Out-of-Field Hippocampus from Partial-Body Irradiated Mice Displays Changes in Multi-Omics Profile and Defects in Neurogenesis

The brain undergoes ionizing radiation exposure in many clinical situations, particularly during radiotherapy for brain tumors. The critical role of the hippocampus in the pathogenesis of radiation-induced neurocognitive dysfunction is well recognized. The goal of this study is to test the potential contribution of non-targeted effects in the detrimental response of the hippocampus to irradiation and to elucidate the mechanisms involved. C57Bl/6 mice were whole body (WBI) or partial body (PBI) irradiated with 0.1 or 2.0 Gy of X-rays or sham irradiated. PBI consisted of the exposure of the lower third of the mouse body, whilst the upper two thirds were shielded. Hippocampi were collected 15 days or 6 months post-irradiation and a multi-omics approach was adopted to assess the molecular changes in non-coding RNAs, proteins and metabolic levels, as well as histological changes in the rate of hippocampal neurogenesis. Notably, at 2.0 Gy the pattern of early molecular and histopathological changes induced in the hippocampus at 15 days following PBI were similar in quality and quantity to the effects induced by WBI, thus providing a proof of principle of the existence of out-of-target radiation response in the hippocampus of conventional mice. We detected major alterations in DAG/IP3 and TGF-β signaling pathways as well as in the expression of proteins involved in the regulation of long-term neuronal synaptic plasticity and synapse organization, coupled with defects in neural stem cells self-renewal in the hippocampal dentate gyrus. However, compared to the persistence of the WBI effects, most of the PBI effects were only transient and tended to decrease at 6 months post-irradiation, indicating important mechanistic difference. On the contrary, at low dose we identified a progressive accumulation of molecular defects that tended to manifest at later post-irradiation times. These data, indicating that both targeted and non-targeted radiation effects might contribute to the pathogenesis of hippocampal radiation-damage, have general implications for human health.     

Visceral Adipose Tissue Displays Unique Metabolomic Fingerprints in Obesity,Pre-Diabetes and Type 2 Diabetes

Visceral adipose tissue (VAT) metabolic profiling harbors the potential to disentangle molecular changes underlying obesity-related dysglycemia. In this study, the VAT exometabolome of subjects with obesity and different glycemic statuses are analyzed. The subjects (n = 19) are divided into groups according to body mass index and glycemic status: subjects with obesity and euglycemia (Ob+NGT, n = 5), subjects with obesity and pre-diabetes (Ob+Pre-T2D, n = 5), subjects with obesity and type 2 diabetes under metformin treatment (Ob+T2D, n = 5) and subjects without obesity and with euglycemia (Non-Ob, n = 4), used as controls. VATs are incubated in culture media and extracellular metabolite content is determined by proton nuclear magnetic resonance (¹H-NMR). Glucose consumption is not different between the groups. Pyruvate and pyroglutamate consumption are significantly lower in all groups of subjects with obesity compared to Non-Ob, and significantly lower in Ob+Pre-T2D as compared to Ob+NGT. In contrast, isoleucine consumption is significantly higher in all groups of subjects with obesity, particularly in Ob+Pre-T2D, compared to Non-Ob. Acetate production is also significantly lower in Ob+Pre-T2D compared to Non-Ob. In sum, the VAT metabolic fingerprint is associated with pre-diabetes and characterized by higher isoleucine consumption, accompanied by lower acetate production and pyruvate and pyroglutamate consumption. We propose that glucose metabolism follows different fates within the VAT, depending on the individuals’ health status.     

Molecular and Physiological Responses of Citrus sinensis Leaves to Long-Term Low pH Revealed by RNA-Seq Integrated with Targeted Metabolomics

Low pH-induced alterations in gene expression profiles and organic acids (OA) and free amino acid (FAA) abundances were investigated in sweet orange [Citrus sinensis (L.) Osbeck cv. Xuegan] leaves. We identified 503 downregulated and 349 upregulated genes in low pH-treated leaves. Further analysis indicated that low pH impaired light reaction and carbon fixation in photosynthetic organisms, thereby lowering photosynthesis in leaves. Low pH reduced carbon and carbohydrate metabolisms, OA biosynthesis and ATP production in leaves. Low pH downregulated the biosynthesis of nitrogen compounds, proteins, and FAAs in leaves, which might be conducive to maintaining energy homeostasis during ATP deprivation. Low pH-treated leaves displayed some adaptive responses to phosphate starvation, including phosphate recycling, lipid remodeling, and phosphate transport, thus enhancing leaf acid-tolerance. Low pH upregulated the expression of some reactive oxygen species (ROS) and aldehyde detoxifying enzyme (peroxidase and superoxidase) genes and the concentrations of some antioxidants (L-tryptophan, L-proline, nicotinic acid, pantothenic acid, and pyroglutamic acid), but it impaired the pentose phosphate pathway and V_E and secondary metabolite biosynthesis and downregulated the expression of some ROS and aldehyde detoxifying enzyme (ascorbate peroxidase, aldo-keto reductase, and 2-alkenal reductase) genes and the concentrations of some antioxidants (pyridoxine and γ-aminobutyric acid), thus disturbing the balance between production and detoxification of ROS and aldehydes and causing oxidative damage to leaves.     

