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1.
Chem Commun (Camb) ; 56(20): 3047-3049, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32048688

RESUMO

A series of aminocarboxylic acid analogues of aspergillomarasmine A (AMA) and ethylenediamine-N,N'-disuccinic acid (EDDS) were chemoenzymatically synthesized via the addition of various mono- and diamine substrates to fumaric acid catalyzed by the enzyme EDDS lyase. Many of these novel AMA and EDDS analogues demonstrate potent inhibition of the bacterial metallo-ß-lactamase NDM-1. Isothermal titration calorimetry assays revealed a strong correlation between the inhibitory potency of the compounds and their ability to bind zinc. Compounds 1a (AMA), 1b (AMB), 5 (EDDS), followed by 1d and 8a, demonstrate the highest synergy with meropenem resensitizing an NDM-1 producing strain of E. coli to this important carbapenem of last resort.


Assuntos
Ácido Aspártico/análogos & derivados , Complexos de Coordenação/farmacologia , Proteínas de Escherichia coli/antagonistas & inibidores , Etilenodiaminas/farmacologia , Succinatos/farmacologia , Zinco/farmacologia , Inibidores de beta-Lactamases/farmacologia , Aminoácidos/química , Aminoácidos/farmacologia , Ácido Aspártico/química , Ácido Aspártico/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Proteínas de Escherichia coli/metabolismo , Etilenodiaminas/química , Estrutura Molecular , Relação Estrutura-Atividade , Succinatos/química , Zinco/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/química , beta-Lactamases/metabolismo
2.
Nat Commun ; 11(1): 982, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080186

RESUMO

Although peptide chemistry has made great progress, the frequent occurrence of aspartimide formation during peptide synthesis remains a formidable challenge. Aspartimide formation leads to low yields in addition to costly purification or even inaccessible peptide sequences. Here, we report an alternative approach to address this longstanding challenge of peptide synthesis by utilizing cyanosulfurylides to mask carboxylic acids by a stable C-C bond. These functional groups-formally zwitterionic species-are exceptionally stable to all common manipulations and impart improved solubility during synthesis. Deprotection is readily and rapidly achieved under aqueous conditions with electrophilic halogenating agents via a highly selective C-C bond cleavage reaction. This protecting group is employed for the synthesis of a range of peptides and proteins including teduglutide, ubiquitin, and the low-density lipoprotein class A. This protecting group strategy has the potential to overcome one of the most difficult aspects of modern peptide chemistry.


Assuntos
Peptídeos/química , Peptídeos/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Ácido Aspártico/análogos & derivados , Ácido Aspártico/síntese química , Ácido Aspártico/química , Ácidos Carboxílicos/química , Cianetos/química , Lipoproteínas LDL/síntese química , Lipoproteínas LDL/química , Dobramento de Proteína , Ubiquitina/química
3.
Chemosphere ; 245: 125672, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31877455

RESUMO

To investigate the anaerobic treatment efficiency and degradation pathways of glutamate-rich wastewater under various hydraulic retention times (HRTs), a lab-scale upflow anaerobic sludge blanket (UASB) reactor was operated continuously for 180 days. Results showed that high chemical oxygen demand (COD) removal efficiencies of 95.5%-96.5% were achieved at HRTs of 4.5 h-6 h with a maximum methane yield of 0.31 L-CH4/g-COD. When the HRT was shortened to less than 3 h, the removal performance of the reactor declined. There also was an excessive accumulation of volatile fatty acids, which implies that an appropriately small HRT is applicable to the UASB reactor treating glutamate-rich wastewater. Methanogenic degradation of glutamate in the UASB reactor depended on the HRT applied, and the typical methane-producing capability of the sludge at an HRT of 3 h, in descending order, was acetate > glutamate > butyrate > H2/CO2 > valerate > propionate. Clostridium and Methanosaeta were predominant in the glutamate-degrading sludge. At least three degradation pathways most likely existed in the UASB reactor, and the pathway via 3-methlaspartate by Clostridium pascui was expected to be dominant.


