Circulating cell adhesion molecules in systemic sclerosis: a systematic review and meta-analysis.

Introduction: Patients with systemic sclerosis (SSc) have an increased risk of endothelial dysfunction, atherosclerosis, and cardiovascular events compared to the general population. Therefore, the availability of robust circulating biomarkers of endothelial dysfunction and atherogenesis may facilitate early recognition and management of cardiovascular risk in SSc. We sought to address this issue by conducting a systematic review and meta-analysis of studies investigating various types of circulating cell adhesion molecules involved in endothelial dysfunction and atherogenesis (i.e., immunoglobulin-like vascular cell, VCAM-1, intercellular, ICAM-1, platelet endothelial cell, PECAM-1, neural cell, NCAM, Down syndrome cell, DSCAM, and endothelial cell-selective, ESAM, adhesion molecules, E-, L-, and P-selectin, integrins, and cadherins) in SSc patients and healthy controls. Methods: We searched PubMed, Scopus, and Web of Science from inception to 1 May 2024. Risk of bias and certainty of evidence were assessed using validated tools. Results: In 43 eligible studies, compared to controls, patients with SSc had significantly higher plasma or serum concentrations of ICAM-1 (standard mean difference, SMD=1.16, 95% CI 0.88 to 1.44, p<0.001; moderate certainty), VCAM-1 (SMD=1.09, 95% CI 0.72 to 1.46, p<0.001; moderate certainty), PECAM-1 (SMD=1.65, 95% CI 0.33 to 2.98, p=0.014; very low certainty), E-selectin (SMD=1.17, 95% CI 0.72 to 1.62, p<0.001; moderate certainty), and P-selectin (SMD=1.10, 95% CI 0.31 to 1.90, p=0.007; low certainty). There were no significant between-group differences in L-selectin concentrations (SMD=-0.35, 95% CI -1.03 to 0.32, p=0.31; very low certainty), whereas minimal/no evidence was available for cadherins, NCAM, DSCAM, ESAM, or integrins. Overall, no significant associations were observed between the effect size and various patient and study characteristics in meta-regression and subgroup analyses. Discussion: The results of this systematic review and meta-analysis suggest that specific circulating cell adhesion molecules, i.e., ICAM-1, VCAM-1, PECAM-1, E-selectin, and P-selectin, can be helpful as biomarkers of endothelial dysfunction and atherogenesis in the assessment of cardiovascular risk in SSc patients. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024549710.

Biomarkers of epithelial-mesenchymal transition: E-cadherin and beta-catenin in malignant transformation of oral lesions.

Objective: Detecting oral lesions at high risk of becoming cancer may enable early interventions to prevent oral cancer. The diagnosis of dysplasia in an oral lesion is used to predict this risk but is subject to interobserver and intraobserver variability. Studying biomarkers or molecular markers that reflect underlying molecular alterations can serve as an additional and objective method of risk assessment. E-cadherin and beta-catenin, molecular markers of epithelial-mesenchymal transition (EMT), potentially contribute to early malignant progression in oral tissue. This narrative review provides an overview of EMT, its relation to oral cancer, and the interaction among E-cadherin, beta-catenin, and the Wnt pathway in malignant progression of oral tissue. Methods: Full-text literature on EMT, E-cadherin, beta-catenin, oral epithelial dysplasia, and oral cancer was retrieved from PubMed and Google Scholar. Results: Sixty original research articles, reviews, and consensus statements were selected for review. Discussion: EMT, a biological mechanism characterized by epithelial and mesenchymal changes, can contribute to cancer development. Molecular markers of EMT including TWIST, vimentin, and N-cadherin may serve as prognostic markers of oral cancer. Dependent on Wnt pathway activity and the loss of membranous E-cadherin, E-cadherin and beta-catenin can play various roles along the spectrum of malignant progression, including tumour inhibition, early tumour progression, and late-stage tumour progression. Cross-sectional immunohistochemical research has found changes in expression patterns of E-cadherin and beta-catenin from normal oral tissue, oral epithelial dysplasia, to oral squamous cell carcinoma. Conclusion: Future research should explore the longitudinal role of EMT markers in predicting malignant progression in oral tissue.

