Fan L.,Shanghai University |
Zong M.,Shanghai University |
Gong R.,Shanghai University |
He D.,Guanghua Integrative Medicine Hospital |
And 4 more authors.
International Journal of Biological Sciences | Year: 2017
Rheumatoid arthritis (RA) is characterized by synovial lining hyperplasia, which involves abnormal growth of fibroblast-like synoviocytes (FLSs). This study aimed to investigate the function and molecular mechanism of peptidylarginine deiminase type 4 (PADI4) in FLSs isolated from RA patients (RA-FLSs). FLSs were isolated from RA patients and transfected with small interfering RNAs (siRNAs) or PADI4 overexpression plasmid. FLSs were treated by Adriamycin (ADR) to induce apoptosis, and apoptotic cells were detected by flow cytometry. The expression of PADI4, p53 and p21 was detected by qRT-PCR and Western blot analysis. The recruitment of PADI4 and histone H3 arginine modifications to p21 promoter was measured by chromatin immunoprecipitation. The results showed that knockdown of PADI4 promoted the apoptosis of RA-FLSs and the expression of p53 and p21. Ectopic expression of PADI4 inhibited ADR-induced apoptosis of RA-FLSs, and down-regulated the expression of p53 and p21. In RA-FLSs, global H3 citrullination (CitH3) and H3 arginine 17 methylation levels were dynamically changed by PADI4 and ADR treatment. PADI4 and H3 could bind p21 promoter region to regulate p21 expression. In conclusion, PADI4 contributes to the pathogenesis of RA by protecting FLSs from apoptosis. PADI4 suppresses p21 transcription through altering histone H3 arginine modifications on p21 promoter region. Our study provides new insight into the anti-apoptotic role of PADI4 in RA development. © Ivyspring International Publisher.
PubMed | Fudan University, Guanghua Integrative Medicine Hospital and Shanghai University
Type: | Journal: Scientific reports | Year: 2016
While previous studies have researched in association analyses between TNF promoter polymorphisms and responses to TNF blockers in spondyloarthritis patients, their results were conflicting. Therefore, we aimed to determine whether TNF promoter polymorphisms could predict response to TNF blockers and find the source of heterogeneity. Data were extracted and analyzed from published articles and combined with our unpublished data. We found that the greatest potential sources of heterogeneity in the results were gender ratio, disease type, continents, and TNF blockers. Then Stratification analysis showed that the TNF -308 G allele and the -238 G allele predicted a good response to TNF blockers (OR=2.64 [1.48-4.73]; 2.52 [1.46-4.37]). However, G alleles of TNF -308 and -238 could predict the response to etanercept (OR=4.02 [2.24-7.23]; 5.17 [2.29-11.67]) much more powerfully than the response to infiliximab/adalimumab (OR=1.68 [1.02-2.78]; 1.28 [0.57-2.86]). TNF -857 could not predict the response in either subgroup. Cumulative meta-analysis performed in ankylosing spondylitis patients presented the odds ratio decreased with stricter response criteria. In conclusion, TNF -308 A/G and -238 A/G are more powerful to predict the response to Etanercept and it is dependent on the criteria of response.
PubMed | Guanghua Integrative Medicine Hospital, Beijing View Solid Biotechnology, Peking Union Medical College, BGI Shenzhen and 8 more.
Type: | Journal: Nature communications | Year: 2015
Age-related macular degeneration (AMD) is a leading cause of irreversible central blindness among the elderly worldwide. We use exome sequencing to analyse nonsynonymous single-nucleotide variants (SNVs) across the whole genome of 216 neovascular AMD cases and 1,553 controls. As a follow-up validation, we evaluate 3,772 neovascular AMD cases and 6,942 controls from five independent cohorts in the East Asian population. Here we show strong evidence of an association at a novel, missense SNV, rs7739323, which is located in the ubiquitin protein ligase E3D (UBE3D) gene (Pmeta=1.46 10(-9), odds ratio (OR)=0.74, 95% confidence interval (CI): 0.63-0.88). Furthermore, ablation of the UBE3D protein lead to an abnormal amount of pigment granules deposited in retinal pigment epithelium microvilli area and an abnormal response on electroretinography (ERG) in UBE3D(+/-) heterozygous mice. Our findings indicate that the ubiquitin-proteasome system may play a role in the pathogenesis of neovascular AMD.
