Increased Transendothelial Cells Permeability Induced by Oxidized Lipoprotein(a) Relates to Reactive Oxygen Species Generation and Desmogleins Expression

Objective: This paper aims at measurement enhanced effect of oxidized lipoprotien(a) [ox Lp(a)] on permeability of monolayer endothelial cells and relationship with reactive oxygen species(ROS) generation and desmogleins(DSGs) expression.Methods and Results: Transendothelial permeability was assayed by transwell and reactive oxygen species(ROS) was determined by DCFH-DA staining. RT-PCR was carried out to determine DSGl and DSC2 expression in m RNA, respectively.Transendothelial permeability was enhanced by ox LP(a) dose and time dependently. The most marked effect appeared at a concentration of 100 mg/L, Transendothelial permeability reached the maximum value after 2 h of FITC-dextran addition, and then gradually decreased after 4 h. ox Lp(a) induces the generation of cellular reactive oxygen species(ROS), and this effect could be inhibited by superoxide dismutase(SOD).Incubation of HUVECs with ox Lp(a) resulted in a dose and time-dependent down-regulation of DSGl and DSC2 expression at transcriptional level. Conclusion:Permeability of monolayer endothelial cells was enhanced by ox Lp(a) which is related to up-regulating ROS formation and down-regulating desmogleins expression.

Esophagitis dissecans superficialis and autoimmune bullous dermatoses: A review

Esophagitis dissecans superficialis(EDS)is a rare and severe endoscopic finding characterized by sloughing of large fragments of esophageal mucosal lining.Although EDS has been reported in association with serious illnesses and certain medications,the pathophysiological association of autoimmune bullous dermatoses with EDS has gained remarkable attention.Among these dermatoses,pemphigus vulgaris and pemphigoid frequently present with various types of esophageal involvement including EDS.We review the pathophysiology and clinical features of this involvement with the presentation of our experiences.The importance of endoscopic evaluation of this entity is discussed.

Effects of chimeric molecule of recombinant Dsg3EC_(1-2) with toxin PE40 on T and B lymphocytes in Pemphigus Vulgaris

Objective:To observe the effects of the recombinant chimeric toxin Dsg3EC 1-2PE40 on T and B lymphocytes isolated from Pemphigus Vulgaris (PV) patients to further study its biological therapeutic function for PV. Methods:Recombinant chimeric toxin Dsg3EC 1-2PE40 was first identified, expressed and purified, and then its effects on T and B lymphocytes of PV patients in vitro were detected and quantified by ELISPOT assay and MTT assay.Results:The purity of the expressed protein Dsg3EC 1-2PE40 was up to 80%. In ELISPOT assay, with Dsg3EC 1-2PE40, the overall number of B cells that produce anti-Dsg3 antibodies among PV patients was only about 60% of the comparable number with Dsg3EC 1-2. The proliferation of T cells of PV patients was inhibited markedly by Dsg3EC 1-2PE40. There was significant difference between the different groups with Dsg3EC 1-2PE40 and Dsg3EC 1-2.Conclusion:The recombinant chimeric toxin Dsg3EC 1-2PE40 decrease the number of B cells that produce anti-Dsg3 antibodies in PV patients and can inhibit or kill T cells of PV patients in vitro.

Desmoglein 2(DSG2) Is A Receptor of Human Adenovirus Type 55 Causing Adult Severe Community-Acquired Pneumonia

Human adenovirus type 55(HAdV-B55) is a re-emergent acute respiratory disease pathogen that causes adult communityacquired pneumonia(CAP). Previous studies have shown that the receptor of HAdV-B14, which genome is highly similar with HAdV-B55, is human Desmoglein 2(DSG2). However, whether the receptor of HAdV-B55 is DSG2 is undetermined because there are three amino acid mutations in the fiber gene between HAdV-B14 and HAdV-B55. Here, firstly we found the 3T3 cells, a mouse embryo fibroblast rodent cell line which does not express human DSG2, were able to be infected by HAdV-B55 after transfected with pcDNA3.1-DSG2, while normal 3T3 cells were still unsusceptible to HAdV-B55 infection. Next, A549 cells with h DSG2 knock-down by siRNA were hard to be infected by HAdV-B3/-B14/-B55, while the control siRNA group was still able to be infected by all these types of HAdVs. Finally, immunofluorescence confocal microscopy indicated visually that Cy3-conjugated HAdV-B55 viruses entered A549 cells by binding to DSG2 protein.Therefore, DSG2 is a major receptor of HAdV-B55 causing adult CAP. Our finding is important for better understanding of interactions between adenoviruses and host cells and may shed light on the development of new drugs that can interfere with these processes as well as for the development of potent prophylactic vaccines.

