Search Results (260)

Early cellular alterations in abdominal aortic aneurysm (AAA) are scarcely investigated. Aortic remodeling inflammation-related suggested the CXCR2/CXCL1/IL-8 axis as a therapeutic target. This study investigates CXCR1/CXCR2 antagonism in primary human aortic endothelial (HAOEC) and smooth muscle cells (HAOSMC) conditioned with IL-8 or serum from patients with AAA (sPT). Ladarixin (10 μM Lad or 25 μM) served as an inhibitor. Readouts included RT-qPCR for CXCL1, CXCL8, CXCR2, MMP9, NFKB1, and VEGF-A; zymography for MMP9 activity confocal microscopy for F-actin and mitochondria; NADPH/NADH diaphorase histochemistry for redox activity; and ATP assay. In HAOEC, IL-8 downregulated CXCR2, increased MMP9 activity, and induced cytoskeletal and mitochondria disorganization without altering NADH/NADPH diaphorases but increasing ATP release. At concentration of 10 μM Lad rescued cell organization and gene expression. sPT upregulated CXCL8, CXCR2, and MMP9, decreased NADH/NADPH diaphorases, and altered cytoskeleton and mitochondria organization in HAOEC. At concentration of 10 μM Lad (partially) and 25 μM Lad reverted gene upregulation and mitochondria distribution; both doses increased diaphorase and released ATP. HAOSMC were scantily susceptible to IL-8 and weakly responsive to sPT, slightly upregulating CXCR2 and VEGF-A but increasing proMMP9 gelatinolysis. Ladarixin recovered proMMP9 activity and modulated CXCL1. AAA-like vascular cell alterations involve multiple inflammatory factors and are modulable by inhibition of IL-8 receptors. The results underline careful dose calibration. Full article

The cytoskeleton has been described as a regulator of adrenal physiology and tumour behaviour. In the adrenal cortex, both cytoskeletal filaments, by mediating cholesterol transfer to mitochondria, and their binding proteins, such as cofilin and diaphanous-related formin 1 (DIAPH1), have been implicated in modulating steroidogenic processes. Beyond hormone production, the cytoskeleton participates in oncogenic signalling and contributes to the acquisition of malignant behaviour in adrenocortical carcinoma (ACC). Cytoskeleton-associated proteins such as filamin A (FLNA), fascin-1 (FSCN1), RASSF1A, and the guanine nucleotide exchange factor VAV2 are involved in signal transduction, cell cycle regulation, and cytoskeletal remodelling. In ACC, dysregulation of the expression or activity of these proteins correlates with ACC aggressiveness, including increased proliferation, motility, and invasion as well as poor prognosis, making them attractive candidates for targeted therapeutic strategies. To date, no review has systematically addressed the role of cytoskeleton and its binding partners in both adrenal physiological regulation and pathological context. This review is the first to provide a comprehensive overview of cytoskeletal involvement in adrenal cortex function and cancer, highlighting emerging molecular players and their possible therapeutic implications. Full article

Understanding the genetic regulatory mechanisms of fat accumulation is crucial for improving beef quality. Hanwoo (Korean native cattle) is renowned for its high intramuscular fat (marbling), yet the genetic regulation of adipose gene expression remains insufficiently understood. In this study, we performed expression quantitative trait loci (eQTL) analysis using RNA-Seq data and genotype data from backfat tissue of 75 Hanwoo steers to identify regulatory variants associated with adipose deposition. A total of 25,042 significant cis-eQTL associations (FDR < 0.05) were identified, and 5362 unique top cis-eQTL pairs were retained after gene-wise filtering. Key cis-regulated genes included AGBL1, CACNG1, MYO18B, and DUSP29, which are involved in cytoskeletal organization, muscle development and calcium signaling. Three major cis-regulatory hotspots were located on BTA15 (BTA15:50354741) and BTA21 (BTA21:21526143, and BTA21:21541921). Permutation-based analysis (100,000 iterations) was conducted to control false positives, identifying 12 statistically significant trans-eQTL hotspots (FDR q < 0.05), of which SNP 6:60512276 and SNP 21:17035557 exhibited extensive trans-regulatory activity influencing 429 and 161 genes, respectively. In particular, SNP 21:17035557 acted as a shared cis- and trans-regulatory hub, indicating hierarchical control of adipose gene networks. Functional enrichment analyses revealed significant involvement of cytoskeleton- and calcium-dependent pathways, highlighting the interplay between structural remodeling and metabolic regulation in adipose tissue. These findings provide a comprehensive, system-level view of adipose gene regulation in Hanwoo cattle and highlight candidate molecular targets for genome-assisted and precision breeding. Moreover, this study offers quantitative genomic resources that can support the development of prediction models and decision-support systems for improving carcass traits in Hanwoo breeding programs. Full article

