Search Results (44)

Background and Aims: Triple-negative breast cancer (TNBC) is a clinically aggressive malignancy marked by rapid disease progression, limited therapeutic avenues, and high recurrence risk. Ferroptosis an iron-dependent, lipid peroxidation-driven form of regulated cell death that has emerged as a promising therapeutic vulnerability in oncology. This study delineates the ferroptosis-associated molecular architecture of TNBC to identify key regulatory genes with prognostic and translational significance. Methods: Transcriptomic profiles from the GSE103091 dataset (130 TNBC and 30 normal breast tissue samples) were analyzed to identify ferroptosis-related differentially expressed genes (DEGs) using GEO2R. Protein–protein interaction (PPI) networks were constructed via STRING and GeneMANIA, with functional enrichment performed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome analyses. Prognostic relevance was evaluated using GEPIA, BC-GenExMiner, and Kaplan–Meier Plotter survival analyses. Results: Six ferroptosis drivers (MAPK1, TLR4, IFNG, ATM, ULK2, and ATF3) and five suppressors (NFS1, GCLC, TP63, CD44, and SRC) were identified alongside HMOX1, a bifunctional regulator with context-dependent pro- and anti-ferroptotic activity. Enrichment analyses revealed significant associations with oxidative stress regulation, autophagy, immune modulation, and tumor progression pathways. Elevated IFNG expression was consistently linked to improve overall, disease-free, and distant metastasis-free survival, underscoring its dual function in antitumor immunity and ferroptosis sensitization. Conclusions: Ferroptosis represents a critical axis in TNBC pathophysiology, with IFNG emerging as both a prognostic biomarker and a viable therapeutic target. These insights provide a mechanistic foundation for integrating ferroptosis-inducing agents with immunotherapeutic modalities to enhance clinical outcomes and overcome therapeutic resistance in TNBC. Full article

Melanoma is a highly aggressive skin cancer with limited therapeutic response. Targeting intracellular signaling pathways and promoting tumor cell differentiation are promising therapeutic strategies. Pentoxifylline (PTX) and norcantharidin (NCTD) have demonstrated antitumor properties, but their combined mechanisms of action in melanoma remain poorly understood. The effects of PTX (30 and 60 mg/kg) and NCTD (0.75 and 3 mg/kg), administered alone or in combination, in a DBA/2J murine B16-F1 melanoma model via intraperitoneal and intratumoral (IT) routes were evaluated. Tumor growth was monitored, and molecular analyses included RNA sequencing and immunofluorescence quantification of PI3K, AKT1, mTOR, ERBB2, BRAF, and MITF protein levels, and molecular docking simulations were performed. In the final stage of the experiment, combination therapy significantly reduced tumor volume compared to monotherapies, with the relative tumor volume decreasing from 18.1 ± 1.2 (SD) in the IT Control group to 0.6 ± 0.1 (SD) in the IT combination-treated group (n = 6 per group; p < 0.001). RNA-seq revealed over 3000 differentially expressed genes in intratumoral treatments, with enrichment in pathways related to oxidative stress, immune response, and translation regulation (KEGG and Reactome analyses). Minimal transcript-level changes were observed for BRAF and PI3K/AKT/mTOR genes; however, immunofluorescence showed reduced total and phosphorylated levels of PI3K, AKT1, mTOR, BRAF, and ERBB2. MITF protein levels and pigmentation increased, especially in PTX-treated groups, indicating enhanced melanocytic differentiation. Docking analyses predicted direct binding of both drugs to PI3K, AKT1, mTOR, and BRAF, with affinities ranging from −5.7 to −7.4 kcal/mol. The combination of PTX and NCTD suppresses melanoma progression through dual mechanisms: inhibition of PI3K/AKT/mTOR signaling and promotion of tumor cell differentiation. Full article

