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The Chinese Journal of Dental Research Mar 2024To explore potential pathogenic processes and possible treatments using unbiased and reliable bioinformatic tools.
OBJECTIVE
To explore potential pathogenic processes and possible treatments using unbiased and reliable bioinformatic tools.
METHODS
Gene expression profiles of control and hepatocyte growth factor (HGF) samples were downloaded from CNP0000995. Analysis of differentially expressed genes (DEGs) was conducted using R software (version 4.2.1, R Foundation, Vienna, Austria). Functional enrichment analyses were performed using the Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) databases, then the proteinprotein interaction (PPI) network was constructed to screen the top 10 hub genes. Finally, five genes related to cell junctions were selected to build gene-miRNA interactions and predict small-molecule drugs.
RESULTS
A total of 342 downregulated genes and 188 upregulated genes were detected. Candidate pathways include the extracellular matrix (ECM) receptor interaction pathway, the TGF-β signalling pathway and the cell adhesion molecule (CAM) pathway, which were discovered through KEGG and GSEA enrichment studies. GO analyses revealed that these DEGs were significantly enriched in cell adhesion, the adherens junction and focal adhesion. Five hub genes (CDH1, SNAP25, RAC2, APOE and ITGB4) associated with cell adhesion were identified through PPI analysis. Finally, the gene-miRNA regulatory network identified three target miRNAs: hsa-miR-7110-5p, hsa-miR-149-3p and hsa-miR-1207-5p. Based on the gene expression profile, the small-molecule drugs zebularine, ecuronium and prostratin were selected for their demonstrated binding activity when docked with the mentioned molecules.
CONCLUSION
This study offered some novel insights into molecular pathways and identified five hub genes associated with cell adhesion. Based on these hub genes, three potential therapeutic miRNAs and small-molecule drugs were predicted, which are expected to provide guidance for the treatment of patients with HGF.
Topics: Humans; Fibromatosis, Gingival; MicroRNAs; Cell Adhesion; Focal Adhesions
PubMed: 38546525
DOI: 10.3290/j.cjdr.b5128671 -
Cells Mar 2024From the moment a cell is on the path to malignant transformation, its interaction with other cells from the microenvironment becomes altered. The flow of molecular... (Review)
Review
From the moment a cell is on the path to malignant transformation, its interaction with other cells from the microenvironment becomes altered. The flow of molecular information is at the heart of the cellular and systemic fate in tumors, and various processes participate in conveying key molecular information from or to certain cancer cells. For instance, the loss of tight junction molecules is part of the signal sent to cancer cells so that they are no longer bound to the primary tumors and are thus free to travel and metastasize. Upon the targeting of a single cell by a therapeutic drug, gap junctions are able to communicate death information to by-standing cells. The discovery of the importance of novel modes of cell-cell communication such as different types of extracellular vesicles or tunneling nanotubes is changing the way scientists look at these processes. However, are they all actively involved in different contexts at the same time or are they recruited to fulfill specific tasks? What does the multiplicity of modes mean for the overall progression of the disease? Here, we extend an open invitation to think about the overall significance of these questions, rather than engage in an elusive attempt at a systematic repertory of the mechanisms at play.
Topics: Humans; Cell Communication; Neoplasms; Extracellular Vesicles; Gap Junctions; Tumor Microenvironment
PubMed: 38534339
DOI: 10.3390/cells13060495 -
Journal of the American Society of... Jun 2024Loss of Rab35 leads to nonobstructive hydronephrosis because of loss of ureter epithelium. Rab35 regulates kidney and ureter epithelial cell adhesion and polarity. Rab35...
KEY POINTS
Loss of Rab35 leads to nonobstructive hydronephrosis because of loss of ureter epithelium. Rab35 regulates kidney and ureter epithelial cell adhesion and polarity. Rab35 is required for embryonic development.
BACKGROUND
Rab35 is a member of a GTPase family of endocytic trafficking proteins. Studies in cell lines have indicated that Rab35 participates in cell adhesion, polarity, cytokinesis, and primary cilia length and composition. In addition, sea urchin Rab35 regulates actin organization and is required for gastrulation. In mice, loss of Rab35 in the central nervous system disrupts hippocampal development and neuronal organization. Outside of the central nervous system, the functions of mammalian Rab35 are unknown.
