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1.
Clin Chim Acta ; 501: 241-251, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31758937

RESUMO

BACKGROUND: Prostate cancer (PCa) is one of the most common cancers in men, but its metabolic characteristics during tumor progression are still far from being fully understood. METHODS: The metabolic profiles of matched tissue, serum and urine samples from the same patients were analyzed using a 1H NMR-based metabolomics approach. We identified several important metabolites that significantly altered at different stages of PCa, including benign prostatic hyperplasia (BPH), early PCa (EPC), advanced PCa (APC), metastatic PCa (MPC) and castration-resistant PCa (CRPC). Metabolic correlation networks among tissue, serum and urine samples were examined using Pearson's correlation. RESULTS: The changes in metabolic phenotypes during the progression of PCa were more noticeable in tissue samples when compared with serum and urine samples. Herein we identified a series of important metabolic disturbances, including decreased trends of citrate, creatinine, acetate, leucine, valine, glycine, lysine, histidine, glutamine and choline as well as increased trends of uridine and formate. These metabolites are mainly implicated in energy metabolism, amino acid metabolism, choline and fatty acid metabolism as well as uridine metabolism. We also found that energy metabolism in tumor tissues was positively associated with amino acid metabolism in serum and urine. Additionally, CRPC patients had a peculiar metabolic phenotype, especially decreased amino acid metabolism in serum. CONCLUSIONS: The present study characterizes metabolic disturbances in both tissue and biofluid samples during PCa progression and provides potential diagnostic biomarkers and therapeutic targets for PCa.

2.
Biochem J ; 476(13): 1943-1954, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31208986

RESUMO

Metabolic remodeling plays an essential role in the pathophysiology of heart failure (HF). Many studies have shown that the disruption of phosphoinositide-dependent protein kinase-1 (PDK1) caused severe and lethal HF; however, the metabolic pattern of PDK1 deletion remains ambiguous. 1H nuclear magnetic resonance-based metabolomics was applied to explore the altered metabolic pattern in Pdk1-deficient mice. Principle component analysis showed significant separation as early as 4 weeks of age, and dysfunction of metabolism precedes a morphological change in Pdk1-deficient mice. A time trajectory plot indicated that disturbed metabolic patterns were related to the pathological process of the HF in Pdk1-deficient mice, rather than the age of mice. Metabolic profiles demonstrated significantly increased levels of acetate, glutamate, glutamine, and O-phosphocholine in Pdk1 deletion mice. Levels of lactate, alanine, glycine, taurine, choline, fumarate, IMP, AMP, and ATP were significantly decreased compared with controls. Furthermore, PDK1 knockdown decreased the oxygen consumption rate in H9C2 cells as determined using a Seahorse XF96 Analyzer. These findings imply that the disruption of metabolism and impaired mitochondrial activity might be involved in the pathogenesis of HF with PDK1 deletion.

3.
Biosci Rep ; 39(4)2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30918104

RESUMO

Background: The present study aimed to explore the changes in the hepatic metabolic profile during the evolution of diabetes mellitus (DM) and verify the key metabolic pathways. Methods: Liver samples were collected from diabetic rats induced by streptozotocin (STZ) and rats in the control group at 1, 5, and 9 weeks after STZ administration. Proton nuclear magnetic resonance spectroscopy (1H NMR)-based metabolomics was used to examine the metabolic changes during the evolution of DM, and partial least squares-discriminate analysis (PLS-DA) was performed to identify the key metabolites. Results: We identified 40 metabolites in the 1H NMR spectra, and 11 metabolites were further selected by PLS-DA model. The levels of α-glucose and ß-glucose, which are two energy-related metabolites, gradually increased over time in the DM rats, and were significantly greater than those of the control rats at the three-time points. The levels of choline, betaine, and methionine decreased in the DM livers, indicating that the protective function in response to liver injury may be undermined by hyperglycemia. The levels of the other amino acids (leucine, alanine, glycine, tyrosine, and phenylalanine) were significantly less than those of the control group during DM development. Conclusions: Our results suggested that the hepatic metabolic pathways of glucose, choline-betaine-methionine, and amino acids were disturbed during the evolution of diabetes, and that choline-betaine-methionine metabolism may play a key role.