Objectif: La détection de lésions buccales présentant un risque élevé d'évoluer en cancer peut permettre des interventions précoces pour prévenir le cancer de la bouche. Le diagnostic de dysplasie dans le cas de lésions buccales sert à prédire ce risque, mais il est soumis à une variabilité d'un observateur à l'autre et avec le même observateur. L'étude de marqueurs biologiques ou de marqueurs moléculaires correspondant à des altérations moléculaires sous-jacentes peut constituer une méthode objective supplémentaire d'évaluation des risques. L'E-cadhérine et la bêta-caténine, des marqueurs moléculaires de la transition épithélio-mésenchymateuse (TEM), pourraient contribuer aux premières étapes de l'évolution maligne du tissu buccal. Cette revue narrative donne un aperçu de la TEM, de ses liens avec le cancer de la bouche et de l'interaction entre l'E-cadhérine, la bêta-caténine et la voie de signalisation Wnt dans l'évolution maligne du tissu buccal. Méthodes: On a obtenu le texte intégral d'études portant sur la TEM, l'E-cadhérine, la bêta-caténine, la dysplasie épithéliale buccale et le cancer de la bouche sur PubMed et Google Scholar. Résultats: Soixante articles sur des études originales, des revues et des déclarations de consensus ont été sélectionnés aux fins d'examen. Discussion: La TEM, un mécanisme biologique caractérisé par des changements épithéliaux et mésenchymateux, peut contribuer à l'apparition d'un cancer. Les marqueurs moléculaires de la TEM, notamment TWIST, la vimentine et la N-cadhérine, peuvent servir de marqueurs pronostiques du cancer de la bouche. En fonction de l'activité de la voie de signalisation Wnt et de la perte de l'E-cadhérine membraneuse, l'E-cadhérine et la bêta-caténine peuvent jouer divers rôles dans le spectre de l'évolution maligne, notamment l'inhibition tumorale, la progression tumorale précoce et l'évolution tumorale avancée. Des études transversales d'immunohistochimie ont révélé des changements dans les modèles d'expression de l'E-cadhérine et de la bêta-caténine avec le passage du tissu buccal normal, de la dysplasie épithéliale buccale au carcinome squameux de la bouche. Conclusion: À l'avenir, des études devraient explorer le rôle longitudinal des marqueurs de la TEM dans la prévision de l'évolution maligne dans les tissus buccaux.

BPA Exposure Affects Mouse Gastruloids Axial Elongation by Perturbing the Wnt/ß-Catenin Pathway.

Mammalian embryos are very vulnerable to environmental toxicants (ETs) exposure. Bisphenol A (BPA), one of the most diffused ETs, exerts endocrine-disrupting effects through estro-gen-mimicking and hormone-like properties, with detrimental health effects, including on reproduction. However, its impact during the peri-implantation stages is still unclear. This study, using gastruloids as a 3D stem cell-based in vitro model of embryonic development, showed that BPA exposure arrests their axial elongation when present during the Wnt/ß-catenin pathway activation period by ß-catenin protein reduction. Gastruloid reshaping might have been impeded by the downregulation of Snail, Slug and Twist, known to suppress E-cadherin expression and to activate the N-cadherin gene, and by the low expression of the N-cadherin protein. Also, the lack of gastruloids elongation might be related to altered exit of BPA-exposed cells from the pluripotency condition and their following differentiation. In conclusion, here we show that the inhibition of gastruloids' axial elongation by BPA might be the result of the concomitant Wnt/ß-catenin perturbation, reduced N-cadherin expression and Oct4, T/Bra and Cdx2 altered patter expression, which all together concur in the impaired development of mouse gastruloids.

Clustered protocadherin cis-interactions are required for combinatorial cell-cell recognition underlying neuronal self-avoidance.

