Search Results (54)

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor in adults, characterized by high intratumoral heterogeneity, therapy resistance, and poor prognosis. Nuclear factor-κB (NF-κB) signaling plays a pivotal role in GBM pathogenesis by promoting proliferation, invasion, inflammation, immune evasion, and treatment resistance. This review provides a comprehensive overview of canonical and non-canonical NF-κB signaling pathways and their molecular mechanisms in GBM, with a focus on their regulation in glioma stem-like cells (GSCs), interactions with key oncogenic factors (including STAT3, FOSL1, and TRPM7), and roles in maintaining tumor stemness, metabolic adaptation, and angiogenesis. We further discuss the reciprocal regulatory dynamics between NF-κB and non-coding RNAs (ncRNAs), particularly microRNAs, highlighting novel ncRNA-mediated epigenetic switches that shape GBM cell plasticity and subtype specification. Additionally, we examine the influence of NF-κB in modulating the tumor microenvironment (TME), where it orchestrates pro-tumorigenic cytokine production, immune cell reprogramming, and stromal remodeling. Finally, we review current NF-κB-targeting therapeutic strategies in GBM, including clinical trial data on small-molecule inhibitors and combinatorial approaches. Understanding the multifaceted roles of NF-κB in GBM offers new insights into targeted therapies aimed at disrupting tumor-promoting circuits within both cancer cells and the TME. Full article

Background/Objectives: Different risk factors are involved in the initiation and progression of melanoma. In particular, genetic and epigenetic pathways are involved in all stages of melanoma and are exploited in therapeutic approaches. This study investigated the role of circular RNA circ_0001591 in melanoma cell migration. Methods: Three different melanoma cell lines were transfected with siRNA targeting circ_0001591 and with mimic or inhibitor molecules for miR-20a-3p and miR-34a-5p. Gene and protein expression levels were analyzed by RT-qPCR and Western blot, respectively. Dual luciferase reporter assays were performed to confirm the direct interaction of miR-20a-3p and miR-34a-5p with circ_0001591, as well as with the 3’UTRs of AXL (for both miRNAs) and FOSL1 (miR-34a-5p only). Wound healing assays were conducted to assess cell migration velocity. Results: The silencing of circ_0001591 significantly reduces the migration ability of melanoma cell lines. This downregulation was associated with an increased expression of miR-20a-3p and miR-34a-5p. Dual luciferase reporter assays confirmed the direct binding of both miRNAs to circ_0001591, supporting its role as a molecular sponge. The same assays also verified that miR-20a-3p directly targets the 3’UTR of AXL, while miR-34a-5p binds the 3’UTRs of both AXL and FOSL1. Western blot analysis showed that the modulation of this axis affects the expression levels of the AXL and FRA1 oncoproteins. Conclusions: Our findings demonstrate that circ_0001591 promotes melanoma migration by sponging miR-20a-3p and miR-34a-5p, thereby indirectly modulating the expression of AXL and FRA1 oncoprotein. Further investigations of this new regulatory network are needed to better understand its role in melanoma progression and to support the development of targeted therapies. Full article

Currently, there are two major theories regarding the pathogenesis of sepsis: hyperimmune and hypoimmune. The hyperimmune theory suggests that a cytokine storm causes the symptoms of sepsis. On the contrary, the hypoimmune theory suggests that immunosuppression causes the manifestations of sepsis. By conducting a microarray analysis on peripheral leukocytes from patients with sepsis, this study found that hyperactivity of TH17 immunity was noted in sepsis patients. Innate immunity-related genes are significantly upregulated, including CD14, TLR1,2,4,5,8, HSP70, CEBP proteins, AP1 (JUNB and FOSL2), TGFB1, IL6, TGFA, CSF2 receptor, TNFRSF1A, S100A binding proteins, CCR2, FPR2, amyloid proteins, pentraxin, defensins, CLEC5A, whole complement machinery, CPD, NCF, MMP, neutrophil elastase, caspases, IgG and IgA Fc receptors (CD64, CD32), ALOX5, PTGS, LTB4R, LTA4H, and ICAM1. The majority of adaptive immunity genes were downregulated, including MHC-related genes, TCR genes, granzymes/perforin, CD40, CD8, CD3, TCR signaling, BCR signaling, T and B cell-specific transcription factors, NK killer receptors, and TH17 helper-specific transcription factors (STAT3, RORA, and REL), as well as Treg-related genes, including TGFB1, IL15, STAT5B, SMAD2/4, CD36, and thrombospondin. The findings of this study show that Th17 with Treg over-presentation play an important role in the pathophysiology of sepsis. Full article

