Search Results (23)

Apigenin, a naturally occurring flavonoid with low toxicity, exhibits anticancer activity, yet its effects on microRNAs (miRNAs) and downstream gene networks in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we evaluated apigenin’s antitumor effects in TE-1 and Eca-109 cells, assessing proliferation, apoptosis, colony formation, and invasion. Differentially expressed miRNAs were identified via small RNA sequencing, and candidate target genes were predicted, annotated using GO and KEGG analyses, and validated by qRT-PCR, revealing miRNA-mediated regulatory mechanisms underlying apigenin’s inhibitory effects in ESCC. Apigenin markedly suppressed cell proliferation, clonogenic growth, wound closure, and invasive capacity, while promoting apoptosis in a dose-dependent manner. In TE-1 cells, apigenin upregulated hsa-let-7c-3p, hsa-miR-374c-3p, hsa-miR-3177-3p hsa-miR-4454, and hsa-miR-4728-3p, while downregulating hsa-miR-573, hsa-miR-548az-5p, hsa-miR-33b-5p, hsa-miR-4479, and hsa-miR-3198. Correspondingly, tumor-associated target genes including ALDH3A2, SEMA3F, MAP4K5, and TRIP13 were upregulated, whereas PIK3IP1, AGO2, MMP2, and RALBP1 were suppressed. In Eca-109 cells, apigenin altered the expression of distinct miRNAs, including the upregulation of hsa-miR-891-5p, hsa-miR-3170, hsa-miR-4421, and hsa-miR-675-5p and the downregulation of hsa-miR-153, hsa-miR-3188, and hsa-miR-4435, thereby modulating key oncogenic targets such as MAPK1, SALL4, and COX15. Functional enrichment analyses indicated that apigenin-regulated genes are involved in multiple cancer-related pathways across cytoplasmic and nuclear compartments. Overall, these results suggest that apigenin suppresses ESCC progression via coordinated miRNA–mRNA regulation, highlighting its potential as a therapeutic agent. Full article

Assessing genetic diversity in various native poultry breeds, including bantam/dwarf ones, is instrumental for their conservation as genetic resources, identifying their specific genetic features, and exploring the history of their genetic divergence. Rare chicken breeds are usually carriers of peculiar phenotypic traits, including adaptations to local conditions, disease resistance, and unique performance features. Here, we report for the first time SNP-based genetic characterization of the Russian Korolyok, translated as “kinglet,” relative to five other dwarf/small breeds: Cochin Bantam, Hamburg Bantam Silver Spangled, Polish White-crested Black, Red White-tailed Dwarf and Silkie White. We estimated phenotypes, heterozygosity, inbreeding, effective population size, and runs of homozygosity (ROHs). Some breeds had higher genetic diversity and others showed elevated inbreeding rates in their genomes. With lower effective population sizes (both presently and in the past), rare breeds came from a limited number of ancestors or were under strong selection pressure over many generations. Within 22 ROHs, we identified 26 prioritized candidate genes (GRB10, RPRD1A, APOOL, EAF2, SEMA5, HACD2, GALANT1, DACH2, CHM, POF1B, HDX, SLC15A2, PDIA5, SEC22, NR2F2, ARRDC4, IGF1R, SYNM, TMEM263, etc.). Our data offer whole-genome insights into genetic variability, history, phylogeny, selective sweeps, and candidate genes of a distinct indigenous Russian chicken breed and other bantam/dwarf breeds. Full article

Differentiated human neuroblastoma (SH-SY5Y) cells were exposed to either 0.2 μM nicotine, a tobacco smoke preparation (TPM) diluted to the same nicotine concentration, or a cocktail of seven tobacco smoke monoamine oxidase inhibitors (MAOIs) at the concentrations measured in the TPM. Treatment occurred for 3 days, such that the cellular monoamine oxidase (MAO) concentration was reduced by approximately 50% in both the TPM and MAOI cocktail exposure groups. Changes in MAO gene expression after exposure to the different treatments were determined using qPCR, and the effect of these exposure treatments on global gene expression was also examined using mRNA sequencing. No change in MAOA and MAOB gene expression levels was observed, after any treatment, either using qPCR or mRNA sequencing. The MAOI versus control treatment comparison revealed that four genes were >2-fold down-regulated (ZNF727, RP11-310E22.4, CRYM, SEMA3F), and 19 genes were up-regulated after 3 days’ exposure to the MAOI cocktail. Many of these differentially expressed genes were linked with disease conditions related to smoking and addiction. Exposure to nicotine and TPM each resulted in up- and down-regulation of different sets of genes. The results indicate that changes in MAO gene expression are unlikely to be responsible for the changes in MAO activity. The association between genes whose expression changes with tobacco MAO treatment and smoking-related diseases and addiction suggests the central role that MAO inhibition may play in mediating the effects of smoking on smokers. Full article