4.
Am J Cancer Res ; 9(2): 378-389, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906635

RESUMO

The aim of this study was to develop an interventional oncologic technique, "Image-guided intratumoral radiofrequency hyperthermia (RFH)-enhanced herpes simplex virus-thymidine kinase (HSV-TK) gene therapy of ovarian cancer. This study consisted of three portions: (1) serial in-vitro experiments to establish "proof-of-principle" of this novel technique using human ovarian cancer cells; (2) serial in-vivo experiments to validate technical feasibility using animal models with the same orthotopic ovarian cancers; and (3) serial investigations into the underlying bio-molecular mechanisms of this technique. We included four subject groups: (i) combination therapy with RFH+HSV-TK gene therapy; (ii) gene therapy-only; (iii) RFH-only; and (iv) Phosphate-buffered saline (PBS). For in-vitro experiments, confocal microscopy and MTS assays were performed to quantify HSV-TK gene expression and assess cell viability. For in-vivo experiments, bioluminescence optical and ultrasound imaging were used to assess therapeutic effectiveness. These results were correlated with subsequent pathologic/laboratory studies to further elucidate the biologic mechanisms of this technique. In in-vitro experiments, combination therapy resulted in the lowest cell proliferation and greatest increase in HSV-TK gene expression among four subject groups. In in-vivo experiments, combination therapy lead to significant decreases of bioluminescence signals and sizes of tumors in combination therapy by optical and ultrasound imaging. Pathology/laboratory examinations confirmed the significantly increased expression of Bax, Caspase-3, HSP70, IL-2, and CD94 in cancer tissues subjected to combination therapy. "Image-guided intratumoral RFH-enhanced direct gene therapy" is an effective interventional oncologic technique which functions through apoptotic/anti-tumor immunity pathways. This technical development may open new avenues for treating ovarian cancer.

5.
Mol Cell Proteomics ; 17(12): 2335-2346, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30171160

RESUMO

Diabetes mellitus causes brain structure changes and cognitive decline, and it has been estimated that diabetes doubles the risk for dementia. Until now, the pathogenic mechanism of diabetes-associated cognitive decline (DACD) has remained unclear. Using metabolomics, we show that lactate levels increased over time in the hippocampus of rats with streptozotocin-induced diabetes, as compared with age-matched control rats. Additionally, mRNA levels, protein levels, and enzymatic activity of lactate dehydrogenase-A (LDH-A) were significantly up-regulated, suggesting increased glycolysis activity. Importantly, by specifically blocking the glycolysis pathway through an LDH-A inhibitor, chronic diabetes-induced memory impairment was prevented. Analyzing the underlying mechanism, we show that the expression levels of cAMP-dependent protein kinase and of phosphorylated transcription factor cAMP response element-binding proteins were decreased in 12-week diabetic rats. We suggest that G protein-coupled receptor 81 mediates cognitive decline in the diabetic rat. In this study, we report that progressively increasing lactate levels is an important pathogenic factor in DACD, directly linking diabetes to cognitive dysfunction. LDH-A may be considered as a potential target for alleviating or treating DACD in the future.


Assuntos
Disfunção Cognitiva/metabolismo , Diabetes Mellitus Experimental/metabolismo , L-Lactato Desidrogenase/metabolismo , Ácido Láctico/metabolismo , Análise de Variância , Animais , Disfunção Cognitiva/complicações , Disfunção Cognitiva/prevenção & controle , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/prevenção & controle , Glicólise , Hipocampo/metabolismo , Imuno-Histoquímica , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , L-Lactato Desidrogenase/antagonistas & inibidores , Imagem por Ressonância Magnética , Masculino , Aprendizagem em Labirinto , Metabolômica/métodos , Análise Multivariada , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Estreptozocina/farmacologia
6.
Front Cell Neurosci ; 12: 207, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30065632

