-
The Journal of Investigative Dermatology Apr 2024During differentiation, keratinocytes acquire a strong, hyper-adhesive state, where desmosomal cadherins interact calcium ion independently. Previous data indicate that...
During differentiation, keratinocytes acquire a strong, hyper-adhesive state, where desmosomal cadherins interact calcium ion independently. Previous data indicate that hyper-adhesion protects keratinocytes from pemphigus vulgaris autoantibody-induced loss of intercellular adhesion, although the underlying mechanism remains to be elucidated. Thus, in this study, we investigated the effect of hyper-adhesion on pemphigus vulgaris autoantibody-induced direct inhibition of desmoglein (DSG) 3 interactions by atomic force microscopy. Hyper-adhesion abolished loss of intercellular adhesion and corresponding morphological changes of all pathogenic antibodies used. Pemphigus autoantibodies putatively targeting several parts of the DSG3 extracellular domain and 2G4, targeting a membrane-proximal domain of DSG3, induced direct inhibition of DSG3 interactions only in non-hyper-adhesive keratinocytes. In contrast, AK23, targeting the N-terminal extracellular domain 1 of DSG3, caused direct inhibition under both adhesive states. However, antibody binding to desmosomal cadherins was not different between the distinct pathogenic antibodies used and was not changed during acquisition of hyper-adhesion. In addition, heterophilic DSC3-DSG3 and DSG2-DSG3 interactions did not cause reduced susceptibility to direct inhibition under hyper-adhesive condition in wild-type keratinocytes. Taken together, the data suggest that hyper-adhesion reduces susceptibility to autoantibody-induced direct inhibition in dependency on autoantibody-targeted extracellular domain but also demonstrate that further mechanisms are required for the protective effect of desmosomal hyper-adhesion in pemphigus vulgaris.
PubMed: 38677661
DOI: 10.1016/j.jid.2024.03.042 -
BMC Cancer Apr 2024Aberrant expressions of desmoglein 2 (Dsg2) and desmocollin 2(Dsc2), the two most widely distributed desmosomal cadherins, have been found to play various roles in...
BACKGROUND
Aberrant expressions of desmoglein 2 (Dsg2) and desmocollin 2(Dsc2), the two most widely distributed desmosomal cadherins, have been found to play various roles in cancer in a context-dependent manner. Their specific roles on breast cancer (BC) and the potential mechanisms remain unclear.
METHODS
The expressions of Dsg2 and Dsc2 in human BC tissues and cell lines were assessed by using bioinformatics analysis, immunohistochemistry and western blotting assays. Wound-healing and Transwell assays were performed to evaluate the cells' migration and invasion abilities. Plate colony-forming and MTT assays were used to examine the cells' capacity of proliferation. Mechanically, Dsg2 and Dsc2 knockdown-induced malignant behaviors were elucidated using western blotting assay as well as three inhibitors including MK2206 for AKT, PD98059 for ERK, and XAV-939 for β-catenin.
RESULTS
We found reduced expressions of Dsg2 and Dsc2 in human BC tissues and cell lines compared to normal counterparts. Furthermore, shRNA-mediated downregulation of Dsg2 and Dsc2 could significantly enhance cell proliferation, migration and invasion in triple-negative MDA-MB-231 and luminal MCF-7 BC cells. Mechanistically, EGFR activity was decreased but downstream AKT and ERK pathways were both activated maybe through other activated protein tyrosine kinases in shDsg2 and shDsc2 MDA-MB-231 cells since protein tyrosine kinases are key drivers of triple-negative BC survival. Additionally, AKT inhibitor treatment displayed much stronger capacity to abolish shDsg2 and shDsc2 induced progression compared to ERK inhibition, which was due to feedback activation of AKT pathway induced by ERK inhibition. In contrast, all of EGFR, AKT and ERK activities were attenuated, whereas β-catenin was accumulated in shDsg2 and shDsc2 MCF-7 cells. These results indicate that EGFR-targeted therapy is not a good choice for BC patients with low Dsg2 or Dsc2 expression. Comparatively, AKT inhibitors may be more helpful to triple-negative BC patients with low Dsg2 or Dsc2 expression, while therapies targeting β-catenin can be considered for luminal BC patients with low Dsg2 or Dsc2 expression.