Background: The skin, a complex organ vital for protecting the body against environmental challenges, undergoes a multifaceted wound healing process involving hemostasis, inflammation, proliferation, and remodeling. The transcription factor FOSL1 has been implicated in various cellular processes crucial for wound healing, including cell cycle regulation, differentiation, and apoptosis. We hypothesize that FOSL1 is a key regulator of wound healing processes. Objective: The objective of this study was to investigate the role of FOSL1 in cutaneous wound healing, identify the core signaling pathways involved, and assess FOSL1′s potential as a therapeutic target. Method: We utilized datasets from the Gene Expression Omnibus (GEO) and applied the ‘limma’ package to discern differentially expressed genes (DEGs). We intersected these DEGs with transcription factor-associated genes from the TRRUST database. Subsequently, we constructed Protein–Protein Interaction (PPI) networks via the STRING database. Machine learning algorithms were instrumental in identifying pivotal genes, a finding corroborated through animal modeling and Western blot analysis of tissue samples. To elucidate biological pathway activities from gene expression data, we deployed the ‘PROGENy’ package, complemented by machine learning for precise pathway identification. Furthermore, Gene Set Variation Analysis (GSVA) was executed across Hallmark, biological process (BP), molecular function (MF), and cellular component (CC) categories to deepen our understanding of the wound healing process. Results: Our analysis revealed that FOSL1 is significantly upregulated in wounded skin. The Mitogen-Activated Protein Kinase (MAPK) and Epidermal Growth Factor Receptor (EGFR) pathways were identified as significantly associated with FOSL1. GSVA identifies critical changes in wound healing processes like ‘apical junction’ and ‘epithelial–mesenchymal transition.’ The upregulation of ‘cytoplasm organization’ and ‘response to gravity’ suggests roles in cellular adaptation. Molecular function analysis indicates alterations in ‘cytokeratin filaments’ and ‘growth factor binding,’ which are key for tissue repair. Cellular component shifts in ‘postsynaptic cytosol’ and ‘endoplasmic reticulum’ suggest changes in communication and protein processing. Conclusions: Our study identifies FOSL1 as a potential regulator of cutaneous wound healing through its modulation of cellular signaling pathways, offering novel insights into the molecular control of tissue repair. These findings highlight FOSL1 as a promising therapeutic target to accelerate healing in chronic or impaired wounds. Full article

Differences in skin and hair phenotypes between the scapular and ventral regions of yaks (Bos grunniens) are obvious and become more prominent with age. However, the genetic mechanism that causes differences in yak skin at different ages has not been reported. In this study, we investigated the transcriptomic profile of yak skin across different ages (0.5 years, 2.5 years, and 4.5 years) and body sites (scapular and ventral regions). Differential gene expression analysis was initially conducted to explore the transcriptomic differences in skin at different ages and different body sites. Subsequently, weighted gene co-expression network analysis (WGCNA) was employed to analyze the transcriptomic data comprehensively. The results showed that, among all comparison groups, the Y2.5_S vs. Y2.5_V group (regional comparison) exhibited the highest number of DEGs, with 491 genes (179 upregulated and 312 downregulated), followed by the Y2.5_V vs. Y0.5_V group (age comparison), which had 370 DEGs (103 upregulated and 267 downregulated). DEGs such as IGF2BP3, ADCY8, FOSL1, and S100A8 were found in all comparison groups of different ages, and multiple members of the HOX gene family including HOXC10, HOXA9, HOXA6, HOXB9, and HOXB6 were differentially expressed in comparison groups at different sites. Functional enrichment analysis showed that there were more obvious differences in immune function between different ages of skin and more obvious differences in endocrine function between different parts of skin. WGCNA revealed that genes related with immunity such as GLYATL2, ACSL5, and SPDEF were the core genes of the co-expression module associated with the scapula region, and multiple genes related to hair follicle development such as FOXN1, OVOL1, DLX3, HOXC13, and TCHH were found to be the hub genes of the co-expression module associated with the ventral region. Overall, our study provides valuable insights into the transcriptomic complexity of yak skin across different ages and body sites. The differential gene expression patterns and co-expression network modules identified in this study lay the foundation for further research on skin biology and adaptation mechanisms in yaks. Full article