In the developing human brain, only 53 stochastically expressed clustered protocadherin (cPcdh) isoforms enable neurites from individual neurons to recognize and self-avoid while simultaneously maintaining contact with neurites from other neurons. Cell assays have demonstrated that self-recognition occurs only when all cPcdh isoforms perfectly match across the cell boundary, with a single mismatch in the cPcdh expression profile interfering with recognition. It remains unclear, however, how a single mismatched isoform between neighboring cells is sufficient to block erroneous recognitions. Using systematic cell aggregation experiments, we show that abolishing cPcdh interactions on the same membrane (cis) results in a complete loss of specific combinatorial binding between cells (trans). Our computer simulations demonstrate that the organization of cPcdh in linear array oligomers, composed of cis and trans interactions, enhances self-recognition by increasing the concentration and stability of cPcdh trans complexes between the homotypic membranes. Importantly, we show that the presence of mismatched isoforms between cells drastically diminishes the concentration and stability of the trans complexes. Overall, we provide an explanation for the role of the cPcdh assembly arrangements in neuronal self/non-self-discrimination underlying neuronal self-avoidance.

Scaling between cell cycle duration and wing growth is regulated by Fat-Dachsous signaling in Drosophila.

The atypical cadherins Fat and Dachsous (Ds) signal through the Hippo pathway to regulate growth of numerous organs, including the Drosophila wing. Here, we find that Ds-Fat signaling tunes a unique feature of cell proliferation found to control the rate of wing growth during the third instar larval phase. The duration of the cell cycle increases in direct proportion to the size of the wing, leading to linear-like growth during the third instar. Ds-Fat signaling enhances the rate at which the cell cycle lengthens with wing size, thus diminishing the rate of wing growth. We show that this results in a complex but stereotyped relative scaling of wing growth with body growth in Drosophila. Finally, we examine the dynamics of Fat and Ds protein distribution in the wing, observing graded distributions that change during growth. However, the significance of these dynamics is unclear since perturbations in expression have negligible impact on wing growth.

Orthologs at the Base of the Olfactores Clade.

Tunicate orthologs in the human genome comprise just 84 genes of the 19,872 protein-coding genes and 23 of the 16,528 non-coding genes, yet they stand at the base of the Olfactores clade, which radiated to generate thousands of tunicate and vertebrate species. What were the powerful drivers among these genes that enabled this process? Many of these orthologs are present in gene families. We discuss the biological role of each family and the orthologs' quantitative contribution to the family. Most important was the evolution of a second type of cadherin. This, a Type II cadherin, had the property of detaching the cell containing that cadherin from cells that expressed the Type I class. The set of such Type II cadherins could now detach and move away from their Type I neighbours, a process which would eventually evolve into the formation of the neural crest, "the fourth germ layer", providing a wide range of possibilities for further evolutionary invention. A second important contribution were key additions to the broad development of the muscle and nerve protein and visual perception toolkits. These developments in mobility and vision provided the basis for the development of the efficient predatory capabilities of the Vertebrata.

The Protective Effect of Crocin on Rat Bone Marrow Mesenchymal Stem Cells Exposed to Aluminum Chloride as an Endocrine Disruptor.

Background: Mesenchymal Stem Cells (MSCs) have the ability to self-renew and proliferate which gives them healing properties in various tissues. Aluminium chloride (AlCl3) is a chemical compound with harmful effects on health; oxidative stress caused by Aluminium has been reported previously. Crocin, a major component of Crocus sativus (saffron), has antioxidant properties and has shown therapeutic potential. Researchers have been looking for ways to reduce the harmful effects of AlCl3. Methods: To investigate whether crocin can reduce AlCl3 cytotoxicity, rat Bone Marrow Mesenchymal Stem Cells (BM-MSCs) were isolated, cultured and divided into four experimental groups. The first group was the control, which was untreated cells. The second and third groups were treated with crocin (50, 100, 250, 500 µM) and AlCl3 (20, 25, 30 mM) for 24 hr. The fourth group was pre-treated with crocin (250, 500 µM) for 24 hr and then treated with AlCl3 (20 mM) overnight. Cytotoxicity was assessed using the MTT assay. Mineralization was evaluated by alizarin red staining. Sox-2 and E-cadherin expression were measured using real-time PCR. Results: The results showed that AlCl3 caused cytotoxicity on BM-MSCs and decreased the mRNA expression of Sox-2 and E-cadherin, which are important for the maintenance of self-renewal and proliferation of BM-MSCs. In contrast, crocin protected the self-renewal characteristic of BM-MSCs by increasing Sox-2 expression and also preserved the proliferative effects on BM-MSCs by upregulating E-cadherin expression (***p≤0.001). Conclusion: Overall, the study suggests that crocin can protect BM-MSCs from AlCl3-induced cytotoxicity by upregulate Sox-2 expression and E-cadherin expression. This suggests that crocin may be a potential therapeutic agent for the treatment of AlCl3-induced toxicity.

