Molecular topography of an entire nervous system.

We have produced gene expression profiles of all 302 neurons of the C. elegans nervous system that match the single-cell resolution of its anatomy and wiring diagram. Our results suggest that individual neuron classes can be solely identified by combinatorial expression of specific gene families. For example, each neuron class expresses distinct codes of ∼23 neuropeptide genes and ∼36 neuropeptide receptors, delineating a complex and expansive "wireless" signaling network. To demonstrate the utility of this comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression and (2) reveal adhesion proteins with potential roles in process placement and synaptic specificity. Our expression data are available at https://cengen.org and can be interrogated at the web application CengenApp. We expect that this neuron-specific directory of gene expression will spur investigations of underlying mechanisms that define anatomy, connectivity, and function throughout the C. elegans nervous system.

Host-derived CEACAM-laden vesicles engage enterotoxigenic Escherichia coli for elimination and toxin neutralization.

Enterotoxigenic Escherichia coli (ETEC) cause hundreds of millions of diarrheal illnesses annually ranging from mildly symptomatic cases to severe, life-threatening cholera-like diarrhea. Although ETEC are associated with long-term sequelae including malnutrition, the acute diarrheal illness is largely self-limited. Recent studies indicate that in addition to causing diarrhea, the ETEC heat-labile toxin (LT) modulates the expression of many genes in intestinal epithelia, including carcinoembryonic cell adhesion molecules (CEACAMs) which ETEC exploit as receptors, enabling toxin delivery. Here, however, we demonstrate that LT also enhances the expression of CEACAMs on extracellular vesicles (EV) shed by intestinal epithelia and that CEACAM-laden EV increase in abundance during human infections, mitigate pathogen-host interactions, scavenge free ETEC toxins, and accelerate ETEC clearance from the gastrointestinal tract. Collectively, these findings indicate that CEACAMs play a multifaceted role in ETEC pathogen-host interactions, transiently favoring the pathogen, but ultimately contributing to innate responses that extinguish these common infections.

CD163+ Macrophages Induce Endothelial-to-Mesenchymal Transition in Atheroma.

BACKGROUND: Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163+ macrophages. Here, we explored the hypothesis that CD163+ macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap. METHODS: Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone ApoE-/- and ApoE-/-/CD163-/- mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments. RESULTS: In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163+ macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa ß) signaling by proinflammatory cytokines released from CD163+ macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163+ macrophage-induced EndMT. Additionally, CD163 deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes. CONCLUSIONS: CD163+ macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.

T cell-dependent bispecific antibodies alter organ-specific endothelial cell-T cell interaction.

Preclinical and clinical studies demonstrate that T cell-dependent bispecific antibodies (TDBs) induce systemic changes in addition to tumor killing, leading to adverse events. Here, we report an in-depth characterization of acute responses to TDBs in tumor-bearing mice. Contrary to modest changes in tumors, rapid and substantial lymphocyte accumulation and endothelial cell (EC) activation occur around large blood vessels in normal organs including the liver. We hypothesize that organ-specific ECs may account for the differential responses in normal tissues and tumors, and we identify a list of genes selectively upregulated by TDB in large liver vessels. Using one of the genes as an example, we demonstrate that CD9 facilitates ICAM-1 to support T cell-EC interaction in response to soluble factors released from a TDB-mediated cytotoxic reaction. Our results suggest that multiple factors may cooperatively promote T cell infiltration into normal organs as a secondary response to TDB-mediated tumor killing. These data shed light on how different vascular beds respond to cancer immunotherapy and may help improve their safety and efficacy.

Insertion of a neomycin selection cassette in the Amigo1 locus alters gene expression in the olfactory epithelium leading to region-specific defects in olfactory receptor neuron development.