Assuntos
Ácido Glutâmico/metabolismo , Metano/metabolismo , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias/química , Purificação da Água/métodos , Anaerobiose , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Análise da Demanda Biológica de Oxigênio , Reatores Biológicos/microbiologia , Difusão , Compostos de Amônio Quaternário/química , Esgotos/química , Esgotos/microbiologia , Águas Residuárias/microbiologia
4.
Gut ; 69(1): 158-167, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30833451

RESUMO

OBJECTIVE: Hepatitis D virus (HDV) is a circular RNA virus coinfecting hepatocytes with hepatitis B virus. Chronic hepatitis D results in severe liver disease and an increased risk of liver cancer. Efficient therapeutic approaches against HDV are absent. DESIGN: Here, we combined an RNAi loss-of-function and small molecule screen to uncover host-dependency factors for HDV infection. RESULTS: Functional screening unravelled the hypoxia-inducible factor (HIF)-signalling and insulin-resistance pathways, RNA polymerase II, glycosaminoglycan biosynthesis and the pyrimidine metabolism as virus-hepatocyte dependency networks. Validation studies in primary human hepatocytes identified the carbamoyl-phosphatesynthetase 2, aspartate transcarbamylase and dihydroorotase (CAD) enzyme and estrogen receptor alpha (encoded by ESR1) as key host factors for HDV life cycle. Mechanistic studies revealed that the two host factors are required for viral replication. Inhibition studies using N-(phosphonoacetyl)-L-aspartic acid and fulvestrant, specific CAD and ESR1 inhibitors, respectively, uncovered their impact as antiviral targets. CONCLUSION: The discovery of HDV host-dependency factors elucidates the pathogenesis of viral disease biology and opens therapeutic strategies for HDV cure.


Assuntos
Aspartato Carbamoiltransferase/genética , Ácido Aspártico/análogos & derivados , Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética , Di-Hidro-Orotase/genética , Receptor alfa de Estrogênio/metabolismo , Fulvestranto/farmacologia , Hepatite D Crônica/tratamento farmacológico , Ácido Fosfonoacéticos/análogos & derivados , Pirimidinas/biossíntese , Antivirais/farmacologia , Aspartato Carbamoiltransferase/antagonistas & inibidores , Aspartato Carbamoiltransferase/metabolismo , Ácido Aspártico/farmacologia , Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/antagonistas & inibidores , Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/metabolismo , Linhagem Celular , Di-Hidro-Orotase/antagonistas & inibidores , Di-Hidro-Orotase/metabolismo , Antagonistas do Receptor de Estrogênio/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Inativação Gênica , Hepatite D Crônica/genética , Hepatite D Crônica/metabolismo , Vírus Delta da Hepatite/fisiologia , Hepatócitos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Resistência à Insulina , Estágios do Ciclo de Vida , Mutação com Perda de Função , Ácido Fosfonoacéticos/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Viral/metabolismo , Transdução de Sinais , Replicação Viral
5.
Korean J Ophthalmol ; 33(5): 406-413, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612650

RESUMO

PURPOSE: To evaluate the effects of idiopathic infantile nystagmus (IN) and bilateral ametropic amblyopia on metabolites in the occipital cortex by magnetic resonance spectroscopy. METHODS: The children included in this prospective study were divided into three groups. Group 1 consisted of 11 patients with idiopathic IN, group 2 consisted of 10 patients with bilateral ametropic amblyopia and group 3 consisted of nine normal children. A single-voxel magnetic resonance spectroscopy examination was performed by placing a region of interest on the occipital cortex of each participant. N-acetyl aspartate (NAA), creatine (Cr) and choline (Cho) concentrations were measured in the occipital cortex. This was followed by calculating and comparing the NAA/Cr and Cho/Cr ratios between the three groups. The Kruskal-Wallis test, Mann-Whitney U-test, and chi-square test were used for statistical analysis. RESULTS: There was no statistically significant difference in NAA/Cr ratios between patients with idiopathic IN and normal children, but there was a statistically significant difference between these groups when Cho/Cr ratios were compared; the ratio was higher in the idiopathic IN group. There were no statistically significant differences in NAA/Cr or Cho/Cr ratios between patients with bilateral ametropic amblyopia and normal children. CONCLUSIONS: Our findings suggest that the neurochemical profile of the occipital cortex is partially affected by idiopathic IN, but not by bilateral ametropic amblyopia.


