Neuropsychiatric Events Associated with Leukotriene-Modifying Agents: A Systematic Review

Introduction: Leukotriene-modifying agents (LTMAs) including montelukast, zafirlukast, and zileuton are approved by the US Food and Drug Administration (FDA) for the treatment of asthma and allergic rhinitis. Various neuropsychiatric events (NEs) have been reported; however, the evidence of the association is conflicting. This systematic review investigates the association between NEs and LTMAs by assessing the relevant published literature. / Methods: PubMed, EMBASE, MEDLINE, and Cochrane Library were searched using keywords. Studies designed to investigate the association were eligible for inclusion without restriction to any study design or language. The primary outcome was defined as suicidal conditions, while secondary outcomes included all other NEs. / Results: Thirty-three studies were included for a narrative review. Four observational studies did not find a significant association, while ten pharmacovigilance studies using different global databases detected the signals. Notably, some studies suggest that the FDA warning issued in 2008 might have influenced the reporting rate of NEs as a result of increased awareness. / Limitations: The risk of NEs was not quantified, because of the lack of randomized controlled trials and observational studies investigating the association. / Conclusion: Many pharmacovigilance studies have been conducted to determine the association between NEs and LTMAs, but there is limited evidence from observational studies. High-quality epidemiological studies should be conducted to evaluate the association and quantify the risk, not only in children, but also in adults

Stanniocalcin-1 Regulates Re-Epithelialization in Human Keratinocytes

Stanniocalcin-1 (STC1), a glycoprotein hormone, is believed to be involved in various biological processes such as inflammation, oxidative responses and cell migration. Riding on these emerging evidences, we hypothesized that STC1 may participate in the re-epithelialization during wound healing. Re-epithelialization is a critical step that involves keratinocyte lamellipodia (e-lam) formation, followed by cell migration. In this study, staurosporine (STS) treatment induced human keratinocyte (HaCaT) e-lam formation on fibronectin matrix and migration via the activation of focal adhesion kinase (FAK), the surge of intracellular calcium level [Ca2+]i and the inactivation of Akt. In accompanied with these migratory features, a time- and dose-dependent increase in STC1 expression was detected. STC1 gene expression was found not the downstream target of FAK-signaling as illustrated by FAK inhibition using PF573228. The reduction of [Ca2+]i by BAPTA/AM blocked the STS-mediated keratinocyte migration and STC1 gene expression. Alternatively the increase of [Ca2+]i by ionomycin exerted promotional effect on STS-induced STC1 gene expression. The inhibition of Akt by SH6 and GSK3β by lithium chloride (LiCl) could respectively induce and inhibit the STS-mediated e-lam formation, cell migration and STC1 gene expression. The STS-mediated e-lam formation and cell migration were notably hindered or induced respectively by STC1 knockdown or overexpression. This notion was further supported by the scratched wound assay. Collectively the findings provide the first evidence that STC1 promotes re-epithelialization in wound healing

Systemic virus distribution and host responses in brain and intestine of chickens infected with low pathogenic or high pathogenic avian influenza virus

<p>Abstract</p> <p>Background</p> <p>Avian influenza virus (AIV) is classified into two pathotypes, low pathogenic (LP) and high pathogenic (HP), based on virulence in chickens.</p> <p>Differences in pathogenicity between HPAIV and LPAIV might eventually be related to specific characteristics of strains, tissue tropism and host responses.</p> <p>Methods</p> <p>To study differences in disease development between HPAIV and LPAIV, we examined the first appearance and eventual load of viral RNA in multiple organs as well as host responses in brain and intestine of chickens infected with two closely related H7N1 HPAIV or LPAIV strains.</p> <p>Results</p> <p>Both H7N1 HPAIV and LPAIV spread systemically in chickens after a combined intranasal/intratracheal inoculation. In brain, large differences in viral RNA load and host gene expression were found between H7N1 HPAIV and LPAIV infected chickens. Chicken embryo brain cell culture studies revealed that both HPAIV and LPAIV could infect cultivated embryonic brain cells, but in accordance with the absence of the necessary proteases, replication of LPAIV was limited. Furthermore, TUNEL assay indicated apoptosis in brain of HPAIV infected chickens only. In intestine, where endoproteases that cleave HA of LPAIV are available, we found minimal differences in the amount of viral RNA and a large overlap in the transcriptional responses between HPAIV and LPAIV infected chickens. Interestingly, brain and ileum differed clearly in the cellular pathways that were regulated upon an AI infection.</p> <p>Conclusions</p> <p>Although both H7N1 HPAIV and LPAIV RNA was detected in a broad range of tissues beyond the respiratory and gastrointestinal tract, our observations indicate that differences in pathogenicity and mortality between HPAIV and LPAIV could originate from differences in virus replication and the resulting host responses in vital organs like the brain.</p