During development of the nervous system, neurons connect to one another in a precisely organized manner. Sensory systems provide a good example of this organization, whereby the composition of the outside world is represented in the brain by neuronal maps. Establishing correct patterns of neural circuitry is crucial, as inaccurate map formation can lead to severe disruptions in sensory processing. In rodents, olfactory stimuli modulate a wide variety of behaviors essential for survival. The formation of the olfactory glomerular map is dependent on molecular cues that guide olfactory receptor neuron axons to broad regions of the olfactory bulb and on cell adhesion molecules that promote axonal sorting into specific synaptic units in this structure. Here, we demonstrate that the cell adhesion molecule Amigo1 is expressed in a subpopulation of olfactory receptor neurons, and we investigate its role in the precise targeting of olfactory receptor neuron axons to the olfactory bulb using a genetic loss-of-function approach in mice. While ablation of Amigo1 did not lead to alterations in olfactory sensory neuron axonal targeting, our experiments revealed that the presence of a neomycin resistance selection cassette in the Amigo1 locus can lead to off-target effects that are not due to loss of Amigo1 expression, including unexpected altered gene expression in olfactory receptor neurons and reduced glomerular size in the ventral region of the olfactory bulb. Our results demonstrate that insertion of a neomycin selection cassette into the mouse genome can have specific deleterious effects on the development of the olfactory system and highlight the importance of removing antibiotic resistance cassettes from genetic loss-of-function mouse models when studying olfactory system development.

Transcriptomic analysis of glucosidase II beta subunit (GluIIß) knockout A549 cells reveals its roles in regulation of cell adhesion molecules (CAMs) and anti-tumor immunity.

Glucosidase II beta subunit (GluIIß), encoded from PRKCSH, is a subunit of the glucosidase II enzyme responsible for quality control of N-linked glycoprotein folding and suppression of GluIIß led to inhibitory effect of the receptor tyrosine kinase (RTKs) activities known to be critical for survival and development of cancer. In this study, we investigated the effect of GluIIß knockout on the global gene expression of cancer cells and its impact on functions of immune cells. GluIIß knockout lung adenocarcinoma A549 cell line was generated using CRISPR/Cas9-based genome editing system and subjected to transcriptomic analysis. Among 23,502 expressed transcripts, 1068 genes were significantly up-regulated and 807 genes greatly down-regulated. The KEGG enrichment analysis showed significant down-regulation of genes related extracellular matrix (ECM), ECM-receptor interaction, cytokine-cytokine receptor interaction and cell adhesion molecules (CAMs) in GluIIß knockout cells. Of 9 CAMs encoded DEG identified by KEGG enrichment analysis, real time RT-PCR confirmed 8 genes to be significantly down-regulated in all 3 different GluIIß knockout clones, which includes cadherin 4 (CDH4), cadherin 2 (CDH2), versican (VCAN), integrin subunit alpha 4 (ITGA4), endothelial cell-selective adhesion molecule (ESAM), CD274 (program death ligand-1 (PD-L1)), Cell Adhesion Molecule 1 (CADM1), and Nectin Cell Adhesion Molecule 3 (NECTIN3). Whereas PTPRF (Protein Tyrosine Phosphatase Receptor Type F) was significantly decreased only in 1 out of 3 knockout clones. Microscopic analysis revealed distinctively different cell morphology of GluIIß knockout cells with lesser cytoplasmic and cell surface area compared to parental A549 cells and non-targeted transfected cells.Further investigations revealed that Jurkat E6.1 T cells or human peripheral blood mononuclear cells (PBMCs) co-cultured with GluIIß knockout A549 exhibited significantly increased viability and tumor cell killing activity compared to those co-cultured with non-target transfected cells. Analysis of cytokine released from Jurkat E6.1 T cells co-cultured with GluIIß knockout A549 cells showed significant increased level of angiogenin and significant decreased level of ENA-78. In conclusion, knockout of GluIIß from cancer cells induced altered gene expression profile that improved anti-tumor activities of co-cultured T lymphocytes and PBMCs thus suppression of GluIIß may represent a novel approach of boosting anti-tumor immunity.

Combined additive effects of neuronal membrane glycoprotein GPM6a and the intercellular cell adhesion molecule ICAM5 on neuronal morphogenesis.

