| Nature Publishing Group Ids | Title | Abstract | Authors | Journal | Publication Date | Product Version |
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| naturepublishinggroup10.1038/jid.2012.87 | Immunology 1: Adaptive Immunity | | [] | Journal of Investigative Dermatology | 2012-05-01 | |
| naturepublishinggroup10.1038/jid.2012.80 | Carcinogenesis, Growth Factors, and Cancer Genetics | | [] | Journal of Investigative Dermatology | 2012-05-01 | |
| naturepublishinggroup10.1038/mi.2012.16 | MiR-375 is downregulated in epithelial cells after IL-13 stimulation and regulates an IL-13-induced epithelial transcriptome | Interleukin 13 (IL-13)-induced epithelial gene and protein expression changes are central to the pathogenesis of multiple allergic diseases. Herein, using human esophageal squamous and bronchial columnar epithelial cells, we identified microRNAs (miRNAs) that were differentially regulated after IL-13 stimulation. Among the IL-13-regulated miRNAs, miR-375 showed a conserved pattern of downregulation. Furthermore, miR-375 was downregulated in the lung of IL-13 lung transgenic mice. We subsequently analyzed miR-375 levels in a human disease characterized by IL-13 overproduction—the allergic disorder eosinophilic esophagitis (EE)—and observed downregulation of miR-375 in EE patient samples compared with control patients. MiR-375 expression levels reflected disease activity, normalized with remission, and inversely correlated with the degree of allergic inflammation. Using a lentiviral strategy and whole-transcriptome analysis in epithelial cells, miR-375 overexpression was sufficient to markedly modify IL-13-associated immunoinflammatory pathways in epithelial cells in vitro, further substantiating interactions between miR-375 and IL-13. Taken together, our results support a key role of miRNAs, particularly miR-375, in regulating and fine-tuning IL-13-mediated responses. | [T X Lu, E-J Lim, T Wen, A J Plassard, S P Hogan, L J Martin, B J Aronow, M E Rothenberg] | Mucosal Immunology | 2012-03-28 | |
| naturepublishinggroup10.1038/ncomms1755 | FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure | | [Shinjiro Hino, Akihisa Sakamoto, Katsuya Nagaoka, Kotaro Anan, Yuqing Wang, Shinya Mimasu, Takashi Umehara, Shigeyuki Yokoyama, Ken-ichiro Kosai, Mitsuyoshi Nakao] | Nature Communications | 2012-03-27 | |
| naturepublishinggroup10.1038/nature10894 | The Shigella flexneri effector OspI deamidates UBC13 to dampen the inflammatory response | Many bacterial pathogens can enter various host cells and then survive intracellularly, transiently evade humoral immunity, and further disseminate to other cells and tissues. When bacteria enter host cells and replicate intracellularly, the host cells sense the invading bacteria as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) by way of various pattern recognition receptors. As a result, the host cells induce alarm signals that activate the innate immune system1. Therefore, bacteria must modulate host inflammatory signalling and dampen these alarm signals2, 3, 4. How pathogens do this after invading epithelial cells remains unclear, however. Here we show that OspI, a Shigella flexneri effector encoded by ORF169b on the large plasmid and delivered by the type ΙΙΙ secretion system, dampens acute inflammatory responses during bacterial invasion by suppressing the tumour-necrosis factor (TNF)-receptor-associated factor 6 (TRAF6)-mediated signalling pathway. OspI is a glutamine deamidase that selectively deamidates the glutamine residue at position 100 in UBC13 to a glutamic acid residue. Consequently, the E2 ubiquitin-conjugating activity required for TRAF6 activation is inhibited, allowing S. flexneri OspI to modulate the diacylglycerol–CBM (CARD–BCL10–MALT1) complex–TRAF6–nuclear-factor-κB signalling pathway. We determined the 2.0 Å crystal structure of OspI, which contains a putative cysteine–histidine–aspartic acid catalytic triad. A mutational analysis showed this catalytic triad to be essential for the deamidation of UBC13. Our results suggest that S. flexneri inhibits acute inflammatory responses in the initial stage of infection by targeting the UBC13–TRAF6 complex. | [Takahito Sanada, Minsoo Kim, Hitomi Mimuro, Masato Suzuki, Michinaga Ogawa, Akiho Oyama, Hiroshi Ashida, Taira Kobayashi, Tomohiro Koyama, Shinya Nagai, Yuri Shibata, Jin Gohda, Jun-ichiro Inoue, Tsunehiro Mizushima, Chihiro Sasakawa] | Nature | 2012-03-11 | |
