Search Results (1,541)

Listeria monocytogenes poses health threats due to its resilience and potential to cause severe infections, especially in vulnerable populations. Plant extracts and/or phytocomplexes have demonstrated the capability of natural compounds in mitigating L. monocytogenes virulence. Here we explored the suitability of a computational pipeline envisioned to identify the molecular determinants for the recognition between the bacterial protein internalin A (InlA) and the human E-cadherin (Ecad), which is the first step leading to internalization. This pipeline consists of molecular docking and extended atomistic molecular dynamics simulations to identify key interaction clusters between InlA and Ecad. It exploits this information in the screening of chemical libraries of natural compounds that might competitively interact with InIA and hence impede the formation of the InIA–Ecad complex. This strategy was effective in providing a molecular model for the anti-adhesive activity of punicalagin and disclosed two natural phenolic compounds with a similar interaction pattern. Besides elucidating key aspects of the mutual recognition between InIA and Ecad, this study provides a molecular basis about the mechanistic underpinnings of the anti-adhesive action of punicalagin that enable application against L. monocytogenes. Full article

Non-small cell lung cancer (NSCLC) is a predominant form of lung cancer that is often diagnosed at an advanced metastatic stage. The processes of cancer cell migration and invasion involve epithelial-to-mesenchymal transition (EMT), which is crucial for metastasis. Targeting cancer aggressiveness with effective plant compounds has gained attention as a potential adjuvant therapy. Eurycomanone (ECN), a bioactive quassinoid found in the root of Eurycoma longifolia Jack, has demonstrated anti-cancer activity against various carcinoma cell lines, including human NSCLC cells. This study aimed to investigate the in vitro effects of ECN on the migration and invasion of human NSCLC cells and to elucidate the mechanisms by which ECN modulates the EMT in these cells. Non-toxic doses (≤IC20) of ECN were determined using the MTT assay on two human NSCLC cell lines: A549 and Calu-1. The results from wound healing and transwell migration assays indicated that ECN significantly suppressed the migration of both TGF-β1-induced A549 and Calu-1 cells. ECN exhibited a strong anti-invasive effect, as its non-toxic doses significantly suppressed the TGF-β1-induced invasion of NSCLC cells through Matrigel and decreased the secretion of MMP-2 from these cancer cells. Furthermore, ECN could affect the TGF-β1-induced EMT process in various ways in NSCLC cells. In TGF-β1-induced A549 cells, ECN significantly restored the expression of E-cadherin by inhibiting the Akt signaling pathway. Conversely, in Calu-1, ECN reduced the aggressive phenotype by decreasing the expression of the mesenchymal protein N-cadherin and inhibiting the TGF-β1/Smad pathway. In conclusion, this study demonstrated the anti-invasive activity of eurycomanone from E. longifolia Jack in human NSCLC cells and provided insights into its mechanism of action by suppressing the effects of TGF-β1 signaling on the EMT program. These findings offer scientific evidence to support the potential of ECN as an alternative therapy for metastatic NSCLC. Full article

In epithelial cells, nonmuscle myosin-2B (NM2B) shows a cortical localization and is tethered to tight junctions (TJs) and adherens junctions (AJs) by the junctional adaptor proteins cingulin and paracingulin. MDCK cells knock-out (KO) for cingulin show decreased apical membrane cortex stiffness and decreased TJ membrane tortuosity, and the rescue of these phenotypes requires the myosin-binding region of cingulin. Here, we investigated whether NM2B contributes to these phenotypes independently of cingulin by generating and characterizing clonal lines of MDCK cells KO for NM2B. The loss of NM2B resulted in decreased stiffness and increased fluidity of the apical cortex and reduced accumulation of E-cadherin and phalloidin-labeled actin filaments at junctions but had no significant effect on TJ membrane tortuosity. Fluorescence recovery after photobleaching (FRAP) showed that the KO of NM2B increased the dynamics of the TJ scaffold protein ZO-1, correlating with decreased ZO-1 accumulation at TJs. Finally, the KO of NM2B increased cell size in cells grown both in 2D and 3D but did not alter lumen morphogenesis of cysts. These results extend our understanding of the functions of NM2B by describing its role in the regulation of the mechanical properties of the apical membrane cortex and cell size and validate our model about the role of cingulin–NM2B interaction in the regulation of ZO-1 dynamics. Full article

