Integrin signaling serves as a fundamental regulator in human pluripotent stem cell (hPSC) biology, mediating adhesion, survival, and pluripotency through interactions with extracellular matrix (ECM) components. Specific integrins, including α6β1, αvβ5, and α3β1, engage ECM ligands such as laminin-511/521 and vitronectin (VTN) to sustain hPSC self-renewal. These engagements trigger essential downstream pathways, including PI3K/AKT, MAPK/ERK, focal adhesion kinase (FAK)-Src, and RhoA/Rho-associated protein kinase (ROCK), thereby maintaining the expression of pluripotency factors like OCT4, NANOG, and SOX2 while integrating mechanotransductive cues. FAK and Src convert ECM-derived mechanical signals into biochemical responses, regulating cytoskeletal reorganization, YAP/TAZ nuclear translocation, and context-dependent gene expression. For scalable, xeno-free culture, recombinant substrates such as truncated vitronectin (VTN-N) and laminin-511/521 E8 fragments, paired with defined media (e.g., Essential 8 or mTeSR1), support robust hPSC expansion under good manufacturing practice (GMP) conditions. Extending to differentiation, integrin-ECM crosstalk directs lineage commitment across diverse fates, including hematopoietic, cardiovascular, neural, hepatic, epithelial, endodermal, and oligodendroglial lineages, by fine-tuning signaling specificity and ECM composition. This review focuses on recent advances in the mechanistic interplay between integrin signaling and ECM proteins in hPSC maintenance, mechanotransduction, and lineage-directed differentiation, emphasizing defined culture systems and their translational potential in regenerative medicine.
Background: This study aims to examine the roles and mechanisms of action of bellidifolin (BEL) in alleviating doxorubicin-mediated cardiotoxicity using network pharmacology and experimental validation .
Materials and methods: Mice with doxorubicin-induced cardiotoxicity were randomly assigned to control, model, BEL, and dexrazoxane (DEX) groups. Echocardiography, histological staining, network pharmacology, and molecular validation were employed to assess cardiac function and myocardial injury. Immunohistochemical staining, western blotting, and RT-qPCR were used to confirm predicted targets and fibrosis biomarkers.
Results: In vivo experiments demonstrated that BEL significantly improved cardiac function, as indicated by enhanced Ejection Fraction (EF) and Fractional Shortening (FS) compared to the model group (p < 0.01). BEL also notably reduced myocardial injury markers, including creatine kinase MB isoenzyme (CK-MB) and lactate dehydrogenase (LDH) (p < 0.01), and alleviated doxorubicin-induced myocardial fibrosis. Network pharmacology identified 61 common target genes for BEL and cardiotoxicity. Proteinprotein interaction (PPI) network analysis highlighted 16 core genes, including transforming growth factor (TGF)-β1. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses revealed that BEL's action pathways were primarily linked to the PI3K-AKT signaling pathway. Molecular docking and dynamic simulations showed a strong binding affinity between BEL and the core target TGF-β1. In vivo validation confirmed that BEL significantly downregulated the expression of TGF-β1, α-smooth muscle actin (SMA), collagen I (Col I), and collagen III (Col III) in myocardial tissue (p < 0.01 or p < 0.05), while activating the PI3K-AKT signaling pathway (p < 0.01 or p < 0.05).
Conclusion: BEL presents as a promising therapeutic candidate for cardiotoxicity, likely through its anti-fibrotic effects via the reduction of TGF-β1, α-SMA, Col I, and Col III expression, alongside regulation in the PI3K-AKT signaling pathway.
Background: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma (MM), but the mechanisms of progression remain unclear.