Cervical cancer remains a significant global health burden, with chemoradioresistance representing a major obstacle to successful treatment. To elucidate the mechanisms underlying this resistance, we established a unique pair of isogenic primary cervical cancer cell lines, AdMer35 and AdMer43, obtained from a patient with squamous cell carcinoma of the cervix before and after radiation therapy. The aim of our study was to characterize the transcriptomic and cellular heterogeneity of these cells. We conducted an in-depth comparative analysis using single-cell RNA sequencing. Analysis of this paired, patient-derived isogenic model suggests that chemoradioresistance can arise through coordinated multilevel cellular adaptations. Resistant AdMer43 cells demonstrated transcriptional reprogramming, with the upregulation of embryonic stemness factors (HOX, POU5F1, SOX2), a shift in extracellular matrix from fibrillar to non-fibrillar collagens, and activation of inflammatory pathways. We identified and characterized critical cell-state dynamics: resistant cells exhibited a remodeled ecosystem with a metabolically reprogrammed senescent-like cell population showing an enhanced pro-tumorigenic communication via EREG, SEMA3C, BMP, and WNT pathways. Furthermore, we identified a progenitor-like cell population with a minimal CNV burden, potentially serving as a reservoir for tumor persistence. These findings offer novel insights for developing targeted strategies to eliminate resistant cell pools and improve cervical cancer outcomes. Full article

In the chicken industry, sex determination significantly affects production efficiency and raises ethical concerns in poultry farming. As a key economic species, maximizing the advantages of each sex is vital in modern intensive breeding. Therefore, understanding the mechanisms of sex determination and regulation is critical to advancing the poultry industry. Transcriptome analysis of 3.5-day-old White Leghorn chicken embryonic genital ridges (n = 30, 15 males and 15 females) was performed using sex-pooled samples (five embryos/replicate, three replicates/sex). Sequencing generated 39.6 GB of high-quality reads for inter-sex comparative analysis, revealing 283 significantly differentially expressed genes (DEGs). The DEGs were primarily enriched in pathways such as ribosome biogenesis, glycan biosynthesis and metabolism, and TGF-β signaling, which are potential candidate pathways for the differentiation of chicken embryonic gonads. Key DEGs (including SMAD2Z, FREM1, NR2F1, SEMA6A, NFIB, RNF165, SMAD7B, SMAD2W, SPIN1W, and HINTW) were validated by RT-qPCR, confirming the transcriptome sequencing results. Among the DEGs, we predict binding sites for NR2F1 and NFIB within the DMRT1 gene promoter and suggest that these factors may serve as potential upstream activators for the expression of DMRT1, and they may initiate high DMRT1 expression in the subsequent stages of male embryos and regulate testicular development. In conclusion, this study investigated DEGs in the gonads of male and female chicken embryos after 3.5 days of incubation and found that NR2F1 and NFIB may serve as potential upstream activators for the expression of DMRT1, which is involved in the early determination of chicken sex. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a modulator of infection severity, yet its impact on the immune response in severe community-acquired pneumonia (sCAP) remains poorly understood. In this prospective cohort study of 108 adults with sCAP, we evaluated the prevalence and prognostic impact of MASLD and performed pathogen-stratified immune profiling of cytokines and semaphorins on hospital days 1 and 5. MASLD was present in 50% of patients and independently associated with early respiratory failure (OR 3.8) and vasopressor-dependent shock (OR 4.0), despite similar sCAP severity at baseline. MASLD patients exhibited distinct immune profiles, including elevated baseline serum levels of SEMA3A, SEMA7A, IL-2, IL-10, IL-17A, CXCL10, and TGF-β1, and reduced SEMA5A. By day 5, the MASLD group exhibited a greater decline in pro-inflammatory mediators compared to non-MASLD patients but failed to upregulate reparative mediators such as SEMA4D and TGF-β1, unlike the non-MASLD group. These kinetics may suggest a maladaptive immune response in MASLD, potentially consistent with early immune exhaustion. Immunokinetic patterns were pathogen-specific, including transient increase in IL-17A and IL-10 in Legionella and Mycoplasma infections, and CXCL10, IL-2, IL-17A, TGF-β1 and IL-10 in influenza. Serum IL-10, CXCL10, SEMA3F, SEMA4D and SEMA7A correlated with organ failure and sCAP complications. These findings underscore the clinical importance of the lung–liver axis and suggest that semaphorins could serve as valuable prognostic biomarkers for identifying high-risk patients. Full article