Biodentine, a tricalcium silicate cement, has emerged as a retrograde root-end filling material to promote periapical lesion (PL) healing after apicoectomy. However, its underlying mechanisms remain unclear. This study tested the hypothesis that Biodentine stimulates the osteogenic differentiation of mesenchymal stromal cells (MSCs) derived from PLs. The Biodentine extract (B-Ex) was prepared by incubating polymerized Biodentine in RPMI medium (0.2 g/mL) for three days at 37 °C. B-Ex, containing both released microparticles and soluble components, was incubated with PL-MSCs cultured in either a basal MSC medium or suboptimal osteogenic medium. Osteogenic differentiation was assessed by Alizarin Red staining and the expression of 20 osteoblastogenesis-related genes. Non-cytotoxic concentrations of B-Ex stimulated the proliferation of PL-MSCs and induced their osteogenic differentiation in a dose-dependent manner, with a significantly enhanced effect in suboptimal osteogenic medium. B-Ex upregulated most early and late osteoblastic genes. However, the differentiation process was prolonged, as indicated by the delayed expression of wingless-type MMTV integration site family member 2 (WNT2), bone gamma-carboxyglutamate protein (BGLAP), bone morphogenic protein-2 (BMP-2), growth hormone receptor (GHR), and FOS-like 2, AP-1 transcription factor subunit (FOSL2), compared with their expression under optimal osteogenic conditions. The stimulatory effect of B-Ex was primarily calcium dependent, as it was reduced by 85% when B-Ex was treated with the calcium-chelating agent EGTA. In conclusion, Biodentine promotes the osteogenic differentiation of PL-MSCs in a calcium-dependent manner, supporting its stimulatory role in periapical healing. Full article

MicroRNA-204-5p (miR-204-5p) is a critical regulator of differentiation, structural maintenance, and inflammation in limbal epithelial cells (LECs). This study examined the role of miR-204-5p in modulating the gene expression related to transcription factors, cell structure, extracellular matrix remodeling, and retinoic acid signaling under normal and lipopolysaccharide (LPS)-induced inflammatory conditions. Using qPCR, we analyzed the mRNA levels of FOSL2, FOXC1, Meis2, PPARγ, ABCG2, PTGES2, IL-1β, IL-6, KRT3, KRT12, MMP2, MMP9, RARA, RARB, RXRA, RXRB, CRABP2, RBP1, RDH10, ADH7, ADH1A1, FABP5, CYP1B1, and CYP26A1, while changes in protein levels were assessed via Western blot or ELISA. Our data revealed that the overexpression of miR-204-5p reduced the mRNA levels of FOXC1, KRT12, and RDH10 under normal and inflammatory conditions (p ≤ 0.039). Additionally, it decreased FOSL2 and RXRA mRNA under normal conditions (p = 0.006, p = 0.011) and KRT3 and FABP5 mRNA under inflammatory conditions (p = 0.010, p = 0.001). The IL-6 mRNA expression was significantly increased following the LPS treatment in cells overexpressing miR-204-5p (p = 0.029). A protein analysis revealed significant reductions in FOXC1 and KRT3 in the miR-204-5p-transfected cells during LPS-induced inflammation (p = 0.020, p = 0.030). These findings suggest that miR-204-5p modulates genes critical to the differentiation, migration, and inflammatory response of LECs. The modulation of FOXC1 and KRT3 by miR-204-5p highlights these proteins as novel targets under inflammatory conditions. Full article