Urinary extracellular vesicles (U-EVs) are gaining increasing interest as non-invasive liquid biopsy tools for clinical use. Prostate cancer (PCa) is amongst the highest cancer-related cause of death in men, and therefore, the identification of non-invasive robust biomarkers is of high importance. This study assessed U-EV profiles from individuals affected by PCa at Gleason scores 6–9, compared with healthy controls. U-EVs were characterised and assessed for proteomic cargo content by LC-MS/MS analysis. The U-EV proteomes were compared for enrichment of gene ontology (GO), KEGG, and Reactome pathways, as well as disease–gene associations. U-EVs ranged in size from 50 to 350 nm, with the majority falling within the 100–200 nm size range for all groups. U-EV protein cargoes from the PCa groups differed significantly from healthy controls, with 16 protein hits unique to the GS 6–7 and 88 hits to the GS 8–9 U-EVs. Pathway analysis showed increased enrichment in the PCa U-EVs of biological process GO (5 and 37 unique to GS 6–7 and GS 8–9, respectively), molecular function GO (3 and 6 unique to GS 6–7 and GS 8–9, respectively), and cellular component GO (10 and 22 unique to GS 6–7 and GS 8–9, respectively) pathways. A similar increase was seen for KEGG pathways (11 unique to GS 8–9) and Reactome pathways (102 unique to GS 8–9). Enrichment of disease–gene associations was also increased in the PCa U-EVs, with highest differences for the GS 8–9 U-EVs (26 unique terms). The pathway enrichment in the PCa U-EVs was related to several key inflammatory, cell differentiation, cell adhesion, oestrogen signalling, and infection pathways. Unique GO and KEGG pathways enriched for the GS 8–9 U-EVs were associated with cell–cell communication, immune and stress responses, apoptosis, peptidase activity, antioxidant activity, platelet aggregation, mitosis, proteasome, mRNA stability oxytocin signalling, cardiomyopathy, and several neurodegenerative diseases. Our findings highlight U-EVs as biomarkers to inform disease pathways in prostate cancer patients and offer a non-invasive biomarker tool for clinical use. Full article

Background: Cadmium (Cd) is a highly toxic heavy metal. There are very few studies about the effects of Cd on reproductive health and metabolism, and even fewer on metabolic disorders in the uterus of mice in labor. This study is the first to establish a model of Cd exposure in the uterus of laboring mice and investigate the underlying metabolic mechanisms through transcriptomic analysis. Methods: Pregnant mice received intraperitoneal injections of CdCl₂ (1.5 mg/kg) on gestational days 12.5, 14.5, and 16.5 were set up as the experimental group (Cd group), and pregnant mice injected with saline were set up as the control group (CT group). A total of 738 differentially expressed genes (DEGs) were screened using DESeq2 software, including 326 upregulated genes and 412 downregulated genes. Results: Through enrichment databases including the KEGG, GO, Reactome, and PANTHER, we identified 76 metabolism-related DEGs and performed protein–protein interaction (PPI) network analysis. The PPI results were visualized using Cytoscape software and further analyzed, with 18 hub genes (maximum clique centrality score > 10) identified through the MCC algorithm of the Cytohubba plugin. The results showed that the highest-scoring hub genes included mt-Co2, mt-Co3, mt-Atp6, mt-Atp8, mt-Nd3, and mt-Nd4l, which are involved in mitochondrial energy metabolism. The remaining lower-scoring hub genes were primarily associated with coagulation processes. Pathway analysis revealed hub genes predominantly involved in oxidative phosphorylation, complement and coagulation cascades, the cGMP-PKG signaling pathway, and thermogenesis. Conclusion: This study successfully established a Cd exposure-induced uterine injury model, providing valuable references for human reproductive health research. Full article

