Search Results (6)

Neuroblastoma (NB), a pediatric cancer of sympatho-adrenal (SA) lineage, is marked by disrupted differentiation and cellular heterogeneity. INSM1, a zinc-finger transcription factor, is highly expressed in NB and developing SA tissues, where it regulates neuroendocrine differentiation, especially in chromaffin cells. We investigated INSM1’s role in maintaining an undifferentiated, progenitor-like state in NB and its regulation via metabolic and epigenetic mechanisms. Transcriptomic profiling, promoter assays, and metabolic flux analysis revealed that INSM1 expression correlates with methionine cycle activity, particularly the S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio. Disruption of SAM/SAH balance altered INSM1 promoter activity and histone methylation, implicating epigenetic control in NB cell fate. Retinoic acid-induced differentiation downregulated INSM1 and N-Myc, linking INSM1 to tumor cell immaturity. INSM1 overexpression in SH-SY-5Y cells upregulated neuroendocrine and thyroid hormone-related genes (CHGA, CHGB, DDC, NCAM1, DIO3, TH), while suppressing genes involved in cell cycle (RRM, CDC25A), methionine metabolism (AHCY, MAT2A), transcriptional regulation (MYBL2, EZH2), and oncogenic signaling (ALK, LINC011667). These findings suggest that INSM1 promotes NB aggressiveness by sustaining a neuroendocrine progenitor-like phenotype through metabolic-epigenetic coupling. Full article

This study investigated the role of the CHGB P413L variant (rs742710) in sporadic amyotrophic lateral sclerosis (sALS) within the Bulgarian population. We analyzed 150 patients with sALS (85 male and 65 female) for the presence of this variant, its potential impact on disease susceptibility, and age of onset. Genotyping was performed using PCR amplification and direct Sanger sequencing. Statistical analyses included comparisons with control data from GnomAD v2.1.1, one-way ANOVA, and Kaplan–Meier survival analysis. Results revealed a higher frequency of the minor T allele in patients with sALS compared to all control groups and a statistically significant increase in carrier genotypes compared to non-Finnish Europeans (χ² = 15.4572, p = 0.000440). However, the impact on age of onset was less clear, with no statistically significant differences observed across genotypes or between carriers and non-carriers of the T allele. Kaplan–Meier analysis suggested a potential 2.5-year-earlier onset in T allele carriers, but the small sample size of carriers limits the reliability of this finding. Our study provides evidence for an association between the CHGB P413L variant and sALS susceptibility in the Bulgarian population, while its effect on age of onset remains uncertain, highlighting the need for further research in larger, diverse cohorts. Full article

The association between Porphyromonas gingivalis (P. gingivalis) and Alzheimer’s disease (AD) remains unclear. The major aim of this study was to elucidate the role of genes and molecular targets in P. gingivalis-associated AD. Two Gene Expression Omnibus (GEO) datasets, GSE5281 for AD (n = 84 Alzheimer’s, n = 74 control) and GSE9723 (n = 4 P. gingivalis, n = 4 control), were downloaded from the GEO database. Differentially expressed genes (DEGs) were obtained, and genes common to both diseases were drawn. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis was performed from the top 100 genes (50 upregulated and 50 downregulated genes). We then proceeded with CMap analysis to screen for possible small drug molecules targeting these genes. Subsequently, we performed molecular dynamics simulations. A total of 10 common genes (CALD1, HES1, ID3, PLK2, PPP2R2D, RASGRF1, SUN1, VPS33B, WTH3DI/RAB6A, and ZFP36L1) were identified with a p-value < 0.05. The PPI network of the top 100 genes showed UCHL1, SST, CHGB, CALY, and INA to be common in the MCC, DMNC, and MNC domains. Out of the 10 common genes identified, only 1 was mapped in CMap. We found three candidate small drug molecules to be a fit for PLK2, namely PubChem ID: 24971422, 11364421, and 49792852. We then performed molecular docking of PLK2 with PubChem ID: 24971422, 11364421, and 49792852. The best target, 11364421, was used to conduct the molecular dynamics simulations. The results of this study unravel novel genes to P. gingivalis-associated AD that warrant further validation. Full article

