Identification of new biomarkers may help in the early diagnosis of inflammatory bowel disease (IBD). In this study, ultrahigh-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UPLC−QTOF-MS) was used to analyze the untargeted lipidomics and compare plasma lipid profiles between IBD patients and control subjects. The principal component analysis and partial least-squares-discriminant analysis were carried out to distinguish IBD patients from control subjects. Using univariate and multivariate analysis, 55 significantly different metabolites from five lipid classes, fatty acyls (n = 19), glycerophospholipids (n = 5), prenol lipids (n = 10), sphingolipids (n = 2), and sterol lipids (n = 19) were identified. Forty-four of the 55 metabolites were analyzed by receiver operating characteristic (ROC) curve and area under curve (AUC) of >0.80. After validation in an independent cohort, IBD patients were differentiated from the control subjects by significantly altered plasma level of palmitic acid, 7alpha, 25-dihydroxycholesterol, 20-hydroxyeicosatetraenoic (HETE)-d6, (+/−)5,6-epoxyeicosatrienoic acid (EpETrE), docosahexaenoic acid (DHA), 9-heptadecylenic acid, lactucaxanthin, α-carotene, traumatic acid, and neoquassin with both sensitivity and specificity above 80%. Pathway analysis suggested that IBD dysregulation was related to the biosynthesis of primary bile acid, the metabolism of arachidonic acid, the metabolism of sphingolipid, fatty acid elongation, and glycerophospholipid metabolism. Our results suggest that the lipidomic profiling of patients plasma could be a potential method for IBD diagnosis.
This study aims to identify biomarkers for evaluating the therapeutic efficacy of mesalazine on ulcerative colitis by metabolomics and lipidomics. A dextran sulfate sodium-induced mouse model was used. The disease status was assessed by a disease activity index, the TNF-α level of colon was measured by an enzyme-linked immunosorbent assay, and the pathological changes of colon tissue was examined by hematoxylin−eosin staining. Serum metabolomics and lipidomics analysis based on ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry were applied to decipher the metabolic profile changes. Multivariate analysis was applied to differentiate the metabolites of controls, models, and mesalazine-treated mice. By the receiver operating characteristic (ROC) analysis, 40 differential metabolites with an area under curve (AUC) >0.80 were screened out between control and model groups. Among them, four potential biomarkers (palmitoyl glucuronide, isobutyrylglycine, PC (20:3 (5Z, 8Z, 11Z)/15:0) and L-arginine) had a signficantly reversed level of peak areas in the mesalazine group, and three of them were closely correlated with mesalazine efficacy by linear regression analysis. Furthermore, metabolic pathway analysis revealed several dysregulated pathways in colitis mice, including glycerophospholipid metabolism, pyrimidine metabolism, linoleic acid metabolism, arginine biosynthesis, etc. This study indicates that serum metabolomics is a useful approach that can noninvasively evaluate the therapeutic effect and provide unique insights into the underlying mechanism of mesalazine.
Methionine aminopeptidases (MetAPs) have been pharmacologically linked to cell growth, angiogenesis, and tumor progression, which make it an attractive target for cancer therapy. We investigated MetAP2's biological role in glioblastoma (GBM), an aggressive tumor characterized by massive neovascularization. We examined the effect of anti-MetAP2 RNA interference on proliferation and angiogenesis in GBM cell line. The biological effects of MetAP2 knockdown were assessed by comparing the proliferation, tumorigenecity, and angiogenesis of parental cells and MetAP2 knockdown cells. We generated MetAP2 knockdown cells using lentiviral short hairpin RNAs against MetAP2 in SNB19 GBM cells, which normally express high levels of MetAP2. MetAP2 knockdown cells were less proliferative and less tumorigenic when compared to the parental cells. MetAP2 knockdown decreased vascular endothelial growth factor (VEGF) secretion and expression at the mRNA and protein levels. Decreased VEGF expression in MetAP2 knockdown cells correlated very well with decreased vessel formation in a tube formation assay. We showed that VEGF suppression in MetAP2 knockdown cells was mediated by the von Hippel-Lindau protein. In in vivo animal studies using an intracranial SNB19 tumor model, MetAP2 knockdown also reduced the tumor growth rate and angiogenesis, which in turn prolonged the survival of mice in xenograft model. Our results show that MetAP2 regulates angiogenesis in GBM and identify MetAP2-specific substrates that may serve as candidates for clinical assay development.
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