Assuntos
Ambliopia/metabolismo , Ácido Aspártico/análogos & derivados , Colina/análise , Creatina/análise , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Nistagmo Congênito/metabolismo , Lobo Occipital/metabolismo , Adolescente , Ácido Aspártico/análise , Biomarcadores/análise , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos
6.
Br J Radiol ; 92(1104): 20190216, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31556332

RESUMO

OBJECTIVE: Magnetic resonance spectroscopy (MRS) has been useful in radiotherapy treatment planning (RTP) especially in tumor delineation. Routinely, 2D/3D MRSI data are used for this application. However, not all centers have access to 2D/3D MRSI. The objective of this study was to introduce a method of using single-voxel spectroscopy (SVS) data in target delineation and assess its reliability. METHODS: A gel-based phantom containing Creatine (Cr), N-acetyl-l-aspartic-acid (NAA), and Choline (Cho) was designed and built. The metabolite ratios simulate the normal and tumoral part of the brain. The jMRUI software (v. 6.0) was used to simulate a 1.5 T GE MRI scanner. The metabolite spectra provided by different time of echos (TE)s of the Point-RESolved Spectroscopy pulse-sequence (PRESS), different data-points, and post-processings were quantized by jMRUI. PseudoMRSI maps of Cho/Cr, NAA/Cr, and Cho + Cr/NAA were created. A conformity index (CI) was used to determine which metabolite-ratio isolines are more appropriate for tumor delineation. RESULTS: The simulation accuracy was verified. There were no differences > 4% between the measured and simulated spectra in peak regions. The pseudoMRSI map of Cho + Cr/NAA smoothly followed the complicated geometry of the tumor inside the gel-based phantom. The results showed that the single-voxel spectra produced by the PRESS pulse sequence with the TE of 144 ms, 512 data-points, and minimum post-processings of water suppression, eddy current correction, and baseline correction can be used for target delineation. CONCLUSION: This study suggests that SVS data can be used to aid target delineation by using a mathematical approach. This can enable a wider use of MR-derived information in radiotherapy. ADVANCES IN KNOWLEDGE: To the best of our knowledge, until now, 2D or 3D MRSI data provided from 3T MRI scanners have been used for MRS-based radiotherapy treatment planning. However, there are a lot of centers that are equipped to 1.5 T MRI scanners and some of them just equipped to SVS. This study introduces a mathematical approach to help these centers to take the benefits of MRS-based treatment planning.


Assuntos
Química Encefálica , Neoplasias Encefálicas/química , Neoplasias Encefálicas/diagnóstico , Espectroscopia de Ressonância Magnética/métodos , Imagens de Fantasmas , Ácido Aspártico/análogos & derivados , Colina , Creatina , Humanos , Reprodutibilidade dos Testes , Software
7.
Soft Matter ; 15(37): 7381-7389, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31513229

RESUMO

Two block copolymers containing two amino-acid derivatives, PEO-b-PLAA and PEO-b-PAAC, were fabricated through atom transfer radical polymerization (ATRP) or reversible addition-fragmentation chain transfer polymerization (RAFT). Then, they were employed as a macro-crosslinker to prepare high-performance poly(acrylic acid) (PAA) hydrogels named "PxAy" or "TyAz". There were numerous synergistic noncovalent interactions with hydrogen bonds between the macro-crosslinker and PAA chains, as well as entanglement of polymer chains. Hence, the hydrogels exhibited desirable mechanical properties and self-healing abilities. For PxAy hydrogels, the maximum fracture elongation and fracture strength were 9800% and 120.01 kPa, respectively. Moreover, the enhanced physical interaction enabled the hydrogels to have rapid self-healing abilities without stimulation. The hydrogels showed >80% self-healing efficiency and exhibited ∼10-3 S cm-1 electrical conductivity upon the introduction of KCl. Meanwhile, benefitting from doubling the number of carboxyl groups in the macro-crosslinker of the TyAz hydrogels compared with the PxAy hydrogels, the mechanical properties of TyAz hydrogels could be promoted further and notch-insensitivity could be observed. Tough, adhesive, self-healable, and conductive PAA hydrogels with different structures of amino-acid derivatives could aid the development of macro-crosslinkers.


