Glioma remains a lethal brain malignancy with a dismal prognosis. Syntaphilin (SNPH), a mitochondrial anchoring protein, shows emerging relevance in cancer biology. This study investigates the diagnostic and prognostic potential of SNPH, while elucidatingits functional mechanisms in glioma progression. The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Genotype-Tissue Expression (GTEx) and Human Protein Atlas (HPA) were utilized to systematically analyze SNPH, including its differential transcriptional and translational expression, survival correlation, functional enrichment, and immune microenvironment in glioma. Subsequently, the effects of SNPH on cell migration, invasion, mitochondria distribution, epithelial-mesenchymal transition, focal adhesion (FA) maturation and FA kinase (FAK) signaling were validated via in vitro. SNPH expression was markedlydownregulatedin glioma (P<0.001), demonstratinghigh diagnostic potential for glioma detection (area under the curve=0.819). Clinically, decreasedSNPH levelswere associatedwith aggressive features(WHO grade G4, glioblastoma subtype) (both P<0.001), unfavorable molecular characteristics[IDH-wildtype (P=0.005), 1p19q non-codeletion (P<0.001)], and significantlypredicted worse overall survival (P<0.001). Functional enrichment analyses revealed SNPH's involvementin immunomodulation and migration-related processes, particularly FA pathway and FAK signaling. Immune profiling indicated an inverse correlation between SNPH expression and the abundance of T helper cells, macrophages and neutrophils. In vitro, SNPH overexpression suppressed invasion and epithelial-mesenchymal transition. Mechanistically, it promoted perinuclear mitochondrial clustering, attenuated FA maturation, FAK phosphorylation and RhoA/Rac1/Cdc42 expression. These findings establish SNPH as a novel diagnostic/prognostic biomarker and metastasis suppressor in glioma, functioning through mitochondrial repositioning-mediated inhibition of migration pathways.

Cyclic tensile stress restores chondrocyte homeostasis via integrin-FAK-RhoA/ROCK2 signaling: A multi-omics study.

We build a model of a general three-dimensional cell migrating across a flat substrate using an interconnected network of viscoelastic elements (damped springs). While the end goal is to use the model to investigate forces in migrating biological cells, the goal here is to demonstrate the model's validity, practical feasibility, and capability. We first show qualitative agreement with experiment including reasonable shape and speed, higher protrusive forces correlating with higher focal adhesion forces, and higher adhesive forces near the cell's front and back. We then show the model can produce estimates of deformation and stresses in migrating cells. We lastly perform a sensitivity analysis demonstrating that 1) cell length is increased by increasing driving force and focal adhesion attachment strength and by decreasing reference volume, 2) cell speed is increased by decreasing cell membrane-substrate interaction and increasing driving force, and 3) focal adhesion forces are increased by decreasing membrane elasticity and number of focal adhesions. Our results suggest that future model calibration will yield useful insights into how cell forces affect migration.

Organ-specific proteomic responses to tetrodotoxin administration in the liver and skin of Takifugu rubripes.

Whole-genome bisulfite sequencing reveals formaldehyde-induced DNA methylation alterations in chicken embryo liver and skeletal muscle.

Fibrosis is a pathological process characterized by persistent fibroblast activation and excessive ECM accumulation. Aortic carboxypeptidase-like protein (ACLP), a secreted ECM protein that binds fibrillar collagen, is up-regulated in fibrotic tissues and promotes fibroblast differentiation through canonical TGFβ receptor signaling. We hypothesized that when presented within the collagen matrix, ACLP would engage integrin-dependent mechanical signaling pathways that contribute to fibrogenic activation. Using 10T1/2 mouse mesenchymal progenitor cells, we identify a previously unrecognized mechanism through which collagen-bound ACLP induces fibrogenic activation via β1 integrin-mediated signaling. Collagen-bound ACLP induced rapid cell spreading, increased β1 integrin activation, and promoted focal adhesion maturation. These adhesion events triggered activation of the GTPases RhoA and Rac1, accompanied by enhanced F-actin assembly and nuclear accumulation of myocardin-related transcription factor A, a key regulator of fibrogenic gene expression. Transcriptomic profiling revealed enrichment of focal adhesion, ECM-receptor interaction, and actin cytoskeletal pathways downstream of collagen-bound ACLP, which was conserved in primary adipose-derived stromal cells. Together, these findings establish collagen-bound ACLP as a matrix-derived cue that links ECM composition to integrin-dependent fibrogenic activation.