| naturepublishinggroup10.1038/jid.2012.33 | Combined Use of Laser Capture Microdissection and cDNA Microarray Analysis Identifies Locally Expressed Disease-Related Genes in Focal Regions of Psoriasis Vulgaris Skin Lesions | Psoriasis vulgaris is a complex disease characterized by alterations in growth and differentiation of epidermal keratinocytes, as well as a marked increase in leukocyte populations. Lesions are known to contain alterations in messenger RNAs encoding more than 1,000 products, but only a very small number of these transcripts has been localized to specific cell types or skin regions. In this study, we used laser capture microdissection (LCM) and gene array analysis to study the gene expression of cells in lesional epidermis (EPI) and dermis, compared with the corresponding non-lesional regions. Using this approach, we detected >1,800 differentially expressed gene products in the EPI or dermis of psoriasis lesions. These results established sets of genes that are differentially expressed between epidermal and dermal compartments, as well as between non-lesional and lesional psoriasis skin. One of our findings involved the local production of CCL19, a lymphoid-organizing chemokine, and its receptor CCR7 in psoriatic dermal aggregates, along with the presence of gene products LAMP3/DC-LAMP and CD83, which typify mature dendritic cells (DCs). Gene expression patterns obtained with LCM and microarray analysis along with T-cell and DC detection by immune staining suggest a possible mechanism for lymphoid organization via CCL19/CCR7 in diseased skin. | [Hiroshi Mitsui, Mayte Su|[aacute]|rez-Fari|[ntilde]|as, Daniel A Belkin, Natasha Levenkova, Judilyn Fuentes-Duculan, Israel Coats, Hideki Fujita, James G Krueger] | Journal of Investigative Dermatology | 2012-03-08 | |
| naturepublishinggroup10.1038/mt.2012.36 | miR-29 Inhibits Bleomycin-induced Pulmonary Fibrosis in Mice | Loss of microRNA-29 (miR-29) is known to be a mechanism of transforming growth factor-β (TGF-β)-mediated pulmonary fibrosis, but the therapeutic implication of miR-29 for pulmonary fibrosis remains unexplored. The present study investigated whether miR-29 had therapeutic potential for lung disease induced by bleomycin in mice. In addition, the signaling mechanisms that regulated miR-29 expression were investigated in vivo and in vitro. We found that miR-29 was a downstream target gene of Smad3 and negatively regulated by TGF-β/Smad signaling in fibrosis. This was evidenced by the findings that mice or pulmonary fibroblasts null for Smad3 were protected against bleomycin or TGF-β1-induced loss of miR-29 along with fibrosis in vivo and in vitro. Interestingly, overexpression of miR-29 could in turn negatively regulated TGF-β and connective tissue growth factor (CTGF) expression and Smad3 signaling. Therefore, Sleeping Beauty (SB)-mediated miR-29 gene transfer into normal and diseased lung tissues was capable of preventing and treating pulmonary fibrosis including inflammatory macrophage infiltration induced by bleomycin in mice. In conclusion, miR-29 is negatively regulated by TGF-β/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis. | [Jun Xiao, Xiao-Ming Meng, Xiao R Huang, Arthur CK Chung, Yu-Lin Feng, David SC Hui, Cheuk-Man Yu, Joseph JY Sung, Hui Y Lan] | Molecular Therapy | 2012-03-06 | |