Assuntos
Resinas Acrílicas/química , Ácido Aspártico/análogos & derivados , Hidrogéis/síntese química , Leucina/análogos & derivados , Polietilenoglicóis/química
8.
Undersea Hyperb Med ; 46(3): 291-297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31394599

RESUMO

Introduction: We evaluated magnetic resonance spectroscopy (MRS) in United States military personnel with persistent symptoms after mild traumatic brain injury (mTBI), comparing over time two groups randomized to receive hyperbaric oxygen or sham chamber sessions and a third group of normative controls. Methods: Active-duty or veteran military personnel and normative controls underwent MRS outcome measures at baseline, 13 weeks (mTBI group only), and six months. Participants received 3.0 Tesla brain MRS for analysis of water-suppressed two-dimensional (2D) multivoxel 1H-MRS of the brain using point resolved spectroscopy (PRESS) with volume selection localized above the lateral ventricles and within the brain parenchyma, of which one voxel was chosen in each hemisphere without artifact. Script-based automatic data processing was used to assess N-acetylaspartate (NAA), creatine (Cr), and choline (Cho). Metabolite ratios for white matter were then calculated for NAA/Cr (Area), Cho/Cr (Area), and Cho/NAA (Area). These ratios were compared using standard analysis methodology. Results: There were no observable differences between participants with mTBI and normative controls nor any observable changes over time in the NAA/Cr (area), Cho/Cr (area), and Cho/NAA (area) ratios. Similarly, the control and injured participants were indistinguishable. Discussion: While participants with mild TBI showed no difference in MRS compared to normative controls, our results are limited by the few voxels chosen and potentially by less sensitive MRS markers.


Assuntos
Ácido Aspártico/análogos & derivados , Química Encefálica , Concussão Encefálica/metabolismo , Colina/análise , Creatina/análise , Espectroscopia de Ressonância Magnética/métodos , Adulto , Ácido Aspártico/análise , Concussão Encefálica/terapia , Estudos de Casos e Controles , Feminino , Humanos , Oxigenação Hiperbárica , Ventrículos Laterais/química , Masculino , Militares , Síndrome Pós-Concussão/metabolismo , Fatores de Tempo , Veteranos
9.
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
10.
J Pept Sci ; 25(7): e3193, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31309675

RESUMO

Aspartimide (Asi) formation is a notorious side reaction in peptide synthesis that is well characterized and described in literature. In this context, we observed significant amounts of chain termination in Fmoc-SPPS while synthesizing the N-terminal Xaa-Asp-Yaa motif. This termination was caused by the formation of piperazine-2,5-diones. We investigated this side reaction using a linear model peptide and independently synthesizing its piperazine-2,5-dione derivative. Nuclear magnetic resonance (NMR) data of the side product present in the crude linear peptide proves that exclusively the six-membered ring is formed whereas the theoretically conceivable seven-membered 1,4-diazepine-2,5-dione is not found. We propose a mechanism where nucleophilic attack of the N-terminal amino function takes place at the α-carbon of the carbonyl group of the corresponding Asi intermediate. In addition, we systematically investigated the impact of (a) different adjacent amino acid residues, (b) backbone protection, and (c) side chain protection of flanking amino acids. The side reaction is directly related to the Asi intermediate. Hence, hindering or avoiding Asi formation reduces or completely suppresses this side reaction.