Characterization of synaptopodin in striated and smooth muscles: isoform spectrum, expression patterns, localization and protein interactions.

Tributyltin (TBT) is a widespread marine contaminant that affects the development and reproduction of marine invertebrates; however, its molecular impacts on early embryonic development remain poorly understood. In this study, we investigated the effects of environmental concentrations of TBT on the miRNA expression profiles of the marine gastropod Tritia mutabilis during intracapsular embryogenesis. Embryos were exposed for 10days to low (10-12M) and high (10-10M) concentrations of TBT, and the differential expression of miRNAs was assessed by high-throughput sequencing. Obtained results revealed a significant modulation of several miRNAs across treatments, with a set of 11 miRNAs responding to both low and high TBT concentrations, while miR-486-5p and miR-183-5p were specifically modulated under the low TBT concentration, and miR-263b, miR-184, and miR-100-5p were exclusive to the highest concentration. Pathway analyses identified a range of biological processes affected, including nervous system development, cellular functions such as proliferation and cell growth, signal transduction, cellular component assembly and cell-cell interactions. Notably, several pathways were highly enriched (i.e., ≥100 regulated target genes) under both conditions, including focal adhesion, Ras signaling, regulation of actin cytoskeleton, Rap1 signaling, cAMP signaling, calcium signaling, and cGMP-PKG signaling pathways, highlighting the vulnerability of developmental and cellular communication networks, and further supported by the expression analysis of the corresponding miRNA-regulated target genes. These findings demonstrate that TBT contributes to the developmental abnormalities of marine gastropod embryos by modulating miRNA-mediated control of gene transcription. Our results contribute to advancing the understanding of miRNAs' potential utility as biomarkers for environmental monitoring.

Kisspeptin-10 regulates glycosaminoglycan and decorin content in human cardiac fibroblast cultures.

G Protein-Coupled estrogen receptor negatively regulates cell rigidity and osteogenic differentiation in bone marrow-derived mesenchymal stem cells.

Mechanical forces altered after unilateral pneumonectomy (PNX) control post-PNX lung growth. Here, we demonstrate that post-PNX endothelial regeneration is stimulated at the peripheral region of the mouse lung, requiring the focal adhesion (FA) protein, paxillin, while inhibition of mechanical tension attenuates the effects. Paxillin mediates stretching-induced YAP1-TEAD1 signaling, which stimulates GATA2 activity on angiogenic factor angiopoietin-2 (ANGPT2) transcription in endothelial cells (ECs), dictating post-PNX endothelial regeneration at the peripheral region. Deleting endothelial paxillin suppresses expression of GATA2 in the specific EC subtype, capillary type 1 ECs (CAP1s) following PNX. Extracellular matrix protein, collagen VI that impacts cell mechanical responses is expressed more at the peripheral region in the post-PNX mouse lungs, which drives paxillin expression, leading to EC regeneration. Mechanosensitive paxillin signaling in ECs mediates spatial control of post-PNX endothelial regeneration.

CaMKIIδ splice variants differentially regulate vascular smooth muscle cell motility.

Human enteric defensin 5 protects intestinal barrier integrity via cell state-dependent P2Y11-FAK-Rac1 signaling.

