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.     

复杂排沙廊道泄流能力分析研究

排沙廊道是水电站设计中常见的一种建筑物,在工程设计中对于一些形态弯曲、结构及流态复杂的排沙廊道,目前能有效测算其泄流能力的计算公式并不多见。以南盘江大桥水电站为例,基于水电站首部枢纽水力学模型试验资料成果,以能量方程为基础,从单位流量所产生的阻力损失进行分析,建立了本工程复杂廊道泄流能力计算公式,计算成果同模型试验成果相吻合,可供类似工程设计参考,也为类似复杂建筑物泄流能力分析提供了研究思路。     

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。     

Quantitative Metabolomic Analysis of Changes in the Rat Blood Serum during Autophagy Modulation: A Focus on Accelerated Senescence

Autophagy is involved in the maintenance of cellular homeostasis and the removal of damaged proteins and organelles and is necessary to maintain cell metabolism in conditions of energy and nutrient deficiency. A decrease in autophagic activity plays an important role in age-related diseases. However, the metabolic response to autophagy modulation remains poorly understood. Here, we for the first time explored the effects of (1) autophagy activation by 48 h fasting, (2) inhibition by chloroquine (CQ) treatment, and (3) combined effects of fasting and CQ on the quantitative composition of metabolites in the blood serum of senescent-accelerated OXYS and control Wistar rats at the age of 4 months. By means of high-resolution ¹H NMR spectroscopy, we identified the quantitative content of 55 serum metabolites, including amino acids, organic acids, antioxidants, osmolytes, glycosides, purine, and pyrimidine derivatives. Groups of 48 h fasting (induction of autophagy), CQ treatment (inhibition of autophagy), and combined effects (CQ + fasting) are clearly separated from control groups by principal component analysis. Fasting for 48 h led to significant changes in the serum metabolomic profile, primarily affecting metabolic pathways related to fatty acid metabolism, and led to metabolism of several amino acids. Under CQ treatment, the most affected metabolites were citrate, betaine, cytidine, proline, tryptophan, glutamate, and mannose. As shown by two-way ANOVA, for many metabolites the effects of autophagy modulation depend on the animal genotype, indicating a dysregulation of metabolome reactivity in OXYS rats. Thus, the metabolic responses to modulation of autophagy in OXYS rats and Wistar rats are different. Altered metabolites in OXYS rats may serve as potential biomarkers of the manifestation of the signs of accelerated aging. Metabolic signatures characteristic to fasting and CQ treatment revealed in this work might provide a better understanding of the connections between metabolism and autophagy.     

Effect of Humic Acid on Soil Physical and Chemical Properties,Microbial Community Structure,and Metabolites of Decline Diseased Bayberry

In recent years, bayberry decline disease has caused significant damage to the bayberry industry. In order to evaluate whether humic acid can be used to effectively control the disease, this research examined the nutritional growth and fruit quality of bayberry, soil physical and chemical properties, soil microbial community structure, and metabolites. Results indicated that the application of humic acid not only improved the vigor and fruit quality of diseased trees, but also increased the diversity of microbial communities in the rhizosphere soil. A great increase was observed in the relative abundance of bacterial genus Mycobacterium and Crossiella; fungal genus Fusarium and Coniosporium. In contrast, a significant decrease was observed in the relative abundance of bacterial genus Acidothermus, Bryobacter, Acidibacter, fungal genus of Geminibasidium and Mycena. Analysis of redundancies (RDA) for microbial communities and soil characteristics showed that the main four variables, including available nitrogen, phosphorus, potassium, and calcium, had a great effect on the composition of bacterial and fungal communities in bayberry rhizosphere soil at the genus level. The main four variables had a greater effect on bacterial communities than on fungal communities. In addition, ABC transporter, arginine and proline metabolism, galactose metabolism, and glutathione metabolism were significantly affected by humic acid, which changed the content of 81 metabolites including 58 significantly down-regulated metabolites such as isohexonic acid and carinitine, and 23 significantly up-regulated metabolites such as acidic acid, guaninosuccinate, lyxose, 2-monoolein, epicatechin, and pentonolactone. These metabolites also significantly correlated with rhizosphere soil microbiota at the phylum, order, and genus levels. In conclusion, the results demonstrated the role of humic acid on plant growth and fruit quality, as well as rhizosphere soil characteristics, microbiota, and secondary metabolites, which provides novel insights into the control of bayberry decline disease.     

