Primary open-angle glaucoma (POAG) is characterized by degeneration of retinal ganglion cells associated with an increase in intraocular pressure (IOP) due to hindered aqueous humor (AH) drainage through the trabecular meshwork and uveoscleral pathway. Polyunsaturated fatty acids and oxylipins are signaling lipids regulating neuroinflammation, neuronal survival and AH outflow. Among them, prostaglandins have been previously implicated in glaucoma and employed for its treatment. This study addressed the role of signaling lipids in glaucoma by determining their changes in AH accompanying IOP growth and progression of the disease. Eye liquids were collected from patients with POAG of different stages and cataract patients without glaucoma. Lipids were identified and quantified by UPLC-MS/MS. The compounds discriminating glaucoma groups were recognized using ANCOVA and PLS-DA statistic approaches and their biosynthetic pathways were predicted by bioinformatics. Among 22 signaling lipids identified in AH, stage/IOP-dependent alterations in glaucoma were provided by a small set of mediators, including 12,13-DiHOME, 9- and 13-HODE/KODE, arachidonic acid and lyso-PAF. These observations correlated with the expression of cytochromes P450 (CYPs) and phospholipases A2 in the ocular tissues. Interestingly, tear fluid exhibited similar lipidomic alterations in POAG. Overall, POAG may involve arachidonic acid/PAF-dependent pathways and oxidative stress as evidenced from an increase in its markers, KODEs and 12,13-DiHOME. The latter is a product of CYPs, one of which, CYP1B1, is known as POAG and primary congenital glaucoma-associated gene. These data provide novel targets for glaucoma treatment. Oxylipin content of tear fluid may have diagnostic value in POAG.

The involvement of oxylipins, metabolites of polyunsaturated fatty acids, in cancer pathogenesis was known long ago, but only the development of the high-throughput methods get the opportunity to study oxylipins on a system level. The study aimed to elucidate alterations in oxylipin metabolism as characteristics of breast cancer patients. We compared the ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) oxylipin profile signatures in the blood plasma of 152 healthy volunteers (HC) and 169 patients with different stages of breast cancer (BC). To integrate lipidomics, transcriptomics, and genomics data, we analyzed a transcriptome of 10 open database datasets obtained from tissues and blood cells of BC patients and SNP data for 33 genes related to oxylipin metabolism. We identified 18 oxylipins, metabolites of omega-3 or omega-6 polyunsaturated fatty acids, that were differentially expressed between BCvsHC patients, including anandamide, prostaglandins and hydroxydocosahexaenoic acids. DEGs analysis of tissue and blood samples from BC patients revealed that 19 genes for oxylipin biosynthesis change their expression level, with CYP2C19, PTGS2, HPGD, and FAAH included in the list of DEGs in the analysis of transcriptomes and the list of SNPs associated with BC. Results allow us to suppose that oxylipin signatures reflect the organism’s level of response to the disease. Our data regarding changes in oxylipins at the system level show that oxylipin profiles can be used to evaluate the early stages of breast cancer.

Polyunsaturated fatty acid (PUFA) metabolism is currently a focus in cancer research due to PUFAs functioning as structural components of the membrane matrix, as fuel sources for energy production, and as sources of secondary messengers, so called oxylipins, important players of inflammatory processes. Although breast cancer (BC) is the leading cause of cancer death among women worldwide, no systematic study of PUFA metabolism as a system of interrelated processes in this disease has been carried out. Here, we implemented a Boruta-based feature selection algorithm to determine the list of most important PUFA metabolism genes altered in breast cancer tissues compared with in normal tissues. A rank-based Random Forest (RF) model was built on the selected gene list (33 genes) and applied to predict the cancer phenotype to ascertain the PUFA genes involved in cancerogenesis. It showed high-performance of dichotomic classification (balanced accuracy of 0.94, ROC AUC 0.99) We also retrieved a list of the important PUFA genes (46 genes) that differed between molecular subtypes at the level of breast cancer molecular subtypes. The balanced accuracy of the classification model built on the specified genes was 0.82, while the ROC AUC for the sensitivity analysis was 0.85. Specific patterns of PUFA metabolic changes were obtained for each molecular subtype of breast cancer. These results show evidence that (1) PUFA metabolism genes are critical for the pathogenesis of breast cancer; (2) BC subtypes differ in PUFA metabolism genes expression; and (3) the lists of genes selected in the models are enriched with genes involved in the metabolism of signaling lipids.

Conduct a reanalysis of transcriptome data for studying intracellular signaling or solving other experimental problems is becoming increasingly popular. Gene expression data are archived as microarray or RNA-seq datasets mainly in two public databases: Gene Expression Omnibus (GEO) and ArrayExpress (AE). These databases were not initially intended to systematically search datasets, making it challenging to conduct a secondary study. Therefore, we have created the ARGEOS service, which has the following advantages that facilitate the search: (1) Users can simultaneously send several requests that are supposed to be used for systematic searches, and it is possible to correct the requests; (2) advanced analysis of information about the dataset is available. The service collects detailed protocols, information on the number of datasets, analyzes the availability of raw data, and provides other reference information. All this contributes to both rapid data analysis with the search for the most relevant datasets and to the systematic search with detailed analysis of the information of the datasets. The efficiency of the service is shown in the example of analyzing transcriptome data of activated (polarized) cells. We have performed a systematic search of studies of cell polarization (when cells are exposed to different immune stimuli). The web interface for ARGEOS is user-friendly and straightforward. It can be used by a person who is not familiar with database searching.

Thiamine (vitamin B1) deficiency is known to cause predominantly neurological and cardiovascular symptoms due to the metabolic function of its diphosphate derivative as a coenzyme. A variety of natural and synthetic thiamine antimetabolites can simulate this deficiency. Oxythiamine may be spontaneously produced from thiamine itself and is known to accumulate in patients with kidney disorders. In this study, tissue specificity of chronic oxythiamine administration was investigated in male rats, focusing on changes in the physiology and thiamine-dependent enzyme activities of the cerebral cortex and heart. While oxythiamine treatment significantly reduced the pyruvate dehydrogenase activity in both tissues, its cerebral effects also included mild downregulation of another thiamine-dependent enzyme, 2-oxoglutarate dehydrogenase, indicating higher susceptibility of the cerebral metabolism to oxythiamine exposure. The oxythiamine neurological effects were also reflected in the rats’ altered anxiety-like behavior and heart rate regulation. Further investigation of the cerebral effects of oxythiamine identified elevated 3-hydroxybutyrate and protein acetylation as indicators of perturbed acetyl-CoA utilization in the TCA cycle. Some heart-specific changes, such as decreased glutathione level, were also observed upon oxythiamine treatment. The present results highlight the consequences of chronic oxythiamine exposure. These finding are potentially relevant for understanding the metabolic changes in the brain and heart upon pathophysiological oxythiamine accumulation.