Mexico has a high burden of chronic kidney disease (CKD). The state of Aguascalientes is among the regions with the highest reported prevalence of end-stage kidney disease worldwide. In this setting, CKD of unknown etiology predominates and has been associated with a low number of nephrons of prenatal origin. This study examines the DNA methylation profile following maternal exposure to fluoride and its relationship with lower kidney volume in neonates. This cross-sectional study included at-term pregnant women without concomitant comorbidities. Neonatal total kidney volume (TKV) was calculated using ultrasound imaging. Maternal urine was collected to quantify xenobiotics, and placental DNA methylation was analyzed using the Illumina MethylationEPIC BeadChip. Neonates were classified by TKV percentile [low kidney volume (LKV) = percentile <10th; control (CTRL) = percentile >10th], and fluoride (F-) exposure (F-≥1.5 mg/L; NF-<1.5mg/L). Bioinformatic analyses were performed to identify differentially methylated genes (DMGs) and enriched biological pathways associated with kidney volume status and fluoride exposure. Thirty-two women were included in the study between March 2023 and April 2024. Principal component analysis (PCA) revealed distinct placental methylation profiles between the groups (LKV/F and CTRL/NF). Epigenome-wide analysis identified 7,540 differentially methylated sites (6,635 hypomethylated and 905 hypermethylated; adjusted p value (FDR)<0.01 and Δβ≥0.1). Integration of stratified comparisons across kidney volume and fluoride exposure identified a shared epigenetic signature of 244 DMGs, including protocadherin clusters and genes related to kidney development, cell adhesion, and developmental signaling. Functional enrichment analyses highlighted pathways involved in calcium signaling, focal adhesion, and organogenesis. Placental DNA methylation profiles associated with neonatal kidney volume were identified in a population with prenatal fluoride exposure. The consistency and biological relevance of the identified epigenetic signature support an association between fluoride exposure and alterations in placental DNA methylation involving pathways critical for early kidney development.

Integrative transcriptomics elucidates core regulatory network governing human megakaryopoiesis: Insights from CD34+-derived megakaryocyte maturation.

While advances have been made in mechano-active and gecko-inspired wound dressings, achieving dynamically coordinated adhesion-contraction coupling within a single-material, stimulus-free system with quantitatively programmable contractile output remains an unmet challenge. Here, we engineer bioinspired mechano-intelligent Janus bandages (MIBs) with dynamically coordinated adhesion-contraction for effective wound healing. The MIBs are fabricated through micromolding of poly(lactide-co-propylene glycol-co-lactide) dimethacrylates (PmLnD), featuring an interior surface with a gecko-mimicking wedged structure. Upon application, the MIBs recapitulate the gecko locomotion principle to achieve precise control of contractile forces with dynamically coordinated adhesion-contraction. The simply pre-strained MIB can precisely program its intrinsic contractile force, while adhesion strength proportionally responds to the contractile force through enhanced van der Waals interactions and interfacial friction. This coordinated mechanism promotes healing in rat and porcine full-thickness skin defect models by accelerating re-epithelialization and enhancing angiogenesis. Mechanistically, the MIBs reduce focal adhesion kinase (FAK) expression, thereby regulating downstream pathways related to wound healing progression, including nuclear factor kappa B (NF-κB), Wnt, and transforming growth factor-beta (TGF-β) pathways, enabling scar-attenuated wound healing. We envision that this Janus design, which integrates strain-programmable contraction with reversible gecko-inspired adhesion, offers a useful addition to current mechanobiological strategies for wound management and soft tissue repair.

BackgroundChronic tendon injury (CTI) is a common musculoskeletal disorder with complex molecular mechanisms, and currently lacks effective targeted therapeutic strategies. A comprehensive analysis of its key pathogenic genes and regulatory networks is crucial for the precise diagnosis and treatment of CTI.MethodsDifferentially expressed genes (DEGs) in CTI and normal tendon tissue were identified using the GEO database, and intersected with genes derived from WGCNA to identify candidate genes. Subsequently, functional enrichment analysis was performed, and four machine learning algorithms were employed to further determine key genes. Finally, a systematic functional analysis of the key genes was performed, including assessments of diagnostic value, regulatory network construction, computational drug prediction and molecular docking.ResultsA total of 271 candidate genes were identified, which were significantly enriched in focal adhesion, ECM-receptor interaction, and p53 signaling pathway. Subsequently, three key genes (FER, TUBA1B, and MICAL2) were prioritized through machine learning analysis, and their marked upregulation in CTI samples was verified by qRT-PCR and immunohistochemical analysis. Furthermore, their expression levels were positively correlate with natural killer T cell infiltration. TF-mRNA-miRNA regulatory network revealed the predicted TFs (such as STAT3, TFAP4, JUN, MYC) and the miRNAs that interact with the key genes. Ultimately, drug screening and molecular docking identified several potential lead compounds and confirmed their stable binding patterns.ConclusionThis study systematically revealed three key genes in CTI through comprehensive bioinformatics analysis. The diagnostic model, regulatory network, and predicted targeted drugs constructed based on these findings laid a solid theoretical foundation for subsequent translational medical research.

