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Mitra D.,University of Colorado at Denver | Fernandez P.,University of Colorado at Denver | Bian L.,Kunming Medical University | Song N.,Shanghai Skin Diseases Hospital | And 4 more authors.
Journal of Investigative Dermatology | Year: 2013

Smad4 loss occurs frequently in human skin squamous cell carcinoma (SCC), but it is unknown whether this loss increases UV-induced carcinogenesis, a major etiological factor in skin cancer. In the present study, mice with keratinocyte-specific Smad4 deletion (K14.Smad4-/-) and wild-type (WT) littermates were chronically UV-irradiated. Compared with WT, K14.Smad4-/-mice exhibited increased DNA damage and increased susceptibility to UV-induced skin cancer. Among genes involved in repairing UV-induced DNA damage, Excision repair cross-complementation group 1 (Ercc1) messenger RNA was significantly reduced in UV-treated K14.Smad4-/-skin compared with WT skin. Further analysis revealed that Smad4 loss confers reduced Snail binding to the Ercc1 regulatory elements, resulting in reduced Ercc1 transcription. Consistently, transient transfection of Snai1 into Smad4-/-keratinocytes led to increased repair of UV-induced DNA lesions. Transfection of Ercc1 into Smad4-/-keratinocytes restored repair of UV-induced DNA damage. Further, immunostaining revealed that the presence of Smad4 protein is associated with the presence of Snail and Ercc1 proteins in human skin SCC and precancerous actinic keratoses. Collectively, Smad4 loss-associated Snail reduction compromises Ercc1-mediated DNA repair, contributing to increased UV-induced skin carcinogenesis. Thus, we identified a role for Snail in UV-induced DNA repair. © 2013 The Society for Investigative Dermatology.

Yang X.,Fudan University | Yang J.,Fudan University | Xing X.,Fudan University | Wan L.,Shanghai Skin Diseases Hospital | Li M.,Fudan University
Arthritis Research and Therapy | Year: 2014

Introduction: Although immune dysfunction plays a role in the pathogenesis of systemic sclerosis (SSc), involvement of T helper 17 (Th17) and T regulatory (Treg) cells remains unclear. We aimed to investigate the presence of Th17 and Treg cells in SSc patients and the role of Th17 cells in collagen production in SSc fibroblasts.Methods: We analyzed inflammatory cell profiles in the skin of 13 SSc patients by immunohistochemistry, the percentage of Th17 and Treg cells in peripheral blood mononuclear cells (PBMCs) of 45 SSc patients and 24 healthy controls by flow cytometry, gene expression in PBMCs by real-time reverse transcription-polymerase chain reaction and interleukin-17 (IL-17) in sera and culture supernatants by enzyme-linked immunosorbent assay. We also investigated the effect of Th17 cell-derived IL-17 on fibroblast growth and collagen production.Results: Infiltration of inflammatory cells including IL-17+ and Foxp3+ lymphocytes was detected in the skin of patients with early SSc. The percentages of circulating Th17 cells and IL-17 production were elevated in samples from patients with active SSc, whereas the percentage of circulating Treg cells was not affected. The number of Th17 cells was closely related to disease activity. IL-17 from SSc patients promoted fibroblast growth and collagen production, whereas IL-17 neutralizing antibody effectively blocked collagen production.Conclusion: SSc progression might be linked to expansion of circulating Th17 cells and increased infiltration of IL-17+ cells in skin. Th17-derived IL-17 is involved in fibroblast growth and collagen production. IL-17 blocking antibody may be a useful tool for intervention in the fibrotic course of SSc. © 2014 Yang et al.; licensee BioMed Central Ltd.