Pregnant women are at an increased risk of severe influenza complications, necessitating vaccination as a preventive measure. Despite World Health Organization (WHO) recommendations for influenza vaccination during pregnancy, vaccination rates remain suboptimal in many regions. This study aims to identify key differentially expressed genes (DEGs) and biological pathways modulated by influenza vaccination in pregnant women pre- and post-vaccination, contributing to improved vaccine strategies. Microarray data from gene expression omnibus GEO dataset GSE166545 was analyzed to identify DEGs in blood samples from pregnant women at three time points: pre-vaccination (Day 0) and post-vaccination (Days 0 and 1) (Days 1 and 7). DEGs were filtered using an adjusted p-value < 0.05 and |log2 fold change| ≥ 1. Protein/protein interaction (PPI) networks, hub gene identification, and pathway enrichment analyses were conducted using STRING, Cytoscape, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome databases. Hub gene validation was performed using the Human Protein Atlas (HPA) and GTEx Portal. The GSE166545 dataset analysis revealed 60 up-regulated and 12,854 down-regulated genes (Day 1 vs. 7), 55 up-regulated and 12,933 down-regulated genes (Day 0 vs. 1), and two up-regulated with no down-regulated genes (Day 0 vs. 7). Key pathways included interferon alpha/beta (IFN-γ\ β) signaling and toll-like receptor signaling (TLR). Hub genes such as GBP1, CXCL10, RSAD2, and IFI44 demonstrated robust up-regulation, correlating with enhanced immune responses. The initial observation of JCHAIN’s notable up-regulation occurred on the seventh day following vaccination. Validation confirmed these genes’ roles in antiviral defense mechanisms and vaccine responses. The findings reveal distinct immune response dynamics in pregnant women following influenza vaccination, highlighting potential biomarkers for vaccine efficacy. This study underscores the importance of tailored vaccine strategies to improve maternal and neonatal outcomes. Full article

Recent evidence indicates that FAM111B is significantly involved in the progression of various cancers. Nonetheless, the potential pan-cancer implications of FAM111B have not been systematically investigated. In this study, FAM111B’s expression and oncogenic potential were studied using TCGA and GTEx data via GEPIA2, TIMER2.0, and STRING tools. Pathway enrichment analyses with the GO, KEGG, Reactome, and WikiPathways databases were conducted to explore its role in cancer development. The results were validated via multiplex immunofluorescence assays of pancreatic cancer tissues, microarray assays of ovarian cancer tissues, and protein transcriptomics of ovarian cancer cells. The expression levels of FAM111B were elevated in most cancer types and were associated with poor prognostic outcomes. Mechanistically, FAM111B expression was positively correlated with the expression of genes involved in DNA homologous recombination repair and with the infiltration of Th2 CD4+ T cells. These observations were further substantiated in ovarian cancer cell lines and tissue specimens from pancreatic and ovarian cancers. FAM111B functions as a biomarker for the DNA repair pathway and Th2 CD4+ T-cell infiltration in human malignancies. Full article

The impacts of air pollution on human health have become a major concern, especially with rising greenhouse gas emissions and urban development. This study investigates the molecular mechanisms using the STITCH 4.0 and STRING 9.0 databases to analyze the interaction networks (PCI and PPI) associated with two air pollutants: carbon monoxide and hydrogen sulfide. The functional and pathway analysis related to these pollutants were performed by OmicsBox v.3.0. Additionally, critical proteins and their essential pathways were also identified by the Cytoscape networking tool v.3.10.3. AutoDock vina was employed to hypothetically determine the direct interactions of CO and H₂S with the proteins that were found by STITCH. This study revealed that CO and H₂S interacted with the different biological processes related to human health, including erythropoiesis, oxidative stress, energy production, amino acids metabolism, and multiple signaling pathways associated with respiratory, cardiovascular, and neurological functions. Six essential proteins were identified based on their degree of centrality, namely, FECH, HMOX1, ALB, CTH, CBS, and CBSL, which regulate various Reactome and KEGG pathways. Molecular docking analysis revealed that CO exhibited a strong interaction with ADI1, demonstrating a binding affinity of −1.9 kcal/mL. Alternately, the binding energy associated with the H₂S interaction was notably weak (below −0.9 kcal/mL). This present research highlights the necessity for ongoing investigation into the molecular effects of air pollution to guide public health policies and interventions. Full article