Assuntos
Aminoácidos/química , Ácido Aspártico/análogos & derivados , Fluorenos/química , Peptídeos/síntese química , Piperazinas/síntese química , Técnicas de Síntese em Fase Sólida , Sequência de Aminoácidos , Ácido Aspártico/química , Estrutura Molecular , Peptídeos/química , Piperazinas/química
11.
Artigo em Russo | MEDLINE | ID: mdl-31156220

RESUMO

AIM: To assess the plasma level of N-acetylaspartate (NAA) before and after combined therapy with antidepressants and actovegin in a group of elderly patients diagnosed with depression. MATERIAL AND METHODS: Nineteen patients, 7 men and 12 women, mean age 70.5±5.8 years, were studied using clinical examination and psychometric scales as well as computed tomography (CT). NAA plasma levels were determined. The duration of treatment with antidepressants (venlafaxine, fluvoxamine) and actovegin was 28 days, patients were examined at baseline and on the 28th day of treatment. RESULTS AND CONCLUSION: The NAA plasma level was reduced in patients compared to healthy volunteers. The increase of this indicator after treatment reflected a significant improvement on clinical and psychometric measures. The dynamics of NAA changes (increase or decrease) showed heterogeneity in the group of patients, which was not related to the efficacy of treatment but was correlated with comorbid diseases, in particular vascular diseases, and CT changes (leukoaraiosis). The authors consider the results of this study as preliminary.


Assuntos
Antidepressivos , Ácido Aspártico/análogos & derivados , Depressão , Idoso , Antidepressivos/uso terapêutico , Ácido Aspártico/uso terapêutico , Depressão/tratamento farmacológico , Feminino , Heme/análogos & derivados , Humanos , Masculino
12.
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
13.
Clin Chim Acta ; 495: 406-416, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31095934

RESUMO

Urea cycle disorders (UCD) are inborn errors of ammonia detoxification in which early diagnosis and treatment are critical to prevent metabolic emergencies. Unfortunately, the diagnosis was often and pronounced delayed. To improve diagnosis, we developed herein a liquid chromatography-tandem mass spectrometry method to investigate the disturbance of amino acid profile caused by UCD. The method enabled absolute quantification of 48 amino acids (AAs) within 20 min. Only 2.5 µL plasma was required for the analysis. The lower limits of quantification for most AAs were 0.01 µmol/L. Method accuracies ranged from 89.9% to 113.4%. The within- and between-run coefficients of variation were 0.8-7.7% and 2.6-14.5%, respectively. With this method, age-specific reference values were established for 42 AAs by analyzing 150 samples from normal controls, and patients with different subtypes of UCD were successfully distinguished. The data of patients revealed that UCD not only disturbed the metabolism of urea cycle AAs and induced accumulation of ammonia detoxification AAs, but also interfered the metabolism of some nervous system related AAs, such as pipecolic acid and N-acetylaspartic acid. This data may provide new insight into pathogenesis for UCD.


Assuntos
Aminoácidos/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Aminoácidos/sangue , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Cromatografia Líquida , Feminino , Humanos , Masculino , Ácidos Pipecólicos/metabolismo , Espectrometria de Massas em Tandem , Distúrbios Congênitos do Ciclo da Ureia/sangue
14.
Dokl Biochem Biophys ; 484(1): 25-28, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31012006

RESUMO

For the first time the intracellular concentrations of N-acetylaspartate (NAA), aspartate (Asp), and glutamate (Glu) were measured in human brain in vivo, and the effect of severe traumatic brain injury on NAA synthesis in acute and remote posttraumatic phases was revealed. In non-damaged (MRI-negative) lobes the next day after injury, Asp and Glu decreased by 45% and 35%, respectively, while NAA decreased only by 16%. A negative correlation between NAA and Asp/Glu ratio was found. The Glu level returned to the norm long after injury, Asp remained below the norm by 60%, NAA decreased by 65% relative to the norm, and Asp/Glu decreased significantly. The results obtained educe the leading role of neuronal aspartate-malate shuttle in NAA synthesis alterations.


Assuntos
Ácido Aspártico/análogos & derivados , Lesões Encefálicas Traumáticas , Encéfalo , Ácido Glutâmico/metabolismo , Imagem por Ressonância Magnética , Adolescente , Ácido Aspártico/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/terapia , Feminino , Humanos , Masculino , Fatores de Tempo
15.
Bipolar Disord ; 21(6): 503-513, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31025452