Identification and characterization of the hypoxia-responsive element in human stanniocalcin-1 gene

In this study, we aimed to identify the hypoxia-inducible factor-1 (HIF-1) binding motif in human STC1 gene promoter and to characterize the associated gene transactivation mechanism. Using normoxic human nasopharyngeal cancer cells (CNE2), we manipulated the stability of HIF-1α protein by overexpressing HIF-1α or the silencing of prolyl hydroxylase-2 (PHD2), to illustrate HIF-1 activation of STC1 promoter-driven luciferase activity. Subsequently luciferase activities of the deletion and mutated STC1 promoter constructs were investigated in HIF-1 overexpressed cells. The data revealed the presence of an authentic HRE motif in STC1 gene. This result was further supported by the chromatin immunoprecipitation (ChIP) assay. Using a similar experimental treatment, however, had no significant effect on the expression level of STC1 mRNA and protein. Moreover the activation of STC1 expression can be restored by the silencing of "factor inhibiting HIF-1" (FIH-1) in either HIF-1 overexpressed or PHD2 silenced cells. The data implied that the HIF-1-mediated STC1 gene expression required the recruitment of p300. This presumption was confirmed by the use of p300 inhibitor, chetomin and HIF-1α/p300 re-ChIP assay. Collectively our data provide the first evidence to show that STC1 is a FIH-inhibited gene with a functional HRE motif located at the upstream region between -2322/-2335. The data support the need for further investigation to reveal if STC1 can be used as a novel tumor marker for HIF-1 induction and for the monitoring of anti-angiogenic therapy. © 2009 Elsevier Ireland Ltd. All rights reserved.link_to_subscribed_fulltex

Histone deacetylase inhibitor-induced cellular apoptosis involves stanniocalcin-1 activation

Our previous studies have demonstrated the involvement of HIF-1 and p53 in the regulation of stanniocalcin-1 (STC1) gene transcription in human cancer cells. In this study, we reported that the treatment of human colon adenoma HT29 cells with a histone deacetylase (HDAC) inhibitor (i.e. trichostatin A, TSA) induced both cellular apoptosis and STC1 expression. The activation of STC1 expression was also observed in other TSA-treated human cancer cells (i.e. SKOV3, CaCo-2, Jurkat and CNE-2 cells). STC1 mRNA was rapidly induced within 4 h in TSA-treated HT29 cells, and was found to be transcriptionally regulated and was independent of new protein synthesis as revealed by ActD and CHX treatment respectively. The induction was correlated with increased cellular levels of acetyl histone H3 and H4 and acetyl NFκB. Chromatin immunoprecipitation (ChIP) assay showed the increased binding of acetyl histone H3 and H4 to STC1 promoter in the TSA-treated cells. A cotreatment of HT29 cells with a NFκB inhibitor (parthenolide) significantly inhibited the TSA-induced cellular levels of acetyl NFκB p65 and abolished the stimulation of STC1 gene expression. ChIP assay also demonstrated that TSA treatment increased while TSA/parthenolide cotreatment decreased NFκB p65 binding to STC1 gene promoter. In the STC1-luciferase promoter construct (1 kb) study, the data implied that the promoter can be activated by TSA treatment. Interestingly, the promoter region contains 2 putative NFκB binding sites. Consistent with the STC1mRNA expression data, TSA/parthenolide cotreatment also significantly inhibited the TSA-induced STC1 promoter-driven luciferase activity. Importantly, TSA-induced apoptotic process was found to be significantly reduced by the silencing of STC1 expression. This is the first study to show that histone hyper-acetylation and the recruitment of activated NFκB stimulated STC1 gene expression. In addition, our results support the notion that STC1 is a pro-apoptotic factor. © 2008 Elsevier Inc. All rights reserved.link_to_subscribed_fulltex

