柴黄益肾颗粒对糖尿病肾病大鼠保护作用的脂质组学研究

目的:研究柴黄益肾颗粒干预对糖尿病肾病(DN)大鼠肾脏脂质代谢异常的调节作用.方法:采用单侧肾切除加i.p.链脲佐菌素诱导的方法复制DN大鼠模型,将38只Wistar大鼠分成4组,包括空白组、模型组、模型+柴黄益肾颗粒组、空白+柴黄益肾颗粒组.模型+柴黄益肾颗粒组ig给予0.56 g·kg-1柴黄益肾颗粒,于造模成功后第20周,采集肾皮质样品进行基于超高压液相-四级杆飞行时间质谱联用仪( UPLC-QTOF MS)的脂质组学研究,考察干预前后脂质代谢物组的变化.结果:造模成功第20周时,大鼠肾皮质中多种甘油磷脂酰胆碱、甘油磷脂酰乙醇胺、甘油磷脂酰甘油醇、甘油磷脂酰肌醇、鞘磷脂酰胆碱等都显著下调,而胆固醇酯和甘油三酯则显著上升.柴黄益肾颗粒干预对部分异常脂质代谢表现出明显的改善作用,包括4种鞘磷脂酰胆碱和2种甘油磷脂酰胆碱,即SM(d18:1/16:1),SM(C33:1),SM( C42:2),SM( C42:3),PC(36:4)和PC(42:10),其相对变化倍数分别为1.38,1.50,1.29,1.23,1.15和1.30.结论:柴黄益肾颗粒干预可以延缓大鼠DN的进展,该机制可能与其对脂质尤其是鞘脂代谢异常的调节有关.     

Developmental changes in rat surfactant lipidomics in the context of species variability

Lung surfactant comprises mainly phosphatidylcholine (PC) species together with phosphatidylglycerols and surfactant proteins (SP) SP-A to -D. Changes in the concentrations of its principal components dipalmitoyl-PC, palmitoylmyristoyl-PC, palmitoylpalmitoleoyl-PC relative to developmental, structural and physiological differences are only partially understood. Particularly, their attribution to differences in air-liquid interface curvature, compared with dynamic parameters, such as respiratory rate, are controversial. We postulated that during alveolarization the changes in these principal PC components of surfactant differ from those in other phospholipid parameters, and that across endothermic vertebrates their concentrations are related to lung physiology rather than structure. We therefore investigated in rats from postnatal day (d)1 to d42 the pattern of surfactant phospholipids relative to alveolarization (d4-d14), and we discuss these changes in terms of molecular adaptation to pulmonary structure or physiology. Contrary to mammals with advanced alveolarization and increased respiratory rate (RR) at term, concentrations of dipalmitoyl-PC (49-52%) and palmitoylmyristoyl-PC (7-9%) in lung lavage fluid were identical at d1 and d42. At d7-d14, when in rats RR is increased, palmitoyl-myristoyl-PC transiently increased by 2.5- to 3.9-fold at the expense of dipalmitoyl-PC (-32% to 34%) and palmitoyl-palmitoleoyl-PC (-16%). Other lipidomic changes followed essentially different patterns of increase or decrease. Palmitoyl-myristoyl-PC was increased in large aggregates suggesting that it is an integral component of active surfactant. In the overall context of vertebrates, irrespective of age and lung structure, fractions of palmitoyl-myristoyl-PC, dipalmitoyl-PC and palmitoyl-palmitoleoyl-PC correlate with differences in RR rather than alveolar curvature. In adult mammals, however, only concentrations of palmitoyl-palmitoleoyl-PC correlate with RR.     

A review of the role of sebum in the mechanism of acne pathogenesis

Acne is one of the most common skin disorders, and its occurrence is closely related to many factors, including sebum secretion, hormone levels, bacterial infection, and inflammatory reactions. Among these, changes in sebum secretion are believed to be one important factor of acne. Increased sebum secretion can induce acne occurrence, and increasing evidence indicates sebum component changes are also strongly related to acne occurrence. Recently, developments in lipidomics have provided effective lipid analysis methods. These can help elucidate the effects of different types of sebum on acne occurrence and provide a theoretical basis for research on the mechanisms of acne pathogenesis and treatment.     

