FK1706 potentiated nerve growth factor-induced neurite outgrowth, putatively mediated via FKBP-52 and the Ras/Raf/MAPK signaling pathway. It also improved mechanical allodynia accompanied by the recovery of intraepidermal nerve fiber density in a painful diabetic neuropathy in rats.
FK1706, a novel non-immunosuppressive immunophilin ligand, modifies gene expression in the dorsal root ganglia during painful diabetic neuropathy.
Specimen part, Treatment
View SamplesScope: As a result of population ageing, the number of Alzheimer’s disease (AD) patients has rapidly increased. There are many hypothesises on the pathogenesis of AD, but its detailed molecular mechanism is still unknown, and so no effective preventive or therapeutic measures have been established. Some reports showed a decrease in levels of norepinephrine (NE) has been suspected to be involved in the decline of cognitive function in AD patients and NE concentrations were decreased in postmortem AD patient brains. Tyr-Trp was identified as being the most effective dipeptide in enhancing norepinephrine (NE) synthesis and metabolism. And Tyr-Trp treatment ameliorated the short-term memory dysfunction in AD model mice caused by amyloid beta (Aβ) 25-35. So, the purpose of this study was to investigate the preventive or/and protective effects of Tyr-Trp administration in AD model mice.
Tyr-Trp administration facilitates brain norepinephrine metabolism and ameliorates a short-term memory deficit in a mouse model of Alzheimer's disease.
Specimen part
View SamplesThe mouse anterior-posterior (A-P) axis polarization is preceded by formation of the distal visceral endoderm (DVE). However, the mechanism of the emergence of DVE cells is not well understood. Here, we show by in vitro culturing of embryos immediately after implantation in micro-fabricated cavities (narrow; 90 micro-meter, wide; 180 miro-meter in diameter) that the external mechanical cues exerted on the embryo, i.e. cultured in the narrow cavity, are crucial for DVE formation as well as elongated egg cylinder shape. This implies that these developmental events immediately after implantation are not simply embryo-autonomous processes but require extrinsic mechanical factors. Further whole genome-wide gene expression profiles with DNA microarray revealed that no significant difference of transcripts were evident with or without mechanical cues except DVE-related markers. Thus, we propose that external mechanical cues rather than not specific molecular pathways can trigger the establishment of the A-P axis polarization, which is one of the fundamental proccesses of mammalian embryogenesis.
External mechanical cues trigger the establishment of the anterior-posterior axis in early mouse embryos.
Specimen part, Treatment
View SamplesOvarian clear cell carcinoma (OCCC) shows unique clinical features including an association with endometriosis and poor prognosis. We previously reported that the contents of endometriotic cysts, especially high concentrations of free iron, are a possible cause of OCCC carcinogenesis through iron-induced persistent oxidative stress. In this study, we conducted gene expression microarray analysis using 38 ovarian cancer cell lines and identified genes commonly expressed in both OCCC cell lines and clinical samples, which comprise an OCCC gene signature. The OCCC signature reproducibly predicts OCCC specimens in other microarray data sets, suggesting that this gene profile reflects the inherent biological characteristics of OCCC. The OCCC signature contains known markers of OCCC, such as hepatocyte nuclear factor-1b (HNF-1b) and versican (VCAN), and other genes that reflect oxidative stress. Expression of OCCC signature genes was induced by treatment of immortalized ovarian surface epithelial cells with the contents of endometriotic cysts, indicating that the OCCC signature is largely dependent on the tumor microenvironment. Induction of OCCC signature genes is at least in part epigenetically regulated, as we found hypomethylation of HNF-1b and VCAN in OCCC cell lines. This genomewide study indicates that the tumor microenvironment induces specific gene expression profiles that contribute to the development of distinct cancer subtypes.
Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes.
