creatine supplementation, the calculated renal function normalized. CONCLUSION: Serum creatinine is a reflection of muscle mass. The use of creatine-containing dietary supplements, such as creatine ethyl ester, can influence serum creatinine levels and therefore the eGFR as calculated with the MDRD formula. The use of supplements deserves attention when taking the history.
Assuntos
Creatina/análogos & derivados , Creatinina/sangue , Suplementos Nutricionais/efeitos adversos , Taxa de Filtração Glomerular/fisiologia , Insuficiência Renal/etiologia , Creatina/administração & dosagem , Creatina/efeitos adversos , Dieta , Feminino , Humanos , Pessoa de Meia-Idade , Insuficiência Renal/sangue , Insuficiência Renal/diagnósticoRESUMO
Creatine is an amino acid that has a pivotal role in energy metabolism of cells. Creatine acts as an "ATP shuttle", carrying ATP to the sites where it is utilized, through its reversible phosphorylation by creatine kinase. Moreover, the creatine-phosphocreatine system delays ATP depletion during anoxia or ischemia, thus exerting a neuroprotective role during those pathological conditions. Thus, its administration has been advocated as a treatment or prevention of several conditions involving the central nervous system. However, creatine crosses poorly the blood-brain barrier and the cell plasma membrane, thus its administration has but a limited effect. The use of more lipophilic creatine derivatives has thus been suggested. However, such a synthesis is complicated by the intrinsic characteristics of the creatine molecule that hardly reacts with other molecules and easily cyclizes to creatinine. We obtained amide derivatives from creatine starting from a new protected creatine molecule synthesized by us, the so-called (Boc)2-creatine. We used a temporary protection only on the creatine guanidine group while allowing a good reactivity on the carboxylic group. This temporary protection ensured efficient creatine dissolution in organic solvents and offered simultaneous protection of creatine toward intramolecular cyclization to creatinine. In this manner, it was possible to selectively conjugate molecules on the carboxylic group. The creatine guanidine group was easily released from the protection at the end of the reaction, thus obtaining the desired creatine derivative.
Assuntos
Técnicas de Química Sintética/métodos , Creatina/análogos & derivados , Creatina/síntese química , Creatina/química , Estrutura MolecularRESUMO
The creatine kinase/phosphocreatine system plays a key role in cell energy buffering and transport, particularly in cells with high or fluctuating energy requirements, like neurons, i.e. it participates in the energetic metabolism of the brain. Creatine depletion causes several nervous system diseases, alleviated by phosphagen supplementation. Often, the supplementation contains both creatine and creatine ethyl ester, known to improve the effect of creatine through an unknown mechanism. In this work we showed that purified creatine kinase is able to phosphorilate the creatine ethyl ester. The K(m) and V(max) values, as well as temperature and pH optima were determined. Conversion of the creatine ethyl ester into its phosphorylated derivative, sheds light on the role of the creatine ethyl ester as an energy source in supplementation for selected individuals.
Assuntos
Creatina Quinase/química , Creatina/análogos & derivados , Estabilidade Enzimática , Cinética , Creatina/química , Metabolismo Energético , Concentração de Íons de Hidrogênio , FosforilaçãoRESUMO
BACKGROUND: The creatine kinase system, the central regulatory system of cellular energy metabolism, provides ATP in situ at ATP-ases involved in ion transport and muscle contraction. Furthermore, the enzyme system provides relative protection from tissue ischaemia and acidosis. The system could therefore be a target for pharmacologic intervention. OBJECTIVES: To systematically evaluate evidence regarding the effectiveness of interventions directly targeting the creatine kinase system as compared to placebo control in adult patients with essential hypertension or cardiovascular disease. SEARCH METHODS: Electronic databases searched: Medline (1950 - Feb 2011), Embase (up to Feb 2011), the Cochrane Controlled Trials Register (issue 3, Aug 2009), Latin-American/Caribbean databank Lilacs; references from textbooks and reviews; contact with experts and pharmaceutical companies; and searching the Internet. There was no language restriction. SELECTION CRITERIA: Randomized controlled trials comparing creatine, creatine phosphate, or cyclocreatine (any route, dose or duration of treatment) with placebo; in adult patients with