RESUMO

Cognitive dysfunction is a central nervous system (CNS) complication of diabetes mellitus (DM) that is characterized by impaired memory and cognitive ability. An in-depth understanding of metabolic alterations in the brain associated with DM will facilitate our understanding of the pathogenesis of cognitive dysfunction. The present study used an in vitro culture of primary neurons in a high-glucose (HG) environment to investigate characteristic alterations in neuron metabolism using nuclear magnetic resonance (NMR)-based metabonomics. High performance liquid chromatography (HPLC) was also used to measure changes in the adenosine phosphate levels in the hippocampal regions of streptozotocin (STZ)-induced diabetic rats. Our results revealed significant elevations in phosphocholine and ATP production in neurons and decreased formate, nicotinamide adenine dinucleotide (NAD+), tyrosine, methionine, acetate and phenylalanine levels after HG treatment. However, the significant changes in lactate, glutamate, taurine and myo-inositol levels in astrocytes we defined previously in astrocytes, were not found in neurons, suggested cell-specific metabolic alterations. We also confirmed an astrocyte-neuron lactate shuttle between different compartments in the brain under HG conditions, which was accompanied by abnormal acetate transport. These alterations reveal specific information on the metabolite levels and transport processes related to neurons under diabetic conditions. Our findings contribute to the understanding of the metabolic alterations and underlying pathogenesis of cognitive decline in diabetic patients.

7.
Cell Physiol Biochem ; 48(3): 934-946, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30036879

RESUMO

BACKGROUND/AIMS: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes. It is therefore crucial to elucidate the characteristic metabolic changes that occur during the development of diabetes to gain an understanding the pathogenesis of this disease and identify potential drug targets involved. METHODS: 1H nuclear magnetic resonance-based metabonomics combined with HPLC measurements were used to determine the metabolic changes in isolated cardiac tissues after 5 weeks, 9 weeks, and 15 weeks in rats treated with streptozotocin. RESULTS: Pattern recognition analysis clearly discriminated the diabetic rats from time-matched control rats, suggesting that the metabolic profile of the diabetic group was markedly different from that of the controls. Quantitative analysis showed that the levels of energy metabolites, such as the high-energy phosphate pool (ATP and creatine), significantly decreased in a time-dependent manner. Correlation analysis revealed the inhibition of glycolysis and the tricarboxylic acid (TCA) cycle, enhanced lipid metabolism, and changes in some amino acids, which may have led to the decline in energy production in the DCM rats. CONCLUSIONS: The results indicated that the administration of energy substances or the manipulation of myocardial energy synthesis induced by increased glucose oxidation may contribute to the amelioration of cardiac dysfunction in diabetes.


Assuntos
Cardiomiopatias Diabéticas/patologia , Metabolismo Energético , Metaboloma , Trifosfato de Adenosina/análise , Aminoácidos/análise , Aminoácidos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Creatina/análise , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/etiologia , Análise Discriminante , Análise dos Mínimos Quadrados , Espectroscopia de Ressonância Magnética , Masculino , Metabolômica , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley
8.
Cancer Res ; 78(16): 4459-4470, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29891507

RESUMO

The acquisition of ectopic fibroblast growthfactor receptor 1 (FGFR1) expression is well documented in prostate cancer progression. How it contributes to prostate cancer progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here, we report that FGFR1 tyrosine kinase reprograms the energy metabolism of prostate cancer cells by regulating the expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis. LDHA depletion compromised, whereas LDHB depletion enhanced the tumorigenicity of prostate cancer cells. Furthermore, FGFR1 overexpression and aberrant LDH isozyme expression were associated with short overall survival and biochemical recurrence times in patients with prostate cancer. Our results indicate that ectopic FGFR1 expression reprograms the energy metabolism of prostate cancer cells, representing a hallmark change in prostate cancer progression.Significance: FGF signaling drives the Warburg effect through differential regulation of LDHA and LDHB, thereby promoting the progression of prostate cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4459/F1.large.jpg Cancer Res; 78(16); 4459-70. ©2018 AACR.