METHODS
We generated and analyzed the consequences of both congenital and conditional null mutations in mice. Using a LacZ reporter allele, we assessed expression during development and postnatally. We assessed Rab35 loss in the kidney and ureter using histology, immunofluorescence microscopy, and western blotting.
RESULTS
Congenital loss of function caused embryonic lethality: homozygous mutants arrested at E7.5 with cardiac edema. Conditional loss of Rab35, either during gestation or postnatally, caused hydronephrosis. The kidney and ureter phenotype were associated with disrupted actin cytoskeletal architecture, altered Arf6 epithelial polarity, reduced adherens junctions, loss of tight junction formation, defects in epithelial growth factor receptor expression and localization, disrupted cell differentiation, and shortened primary cilia.
CONCLUSIONS
Rab35 may be essential for mammalian development and the maintenance of kidney and ureter architecture. Loss of Rab35 leads to nonobstructive hydronephrosis, making the mutant mouse a novel mammalian model to study mechanisms underlying this disease.
Topics: Animals; Homeostasis; Ureter; Mice; Kidney; Epithelial Cells; rab GTP-Binding Proteins; Embryonic Development; Intercellular Junctions
PubMed: 38530365
DOI: 10.1681/ASN.0000000000000335 -
Scientific Reports Mar 2024The destruction of the microvascular structure and function can seriously affect the survival and prognosis of patients with acute myocardial infarction (AMI)....
The destruction of the microvascular structure and function can seriously affect the survival and prognosis of patients with acute myocardial infarction (AMI). Nuciferine has a potentially beneficial effect in the treatment of cardiovascular disease, albeit its role in microvascular structure and function during AMI remains unclear. This study aimed to investigate the protective effect and the related mechanisms of nuciferine in microvascular injury during AMI. Cardiac functions and pathological examination were conducted in vivo to investigate the effect of nuciferine on AMI. The effect of nuciferine on permeability and adherens junctions in endothelial cells was evaluated in vitro, and the phosphorylation level of the PI3K/AKT pathway (in the presence or absence of PI3K inhibitors) was also analyzed. In vivo results indicated that nuciferine inhibited ischemia-induced cardiomyocyte damage and vascular leakage and improved cardiac function. In addition, the in vitro results revealed that nuciferine could effectively inhibit oxygen-glucose deprivation (OGD) stimulated breakdown of the structure and function of human coronary microvascular endothelial cells (HCMECs). Moreover, nuciferine could significantly increase the phosphorylation level of the PI3K/AKT pathway. Finally, the inhibitor wortmannin could reverse the protective effect of nuciferine on HCMECs. Nuciferine inhibited AMI-induced microvascular injury by regulating the PI3K/AKT pathway and protecting the endothelial barrier function in mice.
Topics: Animals; Humans; Mice; Apoptosis; Aporphines; Endothelial Cells; Myocardial Infarction; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 38528077
DOI: 10.1038/s41598-024-57595-w -
MicroPublication Biology 2024Basement membranes are sheet-like extracellular matrices containing Collagen IV, and they are conserved across the animal kingdom. Basement membranes usually line the...
Basement membranes are sheet-like extracellular matrices containing Collagen IV, and they are conserved across the animal kingdom. Basement membranes usually line the basal surfaces of epithelia, where they contribute to structure, maintenance, and signaling. Although adult epithelia contact basement membranes, in early embryos the epithelia contact basement membranes only after basement membranes are assembled in embryogenesis. In , the pupal notum epithelium is a useful model for live imaging epithelial cell behaviors, yet it is unclear when the basement membrane assembles in the pupa, as pupae are undergoing metamorphosis, similar to embryogenesis. To characterize the basement membrane in the pupal notum, we used spinning disk fluorescent microscopy to visualize Collagen IV subunit Vkg-GFP and adherens junction protein p120ctnRFP. Bright punctae of Vkg-GFP were observed in the X-Y plane, possibly representing Vkg-containing cells. We found that a thin continuous Vkg-containing basement membrane was evident at 14 h APF, which became more enriched with Vkg-GFP over the next 6 h, indicating the basement membrane is still assembling during that time. Live imaging of the pupal notum during this time could provide insight into formation, assembly, and repair of the basement membranes.
PubMed: 38525127
DOI: 10.17912/micropub.biology.001105 -
Heliyon Mar 2024The inhalation of zinc chloride (ZnCl) smoke is one of common resources of lung injury, potentially resulting in severe pulmonary complications and even mortality. The...