essential hypertension, heart failure, or myocardial infarction. We did not include papers on the short-term use of creatine during cardiac surgery. DATA COLLECTION AND ANALYSIS: The outcomes assessed were death, total myocardial infarction (fatal or non-fatal), hospitalizations for congestive heart failure, change in ejection fraction, and changes in diastolic and systolic blood pressure in mm Hg or as percent change. MAIN RESULTS: Full reports or abstracts from 1164 papers were reviewed, yielding 11 trials considering treatment with creatine or creatine analogues in 1474 patients with heart failure, ischemic heart disease or myocardial infarction. No trial in patients with hypertension was identified. Eleven trials (1474 patients, 35 years or older) comparing add-on therapy of the creatine-based drug on standard treatment to placebo control in patients with heart failure (6 trials in 1226 / 1474 patients ), or acute myocardial infarction (4 trials in 220 / 1474 patients) or 1 in ischemic heart disease (28 / 1474 patients) were identified. The drugs used were either creatine, creatine phosphate (orally, intravenously, or intramuscular) or phosphocreatinine. In the trials considering heart failure all three different compounds were studied; creatine orally (Gordon 1995, Kuethe 2006), creatine phosphate via intravenous infusion (Ferraro 1996, Grazioli 1992), and phosphocreatinine orally (Carmenini 1994, Maggi 1990). In contrast, the acute myocardial infarction trials studied intravenous creatine phosphate only. In the ischemic heart disease trial (Pedone 1984) creatine phosphate was given twice daily through an intramuscular injection to outpatients and through an intravenous infusion to inpatients. The duration of the study intervention was shorter for the acute patients, from a two hour intravenous infusion of creatine phosphate in acute myocardial infarction (Ruda 1988, Samarenko 1987), to six months in patients with heart failure on oral phosphocreatinine therapy (Carmenini 1994). In the acute myocardial infarction patients the follow-up period varied from the acute treatment period (Ruda 1988) to 28 days after start of the symptoms (Samarenko 1987) or end of the hospitalization period (Zochowski 1994). In the other trials there was no follow-up after discontinuation of treatment, except for Gordon 1995 which followed the patients until four days after stopping the intervention.Only two out of four trials in patients with acute myocardial infarction reported mortality outcomes, with no significant effect of creatine or creatine analogues (RR 0.73, CI: 0.22 - 2.45). In addition, there was no significance on the progression of myocardial infarction or improvement on ejection fraction. The main effect of the interventions seems to be on improvement of dysrhythmia. AUTHORS' CONCLUSIONS: This review found inconclusive evidence to decide on the use of creatine analogues in clinical practice. In particular, it is not clear whether there is an effect on mortality, progression of myocardial infarction and ejection fraction, while there is some evidence that dysrhythmia and dyspnoea might improve. However, it is not clear which analogue, dose, route of administration, and duration of therapy is most effective. Moreover, given the small sample size of the discussed trials and the heterogeneity of the population included in these reports, larger clinical studies are needed to confirm these observations.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Creatina Quinase/antagonistas & inibidores , Creatina/uso terapêutico , Terapia de Alvo Molecular/métodos , Creatina/análogos & derivados , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/mortalidade , Isquemia Miocárdica/tratamento farmacológico , Fosfocreatina/análogos & derivados , Fosfocreatina/uso terapêuticoRESUMO
We evaluated the efficacy of derivatives of creatine and amino acids (CrAA) for decreasing cerebral injury in rats with transient middle cerebral artery occlusion (MCAO). Neuroprotective effects of amides of creatine and glycine (CrGlyOEt), phenylalanine (CrPheNH2), thyrosine (CrTyrNH2), and GABA (CrGABAOEt) were investigated. Brain injury was evaluated on day 2 after transient MCAO using a TTC staining of brain slices. Compared with the MCAO control group, all the CrAms showed decreased cerebral injury (p < 0.05). However CrPheNH2, CrTyrNH2, and CrGABAOEt were toxic after intravenous administration and investigated only after intraperitoneal injection. CrGlyOEt did not show any toxicity at dose of 1 mmol/kg. These data evidenced that creatinyl amides can represent promising candidates for the development of new drugs useful in brain ischemia treatment.