Mancozeb is a broad-spectrum fungicide used extensively in agriculture to protect crops against a wide range of plant diseases. Although its capacity to induce oxidative stress is well documented, the cytotoxic effects of mancozeb on red blood cells (RBCs) remain poorly characterized. The present study aimed to investigate the cytotoxic effects of mancozeb on isolated RBCs, with particular focus on oxidative stress-induced cellular and molecular alterations. Human RBCs were exposed to mancozeb (0.5–100 µM) for 24 h. No hemolytic activity was observed across the tested concentrations. However, 10 and 100 µM mancozeb induced a significant increase in intracellular reactive oxygen species (ROS), leading to lipid and protein oxidation and impaired Na⁺/K⁺-ATPase and anion exchanger 1 (AE1) function. These changes resulted in altered RBC morphology, reduced deformability, and increased methemoglobin levels. Alterations in glycophorin A distribution, anion exchanger 1 (AE1) clustering and phosphorylation, and α/β-spectrin and band 4.1 re-arrangement indicated disrupted membrane–cytoskeleton interactions. A release of extracellular vesicles (EVs) positive for glycophorin A and annexin-V was also observed, consistent with plasma membrane remodeling. Despite increased intracellular calcium, eryptosis remained minimal, possibly due to activation of protective estrogen receptor (ER)-mediated pathways involving ERK1/2 and AKT signaling. Activation of the cellular antioxidant system and the glutathione redox system (GSH/GSSG) occurred, with catalase (CAT) playing a predominant role, while superoxide dismutase (SOD) activity remained largely unchanged. These findings offer mechanistic insights regarding the potential health impact of oxidative stress induced by pesticide exposure. Full article

Background: Cervical cancer (CC) is one of the most common malignancies in women worldwide. Its progression involves a cascade of processes, including proliferation, migration, invasion, and metastasis. Each stage is regulated by specific signaling pathways. Objective: This scoping review aimed to map current evidence on the role of cell adhesion-related molecules, including integrins, focal adhesion (FA) proteins, and actin-binding proteins (ABPs), in CC progression. These protein groups act in a coordinated manner—integrins perceive and transmit extracellular matrix (ECM) signals, FA proteins mediate intracellular signaling, and ABPs reorganize the cytoskeleton, ensuring the continuity of adhesion and motility processes. Methods: A structured literature search was conducted for studies published between 2015 and 2025. Eligible articles described the role of adhesion-related proteins in migration, invasion, or EMT in CC. Data were synthesized thematically according to protein families. Results: The evidence highlights integrins, FA/FAK, and ABPs as interconnected regulators coordinating ECM signaling and cytoskeletal remodeling during CC progression. Their dysregulation is associated with enhanced migration, EMT induction, angiogenesis, and therapy resistance. Conclusions: This review provides a unique, integrated perspective linking adhesion molecules with invasion mechanisms in CC progression, providing new insights into their interplay. Understanding the interaction between these proteins is therefore a crucial step in the treatment of CC and may facilitate the discovery of biomarkers and support the development of targeted therapies. Full article

Pulmonary fibrosis (PF) is a progressive and fatal lung disease characterized by irreversible alveolar destruction and pathological extracellular matrix (ECM) deposition. Currently approved agents (pirfenidone and nintedanib) slow functional decline but do not reverse established fibrosis or restore functional alveoli. Multifunctional bioscaffolds present a promising therapeutic strategy through targeted modulation of critical cellular processes, including proliferation, migration, and differentiation. This review synthesizes recent advances in scaffold-based interventions for PF, with a focus on their dual mechano-epigenetic regulatory functions. We delineate how scaffold properties (elastic modulus, stiffness gradients, dynamic mechanical cues) direct cell fate decisions via mechanotransduction pathways, exemplified by focal adhesion–cytoskeleton coupling. Critically, we highlight how pathological mechanical inputs establish and perpetuate self-reinforcing epigenetic barriers to regeneration through aberrant chromatin states. Furthermore, we examine scaffolds as platforms for precision epigenetic drug delivery, particularly controlled release of inhibitors targeting DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) to disrupt this mechano-reinforced barrier. Evidence from PF murine models and ex vivo lung slice cultures demonstrate scaffold-mediated remodeling of the fibrotic niche, with key studies reporting substantial reductions in collagen deposition and significant increases in alveolar epithelial cell markers following intervention. These quantitative outcomes highlight enhanced alveolar epithelial plasticity and upregulating antifibrotic gene networks. Emerging integration of stimuli-responsive biomaterials, CRISPR/dCas9-based epigenetic editors, and AI-driven design to enhance scaffold functionality is discussed. Collectively, multifunctional bioscaffolds hold significant potential for clinical translation by uniquely co-targeting mechanotransduction and epigenetic reprogramming. Future work will need to resolve persistent challenges, including the erasure of pathological mechanical memory and precise spatiotemporal control of epigenetic modifiers in vivo, to unlock their full therapeutic potential. Full article