The inhalation of zinc chloride (ZnCl) smoke is one of common resources of lung injury, potentially resulting in severe pulmonary complications and even mortality. The influence of ZnCl smoke on lysine succinylation (Ksucc) in the lungs remains uncertain. In this study, we used a ZnCl smoke inhalation mouse model to perform global proteomic and lysine succinylome analyses. A total of 6781 Ksucc sites were identified in the lungs, with injured lungs demonstrating a reduction to approximately 2000 Ksucc sites, and 91 proteins exhibiting at least five differences in the number of Ksucc sites. Quantitative analysis revealed variations in expression of 384 proteins and 749 Ksucc sites. The analysis of protein-protein interactions was conducted for proteins displaying differential expression and differentially expressed lysine succinylation. Notably, proteins with altered Ksucc exhibited increased connectivity compared with that in differentially expressed proteins. Beyond metabolic pathways, these highly connected proteins were also involved in lung injury-associated pathological reactions, including processes such as focal adhesion, adherens junction, and complement and coagulation cascades. Collectively, our findings contribute to the understanding of the molecular mechanisms underlaying ZnCl smoke-induced lung injury with a specific emphasis on lysine succinylation. These findings could pave the way for targeted interventions and therapeutic strategies to mitigate severe pulmonary complications and mortality associated with such injuries in humans.
PubMed: 38524532
DOI: 10.1016/j.heliyon.2024.e27450 -
Microvascular Research Jul 2024Dysfunctional pericytes and disruption of adherens or tight junctions are related to many microvascular diseases, including diabetic retinopathy. In this context,... (Comparative Study)
Comparative Study
Dysfunctional pericytes and disruption of adherens or tight junctions are related to many microvascular diseases, including diabetic retinopathy. In this context, visualizing retinal vascular architecture becomes essential for understanding retinal vascular disease pathophysiology. Although flat mounts provide a demonstration of the retinal blood vasculature, they often lack a clear view of microaneurysms and capillary architecture. Trypsin and elastase digestion are the two techniques for isolating retinal vasculatures in rats, mice, and other animal models. Our observations in the present study reveal that trypsin digestion impacts the association between pericytes and endothelial cells. In contrast, elastase digestion effectively preserves these features in the blood vessels. Furthermore, trypsin digestion disrupts endothelial adherens and tight junctions that elastase digestion does not. Therefore, elastase digestion emerges as a superior technique for isolating retinal vessels, which can be utilized to collect reliable and consistent data to comprehend the pathophysiology of disorders involving microvascular structures.
Topics: Animals; Pancreatic Elastase; Trypsin; Retinal Vessels; Mice, Inbred C57BL; Pericytes; Endothelial Cells; Tight Junctions; Mice; Male
PubMed: 38521153
DOI: 10.1016/j.mvr.2024.104682 -
SAGE Open Medicine 2024Renal cell carcinoma is the most common form of kidney cancer which is a global threat to human health, needing to explore effective therapeutic targets and treatment...
BACKGROUND
Renal cell carcinoma is the most common form of kidney cancer which is a global threat to human health, needing to explore effective therapeutic targets and treatment methods. Aurora kinase B acts as an important carcinogenic role in various kinds of tumors, while its mechanism in renal cell carcinoma is indistinct. Herein we explore the underlying mechanism of Aurora kinase B in renal cell carcinoma.
METHODS AND RESULTS
Label-free quantitative proteomics analysis was employed to analyze the differentially expressed proteins in 786-O cells which were treated with si-Aurora kinase B or si-ctrl. In the current study, 169 differentially expressed proteins were identified. The top 10 upregulated proteins were MX2, IFI44L, ISG20, DDX58, F3, IFI44, ECE1, PRIC285, NIT1, and IFIT2. The top 10 downregulated proteins were FKBP9, FSTL1, DDAH1, TGFB2, HMGN3, COIL, FAM65A, PTPN14, ARFGAP2, and EIF2C2. GO enrichment analysis showed that these differentially expressed proteins participated in biological processes, including defense response to virus, response to virus, and type I interferon signaling pathway. These differentially expressed proteins participated in cellular components, including focal adhesion, cell-substrate adherens junction, cell-substrate junction, and endoplasmic reticulum lumen. These differentially expressed proteins participated in molecule functions, including guanyl nucleotide binding, nucleotidase activity, double-stranded RNA binding, 2'-5'-oligoadenylate synthetase activity, and virus receptor activity. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the significantly changed proteins including OAS3, OAS2, JAK1, TAP1, and RAC1 were involved in Epstein-Barr virus infection.