Sulforaphane Inhibits Adhesion and Migration of Cisplatin- and Gemcitabine-Resistant Bladder Cancer Cells In Vitro.

Only 20% of patients with muscle-invasive bladder carcinoma respond to cisplatin-based chemotherapy. Since the natural phytochemical sulforaphane (SFN) exhibits antitumor properties, its influence on the adhesive and migratory properties of cisplatin- and gemcitabine-sensitive and cisplatin- and gemcitabine-resistant RT4, RT112, T24, and TCCSUP bladder cancer cells was evaluated. Mechanisms behind the SFN influence were explored by assessing levels of the integrin adhesion receptors ß1 (total and activated) and ß4 and their functional relevance. To evaluate cell differentiation processes, E- and N-cadherin, vimentin and cytokeratin (CK) 8/18 expression were examined. SFN down-regulated bladder cancer cell adhesion with cell line and resistance-specific differences. Different responses to SFN were reflected in integrin expression that depended on the cell line and presence of resistance. Chemotactic movement of RT112, T24, and TCCSUP (RT4 did not migrate) was markedly blocked by SFN in both chemo-sensitive and chemo-resistant cells. Integrin-blocking studies indicated ß1 and ß4 as chemotaxis regulators. N-cadherin was diminished by SFN, particularly in sensitive and resistant T24 and RT112 cells, whereas E-cadherin was increased in RT112 cells (not detectable in RT4 and TCCSup cells). Alterations in vimentin and CK8/18 were also apparent, though not the same in all cell lines. SFN exposure resulted in translocation of E-cadherin (RT112), N-cadherin (RT112, T24), and vimentin (T24). SFN down-regulated adhesion and migration in chemo-sensitive and chemo-resistant bladder cancer cells by acting on integrin ß1 and ß4 expression and inducing the mesenchymal-epithelial translocation of cadherins and vimentin. SFN does, therefore, possess potential to improve bladder cancer therapy.

Endothelial Neuropilin-1: a multifaced signal transducer with an emerging role in inflammation and atherosclerosis beyond angiogenesis.

Neuropilin-1 (NRP1) is a transmembrane glycoprotein expressed by several cell types including, neurons, endothelial cells (ECs), smooth muscle cells, cardiomyocytes and immune cells comprising macrophages, dendritic cells and T cell subsets. Since NRP1 discovery in 1987 as an adhesion molecule in the frog nervous system, more than 2300 publications on PubMed investigated the function of NRP1 in physiological and pathological contexts. NRP1 has been characterised as a coreceptor for class 3 semaphorins and several members of the vascular endothelial growth factor (VEGF) family. Because the VEGF family is the main regulator of blood and lymphatic vessel growth in addition to promoting neurogenesis, neuronal patterning, neuroprotection and glial growth, the role of NRP1 in these biological processes has been extensively investigated. It is now established that NRP1 promotes the physiological growth of new vessels from pre-existing ones in the process of angiogenesis. Furthermore, several studies have shown that NRP1 mediates signalling pathways regulating pathological vascular growth in ocular neovascular diseases and tumour development. Less defined are the roles of NRP1 in maintaining the function of the quiescent established vasculature in an adult organism. This review will focus on the opposite roles of NRP1 in regulating transforming growth factor ß signalling pathways in different cell types, and on the emerging role of endothelial NRP1 as an atheroprotective, anti-inflammatory factor involved in the response of ECs to shear stress.

Early gonadogenesis in Columba livia (birds: Columbiformes): Migration, colonization, and differentiation of germ cells.