The mechanisms underlying neuronal development and synaptic formation in the brain depend on intricate cellular and molecular processes. The neuronal membrane glycoprotein GPM6a promotes neurite elongation, filopodia/spine formation, and synapse development, yet its molecular mechanisms remain unknown. Since the extracellular domains of GPM6a (ECs) command its function, we investigated the interaction between ICAM5, the neuronal member of the intercellular adhesion molecule (ICAM) family, and GPM6a's ECs. Our study aimed to explore the functional relationship between GPM6a and ICAM5 in hippocampal culture neurons and cell lines. Immunostaining of 15 days in vitro (DIV) neurons revealed significant co-localization between endogenous GPM6a clusters and ICAM5 clusters in the dendritic shaft. These results were further corroborated by overexpressing GPM6a and ICAM5 in N2a cells and hippocampal neurons at 5 DIV. Moreover, results from the co-immunoprecipitations and cell aggregation assays prove the cis and trans interaction between both proteins in GPM6a/ICAM5 overexpressing HEK293 cells. Additionally, GPM6a and ICAM5 overexpression additively enhanced neurite length, the number of neurites in N2a cells, and filopodia formation in 5 DIV neurons, indicating their cooperative role. These findings highlight the dynamic association between GPM6a and ICAM5 during neuronal development, offering insights into their contributions to neurite outgrowth, filopodia formation, and cell-cell interactions.

MicroRNAs Associated with IgLON Cell Adhesion Molecule Expression.

The IgLON family of cell adhesion molecules consists of five members (LSAMP, OPCML, neurotrimin, NEGR1, and IgLON5) discovered as supporters of neuronal development, axon growth and guidance, and synapse formation and maintenance. Tumour suppression properties have recently been emerging based on antiproliferative effects through the modulation of oncogenic pathways. Available evidence endorses a role for non-coding RNAs or microRNAs as relevant controllers of IgLON molecule expression that can impact their critical physiological and pathological roles. Current findings support a function for long non-coding RNAs and microRNAs in the modulation of LSAMP expression in cell senescence, cancer biogenesis, addiction, and pulmonary hypertension. For OPCML, data point to a role for several microRNAs in the control of tumorigenesis. MicroRNAs were detected in neurotrimin-mediated functions in cancer biogenesis and in Schwann cell responses to peripheral nerve injury. For NEGR1, studies have mainly investigated microRNA involvement in neuronal responses to ischaemic injury, although data also exist about tumorigenesis and endothelial cell dysfunction. For IgLON5, information is only available about microRNA involved in myocardial infarction. In conclusion, despite much information being still missing and further research needed, the emerging picture favours a model in which non-coding RNAs exert a crucial role in modulating IgLON expression, ultimately affecting their important physiological functions.

A systematic review and meta-analysis of circulating adhesion molecules in rheumatoid arthritis.

BACKGROUND: The availability of robust biomarkers of endothelial activation might enhance the identification of subclinical atherosclerosis in rheumatoid arthritis (RA). We investigated this issue by conducting a systematic review and meta-analysis of cell adhesion molecules in RA patients. METHODS: We searched electronic databases from inception to 31 July 2023 for case-control studies assessing the circulating concentrations of immunoglobulin-like adhesion molecules (vascular cell, VCAM-1, intercellular, ICAM-1, and platelet endothelial cell, PECAM-1, adhesion molecule-1) and selectins (E, L, and P selectin) in RA patients and healthy controls. Risk of bias and certainty of evidence were assessed using the JBI checklist and GRADE, respectively. RESULTS: In 39 studies, compared to controls, RA patients had significantly higher concentrations of ICAM-1 (standard mean difference, SMD = 0.81, 95% CI 0.62-1.00, p < 0.001; I2 = 83.0%, p < 0.001), VCAM-1 (SMD = 1.17, 95% CI 0.73-1.61, p < 0.001; I2 = 95.8%, p < 0.001), PECAM-1 (SMD = 0.82, 95% CI 0.57-1.08, p < 0.001; I2 = 0.0%, p = 0.90), E-selectin (SMD = 0.64, 95% CI 0.42-0.86, p < 0.001; I2 = 75.0%, p < 0.001), and P-selectin (SMD = 1.06, 95% CI 0.50-1.60, p < 0.001; I2 = 84.8%, p < 0.001), but not L-selectin. In meta-regression and subgroup analysis, significant associations were observed between the effect size and use of glucocorticoids (ICAM-1), erythrocyte sedimentation rate (VCAM-1), study continent (VCAM-1, E-selectin, and P-selectin), and matrix assessed (P-selectin). CONCLUSIONS: The results of our study support a significant role of cell adhesion molecules in mediating the interplay between RA and atherosclerosis. Further studies are warranted to determine whether the routine use of these biomarkers can facilitate the detection and management of early atherosclerosis in this patient group. PROSPERO Registration Number: CRD42023466662.