Methods and objectives: Transcriptomic datasets procured from the Gene Expression Omnibus (GEO) underwent thorough analysis to ascertain disease-related modules using weighted gene co-expression network analysis. A prognostic model (MGUSscore) was constructed via least absolute shrinkage and selection operator (LASSO) regression within the GSE136337 cohort and validated across independent datasets (The Cancer Genome Atlas - multiple myeloma [TCGA-MM], GSE4581, GSE57317). Crucially, the investigation integrated original single-cell ATAC-seq profiling, immune landscape characterization, and pharmacogenomic sensitivity prediction. Protein-level disparities were validated in clinical specimens using immunohistochemistry and multiplex immunofluorescence.
Results: DAP3 and UBE2S were identified as central drivers of progression. The MGUSscore effectively stratified patients into risk categories, with high-risk individuals exhibiting significantly inferior survival outcomes (p < 0.001). Notably, the high-risk group was characterized by distinct immune infiltration patterns and predicted responsiveness to specific chemotherapies. Experimental validation confirmed markedly elevated DAP3 and UBE2S protein expression in MM compared to MGUS tissues.
Conclusion: Collectively, DAP3 and UBE2S may constitute promising therapeutic targets for MM intervention, meriting additional investigative efforts.
The Rho GTPase and Rho kinase (ROCK) signaling pathway is essential for cellular mechanics, acting as key regulators of the actin cytoskeleton and actomyosin contractility in various cell types and tissues. Rho GTPases, functioning as molecular switches, and ROCKs, their primary downstream effectors, influence vital cellular processes such as cell shape, movement, growth, and gene regulation. This review explores how this pathway maintains tissue tone, especially its significant role in regulating trabecular meshwork (TM) contractility. It also highlights the critical part of the Rho-ROCK pathway in precisely managing intraocular pressure (IOP). Dysregulation of Rho/ROCK signaling is a known factor in increased aqueous humor (AH) outflow resistance, a major cause of glaucoma, which is a leading cause of irreversible blindness worldwide. The review discusses the molecular mechanisms behind these processes, illustrating how the pathway affects the contractile behavior of tissues in the AH outflow pathway-including the TM and Schlemm's canal (SC)-by directly impacting actomyosin dynamics and extracellular matrix (ECM) remodeling. It also examines the extensive interaction between Rho/ROCK and other vital signaling pathways such as MAPK/ERK and serum response factor (SRF), emphasizing its integrated role within the complex cellular signaling systems in the AH drainage pathway. This comprehensive discussion concludes by highlighting the promising therapeutic potential of Rho kinase inhibitors (RKIs) as a new class of drugs for glaucoma. These agents not only effectively lower IOP but also show emerging neuroprotective properties, with broader implications for other eye and systemic diseases. Understanding this pathway-from its molecular structure to clinical applications-provides a strong foundation for future research and the development of more precise interventions.
Background: Glioblastoma (GBM) is an exceptionally aggressive type of brain tumor with a poor prognosis, underscoring the urgent need to identify new molecular targets for therapeutic development. The objective of this research is to clarify the molecular interactions affected by the oncometabolite D-2-hydroxyglutarate (D-2-HG) within the framework of GBM.
Methods: Differential expression analysis of multi-omics data identified potential target genes linked to GBM pathogenesis. To enhance our understanding of the binding interactions between D-2-HG and the identified target proteins, we utilized an integrated methodology encompassing various machine learning algorithms, network pharmacology techniques, and molecular docking.
Results: A sum of 135 genes was recognized as possible targets through which D-2-HG exerts its effects in GBM. The ensuing analysis, utilizing machine learning techniques, identified six crucial genes [eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), fatty acid binding protein 3 (FABP3), potassium voltage-gated channel subfamily Q member 2 (KCNQ2), epithelial cell adhesion molecule (EPCAM), sphingosine-1-phosphate receptor 5 (S1PR5), and metabotropic glutamate receptor 3 (GRM3)] as key regulators. Among these, FABP3, KCNQ2, EPCAM, S1PR5, and GRM3 were significantly downregulated, whereas EIF4EBP1 was markedly upregulated (p < 0.05). Molecular docking simulations indicated a strong binding affinity of D-2-HG towards the target proteins.
