👤 Elisavet Georgiou

Cardiometabolic diseases (CVDs) are the leading cause of premature mortality and disability worldwide, arising from of cardiovascular and metabolic dysregulation. This review focuses on six critical therapeutic targets established in cardiometabolic regulation: GLP-1R, GIPR, FGFR1/β-Klotho, PCSK9, NF-κB, and the NLRP3 inflammasome. Drawing on curated structural datasets, we analyze the mechanisms of action and map key binding domain features that govern ligand efficacy and specificity. Dual GLP-1R/GIPR agonists, such as tirzepatide, demonstrate superior outcomes in glycemic control and weight reduction. Concurrently, inhibiting PCSK9, NF-κB, and NLRP3 helps to lower cholesterol and reduce harmful inflammation, offering cardioprotection. Structural analysis across these targets reveals complementary motifs (aromatic, hydrophobic, and polar residues). These insights guide the rational design of next-generation multi-target ligands (molecules capable of modulating two or more biological targets involved in related disease pathways, producing integrated therapeutic effects). Such integrated agents are promising for providing combined cardiovascular and metabolic benefits, thus reducing the risks associated with complex therapeutic drug combinations. Show less

The hippocampus, vital for memory and learning, is among the first brain regions affected in Alzheimer's Disease (AD) and exhibits adult neurogenesis. Women face twice the risk of developing AD compare to men, making it crucial to understand sex differences in hippocampal function for comprehending AD susceptibility. We conducted a comprehensive analysis of bulk mRNA postmortem samples from the whole hippocampus (GSE48350, GSE5281) and its CA1 and CA3 subfields (GSE29378). Our aim was to perform a comparative molecular signatures analysis, investigating sex-specific differences and similarities in the hippocampus and its subfields in AD. This involved comparing the gene expression profiles among: (a) male controls (M-controls) vs. female controls (F-controls), (b) females with AD (F-AD) vs. F-controls, (c) males with AD (M-AD) vs. M-controls, and (d) M-AD vs. F-AD. Furthermore, we identified AD susceptibility genes interacting with key targets of menopause hormone replacement drugs, specifically the The hippocampal analysis revealed contrasting patterns between M-AD vs. M-controls and F-AD vs. F-controls, as well as M-controls vs. F-controls. Notably, These findings underscore the importance of sex-specific disease mechanisms in AD pathogenesis. Region-specific analysis offers a more detailed examination of localized changes in the hippocampus, enabling to capture sex-specific molecular patterns in AD susceptibility and progression. Show less

Medications used to treat acute lymphoblastic leukemia (ALL), such as L-asparaginase, can cause blood lipid disturbances. These can also be associated with polymorphisms of the lipoprotein lipase (LpL) and apolipoprotein E (APOE) genes. We aimed to investigate the association between lipid profile, certain LpL and APOE gene polymorphisms (rs268, rs328, rs1801177 and rs7412, rs429358 respectively) as well as the risk subgroup in 30 pediatric patients being treated for ALL, compared with 30 pediatric ALL survivors and 30 healthy controls. The only APOE gene polymorphism with significant allelic and genotypic heterogeneity was rs429358. Further analysis of this polymorphism showed that genotype (CC, CT, or TT) was significantly associated with (1) changes in the lipid profile at the end of consolidation (total cholesterol, LDL, apo-B100, and lipoprotein a) and during re-induction (total cholesterol and apo-B100), and (2) classification in the high risk-ALL subgroup (for CC genotype/C allele presence). Lipid abnormalities in children being treated for ALL may be associated with the APOE genotype, which is also possibly associated with risk stratification. Further research is needed to confirm the potential prognostic value of these findings. Show less

To characterize the retinal phenotype of juvenile neuronal ceroid lipofuscinosis (JNCL), highlight delayed and mistaken diagnosis, and propose an algorithm for early identification. Retrospective case series. Eight children (5 female) with JNCL. Review of clinical notes, retinal imaging including fundus autofluorescence and OCT, electroretinography (ERG), and both microscopy and molecular genetic testing. Demographic data, signs and symptoms, visual acuity (VA), fundus autofluorescence and OCT findings, ERG phenotype, and microscopy/molecular genetics. Participants presented with rapid bilateral vision loss over 1 to 18 months, with mean VA deteriorating from 0.44 logarithm of the minimum angle of resolution (logMAR) (range, 0.20-1.78 logMAR) at baseline to 1.34 logMAR (0.30 logMAR - light perception) at last follow-up. Age of onset ranged from 3 to 7 years (mean, 5.3 years). The age at diagnosis of JNCL ranged from 7 to 10 years (mean, 8.3 years). Six children displayed eccentric fixation, and 6 children had cognitive or neurologic signs at the time of diagnosis (75%). Seven patients had bilateral bull's-eye maculopathy at presentation. Coats-like exudative vasculopathy, not previously reported in JNCL, was observed in 1 patient. OCT imaging revealed near complete loss of outer retinal layers and marked atrophy of the nerve fiber and ganglion cell layers at the central macula. An electronegative ERG was present in 4 patients (50%), but with additional a-wave reduction, there was an undetectable ERG in the remaining 4 patients. Blood film microscopy revealed vacuolated lymphocytes, and electron microscopy showed lysosomal (fingerprint) inclusions in all 8 patients. In a young child with bilateral rapidly progressive vision loss and macular disturbance, blood film microscopy to detect vacuolated lymphocytes is a rapid, readily accessible, and sensitive screening test for JNCL. Early suspicion of JNCL can be aided by detailed directed history and high-resolution retinal imaging, with subsequent targeted microscopy/genetic testing. Early diagnosis is critical to ensure appropriate management, counseling, support, and social care for children and their families. Furthermore, although potential therapies for this group of disorders are in early-phase clinical trial, realistic expectations are that successful intervention will be most effective when initiated at the earliest stage of disease. Show less

Signaling via the Rho GTPases provides crucial regulation of numerous cell polarization events, including apicobasal (AB) polarity, polarized cell migration, polarized cell division and neuronal polarity. Here we review the relationships between the Rho family GTPases and epithelial AB polarization events, focusing on the 3 best-characterized members: Rho, Rac and Cdc42. We discuss a multitude of processes that are important for AB polarization, including lumen formation, apical membrane specification, cell-cell junction assembly and maintenance, as well as tissue polarity. Our discussions aim to highlight the immensely complex regulatory mechanisms that encompass Rho GTPase signaling during AB polarization. More specifically, in this review we discuss several emerging common themes, that include: 1) the need for Rho GTPase activities to be carefully balanced in both a spatial and temporal manner through a multitude of mechanisms; 2) the existence of signaling feedback loops and crosstalk to create robust cellular responses; and 3) the frequent multifunctionality that exists among AB polarity regulators. Regarding this latter theme, we provide further discussion of the potential plasticity of the cell polarity machinery and as a result the possible implications for human disease. Show less