Upregulated SKP2 Empowers Epidermal Proliferation Through Downregulation of P27 Kip1.

BACKGROUND: Excessive growth of keratinocytes is the critical event in the etiology of psoriasis. However, the underlying molecular mechanism of psoriatic keratinocyte hyperproliferation is still unclear. OBJECTIVE: This study aimed to figure out the potential contributory role of S-phase kinase-associated protein 2 (SKP2) in promoting the hyperproliferation of keratinocytes in psoriasis. METHODS: We analyzed microarray data (GSE41662) to investigate the gene expression of SKP2 in psoriatic lesion skins compared with their adjacent non-lesional skin. Then, we further confirmed the mRNA and protein expression of SKP2 in human psoriatic skin tissues, imiquimod (IMQ)-induced psoriatic mice back skins and tumor necrosis factor α (TNF-α), interleukin (IL)-17A and IL-6-stimulated keratinocytes by using real-time quantitative polymerase chain reaction and western blot (WB). Furthermore, we explored the potential pathogenic role and its underlying cellular mechanism of SKP2 in promoting keratinocytes hyperproliferation through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle detection, 5-ethynyl-2'-deoxyuridine staining and WB. Finally, we determined whether inhibition of SKP2 can effectively alleviate the keratinocytes hyperproliferation in vivo. RESULTS: We identified that SKP2 is aberrantly upregulated in the psoriatic lesion skin and cytokines-stimulated keratinocytes. Moreover, upregulated SKP2 augments cytokines-induced keratinocytes hyperproliferation. Mechanistically, enhanced SKP2 increased the S phase ratio through inhibiting Cyclin-Dependent Kinase Inhibitor p27 (P27 Kip1) expression. Correspondingly, suppression of SKP2 with SMIP004 can significantly ease the epidermis hyperplasia in vivo. CONCLUSION: Our results suggest that elevated SKP2 can empower keratinocytes proliferation and psoriasis-like epidermis hyperplasia via downregulation of P27 Kip1. Therefore, targeting SKP2-P27 Kip1 axis might be a promising therapeutic strategy for the treatment of psoriasis in future.

Punicalagin Alleviates Psoriasis by Inhibiting NF-κB-Mediated IL-1ß Transcription and Caspase-1-Regulated IL-1ß Secretion.

Psoriasis is a chronic and inflammatory skin disorder characterized by inflammation and epidermal hyperplasia. Punicalagin (PUN) is a main active ingredient of pomegranate (Punica granatum L.) peel with multiple biological activities, such as antibacterial, antioxidant and anti-tumor effects. However, the potential effect of PUN on psoriasis remains unknown. In this study, we want to investigate the pharmacological effect of PUN on psoriasis by using imiquimod (IMQ)-induced psoriatic mice model in vivo and tumor necrosis factor a (TNF-α) and interleukin-17A (IL-17A)-stimulated HaCaT cells in vitro. Our results showed that PUN can effectively alleviate the severity of psoriasis-like symptoms. Mechanistically, PUN potently suppresses the aberrant upregulation of interleukin-1ß (IL-1ß) and subsequent IL-1ß-mediated inflammatory cascade in keratinocytes by inhibiting the nuclear factor kappa B (NF-κB) activation and cleaved caspase-1 expression in vitro and in vivo. Taken together, our findings indicate that PUN can relieve psoriasis by repressing NF-κB-mediated IL-1ß transcription and caspase-1-regulated IL-1ß secretion, which provide evidence that PUN might represent a novel and promising candidate for the treatment of psoriasis.

Downregulated miR-187 contributes to the keratinocytes hyperproliferation in psoriasis.

Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. However, the pathogenesis of psoriasis is multifactorial and is not fully understood. MicroRNAs (miRNAs) represent a promising class of small, noncoding RNA molecules that have a large impact on cellular functions by regulating gene expression. Here we reported that microRNA-187 (miR-187), which is one of the most dynamic microRNAs identified in the deep screening miRNAs profile, is downregulated in inflammatory cytokines-stimulated keratinocytes and psoriatic skins. By luciferase activity assay and gain-of-function studies, we showed that miR-187 inhibits keratinocytes hyperproliferation by targeting CD276. Moreover, overexpression of miR-187 decreases acanthosis and reduces the disease severity in psoriasis mouse models. Taken together, the results of our study implies miR-187 as a critical factor in psoriasis pathogenesis, which could be a potent target for psoriasis treatment.

Cryptotanshinone reduces psoriatic epidermal hyperplasia via inhibiting the activation of STAT3.

The discovery of new therapeutic drugs with the efficacious and safe ability to prevent epidermal hyperplasia is extremely urgent for psoriasis. Cryptotanshinone (CTS), an active component isolated from the root of Salvia miltiorrhiza Bunge, has been reported to have antibacterial and antitumor effects. However, its effects on psoriasis have not been reported. Here, we investigated the therapeutic effects of CTS on imiquimod (IMQ)-induced psoriatic-like skin model and explored the underlying mechanisms. Our results revealed that CTS effectively alleviates IMQ-induced epidermal hyperplasia. In vitro studies also indicated that CTS potently inhibits the growth of keratinocytes. We further found that STAT3, a transcription factor for the cell growth, is the key mediator of CTS on the proliferation of keratinocytes. Taken together, our findings indicated that the curative effects of CTS on psoriasis are accomplished mainly through modulating STAT3, which providing evidences to develop CTS as a potential therapeutic agent for patients with psoriasis.

A new convenient technique for making cell blocks.

Cell block sections serve as an important diagnostic annex for cytological smears, liquid-based SurePath cytology and the Liquid-based Thin-prep Cytology Test (TCT). A variety of methods for the preparation of cell blocks are described in the literature and the techniques in cell blocks are in continuous improvement. A new technique for making cell blocks was introduced in the present study. We first used pregelatinized starch as the frame for the cell block, which is a really simple and economic method, because it can be carried out at room temperature without additional special instruments. We have performed hematoxylin and eosin (HE) staining, immunohistochemistry analysis and fluorescence in situ hybridization (FISH) in the cell block sections in 122 cytological specimens. The results demonstrated in this article show that pregelatinized starch is a useful frame for cell blocks. The pregelatinized starch can effectively collect even a few cells with powerful adhesiveness. Therefore, this new technique for making cell blocks is especially useful for cytologic samples with low cellularity, such as cerebrospinal fluid specimens.