Meat production traits in pigs are critical economic characteristics, primarily influenced by the formation and development of skeletal muscle. Skeletal muscle development is regulated by a complex transcriptional network, which partly relies on chromatin accessibility for initiation. Ningxiang pigs, a renowned Chinese indigenous breed, are highly valued for their tender meat. However, studies focusing on skeletal muscle development in Ningxiang pigs, particularly from the perspective of chromatin accessibility, have not yet been reported. Based on this, the present study selected several key time points in the skeletal muscle development of Ningxiang pigs to perform Transposase-Accessible Chromatin Sequencing (ATAC-seq) and RNA sequencing (RNA-seq). This was carried out to identify key open chromatin regions and genes during different growth stages, which could influence skeletal muscle development in Ningxiang pigs. We collected longissimus dorsi muscle samples at postnatal days 14 (D14), 28 (D28), 85 (D85), 165 (D165), and 250 (D250). For each age, three individuals were collected for ATAC-seq and RNA-seq. After initial differential analysis among different ages, we identified 6412 differentially accessible chromatin peaks and 1464 differentially expressed genes. To clarify the key candidate transcription factors affecting the development of skeletal muscle in Ningxiang pigs, motif analysis of differential peaks revealed potential cis-regulatory elements with binding sites for transcription factors, including Fosl2 and JunB. Correlation analysis identified 56 overlapping genes and a significant positive correlation (r = 0.73, p = 1 × 10⁻¹⁴) between gene expression and chromatin accessibility. Key candidate genes such as HOXA10, closely related to skeletal muscle development, were specifically examined. These results enhance our understanding of the genetic and epigenetic regulatory mechanisms of porcine skeletal muscle development, providing a robust foundation for future molecular studies. Full article

Anthrax represents a disease resulting from infection by toxin-secreting bacteria, Bacillus anthracis. This research aimed to identify new therapeutic targets to combat anthrax. We performed assays to assess cell viability, apoptosis, glycogen consumption, and compound uptake and release in hepatocytes and cardiomyocytes responding to anthrax toxins. Microarray analysis was carried out to identify the genes potentially involved in toxin-induced toxicity. Knockdown experiments were performed to validate the contributions of the identified genes. Our study showed that anthrax edema toxin (EdTx) and lethal toxin (LeTx) induced lethal damage in mouse liver and heart, respectively. Microarray assays showed that 218 genes were potentially involved in EdTx-mediated toxicity, and 18 genes were potentially associated with LeTx-mediated toxicity. Among these genes, the knockdown of Rgs1, Hcar2, Fosl2, Hcar2, Cxcl2, and Cxcl3 protected primary hepatocytes from EdTx-induced cytotoxicity. Plasminogen activator inhibitor 1 (PAI-1)-encoding Serpine1 constituted the most significantly upregulated gene in response to LeTx treatment in mouse liver. PAI-1 knockout mouse models had a higher tolerance to LeTx compared with wild-type counterparts, suggesting that PAI-1 is essential for LeTx-induced toxicity and might represent a therapeutic target in LeTx-induced tissue damage. These results provide potential therapeutic targets for combating anthrax-toxin-induced liver and heart damage. Full article