Dose-Dependent Cytotoxicity of Polypropylene Microplastics (PP-MPs) in Two Freshwater Fishes

The massive accumulation of plastics over the decades in the aquatic environment has led to the dispersion of plastic components in aquatic ecosystems, invading the food webs. Plastics fragmented into microplastics can be bioaccumulated by fishes via different exposure routes, causing several adverse effects. In the present study, the dose-dependent cytotoxicity of 8–10 μm polypropylene microplastics (PP-MPs), at concentrations of 1 mg/g (low dose) and 10 mg/g dry food (high dose), was evaluated in the liver and gill tissues of two fish species, the zebrafish (Danio rerio) and the freshwater perch (Perca fluviatilis). According to our results, the inclusion of PP-MPs in the feed of D. rerio and P. fluviatilis hampered the cellular function of the gills and hepatic cells by lipid peroxidation, DNA damage, protein ubiquitination, apoptosis, autophagy, and changes in metabolite concentration, providing evidence that the toxicity of PP-MPs is dose dependent. With regard to the individual assays tested in the present study, the biggest impact was observed in DNA damage, which exhibited a maximum increase of 18.34-fold in the liver of D. rerio. The sensitivity of the two fish species studied differed, while no clear tissue specificity in both fish species was observed. The metabolome of both tissues was altered in both treatments, while tryptophan and nicotinic acid exhibited the greatest decrease among all metabolites in all treatments in comparison to the control. The battery of biomarkers used in the present study as well as metabolomic changes could be suggested as early-warning signals for the assessment of the aquatic environment quality against MPs. In addition, our results contribute to the elucidation of the mechanism induced by nanomaterials on tissues of aquatic organisms, since comprehending the magnitude of their impact on aquatic ecosystems is of great importance.     

Comparison of the Chemical Components,Efficacy and Mechanisms of Action of Chrysanthemum morifolium Flower and Its Wild Relative Chrysanthemum indicum Flower against Liver-Fire Hyperactivity Syndrome of Hypertension via Integrative Analyses

To clarify the differences in the clinical application scope of Chrysanthemum morifolium flower (CMF) and Chrysanthemum indicum flower (CIF), two herbs of similar origin, an integrated strategy of network pharmacology, molecular pharmacology, and metabolomics was employed, with a view to investigating the commonalities and dissimilarities in chemical components, efficacy and mechanisms of action. Initial HPLC-Q-TOF-MS analysis revealed that CMF and CIF had different flavonoid constituents. The biological processes underlying the therapeutic effects of CMF and CIF on liver-fire hyperactivity syndrome of hypertension (LFHSH) were predicted to be related to inflammatory response, fatty acid production, and other pathways based on network pharmacology analysis. ELISA, molecular docking, Western blot, and metabolomics techniques showed similar effects of CMF and CIF in lowering blood pressure, resistance to tissue, organ and functional damage, and dyslipidemia. However, distinct effects were found in the regulation of inflammatory response, PI3K-Akt and NF-κB signaling pathways, lipid anabolism, renin-angiotensin system, and metabolic abnormalities. The comparable efficacies of CMF and CIF, despite having distinct mechanisms of action, may be attributed to the integration and counteraction of their different regulating capabilities on the above anti-LFHSH mechanisms. This study offers a vital platform for assessment of differential and precise applications of herbs of close origin with similar but slightly different medicinal properties, and provides a research strategy for bridging Chinese medicine and modern precision medicine.     

Quantitative NMR-Based Lipoprotein Analysis Identifies Elevated HDL-4 and Triglycerides in the Serum of Alzheimer’s Disease Patients

Alzheimer’s disease (AD) is the most common form of dementia in the elderly and has been associated with changes in lipoprotein metabolism. We performed quantitative lipoprotein analysis in a local cohort of cognitively impaired elderly and control subjects using standardized nuclear magnetic resonance (NMR) spectroscopy. A commercially available quantitative NMR-based assay covering 112 lipoprotein main and subtype variables was used to investigate blood serum samples from a moderate cohort size of 161 persons (71 female, 90 male), including measures of quality control. Additionally, clinical metadata and cerebrospinal fluid AD biomarkers were collected and used for analysis. High-density lipoprotein (HDL) HDL-4 subfraction levels were mostly high in female individuals with mild cognitive impairment (MCI), followed by AD. Low-density lipoprotein (LDL) LDL-2 cholesterol was slightly elevated in male AD patients. HDL-2 apolipoprotein Apo-A1, HDL-2 phospholipids, and HDL-3 triglycerides were highly abundant in AD and MCI women compared to men. When considering clinical biomarkers (Aβ, tau), very low-density lipoprotein (VLDL) VLDL-1 and intermediate-density lipoprotein (IDL) triglycerides were substantially higher in AD compared to MCI. In addition, triglyceride levels correlated positively with dementia. Different lipoprotein serum patterns were identified for AD, MCI, and control subjects. Interestingly, HDL-4 and LDL-2 cholesterol parameters revealed strong gender-specific changes in the context of AD-driven dementia. As gender-based comparisons were based on smaller sub-groups with a low n-number, several statistical findings did not meet the significance threshold for multiple comparisons testing. Still, our finding suggests that serum HDL-4 parameters and various triglycerides correlate positively with AD pathology which could be a read-out of extended lipids traveling through the blood-brain barrier, supporting amyloid plaque formation processes. Thereof, we see herein a proof of concept that this quantitative NMR-based lipoprotein assay can generate important and highly interesting data for refined AD diagnosis and patient stratification, especially when larger cohorts are available.