Biology subjects

Lialios, P.

Publications and source records attributed to Lialios, P..

4 recordsLinked to original sources

bioRxiv2026

Integrative prioritization of clinically and biologically relevant long noncoding RNAs across gastrointestinal cancers

Across gastrointestinal (GI) cancers, shared malignant programs are layered onto strong anatomical, lineage, and microenvironmental variation, making it difficult to distinguish disease-relevant long noncoding RNAs (lncRNAs) from context-dependent transcriptional signals. We developed a pan-GI integrative framework to classify lncRNAs across colorectal adenocarcinoma, gastric adenocarcinoma, and esophageal cancer using bulk and single-cell transcriptomic resources. This framework evaluates lncRNAs across four complementary dimensions: recurrent tumor-associated expression, clinical association with disease progression and overall survival, co-expression network context, and malignant epithelial expression at single-cell resolution. Paired tumor-normal RNA-seq analyses identified extensive tumor-associated lncRNA dysregulation and defined recurrent pan-GI lncRNAs consistently upregulated across cancer types. Clinical analyses further nominated transcripts linked to tumor extension, nodal involvement, metastatic dissemination, progression-linked expression, and adverse overall survival. Co-expression network analysis identified lncRNAs embedded within disease-associated transcriptional modules, providing functional context for otherwise poorly annotated transcripts. In parallel, single-cell-derived metacell analysis nominated malignant epithelial-associated and detection-supported lncRNAs, helping distinguish tumor-compartment-associated signals from stromal, immune, endothelial, and other microenvironmental contributions. Together, this study establishes an evidence-structured pan-GI lncRNA resource and a generalizable prioritization strategy for nominating disease-associated noncoding transcripts. More broadly, the framework provides a transferable strategy for systematic lncRNA prioritization across other cancers and heterogeneous disease contexts.

cancer biology↗

bioRxiv2025

Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice

Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient to extend healthspan and lifespan in mice. While the BCAAs have often been considered as a group, it has become apparent that they have distinct metabolic roles, and we recently found that restriction of isoleucine is sufficient to extend the healthspan and lifespan of male and female mice. Here, we test the effect of lifelong restriction of the BCAA valine on healthy aging. We find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promotes leanness and glycemic control across ages, and reduces frailty, cancer prevalence, and senescent cell burden in multiple tissues in both sexes. Val-R reduces glial activation in the brain in a male-specific manner, and extends the lifespan of male, but not female, mice by 23%. To investigate the molecular mechanisms engaged by Val-R with aging, we conducted multi-tissue transcriptional profiling and gene network analysis. While Val-R had a greater molecular impact in the liver, muscle, and brown adipose tissue of females, the enrichment of genes associated with phenotypic traits was stronger in males. Assessing novel gene relationships across tissues, we identified a liver gene module enriched in mitochondrial-related pathways as a central hub. Assessing mitochondrial function, we identified a Val-R-induced male-specific increase in mitochondrial respiration. Our results demonstrate for the first time that Val-R improves multiple aspects of healthspan in mice of both sexes and extends lifespan in males, and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.

physiology↗

bioRxiv2025

A 3D Endothelium-on-a-Chip Model Uncovers Cx43-Dependent Glycolytic Shift and Endothelial Barrier Dysfunction in Diabetic Kidney Disease

Endothelial dysfunction is a key pathological feature of diabetic kidney disease (DKD), characterized by increased vascular leakiness and altered metabolic signaling. In this study, we investigated how diabetic conditions affect endothelial barrier integrity and identified the molecular mechanisms contributing to this dysfunction. Using a 3D microfluidic model that recapitulates in vivo vascular architecture and flow, we demonstrated that high glucose (HG) and high fat (HF) conditions significantly impair endothelial barrier function, as demonstrated by increased dextran permeability and loss of VE-cadherin from the cellular membrane site. Metabolomic profiling and functional assays revealed a shift toward glycolysis, marked by elevated lactate levels and upregulation of lactate dehydrogenase A (LDHA), which contributed to barrier disruption. Pharmacological inhibition of LDHA effectively restored barrier function, underscoring the pathogenic role of glycolytic reprogramming. Transcriptomic analyses of mouse and human DKD datasets further identified connexin 43 (Cx43) as a candidate mediator of this dysfunction. Cx43 expression was progressively deregulated in diabetic mouse kidneys and across multiple cell types in human DKD samples. In vitro, Cx43 overexpression in endothelial cells enhanced glycolytic flux, suppressed oxidative metabolism, disrupted VE-cadherin localization, and promoted angiogenic sprouting. Collectively, our findings establish a mechanistic link between Cx43-driven metabolic reprogramming and endothelial barrier dysfunction in DKD, highlighting Cx43 as a potential therapeutic target for preserving vascular integrity in diabetic conditions.

bioengineering↗

bioRxiv2025

Tissue-specific effects of dietary protein on cellular senescence are mediated by branched-chain amino acids

Dietary protein is a key regulator of healthy aging in both mice and humans. In mice, reducing dietary levels of the branched-chain amino acids (BCAAs) recapitulates many of the benefits of a low protein diet; BCAA-restricted diets extend lifespan, reduce frailty, and improve metabolic health, while BCAA supplementation shortens lifespan, promotes obesity, and impairs glycemic control. Recently, high protein diets have been shown to promote cellular senescence, a hallmark of aging implicated in many age-related diseases, in the liver of mice. Here, we test the hypothesis that the effects of high protein diets on metabolic health and on cell senescence are mediated by BCAAs. We find that reducing dietary levels of BCAAs protects male and female mice from the negative metabolic consequences of both normal and high protein diets. Further, we identify tissue-specific effects of BCAAs on cellular senescence, with restriction of all three BCAAs - but not individual BCAAs - protecting from hepatic cellular senescence while potentiating cell senescence in white adipose tissue. We find that the effects of BCAAs on hepatic cellular senescence are cell-autonomous, with lower levels of BCAAs protecting cultured cells from antimycin-A induced senescence. Our results demonstrate a direct effect of a specific dietary component on a hallmark of aging and suggest that cellular senescence may be highly susceptible to dietary interventions.

physiology↗