Background: TSPX is an X-linked tumor suppressor that was initially identified in non-small cell lung cancer (NSCLC) cell lines. However, its expression patterns and downstream mechanisms in NSCLC remain unclear. This study aims to investigate the functions of TSPX in NSCLC by identifying its potential downstream targets and their correlation with clinical outcomes. Methods: RNA-seq transcriptome and pathway enrichment analyses were conducted on the TSPX-overexpressing NSCLC cell lines, A549 and SK-MES-1, originating from lung adenocarcinoma and squamous cell carcinoma subtypes, respectively. In addition, comparative analyses were performed using the data from clinical NSCLC specimens (515 lung adenocarcinomas and 502 lung squamous cell carcinomas) in the Cancer Genome Atlas (TCGA) database. Results: TCGA data analysis revealed significant downregulation of TSPX in NSCLC tumors compared to adjacent non-cancerous tissues (Wilcoxon matched pairs signed rank test p < 0.0001). Notably, the TSPX expression levels were inversely correlated with the cancer stage, and higher TSPX levels were associated with better clinical outcomes and improved survival in lung adenocarcinoma, a subtype of NSCLC (median survival extended by 510 days; log-rank test, p = 0.0025). RNA-seq analysis of the TSPX-overexpressing NSCLC cell lines revealed that TSPX regulates various genes involved in the cancer-related signaling pathways and cell viability, consistent with the suppression of cell proliferation in cell culture assays. Notably, various potential downstream targets of TSPX that correlated with patient survival (log-rank test, p = 0.016 to 4.3 × 10⁻¹⁰) were identified, including EGFR pathway-related genes AREG, EREG, FOSL1, and MYC, which were downregulated. Conclusions: Our results suggest that TSPX plays a critical role in suppressing NSCLC progression by downregulating pro-oncogenic genes, particularly those in the EGFR signaling pathway, and upregulating the tumor suppressors, especially in lung adenocarcinoma. These findings suggest that TSPX is a potential biomarker and therapeutic target for NSCLC management. Full article

This study investigates the impact of single prolonged stress (SPS), a model of post-traumatic stress disorder (PTSD), on cardiovascular responses, hypothalamic paraventricular nucleus (PVN) activity, and vascular function to elucidate the mechanisms linking traumatic stress to hypertension. Although SPS did not directly cause chronic hypertension in male Sprague Dawley (SD) rats, it induced acute but transient increases in blood pressure and heart rate and significantly altered the expression of hypertension-associated genes, such as vasopressin, angiotensin II type 1 receptor (AT1R), and FOSL1 in the PVN. Notably, mitochondrial reactive oxygen species (mtROS) were predominantly elevated in the pre-autonomic regions of the PVN, colocalizing with AT1R- and FOSL1-expressing cells, suggesting that oxidative stress may amplify sympathetic activation and stress responses. SPS also increased mRNA levels of pro-inflammatory cytokines (TNFα and IL1β) and inducible nitric oxide synthase (iNOS) in the aorta, and impaired vascular reactivity to vasoconstrictor and vasodilator stimuli, reflecting compromised vascular function. These findings suggest that SPS-sensitize neuroendocrine, autonomic, and vascular pathways create a state of cardiovascular vulnerability that could predispose individuals to hypertension when exposed to additional stressors. Understanding these mechanisms provides critical insights into the pathophysiology of stress-related cardiovascular disorders and underscores the need for targeted therapeutic interventions that address oxidative stress and modulate altered PVN pathways to mitigate the cardiovascular impact of PTSD and related conditions. Full article

Normotensive and hypertensive organisms respond differently to stress factors; however, the features of the central molecular genetic mechanisms underlying the reaction of the hypertensive organism to stress have not been fully established. In this study, we examined the transcriptome profiles of the hypothalamus of hypertensive ISIAH rats, modeling a stress-sensitive form of arterial hypertension, and normotensive WAG rats at rest and after exposure to a single short-term restraint stress. It was shown that oxidative phosphorylation is the most significantly enriched process among metabolic changes in the hypothalamus of rats of both strains when exposed to a single short-term restraint stress. The analysis revealed DEGs representing both a common response to oxidative stress for both rat strains and a strain-specific response to oxidative stress for hypertensive ISIAH rats. Among the genes of the common response to oxidative stress, the most significant changes in the transcription level were observed in Nos1, Ppargc1a, Abcc1, Srxn1, Cryab, Hspb1, and Fosl1, among which Abcc1 and Nos1 are associated with hypertension, and Fosl1 and Ppargc1a encode transcription factors. The response to oxidative stress specific to hypertensive rats is associated with the activation of the Fos gene. The DEG’s promoter region enrichment analysis allowed us to hypothesize that the response to oxidative stress may be mediated by the participation of the transcription factor CREB1 (Cyclic AMP-responsive element-binding protein 1) and the glucocorticoid receptor (NR3C1) under restraint stress in the hypothalamus of both rat strains. The results of the study revealed common and strain-specific features in the molecular mechanisms associated with oxidative phosphorylation and oxidative stress response in the hypothalamus of hypertensive ISIAH and normotensive WAG rats following a single short-term restraint stress. The obtained results expand the understanding of the most significant molecular targets for further research aimed at developing new therapeutic strategies for the prevention of the consequences of acute emotional stress, taking into account the hypertensive state of the patient. Full article

