A biomarker for severity of Alzheimer’s disease: 1H-NMR resonances in cerebrospinal fluid correlate with performance in mini-mental-state-exam

Context: There is no valid biomarker for severity of Alzheimer’s disease (AD) available until now.

Objective: Therefore, we investigated ¹H-NMR spectroscopy for specific resonances as biomarkers for severity of AD.

Materials and methods: Cerebrospinal fluid (CSF) of patients with diagnosed AD and healthy control subjects was analysed by one-dimensional water-suppressed ¹H-NMR spectroscopy. The resonances were correlated with the cognitive performance of the patients and controls.

Results: Specific ¹H-NMR resonances showed higher intensities in AD patients than in control subjects. Mini-mental-state-exam scores correlated with ¹H-NMR resonances in AD patients.

Discussion and conclusion: ¹H-NMR resonances of CSF are obviously valid biomarker for severity of AD, despite the lack of knowledge of the underlying molecular structure. Successful isolation and identification of these substances will most likely provide details to the pathophysiology of AD.     

系统生物学在认知功能障碍研究中的应用

认知功能障碍可导致患者日常生活能力、社会适应能力明显下降,严重影响患者的生活质量。根据近年来众多研究显示,认知功能障碍的发生发展与基因、蛋白质、微生物等内环境因素的失调和紊乱有关。基于系统生物学的研究,梳理了近年来国内外研究学者在代谢组学、蛋白质组学、基因组学和肠道微生物组学层面对认知功能障碍的研究,并对系统生物学在认知功能障碍中的应用前景进行了展望,以期为认知功能障碍相关研究提供参考。     

Development of a multivariate statistical model to predict peroxisome proliferation in the rat,based on urinary 1H-NMR spectral patterns

A previous report of this work (Ringeissen et al. 2003) described the use of nuclear magnetic resonance (NMR) spectroscopy coupled with multivariate statistical data analysis (MVDA) to identify novel biomarkers of peroxisome proliferation (PP) in Wistar Han rats. Two potential biomarkers of peroxisome proliferation in the rat were described, N-methylnicotinamide (NMN) and N-methyl-4-pyridone-3-carboxamide (4PY). The inference from these results was that the tryptophan-nicotinamide adenine dinucleotide (NAD⁺) pathway was altered in correlation with peroxisome proliferation, a hypothesis subsequently confirmed by TaqMan® analysis of the relevant genes encoding two key enzymes in the pathway, aminocarboxymuconate-semialdehyde decarboxylase (EC 4.1.1.45) and quinolinate phosphoribosyltransferase (EC 2.4.2.19). The objective of the present study was to investigate these data further and identify other metabolites in the NMR spectrum correlating equally with PP. MVDA Partial Least Squares (PLS) models were constructed that provided a better prediction of PP in Wistar Han rats than levels of 4PY and NMN alone. The resulting Wistar Han rat predictive models were then used to predict PP in a test group of Sprague Dawley rats following administration of fenofibrate. The models predicted the presence or absence of PP (above on arbitrary threshold of >2-fold mean control) in all Sprague Dawley rats in the test group.     

小鼠负重游泳后血清代谢模式变化分析

目的：研究小鼠负重游泳导致疲劳过程中血清代谢模式改变,为营养抗疲劳研究提供依据。方法：雄性昆明小鼠,随机分为4组,以AIN-93饲料喂养14 d,分别接受0（正常对照）、30、601、20 min等不同时间的尾部负重游泳,游泳后处死小鼠,分离血清进行代谢组分析。采用驰豫编辑脉冲序列（CPMG）和扩散编辑脉冲序列（LED）采集血清样本的数据,经傅立叶变换得到1H NMR谱图,SIMCA-P＋软件进行主成分分析。结果：游泳后小鼠血清代谢组发生显著改变,较正常对照组升高的化合物有β-羟基丁酸、乙酸、乳酸、脂类物质等,降低的化合物有葡萄糖、胆碱、磷酸胆碱、丙氨酸、磷脂酰胆碱等,随游泳时间延长变化趋势相应逐渐增大。结论：小鼠游泳后血清代谢模式产生一些规律性变化,其中脂肪代谢相关物质变化较为显著,针对胆碱类物质在脂肪代谢中的作用开展研究对于揭示疲劳过程本质及其机制具有一定意义。     

A strategy for modelling dynamic responses in metabolic samples characterized by GC/MS

A multivariate strategy for studying the metabolic response over time in urinary GC/MS data is presented and exemplified by a study of drug-induced liver toxicity in the rat. The strategy includes the generation of representative data through hierarchical multivariate curve resolution (H-MCR), highlighting the importance of obtaining resolved metabolite profiles for quantification and identification of exogenous (drug related) and endogenous compounds (potential biomarkers) and for allowing reliable comparisons of multiple samples through multivariate projections. Batch modelling was used to monitor and characterize the normal (control) metabolic variation over time as well as to map the dynamic response of the drug treated animals in relation to the control. In this way treatment related metabolic responses over time could be detected and classified as being drug related or being potential biomarkers. In summary the proposed strategy uses the relatively high sensitivity and reproducibility of GC/MS in combination with efficient multivariate curve resolution and data analysis to discover individual markers of drug metabolism and drug toxicity. The presented results imply that the strategy can be of great value in drug toxicity studies for classifying metabolic markers in relation to their dynamic responses as well as for biomarker identification.     

