Biology subjects

Zeleznik, O. A.

Publications and source records attributed to Zeleznik, O. A..

5 recordsLinked to original sources

bioRxiv2025

Plasma plasmalogen levels and risk of lymph node positive breast cancer

Lymph node involvement is a key predictor of poor breast cancer prognosis. Systemic lipid alterations can contribute to cancer cell survival in lymph nodes, but their relevance in humans remains unclear. Here, we combine human epidemiologic analyses from the Nurses Health Study 2 and complementary mechanistic studies in mouse models to investigate how systemic lipid profiles relate to lymph node positive breast cancer. We show that in pre-diagnostic human plasma (n=511), lower levels of phosphatidylethanolamine (PE) and phosphatidylcholine (PC)-enriched plasmalogens are associated with increased risk of lymph node positivity, with stronger associations in samples collected closer to diagnosis. Consistent with the human data, lower levels of PE and PC-enriched plasma plasmalogens are found in mice with nodal involvement. Furthermore, in mice, dietary PUFA depletion reduces lipid oxidation in breast cancer cells in lymph nodes and promotes their survival and metastatic spread. These findings suggest that reduced levels of PE and PC-plasmalogens and decreased PUFA availability creates a lipid environment that enables breast cancer lymph node involvement.

cancer biology↗

bioRxiv2025

Pyruvate and Related Energetic Metabolites Modulate Resilience Against High Genetic Risk for Glaucoma

A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve=0.579), they offered marginal prediction improvement in PRS-only-based models (P=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites--lactate (P=8.8E-12), pyruvate (P=1.9E-10), and citrate (P=0.02)--linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction=0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval=0.64-0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (P=0.002) and optic nerve damage (P<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

genomics↗

bioRxiv2022

Plasma and ovarian metabolomics responses to chronic stress in female mice

BackgroundChronic stress may affect metabolism of amino acids, lipids, and other small molecule metabolites, but these alterations may differ depending on tissue evaluated. We examined metabolomic changes in plasma and ovarian tissue samples from female mice due to chronic stress exposure. MethodsAt 12 weeks old, healthy, female, C57 black mice were randomly assigned to three weeks of chronic stress using daily restraint (2 hours/day; n=9) or normal care (n=10). Metabolomic profiling was conducted on plasma and ovarian tissues. Using the Wilcoxon Rank Test, Metabolite Set Enrichment Analysis, and Differential Network Analysis we identified metabolomic alterations occurring in response to restraint stress. All p-values were corrected for multiple testing using the false discovery rate approach. ResultsIn plasma, individual lysophosphatidylcholines (positively) and the metabolite classes carnitines (positively), diacylglycerols and triacylglycerols (inversely) were associated with restraint stress (adjusted-ps<0.2). In contrast, diacylglycerols and triacylglycerols were increased while carnitines were decreased in ovarian tissue from stressed mice (adjusted-ps<0.2). However, several metabolites (cholesteryl esters, phosphatidylcholines/ phosphatidylethanolamines plasmalogens and multiple amino acids) were consistently inversely associated with restraint stress in plasma and ovarian tissue (adjusted-ps<0.2). ConclusionWe identified differences in multiple lipid and amino acid metabolites in plasma and ovarian tissue of female mice after exposure to chronic stress. Some affected metabolites (primarily triacylglycerols and diacylglycerols) exhibited opposite associations with chronic stress in plasma (a marker of systemic influences) versus in ovarian tissue (representing local changes), suggesting research to understand the biological impact of chronic stress needs to consider both systemic and tissue-specific alterations.

animal behavior and cognition↗

bioRxiv2019

A prospective analysis of circulating plasma metabolomics and ovarian cancer risk

We assessed the association of pre-diagnostic plasma metabolites (N=420) with ovarian cancer risk. We included 252 cases and 252 matched controls from the Nurses Health Studies. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) comparing the 90th-10th percentile in metabolite levels, using permutation tests to account for testing multiple correlated hypotheses. Weighted gene co-expression network analysis (WGCNA) modules (n=10) and metabolite set enrichment analysis (MSEA; n=23) were also evaluated. Pseudouridine had the strongest statistical association with ovarian cancer risk overall (OR=2.56, 95%CI=1.48-4.45; p=0.001/adjusted-p=0.15). C36:2 phosphatidylcholine (PC) plasmalogen had the strongest statistical association with lower risk (OR=0.11, 95%CI=0.03-0.35; p<0.001/adjusted-p=0.06) and pseudouridine with higher risk (OR=9.84, 95%CI=2.89-37.82; p<0.001/adjusted-p=0.07) of non-serous tumors. Seven WGCNA modules and 15 classes were associated with risk at FDR[≤]0.20. Triacylglycerols (TAGs) showed heterogeneity by tumor aggressiveness (case-only heterogeneity-p<0.0001). TAG association with risk overall and serous tumors differed by acyl carbon content and saturation. Pseudouridine may be a novel risk factor for ovarian cancer. TAGs may also be important, particularly for rapidly fatal tumors, with associations differing by structural features. Validation in independent prospective studies and complementary experimental work to understand biological mechanisms is needed.

epidemiology↗

bioRxiv2019

Circulating Lysophosphatidylcholines, Phosphatidylcholines, Ceramides, and Sphingomyelins and Ovarian Cancer Risk: a 23-year Prospective Study

BackgroundExperimental evidence supports a role of lipid dysregulation in ovarian cancer progression and metastasis. We estimated associations with ovarian cancer risk for circulating levels of four lipid groups measured 3-23 years before diagnosis.\n\nMethodsAnalyses were conducted among cases (N = 252) and matched controls (N = 252) from the Nurses Health Studies. We used logistic regression adjusting for risk factors to investigate associations of lysophosphatidylcholines (LPC), phosphatidylcholines (PC), ceramides (CER), and sphingomyelins (SM) with ovarian cancer risk overall and by histotype. A Bonferroni adjusted p-value threshold of 0.0125 (0.05/4; 4 measured lipid groups) was used to evaluate statistical significance. Odds ratios (OR; 10th to the 90th percentile) and 95% confidence intervals of ovarian cancer risk were estimated.\n\nResultsC16:0 SM, C18:0 SM, C16:0 CER and SM sum were significantly positively associated with ovarian cancer risk, with ORs ranging from 1.95-2.10, with stronger ORs for postmenopausal women (2.02-3.22). ORs were generally similar for serous/poorly differentiated and endometrioid/clear cell tumors, although most did not meet the Bonferroni-adjusted p-value for significance. C18:1 LPC and the ratio of LPC to PC were significantly inversely, while C18:0 SM was significantly positively, associated with risk of endometrioid/clear cell tumors.\n\nConclusionElevated levels of circulating SMs 3-23 years before diagnosis were associated with increased risk of ovarian cancer, regardless of histotype, with stronger associations among postmenopausal women. Prospective and experimental studies are required to validate our findings and understand the role of lipid dysregulation, SMs in particular, in ovarian carcinogenesis.

epidemiology↗