The development of low-resistance blood flow within the developing placenta in the early weeks of pregnancy requires trophoblast invasion of the uterine spiral arteries. Therefore, understanding the migration and differentiation of trophoblasts is necessary. Recently, researchers have focused increasingly on the regulation of the response of endovascular extravillous trophoblasts (enEVTs) to mechanical stimuli associated with shear stress. The starting point for these studies is that enEVTs, which adopt a pseudoendothelial phenotype, functionally resemble endothelial cells in terms of ability to promote angiogenesis, vascular remodeling and cell–cell communication. The complex process of mechanotransduction requires the coordinated participation of many types of mechanoreceptors, whose activated signaling pathways are translated into whole-cell mechanosensing involving components of the cytoskeleton and extracellular matrix. The aim of this review is to comprehensively present the current knowledge on the importance of mechanical stimuli associated with shear stress in the development of local changes in the vascular system at the site of blastocyst implantation. The characteristics of individual mechanoreceptors are determined, and the most important factors influencing mechanotransduction are discussed. Understanding the importance of mechanosensing disorders in trophoblasts in the pathogenesis of unexplained recurrent abortions or preeclampsia may be helpful in the development of new therapeutic strategies based on the regulation of mechanotransduction in response to shear stress. Full article

Reperfusion therapy uses thrombolysis and clot removal to restore blood flow in the brain after stroke; however, three months after reperfusion therapy, roughly 46% of stroke patients become independent again. MiRNAs (micro RNA) regulate cerebral ischemia/reperfusion injury, and their transfer between cells via exosomes may differentially affect recipient cells. We examined serum exosomal miRNA levels, stroke treatments, and functional outcomes in stroke patients, and we explored the potential role of estimated differentially expressed miRNA (DEmiRNA) target genes in the brain’s reaction to reperfusion after ischemia. The patients in the study received aspirin or reperfusion therapy with either intravenous thrombolysis (rt-PA), mechanical thrombectomy (MT), or a combination of both (rt-PA/MT). Serum samples were collected from stroke patients on days 1 and 10 post-stroke. Serum exosomes’ miRNA was analyzed using qRT-PCR. We identified DEmiRNAs, estimated their targets, and performed enrichment analysis. Functional outcomes were assessed using the modified Rankin Scale (mRS) on days 10 and 90 post-stroke. Among studied treatments, only rt-PA/MT lowered DEmiRNA by day 10 vs. other groups. Specifically, patients with unfavorable mRS score exhibited decreased levels of miR-17, miR-20, miR-186 and miR-222 after combined stroke therapy. Functional analysis identified target genes and pathways associated with cytoskeleton remodeling, cell death, autophagy, inflammation, and dementia. In conclusion, unfavorable stroke outcomes following poor rt-PA/MT response could result from lower miRNA expression levels, thus activating cell death and neurodegenerative processes in brain. Full article

In exerting its actions on the utilization and storage of nutrients, the hormonal effects of insulin (INS) on target cells include important changes in terms of cell morphology involving cytoskeletal actin. Sensitivity to INS affects intestinal epithelial cells, which express receptors through which tight junctions and barrier permeability are also modulated. Nevertheless, the impact of INS on physiological rather than pathophysiological processes along gastrointestinal epithelia is not fully established. Here, we investigate INS effects on differentiated Caco-2 monolayers challenged by inflammatory stimuli, i.e., interleukin 1 beta (IL-1β) and interferon gamma (IFN-γ), aiming to identify morpho-functional variations potentially associated with INS-dependent responses in intestinal epithelia differentially driven by different inflammation mediators. By observing the actin cytoskeleton, we characterized the impact of INS on actin structures’ organization, both in the absence and presence of pro-inflammatory treatments. Coherently, we observed altered expression of proteins interrelated to cytoskeletal dynamics (FAK, ITGB1), particularly evident in the synergistic action of IFN-γ and INS, also confirmed by the impact on INS-mediated regulation of the MAPK signalling pathway. Overall, the results describe a modular responsiveness of enterocyte-like monolayers to INS, depending on different inflammatory mediators, hinting at the interplay between INS signalling and morpho-functional remodelling in intestinal epithelial cells. Full article