The talin2-β-integrin interaction modulates focal adhesion dynamics, promoting tumor cell migration and invasion, and thus represents an attractive anticancer target. Here, we identified the first talin2-β-integrin peptide inhibitor using structure-based virtual screening. Peptide-2 exhibited nanomolar binding affinity for talin2 (Kd = 8.05 ± 0.17 nM) and favorable in vitro selective inhibition. Molecular dynamics (MD) simulations indicated that Peptide-2 binds stably to talin2. Further studies showed that Peptide-2 significantly suppressed the proliferation, migration, and invasion of MDA-MB-231 cells as well as tube formation in HUVECs, with no significant toxicity toward normal cells. It inhibited FAK phosphorylation at Y397 and Y576, and displayed good cellular uptake and cytoplasmic localization. Moreover, Peptide-2 showed strong in vivo antitumor activity without obvious toxicity. Peptide-2 exhibited favorable in vitro serum stability and in vivo pharmacokinetic characteristics. In conclusion, Peptide-2 is a novel inhibitor that offers a potential new strategy for breast cancer therapy.

Lung cancer remains the predominant cause of cancer-related mortality worldwide. Piperlongumine is a natural extract that has antitumor effects. However, the mechanism of Piperlongumine on lung cancer remains to be elucidated. This study aimed to investigate the effects and potential mechanisms of Piperlongumine on non-small cell lung cancer. The anti-proliferative ability of Piperlongumine on lung cancer was assessed using the Cell Counting Kit-8 (CCK-8) and colony formation assays. The cell migration ability was evaluated by the wound healing assay. Additionally, western blot and immunofluorescence assays were performed to examine the expression levels of relevant proteins. Our results indicated that Piperlongumine effectively inhibited the proliferation and migration of A549 and H1299 cells. Mechanistically, Piperlongumine suppressed the phosphorylation of epidermal growth factor receptor (EGFR), focal adhesion kinase (FAK), and signal transducer and activator of transcription 3 (STAT3). It also blocked EGF-induced phosphorylation of FAK and STAT3, as well as EGF-induced cell proliferation. Furthermore, Piperlongumine reduced the expression of Cyclin D1. Piperlongumine inhibits lung cancer cell proliferation and migration by modulating the EGFR/FAK/STAT3 signaling pathway. These findings suggest that Piperlongumine may serve as a potential drug for the treatment of lung cancer.

Mechanotransduction is a process in which cells sense extracellular cues from their microenvironment and convert mechanical changes into biochemical signals, thereby regulating gene expression and various cellular processes. LIM-domain proteins have recently been identified as essential players in several mechanotransduction pathways. They have been shown to bind tensed actin filaments, which are enriched at focal adhesions, and to regulate various cellular signalling pathways by shuttling between the cytoplasm and the nucleus. Mainly, the stress sensitivity of the selected LIM proteins is demonstrated in contractile stress fibres and focal adhesion in fibroblasts, with the presence of at least three LIM domains required for force-induced interaction with stressed actin filaments. However, recent studies have expanded our understanding by identifying the LIM-only class of these proteins (LMOs), which contain only two LIM domains, at keratin intermediate filaments in epithelial cells, indicating their importance as signalling hubs in mechanotransduction pathways. In addition, members of the CRP class of LIM domain proteins with only two LIM domains linked to a short glycine-rich repeat can directly bind F-actin even in the absence of mechanical load and can also recruit to the stress fibres in response to stretch. Their dysregulation is linked with several pathological conditions, like cancer metastasis, cardiovascular disorders, muscle disorders, and inflammatory disorders, emphasising their importance in disease progression. This review highlights the diverse roles of LIM-only proteins, LMOs & CRPs in mechanotransduction, emphasising their emerging significance in integrating cytoskeleton dynamics with gene expression and the therapeutic potential of targeting LIM-only proteins to modulate the mechanotransduction pathway in a clinical context.