Impact of dairy fat manipulation on endothelial function and lipid regulation in human aortic endothelial cells exposed to human plasma samples: an in vitro investigation from the RESET study.

PURPOSE: Longer-term intake of fatty acid (FA)-modified dairy products (SFA-reduced, MUFA-enriched) was reported to attenuate postprandial endothelial function in humans, relative to conventional (control) dairy. Thus, we performed an in vitro study in human aortic endothelial cells (HAEC) to investigate mechanisms underlying the effects observed in vivo. METHODS: This sub-study was conducted within the framework of the RESET study, a 12-week randomised controlled crossover trial with FA-modified and control dairy diets. HAEC were incubated for 24 h with post-intervention plasma samples from eleven adults (age: 57.5 ± 6.0 years; BMI: 25.7 ± 2.7 kg/m2) at moderate cardiovascular disease risk following representative sequential mixed meals. Markers of endothelial function and lipid regulation were assessed. RESULTS: Relative to control, HAEC incubation with plasma following the FA-modified treatment increased postprandial NOx production (P-interaction = 0.019), yet up-regulated relative E-selectin mRNA gene expression (P-interaction = 0.011). There was no impact on other genes measured. CONCLUSION: Incubation of HAEC with human plasma collected after longer-term dairy fat manipulation had a beneficial impact on postprandial NOx production. Further ex vivo research is needed to understand the impact of partial replacement of SFA with unsaturated fatty acids in dairy foods on pathways involved in endothelial function.

Ankyrin B promotes developmental spine regulation in the mouse prefrontal cortex.

Postnatal regulation of dendritic spine formation and refinement in cortical pyramidal neurons is critical for excitatory/inhibitory balance in neocortical networks. Recent studies have identified a selective spine pruning mechanism in the mouse prefrontal cortex mediated by class 3 Semaphorins and the L1 cell adhesion molecules, neuron-glia related cell adhesion molecule, Close Homolog of L1, and L1. L1 cell adhesion molecules bind Ankyrin B, an actin-spectrin adaptor encoded by Ankyrin2, a high-confidence gene for autism spectrum disorder. In a new inducible mouse model (Nex1Cre-ERT2: Ank2flox: RCE), Ankyrin2 deletion in early postnatal pyramidal neurons increased spine density on apical dendrites in prefrontal cortex layer 2/3 of homozygous and heterozygous Ankyrin2-deficient mice. In contrast, Ankyrin2 deletion in adulthood had no effect on spine density. Sema3F-induced spine pruning was impaired in cortical neuron cultures from Ankyrin B-null mice and was rescued by re-expression of the 220 kDa Ankyrin B isoform but not 440 kDa Ankyrin B. Ankyrin B bound to neuron-glia related CAM at a cytoplasmic domain motif (FIGQY1231), and mutation to FIGQH inhibited binding, impairing Sema3F-induced spine pruning in neuronal cultures. Identification of a novel function for Ankyrin B in dendritic spine regulation provides insight into cortical circuit development, as well as potential molecular deficiencies in autism spectrum disorder.

Regulation of young-adult neurogenesis and neuronal differentiation by neural cell adhesion molecule 2 (NCAM2).