Background/Objectives: Pathway annotations of non-macromolecular (relatively small) biomolecules facilitate biological and biomedical interpretation of metabolomics datasets. However, low pathway annotation levels of detected biomolecules hinder this type of interpretation. Thus, predicting the pathway involvement of detected but unannotated biomolecules has a high potential to improve metabolomics data analysis and omics integration. Past publications have only made use of the Kyoto Encyclopedia of Genes and Genomes-derived datasets to develop machine learning models to predict pathway involvement. However, to our knowledge, the Reactome knowledgebase has not been utilized to develop these types of predictive models. Methods: We created a dataset ready for machine learning using chemical representations of all pathway-annotated compounds available from the Reactome knowledgebase. Next, we trained and evaluated a multilayer perceptron binary classifier using combined metabolite-pathway paired feature vectors engineered from this new dataset. Results: While models trained on a prior corresponding KEGG dataset with 502 pathways scored a mean Matthew’s correlation coefficient (MCC) of 0.847 and a 0.0098 standard deviation, the models trained on the Reactome dataset with 3985 pathways demonstrated improved performance with a mean MCC of 0.916, but with a higher standard deviation of 0.0149. Conclusions: These results indicate that the pathways in Reactome can also be effectively predicted, greatly increasing the number of human-defined pathways available for prediction. Full article

(1) Background: Nutrigenomics investigates how diet influences gene expression and how genetic variation impacts dietary responses. Grapes, rich in phytochemicals, exhibit potential disease-preventive properties through nutrigenomic mechanisms rather than direct chemical interactions. This study aimed to explore the modulation of gene expression in muscle tissue resulting from long-term grape consumption. (2) Methods: A mouse model was employed to assess gene expression in the skeletal muscles of males and females fed a grape-enriched diet versus a bland diet over 2.5 years. Heatmaps and principal component analyses were performed to identify patterns, and pathway analyses using KEGG, GO, and Reactome were conducted. (3) Results: Significant sex-specific gene expression changes were observed, with female phenotypes showing greater alterations and converging toward male-like characteristics. Twenty-five differentially expressed genes associated with muscle health were identified. Up-regulated genes such as Ahsg, Alb, Apoa1, and Arg1, and down-regulated genes including Camp, Lcn2, and Irf4, suggest improved muscle function. (4) Conclusions: Long-term grape consumption appears to enhance female muscle traits toward a male-like phenotype, potentially indicating broader health benefits. Further studies and clinical trials are needed to confirm human applicability and the physiological implications of these findings. Nonetheless, this research underscores the role of nutrigenomics in understanding dietary influences on gene expression and sex-specific responses. Full article

It is unknown whether there are differentially expressed proteins (DEPs) in the circulating exosomes of appropriate- vs. small-for-gestational-age (AGA vs. SGA) infants, and if so, whether such DEPs relate to measures of endocrine–metabolic health and body composition in childhood. Proteomic analysis in cord-blood-derived exosomes was performed by label-free quantitative mass spectrometry in AGA (n = 20) and SGA infants (n = 20) and 91 DEPs were identified. Enrichment analysis revealed that they were related to complement and coagulation cascades, lipid metabolism, neural development, PI3K/Akt and RAS/RAF/MAPK signaling pathways, phagocytosis and focal adhesion. Protein–protein interaction (PPI) analysis identified 39 DEPs involved in the pathways enriched by the KEGG and Reactome. Those DEPs were associated with measures of adiposity and insulin resistance and with liver fat at age 7 (all p < 0.01). Multivariate linear regression analysis uncovered that two DEPs (up-regulated in SGA), namely PCYOX1 (related to adipogenesis) and HSP90AA1 (related to lipid metabolism and metabolic-dysfunction-associated steatotic liver disease progression), were independent predictors of the hepatic fat fraction at age 7 (β = 0.634; p = 0.002; R² = 52% and β = 0.436; p = 0.009; R² = 24%, respectively). These data suggest that DEPs at birth may predict insulin resistance, adrenarche and/or ectopic adiposity in SGA children at age 7, when an early insulin-sensitizing intervention could be considered. Full article