Ma X.,Guanghua Integrative Medicine Hospital |
Zou J.,Shanghai JiaoTong University |
He L.,Guanghua Integrative Medicine Hospital |
Zhang Y.,Chinese Academy of Sciences
Diagnostic Pathology | Year: 2014
Background: To investigate the therapeutic effect of p38-MAPK inhibitor, SB203580, on dry eye in a mouse model of Sjögren's syndrome (MRL/lpr mice).Methods: 18 female BALB/c mice and 44 female MRL/lpr mice were included. Mice were randomly assigned to the control or treatment group. The expression of phospho-p38 MAPK in lacrimal glands of BALB/c mice was determined by Western blot analysis following IL-1β treatment at various time points. Different doses of SB203580 were injected into lacrimal glands of MRL/lpr mice and phenol red thread test was performed seven days post-injection. Moreover, the levels of acetylcholine and norepinephrine expression in lacrimal glands of MRL/lpr mice were measured using spectrofluoremetric assay and the histopathology of lacrimal glands was also evaluated.Results: The expression of p-p38 MAPK in lacrimal glands of BALB/c mice gradually increased following incubation with IL-1β ex vivo. Injection of SB203580 into lacrimal glands significantly improved the results of phenol red thread test in MRL/lpr mice. In addition, the secretions of acetylcholine and norepinephrine increased significantly compared to the control group. Less lymphocytes infiltration was observed in pathological section of lacrimal glands following SB203580 injection.Conclusions: Our results indicate that the activation of p38-MAPK pathway plays an important role in dry eye of a Sjögren's syndrome mouse model. Inhibition of p38-MAPK pathway by SB203580 might have potential therapeutic effect on Sjögren's syndrome associated dry eye. © 2014 Ma et al.; licensee BioMed Central Ltd.
Ma X.-Y.,Guanghua Integrative Medicine Hospital |
Bao H.-J.,Shanghai JiaoTong University |
Cui L.,Henan University |
Zou J.,Shanghai JiaoTong University
PLoS ONE | Year: 2013
This study was designed to explore the feasibility of using autologous rabbit adipose derived stem cells (rASCs) as seed cells and polylactic-co-glycolic acid (PLGA) as a scaffold for repairing corneal stromal defects. rASCs isolated from rabbit nape adipose tissue were expanded and seeded on a PLGA scaffold to fabricate cell-scaffold constructs. After 1 week of cultivation in vitro, the cell-scaffold complexes were transplanted into corneal stromal defects in rabbits. In vivo, the autologous rASCs-PLGA constructed corneal stroma gradually became transparent without corneal neovascularization after 12 weeks. Hematoxylin and eosin staining and transmission electron microscopy examination revealed that their histological structure and collagen fibril distribution at 24 weeks after implantation were similar to native counterparts. As to the defect treated with PLGA alone, the stromal defects remained. And scar tissue was observed in the untreated-group. The implanted autologous ASCs survived up to 24 weeks post-transplantation and differentiated into functional keratocytes, as assessed by the expression of aldehyde-3-dehydrogenase1A1 (ALDH1A1) and cornea-specific proteoglycan keratocan. Our results revealed that autologous rASCs could be one of the cell sources for corneal stromal restoration in diseased corneas or for tissue engineering of a corneal equivalent. © 2013 Ma et al.
Zheng Y.,Shanghai JiaoTong University |
Sun L.,Shanghai JiaoTong University |
Jiang T.,Guanghua Integrative Medicine Hospital |
Zhang D.,Shanghai JiaoTong University |
And 3 more authors.
Journal of Immunology Research | Year: 2014
TNFα plays an important role in autoimmune pathogenesis and is the main therapeutic target of rheumatoid arthritis. However, its underlying mechanism is not completely understood. In this study, we described that Th17 cells were accumulated in synovial fluid, which was attributable to TNFα aberrantly produced in rheumatoid synovium. Interestingly, TNFα cannot induce IL-17 production of CD4+ T cells directly, but through the monocytes high levels of IL-1β and IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFα was shown to enhance the phosphorylation level of STAT3 and the expression level of transcription factor RORC of CD4+ T cells when cultured with CD14+ monocytes. Treatment with an approved TNFα blocking antibody showed marked reduction in the levels of IL-6, IL-1β, and IL-17 and the expression level of STAT3 phosphorylation in relation to Th17 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNFα in the pathogenic Th17 cell differentiation in rheumatoid arthritis. © 2014 Yingxia Zheng et al.
PubMed | Guanghua Integrative Medicine Hospital, Tongji University and Shanghai JiaoTong University
Type: | Journal: Oncotarget | Year: 2017
Corneal neovascularization may result in loss of corneal transparency and blindness. However, developing successful and inexpensive medical treatments for corneal neovascularization remains an unresolved issue. Recently, several studies have implicated miRNA functions in the regulation of cornea homeostasis. This study aimed to identify the miRNA expression profile in the neovascularized cornea after an alkali burn and to investigate the related underlying mechanisms. Here, alkali-burned corneas and matched normal tissues were pooled to perform miRNA sequencing. MiR-21 in alkali-burned cornea showed the greatest increment of abundance at 4 and 7 d after injury compared to the healthy cornea. The miR-21 expression was positively correlated with both the mRNA and protein level of key angiogenic factors including vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1 (HIF-1). At 2 and 8 d after alkali burn, the mice received subconjunctival injections of antagomir-21 (1 or 5 nmol per injection). The injection of antagomir-21 (5 nmol) inactivated miR-21 and attenuated neovascularization progression by inhibiting the expression of VEGF-A and HIF-1. Western blot analysis of the corneas demonstrated that antagomir-21 restored Sprouty 2/4 expression and silenced p-ERK activation. Therefore, these data reveal that antagomir-21 ameliorates the progression of corneal neovascularization likely via Sprouty 2/4-mediated inactivation of p-ERK. Delivery of antagomir-21 might be a potential therapeutic approach to prevent or treat visual loss caused by corneal neovascularization.