The actin cytoskeleton determines a huge number of intracellular processes, as well as maintaining the cell shape, transport, formation of intercellular contacts, etc. The actin cytoskeleton’s function is largely determined by actin-binding proteins. Here, the mutual influence of two actin-binding proteins, cofilin (cof) and tropomyosin (Tpm), is studied. In the present work, using various biochemical approaches, we reveal the effects of two TPM4 gene-derived isoforms (Tpm4.1 and Tpm4.2) in the presence of cofilin-1 and cofilin-2. The cofilin severing activity was estimated in F-actin and Tpm/F-actin complexes using viscosity measurements and electron microscopy. Both cofilins prompted the disassembly of F-actin filaments with Tpms attached to them, and the Tpm4.2 isoform demonstrated a better protective effect. We also estimated the ability of cofilin-1 and cofilin-2 to displace Tpms from actin filaments by using the co-sedimentation method. Both cofilin isoforms efficiently displaced Tpm4.1 and Tpm4.2 and bound to actin filaments. Both Tpms decreased the initial rate of actin polymerization in the presence of cofilin-1 and cofilin-2. Overall, we can assume that Tpm4.1 and Tpm4.2 do not affect the binding of cofilin to actin filaments, which may be important for cofilin to exhibit its severing activity and lead to the remodeling of the actin cytoskeleton. Full article

Mechanical and contractile forces in the vascular wall regulate smooth muscle cell migration. We previously demonstrated the presence of C3 complement products in atherosclerotic lesions of human aortas and showed that that C3-derived fragments promote key cellular processes, such as actin cytoskeleton organization and cell migration, in lipid-loaded human vascular smooth muscle cells (hVSMCs). In the present study, we aimed to investigate gene expression profiles related to cytoskeletal remodeling and cell adhesion in migrating hVSMCs with a particular focus on modulatory effect of the C3 complement pathway on these processes. We analyzed gene expression in migrating and non-migrating hVSMCs using real-time PCR and in silico network analysis. Additionally, we investigated cytoskeletal remodeling through Western blotting and confocal microscopy. PCR profiling revealed 30 genes with significantly altered expression in migrating hVSMCs compared to non-migrating control cells. In silico analysis identified six of these genes—PXN, AKT1, RHOA, VCL, CTNNB1, and FN1—as being associated with cytoskeletal remodeling and focal adhesion, with PXN occupying a central position in the interaction network. PXN expression was reduced at both the transcript and protein levels and showed altered subcellular localization in migrating lipid-loaded hVSMCs. Protein–protein interaction analysis using STRING predicted an association between PXN and the integrin complex αMβ2 (comprising ITGAM (CD11b) and ITGB2 (CD18)), which functions as receptors for the iC3b complement fragment. Confocal imaging of cell adhesion structures revealed that lipid-loaded hVSMCs stimulated with iC3b displayed a more diffuse PXN distribution and significantly increased PXN–F-actin colocalization in active cytoplasmic regions compared to lipid-loaded control cells. PXN–F-actin colocalization increased from 1.26% to 19.68%. Subcellular fractionation further confirmed enhanced PXN enrichment in the membrane fraction, with no significant changes observed in the cytosolic or cytoskeletal compartments. In conclusion, iC3b-mediated molecular signaling in lipid-loaded hVSMCs alters PXN distribution and enhances cytoskeletal remodeling, revealing novel molecular interactions in vascular remodeling and the progression of atherosclerotic lesions. Full article