Background/Objectives: Finding single nucleotide polymorphisms (SNPs) and candidate genes that influence the expression of key traits is essential for genomic selection and helps improve the efficiency of poultry production. Here, we aimed to conduct a genome-wide association study (GWAS) for egg production traits in an F₂ resource population of chickens (Gallus gallus). Methods: The examined F₂ population was produced by crossing two divergently selected breeds with contrasting phenotypes for egg performance traits, namely Russian White (of higher egg production) and Cornish White (of lower egg production). Sampled birds (n = 142) were genotyped using the Illumina Chicken 60K SNP iSelect BeadChip. Results: In the course of the GWAS analysis, we were able to clarify significant associations with phenotypic traits of interest and economic value by using 47,432 SNPs after the genotype dataset was filtered. At the threshold p < 1.06 × 10⁻⁶, we found 23 prioritized candidate genes (PCGs) associated with egg weight at the age of 42–52 weeks (FGF14, GCK), duration of egg laying (CNTN4), egg laying cycle (SAMD12) and egg laying interval (PHF5A, AKR1B1, CALD1, ATP7B, PIK3R4, PTK2, PRKCE, FAT1, PCM1, CC2D2A, BMS1, SEMA6D, CDH13, SLIT3, ATP10B, ISCU, LRRC75A, LETM2, ANKRD24). Moreover, two SNPs were co-localized within the FGF14 gene. Conclusions: Based on our GWAS findings, the revealed SNPs and candidate genes can be used as genetic markers for egg weight and other performance characteristics in chickens to attain genetic enhancement in production and for further genomic selection. Full article

Objective: Lop sheep species exhibit remarkable adaptability to desert pastures and extreme arid climates, demonstrating tolerance to rough feeding and high resistance to stress. However, little is known about the population genetic diversity of Lop sheep and the genetic mechanisms underlying their adaptability to extreme environments. Methods: Blood samples were collected from a total of 110 individuals comprising 80 Ruoqiang Lop sheep and 30 Yuli Lop sheep. A total of 110 Lop sheep were subjected to whole genome resequencing to analyze genetic diversity, population structure, and signatures of selection in both regions. Results: The genetic diversity of the Lop sheep population is substantial, and the degree of inbreeding is low. In comparison to the Lop sheep in Yuli County, the genetic diversity and linkage disequilibrium analysis results for the Lop sheep population in Ruoqiang County are slightly lower. Population structure analysis indicates that Ruoqiang and Yuli Lop sheep have differentiated into two independent groups. Using Yuli Lop sheep as the reference group, an analysis of the extreme environmental adaptability selection signal of Lop sheep was conducted. The FST and π ratio under the 1% threshold identified 1686 and 863 candidate genes, respectively, with their intersection yielding a total of 122 candidate genes. Functional annotation revealed that these genes are associated with various traits, including immune response (SLC12A2, FOXP1, PANX1, DYNLRB2, RAP1B, and SEMA4D), heat and cold resistance (DNAJC13, PLCB1, HIKESHI, and PITPNC1), desert adaptation (F13A1, PANX1, ST6GAL1, STXBP3, ACTN4, and ATP6V1A), and reproductive performance (RAP1B, RAB6A, PLCB1, and METTL15). Conclusions: These research findings provide a theoretical foundation for understanding the survival and reproductive characteristics of Lop sheep in extreme environments, and they hold practical value for the conservation and utilization of Lop sheep genetic resources, as well as for genetic improvement efforts. Full article

The last two decades have provided far more options f both patients and their physicians in the treatment of diabetes mellitus. While dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been approved for nearly two decades, sodium–glucose cotransporter 2 inhibitors (SGLT-2is) are relatively new. Of interest to perioperative physicians, these drugs present specific perioperative concerns, prompting many societies to issue guidelines. Retained gastric contents due to slow gastric emptying is a significant drawback of GLP-1RAs, increasing the risk of aspiration. Recommendations include withholding GLP-1RAs for a predefined period of time, performing gastric ultrasound to evaluate gastric contents, modifying anesthesia management, particularly with regard to the airway, or canceling the scheduled (elective) surgery or procedure. SGLT-2is are known to increase the risk of euglycemic ketoacidosis. The benefits of both GLP-1RAs and SGLT-2is extend beyond the treatment of diabetes. As a result, perioperative physicians may encounter their use outside of their traditional indications. SGLT-2is are being used extensively to treat heart failure and obesity, for example. There have been other developments as well. For instance, Imeglimin, a variant of metformin available in Japan and India, Icodec, a once-weekly basal insulin formulation, and IcoSema, a once-weekly combination of Icodec plus semaglutide, are all being explored, although in their early stages or facing approval challenges. Full article

