👤 Kim C Vo

ObjectivesTo characterize the rs1042034 allele distribution in Vietnamese adults with untreated hypercholesterolemia and evaluate its impact on baseline lipid profiles and the early lipid-lowering response to rosuvastatin 20 mg.Materials and MethodsIn this cross-sectional exploratory study, 79 adults with low-density lipoprotein cholesterol [LDL-C] ≥ 3.4 mmol/L were enrolled and treated with rosuvastatin 20 mg plus lifestyle advice for 3 months. Genotypes were determined by TaqMan real-time PCR with Sanger sequencing validation. Baseline and 3-month lipid panels (LDL-C, high-density lipoprotein cholesterol [HDL-C], total cholesterol, non-HDL-C, triglycerides) were measured. Between-group comparisons used Kruskal-Wallis/ANOVA as appropriate; analysis of covariance (ANCOVA) models adjusted for baseline values assessed genotype (TT vs. CT + CC) effects on posttreatment lipids. Multivariable linear regression examined age, sex, and body-mass index as predictors; false discovery rate correction was applied.ResultsBaseline lipid concentrations did not differ significantly by genotype (overall LDL-C 4.37 ± 0.62 mmol/L; total cholesterol 6.62 ± 0.77 mmol/L). After three months, LDL-C reductions differed markedly by genotype ( Show less

Atherosclerosis, a chronic inflammatory disease, presents significant "residual risk" even with effective lipid-lowering therapies, primarily due to persistent vascular inflammation. Apolipoprotein B100 (ApoB100) acquires pro-inflammatory properties upon modification and binds to cell-surface enolase 1 (ENO1), an immune modulator upregulated in inflammatory conditions. This interaction induces inflammatory responses via NF-κB activation. Targeting the ApoB100-ENO1 interaction may offer a novel strategy to reduce vascular inflammation and atherosclerosis progression. We developed PP3m, a stabilized ApoB100-derived peptide, to selectively inhibit the ApoB100-ENO1 interaction. Single-cell RNA sequencing (scRNA-seq) data from human atherosclerotic plaques were reanalyzed to characterize ENO1 expression in myeloid cells. In vitro, PP3m's anti-inflammatory effects were evaluated across various macrophage models stimulated by diverse inflammatory stimuli. Outcomes included cytokine secretion, inflammatory gene expression, foam cell formation, oxidized low-density lipoprotein (oxLDL) uptake, and signaling pathways activation. In vivo, Ldlr scRNA-seq analysis revealed that human atherosclerotic plaques harbor significantly more ENO1 macrophages, with ENO1 expression enriched in CD68 The ApoB100-ENO1 axis is a critical driver of macrophage-mediated inflammation in atherosclerosis. The novel peptide PP3m effectively inhibits this interaction, reducing vascular inflammation and plaque progression without altering lipid levels. PP3m represents a promising therapeutic candidate for cardiovascular disease by targeting residual inflammatory risk through a lipid-independent mechanism. Show less

Over 90% of the U.S. adult population suffers from tooth structure loss due to caries. Most of the mineralized tooth structure is composed of dentin, a material produced and mineralized by ectomesenchyme derived cells known as odontoblasts. Clinicians, scientists, and the general public share the desire to regenerate this missing tooth structure. To bioengineer missing dentin, increased understanding of human tooth development is required. Here we interrogate at the single cell level the signaling interactions that guide human odontoblast and ameloblast development and which determine incisor or molar tooth germ type identity. During human odontoblast development, computational analysis predicts that early FGF and BMP activation followed by later HH signaling is crucial. Application of this sci-RNA-seq analysis generates a differentiation protocol to produce mature hiPSC derived odontoblasts Show less

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention. Show less

Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML. Show less

Like other single-gene disorders, muscular dystrophy displays a range of phenotypic heterogeneity even with the same primary mutation. Identifying genetic modifiers capable of altering the course of muscular dystrophy is one approach to deciphering gene-gene interactions that can be exploited for therapy development. To this end, we used an intercross strategy in mice to map modifiers of muscular dystrophy. We interrogated genes of interest in an interval on mouse chromosome 10 associated with body mass in muscular dystrophy as skeletal muscle contributes significantly to total body mass. Using whole-genome sequencing of the two parental mouse strains combined with deep RNA sequencing, we identified the Met62Ile substitution in the dual-specificity phosphatase 6 (Dusp6) gene from the DBA/2 J (D2) mouse strain. DUSP6 is a broadly expressed dual-specificity phosphatase protein, which binds and dephosphorylates extracellular-signal-regulated kinase (ERK), leading to decreased ERK activity. We found that the Met62Ile substitution reduced the interaction between DUSP6 and ERK resulting in increased ERK phosphorylation and ERK activity. In dystrophic muscle, DUSP6 Met62Ile is strongly upregulated to counteract its reduced activity. We found that myoblasts from the D2 background were insensitive to a specific small molecule inhibitor of DUSP6, while myoblasts expressing the canonical DUSP6 displayed enhanced proliferation after exposure to DUSP6 inhibition. These data identify DUSP6 as an important regulator of ERK activity in the setting of muscle growth and muscular dystrophy. Show less

Epidemiological studies demonstrate that the link between impaired fetal development and glucose intolerance in later life is exacerbated by postnatal catch-up growth. Maternal protein restriction (MPR) during pregnancy and lactation in the rat has been previously demonstrated to lead to impaired glucose tolerance in adulthood, however the effects of protein restoration during weaning on glucose homeostasis are largely unknown. Recent in vitro studies have identified that the liver X receptor α (LXRα) maintains glucose homeostasis by inhibiting critical genes involved in gluconeogenesis including G6pase (G6pc), 11β-Hsd1 (Hsd11b1) and Pepck (Pck1). Therefore, we hypothesized that MPR with postnatal catch-up growth would impair LXRα in vivo, which in turn would lead to augmented gluconeogenic LXRα-target gene expression and glucose intolerance. To examine this hypothesis, pregnant Wistar rats were fed a control (20%) protein diet (C) or a low (8%) protein diet during pregnancy and switched to a control diet at birth (LP). At 4 months, the LP offspring had impaired glucose tolerance. In addition, LP offspring had decreased LXRα expression, while hepatic expression of 11β-HSD1 and G6Pase was significantly higher. This was concomitant with decreased binding of LXRα to the putative LXRE on 11β-Hsd1 and G6pase. Finally, we demonstrated that the acetylation of histone H3 (K9,14) surrounding the transcriptional start site of hepatic Lxrα (Nr1h3) was decreased in LP offspring, suggesting MPR-induced epigenetic silencing of the Lxrα promoter. In summary, our study demonstrates for the first time the important role of LXRα in mediating enhanced hepatic gluconeogenic gene expression and consequent glucose intolerance in adult MPR offspring. Show less