Molecular omics最新文献

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific hepatobiliary disease, leading to an abnormal increase in total bile acid in the blood of pregnant women. To systematically explore the similarities and differences in metabolites and metabolic pathways among three types of biological samples from ICP women, a study of 18 ICP and 6 healthy (as a normal control) pregnant women was performed to investigate their clinical information and biochemical features. Based on validated LC–MS/MS methods 1–5 for hydrophilic and hydrophobic metabolites (molecular weight <2000 Dalton), an untargeted-metabolomic strategy was applied to 24 pregnant women to determine the metabolites from 22 serum, 15 placental and 22 urine samples. Then 1137 metabolites from serum, 876 metabolites from placental tissue and 311 metabolites from urine with a coefficient of variation <30% in the pooled quality control samples were found. Furthermore, orthogonal partial least squares–discriminate analysis (OPLS–DA), correlation analysis, chemical enrichment analysis and metabolic pathway analysis were carried out by a bioinformatics process. On the OPLS–DA model analysis, the metabolites in urine were better than those in serum or placental tissue to reflect the metabolic changes of ICP disease. Some metabolites were significantly changed in serum (n = 71), placental tissue (n = 46) and urine (n = 36), such as bile acids, triacylglycerols, lysoPCs, and steroids. Primary bile acid biosynthesis was the main metabolic pathway in ICP disease, and taurine and hypotaurine metabolism and sphingolipid metabolism were also found. More specifically, bile acids increased and steroids decreased in the serum, placental and urine samples. For complex metabolic diseases such as ICP disease, untargeted-metabolomic analysis of multiple biological samples could provide a systematic understanding of the changes in metabolic types and pathways.

Despite some advances in the study of radiation injuries, effective methods of prevention and treatment of severe acute radiation syndrome or illness (ARS) are still lacking. Therefore, an in-depth understanding of the biological characteristics associated with high dose radiation is essential to reveal the mechanisms underlying the varied biological processes following high dose radiation and the development of novel potent radioprotective agents. In the present study, plasma metabolic characteristics were investigated using hematopoietic stem cell transplantation patients (n = 36) undergoing total body ionizing irradiation (TBI) utilizing gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). Plasma was collected pre-irradiation, 3 days after completion of fractionated radiation therapy with a total dose of 12 Gy delivered at a dose rate of 8 cGy min⁻¹. These metabolic disorders involve the dysregulation of the gut microflora, a shift in energy supply from aerobic respiration toward ketogenesis, protein synthesis and metabolism in response to TBI. Furthermore, the panel of four metabolic markers with most potential consisting of PC (O-38:5), urate, ornithine, and GCDCS for radiation injury was chosen by combining multiple methods of data processing that included univariate analysis, partial least squares discriminant analysis (PLS-DA), and multivariable stepwise linear regression analysis. While similar patterns of metabolic alterations were observed in patients of different genders, disease types and ages, specific changes were also found in specific patients following high doses of exposure. These findings provide valuable information for selecting metabolic biomarker panels for radiation injury, clues for radiation pathology and therapeutic interventions involved in high-dose radiation exposure.

Colorectal cancer (CRC) is one of the most common types of cancer, with many studies associating its development with changes in the gut microbiota. Recent developments in sequencing technologies and subsequent meta-analyses of gut metagenome provided a better understanding of species related to CRC tumorigenesis. Still, the importance of high-importance taxonomic singletons (i.e. species highly associated with a given condition but observed only in the minority of datasets) and the species interactions and co-occurrence across cohorts need further exploration. It has been shown that the gut metagenome presents a high functional redundancy, meaning that species interactions could mitigate the absence of any given species. In a CRC framework, this implies that species co-occurrence could play a role in tumorigenesis, even if CRC-associated species show low abundance. We propose to evaluate the prevalence of microbial species in tumor by initially analyzing each dataset individually and subsequently intersecting the results for differentially abundant species between CRC and healthy samples. We then identify metabolic pathways from these species based on KEGG orthologs, highlighting metabolic pathways associated with CRC. Our results indicate seven species with high prevalence across all projects and with high association to CRC, including the genus Bacteroides, Enterocloster and Prevotella. Finally, we show that CRC is also characterized by the co-occurrence of species that do not present significant differential abundance, but have been described in the literature as potential CRC biomarkers. These results indicate that between-species interactions could also play a role in CRC tumorigenesis.