In sepsis, a balanced pro-inflammatory and anti-inflammatory response results in the bacterial clearance and resolution of inflammation, promoting clinical recovery and survival. Semaphorins, a large family of secreted and membrane-bound glycoproteins, are newly recognized biomarkers and therapeutic targets in immunological and neoplastic disorders. Although semaphorins might also be a crucial part of host defense responses to infection, their role in sepsis is yet to be determined. This study aimed to analyze the association of serum semaphorin concentrations with sepsis severity and outcomes. Serum semaphorin concentrations (SEMA3A, SEMA3C, SEMA3F, SEMA4D, and SEMA7A) were measured in 115 adult patients with community-acquired sepsis and 50 healthy controls. While SEMA3A was decreased, SEMA3C, SEMA3F, SEMA4D, and SEMA7A were increased in sepsis patients. All analyzed SEMA showed good accuracy in identifying patients with sepsis. SEMA kinetics were related to sepsis complications; SEMA3A, SEMA3C, SEMA3F, and SEMA4D with respiratory failure; SEMA3C and SEMA7A with acute kidney injury; and SEMA3C and SEMA3F were related to septic shock. Importantly, SEMA3A, SEMA3C, SEMA4D, and SEMA7A were associated with 28-day mortality. In conclusion, we provide evidence that semaphorins are associated with sepsis course and outcomes. Full article

Mutations in the GBA1 gene increase the risk of developing Parkinson’s disease (PD). However, most carriers of GBA1 mutations do not develop PD throughout their lives. The mechanisms of how GBA1 mutations contribute to PD pathogenesis remain unclear. Cerebrospinal fluid (CSF) is used for detecting pathological conditions of diseases, providing insights into the molecular mechanisms underlying neurodegenerative disorders. In this study, we utilized the proximity extension assay to examine the levels of metabolism-linked protein in the CSF from 17 PD patients carrying GBA1 mutations (GBA1-PD) and 17 idiopathic PD (iPD). The analysis of CSF secretome in GBA1-PD identified 11 significantly altered proteins, namely FKBP4, THOP1, GLRX, TXNDC5, GAL, SEMA3F, CRKL, APLP1, LRP11, CD164, and NPTXR. To investigate GBA1-associated CSF changes attributed to specific neuronal subtypes responsible for PD, we analyzed the cell culture supernatant from GBA1-PD-induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic (mDA) neurons. The secretome analysis of GBA1-PD iPSC-derived mDA neurons revealed that five differently regulated proteins overlapped with those identified in the CSF analysis: FKBP4, THOP1, GLRX, GAL, and CRKL. Reduced intracellular level of the top hit, FKPB4, was confirmed via Western Blot. In conclusion, our findings identify significantly altered CSF GBA1-PD-associated proteins with FKPB4 being firmly attributed to mDA neurons. Full article

Semaphorins have recently been recognized as crucial modulators of immune responses. In the pathogenesis of COVID-19, the activation of immune responses is the key factor in the development of severe disease. This study aimed to determine the association of serum semaphorin concentrations with COVID-19 severity and outcomes. Serum semaphorin concentrations (SEMA3A, -3C, -3F, -4D, -7A) were measured in 80 hospitalized adult patients with COVID-19 (moderate (n = 24), severe (n = 32), critical, (n = 24)) and 40 healthy controls. While SEMA3C, SEMA3F and SEMA7A serum concentrations were significantly higher in patients with COVID-19, SEMA3A was significantly lower. Furthermore, SEMA3A and SEMA3C decreased with COVID-19 severity, while SEMA3F and SEMA7A increased. SEMA4D showed no correlation with disease severity. Serum semaphorin levels show better predictive values than CRP, IL-6 and LDH for differentiating critical from moderate/severe COVID-19. SEMA3F and SEMA7A serum concentrations were associated with the time to recovery, requirement of invasive mechanical ventilation, development of pulmonary thrombosis and nosocomial infections, as well as with in-hospital mortality. In conclusion, we provide the first evidence that SEMA3A, SEMA3C, SEMA3F and SEMA7A can be considered as new biomarkers of COVID-19 severity. Full article