In birds, primordial germ cells (PGCs) use the bloodstream to travel to a specific region, where the cells undergo extravasation followed by intrastromal migration to the gonadal crest for further colonization. Currently, DDX4, SSEA1, and Oct4 are used to identify germ cells. Other germline cell-associated molecules are N-cadherin, GnRHR, and 3ß hydroxysteroid dehydrogenase (3ßHSD), which have been used in mice and birds during gonadal development; however, its role in early gonadogenesis in birds is poorly described. This study aimed to evaluate the differential immunodetection of N-cadherin binding molecule, Oct4 pluripotency protein, GnRHR receptor, and 3ßHSD enzyme in Columba livia embryos during migration colonization of PGCs in the gonadal crest and early gonadogenesis. These markers were revealed by immunohistochemistry in histological preparations of C. livia corresponding to stages (S)15 to S40. Immunodetection of N-cadherin, Oct4, GnRHR, and 3ßHSD in the germ line of C. livia allowed the identification of PGCs in the yolk sac membrane at the level of the splanchnic mesoderm during migration to the genital crest and its colonization. In the same way, it was possible to characterize and localize PGCs during early gonadogenesis. This study in C. livia demonstrates that Oct4, N-cadherin, GNRHR, and 3ßHSD are immunodetected in PGCs and could be used as potential germline cell markers during cell migration out of blood vessels, colonization in the genital crest, and early gonadogenesis. Furthermore, this study could be used as a novel general model to understand the early gonadogenesis in altricial species.

The pathophysiological role of circulating adhesion molecules in schizophrenia: A systematic review and meta-analysis.

BACKGROUND: Increasing evidence suggests an association between schizophrenia and atherosclerosis. We conducted a systematic review and meta-analysis of cell adhesion molecules, critically involved in early atherosclerosis, in schizophrenia. METHODS: We searched electronic databases from inception to 11 November 2023 for case-control studies assessing vascular cell, VCAM-1, intercellular, ICAM-1, platelet endothelial cell, PECAM-1, neural cell, NCAM, and Down syndrome cell, DSCAM, adhesion molecules, selectins (E-, L-, and P-selectin), integrins, and cadherins in patients with schizophrenia and healthy controls. Risk of bias and certainty of evidence were assessed using the JBI checklist and GRADE, respectively. RESULTS: In 19 eligible studies, there were non-significant between-group differences in the concentrations of cell adhesion molecules, barring higher P-selectin in patients with schizophrenia (standard mean difference, SMD = 2.05, 95 % CI 0.72 to 3.38, p = 0.003; I2 = 97.2 %, p<0.001; very low certainty of evidence). Limited or no information was available regarding PECAM-1, DSCAM, ESAM, integrins, and cadherins. In meta-regression and subgroup analysis, there were significant associations between the SMD of ICAM-1 and matrix used (plasma or serum) and pharmacological treatment of schizophrenia, and between the SMD of VCAM-1 and pharmacological treatment, but not with other study and patient characteristics. CONCLUSIONS: The results of our systematic review and meta-analysis do not support a significant role of immunoglobulin-like adhesion molecules, selectins, integrins, or cadherins in mediating the associations between schizophrenia, atherosclerosis, and cardiovascular disease. Further studies are warranted to investigate these associations in patients with different cardiovascular risk and the effects of antipsychotic treatments on cell adhesion molecules and surrogate markers of atherosclerosis (PROSPERO registration number: CRD42023463916).

Interfacial Organization and Forces Arising from Epithelial-Cancerous Monolayer Interactions.

The interfacial interactions between epithelia and cancer cells have profound relevance for tumor development and metastasis. Through monolayer confrontation of MCF10A (nontumorigenic human breast epithelial cells) and MDA-MB-231 (human epithelial breast cancer cells) cells, we investigate the epithelial-cancerous interfacial interactions at the tissue level. We show that the monolayer interaction leads to competitive interfacial morphodynamics and drives an intricate spatial organization of MCF10A cells into multicellular finger-like structures, which further branch into multiple subfinger-like structures. These hierarchical interfacial structures penetrate the cancer monolayer and can spontaneously segregate or even envelop cancer cell clusters, consistent with our theoretical prediction. By tracking the substrate displacements via embedded fluorescent nanobeads and implementing nanomechanical modeling that combines atomic force microscopy and finite element simulations, we computed mechanical force patterns, including traction forces and monolayer stresses, caused by the monolayer interaction. It is found that the heterogeneous mechanical forces accumulated in the monolayers are able to squeeze cancer cells, leading to three-dimensional interfacial bulges or cell extrusion, initiating the p53 apoptosis signaling pathways of cancer cells. We reveal that intercellular E-cadherin and P-cadherin of epithelial cells differentially regulate the interfacial organization including migration speed, directionality, spatial correlation, F-actin alignment, and subcellular protrusions of MCF10A cells; whereas E-cadherin governs interfacial geometry that is relevant to force localization and cancer cell extrusion, P-cadherin maintains interfacial integrity that enables long-range force transmission. Our findings suggest that the collaborative molecular and mechanical behaviors are crucial for preventing epithelial tissues from undergoing tumor invasion.