MALDI mass spectrometry reveals that cumulus cells modulate the lipid profile of in vitro-matured bovine oocytes

The influence of cumulus cells (CC) on the lipid profile of bovine oocytes matured in two different lipid sources was investigated. Cumulus-oocyte complexes (COC) or denuded oocytes (DO) were matured in tissue culture medium (TCM) supplemented with fetal bovine serum (FBS) or serum substitute supplement (SSS). Lipid profiles of TCM, serum supplements, immature CC and oocyte (IO), and in vitro-matured oocytes from COC and DO were then analyzed by matrix assisted laser desorption ionization mass spectrometry (MALDI-MS) and submitted to partial least squares-discriminant analysis (PLS-DA). The developmental competence of such oocytes was also assessed. Differences in lipid composition were observed between two types of sera and distinctly influenced the lipid profile of CC. As revealed by PLS-DA, the abundance of specific ions corresponding to triacylglycerols (TAG) or phospholipids (PL) were higher in COC compared to DO both supplemented with FBS or SSS and to some extent affected the subsequent DO in vitro embryo development. DO exposed to SSS had however a marked diminished ability to develop to the blastocyst stage. These results indicate a modulation by CC of the oocyte TAG and PL profiles associated with a specific cell response to the serum supplement used for in vitro maturation.     

A case study of normalization,missing data and variable selection methods in lipidomics

Lipidomics is an emerging field of science that holds the potential to provide a readout of biomarkers for an early detection of a disease. Our objective was to identify an efficient statistical methodology for lipidomics—especially in finding interpretable and predictive biomarkers useful for clinical practice. In two case studies, we address the need for data preprocessing for regression modeling of a binary response. These are based on a normalization step, in order to remove experimental variability, and on a multiple imputation step, to make the full use of the incompletely observed data with potentially informative missingness. Finally, by cross‐validation, we compare stepwise variable selection to penalized regression models on stacked multiple imputed data sets and propose the use of a permutation test as a global test of association. Our results show that, depending on the design of the study, these data preprocessing methods modestly improve the precision of classification, and no clear winner among the variable selection methods is found. Lipidomics profiles are found to be highly important predictors in both of the two case studies. Copyright © 2014 John Wiley & Sons, Ltd.     

Analysis of tissue lipidomics and computed tomography pulmonary fat attenuation volume (CTPFAV) in idiopathic pulmonary fibrosis

Background and Objective

There is increasing interest in the role of lipids in processes that modulate lung fibrosis with evidence of lipid deposition in idiopathic pulmonary fibrosis (IPF) histological specimens. The aim of this study was to identify measurable markers of pulmonary lipid that may have utility as IPF biomarkers.

Study Design and Methods

IPF and control lung biopsy specimens were analysed using a unbiased lipidomic approach. Pulmonary fat attenuation volume (PFAV) was assessed on chest CT images (CT_PFAV) with 3D semi-automated lung density software. Aerated lung was semi-automatically segmented and CT_PFAV calculated using a Hounsfield-unit (−40 to −200HU) threshold range expressed as a percentage of total lung volume. CT_PFAV was compared to pulmonary function, serum lipids and qualitative CT fibrosis scores.

Results

There was a significant increase in total lipid content on histological analysis of IPF lung tissue (23.16 nmol/mg) compared to controls (18.66 mol/mg, p = 0.0317). The median CT_PFAV in IPF was higher than controls (1.34% vs. 0.72%, p < 0.001) and CT_PFAV correlated significantly with DLCO% predicted (R² = 0.356, p < 0.0001) and FVC% predicted (R² = 0.407, p < 0.0001) in patients with IPF. CT_PFAV correlated with CT features of fibrosis; higher CT_PFAV was associated with >10% reticulation (1.6% vs. 0.94%, p = 0.0017) and >10% honeycombing (1.87% vs. 1.12%, p = 0.0003). CT_PFAV showed no correlation with serum lipids.