PubMed | Guanghua Integrative Medicine Hospital and Shanghai JiaoTong University
Type: | Journal: Mediators of inflammation | Year: 2015
To expand upon the role of iguratimod (T-614) in the treatment of rheumatoid arthritis (RA), we investigated whether the Th1, Th17, follicular helper T cells (Tfh), and regulatory T cells (Treg) imbalance could be reversed by iguratimod and the clinical implications of this reversal.In this trial, 74 patients were randomized into iguratimod-treated (group A) and control (broup B) group for a 24-week treatment period. In the subsequent 28 weeks, both groups were given iguratimod. Frequencies of Th1, Th17, Tfh, and Treg were quantified using flow cytometry, and serum cytokines were detected by enzyme-linked immunosorbent assay. mRNA expression of cytokines and transcriptional factor were quantified by RT-PCR. The composite Disease Activity Score, erythrocyte sedimentation rate, and C-reactive protein were assessed at each visit.The clinical scores demonstrated effective suppression of disease after treatment with iguratimod. In addition, iguratimod downregulated Th1, Th17-type response and upregulated Treg. Furthermore, the levels of Th1, Th17, and Tfh associated inflammatory cytokines and transcription factors were reduced after treatment with iguratimod, while the levels of Treg associated cytokines and transcription factors were increased.
Zhao H.,Guanghua Integrative Medicine Hospital |
Zhao H.,Chinese Academy of Sciences |
Wang D.,Shanghai University of Traditional Chinese Medicine |
Fu D.,Shanghai University of Traditional Chinese Medicine |
Xue L.,Shanghai University of Traditional Chinese Medicine
Rheumatology International | Year: 2015
Given that ankylosing spondylitis (AS) occurs in approximately 5 out of 1,000 adults of European descent and the unclear pathogenesis, the aim of the research was to further predict the molecular mechanism of this disease. The Affymetrix chip data GSE25101 were available from Gene Expression Omnibus database. First of all, differentially expressed genes (DEGs) were identified by Limma package in R. Moreover, DAVID was used to perform gene set enrichment analysis of DEGs. In addition, miRanda, miRDB, miRWalk, RNA22 and TargetScan were applied to predict microRNA-target associations. Meanwhile, STRING 9.0 was utilized to collect protein–protein interactions (PPIs) with confidence score >0.4. Then, the PPI networks for up- and down-regulated genes were constructed, and the clustering analysis was undergone using ClusterONE. Finally, protein-domain enrichment analysis of modules was conducted using DAVID. Total 145 DEGs were identified, including 103 up-regulated and 42 down-regulated genes. These DEGs were significantly enriched in phosphorylation (p = 1.21E−05) and positive regulation of gene expression (p = 1.25E−03). Furthermore, one module was screened out from the up-regulated network, which contained 39 nodes and 205 edges. Moreover, the nodes in the module were significantly enriched in ribosomal protein (RPL17, ribosomal protein L17 and MRPL22, mitochondrial ribosomal protein L22) and proteasome (PSMA6, proteasome subunit, alpha type 6, PSMA4)-related domains. Our findings that might explore the potential pathogenesis of AS and RPL17, MRPL22, PSMA6 and PSMA4 have the potential to be the biomarkers for the disease. © 2014, Springer-Verlag Berlin Heidelberg.
PubMed | Guanghua Integrative Medicine Hospital and Tongji University
Type: Journal Article | Journal: Oncology letters | Year: 2014
Bone metastasis as the first symptom of lung cancer is common, particularly in the axial skeleton. The calcaneus is an unusual site of metastatic involvement. Chronic plantar heel pain (CPHP) is one of the most common complaints of the foot requiring medical treatment. The most typical symptom of CPHP is pain under the medial heel during weight-bearing, and this symptom is therefore generally initially diagnosed as CPHP by clinicians. The current case study reports a female patient never-smoker with non-small cell lung cancer accompanied by calcaneal metastasis presenting as heel pain. The patient was initially diagnosed with CPHP without any imaging examinations. As there was no relief from the heel pain six months later, a foot X-ray was performed, which revealed a lesion of the calcaneus. The analysis of a biopsy obtained from the lesion resulted in a diagnosis of adenocarcinoma. The present case indicates that patients suspected to have CPHP should be conventionally examined with radiography of the foot during the initial diagnosis. Similarly, if a patient with lung cancer has symptoms such as CPHP, distant metastasis should be accounted for; despite their rarity, clinicians should maintain a high level of suspicion, since accurate diagnosis and timely treatment is important in management and outcome.