Understanding the Role of CDH4 in Multiple System Atrophy Brain.

BACKGROUND: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunction. A major pathological feature of MSA is the presence of α-synuclein aggregates in oligodendrocytes, the myelinating cells of the central nervous system. A genome-wide association study revealed that the CDH4 gene is associated with MSA. However, virtually nothing is known about the role of CDH4 in the context of MSA. OBJECTIVE: Our aim was to compare the expression of CDH4 between MSA and control brains, and to investigate its relationship with α-synuclein in oligodendrocytes. METHODS: RNA and protein were prepared from putamen, motor cortex white matter, cerebellum, and superior occipital cortex tissues collected from MSA (N = 11) and control (N = 13) brains. The expression of CDH4 was measured at mRNA and protein levels by qPCR and western blotting. Oligodendrocyte cells were cultured on plates and transfected with CDH4 cDNA and its impact on α-synuclein was analyzed. RESULTS: Firstly, we found that CDH4 in MSA brain was significantly elevated in the disease-affected motor cortex white matter in MSA (N = 11) compared to controls (N = 13) and unaltered in the disease-unaffected superior occipital cortex. Secondly, we determined that increases in CDH4 expression caused changes in the cellular levels of α-synuclein in oligodendrocytes. CONCLUSIONS: When put together, these results provide evidence that support the GWAS association of CDH4 with MSA.

Trichomonas vaginalis: Monolayer and Cluster Formation-Ultrastructural Aspects Using High-Resolution Scanning Electron Microscopy.

Trichomonas vaginalis is an extracellular protozoan parasite that causes human trichomoniasis, a sexually transmitted infection (STI) that affects approximately 270 million people worldwide. The phenomenon of T. vaginalis adhesion to inert substrates has been described in several reports. Still, very few studies on cluster formation have been conducted, and more detailed analyses of the contact regions between the parasites' membranes in these aggregate formations have not been carried out. The present study aims to show that T. vaginalis forms a tight monolayer, similar to an epithelium, with parasites firmly adhered to the culture flask bottom by interdigitations and in the absence of host cells. In addition, we analyzed and compared the formation of the clusters, focusing on parasite aggregates that float in the culture flasks. We employed various imaging techniques, including high-resolution scanning electron microscopy, transmission electron microscopy, cytochemistry, TEM tomography, and dye injection. We analyzed whether the monolayer behaves as an epithelium, analyzing cell junctions, cell communication, and ultrastructural aspects, and concluded that monolayer formation differs from cluster formation in many aspects. The monolayers form strong adhesion, whereas the clusters have fragile attachments. We did not find fusion or the passage of molecules between neighbor-attached cells; there is no need for different strains to form filopodia, cytonemes, and extracellular vesicles during cluster and monolayer formation.

Extracellular molecular signals shaping dendrite architecture during brain development.

Proper growth and branching of dendrites are crucial for adequate central nervous system (CNS) functioning. The neuronal dendritic geometry determines the mode and quality of information processing. Any defects in dendrite development will disrupt neuronal circuit formation, affecting brain function. Besides cell-intrinsic programmes, extrinsic factors regulate various aspects of dendritic development. Among these extrinsic factors are extracellular molecular signals which can shape the dendrite architecture during early development. This review will focus on extrinsic factors regulating dendritic growth during early neuronal development, including neurotransmitters, neurotrophins, extracellular matrix proteins, contact-mediated ligands, and secreted and diffusible cues. How these extracellular molecular signals contribute to dendritic growth has been investigated in developing nervous systems using different species, different areas within the CNS, and different neuronal types. The response of the dendritic tree to these extracellular molecular signals can result in growth-promoting or growth-limiting effects, and it depends on the receptor subtype, receptor quantity, receptor efficiency, the animal model used, the developmental time windows, and finally, the targeted signal cascade. This article reviews our current understanding of the role of various extracellular signals in the establishment of the architecture of the dendrites.

