Metabolomics and triple-negative breast cancer: A systematic review.

Triple-negative breast cancer stands out as the most aggressive subtype of breast malignancy and is characterized by an unfavourable prognosis. Objective: This systematic review summarizes the insights gleaned from metabolomic analyses of individuals afflicted with this cancer variant. The overarching goal was to delineate the molecular alterations associated with triple-negative breast cancer, pinpointing potential therapeutic targets and novel biomarkers. Methods: We systematically searched for evidence using the PubMed database and followed the PRISMA and STARLITE guidelines. The search parameters were delimited to articles published within the last 13 years. Results: From an initial pool of 148 scrutinized articles, 17 studies involving 1686 participants were deemed eligible for inclusion. The current body of research shows a paucity of studies, and the available evidence presents conflicting outcomes. Notwithstanding, Pathway Enrichment Analysis identified the urea and glucose-alanine cycles as the most affected metabolic pathways, followed by arginine, proline, and aspartate metabolism. Conclusion: Future investigations need to focus on elucidating which of those metabolites and/or pathways might be reliable candidates for novel therapeutic interventions or reliable biomarkers for diagnosis and prognosis of this subtype of breast cancer.

Metabolic adaptations in severe obesity: Insights from circulating oxylipins before and after weight loss.

BACKGROUND: The relationship between lipid mediators and severe obesity remains unclear. Our study investigates the impact of severe obesity on plasma concentrations of oxylipins and fatty acids and explores the consequences of weight loss. METHODS: In the clinical trial identifier NCT05554224 study, 116 patients with severe obesity and 63 overweight/obese healthy controls matched for age and sex (≈2:1) provided plasma. To assess the effect of surgically induced weight loss, we requested paired plasma samples from 44 patients undergoing laparoscopic sleeve gastrectomy one year after the procedure. Oxylipins were measured using ultra-high-pressure liquid chromatography coupled to a triple quadrupole mass spectrometer via semi-targeted lipidomics. Cytokines and markers of interorgan crosstalk were measured using enzyme-linked immunosorbent assays. RESULTS: We observed significantly elevated levels of circulating fatty acids and oxylipins in patients with severe obesity compared to their metabolically healthier overweight/obese counterparts. Our findings indicated that sex and liver disease were not confounding factors, but we observed weak correlations in plasma with circulating adipokines, suggesting the influence of adipose tissue. Importantly, while weight loss restored the balance in circulating fatty acids, it did not fully normalize the oxylipin profile. Before surgery, oxylipins derived from lipoxygenase activity, such as 12-HETE, 11-HDoHE, 14-HDoHE, and 12-HEPE, were predominant. However, one year following laparoscopic sleeve gastrectomy, we observed a complex shift in the oxylipin profile, favoring species from the cyclooxygenase pathway, particularly proinflammatory prostanoids like TXB2, PGE2, PGD2, and 12-HHTrE. This transformation appears to be linked to a reduction in adiposity, underscoring the role of lipid turnover in the development of metabolic disorders associated with severe obesity. CONCLUSIONS: Despite the reduction in fatty acid levels associated with weight loss, the oxylipin profile shifts towards a predominance of more proinflammatory species. These observations underscore the significance of seeking mechanistic approaches to address severe obesity and emphasize the importance of closely monitoring the metabolic adaptations after weight loss.

Galectin-9 interacts with Vamp-3 to regulate cytokine secretion in dendritic cells.

Intracellular vesicle transport is essential for cellular homeostasis and is partially mediated by SNARE proteins. Endosomal trafficking to the plasma membrane ensures cytokine secretion in dendritic cells (DCs) and the initiation of immune responses. Despite its critical importance, the specific molecular components that regulate DC cytokine secretion are poorly characterised. Galectin-9, a ß-galactoside-binding protein, has emerged as a novel cellular modulator although its exact intracellular roles in regulating (immune) cell homeostasis and vesicle transport are virtually unknown. We investigated galectin-9 function in primary human DCs and report that galectin-9 is essential for intracellular cytokine trafficking to the cell surface. Galectin-9-depleted DCs accumulate cytokine-containing vesicles in the Golgi complex that eventually undergo lysosomal degradation. We observed galectin-9 to molecularly interact with Vamp-3 using immunoprecipitation-mass-spectrometry and identified galectin-9 was required for rerouting Vamp-3-containing endosomes upon DC activation as the underlying mechanism. Overall, this study identifies galectin-9 as a necessary mechanistic component for intracellular trafficking. This may impact our general understanding of vesicle transport and sheds new light into the multiple roles galectins play in governing cell function.