Snail and Zeb1 have been suggested as markers for the hybrid/mixed epithelial (E)/mesenchymal (M) state of cancer cells. Such cancer cells co-express E- and M-specific transcripts and possess cancer stem cell properties. M13HS-2/-8 tumor hybrid clones derived from human M13SV1-EGFP-Neo breast epithelial cells and human HS578T-Hyg breast cancer cells exhibited co-expression of Snail and Zeb1. To explore the impact of Snail on stemness/epithelial-to-mesenchymal transition (EMT)-related properties in M13HS-2/-8 tumor hybrid clones, Snail was knocked out (KO) using CRISPR/Cas9. Mammosphere formation, colony formation, Western blot analyses, cell migration, and invasion assays were conducted for the characterization of Snail knockout cells. Interestingly, Snail-KO in M13SV1-EGFP-Neo cells resulted in the up-regulation of vimentin and N-cadherin, suggesting EMT induction, which was associated with a significantly enhanced colony formation capacity. In contrast, EMT marker pattern and colony formation capacities of M13HS-2/-8 Snail-KO tumor hybrid clones remained unchanged. Notably, the mammosphere formation capacities of M13HS-2/-8 Snail-KO tumor hybrid clones were significantly reduced. The migratory behavior of all Snail-KO cells was not altered compared with their wild-type counterparts. In contrast, M13HS-2 hybrids and their M13HS-2 Snail-KO variant exhibited a markedly enhanced invasive capacity. Therefore, Snail plays a role as a mediator of stemness properties rather than mediating EMT. Full article

The anodic oxidation of titanium implants is a practical, cost-effective method to enhance implant success, especially due to rising hypersensitivity concerns. This study investigated the electrochemical behavior, surface characteristics, and biocompatibility of anodized commercially pure titanium (cpTi, grade IV). Anodization is performed on polished, cleaned cpTi sheet samples in 1 M H₂SO₄ using a constant voltage of 15 V for 15 and 45 min. The color of the oxide layer is evaluated using the CIELab color space, while composition is analyzed by a scanning electron microscope (SEM) equipped with an energy dispersive spectrometer (EDS). Additionally, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) are performed to identify and monitor the phase transformations of the formed titanium oxides. Corrosion measurements are performed in 9 g L⁻¹ NaCl, pH = 7.4, and show the excellent corrosion stability of the anodized samples in comparison with pure titanium. The biological response is assessed by determining mitochondrial activity and gene expression in human fibroblasts. Anodized surfaces, particularly Ti-45, promote higher mitochondrial activity and the upregulation of adhesion-related genes (N-cadherin and Vimentin) in human gingival fibroblasts, indicating improved biocompatibility and the potential for enhanced early soft tissue integration. Full article

The oral epithelium is essential for maintaining oral health and plays a key role in the onset and progression of periodontitis. It serves as both a mechanical and immunological barrier and possesses antimicrobial activity. Vitamin D₃, a hormone with known immunomodulatory functions, may influence oral epithelial responses. This study investigated the effects of two vitamin D₃ metabolites on key immunological and antimicrobial functions of oral epithelial cells, both under basal conditions and during bacterial challenge. Ca9-22 oral epithelial cells were treated with 1,25(OH)₂D₃ or 25(OH)D₃ in the presence or absence of Tannerella forsythia, Fusobacterium nucleatum, or Porphyromonas gingivalis. Inflammatory responses were assessed by measuring gene and protein expression of IL-1β and IL-8. Antimicrobial activity was evaluated via expression of LL-37, hBD-2, and hBD-3, as well as direct bacterial killing assays. Expression of epithelial integrity markers E-cadherin and ICAM-1 was also analyzed. Vitamin D₃ metabolites reduced IL-8 expression and significantly increased LL-37 expression and production in Ca9-22 cells. Both forms enhanced antimicrobial activity against all tested pathogens and modulated epithelial integrity markers. Vitamin D₃ positively regulates antimicrobial and barrier functions in oral epithelial cells, suggesting a potential role in supporting oral health and preventing periodontitis progression. Full article