Plasma phospholipid metabolic profiling and biomarkers of mouse IgA nephropathy

IgA nephropathy is the most common form of glomerulonephritis (GN) and it could progress to end-stage renal failure within 10 years. Participating in biological processes in various pathways, phospholipids as a class of important constituents in the biomembranes have been paid increasing attention in many fields. However, phospholipids metabolism in glomerular disease was not clear, especially in IgA nephropathy. In this paper, the plasma phospholipid metabolic profile in mouse IgA nephropathy was investigated to discover the potential biomarkers on the progression of this disease by using high performance liquid chromatography/mass spectrometry (HPLC/MS) and the principal components analysis (PCA) as well as partial least squares-discriminant analysis (PLS-DA). The experimental mouse models of IgA nephropathy were established by oral immune and BSA injection. It was found that expression of intercellular adhesion molecule-1 (ICAM-1) in the glomeruli had a significant correlation with proteinuria in mouse IgA nephropathy. The association between plasma phospholipids and expression of ICAM-1 in the glomeruli of IgA nephropathy suggested C18:0/C18:0 PS (phosphatidylserine), C18:0/C22:5 PS (phosphatidylserine) and C18:0/C20:4 PI (phosphatidylinositol) were possible biomarkers of IgA nephropathy. The results show that the plasma phospholipid metabolic profiles from HPLC/MS combining with PCA and PLS-DA can be used not only to differentiate the IgA nephropathy from the controls, but also to discover and identify the potential biomarkers.     

Combination of 'omics' data to investigate the mechanism(s) of hydrazine-induced hepatotoxicity in Rats and to identify potential biomarkers

To gain novel insight into the molecular mechanisms underlying hydrazine-induced hepatotoxicity, mRNAs, proteins and endogenous metabolites were identified that were altered in rats treated with hydrazine compared with untreated controls. These changes were resolved in a combined genomics, proteomics and metabonomics study. Sprague-Dawley rats were assigned to three treatment groups with 10 animals per group and given a single oral dose of vehicle, 30 or 90 mg kg^-1 hydrazine, respectively. RNA was extracted from rat liver 48 h post-dosing and transcribed into cDNA. The abundance of mRNA was investigated on cDNA microarrays containing 699 rat-specific genes involved in toxic responses. In addition, proteins from rat liver samples (48 and 120/168 h post-dosing) were resolved by two-dimensional differential gel electrophoresis and proteins with changed expression levels after hydrazine treatment were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry peptide mass fingerprinting. To elucidate how regulation was reflected in biochemical pathways, endogenous metabolites were measured in serum samples collected 48 h post-dosing by 600-MHz ¹H-NMR. In summary, a single dose of hydrazine caused gene, protein and metabolite changes, which can be related to glucose metabolism, lipid metabolism and oxidative stress. These findings support known effects of hydrazine toxicity and provide potential new biomarkers of hydrazine-induced toxicity.     

Dynamic metabolic responses of brown planthoppers towards susceptible and resistant rice plants

Brown planthopper (Nilaparvata lugens Stål, BPH) causes huge economic losses in rice‐growing regions, and new strategies for combating BPH are required. To understand how BPHs respond towards BPH‐resistant plants, we systematically analysed the metabolic differences between BPHs feeding on the resistant and susceptible plants using NMR and GC‐FID/MS. We also measured the expression of some related genes involving glycolysis and biosyntheses of trehalose, amino acids, chitin and fatty acids using real‐time PCR. BPH metabonome was dominated by more than 60 metabolites including fatty acids, amino acids, carbohydrates, nucleosides/nucleotides and TCA cycle intermediates. After initial 12 h, BPHs feeding on the resistant plants had lower levels of amino acids, glucose, fatty acids and TCA cycle intermediates than on the susceptible ones. The levels of these metabolites recovered after 24 h feeding. This accompanied with increased level in trehalose, choline metabolites and nucleosides/nucleotides compared with BPH feeding on the susceptible plants. Decreased levels of BPH metabolites at the early feeding probably resulted from less BPH uptakes of sap from resistant plants and recovery of BPH metabolites at the later stage probably resulted from their adaptation to the adverse environment with their increased hopping frequency to ingest more sap together with contributions from yeast‐like symbionts in BPHs. Throughout 96 h, BPH feeding on the resistant plants showed significant up‐regulation of chitin synthase catalysing biosynthesis of chitin for insect exoskeleton, peritrophic membrane lining gut and tracheae. These findings provided useful metabolic information for understanding the BPH–rice interactions and perhaps for developing new BPH‐combating strategies.     

代谢组学及其在环境毒理学中的应用

代谢组学作为系统生物学的一部分,因其具有分析速度快的特点,被广泛用于生物医学等方面的研究。目前代谢组学在环境毒理学方面的研究主要针对单一污染物,但也需要考虑到被污染地的复杂情况。通过介绍代谢组学及其发展历程,总结了目前主流代谢组学技术的各自特点,讨论了代谢组学在环境重金属、有机污染物和抗生素中的毒性评估以及环境胁迫耐受性中的评价等方面内容,综述了其在环境毒理学中的应用,并指出其应用不足,旨在为代谢组学应用于环境毒理学的研究提供参考。