Assuntos
L-Lactato Desidrogenase/genética , Lactato Desidrogenases/genética , Neoplasias da Próstata/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Testes de Carcinogenicidade , Proliferação de Células , Sobrevivência Celular , Reprogramação Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/patologia , Isoformas de Proteínas/genética , Estabilidade Proteica , Transdução de Sinais/genética
9.
Neural Plast ; 2018: 6473728, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29849562

RESUMO

Diabetic patients often present with comorbid depression. However, the pathogenetic mechanisms underlying diabetic depression (DD) remain unclear. To explore the mechanisms underpinning the pathogenesis of the disease, we used ex vivo 1H nuclear magnetic resonance spectroscopy and immunohistochemistry to investigate the main metabolic and pathological changes in various rat brain areas in an animal model of DD. Compared with the control group, rats in the DD group showed significant decreases in neurotransmitter concentrations of glutamate (Glu) and glutamine (Gln) in the prefrontal cortex (PFC), hippocampus, and hypothalamus and aspartate and glycine in the PFC and hypothalamus. Gamma-aminobutyric acid (GABA) was decreased only in the hypothalamus. Levels of the energy product, lactate, were higher in the PFC, hippocampus, and hypothalamus of rats with DD than those in control rats, while creatine was lower in the PFC and hippocampus, and alanine was lower in the hypothalamus. The levels of other brain metabolites were altered, including N-acetyl aspartate, taurine, and choline. Immunohistochemistry analysis revealed that expressions of both glutamine synthetase and glutaminase were decreased in the PFC, hippocampus, and hypothalamus of rats with DD. The metabolic changes in levels of Glu, Gln, and GABA indicate an imbalance of the Glu-Gln metabolic cycle between astrocytes and neurons. Our results suggest that the development of DD in rats may be linked to brain metabolic changes, including inhibition of the Glu-Gln cycle, increases in anaerobic glycolysis, and disturbances in the lactate-alanine shuttle, and associated with dysfunction of neurons and astrocytes.


Assuntos
Depressão/metabolismo , Complicações do Diabetes/metabolismo , Hipocampo/metabolismo , Hipotálamo/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Depressão/etiologia , Modelos Animais de Doenças , Glutamato-Amônia Ligase/metabolismo , Glutaminase/metabolismo , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Ratos Wistar
10.
Molecules ; 23(4)2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29614759

RESUMO

High glucose-induced cardiomyocyte death is a common symptom in advanced-stage diabetic patients, while its metabolic mechanism is still poorly understood. The aim of this study was to explore metabolic changes in high glucose-induced cardiomyocytes and the heart of streptozotocin-induced diabetic rats by ¹H-NMR-based metabolomics. We found that high glucose can promote cardiomyocyte death both in vitro and in vivo studies. Metabolomic results show that several metabolites exhibited inconsistent variations in vitro and in vivo. However, we also identified a series of common metabolic changes, including increases in branched-chain amino acids (BCAAs: leucine, isoleucine and valine) as well as decreases in aspartate and creatine under high glucose condition. Moreover, a reduced energy metabolism could also be a common metabolic characteristic, as indicated by decreases in ATP in vitro as well as AMP, fumarate and succinate in vivo. Therefore, this study reveals that a decrease in energy metabolism and an increase in BCAAs metabolism could be implicated in high glucose-induced cardiomyocyte death.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Metabolismo Energético/efeitos dos fármacos , Glucose/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Humanos , Isoleucina/metabolismo , Leucina/metabolismo , Metabolômica/métodos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Valina/metabolismo
11.
Front Neurosci ; 12: 90, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29515360