Wool fineness affects the quality of wool, and some studies have identified about forty candidate genes that affect sheep wool fineness, but these genes often reveal only a certain proportion of the variation in wool thickness. We further explore additional genes associated with the fineness of sheep wool. Whole-genome resequencing of eight sheep breeds was performed to reveal selection signals associated with wool fineness, including four coarse wool and four fine/semi-fine wool sheep breeds. Multiple methods to reveal selection signals (Fst and θπ Ratio and XP-EHH) were applied for sheep wool fineness traits. In total, 269 and 319 genes were annotated in the fine wool (F vs. C) group and the coarse wool (C vs. F) group, such as LGR4, PIK3CA, and SEMA3C and NFIB, OPHN1, and THADA. In F vs. C, 269 genes were enriched in 15 significant GO Terms (p < 0.05) and 38 significant KEGG Pathways (p < 0.05), such as protein localization to plasma membrane (GO: 0072659) and Inositol phosphate metabolism (oas 00562). In C vs. F, 319 genes were enriched in 21 GO Terms (p < 0.05) and 16 KEGG Pathways (p < 0.05), such as negative regulation of focal adhesion assembly (GO: 0051895) and Axon guidance (oas 04360). Our study has uncovered genomic information pertaining to significant traits in sheep and has identified valuable candidate genes. This will pave the way for subsequent investigations into related traits. Full article

Background: The mechanism by which infiltrating CD8+ T lymphocytes in the tumour microenvironment influence the survival of patients with ovarian cancer (OC) remains unclear. Methods: To identify biomarkers to optimise OC treatment, 13 immune-cell-line-associated datasets, RNA sequencing data, and clinical data from the GEO, TCGA, and the ICGC were collected. Gene expression in OC was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) staining. Results: We identified 520 genes and three immunological clusters (IC1, IC2, and IC3) associated with CD8+ T cells. Higher IFN scores, immune T cell lytic activity, and immune cell infiltration and upregulated expression of immune-checkpoint-related genes indicated that IC3 is more responsive to immunotherapy, whereas IC1 and IC2 have a poorer prognosis. A 10-gene signature, including SEMA4F, CX3CR1, STX7, PASK, AKIRIN2, HEMGN, GBP5, NSG1, and CXorf65, was constructed, and a multivariate Cox regression analysis revealed a significant association between the 10-gene signature-based risk model and overall survival (p < 0.001). A nomogram was constructed with age and the 10-gene signature. Consistent with the bioinformatics analysis, IHC and qRT-PCR confirmed the accuracy of the signatures in OC tissue samples. The predictive ability of the risk model was demonstrated using the Imvigor210 immunotherapy dataset. Conclusions: The development of a novel gene signature associated with CD8+ T cells could facilitate more accurate prognostics and prediction of the immunotherapeutic response of patients with OC. Full article

Neural crest (NC) is a unique vertebrate cell type arising from the border of the neural plate and epidermis that gives rise to diverse tissues along the entire body axis. Roberto Mayor and colleagues have made major contributions to our understanding of NC induction, delamination, and migration. We report that a truncating mutation of the classical tumor suppressor Adenomatous Polyposis Coli (apc) disrupts craniofacial development in zebrafish larvae, with a marked reduction in the cranial neural crest (CNC) cells that contribute to mandibular and hyoid pharyngeal arches. While the mechanism is not yet clear, the altered expression of signaling molecules that guide CNC migration could underlie this phenotype. For example, apc^mcr/mcr larvae express substantially higher levels of complement c3, which Mayor and colleagues showed impairs CNC cell migration when overexpressed. However, we also observe reduction in stroma-derived factor 1 (sdf1/cxcl12), which is required for CNC migration into the head. Consistent with our previous work showing that APC directly enhances the activity of glycogen synthase kinase 3 (GSK-3) and, independently, that GSK-3 phosphorylates multiple core mRNA splicing factors, we identify 340 mRNA splicing variations in apc mutant zebrafish, including a splice variant that deletes a conserved domain in semaphorin 3f (sema3f), an axonal guidance molecule and a known regulator of CNC migration. Here, we discuss potential roles for apc in CNC development in the context of some of the seminal findings of Mayor and colleagues. Full article