Differential expression of Cadherins switch and Caveolin-2 during stages of oral carcinogenesis.

Background: Oral squamous cell carcinoma (OSCC) accounts for 90% of oral malignancies, which may be preceded by oral potentially malignant disorders (OPMDs). Cancer progression involves the downregulation of epithelial markers (E-cadherin) and the upregulation of mesenchymal markers (N-cadherin), which together characterise the epithelial-mesenchymal transition (EMT). Furthermore, caveolin can act on cell adhesion and migration events that regulate the expression of the E-cadherin/α-ß-catenin complex, thus favouring aggressive biological behaviour. This study aimed to analyse the immunoexpression of E-cadherin, N-cadherin and caveolin-2 at different stages of oral carcinogenesis to identify reliable biomarkers to predict malignant potential. Methods: Expressions of E-cadherin and N-cadherin in 14 normal oral mucosae (NOM), 14 OPMD and 33 OSCC specimens were evaluated using immunohistochemistry. Clinicopathological parameters were also assessed. Results: E-cadherin immunoexpression was significantly reduced during the progression of oral carcinogenesis (P = 0.0018). N-cadherin immunoexpression did not show any statistical differences between these groups. However, a representative number of N-cadherin-positive OSCC cases did not express E-cadherin. The expression of caveolin-2 increased significantly with the progression of the disease, from NOM to OSCC (P value: 0.0028). Conclusion: These findings indicate that cadherin switch and caveolin-2 immunoexpression may be regulatory events in oral carcinogenesis.

Role of desmosomal components in the initiation and metastasis of oral cancer-A review.

Desmosomes are composed of a number of proteins, including cadherins, armadillo proteins and plakoplilins, which are responsible for mediating cell-cell adhesion. Cadherins are transmembrane proteins that bind to each other on adjacent cells, forming a strong adhesive bond between the cells. In normal tissues, desmosomes help to maintain the structural integrity of the tissue by holding the cells together. During carcinogenesis, the structure and function of desmosomes may be altered. For example, in oral cancer, the expression of certain cadherins may be increased, leading to increased cell-cell adhesion and a more cohesive tumour mass. This may contribute to the ability of cancer cells to evade the immune system and resist chemotherapy. In addition to their role in cell adhesion, desmosomes also play a role in cell signaling. The proteins that make up desmosomes can interact with signaling pathways that regulate cell proliferation, migration and survival. Dysregulation of these pathways may contribute to the development and progression of oral cancer. There is also evidence that desmosomes may be involved in the process of invasion and metastasis, which is the spread of cancer cells from the primary tumour to other parts of the body. Cancer cells that have disrupted or abnormal desmosomes may be more likely to migrate and invade other tissues. Overall, desmosomes appear to be important in the development and progression of oral cancer. Further research is needed to fully understand the role of these cell-cell junctions in the disease and to identify potential therapeutic targets.

High temporal frequency light response in mouse retina is mediated by ON and OFF bipolar cells and requires FAT3 signaling.

Vision is initiated by the reception of light by photoreceptors and subsequent processing via parallel retinal circuits. Proper circuit organization depends on the multi-functional tissue polarity protein FAT3, which is required for amacrine cell connectivity and retinal lamination. Here we investigated the retinal function of Fat3 mutant mice and found decreases in physiological and perceptual responses to high frequency flashes. These defects did not correlate with abnormal amacrine cell wiring, pointing instead to a role in bipolar cell subtypes that also express FAT3. Indeed, similar deficits were observed in mice lacking the bipolar cell glutamate receptors GRIK1 (OFF-bipolar cells) and GRM6 (ON-bipolar cells). Mechanistically, FAT3 binds to the synaptic protein PTPσ and is required to localize GRIK1 to OFF-cone bipolar cell synapses with cone photoreceptors. How FAT3 impacts ON-cone bipolar cell function at high temporal frequency remains to be uncovered. These findings expand the repertoire of FAT3's functions and reveal the importance of both ON- and OFF-bipolar cells for high frequency light response.