RESUMO

Metabolic confusion has been linked to the pathogenesis of Parkinson's disease (PD), while the dynamic changes associated with the onset and progression of PD remain unclear. Herein, dynamic changes in metabolites were detected from the initiation to the development of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -induced Parkinsonism model to elucidate its potential metabolic mechanism. Ex vivo1H nuclear magnetic resonance (NMR) spectroscopy was used to measure metabolite changes in the striatum and substantia nigra (SN) of mice at 1, 7, and 21 days after injection of MPTP. Metabolomic analysis revealed a clear separation of the overall metabolites between PD and control mice at different time points. Glutamate (Glu) in the striatum was significantly elevated at induction PD day 1 mice, which persisted to day 21. N-acetylaspartate (NAA) increased in the striatum of induction PD mice on days 1 and 7, but no significant difference was found in striatum on day 21. Myo-Inositol (mI) and taurine (Tau) were also disturbed in the striatum in induction PD day 1 mice. Additionally, key enzymes in the glutamate-glutamine cycle were significantly increased in PD mice. These findings suggest that neuron loss and motor function impairment in induction PD mice may be linked to overactive glutamate-glutamine cycle and altered membrane metabolism.

12.
Brain Res ; 1684: 67-74, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29408682

RESUMO

Understanding the subacute may shed light on the mechanism of cerebral ischemia. The present study aimed to explore metabolic features underlying subacute stage of ischemia-reperfusion injury and developing effective treatments. Rats were divided into three groups: the permanent middle cerebral artery occlusion (pMCAO), transient cerebral focal ischemia (tMCAO) and sham group. Evaluation of animal models was performed by the neurological deficit, MR images and pathological morphological abnormality. To elucidate metabolic changes, we conducted a comparative analysis of metabolic composition of unilateral brain tissue using 1H nuclear magnetic resonance spectroscopy. The successful model was observed low signal on T1WI and high signal on T2WI lesions in the left cerebral. Histopathological results confirmed the formation of apparent lesions in the left striatum, hippocampus CA1 and cortex tissues of subacute cerebral ischemia rats and showed that rats with focal cerebral ischemia-reperfusion could alleviate the extent of pathological damage degree. In pMCAO rats 7 days after surgery, decreased levels of N-acetyl aspartate (NAA), γ-aminobutyric acid (GABA), glutamate (Glu) and succinate (Suc) concomitantly with increased levels of glutamine (Gln), myo-inositol (m-Ins) and lactate (Lac) were observed compared to the control. Whereas, increased level of Lac with decreased levels of NAA, GABA, Glu, Suc, creatine (Cre) were observed in the tMCAO rats. This demonstrated that experimental subacute ischemic stroke in rats caused extensive perturbation in energy metabolism, the tricarboxylic acid cycle and GABA shunt, which provided essential information for understanding the pathogenesis of subacute cerebral ischemia-reperfusion and provided guidance in choosing the suitable therapeutic schedule.


Assuntos
Isquemia Encefálica/patologia , Infarto da Artéria Cerebral Média/patologia , Ataque Isquêmico Transitório/patologia , Imagem por Ressonância Magnética , Traumatismo por Reperfusão/patologia , Animais , Isquemia Encefálica/metabolismo , Metabolismo Energético/fisiologia , Infarto da Artéria Cerebral Média/metabolismo , Ataque Isquêmico Transitório/metabolismo , Imagem por Ressonância Magnética/métodos , Masculino , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo
13.
Mol Med Rep ; 17(1): 531-541, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29115616

RESUMO

Supratentorial focal ischemia may reduce cerebral blood volume and cerebellar glucose metabolic rate contralateral to the region of ischemia. The present study investigated the effects of middle cerebral artery occlusion (MCAO) on cerebral metabolism in the ischemic cerebral hemisphere and the non­ischemic cerebellum in rats 1, 3, 9 and 24 h following ischemia using ex vivo proton nuclear magnetic resonance (1H NMR) spectroscopy. The results demonstrated that focal ischemia induced increases in the levels of lactate and alanine, and a decrease in succinate, as early as 1 h following ischemia in the left cerebral hemisphere and the right cerebellum. A continuous increase in lactate levels and decrease in creatine levels were detected in both cerebral areas 3 and 24 h post­MCAO. The most obvious difference between the two cerebral areas was that there was no statistically significant difference in N­acetyl aspartate (NAA) levels in the right cerebellum at all time points; however, the amino acid levels of NAA in the left cerebral hemisphere were markedly decreased 3, 9 and 24 h post­MCAO. In addition, an obvious increase in glutamine was observed in the right and left cerebellum at 3, 9 and 24 h post­MCAO. Furthermore, the present study demonstrated that γ­aminobutyric acid levels were decreased at 1 h in the left and right cerebellum and were evidently increased at 24 h in the right cerebellum post­MCAO. In conclusion, supratentorial ischemia has been indicated to affect the activities of the non­ischemic contralateral cerebellum. Therefore, these results suggested that an NMR­based metabonomic approach may be used as a potential means to elucidate cerebral and cerebellar metabolism following MCAO, which may help improve understanding regarding cerebral infarction at a molecular level. Ex vivo 1H NMR analysis may be useful for the assessment of clinical biopsies.