Conclusions: Our study suggests that D-2-HG plays a significant role in the pathogenesis of GBM by modulating specific genes and signaling pathways. Utilizing machine learning techniques, we identified six essential regulatory genes, and further molecular docking simulations revealed a strong affinity of D-2-HG for these critical targets. Collectively, these results establish a substantial basis for future investigations into the mechanistic role of D-2-HG in GBM oncogenesis.
Background: Gastric cancer (GC) remains a major global health burden, particularly in East Asia, with complex etiologies involving Helicobacter pylori infection, diet, host genetics, and environmental exposures. GC development follows the Correa sequence (CS), a multistep cascade from gastritis to atrophy, erosion, and carcinoma. Although gut microbiota (GM) dysbiosis and metabolic reprogramming have each been implicated in GC, their integrated dynamics across CS remain incompletely defined.
Methods: We recruited participants across five groups: normal controls (G1), gastritis (G2), atrophy (G3), erosion (G4), and GC (G5). Fecal and gastric tissue samples were analyzed using 16S rRNA sequencing and untargeted metabolomics under both ion modes. Microbial diversity was assessed by α- and β-diversity indices, linear discriminant analysis effect size (LEfSe), and functional prediction. Metabolic features were profiled by UHPLC-Q Exactive Orbitrap MS, and differential metabolites were identified using t-tests and partial least squares discriminant analysis (PLS-DA). Diagnostic potential was evaluated using receiver operating characteristic (ROC) curves.
Results: Microbial α-diversity decreased significantly with progression, particularly in G3, while compositional shifts included depletion of Bacteroides and Faecalibacterium alongside enrichment of Actinobacteria, Peptostreptococcaceae, and Lachnoclostridium. LEfSe identified Bifidobacterium and Oscillospiraceae as potential biomarkers of advanced stages. ROC analyses demonstrated strong discriminatory power, with the class Actinobacteria achieving an area under the ROC curve (AUC) of 0.935 in distinguishing controls from GC. Fecal metabolomics revealed reductions in anti-inflammatory short-chain fatty acids (SCFAs) and increases in pro-inflammatory metabolites emerging at G3, while tissue metabolomics showed broader reprogramming in GC involving amino acid, nucleotide, lipid, and energy metabolism. Notably, erosion (G4) exhibited transitional features, whereas atrophy (G3) marked a distinct metabolic "breakpoint".
Conclusions: By integrating GM and metabolomic data, this study delineates stage-specific microbial and metabolic alterations along the CS. Atrophy represents a pivotal inflection point in the transition from homeostasis to carcinogenesis, while erosion serves as a transitional state. Combined microbiota-metabolite signatures hold promise for non-invasive early detection, disease stratification, and mechanistic insights into metabolic dependencies in GC.
Endometriosis is a chronic pathological condition characterized by the growth of endometrial-like tissue outside the uterine cavity and is frequently associated with severe pain, persistent inflammation, and fibrosis within the pelvic region and other parts of the body. The exact causes of endometriosis are not clear, but an innate or adaptive immune response defect has recently been suggested as a factor in the disease's development. Carnosine is a natural dipeptide formed by the ligation of β-alanine and L-histidine and characterized by a multimodal mechanism of action that includes antioxidant and anti-inflammatory activities. Carnosine has also been shown to modulate glucose, nucleotide, and lipid metabolism as well as the response of immune cells, all processes that play a key role in the context of endometriosis. Despite numerous reviews published on the structure, role, function, and biological activities of carnosine in preclinical and clinical settings, none have focused on its therapeutic potential for the prevention or treatment of reproductive disorders, including endometriosis. In this review, after a brief introduction to the pathogenesis and pathophysiology of endometriosis, we focus on the use of carnosine for the management of reproductive disorders, concluding with its ability to modulate specific cellular and molecular mechanisms closely related to endometriosis. Given the central role of oxidative stress and inflammation across several reproductive disorders, carnosine may represent a promising therapeutic candidate not only in endometriosis, but also in broader reproductive health contexts.
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