RESUMO

OBJECTIVES: Bipolar disorder is marked by progressive symptomatic changes, which have been linked with episode-related structural findings-particularly in the prefrontal cortex. However, few studies have examined neurofunctional and neurochemical effects of disease burden. In this study, we compared first- and multi-episode bipolar individuals. We hypothesized that the latter would demonstrate evidence of neurophysiological differences consistent with a model of progressive functional degradation of these networks. METHODS: First- and multi-episode manic bipolar subjects participated in functional magnetic resonance imaging (fMRI) including a continuous performance task with emotional distractors, and in single-voxel (1 H) magnetic resonance spectroscopy (MRS). A priori fMRI regions-of-interest (ROI) included structures comprising prefrontal-striatal-amygdala networks; (1 H)MRS voxels were placed within bilateral ventrolateral prefrontal (VLPFC) and anterior cingulate cortex (ACC). Both ROI and voxel-based brain activation in response to emotional stimuli, and neurochemical concentrations derived from (1 H)MRS were compared across bipolar groups. RESULTS: Multi-episode bipolar subjects showed relatively lower regional activation across prefrontal-striatal-amygdala networks, including bilateral VLPFC, orbitofrontal cortex, ACC, putamen, caudate, and amygdala. Exploratory whole-brain, voxel-based analysis suggested additional areas of lower activation extending into Brodmann area 22, posterior parietal regions, and right thalamus. Glutamate and N-acetylaspartate (NAA) concentrations were also relatively lower in the ACC of multi-episode subjects. CONCLUSIONS: Disease burden, exemplified by multiple affective episodes is associated with evidence of widespread decrements in affective network activity. Lower ACC NAA concentration is similarly consistent with a model of progressive functional deficits. These findings support the functional significance of previously observed progressive structural changes throughout these regions.


Assuntos
Afeto/fisiologia , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/psicologia , Adulto , Tonsila do Cerebelo/fisiopatologia , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Atenção/fisiologia , Transtorno Bipolar/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Mapeamento Encefálico , Córtex Cerebral/fisiopatologia , Corpo Estriado/fisiopatologia , Emoções/fisiologia , Feminino , Giro do Cíngulo/metabolismo , Giro do Cíngulo/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Testes Neuropsicológicos , Córtex Pré-Frontal/fisiopatologia , Tálamo/fisiopatologia
16.
Front Biosci (Landmark Ed) ; 24: 648-687, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844704

RESUMO

Glutamate carboxypeptidases II and III (GCPII and GCPIII) are highly homologous di-zinc metallopeptidases belonging to the M28 family. These enzymes are expressed in a variety of tissues, including the brain, prostate, kidney, testis and jejunum. GCPII has been recognized as a neuropeptidase in the central nervous system, as a folate hydrolase participating in absorption of folates in the jejunum and, most importantly, as a prostate-specific membrane antigen that is highly expressed in prostate adenocarcinoma. Furthermore, it has been identified in the neovasculature of most human solid tumors. In contrast, GCPIII has not been associated with any specific physiological function or pathology, and its expression, activity and inhibition have not been as well-studied. In this review, we provide an overview of the current understanding of the structure, enzymatic activity, substrate specificity, and tissue distribution of these two homologous enzymes. We discuss their potential physiological functions and describe the available animal models, including genetically modified mice. We also review the potential use of specific monoclonal antibodies and small-molecule inhibitors recognizing GCPII/III for diagnosis, imaging and experimental therapy of human cancers and other pathologies.


Assuntos
Antígenos de Superfície/metabolismo , Biomarcadores Tumorais/metabolismo , Carboxipeptidases/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Neuropeptídeos/química , Peptídeo Hidrolases/metabolismo , Adenocarcinoma/metabolismo , Animais , Anticorpos Monoclonais/química , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Encéfalo/metabolismo , Modelos Animais de Doenças , Glutamatos/química , Humanos , Hidrólise , Doenças Inflamatórias Intestinais/metabolismo , Intestino Delgado/metabolismo , Jejuno/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Fenótipo , Neoplasias da Próstata/metabolismo , Ratos
17.
Oncology ; 96(4): 217-222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30844808