CONCLUSION
Our finding demonstrate that single knockdown of Dsg2 or Dsc2 could promote proliferation, motility and invasion in triple-negative MDA-MB-231 and luminal MCF-7 cells. Nevertheless, the underlying mechanisms were cellular context-specific and distinct.
Topics: Humans; Desmocollins; Desmoglein 2; Female; Cell Proliferation; Cell Movement; Triple Negative Breast Neoplasms; Cell Line, Tumor; Breast Neoplasms; Neoplasm Invasiveness; Gene Expression Regulation, Neoplastic; beta Catenin; Signal Transduction
PubMed: 38671389
DOI: 10.1186/s12885-024-12229-2 -
Frontiers in Cell and Developmental... 2024
PubMed: 38665429
DOI: 10.3389/fcell.2024.1408075 -
Plastic and Reconstructive Surgery Apr 2024Radiofrequency (RF)-based devices are frequently used in plastic surgeries. In the current literature, no comparative experimental study has demonstrated the...
BACKGROUND
Radiofrequency (RF)-based devices are frequently used in plastic surgeries. In the current literature, no comparative experimental study has demonstrated the histological and immunological effects of these devices that are frequently used in the facial area. In this study, we investigated the histological and immunological effects of Bipolar RF (BodyTite) and Microneedle RF (Morpheus 8) devices in the rat abdominal region.
METHODS
24 rats were used in this study. The rats were divided into four groups: group I: Control. In group II, BodyTite was applied to the abdominal region. Group III: Morpheus 8 was applied to the abdominal region. Group IV: Both Morpheus 8 and BodyTite were applied to the abdominal region. The histological and immunological features of the tissues in the groups were examined using light microscopy, and collagen formation and desmosome structures were examined using light microscopy.
RESULTS
Collagens in Group II were thinner than those in the other groups. In addition, there were fewer vessels in Group III. The collagen scores were as follows: Group II:1.5; Group III:2; and Group IV:3. The VEGF scores were II:2.5, group III:2, and IV:3, respectively. The collagen score in group II and VEGF score in group III were significantly lower than those in the other groups. In addition, the bonds between desmosomes in group III were found to be looser using electron microscopy. Collagen morphology in groups III and IV was found to be similar to that in group I.
CONCLUSIONS
The conclusion of comparison RF-based devices increased tissue regeneration and healing.
CLINICAL RELEVANCE STATEMENT
The use of radiofrequency devices has increased in plastic surgery practice over the past two decades, particularly emerging as a unique alternative for non-surgical candidates. There is a lack of experimental studies concerning these commonly used devices in clinical practice.
PubMed: 38652818
DOI: 10.1097/PRS.0000000000011490 -
The Journal of Investigative Dermatology Apr 2024Pemphigus is a severe blistering disease caused by autoantibodies primarily against the desmosomal cadherins desmoglein (DSG)1 and DSG3 which impair desmosome integrity....
Pemphigus is a severe blistering disease caused by autoantibodies primarily against the desmosomal cadherins desmoglein (DSG)1 and DSG3 which impair desmosome integrity. Especially for the acute phase, additional treatment options allowing to reduce corticosteroids would fulfill an unmet medical need. Here, we provide evidence that epidermal growth factor receptor (EGFR) inhibition by erlotinib ameliorates pemphigus vulgaris immunoglobulin G (PV-IgG) -induced acantholysis in intact human epidermis. PV-IgG caused phosphorylation of EGFR (Y845) and SRC in human epidermis. In line with that, a phosphotyrosine kinome analysis revealed a robust response associated with EGFR and SRC family kinase signaling in response to PV-IgG but not pemphigus foliaceus autoantibodies. Erlotinib inhibited PV-IgG-induced epidermal blistering and EGFR phosphorylation, loss of desmosomes as well as ultrastructural alterations of desmosome size, plaque symmetry, keratin filament insertion and restored the desmosome midline considered as hallmark of mature desmosomes. Erlotinib enhanced both single molecule DSG3 binding frequency and strength and delayed DSG3 fluorescence recovery supporting that EGFR inhibition increases DSG3 availability and cytoskeletal anchorage. Our data indicate that EGFR is a promising target for pemphigus therapy due to its link to several signaling pathways known to be involved in pemphigus pathogenesis.