Induction of stanniocalcin-1 expression in apoptotic human nasopharyngeal cancer cells by p53

There is growing evidence to suggest that altered patterns of STC1 gene expression relate to the process of human cancer development. Our previous study has demonstrated the involvement of HIF-1 in the regulation of STC1 expression in human cancer cells. Recently, STC1 has been implicated as a putative pro-apoptotic factor in regulating the cell-death mechanism. Thus it would be of interest to know if STC1 is regulated by a tumor suppressor protein, p53. In this study, we provide evidence to demonstrate that the induction of STC1 expression in apoptotic human nasopharyngeal cancer cells (CNE2) is mediated by the activation of p53. Our study indicated that the activation of STC1 and heat-shock protein (hsp70) accompanied iodoacetamide (IDAM)-induced apoptosis in CNE-2. In addition, cellular events such as GSH depletion, mitochondrial membrane depolarization, reduction of pAkt and procaspase-3, and the induction of total p53 protein, acetylated p53, and annexin V positive cells were observed. The activation of STC1 was found to be at the transcriptional level and was independent of prior protein synthesis. Co-treatment of IDAM exposed cells with N-acetyl cysteine (NAC) prevented cell death by restoring mitochondrial membrane potential and cellular levels of GSH. NAC co-treatment also suppressed STC1 expression but had no effect on IDAM-induced hsp70 expression. RNA interference studies demonstrated that endogenous p53 was involved in activating STC1 gene expression. Collectively, the present findings provide the first evidence of p53 regulation of STC1 expression in human cancer cells. © 2007 Elsevier Inc. All rights reserved.link_to_subscribed_fulltex

Epigenetic and HIF-1 regulation of stanniocalcin-2 expression in human cancer cells

Mammalian stanniocalcin-2 (STC2) is a secreted glycoprotein hormone with a putative role in unfolded protein response and apoptosis. Here we reported that STC2 expression was sporadically abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. Direct sequencing of bisulfite-modified DNA from a panel of seven human cancer cell lines revealed that CpG dinucleotides in STC2 promoter was methylated in human ovarian epithelial cancer (SKOV3, OVCAR3 and CaOV3), pancreatic cancer (BxP3), colon adenoma (HT29), and leukemia (Jurkat cells). STC2 CpG island hypermethylation was accompanied with a low basal STC2 expression level. Treatment of these cancer cells with 5-aza-2′-deoxycytidine (5-aza-CdR), an inhibitor of DNA methylation significantly induced STC2 expression. Using SKOV3 cells as a model, the link between DNA demethylation and STC2 expression was consistently demonstrated with hydralazine treatment, which was shown to reduce the protein level of DNA methyltransferase 1 (DNMT1) but stimulated STC2 expression. Two human normal surface ovarian cell-lines (i.e. IOSE 29 and 398) showed no methylation at CpG dinucleotides in the examined promoter region and were accompanied with high basal STC2 levels. Hypoxia stimulated STC2 expression in SKOV3 cells was markedly increased in 5-aza-CdR pretreated cells, showing that DNA methylation may hinder the HIF-1 mediated activation. To elucidate this possibility, RNA interference studies confirmed that endogenous HIF-1α was a key factor for STC2 gene activation as well as in the synergistic induction of STC2 expression in 5-aza-CdR pretreated cells. Chromatin immunoprecipitation (ChIP) assay demonstrated the binding of HIF-1α to STC2 promoter. The binding was increased in 5-aza-CdR pretreated cells. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression. © 2008 Elsevier Inc. All rights reserved.link_to_subscribed_fulltex

Data for transcriptomic and iTRAQ proteomic analysis of Anguilla japonica gills in response to osmotic stress

This article contains data related to the two research articles titled Transcriptomic and iTRAQ proteomic approaches reveal novel short-term hyperosmotic stress responsive proteins in the gill of the Japanese eel (Anguilla japonica) and iTRAQ-based quantitative proteomic analysis reveals acute hypo-osmotic responsive proteins in the gills of the Japanese eel (Anguilla japonica). The two research articles show the usefulness of combining transcriptomic and proteomic approaches to provide molecular insights of osmoregulation mechanism in a non-model organism, the Japanese eel. The information presented here combines the raw data from the two studies and provides an overview on the physiological functions of fish gills