Adult neurogenesis persists in mammals in the neurogenic zones, where newborn neurons are incorporated into preexisting circuits to preserve and improve learning and memory tasks. Relevant structural elements of the neurogenic niches include the family of cell adhesion molecules (CAMs), which participate in signal transduction and regulate the survival, division, and differentiation of radial glial progenitors (RGPs). Here we analyzed the functions of neural cell adhesion molecule 2 (NCAM2) in the regulation of RGPs in adult neurogenesis and during corticogenesis. We characterized the presence of NCAM2 across the main cell types of the neurogenic process in the dentate gyrus, revealing different levels of NCAM2 amid the progression of RGPs and the formation of neurons. We showed that Ncam2 overexpression in adult mice arrested progenitors in an RGP-like state, affecting the normal course of young-adult neurogenesis. Furthermore, changes in Ncam2 levels during corticogenesis led to transient migratory deficits but did not affect the survival and proliferation of RGPs, suggesting a differential role of NCAM2 in adult and embryonic stages. Our data reinforce the relevance of CAMs in the neurogenic process by revealing a significant role of Ncam2 levels in the regulation of RGPs during young-adult neurogenesis in the hippocampus.

Exposure to Radiofrequency Induces Synaptic Dysfunction in Cortical Neurons Causing Learning and Memory Alteration in Early Postnatal Mice.

The widespread use of wireless communication devices has necessitated unavoidable exposure to radiofrequency electromagnetic fields (RF-EMF). In particular, increasing RF-EMF exposure among children is primarily driven by mobile phone use. Therefore, this study investigated the effects of 1850 MHz RF-EMF exposure at a specific absorption rate of 4.0 W/kg on cortical neurons in mice at postnatal day 28. The results indicated a significant reduction in the number of mushroom-shaped dendritic spines in the prefrontal cortex after daily exposure for 4 weeks. Additionally, prolonged RF-EMF exposure over 9 days led to a gradual decrease in postsynaptic density 95 puncta and inhibited neurite outgrowth in developing cortical neurons. Moreover, the expression levels of genes associated with synapse formation, such as synaptic cell adhesion molecules and cyclin-dependent kinase 5, were reduced in the cerebral cortexes of RF-EMF-exposed mice. Behavioral assessments using the Morris water maze revealed altered spatial learning and memory after the 4-week exposure period. These findings underscore the potential of RF-EMF exposure during childhood to disrupt synaptic function in the cerebral cortex, thereby affecting the developmental stages of the nervous system and potentially influencing later cognitive function.

Distinct Alterations in Dendritic Spine Morphology in the Absence of ß-Neurexins.

Dendritic spines are essential for synaptic function because they constitute the postsynaptic compartment of the neurons that receives the most excitatory input. The extracellularly shorter variant of the presynaptic cell adhesion molecules neurexins, ß-neurexin, has been implicated in various aspects of synaptic function, including neurotransmitter release. However, its role in developing or stabilizing dendritic spines as fundamental computational units of excitatory synapses has remained unclear. Here, we show through morphological analysis that the deletion of ß-neurexins in hippocampal neurons in vitro and in hippocampal tissue in vivo affects presynaptic dense-core vesicles, as hypothesized earlier, and, unexpectedly, alters the postsynaptic spine structure. Specifically, we observed that the absence of ß-neurexins led to an increase in filopodial-like protrusions in vitro and more mature mushroom-type spines in the CA1 region of adult knockout mice. In addition, the deletion of ß-neurexins caused alterations in the spine head dimension and an increase in spines with perforations of their postsynaptic density but no changes in the overall number of spines or synapses. Our results indicate that presynaptic ß-neurexins play a role across the synaptic cleft, possibly by aligning with postsynaptic binding partners and glutamate receptors via transsynaptic columns.

FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer.