Assuntos
Isquemia Encefálica/metabolismo , Cerebelo/metabolismo , Metabolismo Energético , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Cerebelo/patologia , Infarto da Artéria Cerebral Média , Masculino , Metabolômica/métodos , Espectroscopia de Prótons por Ressonância Magnética , Ratos
14.
Mol Neurobiol ; 55(2): 1112-1122, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28092089

RESUMO

Accumulating investigations have focused on the severity of central nervous system (CNS) complications in diabetic patients. The effects of the high glucose (HG) probably attribute to the metabolic disturbances in CNS. Astrocytes, with powerful ability of metabolic regulation, play crucial roles in physiological and pathological processes in CNS. Hence, an in-depth analysis as to metabolic alterations of astrocytes exposure to HG would facilitate to explore the underlying pathogenesis. In this study, the 1H NMR-based metabonomic approach was performed to characterize the metabolic variations of intracellular metabolites and corresponding culture media in a time-dependent manner. Our results revealed a significant elevation in lactate production and release. Four amino acids, leucine, isoleucine, methionine and tyrosine, were the most important metabolites for utilization. Also, profound disturbances of several metabolic pathways, including osmoregulation, energy metabolism, and cellular biosynthesis were observed. In that sense, the detailed information of astrocyte metabolism under HG exposure provides us a comprehensive understanding of the intrinsic metabolic disorders in CNS during hyperglycemia or diabetes.


Assuntos
Aminoácidos/metabolismo , Astrócitos/metabolismo , Metabolismo Energético/fisiologia , Glucose/farmacologia , Ácido Láctico/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Metabolismo Energético/efeitos dos fármacos , Metabolômica , Ratos , Ratos Sprague-Dawley
15.
Front Cell Neurosci ; 12: 527, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30692917

RESUMO

Diabetic encephalopathy (DE) is a diabetic complication characterized by alterations in cognitive function and nervous system structure. The pathogenic transition from hyperglycemia to DE is a long-term process accompanied by multiple metabolic disorders. Exploring time-dependent metabolic changes in hippocampus will facilitate our understanding of the pathogenesis of DE. In the present study, we first performed behavioral and histopathological experiments to confirm the appearance of DE in rats with streptozotocin-induced diabetes. We then utilized nuclear magnetic resonance-based metabonomics to analyze metabolic disorders in the hippocampus at different stages of DE. After 1 week, we observed no cognitive or structural impairments in diabetic rats, although some metabolic changes were observed in local hippocampal extracts. At 5 weeks, while cognitive function was still normal, we then examined initial levels of neuronal apoptosis. The characteristic metabolic changes of this stage included elevated levels of energy metabolites (i.e., ATP, ADP, AMP, and creatine phosphate/creatine). At 9 weeks, significant cognitive decline and histopathological brain damage were observed, in conjunction with reduced levels of some amino acids. Thus, this stage was classified as the DE period. Our findings indicated that the pathogenesis of DE is associated with time-dependent alterations in metabolic features in hippocampal regions, such as glycolysis, osmoregulation, energy metabolism, choline metabolism, branched-chain amino acid metabolism, and the glutamate-glutamine cycle. Furthermore, we observed alterations in levels of lactate and its receptor in hippocampal cells, which may be involved in the pathogenesis of DE.