| naturepublishinggroup10.1038/jid.2012.13 | Molecular Markers of Early-Stage Mycosis Fungoides | The lack of a specific marker differentiating early mycosis fungoides (eMF) from benign inflammatory dermatitis presents significant difficulties in the assessment and management of suspected MF patients, which often leads to delayed diagnosis and improper medical approaches. To address this, an investigation was carried out to characterize positive identification markers for eMF by comparing eMF lesions with healthy skin and benign inflammatory dermatitis, using high-throughput genomic transcription profiling. A total of 349 genes were differentially expressed in eMF lesions compared with normal skin. These genes belong to pathways associated with inflammation, immune activation, and apoptosis regulation. Most of them (N=330) also demonstrated significant upregulation in chronic dermatitis, making them nonideal markers for eMF. Among them, 19 genes with specific enrichment in eMF lesions were identified that showed no significant upregulation in chronic dermatitis. Two of them, TOX and PDCD1, showed high discrimination power between eMF lesions and biopsies from benign dermatitis by RNA expression. Furthermore, TOX demonstrated highly specific staining of MF cells in eMF skin biopsies in immunohistochemistry and immunofluorescence, including the early epidermotropic cells in Pautrier's microabscesses. This study demonstrates the potential of eMF-enriched genes, especially TOX, as molecular markers for histological diagnosis of eMF, which currently is a major diagnostic challenge. | [Yaohua Zhang, Yang Wang, Richard Yu, Yuanshen Huang, Mingwan Su, Cheng Xiao, Magdalena Martinka, Jan P Dutz, Xuejun Zhang, Zhizhong Zheng, Youwen Zhou] | Journal of Investigative Dermatology | 2012-03-01 | |
| naturepublishinggroup10.1038/nature10841 | Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain | All attempts at treating strokes by pharmacologically reducing the human brain’s vulnerability to ischaemia have failed, leaving stroke as a leading cause of death, disability and massive socioeconomic loss worldwide1. Over decades, research has failed to translate over 1,000 experimental treatments from discovery in cells and rodents to use in humans2, 3, 4, a scientific crisis that gave rise to the prevailing belief that pharmacological neuroprotection is not feasible or practicable in higher-order brains. To provide a strategy for advancing stroke therapy, we used higher-order gyrencephalic non-human primates, which bear genetic, anatomical and behavioural similarities to humans5, 6 and tested neuroprotection by PSD-95 inhibitors—promising compounds that uncouple postsynaptic density protein PSD-95 from neurotoxic signalling pathways7, 8, 9, 10. Here we show that stroke damage can be prevented in non-human primates in which a PSD-95 inhibitor is administered after stroke onset in clinically relevant situations. This treatment reduced infarct volumes as gauged by magnetic resonance imaging and histology, preserved the capacity of ischaemic cells to maintain gene transcription in genome-wide screens of ischaemic brain tissue, and significantly preserved neurological function in neurobehavioural assays. The degree of tissue neuroprotection by magnetic resonance imaging corresponded strongly to the preservation of neurological function, supporting the intuitive but unproven dictum that integrity of brain tissue can reflect functional outcome. Our findings establish that tissue neuroprotection and improved functional outcome after stroke is unequivocally achievable in gyrencephalic non-human primates treated with PSD-95 inhibitors. Efforts must ensue to translate these findings to humans. | [Douglas J. Cook, Lucy Teves, Michael Tymianski] | Nature | 2012-02-29 | |
| naturepublishinggroup10.1038/emboj.2012.25 | miR-493 induction during carcinogenesis blocks metastatic settlement of colon cancer cells in liver | Liver metastasis is a major lethal complication associated with colon cancer, and post-intravasation steps of the metastasis are important for its clinical intervention. In order to identify inhibitory microRNAs (miRNAs) for these steps, we performed ‘dropout’ screens of a miRNA library in a mouse model of liver metastasis. Functional analyses showed that miR-493 and to a lesser extent miR-493* were capable of inhibiting liver metastasis. miR-493 inhibited retention of metastasized cells in