Colorectal cancer (CRC) diagnosed in an advanced stage has an increased predisposition for invasion and metastasis, requiring upgraded prognostic markers. CDH17, a liver-intestine cadherin, is an adhesion molecule implicated in tumor progression. This retrospective study assessed the immunohistochemical expression of CDH17 in 84 CRC cases with lymphovascular invasion (LVI), analyzing its correlation with clinicopathological features and survival outcomes. CDH17 expression was evaluated in the tumor core, invasive front, tumor emboli, and lymph node metastases. Statistical analyses showed significant associations between high CDH17 expression and favorable histological types, as well as low-grade differentiation. However, high CDH17 levels in tumor emboli correlated with advanced T stage and poorer overall survival. Multivariable Cox regression confirmed CDH17 expression in tumor emboli as an independent prognostic factor, indicating an approximately twofold risk of death. These findings suggest that CDH17 may have a dual role—maintaining adhesion in low-grade tumors while facilitating tumor emboli-related dissemination. CDH17 expression, particularly in the tumor emboli, could serve as a valuable prognostic biomarker in CRC with LVI. 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

Heart failure (HF) has become an epidemic, with a prevalence of ~7 million cases in the USA. Despite accounting for nearly 50% of all HF cases, heart failure with a preserved ejection fraction (HFpEF) remains challenging to treat. Common pathophysiological mechanisms in HFpEF include oxidative stress, microvascular dysfunction, and chronic unresolved inflammation. Our lab focuses on oxidative stress-mediated cellular dysfunction, particularly the toxic effects of lipid peroxidation products like 4-hydroxy-2-nonenal (4HNE). Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, plays a vital role in detoxifying 4HNE and thereby protecting the heart against pathological stress. ALDH2 activity is reduced in various metabolic stress-mediated cardiac pathologies. The dysfunction of coronary vascular endothelial cells (CVECs) is critical in initiating HFpEF development. Thus, we hypothesized that ectopic overexpression of ALDH2 in CVECs could mitigate metabolic stress-induced HFpEF pathogenesis. In this study, we tested the efficacy of intracardiac injections of the ALDH2 gene into CVECs in db/db mice—a model of obesity-induced type 2 diabetes mellitus (T2DM)—and their controls, db/m mice, by injection with ALDH2 constructs (AAV9-VE-cadherin-hALDH2-HA tag-P2A) or control constructs (AAV9-VE-cadherin-HA tag-P2A-eGFP). We found that intracardiac ALDH2 gene transfer increased ALDH2 levels specifically in CVECs compared to other myocardial cells. Additionally, we observed increased ALDH2 levels and activity, along with decreased 4HNE adducts, in the hearts of mice receiving ALDH2 gene transfer compared to control GFP transfer. Furthermore, ALDH2 gene transfer to CVECs improved diastolic function compared to GFP control alone. In conclusion, ectopic ALDH2 expression in CVECs can contribute, at least partially, to the amelioration of HFpEF. Full article