Sun H.,Central Laboratory | Yu T.,Jining Medical University | Li J.,Shanghai Skin Diseases Hospital
Cancer Letters | Year: 2011

Here we report an oral alkylphospholipid perifosine dramatically sensitizes chemo-resistant ovarian cancer cells to paclitaxel induced cell death and apoptosis in vitro. We found that co-administration perifosine with paclitaxel in human ovarian cancer cells led to the inhibition of AKT/mTOR complex 1 (mTORC1), a marked increase in ceramide and reactive oxygen species (ROS) production, and a striking increase in the activation of pro-apoptosis pathways, including caspase 3, c-Jun N-terminal kinases (JNK) and AMP-activated protein kinase (AMPK). These signaling events together caused a marked increase of cancer cell apoptosis. Combining paclitaxel with perifosine may represent a novel anti-ovarian cancer strategy. © 2011 Elsevier Ireland Ltd.

Wang X.,Shanghai Skin Diseases Hospital
Photonics and Lasers in Medicine | Year: 2015

Our research group started to utilize 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (ALA-PDT) as a possible treatment of skin cancers in 1995. Nowadays, ALA-PDT has become one of the most popular modalities in dermatology and venereology in China. In particular, the pioneering work done by our group in ALA-PDT of urethral condylomata acminata helped Shanghai Fudan Zhangjiang Bio-Pharmaceutical Co., Ltd.To obtain the regulatory approval from the China Food and Drug Administration (CFDA) for ALA to be used in the topical PDT of Condyloma acuminatum in 2007. Since then, ALA and dermatological PDT have been rapidly developed in China. To date, ALA-PDT has been carried out routinely in over 600 clinics across China. Approved and off-label indications include condylomata acminata, acne, flat warts, photoaging, actinic kerotosis, folliculitis, extramammary Paget's disease, lichen sclerosus, and superficial skin cancers. Meanwhile, numerous research teams have been actively engaged in basic researches of ALA-PDT. This presentation will provide an overview on clinical and basic researches carried out by our group and other groups in China.

Zhang L.,Fudan University | Fu X.-H.,Shanghai Pudong Gongli Hospital | Yu Y.,Fudan University | Shui R.-H.,Fudan University | And 5 more authors.
Laboratory Investigation | Year: 2015

Cathepsin B (CB) is involved in the turnover of proteins and has various roles in maintaining the normal metabolism of cells. In our recent study, CB is increased in the muscles of polymyositis/dermatomyositis (PM/DM). However, the role of CB in interstitial lung disease (ILD) has not been reported. ILD is a frequent complication of PM/DM, which is the leading cause of death in PM/DM. It carries high morbidity and mortality in connective tissue diseases, characterized by an overproduction of inflammatory cytokines and induced fibrosis, resulting in respiratory failure. The etiology and pathogenesis of ILD remain incompletely understood. This study investigated whether treatment with CA-074Me, a specific inhibitor of CB, attenuates ILD in PM. CB expression, inflammation, and fibrosis were analyzed in the lung tissues from patients with PM/DM. The animal model of PM was induced in guinea pigs with Coxsackie virus B1 (CVB1). CA-074Me was given 24 h after CVB1 injection for 7 consecutive days. At the end of the experiment, the animals were killed and lung tissues were collected for the following analysis. Inflammation, fibrosis and apoptosis cells, and cytokines were assessed by histological examinations and immunohistochemical analyses, western blot analysis and transferase-mediated dUTP nick-end labeling assay. In patients with PM/DM, the protein levels of CB were significantly elevated in lung tissues compared with healthy controls, which correlated with increases in inflammation and fibrosis. Similarly, the expression of CB, inflammation and fibrosis, CD8+ T cell, CD68+ cell, tumor necrosis factor-alpha, transforming growth factor-beta1 infiltrations, and apoptotic cell death were significantly increased in lung tissues of the guinea-pig model of CVB1-induced PM. These changes were attenuated by the administration of CA-074Me. In conclusion, this study demonstrates that PM/DM increases CB expression in lung tissues and inhibition of CB reduces ILD in a guinea-pig model of CVB1-induced PM. This finding suggests that CB may be a potential therapeutic target for ILD. © 2015 USCAP, Inc All rights reserved.

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