Biology subjects

Le, S. M.

Publications and source records attributed to Le, S. M..

3 recordsLinked to original sources

bioRxiv2026

Interplay between ferroptosis and guttae in an early-onset murine model of Fuchs endothelial corneal dystrophy (FECD)

Col8a2Q455K/Q455K (Q455K) mice exhibit features of early-onset Fuchs endothelial corneal dystrophy (FECD), including decreased endothelial cell density (ECD) and guttae formation. Within the context of these clinical features, this study longitudinally evaluates ferroptosis in Q455K and wild-type (WT) mice using in vivo imaging, PCR and immunohistochemistry. Fifty-six Q455K and 56 WT mice were evaluated from 3 to 24 months of age with in vivo confocal microscopy; ECD and guttae were measured. Ferroptosis marker expression was determined with PCR and immunohistochemistry (IHC). Data were analyzed using two-way ANOVA with Tukeys post hoc test, Chi-square test and a paired t-test. The ECD significantly decreased in both groups from 3 to 24 months of age, but more markedly in Q455K (2285 {+/-} 317 to 1012 {+/-} 58 cells/mm{superscript 2}) versus WT mice (2714 {+/-} 139 to 2057 {+/-} 149 cells/mm{superscript 2}, P<0.0001). Guttae were observed exclusively in Q455K mice beginning at 3 months of age and increased over time (P=0.0003). The Q455K mice demonstrate guttae at the vertices of corneal endothelial cells rather than their centers (74.3% vs. 25.7%P<0.001). Expression of ferroptosis-related genes (Tfrc, Slc40a1, Ftl1, Gpx4) were significantly increased in the Q455K versus WT mice (P<0.05). Furthermore, corresponding protein expression (transferrin receptor 1, ferroportin, ferritin and glutathione peroxidase 4) was significantly elevated adjacent to guttae in Q455K versus WT mice (P<0.05). These findings implicate guttae in the initiation of ferroptosis as it relates to the pathophysiology of FECD and provide an optimal window for testing novel FECD therapies using this murine model, particularly those that target ferroptosis. Significance StatementFuchs endothelial corneal dystrophy (FECD) is a major cause of corneal blindness, yet the mechanisms driving endothelial cell loss remain unclear. Using an early-onset Q455K murine model, we show that disease onset occurs by 3 months of age and progresses with characteristic corneal guttae, endothelial cell loss, and morphological abnormalities replicating human FECD. By identifying ferroptosis adjacent to guttae in the Q455K, we demonstrate this mechanism is not specific to genetic mutations, but rather a conserved driver of corneal endothelial loss within the context of guttae formation. These findings establish an FECD progression timeline and reveal a mechanistic link between ferroptosis and guttae, validating this model as a critical tool for evaluating targeted therapeutic strategies.

developmental biology↗

bioRxiv2026

Benzoxaboroles are structurally unique binders of eukaryotic translation initiation factor 4E

Benzoxaboroles offer unusual reactivity and protein recognition for the development of small molecule drugs. Despite this potential, they are uncommon in drug discovery or in fragment screening libraries. We synthesized a series of structurally related benzoxaboroles containing a diazirine/alkyne tag to enable in-cell photoaffinity labeling experiments. A subset of this library was found to have high selectivity for eukaryotic translation initiation factor 4E (eIF4E). The benzoxaborole-eIF4E interaction was found to be stereoselective in nature and competitive with the 7-methylguanosine cap of mRNA. Site of labeling experiments revealed that the benzoxaborole fragment interacts with the cap binding pocket of eIF4E. In silico modeling of the modified protein suggests that H-bonding interactions between the main chain of Trp102 and the side chain of Asn155 to the amide carbonyl and anionic boronate of the benzoxaborole, respectively, drive affinity for this challenging to drug pocket.

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↗