To date, there is no effective treatment for glioblastoma (GBM). This study aimed to compare the effectiveness of sodium dichloroacetate (NaDCA), a valproic acid and NaDCA combination (VPA–NaDCA), or temozolomide (TMZ) on U87 and T98G cell tumors on the chick embryo chorioallantoic membrane (CAM), and on the expression of proliferating cell nuclear antigen (PCNA), polycomb inhibitory complex catalytic subunit 2 (EZH2), and TP53 gene-encoded p53 protein (p53) in tumors on the CAM, and SLC12A2 (gene encoding Na⁺-K⁺-2Cl⁻ (NKCC1) co-tarnsporter), SLC12A5 (gene encoding K⁺-Cl⁻ (KCC2) co-transporter), SLC5A8 (gene encoding Na⁺-dependent monocarboxylate transporter) and CDH1 (gene encoding the E-cadherin protein) and CDH2 (gene encoding the N-cadherin protein) in cells. VPA–NaDCA and TMZ reduced the invasion of U87 and T98G tumors, as well as the expression of PCNA and EZH2 in the tumor. TMZ reduced p53 expression in tumors from both cell lines, whereas VPA–NaDCA did not affect the expression of this marker. VPA–NaDCA, but not TMZ, reduced SLC12A2 expression in T98G cells. However, VPA–NaDCA and TMZ did not affect SLC12A2 expression in U87 cells. VPA–NaDCA increased SLC5A8 expression only in U87 cells, and TMZ did not affect gene expression in either cell line. Only VPA–NaDCA increased CDH1 expression and decreased CDH2 expression in T98G cells, whereas TMZ had no effect on gene expression in the study cells. This study demonstrated that VPA–NaDCA exhibits a more effective anticancer effect than NaDCA. The data suggest that VPA–NaDCA has a more effective impact than TMZ; however, the effect of investigational medicines on carcinogenesis varies depending on the cell line. The study of the efficacy of drugs used to treat tumors on the CAM and cells demonstrates that it is essential to assess the effectiveness of treatment, which should be personalized, before administering chemotherapy. Full article

In endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions can lead to altered tissue perfusion, development of tissue inflammation through increased endothelial permeability, and ultimately organ damage. As intracellular cyclic AMP (cAMP) levels are known to control intercellular junctions or apoptosis in the endothelium, we investigated here the effect of the Phosphodiesterase 4 inhibitor Roflumilast, a drug increasing cAMP levels, on irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). Using continuous impedance measurements in confluent endothelial cell monolayers, Roflumilast was found to rapidly reinforce the endothelial barrier and to prevent irradiation-induced barrier disruption. In accordance, irradiation-induced alteration in membrane VE-Cadherin-composed adherens junctions was prevented by Roflumilast treatment after irradiation, which was correlated with its protective effect of the actin cytoskeleton. Post-irradiation treatment with Roflumilast also protected HPMECs from irradiation-induced late apoptosis, but was without effect on irradiation-induced ICAM-1 overexpression. Overall, our results indicate that the beneficial effects of Roflumilast after irradiation are linked to the strengthening/protection of the endothelial barrier and reduced apoptosis, suggesting that this medicine may be useful for the treatment of endothelial damages after exposure to a high dose of radiation. Full article

T-cadherin (CDH13) is an atypical, glycosyl-phosphatidylinositol-anchored cadherin with functions ranging from axon guidance and vascular patterning to adipokine signaling and cell-fate specification. Originally identified as a homophilic cue for migrating neural crest cells, projecting axons, and growing blood vessels, it later emerged as a dual metabolic receptor for cardioprotective high-molecular-weight adiponectin and atherogenic low-density lipoproteins. We recently showed that mesenchymal stem/stromal cells lacking T-cadherin are predisposed to adipogenesis, underscoring its role in lineage choice. Emerging evidence indicates that CDH13 expression and function are fine-tuned by non-coding RNAs (ncRNAs). MiR-199b-5p, miR-377-3p, miR-23a/27a/24-2, and the miR-142 family directly bind CDH13 3′-UTR or its epigenetic regulators, affecting transcription or accelerating decay. Long non-coding RNAs (lncRNAs), including antisense transcripts CDH13-AS1/AS2, brain-restricted FEDORA, and context-dependent LINC00707 and UPAT, either sponge these miRNAs or recruit DNMT/TET enzymes to the CDH13 promoter. Circular RNAs (circRNAs), i.e.circCDH13 and circ_0000119, can add a third level of complexity by sequestering miRNA repressors or boosting DNMT1. Collectively, this ncRNA circuitry regulates T-cadherin across cardiovascular, metabolic, oncogenic, and neurodegenerative conditions. This review integrates both experimentally validated data and in silico predictions to map the ncRNA-CDH13 crosstalk between health and disease, opening new avenues for biomarker discovery and RNA-based therapeutics. Full article