Reactivation of PPARαalleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acidβ-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy(ACM),a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes,accounts for 20%of sudden cardiac death and lacks effective treatment.It is often caused by mutations in desmosome proteins,with Desmoglein-2(DSG2)mutations as a common etiology.However,the mechanism underlying the accumulation of fibrofatty in ACM remains unknown,which impedes the development of curative treatment.Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2(CS-Dsg2^(-/-)).Heart failure and cardiac lipid accumulation were observed in CSDsg2^(-/-)mice.We demonstrated that these phenotypes were caused by decline of fatty acid(FA)β-oxidation resulted from impaired mammalian target of rapamycin(m TOR)signaling.Rapamycin worsened while overexpression of m TOR and 4EBP1 rescued the FAβ-oxidation pathway in CS-Dsg2^(-/-)mice.Reactivation of PPARa by fenofibrate or AAV9-Ppara significantly alleviated the lipid accumulation and restored cardiac function.Our results suggest that impaired m TOR-4EBP1-PPARa-dependent FAβ-oxidation contributes to myocardial lipid accumulation in ACM and PPARa may be a potential target for curative treatment of ACM.

Epidemiology of Pemphigus: A Single Center Experience in Morocco

Objective:Pemphigus is a life threatening autoimmune bullous disease which involves the skin and mucous membranes of the stratified squamous epithelium.The global distribution of Pemphigus varies according to genetic,ethnic,socioeconomic,and cultural backgrounds.The purpose of our study is to evaluate the epidemiological features of pemphigus a single center in Morocco and compare our results with those reported elsewhere.Methods:A retrospective analysis was conducted of 302 pemphigus patients seen between 1990 and 2020 in the Dermatology Department of Ibn Sina Hospital(Rabat,Morocco).We further collected all the Moroccan scientific researches published by now to compare.Results:The average annual incidence was 0.32/100,000 inhabitants.The incidence doubled to 0.72 in 2020.The most common variant was pemphigus vulgaris(125 cases)followed by pemphigus erythematosus(99 cases),pemphigus foliaceous(40 cases),and vegetans(27 cases).The female to male ratio was 0.75,the average age at onset was 53 years old and the mean duration of the disease before diagnosis was 13.36months.Conclusion:This study joins the main characteristics of pemphigus in the Maghreb and around the world(pemphigus vulgaris most frequent subtype).In 2020,an epidemiological peak occurred during the coronavirus disease 2019 pandemic;probably related to stress and delayed time consultation for fear of contracting the severe acute respiratory syndrome coronavirus 2.

Effects of Pemphigus Vulgaris Serum on the Expression of ATP2C1 and PKP3 in HaCaT Cells

Objective:To investigate the effects of serum from patients with pemphigus vulgaris(PV)on the transcription and protein expression level of calcium-transporting ATPase type 2C member 1(ATP2C1)and plakophilin 3(PKP3)in HaCaT cells.Methods:The HaCaT cells were divided into four groups:PV sera group,anti-Dsg3 monoclonal antibody group(AK23,positive control group),normal healthy serum group,and blank cell group.The groups were treated with corresponding different conditions for 24 hours.Quantitative polymerase chain reaction and Western blot were used to detect mRNA and protein levels of ATP2C1 and PKP3.Results:Compared with the blank group,the mRNA level of theATP2C1 and PKP3 genes in PV sera group was significantly increased by 384%and 404%,respectively(bothP<0.001).The treatment of PV sera and anti-Dsg3 antibody increased PKP3 protein expression(P=0.03 andP=0.004)but decreased protein expression of ATP2C1 in HaCaT cells(bothP<0.001).Conclusions:Our study indicates that serum from patients with PV promotes bothATP2C1 andPKP3 transcription in HaCaT cells,implying that the two genes may be involved in the pathological process of PV.

Mutations of Desmoglein‑2 in Sudden Unexplained Death in the Chinese Han Population

Sudden unexplained death(SUD)remains a puzzle in forensic medicine.Desmoglein‑2(DSG2)has been linked to arrhythmogenic right ventricular cardiomyopathy which may cause life‑threatening ventricular arrhythmias and sudden death.Fatal arrhythmias resulting in sudden death also occur in the absence of morphologic cardiac abnormalities at autopsy.We hypothesized that DSG2 mutations may be responsible for certain Chinese SUD cases.We sequenced all 15 exons of DSG2 in DNA extracted from postmortem heart tissues of 25 Chinese patients dying from SUD.The primers were designed using the Primer Express 3.0 software.Direct sequencing for both sense and antisense strands was performed with a BigDye Terminator DNA sequencing kit on a 3130 Xl Genetic Analyzer.Mutation damage prediction was made using Mutation Taster,PolyPhen,and SIFT software.In 2 of 25 cases of Chinese SUD samples,two DSG2 heterozygous mutations(p.P927 L and p.T1070M)were identified,and one is probably damaging.We concluded that DSG2 mutations may be related to the occurrence of part of SUD cases in the Chinese Han population.