OBJECTIVE: Immunotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC) has shown limited efficacy. Poor CD8 T-cell infiltration, low neoantigen load and a highly immunosuppressive tumour microenvironment contribute to this lack of response. Here, we aimed to further investigate the immunoregulatory function of focal adhesion kinase (FAK) in PDAC, with specific emphasis on regulation of the type-II interferon response that is critical in promoting T-cell tumour recognition and effective immunosurveillance. DESIGN: We combined CRISPR, proteogenomics and transcriptomics with mechanistic experiments using a KrasG12Dp53R172H mouse model of pancreatic cancer and validated findings using proteomic analysis of human patient-derived PDAC cell lines and analysis of publicly available human PDAC transcriptomics datasets. RESULTS: Loss of PDAC cell-intrinsic FAK signalling promotes expression of the immunoproteasome and Major Histocompatibility Complex class-I (MHC-I), resulting in increased antigen diversity and antigen presentation by FAK-/- PDAC cells. Regulation of the immunoproteasome by FAK is a critical determinant of this response, optimising the physicochemical properties of the peptide repertoire for high affinity binding to MHC-I. Expression of these pathways can be further amplified in a STAT1-dependent manner via co-depletion of FAK and STAT3, resulting in extensive infiltration of tumour-reactive CD8 T-cells and further restraint of tumour growth. FAK-dependent regulation of antigen processing and presentation is conserved between mouse and human PDAC, but is lost in cells/tumours with an extreme squamous phenotype. CONCLUSION: Therapies aimed at FAK degradation may unlock additional therapeutic benefit for the treatment of PDAC through increasing antigen diversity and promoting antigen presentation.

Structures of neurexophilin-neurexin complexes reveal a regulatory mechanism of alternative splicing.

Neurexins are presynaptic, cell-adhesion molecules that specify the functional properties of synapses via interactions with trans-synaptic ligands. Neurexins are extensively alternatively spliced at six canonical sites that regulate multifarious ligand interactions, but the structural mechanisms underlying alternative splicing-dependent neurexin regulation are largely unknown. Here, we determined high-resolution structures of the complex of neurexophilin-1 and the second laminin/neurexin/sex-hormone-binding globulin domain (LNS2) of neurexin-1 and examined how alternative splicing at splice site #2 (SS2) regulates the complex. Our data reveal a unique, extensive, neurexophilin-neurexin binding interface that extends the jelly-roll ß-sandwich of LNS2 of neurexin-1 into neurexophilin-1. The SS2A insert of LNS2 augments this interface, increasing the binding affinity of LNS2 for neurexophilin-1. Taken together, our data reveal an unexpected architecture of neurexophilin-neurexin complexes that accounts for the modulation of binding by alternative splicing, which in turn regulates the competition of neurexophilin for neurexin binding with other ligands.

Cadherin-11 Regulates Cell Proliferation via the PDGFRß-ERK1/2 Signaling Pathway in Human Mesenchymal Stem Cells.

Controlling stem cell fate is the cornerstone of regenerative medicine. Cadherins have an important role in cell fate commitment and the function of cadherin-11 in the regulation of differentiation in human mesenchymal stem cells (hMSCs) has recently come to light. To better understand how cadherin-11 regulates hMSC behavior, we explored its interaction with receptor tyrosine kinases (RTK), an important family of proteins involved in a myriad of cellular functions. In this study, we provide evidence that cadherin-11, a cell adhesion protein expressed in hMSCs, regulates the activity of several RTKs, including PDGFRß and PDGFRα. By knocking down cadherin-11 we found that the changes in the RTK activity caused hyperactivation of the MAPK pathways, which were sustained through the phosphorylation and nuclear translocation of ERK1/2 and subsequently caused a decrease in cell proliferation. Together these results provide compelling evidence for the important role of the interaction of cadherin-11 and RTKs in the behavior of hMSCs.

Extracellular vesicle-cell adhesion molecules in tumours: biofunctions and clinical applications.

Cell adhesion molecule (CAM) is an umbrella term for several families of molecules, including the cadherin family, integrin family, selectin family, immunoglobulin superfamily, and some currently unclassified adhesion molecules. Extracellular vesicles (EVs) are important information mediators in cell-to-cell communication. Recent evidence has confirmed that CAMs transported by EVs interact with recipient cells to influence EV distribution in vivo and regulate multiple cellular processes. This review focuses on the loading of CAMs onto EVs, the roles of CAMs in regulating EV distribution, and the known and possible mechanisms of these actions. Moreover, herein, we summarize the impacts of CAMs transported by EVs to the tumour microenvironment (TME) on the malignant behaviour of tumour cells (proliferation, metastasis, immune escape, and so on). In addition, from the standpoint of clinical applications, the significance and challenges of using of EV-CAMs in the diagnosis and therapy of tumours are discussed. Finally, considering recent advances in the understanding of EV-CAMs, we outline significant challenges in this field that require urgent attention to advance research and promote the clinical applications of EV-CAMs. Video Abstract.