Background/Objectives: Alopecia is a hair disorder with a significant impact on quality of life, and its incidence has been increasing in recent years. Current therapeutic options are limited and may cause adverse side effects, highlighting the need to develop safer and more effective formulations. Therefore, the objective of this study was to evaluate the effect of a formulation based on the bioactive fraction of Bacopa procumbens (BFNB), conjugated with gold nanoparticles, on hair growth through the modulation of apoptosis in C57BL/6 mice. Methods: The potential biological activities of the secondary metabolites of B. procumbens present in BFNB were analyzed in silico. In vivo experiments evaluated the expression of pro-apoptotic markers p53, caspase 3-p11, caspase 9-p10, and Bax, as well as anti-apoptotic marker Bcl-2, through Western blotting. Immunohistochemistry further assessed the expression and localization of some of these markers. Additionally, molecular docking and interactomic analyses were performed, complemented by functional enrichment, to explore molecular pathways modulated by the evaluated proteins. Results: In silico analyses suggested that BFNB metabolites are involved in the modulation of hair growth, hair fragility, and apoptosis. This finding was supported by in vivo experiments in mice, where BFNB significantly decreased the expression of p53, caspase 3-p11, caspase 9-p10, and Bax while increasing Bcl-2 levels. Immunohistochemistry showcased a reduction in pro-apoptotic markers in dermal and follicular bulb cells. Furthermore, molecular docking studies identified BFNB metabolites as potential direct modulators of these key proteins, strengthening evidence of their role in apoptotic regulation. The interactomic analysis highlighted 50 proteins associated with apoptosis, and functional enrichment underscored key processes such as p53 signaling, regulation of the apoptosome, and mitochondrial membrane involvement in the intrinsic apoptosis mechanism, among other pathways. Conclusions: This study demonstrates that BFNB effectively modulates apoptosis through key molecular mechanisms, highlighting its potential as an innovative therapy for promoting hair growth. Full article

Background: Incomptine A (IA) has been reported to have cytotoxic activity in non-Hodgkin lymphoma cancer cell lines and have effects on U-937 cells, including the induction of apoptosis, the production of reactive oxygen species, and the inhibition of glycolytic enzymes. Also, IA has cytotoxic activity in the triple-negative subtypes, HER2+, and luminal A of breast cancer cells, with its properties being associated with an effect on the antiapoptotic function of Hexokinase II (HKII). Objectives: In this research, we reviewed the altered levels of proteins present in the lymph nodes of male Balb/c mice inoculated with U-937 cells and treated with IA or methotrexate, as well as mice only inoculated with cancer cells. Methods: Five approaches, including Tandem Mass Tag (TMT), Gene ontology (GO), Reactome, KEGG pathway analysis, and molecular docking, were used. Results: TMT showed that 74 proteins were differentially expressed, out of which 12 presented overexpression (FC ≥ 1.5) and 62 were under expressed (FC ≤ 0.67). In general, the TMT approach showed that IA had a better effect on proteins than methotrexate. Gene ontology, Reactome, and KEGG pathway analysis showed that proteins with altered levels may be implicated in several processes, including gene silencing by RNA, oxidative phosphorylation, glycolysis/gluconeogenesis, cytoskeleton organization, and ATP metabolic and energetic processes. The molecular docking analysis, which used 23 altered proteins as targets, revealed that IA interacted with all the proteins used. Conclusions: The results obtained using the five bioinformatic approaches provide information and show that IA could be used to treat non-Hodgkin lymphoma induced with the U-937 cell line. Also, it could provide a basis for future research and the development of clinical trials. Full article