Assuntos
Amidas/administração & dosagem , Isquemia Encefálica/tratamento farmacológico , Creatina/administração & dosagem , Glicina/química , Ataque Isquêmico Transitório/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Amidas/síntese química , Amidas/uso terapêutico , Animais , Isquemia Encefálica/patologia , Creatina/análogos & derivados , Creatina/síntese química , Creatina/uso terapêutico , Feminino , Hemodinâmica , Processamento de Imagem Assistida por Computador , Infarto da Artéria Cerebral Média , Injeções Intraperitoneais , Injeções Intravenosas , Ataque Isquêmico Transitório/patologia , Masculino , Microscopia , Microtomia , Modelos Animais , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/uso terapêutico , Fenilalanina/química , Ratos , Ratos Wistar , Sais de Tetrazólio/análise , Tirosina/química , Ácido gama-Aminobutírico/químicaRESUMO
Creatine, an ergogenic compound essential for brain function, is very hydrophilic and needs a transporter to cross lipid-rich cells' plasma membranes. Hereditary creatine transporter deficiency is a severe incurable neurological disease where creatine is missing from the brain. Creatine esters are more lipophylic than creatine and may not need the transporter to cross plasma membranes. Thus, they may represent a useful therapy for hereditary creatine transporter deficiency. Creatine ethyl ester (CEE) is commercially available and widely used as a nutritional supplement. It was reported that it enters the cells of patients lacking the transporter but was not useful when administered in vivo, by oral route, to affected patients. In this paper we investigated the effects of CEE in in vitro brain slices before and after biochemical block of the creatine transporter. We found that CEE is rapidly degraded in the aqueous incubation medium to creatinine, however it remains in solution long enough to cause an increase in tissue content of creatine and, more prominently, phosphocreatine. Both CEE and creatine delayed the anoxia-induced failure of synaptic transmission, and there was no difference between the two compounds. Contrary to what we expected, CEE did not increase tissue creatine content after the creatine transporter was blocked. We confirm that CEE is probably not an effective treatment for hereditary creatine transporter deficiency. Two factors seem to affect the possibility for creatine esters to be exploited in the therapy of creatine transporter deficiency. First, the size of their alcohol moiety should be increased since this would increase the lipophilicity of the compound and improve its ability to diffuse through biological membranes. Second, creatine esters should be further modified to slow their degradation to creatinine and increase their half-life in aqueous solutions. Moreover, we should not forget the possibility that they are degraded in vivo by plasma esterases.
Assuntos
Creatina/análogos & derivados , Hipocampo/metabolismo , Proteínas de Membrana Transportadoras/deficiência , Animais , Cromatografia Líquida de Alta Pressão , Creatina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Técnicas de Cultura de Órgãos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Despite the widespread availability and use of dietary supplements, minimal work has been performed to assess the potential dangers many of these supplements may have on the host's well-being, in particular the host's ability to respond to infection. One supplement extensively used by both adolescents and adults is creatine. Using Real-time PCR, we examined the impact of short-term exposure of a mouse macrophage cell line (RAW 264.7 cells) to two readily available forms of creatine used in supplements--creatine monohydrate (CR) and creatine ethyl ester (CEE) as well as the end product of creatine metabolism, creatinine (CRN), on expression of toll-like receptor-2 (TLR-2), TLR-3, TLR-4, and TLR-7. CR down-regulated TLR-2, TLR-3, TLR-4 and TLR-7 mRNA levels in RAW cells. Similar results were observed following exposure of RAW cells to CRN. Conversely CEE appears to possess immunostimulatory properties and increases expression of TLR-2, TLR-3, TLR-4, and TLR-7 in RAW cells. These data are supported by immunostaining using antibodies specific for the individual TLRs before and after exposure of RAW cells to CR, CRN, or CEE. To extend these findings, we isolated murine splenocytes and exposed the cells to CR, CEE, or CRN for 24 hours and performed immunofluorescent staining for TLR-2, TLR-3, TLR-4 and TLR-7. The results obtained from this study with primary splenocytes were consistent with the studies using RAW cells. Together, these data suggest that creatine and creatine derivatives may impact the ability of immune cells to sense a wide array of viral and bacterial pathogens. Of great interest, CRN--largely considered to be a waste product of the argenine biosynthesis pathway may also have immunosuppressive properties similar to those of CR.