Zhengxiao Li

Apoptosis induced by synthetic retinoic acid CD437 on human melanoma A375 cells involves RIG-I pathway

Human malignant melanoma is notoriously resistant to currently available pharmacological modulation. Our aim was to evaluate the anti-tumor effect of a novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carbo-xylic acid (CD437) on melanoma cell line A375. Analysis of cell morphology showed that CD437 promoted marked apoptosis in A375 cells. To explore the mechanisms of CD437-induced apoptosis, an NF-κB-luciferase reporter assay was performed, demonstrating that apoptosis induction by CD437 required activation of transcription factor NF-κB. Importantly, based on the findings that RIG-I (retinoic acid inducible gene I) can be induced by retinotic acid and can activate NF-κB through a CARD-containing adaptor protein VISA, we proposed a hypothesis that RIG-I was involved in the signal pathway of NF-κB activation induced by CD437 through the adaptor protein VISA. By specially cleaving VISA with hepatitis C virus (HCV) non-structural (NS)3/4A, the RIG-I pathway was blocked, with subsequent simultaneous inhibition of CD437-induced NF-κB activation and cell apoptosis in A375 cells. These results support our hypothesis and suggest that RIG-I may be a useful intermediate biologic marker for retinoid chemoprevention and treatment studies.

RNAi-mediated inhibition of COL1A1 and COL3A1 in human skin fibroblasts.

Abstract:  Types I and III collagens are the major collagens comprising skin connective tissue. Defects in these collagens lead to diseases of dermal connective tissue and fibre hyperplasia. RNA interference (RNAi) provides a powerful tool to inhibit specific gene expression. In this study, we generated small interfering RNAs (siRNA) expression cassettes (SECs) by polymerase chain reaction (PCR) as a method to quickly screen the efficacy of siRNAs. We then cloned the most efficient SECs into vectors, using a rapid and novel method intrinsic to the design of the SEC, and transfected human skin fibroblasts (HSF) to generate stable lines. We show that the transfection of SECs into HSFs resulted in specific and effective repression of COL1A1 and COL3A1 expression (5.00% and 6.48% of control levels) provided a rapid method for testing candidate siRNA sequences. We report the use of vector‐based RNAi to establish stable HSF cell lines with persistent knockdown over at least 30 days (25.21% and 22.12% of control levels). These stably modified HSF cell lines may be used for the study of other types of collagen or proteins of the extracellular matrix (ECM).

Decreased expression of E-cadherin and β-catenin in the lesional skin of patients with active psoriasis

Correspondence Decreased expression of E-cadherin and β -catenin in the lesional skin of patients with active psoriasis Keratinocyte proliferation outside the basal layer suggests an alteration in cell–cell interactions in active psoriasis. The molecular alterations in epidermal barrier function and the mechanisms underlying the perturbed state of proliferation and differentiation in psoriatic epidermis remain poorly understood. Keratinocytes interact with each other through intercellular junctions to regulate cellular shape, proliferation, and the passage of ions and molecules through the paracellular pathway. 1,2 Adherens junctions (AJs) are required for the establishment and maintenance of epithelial layers, mediating intercellular adhesion, sensing the presence of neighboring cells, and anchoring the actin cytoskeleton to protein complexes and the membrane in this region of the cell. 3

Wnt/β-Catenin and Wnt5a/Ca Pathways Regulate Proliferation and Apoptosis of Keratinocytes in Psoriasis Lesions.

Background/Aims: Wnt5a is overexpressed in psoriasis lesions, however the mechanism by which Wnt5a is involved in the pathogenesis of psoriasis is not clear. To address this, the expression of Wnt5a in psoriatic lesions and its effect on keratinocyte cell proliferation and apoptosis was examined in vitro. Methods: The expression levels of WNT5A, and genes encoding its receptors frizzled2 (FZD2) and frizzled5 (FZD5) were examined in samples obtained from individuals with psoriasis and healthy controls. Knockdown of Wnt5a with short interfering (si)RNAs was performed in cultured HaCaT keratinocytes and normal human keratinocytes (NHK), and the expression of Wnt5a, protein kinase C (PKC), and β-catenin were determined, and cell cycle activity, proliferation and apoptosis were assessed. Results: The expression of WNT5A, FZD2 and FZD5 mRNA and protein were increased in psoriatic lesions. Wnt5a knockdown suppressed proliferation and induced apoptosis in HaCaT and NHK cells. Additionally, expression of PCNA, MKI67, CCND1, BCL2, CTNNB1, and genes encoding PKC and survivin were downregulated, whereas CASP3 was upregulated. The mRNA levels of the Wnt pathway inhibitors DKK1 and SFRP1 were upregulated, Western blotting analyses demonstrated reduction in β-catenin and PKC protein levels. Conclusion: Knockdown of Wnt5a suppresses the proliferation of keratinocytes and induces apoptosis by inhibiting the Wnt/β-catenin or Wnt5a/Ca2+ pathways.