Background/Objectives: Tonsil-derived mesenchymal stem cells (TMSCs) are in the limelight in regenerative medicine due to their high proliferation and differentiation potential. It is important to conduct studies to determine the optimal conditions for achieving the maximum yield while maintaining the optimal differentiation capacity of TMSCs. Methods: This study explores the impact of serial subculture on TMSCs by analyzing gene expression at passages 2, 4, 6, and 8. For each culture passage, genes with significant differences in RNA expression from previous passages were selected and their characteristics were observed performing enrichment analysis including KEGG (Kyoto Encyclopedia of Genes and Genomes) and Reactome pathway. Results: At each passage, a “cell cycle” term was ranked high with statistical significance in the KEGG and Reactome pathway. Cell cycle gene expression, including Cyclin-dependent kinases (CDKs) and cyclins, increased until passage 6, then decreased by passage 8. The cell cycle is known to be important not only for proliferation but also for determining whether stem cells maintain pluripotency or differentiate into various lineages. Conclusions: The results suggest that cell cycle gene expression can guide the timing for differentiation induction, with passage 6 potentially being a critical point for initiating differentiation. Full article

Long-term treatment with bisphosphonates is accompanied by an increased risk of medication-related osteonecrosis of the jaw (MRONJ). Currently, no clinically useful biomarkers for the predictive diagnosis of MRONJ are available. To investigate the potential key proteins involved in the pathogenesis of MRONJ, a proteomic LC-MS/MS analysis of saliva was performed. Differentially expressed proteins (DEPs) were analyzed using BiNGO, ClueGO, cytoHubba, MCODE, KEGG, and ReactomeFI software packages using Cytoscape platforms. In total, 1545 DEPs were identified, including 43 up- and 11 down-regulated with a 1.5-fold cut-off value and adj. p-value < 0.05. The analysis provided a panel of hub genes, including APOA2, APOB, APOC2, APOC3, APOE, APOM, C4B, C4BPA, C9, FGG, GC, HP, HRG, LPA, SAA2-SAA4, and SERPIND1. The most prevalent terms in GO of the biological process were macromolecular complex remodeling, protein–lipid complex remodeling, and plasma lipoprotein particle remodeling. DEPs were mainly involved in signaling pathways associated with lipoproteins, the innate immune system, complement, and coagulation cascades. The current investigation advanced our knowledge of the molecular mechanisms underlying MRONJ. In particular, the research identified the principal salivary proteins that are implicated in the onset and progression of this condition. Full article

Lung cancer stands out as a leading cause of death among various cancer types, highlighting the urgent need for effective anticancer drugs and the discovery of new compounds with potent therapeutic properties. Natural sources, such as the Conamomum genus, offer various bioactive compounds. Adunctin E (AE), a dihydrochalcone derived from Conamomum rubidum, exhibited several pharmacological activities, and its potential as an anticancer agent remains largely unexplored. Thus, this study aimed to elucidate its apoptotic-inducing effect and identify its molecular targets. The network pharmacology analysis led to the identification of 71 potential targets of AE against lung cancer. Subsequent gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway enrichment analyses revealed the involvement of these targets in cancer-associated signaling pathways. Notably, HSP90AA1, MAPK1, and PIK3CA emerged as key players in apoptosis. In silico molecular docking and dynamic simulations suggested a strong and stable interaction between AE and HSP90AA1. In vitro experiments further confirmed a significant apoptotic-inducing effect of AE on lung cancer cell lines A549 and H460. Furthermore, immunoblot analysis exhibited a substantial decrease in HSP90AA1 levels in response to AE treatment. These findings support the potential anticancer activity of AE through the HSP90AA1 mechanism, underscoring its promise as a novel compound worthy of further research and development for anti-lung cancer therapy. Full article