LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common non-coding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (odds ratio, OR = 0.63; P = 6.33 × 10⁻³¹) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 [stimulated by retinoic acid (RA) receptor 6], apparently mediated by allele-specific binding of the transcription factor thyroid hormone receptor beta. We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven RA signaling pathway. siRNA-mediated downregulation of RA signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.

Background: Association studies of vitamin D receptor (VDR) polymorphisms with COVID-19 severity have produced inconsistent results in different populations. Herein we examined VDR gene polymorphisms in a Caucasian Greek cohort of COVID-19 patients. Methods: This was a case-control study in a tertiary university hospital in Greece including 137 COVID-19 patients with varying disease severities and 72 healthy individuals. In total 209 individuals were genotyped for the FokI (rs10735810), ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410) single-nucleotide polymorphisms (SNP) of the VDR gene by polymerase chain reaction and restriction fragment length polymorphism analysis (PCR-RFLPs). Statistical analyses were performed to determine the association between genotype and disease severity, adjusting for various confounding factors. Results: Genotype distribution of the studied VDR SNPs in the control group was in Hardy–Weinberg equilibrium. The TaqI variant was differentially distributed between controls and COVID-19 patients according to the additive model (p = 0.009), and the CC genotype was significantly associated with an increased risk for severe COVID-19 according to the recessive model [OR: 2.52, 95%CI:1.2–5.29, p = 0.01]. Multivariate analysis demonstrated a robust association of COVID-19 severity and TaqI polymorphism in the recessive model even after adjusting for multiple confounders, including age, sex and CRP levels [Adj.OR:3.23, 95%CI:1.17–8.86, p = 0.023]. The distribution of FokI, ApaI and BsmI genotypes was similar between COVID-19 patients and controls. Conclusions: The CC genotype of TaqI polymorphism is significantly associated with an increased risk for severe COVID-19 independently of age, sex or degree of inflammation.

A randomized, placebo-controlled, quadruple-blind trial was performed to evaluate the effect of oral administration of the antioxidant combination Spermotrend^® for three months on semen quality in infertile men with at least one abnormal variable in semen analysis. Eighty men were randomized between 2019 and 2022, receiving either the antioxidant combination Spermotrend^® (n = 40, spermotrend-group) or placebo (n = 40, placebo-group). Although a total of 80 patients were enrolled in the study, the final data is only from 70 patients. The primary outcome measure was sperm motility (rapid progressive, progressive, and total motility). The values of primary and secondary outcomes between treatment initiation and treatment completion were compared within groups. Moreover, their changes between treatment initiation and treatment completion were compared between the placebo- and the spermotrend-groups. Sperm rapid progressive motility significantly increased in infertile men treated for three months with antioxidant combination Spermotrend^® (+1.0%, 95% CI: 0.0 to +2.0, p = 0.04), while this increase was not observed in the placebo-group. Sperm progressive motility significantly increased in infertile men treated for three months with antioxidant combination Spermotrend^® (+3.0%, 95% CI: 0.0 to +15.1, p = 0.02), while this increase was not observed in the placebo-group. Similarly, DFI was significantly decreased in infertile men treated for three months by antioxidant combination Spermotrend^® (−3.2%, 95% CI: −5.8 to −0.5, p = 0.02). However, no statistically significant differences were observed in the changes of pre- and post-treatment values between the spermotrend- and the placebo-group regarding sperm progressive motility, concentration, normal morphology, DFI, and formation of 8-OH-dG. The antioxidant combination Spermotrend^® appears to exert limited benefit on sperm motility and DFI in infertile men with at least one abnormal variable in semen analysis.

Non-alcoholic fatty liver disease (NAFLD) shares several risk factors with atherosclerosis, as it is associated with components of the metabolic syndrome. However, genetic variations have also been linked to the risk of NAFLD, such as adiponutrin/patatin-like phospholipase domain-containing the protein 3 (PNPLA3) rs738409 polymorphism. The aim of the study was to determine the associations of thePNPLA3 rs738409 polymorphism with NAFLD and atherosclerosis risk factors in children and adolescents from northern Greece. A total of 91 children/adolescents who followed a Mediterranean eating pattern with no particular restrictions were studied. They were divided into three subgroups, according to their body mass index (BMI) and the presence or absence of liver disease. Diagnosis of NAFLD was based on a liver ultrasound, while the distribution of the PNPLA3 rs738409 polymorphism was investigated in all the participants. From the components of metabolic syndrome, only BMI, waist circumference, blood pressure, and the homeostasis model of insulin resistance (HOMA-IR) differed significantly between groups. The rs738409 polymorphism was significantly associated with BMI and NAFLD, while lipid values had no significant association with either NAFLD or gene polymorphism. This study shows that in Greekchildren, there is a significant association between the rs738409polymorphism in the PNPLA3 gene and hepatic steatosis, regardless of bodyweight.

Neurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5 , encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila , we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor cell stemness, causing deficits in higher-order functions, including learning and locomotion. Pharmacological targeting of integrated stress response kinases reveals a mechanistic link between proteotoxic stress and spontaneous type I interferon activation. These findings expand our understanding of proteasome-dependent quality control in neurodevelopment and suggest potential therapeutic strategies for neurodevelopmental proteasomopathies.

To investigate a possible central mechanism of action of Botulinum toxin A (BoNT/A) following injection in the bladder, complementary to the acknowledged peripheral bladder effect, we studied changes in the expression of neuropeptides and receptors involved in lower urinary tract function in the spinal cord (SC) and dorsal root ganglia (DRG) of normal rats following BoNT/A bladder injection. Thirty-six Sprague-Dawley rats, divided into three groups of n = 12, received bladder injections of 2U or 5U OnabotulinumtoxinA (BOTOX^®), or saline. Six animals from each group were sacrificed on days 7 and 14. Expression of Tachykinin 1 (Tac1), capsaicin receptor (TRPV1), neuropeptide Y (NPY), proenkephalin (PENK) and muscarinic receptors M1, M2, M3, was evaluated in the bladder, L6-S1 DRG, and SC segments using real-time PCR and Western blotting. Real-time PCR revealed increased expression of NPY in all tissues except for SC, and increased TRPV1 and PENK expression in DRG and SC, whereas expression of Tac1, M1 and M2 was decreased. Less significant changes were noted in protein levels. These findings suggest that bladder injections of OnabotulinumtoxinA may be followed by changes in the expression of sensory, sympathetic and cholinergic bladder function regulators at the DRG/SC level.