Tendinopathies are a significant challenge in musculoskeletal medicine, with current treatments showing variable efficacy. Electromagnetic transduction therapy (EMTT) has emerged as a promising therapeutic approach, but its biological effects on tendon cells remain largely unexplored. Here, we investigated the effects of EMTT on primary cultured human tenocytes’ behavior and functions in vitro, focusing on cellular responses, senescence-related pathways, and molecular mechanisms. Primary cultures of human tenocytes were established from semitendinosus tendon biopsies of patients undergoing anterior cruciate ligament (ACL) reconstruction (n = 6, males aged 17–37 years). Cells were exposed to EMTT at different intensities (40 and 80 mT) and impulse numbers (1000–10,500). Cell viability (MTT assay), proliferation (Ki67), senescence markers (CDKN2a/INK4a), migration (scratch test), cytoskeleton organization (immunofluorescence), and gene expression (RT-PCR) were analyzed. A 40 mT exposure elicited minimal effects, whereas 80 mT treatments induced significant cellular responses. Repeated 80 mT exposure demonstrated a dual effect: despite a moderate decrease in overall cell vitality, increased Ki67 expression (+7%, p ≤ 0.05) and significant downregulation of senescence marker CDKN2a/INK4a were observed, suggesting potential senolytic-like activity. EMTT significantly enhanced cell migration (p < 0.001) and triggered cytoskeletal remodeling, with amplified stress fiber formation and paxillin redistribution. Molecular analysis revealed upregulation of tenogenic markers (Scleraxis, Tenomodulin) and enhanced Collagen I and III expressions, particularly with treatments at 80 mT, indicating improved matrix remodeling capacity. EMTT significantly promotes tenocyte proliferation, migration, and matrix production, while simultaneously exhibiting senolytic-like effects through downregulation of senescence-associated markers. These results support EMTT as a promising therapeutic approach for the management of tendinopathies through multiple regenerative mechanisms, though further studies are needed to validate these effects in vivo. Full article

Migrastatic strategies are considered as candidate therapeutic approaches to suppress cancer invasion into local surrounding tissues and metastatic spread. The F-actin cytoskeleton is responsible for key properties regulating (cancer) cell migration. The cortical F-actin network controls cell stiffness, which, in turn, determines cell migration strategies and efficiency. Moreover, the dynamic remodeling of F-actin networks mediating filopodia, lamellipodia, and F-actin stress fibers is crucial for cell migration. Here, we have used a conditional knockout approach to delete cofilin, an F-actin-binding protein that controls severing. We find that the deletion of cofilin prevents the migration of cancer cells from tumoroids into the surrounding extracellular matrix without affecting their viability. This identifies cofilin as a candidate target to suppress metastatic spread. Pharmacological inhibitors interfering with F-actin dynamics have been developed but their effects are pleiotropic, including severe toxicity, and their impact on 3D tumor cell migration has not been tested or separated from this toxicity. Using concentration ranges of a panel of inhibitors, we select cytochalasins based on the suppression of 2D migration at non-toxic concentrations. We then show that these attenuate the escape of tumor cells from tumoroids and their migration into the surrounding extracellular matrix without toxicity in 3D cultures. This effect is accompanied by suppression of cell stiffness at such non-toxic concentrations, as measured by acoustic force spectroscopy. These findings identify cytochalasins B and D as candidate migrastatic drugs to suppress metastatic spread. Full article

Cell adhesion molecules (CAMs) are cell-surface-localized proteins mediating interactions of cells with other cells and the extracellular matrix. CAMs influence cell behavior and survival by inducing various intracellular signaling cascades that regulate diverse cellular processes including cytoskeleton remodeling and gene expression. Here, we review the evidence demonstrating that the levels, subcellular distribution, and binding affinities of CAMs of several major families including integrins, cadherins, immunoglobulin superfamily, and selectins are regulated by intracellularly generated or extracellular reactive oxygen species (ROS). Remarkably, CAMs themselves induce ROS production in response to binding to their ligands by activating lipoxygenases or NADPH oxidases or influencing ROS generation in mitochondria. CAM-dependent ROS production is essential for CAM-mediated cell adhesion and CAM-dependent intracellular signaling. Importantly, CAMs also protect cells from the ROS-induced cell death by stimulating the synthesis of antioxidants and suppressing the cell death signaling. A better understanding of the role ROS play in controlling CAM functions and mechanisms of this control may pave the way to modulating the functions of CAMs in various disorders associated with abnormal cell adhesion. Full article

The aggregation of Tau protein into neurofibrillary tangles (NFTs), a hallmark of Alzheimer’s disease (AD), is associated with cognitive decline. Recent studies have revealed that neuronal cytoskeletal instability drives early AD pathogenesis. The physiological interaction between tau and the microtubule (MT) is crucial for maintaining axonal transport and stability. However, aberrant post-translational modifications (PTMs) in the MT binding domain—such as phosphorylation, acetylation and ubiquitination—trigger tau dissociation, causing microtubule collapse, transport deficits, and synaptic dysfunction. MT dysregulation also affects actin/cofilin-mediated dendritic spine destabilization and causes the hyperplasia of the glial intermediate filament, which exacerbates neuroinflammation and synaptic toxicity. This review systematically explores the functions of neuronal cytoskeletons, deciphers the molecular crosstalk between tau pathology and cytoskeletal remodeling, and proposes multi-target therapeutic strategies to restore cytoskeletal homeostasis, thereby providing novel perspectives for precision interventions in AD Full article