Sex, Specimen part, Cell line, Treatment
View SamplesDietary restriction extends lifespan and delays the age-related physiological decline in many species. Intermittent fasting (IF) is one of the most effective dietary restriction regimens that extends lifespan in C. elegans and mammals1,2. In C. elegans, the FOXO transcription factor DAF-16 is implicated in fasting-induced gene expression changes and the longevity response to IF3; however, the mechanisms that sense and transduce fasting-stress stimuli have remained largely unknown. Here we show that a KGB-1/AP1 (activator protein 1) module is a key signalling pathway that mediates fasting-induced transcriptional changes and IF-induced longevity. Our promoter analysis coupled to genome-wide microarray results has shown that the AP-1-binding site, together with the FOXO-binding site, is highly over-represented in the promoter regions of fasting-induced genes. We find that JUN-1 (C. elegans c-Jun) and FOS-1 (C. elegans c-Fos), which constitute the AP-1 transcription factor complex, are required for IF-induced longevity. We also find that KGB-1 acts as a direct activator of JUN-1 and FOS-1, is activated in response to fasting, and, among the three C. elegans JNKs, is specifically required for IF-induced longevity. Our results demonstrate that most fasting-induced upregulated genes, including almost all of the DAF-16-dependent genes, require KGB-1 and JUN-1 function for their induction, and that the loss of kgb-1 suppresses the fasting-induced upregulation of DAF-16 target genes without affecting fasting-induced DAF-16 nuclear translocation. These findings identify the evolutionarily conserved JNK/AP-1 module as a key mediator of fasting-stress responses, and suggest a model in which two fasting-induced signalling pathways leading to DAF-16 nuclear translocation and KGB-1/AP-1 activation, respectively, integrate in the nucleus to coordinately mediate fasting-induced transcriptional changes and IF-induced longevity.
A fasting-responsive signaling pathway that extends life span in C. elegans.
Treatment
View SamplesWe used microarrays to detail the global gene expression of primary RPE and immortalized RPE.
Identification of a Gene Encoding Slow Skeletal Muscle Troponin T as a Novel Marker for Immortalization of Retinal Pigment Epithelial Cells.
Specimen part, Cell line
View SamplesIL-1R-associated kinases (IRAKs) participate in Toll-like receptor (TLR) signal transduction. MALP-2 is a TLR2 ligand, and stimulation of macrophages with MALP-2 activates expression of various genes including proinflammatory cytokines.
Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2.
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View SamplesDespite advance in interferon-based treatment for chronic hepatitis C, difficult-to-treat patients remain in existence yet. To identify key genes involved in difficult-to-treat characteristics, gene expression patterns of miRNA and RNA were analyzed by profiling pretreatment liver tissues from five sustained virological responders (SVR), three relapsers (R) and four non-responders (NR). Expression levels of miRNA and mRNA were compared between SVR/R and NR groups by using microarray, respectively. Quantitative real-time reverse-transcriptase polymerase chain reaction and statistical analyses validated genes with significantly differential expression levels in 50 liver tissues: proliferation-, inflammation- and anti-apoptosis-related mRNA expression levels increased significantly in NR, compared to SVR/R. Of miRNA with significantly differential expression levels on microarray, several miRNA were correlated inversely with those significant mRNA. In vitro studies by using miRNA inhibitors and mimics verified the inverse correlation between the miRNA and mRNA. These findings enhance our understanding of the difficult-to-treat molecular mechanism and identification of target molecules for novel treatments.
Involvement of MAP3K8 and miR-17-5p in poor virologic response to interferon-based combination therapy for chronic hepatitis C.
Sex, Specimen part
View SamplesInduced pluripotent stem (iPS) cells give rise to neural stem cells, which are applicable for therapeutic transplantation in treatment of neural diseases. However, generation of neural stem cells from iPS cells requires a careful selection of safe iPS clones. We sought to determine whether direct induction of neural stem cells from partially reprogrammed somatic cells is able to generate safer cells rapidly. We have successfully established direct induction system from fibroblast to neural stem cells. To characterize these directly induced neural stem cells, Gene expression profiles were compared with iPS cell or ES cell-derived neurosphere. We used affymetrix microarrays to compare the global gene expression of neurospheres prepared several method.
Neural stem cells directly differentiated from partially reprogrammed fibroblasts rapidly acquire gliogenic competency.
Specimen part
View SamplesIntermittent fasting is one of the most effective dietary restriction regimens that extend life-span in C. elegans and mammals. Fasting-stimulus responses are key to the longevity response; however, the mechanisms that sense and transduce fasting-stimulus have remained largely unknown. Through a comprehensive transcriptome analysis in C. elegans, we have found that along with the FOXO transcription factor DAF-16, AP-1 (JUN-1/FOS-1) plays a central role in fasting-induced transcriptional changes. KGB-1, one of the C. elegans JNKs, acted as an activator of AP-1, and was activated in response to fasting. KGB-1 and AP-1 were involved in intermittent fasting-induced longevity. Fasting-induced upregulation of the components of the SCF E3 ubiquitin ligase complex via AP-1 and DAF-16 enhanced protein ubiquitination, and reduced protein carbonylation. Our results have thus identified a fasting-responsive KGB-1/AP-1 signaling pathway, which, together with DAF-16, causes transcriptional changes that mediate longevity partly through regulating proteostasis.
A fasting-responsive signaling pathway that extends life span in C. elegans.
Treatment
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