Conclusion

CT_PFAV is an easily quantifiable non-invasive measure of pulmonary lipids. In this pilot study, CT_PFAV correlates with pulmonary function and radiological features of IPF and could function as a potential biomarker for IPF disease severity assessment.     

Amyloid-β42 signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

Perturbation of lipid second messenger networks is associated with the impairment of synaptic function in Alzheimer disease. Underlying molecular mechanisms are unclear. Here, we used an unbiased lipidomic approach to profile alkylacylglycerophosphocholine second messengers in diseased tissue. We found that specific isoforms defined by a palmitic acid (16:0) at the sn-1 position, namely 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) and 1-O-hexadecyl-sn-glycero-3-phosphocholine (C16:0 lyso-PAF), were elevated in the temporal cortex of Alzheimer disease patients, transgenic mice expressing human familial disease-mutant amyloid precursor protein, and human neurons directly exposed to amyloid-β₄₂ oligomers. Acute intraneuronal accumulation of C16:0 PAF but not C16:0 lyso-PAF initiated cyclin-dependent kinase 5-mediated hyperphosphorylation of tau on Alzheimer disease-specific epitopes. Chronic elevation caused a caspase 2 and 3/7-dependent cascade resulting in neuronal death. Pharmacological inhibition of C16:0 PAF signaling, or molecular strategies increasing hydrolysis of C16:0 PAF to C16:0 lyso-PAF, protected human neurons from amyloid-β₄₂ toxicity. Together, these data provide mechanistic insight into how disruptions in lipid metabolism can determine neuronal response to accumulating oligomeric amyloid-β₄₂.     

Diagnostic significance of plasma lipid markers and machine learning-based algorithm for gastric cancer

Biomarkers may be of value for the early detection of gastric cancer (GC) and the preoperative identification of tumor characteristics to guide treatment strategies. The present study analyzed the expression levels of phospholipids in plasma from patients with GC using liquid chromatography/electrospray ionization-mass spectrometry (LC/ESI-MS) to detect reliable biomarkers for GC. Furthermore, combining the results with a machine learning strategy, the present study attempted to establish a diagnostic system for GC. A total of 20 plasma samples from preoperative patients with GC and 16 plasma samples from tumor-free patients (controls) were selected from our biobank named ‘SHINGEN (Yamanashi Biobank of Gastroenterological Cancers)’, which includes a total of 1,592 plasma samples, and were analyzed by LC/ESI-MS. The obtained data were discriminated using a machine learning-based diagnostic algorithm, whose discriminant ability was confirmed through leave-one-out cross-validation. Using LC/ESI-MS, the levels of 236 lipid molecules were determined. Biomarker analysis revealed that a few lipids that were downregulated in the GC group could discriminate between the GC and control groups. Whole lipid composition analysis using partial least squares regression revealed good discrimination ability between the GC and control groups. Integrative analysis of all molecules using the aforementioned machine learning method exhibited a diagnostic accuracy of 94.4% (specificity, 93.8%; sensitivity, 95.0%). In conclusion, the outcomes of the present study suggested the potential future application of the aforementioned system in clinical settings. By accumulating more reliable data, the present system will be able to detect early-stage cancer and will be capable of predicting the efficacy of each therapeutic strategy.     

Lipidome and proteome map of myelin membranes

To understand the molecular anatomy of myelin membranes, we performed a large‐scale, liquid chromatography‐coupled tandem mass spectrometry (LC‐MS/MS)‐based lipidome and proteome screen on freshly purified human and murine myelin fractions. We identified more than 700 lipid moieties and above 1,000 proteins in the two species, including 284 common lipids and 257 common proteins. This study establishes the first comprehensive map of myelin membrane components in human and mice. Although this study demonstrates many similarities between human and murine myelin, several components have been identified exclusively in each species. Future quantitative validation studies focused on interspecies differences will authenticate the myelin membrane anatomy. The combined lipidome and proteome map presented here can nevertheless be used as a reference library for myelin health and disease. © 2012 Wiley Periodicals, Inc.