PubMed: 38642796
DOI: 10.1016/j.jid.2024.03.040 -
Comparative Biochemistry and... Aug 2024The Notch signaling pathway plays a pivotal role in governing cell fate determinations within the gonadal niche. This study provides an extensive elucidation of the male...
The Notch signaling pathway plays a pivotal role in governing cell fate determinations within the gonadal niche. This study provides an extensive elucidation of the male and female gonadal niches within Crassostrea gigas. Examination via transmission electron microscopy revealed the presence of desmosome-like connection not only between germ cells and niche cells but also among adjacent niche cells within the oyster gonad. Transcriptomic analysis identified several putative Notch pathway components, including CgJAG1, CgNOTCH1, CgSuh, and CgHey1. Phylogenetic analysis indicated a close evolutionary relationship between CgJAG1, CgNOTCH1, and CgHey1 and Notch members present in Drosophila. Expression profiling results indicated a notable abundance of CgHey1 in the gonads, while CgJAG1 and CgNOTCH1 displayed distinct expression patterns associated with sexual dimorphism. In situ hybridization findings corroborated the predominant expression of CgJAG1 in male niche cells, while CgNOTCH1 was expressed in both male and female germ cells, as well as female niche cells. These findings demonstrate the important role of the Notch signaling pathway in the gonadal niche of oysters.
Topics: Animals; Crassostrea; Receptors, Notch; Signal Transduction; Male; Female; Gonads; Cell Communication; Phylogeny; Germ Cells
PubMed: 38641164
DOI: 10.1016/j.cbpa.2024.111639 -
Journal of Translational Medicine Apr 2024
Topics: Humans; Desmosomes; Skin; Heart
PubMed: 38627794
DOI: 10.1186/s12967-024-05137-3 -
Phenomics (Cham, Switzerland) Feb 2024This study aimed to determine the prevalence and clinical features of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) caused by pathogenic mutations in the...
UNLABELLED
This study aimed to determine the prevalence and clinical features of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) caused by pathogenic mutations in the () gene. The study included 170 patients who had a confirmed diagnosis of ARVC and underwent genetic screening using next-generation sequencing. The findings of this study provide valuable insights into the association between mutations and ARVC, which can aid in the development of more effective diagnostic and treatment strategies for ARVC patients. Out of the patients evaluated, six had a rare pathogenic mutation in with the same p.R14del variant. Family screening revealed that heterozygous carriers of p.R14del exhibited a definite ARVC phenotype. In clinical studies, individuals with the p.R14del mutation experienced a similar rate of malignant arrhythmia events as those with classic desmosome mutations. After adjusting for covariates, individuals with mutations had a two point one seven times greater likelihood of experiencing transplant-related risks compared to those who did not possess mutations (95% CI 1.08-6.82, = 0.035). The accumulation of left ventricular fat and fibers is a pathological marker for ARVC patients with p.R14del mutations. In a cohort of 170 Chinese ARVC patients, three point five percent of probands had the pathogenic variant (p.R14del) and all were female. Our data shows that -related ARVC patients are at high risk for ventricular arrhythmias and heart failure, which requires clinical differentiation from classic ARVC. Furthermore, carrying the p.R14del mutation can be an independent prognostic risk factor in ARVC patients.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s43657-023-00126-w.
PubMed: 38605909
DOI: 10.1007/s43657-023-00126-w -
Molecular Vision 2024Diabetic macular edema (DME) is a sight-threatening complication of diabetes. Consequently, studying the proteome of DME may provide novel insights into underlying...
PURPOSE
Diabetic macular edema (DME) is a sight-threatening complication of diabetes. Consequently, studying the proteome of DME may provide novel insights into underlying molecular mechanisms.