CONCLUSIONS
Taken together, our results demonstrate the possible mechanisms that Aurora kinase B may participate in renal cell carcinoma. These findings may provide insights into tumorigenesis and a theoretical basis for developing potential therapies of renal cell carcinoma.
PubMed: 38516642
DOI: 10.1177/20503121241228474 -
Molecular Biology of the Cell May 2024α-catenin (α-cat) displays force-dependent unfolding and binding to actin filaments through direct and indirect means, but features of adherens junction structure and...
α-catenin (α-cat) displays force-dependent unfolding and binding to actin filaments through direct and indirect means, but features of adherens junction structure and function most vulnerable to loss of these allosteric mechanisms have not been directly compared. By reconstituting an α-cat F-actin-binding domain unfolding mutant known to exhibit enhanced binding to actin (α-cat-H0-FABD) into α-cat knockout Madin Darby Canine Kidney (MDCK) cells, we show that partial loss of the α-cat catch bond mechanism (via an altered H0 α-helix) leads to stronger epithelial sheet integrity with greater colocalization between the α-cat-H0-FABD mutant and actin. α-cat-H0-FABD -expressing cells are less efficient at closing scratch-wounds, suggesting reduced capacity for more dynamic cell-cell coordination. Evidence that α-cat-H0-FABD is equally accessible to the conformationally sensitive α18 antibody epitope as WT α-cat and shows similar vinculin recruitment suggests this mutant engages lower tension cortical actin networks, as its M-domain is not persistently open. Conversely, α-cat-M-domain salt-bridge mutants with persistent recruitment of vinculin and phosphorylated myosin light chain show only intermediate monolayer adhesive strengths, but display less directionally coordinated and thereby slower migration speeds during wound-repair. These data show α-cat M- and FABD-unfolding mutants differentially impact cell-cell cohesion and migration properties, and suggest signals favoring α-cat-cortical actin interaction without persistent M-domain opening may improve epithelial monolayer strength through enhanced coupling to lower tension actin networks.
Topics: Dogs; Animals; alpha Catenin; Madin Darby Canine Kidney Cells; Actins; Cell Movement; Epithelial Cells; Actin Cytoskeleton; Protein Binding; Protein Domains; Mutation; Adherens Junctions; Protein Unfolding; Cell Adhesion; Vinculin
PubMed: 38507238
DOI: 10.1091/mbc.E23-01-0036 -
Food & Function Apr 2024The Mediterranean diet (MD), characterized by olive oil, olives, fruits, vegetables, and wine intake, is associated with a reduced risk of dementia. These foods are rich...
The Mediterranean diet (MD), characterized by olive oil, olives, fruits, vegetables, and wine intake, is associated with a reduced risk of dementia. These foods are rich in bioactives with neuroprotective and antioxidant properties, including hydroxytyrosol (HT), tyrosol (TYRS), serotonin (SER) and protocatechuic acid (PCA), a phenolic acid metabolite of anthocyanins. It remains to be established if these molecules cross the blood-brain barrier (BBB), a complex interface that strictly controls the entrance of molecules into the brain. We aimed to assess the ability of tyrosine (TYR), HT, TYRS, PCA and SER to pass through the BBB without disrupting its properties. Using Human Brain Microvascular Endothelial Cells as an model of the BBB, we assessed its integrity by transendothelial electrical resistance, paracellular permeability and immunocytochemical assays of the adherens junction protein β-catenin. The transport across the BBB was evaluated by ultra-high-performance liquid chromatography high resolution mass spectrometry. Results show that tested bioactives did not impair BBB integrity regardless of the concentration evaluated. Additionally, all of them cross the BBB, with the following percentages: HT (∼70%), TYR (∼50%), TYRS (∼30%), SER (∼30%) and PCA (∼9%). These results provide a basis for the MD neuroprotective role.
Topics: Humans; Blood-Brain Barrier; Endothelial Cells; Anthocyanins; Brain; Biological Transport
PubMed: 38497922
DOI: 10.1039/d3fo04760a