The aim of this study was to explore the effect of zearalenone (ZEA) exposure on uterine development in weaned gilts by quantitative proteome analysis with tandem mass spectrometry tags (TMT). A total of 16 healthy weaned gilts were randomly divided into control (basal diet) and ZEA3.0 treatments groups (basal diet supplemented with 3.0 mg/kg ZEA). Results showed that vulva size and uterine development index were increased (p < 0.05), whereas serum follicle stimulation hormone, luteinizing hormone and gonadotropin-releasing hormone were decreased in gilts fed the ZEA diet (p < 0.05). ZEA, α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL) were detected in the uteri of gilts fed a 3.0 mg/kg ZEA diet (p < 0.05). The relative protein expression levels of creatine kinase M-type (CKM), atriopeptidase (MME) and myeloperoxidase (MPO) were up-regulated (p < 0.05), whereas aldehyde dehydrogenase 1 family member (ALDH1A2), secretogranin-1 (CHGB) and SURP and G-patch domain containing 1 (SUGP1) were down-regulated (p < 0.05) in the ZEA3.0 group by western blot, which indicated that the proteomics data were dependable. In addition, the functions of differentially expressed proteins (DEPs) mainly involved the cellular process, biological regulation and metabolic process in the biological process category. Some important signaling pathways were changed in the ZEA3.0 group, such as extracellular matrix (ECM)-receptor interaction, focal adhesion and the phosphoinositide 3-kinase–protein kinase B (PI3K-AKT) signaling pathway (p < 0.01). This study sheds new light on the molecular mechanism of ZEA in the uterine development of gilts. Full article

In recent years, erythropoietin (EPO) has emerged as a useful neuroprotective and neurotrophic molecule that produces antidepressant and cognitive-enhancing effects in psychiatric disorders. However, EPO robustly induces erythropoiesis and elevates red blood cell counts. Chronic administration is therefore likely to increase blood viscosity and produce adverse effects in non-anemic populations. Carbamoylated erythropoietin (CEPO), a chemically engineered modification of EPO, is non-erythropoietic but retains the neurotrophic and neurotrophic activity of EPO. Blood profile analysis after EPO and CEPO administration showed that CEPO has no effect on red blood cell or platelet counts. We conducted an unbiased, quantitative, mass spectrometry-based proteomics study to comparatively investigate EPO and CEPO-induced protein profiles in neuronal phenotype PC12 cells. Bioinformatics enrichment analysis of the protein expression profiles revealed the upregulation of protein functions related to memory formation such as synaptic plasticity, long term potentiation (LTP), neurotransmitter transport, synaptic vesicle priming, and dendritic spine development. The regulated proteins, with roles in LTP and synaptic plasticity, include calcium/calmodulin-dependent protein kinase type 1 (Camk1), Synaptosomal-Associated Protein, 25 kDa (SNAP-25), Sectretogranin-1 (Chgb), Cortactin (Cttn), Elongation initiation factor 3a (Eif3a) and 60S acidic ribosomal protein P2 (Rplp2). We examined the expression of a subset of regulated proteins, Cortactin, Grb2 and Pleiotrophin, by immunofluorescence analysis in the rat brain. Grb2 was increased in the dentate gyrus by EPO and CEPO. Cortactin was induced by CEPO in the molecular layer, and pleiotrophin was increased in the vasculature by EPO. The results of our study shed light on potential mechanisms whereby EPO and CEPO produce cognitive-enhancing effects in clinical and preclinical studies. Full article

The article presents the results of the clinical evaluation (Apgar scores, AS) and umbilical cord blood gas analysis (UCBGA) obtained from clamped umbilical cords of newborn pups delivered by the elective Caesarean section. The study was planned as a controlled clinical study, the newborns were allocated into one of the groups, I—critical neonates (severe distress, AS ≤ 3), II—weak neonates (moderate distress, AS 4–6) and III—healthy neonates (no distress, AS ≥ 7). The following parameters were evaluated: pH (pH units), carbon dioxide partial pressure (pCO₂; mmHg), oxygen partial pressure (pO₂; mmHg), actual bicarbonate (cHCO₃⁻; mmol/L), total carbon dioxide (cTCO₂; mmol/L), base excess of extracellular fluid (BE(ecf); mmol/L), base excess of blood (BE(b); mmol/L), oxygen saturation (csO₂; %), lactate (Lac; mg/dL), hematocrit (Hct; %PCV), hemoglobin (cHgb; g/dL), glucose (Glu; mg/dL), ions (Na, K, Ca, Cl). The majority of puppies had low AS at birth (AS 4–6 in 38.1% and AS ≤ 3 in 57.1% of the neonates), but most of them (85.7%) improved by the 20th min. reaching AS of 7 and more. Moreover, puppies with lower AS (≤ 3) were at higher risk of death within the first 24h (20.8% did not survive). The positive correlation was found between Apgar score measured at 0 min and pH (r = 0.46, p = 0.01), and between Apgar score (at 0 min) and base excess in whole blood measured [BE(b)] r = 0.36, p = 0.03). Whereas, a negative correlation was detected between Apgar score at 0 and 5th min and glycemia (r = −0.42, p = 0.05, r = −0.34, p = 0.02 respectively. Overall, the puppies with higher glucose levels had lower Apgar scores and were at higher risk of death. Furthermore, in our study, the newborn puppies had mild acidemia with elevated pCO₂ levels and the HCO₃ at the lower range of normal limits, suggesting the mixed component in the acidemic state. Adaptation to extra-uterine life is crucial and any practical improvement in neonatal diagnostics and care would be beneficial for newborn puppy survival. Full article