Effects of marine-derived n-3 PUFA supplementation on soluble adhesion molecules: A systematic review and dose-response meta-analysis of randomized controlled trials.

Long-chain n-3 poly unsaturated fatty acids have anti-inflammatory effects but their effects on serum levels of adhesion molecules are inconsistent and contradictory. In this updated systematic review and meta-analysis, marine sources of omega-3 fatty acids were pooled up to determine the effects of omega-3 supplementation on adhesion molecules. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (from inception to April 2023) were searched and all RCTs investigating the effects of marine sources of omega-3, on blood concentrations of adhesion molecules were included and a meta-analysis undertaken. Forty-two RCTs were included involving 3555 participants aged from 18 to 75 years. Meta-analysis of 38 arms from 30 RCTs reporting serum concentrations of vascular cell adhesion molecule-1 (VCAM-1) showed a significant reduction after omega-3 supplementation (WMD: -1.26, 95% CI: -1.88 to -0.64 ng/mL, P < 0.001). Meta-analysis of 40 arms from 30 RCTs reporting serum concentrations of intercellular adhesion molecule-1 (ICAM-1) revealed a reduction following omega-3 supplementation, although it was not significant (WMD: -1.76, 95%CI: -3.68 to 0.16 ng/mL, P = 0.07). Meta-analysis of 27 arms from 21 trials showed no effect on E-selectin (WMD: 0.01, 95%CI: -0.02 to 0.04 ng/mL, P = 0.62). Pooling 15 arms from 11 RCTs showed a marginally significant reducing effect on P-selectin concentrations (WMD: -2.67, 95%CI: -5.53 to 0.19 ng/mL, P = 0.06). A considerable decrease in VCAM concentration was observed after omega-3 supplementation in this meta-analysis with a trend to decreases in both ICAM and P-selectin levels, with effects that may be significant depending on study design, and there was no effect on E-selectin.

Baseline severity and soluble vascular cell adhesion molecule 1 (sVCAM-1) as biomarker predictors of short-term mortality in acute ischemic stroke.

The aim was to investigate the association between plasma levels of cellular adhesion molecules (CAMs) and risk factors, subtypes, severity and short-term mortality of acute ischemic stroke (IS), and to identify a panel of biomarkers to predict short-term mortality after IS. The prospective study evaluated 132 IS patients within 24 h of their hospital admission. The baseline IS severity was assessed using the National Institutes Health Stroke Scale (NIHSS) and categorized as mild (NIHSS < 5), moderate (NIHSS 5-14) and severe (NIHSS ≥ 15). After three-month follow-up, the disability was assessed using the modified Rankin Scale (mRS); moreover, the patients were classified as survivors and non-survivors. Baseline inflammatory and anti-inflammatory cytokines and soluble CAMs were evaluated. Twenty-nine (21.9%) IS patients were non-survivors and showed higher NIHSS and soluble vascular cellular adhesion molecule 1 (sVCAM-1) than the survivors. The sVCAM-1 levels positively correlated with age, homocysteine, severity, and disability. The model #3 combining sVCAM-1 and NIHSS showed better results to predict short-term mortality with an area under the curve receiving operating characteristics (AUC/ROC) of 0.8841 [95% confidence interval (CI): 0.795-0.941] than the models with sVCAM-1 and NIHSS alone, with positive predictive value of 68.0%, negative predictive value of 91.3%, and accuracy of 86.5%. In conclusion, the combined model with baseline severity of IS and sVCAM-1 levels can early predict the prognosis of IS patients who may benefit with therapeutic measures of personalized therapy that taken into account these biomarkers. Moreover, this result suggests that VCAM-1 might be a potential target for the therapeutic strategies in IS.