liver parenchyma and induced their cell death. IGF1R was identified as a direct target of miR-493, and its inhibition partially phenocopied the anti-metastatic effects. High levels of miR-493 and miR-493*, but not pri-miR-493, in primary colon cancer were inversely related to the presence of liver metastasis, and attributed to an increase of miR-493 expression during carcinogenesis. We propose that, in a subset of colon cancer, upregulation of miR-493 during carcinogenesis prevents liver metastasis via the induction of cell death of metastasized cells. | [Koji Okamoto, Tatsuya Ishiguro, Yutaka Midorikawa, Hirokazu Ohata, Masashi Izumiya, Naoto Tsuchiya, Ai Sato, Hiroaki Sakai, Hitoshi Nakagama] | The EMBO Journal | 2012-02-28 | |
| naturepublishinggroup10.1038/jid.2012.22 | miR-196a Downregulation Increases the Expression of Type I and III Collagens in Keloid Fibroblasts | Keloids are a fibroproliferative disease due to abnormal wound healing process after skin injury. They are characterized by overproduction of extracellular matrix (ECM) such as collagens. MicroRNAs (miRNAs) are noncoding small RNAs and negatively regulate protein expression. Several miRNAs that have critical roles in tissue fibrosis and ECM metabolism have been reported. However, regulation and function of miRNAs in keloid remain to be explored. The purpose of this study was to identify miRNAs involved in keloid pathogenesis. We performed miRNA microarray analysis to compare miRNA expression profiles between keloid-derived fibroblasts (KFs) and normal fibroblasts (NFs). In all, 7 upregulated and 20 downregulated miRNAs were identified. Among these, we focused on miR-196a, which showed the highest fold change. Overexpression or knockdown of miR-196a led to a decreased or increased level of secreted type I/III collagens, respectively. Reporter analysis showed direct binding of miR-196a to the 3′ untranslated region (UTR) of COL1A1 and COL3A1. In conclusion, we demonstrate for the first time that miRNA expression profile is altered in KFs compared with NFs. Downregulation of miR-196a may be one of the mechanisms by which collagens are highly deposited in keloid tissues. Our findings suggest that miR-196a could be a new therapeutic target for keloid lesions. | [Kazuya Kashiyama, Norisato Mitsutake, Michiko Matsuse, Tomoo Ogi, Vladimir A Saenko, Kenta Ujifuku, Atsushi Utani, Akiyoshi Hirano, Shunichi Yamashita] | Journal of Investigative Dermatology | 2012-02-23 | |
| naturepublishinggroup10.1038/gene.2012.1 | MicroRNAs regulate B-cell receptor signaling-induced apoptosis | Apoptosis induced by B-cell receptor (BCR) signaling is critical for antigen-driven selection, a process critical to tolerance and immunity. Here, we examined the roles of microRNAs (miRNAs) in BCR signaling-induced apoptosis using the widely applied WEHI-231 model. Comparison of miRNA levels in BCR-stimulated and -unstimulated cells revealed that 39 miRNAs were differentially expressed upon stimulation of the BCR. Importantly, stimulation in the presence of anti-CD40 antibodies, which rescues cells from BCR-induced apoptosis, prevented most changes in miRNA expression. Ectopic expression of mir-150 and mir-181a1b1, miRNAs that were upregulated upon BCR stimulation, resulted in inhibition of cell growth. Finally, we showed that ectopic expression of mir-150, mir-181a1b1 and mir-17~92 sensitized cells to anti-IgM stimulation-induced growth inhibition. Together, these results demonstrate that miRNAs are involved in BCR signaling, suggesting that they may have important roles in the regulation of B cell-mediated tolerance and immunity. | [J L Kluiver, C-Z Chen] | Genes and Immunity | 2012-02-23 | |
| naturepublishinggroup10.1038/bjc.2012.35 | Overexpression of PFTK1 predicts resistance to chemotherapy in patients with oesophageal squamous cell carcinoma | | [H Miyagaki, M Yamasaki, H Miyata, T Takahashi, Y Kurokawa, K Nakajima, S Takiguchi, Y Fujiwara, H Ishii, F Tanaka, M Mori, Y Doki] | British Journal of Cancer | 2012-02-14 | |
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