Background/Objectives: Estrogens and HPV are necessary for cervical cancer (CC) development. The levels of the G protein-coupled estrogen receptor (GPER) increase as CC progresses, and HPV oncoproteins promote GPER expression. The role of this receptor is controversial due to its anti- and pro-tumor effects. This study aimed to determine the effect of GPER activation, using its agonist G-1, on the transcriptome, cell migration, and invasion in SiHa cells and non-tumorigenic keratinocytes transduced with the HPV16 E6 or E7 oncogenes. Methods: Transcriptome analysis was performed to identify G-1-enriched pathways in SiHa cells. We evaluated cell migration, invasion, and the expression of associated proteins in SiHa, HaCaT-16E6, and HaCaT-16E7 cells using various assays. Results: Transcriptome analysis revealed pathways associated with proliferation/apoptosis (TNF-α signaling, UV radiation response, mitotic spindle formation, G2/M cell cycle, UPR, and IL-6/JAK/STAT), cellular metabolism (oxidative phosphorylation), and cell migration (angiogenesis, EMT, and TGF-α signaling) in SiHa cells. Key differentially expressed genes included PTGS2 (pro/antitumor), FOSL1, TNFRSF9, IL1B, DIO2, and PHLDA1 (antitumor), along with under-expressed genes with pro-tumor effects that may inhibit proliferation. Additionally, DKK1 overexpression suggested inhibition of cell migration. G-1 increased vimentin expression in SiHa cells and reduced it in HaCaT-16E6 and HaCaT-16E7 cells. However, G-1 did not affect α-SMA expression or cell migration in any of the cell lines but increased invasion in HaCaT-16E7 cells. Conclusions: GPER is a promising prognostic marker due to its ability to activate apoptosis and inhibit proliferation without promoting migration/invasion in CC cells. G-1 could potentially be a tool in the treatment of this neoplasia. Full article

(1) Background: GHaK is derived from the antimicrobial peptide temporin-GHa by substituting the amino acid H with K to enhance its bactericidal activity. The present research aims to broaden the pharmacological potential of GHaK by exploring its antineoplastic activity against human lung adenocarcinoma. (2) Methods: The cell viability, migration, invasion, apoptosis, and cell cycle of A549 and PC-9 cells were tested after GHaK treatment. miRNA sequencing, RT-PCR, Western blotting, and luciferase reporter gene assay were further performed to reveal the potential mechanism. (3) Results: GHaK significantly suppressed cell viability, migration, and invasion; induced apoptosis; and caused cell cycle arrest in the G2/M and S phase in PC-9 and A549 cells, respectively. The miRNA sequencing results show a total of 161 up-regulated and 115 down-regulated miRNAs. Furthermore, the study identified six up-regulated miRNAs (miR-4516, miR-4284, miR-204-5p, miR-12136, miR-4463, and miR-1296-3p) and their inhibitory effects on the expressions of target genes (Wnt 8B, FZD2, DVL3, and FOSL1) caused by miR-4516 directly interacting with Wnt 8B. Western blotting revealed the down-regulation of p-GSK-3β, along with a decreased expressions of cyclin A1 and CDK2 in A549 cells and cyclin B1 and CDK1 in PC-9 cells. (4) Conclusions: Temporin-GHaK exhibits antineoplastic activity against human lung adenocarcinoma by inhibiting the Wnt signaling pathway through miRNA-4516. Full article