Wnt5a is involved in the pathogenesis of cutaneous lichen planus.

Cutaneous lichen planus (CLP) is a chronic inflammatory and immune‐mediated disease. Wnt5a is one of the most extensively studied Wnt proteins, and has important functions in stimulating inflammation, cell proliferation, cell fate determination and cell differentiation. Wnt5a expression in CLP has not been comprehensively studied to date.

Extranodal natural killer/T-cell lymphoma, nasal type, involving the skin, misdiagnosed as nasosinusitis and a fungal infection: A case report and literature review.

The present study reports a case of extranodal natural killer (NK)/T-cell lymphoma, nasal type, involving the skin. The clinical manifestations, pathological characteristics, treatment and prognosis of the case were analyzed to improve the clinical diagnosis and treatment for this disease. The patient was a 56-year-old male, presenting with dark red nodules and plaques that had been visible on the nose for half a year. Based on the skin lesions and histopathological and immunohistochemical examination results, the patient was diagnosed with extranodal NK/T-cell lymphoma, nasal type. This disease has unique histopathological and immunohistochemical features and a high malignancy. The condition tends to be misdiagnosed and has a poor prognosis, but seldom involves the skin. In the present case, only radiotherapy was performed, with no relapse occurring within 6 months.

Antimicrobial peptide LL-37 promotes YB-1 expression, and the viability, migration and invasion of malignant melanoma cells

The cathelicidin antimicrobial peptide, LL-37, is a multifunctional peptide with a broad spectrum of antimicrobial activities, such as chemotaxis and neutralizing endotoxins. Previous studies have demonstrated that it LL-37 serves a functional role in the development of numerous types of cancer including ovarian, breast, prostate and lung cancer. However, its role in the development of malignant melanoma (MM) remains unclear. To determine the role of LL-37 and the potential interaction with Y-box binding protein 1 (YB-1) in MM, RNA interference, western blot, reverse transcription-quantitative polymerase chain reaction, MTT and Transwell assays were performed. The current study demonstrated that LL-37 induced YB-1 expression, and increased tumor cell proliferation, migration and invasion of A375 and A875 MM cell lines. In addition, inhibition of nuclear factor-κB (NF-κB) attenuated LL-37-induced YB-1 expression. These results demonstrate that, through the upregulation of YB-1 expression and the activation of the NF-κB signaling pathway, LL-37 may promote the malignant progression of MM cells in vitro.

Failure of rapamycin in the treatment of multiple haemangiomas associated with Maffucci syndrome.

Maffucci syndrome is a rare, nonhereditary, congenital, mesodermal dysplasia presenting as multiple enchondromas and haemangiomas, which was first described in 1881. Cartilaginous and vascular lesions are exclusively or predominantly unilateral, and may progress to malignancy. Mutant isocitrate dehydrogenase (IDH)1 or IDH2 pathways can substantially contribute to tumourigenesis. There is currently no effective medical treatment for the vascular lesions associated with Maffucci syndrome, although Riou et al. reported a case with spindle-cell haemangioma in 2012, which was successfully treated with low doses of rapamycin. We present a case of Maffucci syndrome with vascular lesions presenting as exclusively cavernous haemangioma, which was not responsive to rapamycin treatment.

Apoptotic effect and mechanisms of AHPN on human skin malignant melanoma cell A375

Abstract Objective To study apoptotic effects of synthetic retinoic acid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid(AHPN) on human skin malignant melanoma A375 cells in comparison with the natural ligand all-trans-retinoic acid(ATRA) in vitro and the mechanisms related to the actions of AHPN. Methods MTT assay was used to determine the anti-proliferative effects of AHPN and ATRA on A375 cells. Flow cytometry was performed to investigate the influence of AHPN and ATRA on cell cycle and cell apoptosis. In addition, transfection and luciferase activity assays were employed to explore the mechanisms of how AHPN executes its proapoptotic function. Results Firstly, AHPN promoted apoptosis and G1 arrest in A375 cells compared with ATRA. Secondly, the activity of NF-κ B in A375 cells treated with AHPN increased 2–3 times compared with solvent DMSO treatment. Conclusion AHPN, in comparison with ATRA, is a more effective alternative for therapy of malignant melanoma. The potentially proapoptotic function of AHPN requires activation of NF-κ B.

Compression therapy: an adjuvant treatment for orofacial granulomatosis in Melkersson-Rosenthal syndrome?

ejd.2011.1517 Auteur(s) : Zhengxiao Li lizhengxiao1979@163.com, Jingyi Yuan, Ping Liu, Shengxiang Xiao Department of Dermatology and Venereology, The Second Affiliated Hospital, Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an 710004, Shaanxi Province, PR. China Melkersson-Rosenthal syndrome (MRS) is a rare neuromucocutaneous disorder of unknown etiology characterized by the triad of recurrent or persistent orofacial swelling, facial nerve palsy and fissured tongue. Infections, autoimmunity, [...]