16.
Anal Chim Acta ; 991: 68-75, 2017 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-29031300

RESUMO

Accurate classification of cancer stages will achieve precision treatment for cancer. Metabolomics presents biological phenotypes at the metabolite level and holds a great potential for cancer classification. Since metabolomic data can be obtained from different samples or analytical techniques, data fusion has been applied to improve classification accuracy. Data preprocessing is an essential step during metabolomic data analysis. Therefore, we developed an innovative optimization method to select a proper data preprocessing strategy for metabolomic data fusion using a design of experiment approach for improving the classification of prostate cancer (PCa) stages. In this study, urine and serum samples were collected from participants at five phases of PCa and analyzed using a 1H NMR-based metabolomic approach. Partial least squares-discriminant analysis (PLS-DA) was used as a classification model and its performance was assessed by goodness of fit (R2) and predictive ability (Q2). Results show that data preprocessing significantly affect classification performance and depends on data properties. Using the fused metabolomic data from urine and serum, PLS-DA model with the optimal data preprocessing (R2 = 0.729, Q2 = 0.504, P < 0.0001) can effectively improve model performance and achieve a better classification result for PCa stages as compared with that without data preprocessing (R2 = 0.139, Q2 = 0.006, P = 0.450). Therefore, we propose that metabolomic data fusion integrated with an optimal data preprocessing strategy can significantly improve the classification of cancer stages for precision treatment.


Assuntos
Metabolômica , Estadiamento de Neoplasias/métodos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/urina , Análise Discriminante , Humanos , Análise dos Mínimos Quadrados , Masculino
17.
Biomed Res Int ; 2017: 3262495, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28243597

RESUMO

Amyloid ß (Aß) deposition has been implicated in the pathogenesis of Alzheimer's disease. However, the early effect of Aß deposition on metabolism remains unclear. In the present study, thus, we explored the metabolic changes in the hippocampus and serum during first 2 weeks of Aß25-35 injection in rats by using an integrated method of NMR-based metabolomics and ANOVA-simultaneous component analysis (ASCA). Our results show that Aß25-35 injection, time, and their interaction had statistically significant effects on the hippocampus and serum metabolome. Furthermore, we identified key metabolites that mainly contributed to these effects. After Aß25-35 injection from 1 to 2 weeks, the levels of lactate, N-acetylaspartate, creatine, and taurine were decreased in rat hippocampus, while an increase in lactate and decreases in LDL/VLDL and glucose were observed in rat serum. Therefore, we suggest that the reduction in energy and lipid metabolism as well as an increase in anaerobic glycolysis may occur at the early stage of Aß25-35 deposition.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Hipocampo/metabolismo , Metabolômica , Fragmentos de Peptídeos/toxicidade , Espectroscopia de Prótons por Ressonância Magnética/métodos , Análise de Variância , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Memória/efeitos dos fármacos , Ratos Sprague-Dawley
18.
Metab Brain Dis ; 32(2): 585-593, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28070703

RESUMO

Diabetes mellitus (DM) can result in cognitive dysfunction, but its potential metabolic mechanisms remain unclear. In the present study, we analyzed the metabolite profiling in eight different brain regions of the normal rats and the streptozotocin (STZ)-induced diabetic rats accompanied by cognitive dysfunction using a 1H NMR-based metabolomic approach. A mixed linear model analysis was performed to assess the effects of DM, brain region and their interaction on metabolic changes. We found that different brain regions in rats displayed significant metabolic differences. In addition, the hippocampus was more susceptible to DM compared with other brain regions in rats. More interestingly, significant interaction effects of DM and brain region were observed on alanine, creatine/creatine-phosphate, lactate, succinate, aspartate, glutamate, glutamine, γ-aminobutyric acid, glycine, choline, N-acetylaspartate, myo-inositol and taurine. Based on metabolic pathway analysis, we speculate that cognitive dysfunction in the STZ-induced diabetic rats may be associated with brain region-specific metabolic alterations involving energy metabolism, neurotransmitters, membrane metabolism and osmoregulation.