METHODS
In this study, aqueous humor samples from eyes with treatment-naïve clinically significant DME (n = 13) and age-matched controls (n = 11) were compared with label-free liquid chromatography-tandem mass spectrometry. Additional aqueous humor samples from eyes with treatment-naïve DME (n = 15) and controls (n = 8) were obtained for validation by enzyme-linked immunosorbent assay (ELISA). Best-corrected visual acuity (BCVA) was evaluated, and the severity of DME was measured as central subfield thickness (CST) employing optical coherence tomography. Control samples were obtained before cataract surgery. Significantly changed proteins were identified using a permutation-based calculation, with a false discovery rate of 0.05. A human donor eye with DME and a control eye were used for immunofluorescence.
RESULTS
A total of 101 proteins were differentially expressed in the DME. Regulated proteins were involved in complement activation, glycolysis, extracellular matrix interaction, and cholesterol metabolism. The highest-fold change was observed for the fibrinogen alpha chain (fold change = 17.8). Complement components C2, C5, and C8, fibronectin, and hepatocyte growth factor-like protein were increased in DME and correlated with best-corrected visual acuity (BCVA). Ceruloplasmin and complement component C8 correlated with central subfield thickness (CST). Hemopexin, plasma kallikrein, monocyte differentiation antigen CD14 (CD14), and lipopolysaccharide-binding protein (LBP) were upregulated in the DME. LBP was correlated with vascular endothelial growth factor. The increased level of LBP in DME was confirmed using ELISA. The proteins involved in desmosomal integrity, including desmocollin-1 and desmoglein-1, were downregulated in DME and correlated negatively with CST. Immunofluorescence confirmed the extravasation of fibrinogen at the retinal level in the DME.
CONCLUSION
Elevated levels of pro-inflammatory proteins, including the complement components LBP and CD14, were observed in DME. DME was associated with the loss of basal membrane proteins, compromised desmosomal integrity, and perturbation of glycolysis.
Topics: Humans; Macular Edema; Diabetic Retinopathy; Proteome; Vascular Endothelial Growth Factor A; Aqueous Humor; Tomography, Optical Coherence; Fibrinogen; Intravitreal Injections; Angiogenesis Inhibitors; Diabetes Mellitus
PubMed: 38586604
DOI: No ID Found -
JACC. Heart Failure Jun 2024Acute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Acute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy.
OBJECTIVES
The aim of this study was to investigate the reported prevalence of pathogenic or likely pathogenic (P/LP) variants in cardiomyopathy-associated genes in patients with acute myocarditis.
METHODS
For this systematic review and meta-analysis, the PubMed and Embase databases were searched on March 4, 2023. Observational studies evaluating the prevalence of P/LP variants in cardiomyopathy-associated genes in patients with acute myocarditis were included. Studies were stratified into adult and pediatric age groups and for the following scenarios: 1) complicated myocarditis (ie, presenting with acute heart failure, reduced left ventricular ejection fraction, or life-threatening ventricular arrhythmias); and 2) uncomplicated myocarditis. The study was registered with the International Prospective Register of Systematic Reviews (CRD42023408668) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
RESULTS
Of 732 studies identified, 8 met the inclusion criteria, providing data for 586 patients with acute myocarditis. A total of 89 P/LP variants in cardiomyopathy-associated genes were reported in 85 patients. For uncomplicated myocarditis, the pooled prevalence was 4.2% (95% CI: 1.8%-7.4%; I = 1.4%), whereas for complicated myocarditis, the pooled prevalence was 21.9% (95% CI: 14.3%-30.5%; I = 38.8%) and 44.5% (95% CI: 22.7%-67.4%; I = 52.8%) in adults and children, respectively. P/LP variants in desmosomal genes were predominant in uncomplicated myocarditis (64%), whereas sarcomeric gene variants were more prevalent in complicated myocarditis (58% in adults and 71% in children).
CONCLUSIONS
Genetic variants are present in a large proportion of patients with acute myocarditis. The prevalence of genetic variants and the genes involved vary according to age and clinical presentation.
Topics: Humans; Myocarditis; Acute Disease; Prevalence; Cardiomyopathies
PubMed: 38573261
DOI: 10.1016/j.jchf.2024.02.012