RESUMO

OBJECTIVES: Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor. METHODS: This was an open-label, multicenter phase 2 trial of patients with advanced pancreatic cancer. Part A of the study was an intrapatient dose escalation lead-in portion in patients concurrently receiving gemcitabine, and in part B, patients were randomized 1: 1 to the recommended phase 2 dose combination PCI-27483-gemcitabine versus gemcitabine alone. RESULTS: Target international normalized ratio (between 2.0-3.0) was achieved following PCI-27483 treatment. Overall safety of PCI-27483-gemcitabine (n = 26) was similar to gemcitabine alone (n = 16), with a higher incidence of mostly low-grade bleeding events (65% vs. 19%). Progression-free survival (PFS) and overall survival (OS) were not significantly different between patients treated with PCI-27483-gemcitabine (PFS: 3.7 months, OS: 5.7 months) and those treated with gemcitabine alone (PFS: 1.9 months, OS: 5.6 months). CONCLUSIONS: Targeted inhibition of the coagulation cascade was achieved by administering PCI-27483. PCI-27483-gemcitabine was well tolerated, but superiority to single agent gemcitabine was not demonstrated.


Assuntos
Anticoagulantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácido Aspártico/análogos & derivados , Benzimidazóis/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fator VIIa/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácido Aspártico/administração & dosagem , Ácido Aspártico/efeitos adversos , Ácido Aspártico/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Monitoramento de Medicamentos/métodos , Fator VIIa/metabolismo , Feminino , Hemorragia/induzido quimicamente , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Fatores de Tempo
18.
Biol Psychiatry ; 85(7): 584-595, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711191

RESUMO

BACKGROUND: Our aim was to assess resting cerebral blood flow (rCBF) in children and adults with autism spectrum disorder (ASD). METHODS: We acquired pulsed arterial spin labeling magnetic resonance imaging data in 44 generally high-functioning participants with ASD simplex and 66 typically developing control subjects with comparable mean full-scale IQs. We compared rCBF values voxelwise across diagnostic groups and assessed correlations with symptom scores. We also assessed the moderating influences of participant age, sex, and IQ on our findings and the correlations of rCBF with N-acetylaspartate metabolite levels. RESULTS: We detected significantly higher rCBF values throughout frontal white matter and subcortical gray matter in participants with ASD. rCBF correlated positively with socialization deficits in participants with ASD in regions where hyperperfusion was greatest. rCBF declined with increasing IQ in the typically developing group, a correlation that was absent in participants with ASD, whose rCBF values were elevated across all IQ levels. rCBF in the ASD group correlated inversely with N-acetylaspartate metabolite levels throughout the frontal white matter, with greater rCBF accompanying lower and increasingly abnormal N-acetylaspartate levels relative to those of typically developing control subjects. CONCLUSIONS: These findings taken together suggest the presence of altered metabolism, likely of mitochondrial origin, and dysfunctional maintenance processes that support axonal functioning in ASD. These disturbances in turn likely reduce neural efficiency for cognitive and social functioning and trigger compensatory responses from supporting glial cells, which subsequently increase rCBF to affected white matter. These findings, if confirmed, suggest cellular and molecular targets for novel therapeutics that address axonal pathology and bolster glial compensatory responses in ASD.


Assuntos
Ácido Aspártico/análogos & derivados , Transtorno do Espectro Autista , Circulação Cerebrovascular/fisiologia , Lobo Frontal , Substância Cinzenta , Substância Branca , Adolescente , Adulto , Ácido Aspártico/metabolismo , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/fisiopatologia , Criança , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/metabolismo , Lobo Frontal/fisiopatologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Substância Cinzenta/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Marcadores de Spin , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Substância Branca/fisiopatologia , Adulto Jovem
19.
Eur Neuropsychopharmacol ; 29(3): 365-375, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30600114