An Overview of the Latest Metabolomics Studies on Atopic Eczema with New Directions for Study

Atopic eczema (AE) is an inflammatory skin disorder affecting approximately 20% of children worldwide and early onset can lead to asthma and allergies. Currently, the mechanisms of the disease are not fully understood. Metabolomics, the analysis of small molecules in the skin produced by the host and microbes, opens a window to observe the mechanisms of the disease which then may lead to new drug targets for AE treatment. Here, we review the latest advances in AE metabolomics, highlighting both the lipid and non-lipid molecules, along with reviewing the metabolites currently known to reside in the skin.     

Dried Blood Spots as Matrix for Evaluation of Valproate Levels and the Immediate and Delayed Metabolomic Changes Induced by Single Valproate Dose Treatment

The immediate and delayed metabolic changes in rats treated with valproate (VPA), a drug used for the treatment of epilepsy, were profiled. An established approach using dried blood spots (DBS) as sample matrices for gas chromatography/mass spectrometry-based metabolomics profiling was modified using double solvents in the extraction of analytes. With the modified method, some of the previously undetectable metabolites were recovered and subtle differences in the metabolic changes upon exposure to a single dose of VPA between males and female rats were identified. In male rats, changes in 2-hydroxybutyric acid, pipecolic acid, tetratriacontane and stearic acid were found between the control and treatment groups at various time points from 2.5 h up to 24 h. In contrast, such differences were not observed in female rats, which could be caused by the vast inter-individual variations in metabolite levels within the female group. Based on the measured DBS drug concentrations, clearance and apparent volume of distribution of VPA were estimated and the values were found to be comparable to those estimated previously from full blood drug concentrations. The current study indicated that DBS is a powerful tool to monitor drug levels and metabolic changes in response to drug treatment.     

Experimental Evidence for Seed Metabolic Allometry in Barrel Medic (Medicago truncatula Gaertn.)

Seed size is often considered to be an important trait for seed quality, i.e., vigour and germination performance. It is believed that seed size reflects the quantity of reserve material and thus the C and N sources available for post-germinative processes. However, mechanisms linking seed size and quality are poorly documented. In particular, specific metabolic changes when seed size varies are not well-known. To gain insight into this aspect, we examined seed size and composition across different accessions of barrel medic (Medicago truncatula Gaertn.) from the genetic core collection. We conducted multi-elemental analyses and isotope measurements, as well as exact mass GC–MS metabolomics. There was a systematic increase in N content (+0.17% N mg⁻¹) and a decrease in H content (–0.14% H mg⁻¹) with seed size, reflecting lower lipid and higher S-poor protein quantity. There was also a decrease in ²H natural abundance (δ²H), due to the lower prevalence of ²H-enriched lipid hydrogen atoms that underwent isotopic exchange with water during seed development. Metabolomics showed that seed size correlates with free amino acid and hexoses content, and anticorrelates with amino acid degradation products, disaccharides, malic acid and free fatty acids. All accessions followed the same trend, with insignificant differences in metabolic properties between them. Our results show that there is no general, proportional increase in metabolite pools with seed size. Seed size appears to be determined by metabolic balance (between sugar and amino acid degradation vs. utilisation for storage), which is in turn likely determined by phloem source metabolite delivery during seed development.     

三维非负矩阵因子分解代谢组学数据解析

多维数据解析方法越来越引起人们的重视,非负矩阵因子分解算法已较广泛地用于图像分析。基于PARAFAC模型,将非负矩阵因子分解算法拓展为三维非负矩阵因子分解算法(three dimension non-negative matrix factorization,NMF3)。其原理简明,算法易于执行。与基于向量计算的其他三维化学计量学算法不同,NMF3基于矩阵计算单个元素,所以不必将三维数据平铺处理,就可直接解析,为三维数据解析研究提供了一种全新的思路和方法。应用NMF3解析模拟三维数据和代谢组学数据,结果令人满意。     

基于PCA的代谢组学数据滤噪方法

代谢组学数据不可避免地受到各种刺激因素的作用,如何降低干扰因素的影响是代谢组学数据预处理的一个重要任务。详细分析了代谢组学数据方差的构成及其在特征空间中的分布特点,并在此基础上提出一种滤除未知干扰因素的新方法,提高感兴趣因素的显著性。文中采用真实的代谢组学数据验证新滤波算法的有效性,并与正交信号校正（orthogona...     

Metabolic Pathways for Observed Impacts of Crop Load on Floral Induction in Apple

The triggers of biennial bearing are thought to coincide with embryonic development in apple and occurs within the first 70 days after full bloom (DAFB). Strong evidence suggests hormonal signals are perceived by vegetative apple spur buds to induce flowering. The hormonal response is typically referred to as the floral induction (FI) phase in bud meristem development. To determine the metabolic pathways activated in FI, young trees of the biennial bearing cultivar ‘Nicoter’ and the less susceptible cultivar ‘Rosy Glow’ were forced into an alternate cropping cycle over five years and an inverse relationship of crop load and return bloom was established. Buds were collected over a four-week duration within 70 DAFB from trees that had maintained a four-year biennial bearing cycle. Metabolomics profiling was undertaken to determine the differentially expressed pathways and key signalling molecules associated with biennial bearing. Marked metabolic differences were observed in trees with high and low crop load treatments. Significant effects were detected in members of the phenylpropanoid pathway comprising hydroxycinnamates, salicylates, salicylic acid biosynthetic pathway intermediates and flavanols. This study identifies plant hormones associated with FI in apples using functional metabolomics analysis.