Glioblastoma (GBM), a highly malignant brain tumor, arises within a complex microenvironment that plays a critical role in facilitating tumor progression, ensuring survival, and enabling immune evasion, ultimately contributing to therapeutic resistance. Cancer-associated fibrosis is increasingly recognized as a key factor in the tumor pathophysiology, particularly in extracranial cancers, and reported therapeutic strategies in several cancers consist of the current use of the standard-of-care treatment combined with anti-fibrotic drugs. However, it remains unclear how the fibrotic changes associated with the GBM microenvironment contribute to the transformation of GBM from a chemosensitive state to a chemoresistant one. Here, we developed an in vitro model that mimics a fibrosis-like mechanism using the U-87MG GBM cell line. To achieve this, we identified the optimal experimental conditions (i.e., U-87MG cultured in serum-deprivation medium in the presence of recombinant TGF-B1 at 5 ng/mL for 72 h) that effectively induced fibrosis, as suggested by the counter-regulated expression of E- and N-cadherin and sustained levels of α-SMA and collagen I. As expected, U-87MG fibrotic cells were demonstrated to be more resistant to TMZ (predicted EC₅₀ = 35 µM) as compared to the non-fibrotic counterpart (EC₅₀ not achieved here; predicted EC₅₀ = 351 µM). Accordingly, the anti-fibrotic uPAcyclin—a new derivative cyclic compound inspired as a A6 decapeptide drug—showed a significant cytotoxic effect, sensitizing resistant U-87MG fibrotic cells to TMZ. This highlights that targeting fibrosis may help to overcome TMZ resistance in GBM. Full article

Peritoneal adhesions following surgical injury remain a major clinical challenge, often resulting in severe complications, such as intestinal obstruction, chronic pain, and infertility. This review systematically integrates recent genomic and molecular biology insights into the pathogenesis of peritoneal adhesions, explicitly focusing on molecular pathways, including TGF-β signaling, COX-2-mediated inflammatory responses, fibrinolytic balance (tPA/PAI-1), angiogenesis pathways (VEGF, PDGF), and extracellular matrix remodeling (MMPs/TIMPs). Newly conducted transcriptomic and proteomic analyses highlight distinct changes in gene expression patterns in peritoneal fibroblasts during adhesion formation, pinpointing critical roles for integrins, cadherins, selectins, and immunoglobulin superfamily molecules. Recent studies indicate significant shifts in TGF-β isoforms expression, emphasizing isoform-specific impacts on fibrosis and scarring. These insights reveal substantial knowledge gaps, particularly the differential regulatory mechanisms involved in fibrosis versus normal reparative reperitonealization. Future therapeutic strategies could target these molecular pathways and inflammatory mediators to prevent or reduce adhesion formation. Further research into precise genetic markers and the exploration of targeted pharmacological interventions remain pivotal next steps in mitigating postoperative adhesion formation and improving clinical outcomes. Full article

Posidonia oceanica (L.) Delile, a Mediterranean seagrass, is rich in bioactive compounds with anti-inflammatory potential. While marine-derived molecules are increasingly studied, their direct effects on blood–brain barrier (BBB) integrity under inflammatory conditions remain largely unexplored. This study evaluated the ability of aqueous extracts from its green leaves (GLEs) and rhizomes (REs) to protect the BBB using a human in vitro model consisting of brain-like endothelial cells co-cultured with brain pericytes. The model was exposed to TNFα, with or without GLEs or REs. We assessed NO production, endothelial permeability, expression of IL-6, NLRP3, ICAM-1, VCAM-1, CLAUDIN-5, and VE-CADHERIN, and the localization of junctional proteins. TNFα increased NO and IL-6 release, upregulated ICAM-1, VCAM-1, and NLRP3, and impaired BBB integrity by altering junctional protein levels and distribution. Co-treatment with GLEs or REs reduced the production of NO, the expression of NLRP3 and adhesion molecules and restored tight and adherens junction integrity. IL-6 levels remained unaffected. These findings suggest that P. oceanica’s extracts may help preserve BBB function and mitigate inflammation-induced damage. While further studies are needed to assess their bioavailability and in vivo efficacy, these natural compounds represent promising candidates for developing preventive strategies against neuroinflammatory disorders. Full article