RESUMO

Individual differences in anxiety provide a differential predisposition to develop neuropsychiatric disorders. The neurochemical underpinnings of anxiety remain elusive, particularly in deep structures, such as the nucleus accumbens (NAc) whose involvement in anxiety is being increasingly recognized. We examined the associations between the neurochemical profile of human NAc metabolites involved in neural excitation and inhibition and inter-individual variation in temperamental and situational anxiety. Twenty-seven healthy 20-30 years-old human males were phenotyped with questionnaires for state and trait anxiety (State-Trait Anxiety Inventory, STAI), social anxiety (Liebowitz Social Anxiety Scale), negative mood (Beck Depression Inventory, BDI) and fatigue (Mental and Physical State Energy and Fatigue Scales, SEF). Using proton magnetic resonance spectroscopy (1H-MRS) at 7 Tesla (7T), we measured metabolite levels for glutamate, glutamine, GABA and taurine in the NAc. Salivary cortisol was also measured. Strikingly, trait anxiety was negatively associated with NAc taurine content. Perceived situational stress was negatively associated with NAc GABA, while positively with the Glu/GABA ratio. No correlation was observed between NAc taurine or GABA and other phenotypic variables examined (i.e., state anxiety, social anxiety, negative mood, or cortisol), except for a negative correlation between taurine and state physical fatigue. This first 7T study of NAc neurochemistry shows relevant metabolite associations with individual variation in anxiety traits and situational stress and state anxiety measurements. The novel identified association between NAc taurine levels and trait anxiety may pave the way for clinical studies aimed at identifying new treatments for anxiety and related disorders.


Assuntos
Ansiedade/patologia , Ácido Aspártico/análogos & derivados , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Adulto , Ansiedade/diagnóstico por imagem , Ansiedade/metabolismo , Ácido Aspártico/metabolismo , Correlação de Dados , Feminino , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Hidrocortisona/metabolismo , Masculino , Neuroquímica , Personalidade , Escalas de Graduação Psiquiátrica , Psicometria , Saliva/química , Taurina/metabolismo , Trítio/metabolismo , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
20.
JAMA Psychiatry ; 76(3): 314-323, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30624573

RESUMO

Importance: The use of high-field magnetic resonance spectroscopy (MRS) in multiple brain regions of a large population of human participants facilitates in vivo study of localized or diffusely altered brain metabolites in patients with first-episode psychosis (FEP) compared to healthy participants. Objective: To compare metabolite levels in 5 brain regions between patients with FEP (evaluated within 2 years of onset) and healthy controls, and to explore possible associations between targeted metabolite levels and neuropsychological test performance. Design, Setting, and Participants: Cross-sectional design used 7-T MRS at a research MR imaging facility in participants recruited from clinics at the Johns Hopkins Schizophrenia Center and the local population. Eighty-one patients who had received a DSM-IV diagnosis of FEP within the last 2 years and 91 healthy age-matched (but not sex-matched) volunteers participated. Main Outcomes and Measures: Brain metabolite levels including glutamate, glutamine, γ-aminobutyric acid (GABA), N-acetylaspartate, N-acetylaspartyl glutamate, and glutathione, as well as performance on neuropsychological tests. Results: The mean (SD) age of 81 patients with FEP was 22.3 (4.4) years and 57 were male, while the mean (SD) age of 91 healthy participants was 23.3 (3.9) years and 42 were male. Compared with healthy participants, patients with FEP had lower levels of glutamate (F1,162 = 8.63, P = .02), N-acetylaspartate (F1,161 = 5.93, P = .03), GABA (F1,163 = 6.38, P = .03), and glutathione (F1,162 = 4.79, P = .04) in the anterior cingulate (all P values are corrected for multiple comparisons); lower levels of N-acetylaspartate in the orbitofrontal region (F1,136 = 7.23, P = .05) and thalamus (F1,133 = 6.78, P = .03); and lower levels of glutathione in the thalamus (F1,135 = 7.57, P = .03). Among patients with FEP, N-acetylaspartate levels in the centrum semiovale white matter were significantly correlated with performance on neuropsychological tests, including processing speed (r = 0.48; P < .001), visual (r = 0.33; P = .04) and working (r = 0.38; P = .01) memory, and overall cognitive performance (r = 0.38; P = .01). Conclusions and Relevance: Seven-tesla MRS offers insights into biochemical changes associated with FEP and may be a useful tool for probing brain metabolism that ranges from neurotransmission to stress-associated pathways in participants with psychosis.


Assuntos
Encéfalo/metabolismo , Espectroscopia de Prótons por Ressonância Magnética/instrumentação , Transtornos Psicóticos/metabolismo , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Dipeptídeos/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Masculino , Testes Neuropsicológicos , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
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