Roxadustat (FG-4592) is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) prescribed to patients with low hemoglobin associated with chronic kidney disease. Due to the various HIF-mediated adaptive responses, FG-4592 has attracted significant interest for therapeutic use against various diseases. However, the clinical application of Roxadustat remains limited due to a lack of understanding of its underlying mechanisms. Herein, we performed label-free quantitative liquid chromatography with tandem mass spectrometry (LC-MS–MS) proteomics and un-targeted metabolomics to study the protein and metabolite alterations in the urine of renal anemia patients before and after Roxadustat therapy. The results were validated by parallel reaction monitoring (PRM). A total of 46 proteins (including 15 upregulated and 31 downregulated proteins) and 207 metabolites were significantly altered after Roxadustat treatment in urine samples obtained from renal anemia patients. Then, the altered proteins were further validated by PRM. Finally, proteomics combined with metabolomics analysis revealed that the Ras signalling pathway, cysteine and methionine metabolism, arginine and proline metabolism, and cholesterol metabolism were the main pathways altered by Roxadustat treatment. The multi-omics analysis revealed that Roxadustat could alter the protein expression and reverse the potential metabolic changes to exert hypotensive, lipid metabolic regulation, and renoprotective effects in clinical practice.

The lipid environment changes throughout pregnancy both physiologically with emergent insulin resistance and pathologically e.g., gestational diabetes mellitus (GDM). Novel mass spectrometry (MS) techniques applied to minimally processed blood might lend themselves to monitoring changing lipid profiles to inform care decisions across pregnancy. In this study we use an intact-sandwich, MALDI-ToF MS method to identify phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) species and calculate their ratio as an indicator of inflammation. Plasma and sera were prepared from venous blood of non-pregnant women (aged 18–40) and pregnant women at 16 weeks, 28 weeks (including GDM-positive women), and 37+ weeks (term) of gestation alongside umbilical cord blood (UCB). Women with a normal menstrual cycle and age-matched men provided finger-prick derived capillary sera at 6 time-points over a month. Serum rather than plasma was preferable for PC/LPC measurement. As pregnancy progresses, an anti-inflammatory phenotype dominates the maternal circulation, evidenced by increasing PC/LPC ratio. In contrast, the PC/LPC ratio of UCB was aligned to that of non-pregnant donors. BMI had no significant effect on the PC/LPC ratio, but GDM-complicated pregnancies had significantly lower PC/LPC at 16 weeks of gestation. To further translate the use of the PC/LPC ratio clinically, the utility of finger-prick blood was evaluated; no significant difference between capillary versus venous serum was found and we revealed the PC/LPC ratio oscillates with the menstrual cycle. Overall, we show that the PC/LPC ratio can be measured simply in human serum and has the potential to be used as a time-efficient and less invasive biomarker of (mal)adaptative inflammation.

Chronic stress, a leading factor for high blood pressure (BP) and even hypertension, affects health quality seriously. However, the management is rather difficult in our rapidly developing modern society, and the underlying mechanism that caused hypertension remains incompletely understood. In this study, we established a rat model of high BP induced by chronic unpredictable mild stress (CUMS). The results showed that CUMS increased the BP and heart rate, as well as the concentrations of CORT, NA, and ACTH. Based on tandem mass tag (TMT)-labeled proteomics, 13 proteins changed in RVLM. Then, targeted metabolomics together with real-time qPCR were applied to validate the levels of the biomolecules quantitatively. The related molecules were confirmed to reveal that CUMS has a great role in the upregulation of muscle contraction, synthesis of cAMP and transport of metals, while down-regulating ralaxin signaling. This finding facilitates a better understanding of the mechanism of hypertension induced by chronic stress and could provide an insight into the prevention and treatment of hypertension.

Alterations in brain metabolism are closely associated with the molecular hallmarks of Parkinson's disease (PD). A clear understanding of the main metabolic perturbations in PD is therefore important. Here, we retrospectively analysed the expression of metabolic genes from 34 PD-control post-mortem human brain transcriptome data comparisons from literature, spanning multiple brain regions. We found high metabolic correlations between the Substantia nigra (SN)- and cerebral cortex-derived tissues. Moreover, three clusters of PD patient cohorts were identified based on perturbed metabolic processes in the SN – each characterised by perturbations in (a) bile acid metabolism (b) omega-3 fatty acid metabolism, and (c) lipoic acid and androgen metabolism – metabolic themes not comprehensively addressed in PD. These perturbations were supported by concurrence between transcriptome and proteome changes in the expression patterns for CBR1, ECI2, BDH2, CYP27A1, ALDH1B1, ALDH9A1, ADH5, ALDH7A1, L1CAM, and PLXNB3 genes, providing a valuable resource for drug targeting and diagnosis. Also, we analysed 58 PD-control transcriptome data comparisons from in vivo/in vitro disease models and identified experimental PD models with significant correlations to matched human brain regions. Collectively, our findings suggest metabolic alterations in several brain regions, heterogeneity in metabolic alterations between study cohorts for the SN tissues and the need to optimize current experimental models to advance research on metabolic aspects of PD.

