Background: Mycotoxins are fungal secondary metabolites commonly present in feed and food, and are widely regarded as hazardous contaminants. Citrinin, one of the very well known mycotoxins that was first isolated from Penicillium citrinum, is produced by more than 10 kinds of fungi, and is possibly spread all over the world. However, the information on the action mechanism of the toxin is limited. Thus, we investigated the citrinin-induced genomic response for evaluating its toxicity.

BackgroundAccording to EULAR recommendations, biologic DMARDs (bDMARDs) such as tumor necrosis factor inhibitor, tocilizumab (TCZ), and abatacept (ABT) are in parallel when prescribing to rheumatoid arthritis (RA) patients who have shown insufficient response to conventional synthetic DMARDs. However, most prediction studies of therapeutic response to bDMARDs using gene expression profiles were focused on a single bDMARD, and consideration of the results from the perspective of RA pathophysiology was insufficient. The aim of this study was to identify the specific molecular biological features predicting the therapeutic outcomes of three bDMARDs (infliximab [IFX], TCZ, and ABT) by studying blood gene expression signatures of patients before biologic treatment in a unified test platform.MethodsRA patients who responded inadequately to methotrexate and were later commenced on any one of IFX (n = 140), TCZ (n = 38), or ABT (n = 31) as their first biologic between May 2007 and November 2011 were enrolled. Whole-blood gene expression data were obtained before biologic administration. Patients were categorized into remission (REM) and nonremission (NON-REM) groups according to CDAI at 6 months of biologic therapy. We employed Gene Set Enrichment Analysis (GSEA) to identify functional gene sets differentially expressed between these two groups for each biologic. Then, we compiled “signature scores” for these gene sets, and the prediction performances were assessed.ResultsGSEA showed that inflammasome genes were significantly upregulated with IFX in the NON-REM group compared with the REM group. With TCZ in the REM group, B-cell-specifically expressed genes were upregulated. RNA elongation, apoptosis-related, and NK-cell-specifically expressed genes were upregulated with ABT in the NON-REM group. Logistic regression analyses showed that “signature scores” of inflammasomes, B-cell-specifically expressed, and NK-cell-specifically expressed genes were significant, independently predictive factors for treatment outcome with IFX, TCZ, and ABT, respectively. The AUCs of ROC curves of these signature scores were 0.637, 0.796, and 0.768 for IFX, TCZ, and ABT, respectively.ConclusionsWe have identified original gene expression predictive signatures uniquely underlying the therapeutic effects of IFX, TCZ, and ABT. This is, to our knowledge, the first attempt to predict therapeutic effects of three drugs concomitantly using a unified gene expression test platform.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1052-8) contains supplementary material, which is available to authorized users.

Signaling through the tumor necrosis factor receptor (TNFR) superfamily can lead to apoptosis or promote cell survival, proliferation, and differentiation. A subset of this family, including TNFR1 and Fas, signals cell death via an intracellular death domain and therefore is termed the death receptor (DR) family. In this study, we identified new members of the DR family, designated xDR-M1 and xDR-M2, in Xenopus laevis. The two proteins, which show high homology (71.7% identity), have characteristics of the DR family, that is, three cysteinerich domains, a transmembrane domain, and a death domain. To elucidate how members of xDR-M subfamily regulate cell death and survival, we examined the intracellular signaling mediated by these receptors in 293T and A6 cells. Overexpression of xDR-M2 induced apoptosis and activated caspase-8, c-Jun N-terminal kinase, and nuclear factor-B, although its death domain to a greater extent than did that of xDR-M1 in 293T cells. A caspase-8 inhibitor potently blocked this apoptosis induced by xDR-M2. In contrast, xDR-M1 showed a greater ability to induce apoptosis through its death domain than did xDR-M2 in A6 cells. Interestingly, a general serine protease inhibitor, but not the caspase-8 inhibitor, blocked the xDR-M1-induced apoptosis. These results imply that activation of caspase-8 or serine protease(s) may be required for the xDR-

Background information. Death receptors (DRs) induce intracellular signalling upon engagement of their cognate ligands, leading to apoptosis, cell survival or pro-inflammatory responses. In mammals, DR signalling is mediated by the recruitment of several DD (death domain)-containing molecules, such as FADD (Fas-associated DD) and RIP1 (receptor-interacting protein 1).Results. To elucidate the molecular mechanisms of intracellular DR signalling in Xenopus, we have isolated cDNAs encoding xFADD (Xenopus FADD), and xRIP1 and its short isoform xRIP1β, which is produced by alternative splicing of the xRIP1 gene. These DD-containing proteins interacted with Xenopus DR members xDR-M1 and xDR-M2 through their DDs in co-transfected HEK-293T cells. Overexpression of xFADD activated not only xCaspase 8, but also AP-1 (activator protein 1), which reflects activation of JNK (c-Jun N-terminal kinase) and NF-κB (nuclear factor κB). A comparative analysis of xRIP1, a kinase-dead mutant of xRIP1 and xRIP1β indicated that the kinase activity of xRIP1 was required for the activation of AP-1 and NF-κB. Interestingly, xFADD and xRIP1 interacted with each other via their DDs, and the expression of a mutant xRIP1 containing only the DD (xRIP1-DD) repressed the xFADD-induced activation of NF-κB and AP-1. xFADD and xRIP1 synergistically induced the activation of AP-1 and NF-κB, both of which were partially mediated by TRAF2 (tumour-necrosis-factor-receptor-associated factor 2) and TAK1 (transforming-growth-factor-β-activated kinase 1). We also found that the activation pathways of NF-κB induced by xDR-M2 were inhibited by xRIP1-DD.Conclusions. Xenopus FADD, RIP1 and its splice variant RIP1β have been characterized. Interaction of xFADD and xRIP1 induced synergistic activation of JNK and NF-κB. In addition, the NF-κB activation induced by xDR-M2 was partially mediated by xRIP1.

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