Assuntos
Química Encefálica/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/psicologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/psicologia , Espectroscopia de Ressonância Magnética/métodos , Metabolômica/métodos , Animais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Redes e Vias Metabólicas , Ratos Sprague-Dawley
19.
J Cereb Blood Flow Metab ; 37(1): 332-343, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-26762505

RESUMO

Type 2 diabetes has been linked to cognitive impairment, but its potential metabolic mechanism is still unclear. The present study aimed to explore neuron-astrocyte metabolic cooperation in the brain of diabetic (db/db, BKS.Cg-m+/+ Leprdb/J) mice with cognitive decline using 13C NMR technique in combination with intravenous [2-13C]-acetate and [3-13C]-lactate infusions. We found that the 13C-enrichment from [2-13C]-acetate into tricarboxylic acid cycle intermediate, succinate, was significantly decreased in db/db mice with cognitive decline compared with wild-type (WT, C57BLKS/J) mice, while an opposite result was obtained after [3-13C]-lactate infusion. Relative to WT mice, db/db mice with cognitive decline had significantly lower 13C labeling percentages in neurotransmitters including glutamine, glutamate, and γ-aminobutyric acid after [2-13C]-acetate infusion. However, [3-13C]-lactate resulted in increased 13C-enrichments in neurotransmitters in db/db mice with cognitive decline. This may indicate that the disturbance of neurotransmitter metabolism occurred during the development of cognitive decline. In addition, a reduction in 13C-labeling of lactate and an increase in gluconeogenesis were found from both labeled infusions in db/db mice with cognitive decline. Therefore, our results suggest that the development of cognitive decline in type 2 diabetes may be implicated to an unbalanced metabolism in neuron-astrocyte cooperation and an enhancement of gluconeogenesis.


Assuntos
Astrócitos/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Neurônios/metabolismo , Animais , Isótopos de Carbono , Ciclo do Ácido Cítrico/fisiologia , Gluconeogênese/fisiologia , Ácido Láctico/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos , Neurotransmissores/metabolismo
20.
Biochim Biophys Acta Mol Basis Dis ; 1863(1): 266-273, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27816519

RESUMO

Type 2 diabetes has been associated with cognitive decline, but its metabolic mechanism remains unclear. In the present study, we attempted to investigate brain region-specific metabolic changes in db/db mice with cognitive decline and explore the potential metabolic mechanism linking type 2 diabetes and cognitive decline. We analyzed the metabolic changes in seven brain regions of two types of mice (wild-type mice and db/db mice with cognitive decline) using a 1H NMR-based metabolomic approach. Then, a mixed-model analysis was used to evaluate the effects of mice type, brain region, and their interaction on metabolic changes. Compared with the wild-type mice, the db/db mice with cognitive decline had significant increases in lactate, glutamine (Gln) and taurine as well as significant decreases in alanine, aspartate, choline, succinate, γ-Aminobutyric acid (GABA), glutamate (Glu), glycine, N-acetylaspartate, inosine monophosphate, adenosine monophosphate, adenosine diphosphate, and nicotinamide adenine dinucleotide. Brain region-specific metabolic differences were also observed between these two mouse types. In addition, we found significant interaction effects of mice type and brain region on creatine/phosphocreatine, lactate, aspartate, GABA, N-acetylaspartate and taurine. Based on metabolic pathway analysis, the present study suggests that cognitive decline in db/db mice might be linked to a series of brain region-specific metabolic changes, involving an increase in anaerobic glycolysis, a decrease in tricarboxylic acid (TCA) and Gln-Glu/GABA cycles as well as a disturbance in lactate-alanine shuttle and membrane metabolism.


Assuntos
Encefalopatias Metabólicas/complicações , Encéfalo/metabolismo , Disfunção Cognitiva/complicações , Diabetes Mellitus Tipo 2/complicações , Metaboloma , Animais , Encéfalo/patologia , Encefalopatias Metabólicas/metabolismo , Encefalopatias Metabólicas/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Masculino , Metabolômica , Camundongos Endogâmicos C57BL
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