Abemaciclib (Ab) and palbociclib (Pb) are CDK4/6 inhibitors used to cure advanced breast cancer (BC). However, acquired resistance is a major challenge. The molecular mechanisms and signature proteins of therapy resistance for Ab and Pb drugs need to be explored. Here we developed resistant cells for Ab and Pb drugs in MCF-7 cell lines and explored the mechanisms and signature proteins of therapy resistance in BC. Proteome profiling was performed using the label-free proteome-orbitrap-fusion-MS-MS technique. Gene ontology (GO)-terms, KEGG pathways and network analysis were performed for the proteome data. Drug-resistant cells showed increased drug tolerance, enhanced colony formation potential and an increased gap-healing tendency for the respective drug. Up-regulation of survival genes (BCL-2 and MCL-1) and down-regulation of apoptosis inducers were observed. Drug-resistance markers (MDR-1 and ABCG2 (BCRP)) along with ESR-1, CDK4, CDK6, and cyclin-D1 genes were up-regulated in resistant cells. A total of 237 and 239 proteins were found to be differentially expressed in the Ab and Pb-resistant cells, respectively. Down-regulated proteins induce apoptosis signalling and nucleotide metabolisms and restrict EGFR signalling; however, up-regulated proteins induce Erk, wnt-β-catenin, VEGFR-PI3K-AKT, glucose transportation, and hypoxia signalling pathways and regulate hydrogen peroxide signalling pathways. The panel of identified proteins associated with these pathways might have characteristics of molecular signature and new drug targets for overcoming drug resistance in breast cancer.

Antibiotics are useful for treating infections caused by bacteria, but they have negative effects on the host body. The goal of this study was to determine whether antibiotics alter the metabolic phenotype of the host. We found that taking antibiotics reduced the diversity and richness of gut microbiota and affected the composition of the microbiome, which in turn altered the metabolic profiles of plasma and fecal samples. Additionally, plasma and fecal metabolites and gut microbiota genera showed a significant association. The most significant pathways related to the gut dysbiosis induced by antibiotics including purine, pentose, and glucuronate metabolism, histidine, ascorbate and alternate, lysine degradation, and fatty acid biosynthesis. The relationship between gut microbiota and altered metabolites of plasma and feces provides information about bacterial action, which is useful for designing new microbiota-based disease prevention and treatment interventions.

Background: Individualized pain therapy conforms to the concept of precision medicine and contributes to adequate pain management after surgery. Preoperative biomarkers associated with postoperative pain may instruct anesthesiologists to improve personalized suitable analgesia. Therefore, it is essential to explore the association between preoperative proteins and postoperative acute pain using the proteomics platform. Methods: In this study, the 24 hours postoperative sufentanil consumption of 80 male patients with gastric cancer was ranked. Patients with sufentanil consumption in the lowest 12% were included in the sufentanil low consumption group, while patients with sufentanil consumption in the highest 12% were included in the sufentanil high consumption group. The secretion of serum proteins in both groups was analyzed using label-free proteomics technology. The results were validated by ELISA. Results: Proteomics identified 29 proteins that were significantly differentially expressed between groups. ELISA confirmed that secretion of TNC and IGFBP2 was down-regulated in the SLC group. The differential proteins were mainly extracellular and were involved in several terms, including calcium ion binding, laminin-1 binding, and so on. Pathway analysis showed that they were mainly enriched in focal adhesion and extracellular matrix-receptor interaction. The protein–protein interaction network analysis showed 22 proteins that interacted with other proteins. F13B had the strongest correlation with sufentanil consumption and its AUC value was 0.859. Conclusions: Several differential proteins are associated with postoperative acute pain and are involved in ECM-related processes, inflammation, and blood coagulation cascades. F13B may be a novel marker for postoperative acute pain. Our results may benefit postoperative pain management.