Showing papers by "Nancy Y. Ip published in 2009"

Induction of Proinflammatory Cytokines in Primary Human Macrophages by Influenza A Virus (H5N1) Is Selectively Regulated by IFN Regulatory Factor 3 and p38 MAPK

Abstract: The hyperinduction of proinflammatory cytokines and chemokines such as TNF-alpha, IFN-beta, and CCL2/MCP-1 in primary human macrophages and respiratory epithelial cells by the highly pathogenic avian influenza H5N1 is believed to contribute to the unusual severity of human H5N1 disease. Here we show that TNF-alpha, IFN-beta, and IFN-lambda1 are the key mediators directly induced by the H5N1 virus in primary human macrophages. In comparison with human influenza (H1N1), the H5N1 virus more strongly activated IFN regulatory factor 3 (IRF3). IRF3 knockdown and p38 kinase inhibition separately and in combination led to a substantial reduction of IFN-beta, IFN-lambda1, and MCP-1 but only to a partial reduction of TNF-alpha. IRF3 translocation was independent of p38 kinase activity, indicating that IRF3 and p38 kinase are distinct pathways leading to cytokine production by H5N1 virus. We conclude that IRF3 and p38 kinase separately and predominantly contribute to H5N1-mediated induction of IFN-beta, IFN-lambda1, and MCP-1 but only partly control TNF-alpha induction. A more precise identification of the differences in the regulation of TNF-alpha and IFN-beta could provide novel targets for the design of therapeutic strategies for severe human H5N1 influenza and also for treating other causes of acute respiratory distress syndrome.

Systems-level comparison of host-responses elicited by avian H5N1 and seasonal H1N1 influenza viruses in primary human macrophages.

Abstract: Human disease caused by highly pathogenic avian influenza (HPAI) H5N1 can lead to a rapidly progressive viral pneumonia leading to acute respiratory distress syndrome. There is increasing evidence from clinical, animal models and in vitro data, which suggests a role for virus-induced cytokine dysregulation in contributing to the pathogenesis of human H5N1 disease. The key target cells for the virus in the lung are the alveolar epithelium and alveolar macrophages, and we have shown that, compared to seasonal human influenza viruses, equivalent infecting doses of H5N1 viruses markedly up-regulate proinflammatory cytokines in both primary cell types in vitro. Whether this H5N1-induced dysregulation of host responses is driven by qualitative (i.e activation of unique host pathways in response to H5N1) or quantitative differences between seasonal influenza viruses is unclear. Here we used microarrays to analyze and compare the gene expression profiles in primary human macrophages at 1, 3, and 6 h after infection with H5N1 virus or low-pathogenic seasonal influenza A (H1N1) virus. We found that host responses to both viruses are qualitatively similar with the activation of nearly identical biological processes and pathways. However, in comparison to seasonal H1N1 virus, H5N1 infection elicits a quantitatively stronger host inflammatory response including type I interferon (IFN) and tumor necrosis factor (TNF)-a genes. A network-based analysis suggests that the synergy between IFN-b and TNF-a results in an enhanced and sustained IFN and proinflammatory cytokine response at the early stage of viral infection that may contribute to the viral pathogenesis and this is of relevance to the design of novel therapeutic strategies for H5N1 induced respiratory disease.

The emerging role of autophagy in Parkinson's disease

Abstract: Parkinson's disease (PD) is the most common neurodegenerative movement disorder that affects about 1% of the population worldwide. Despite significant advances in the identification of genetic mutations and signaling pathways that are associated with the disease, the precise mechanisms implicated in the pathophysiology of the disease are not well understood. More importantly, treatments that are effective in reversing the progression of the disease is essentially lacking. Further investigation into the pathogenic mechanisms of PD thus presents a pressing concern for neuroscientists. Recently, deregulation of the autophagic pathway is observed in the brains of PD patients and in models of PD. In this review we summarize current literature on the emerging involvement of autophagy in PD, and the implication for future development of treatment against the disorder.

Identification of retinoic acid-regulated nuclear matrix-associated protein as a novel regulator of gastric cancer

Abstract: BACKGROUND: Retinoic acid-regulated nuclear matrix-associated protein (RAMP) is a WD40 repeat-containing protein that is involved in various biological functions, but little is known about its role in human cancer. This study aims to delineate the oncogenic role of RAMP in gastric carcinogenesis. METHODS: RAMP expression was examined by real-time quantitative RT-PCR, immunohistochemistry and western blotting. Inhibition of RAMP expression was performed by siRNA-mediated knockdown. The functional effects of RAMP on cell kinetics were measured by cell viability assay, colony formation assay and flow cytometry. Cell lines stably expressing RAMP were established to investigate the oncogenic effects of RAMP in vitro. RESULTS: Ramp was readily expressed in all seven gastric cancer cell lines and was significantly increased in human gastric cancer tissues when compared with their adjacent non-cancerous tissues (Po0.001). In keeping with this, expression of RAMP protein was higher in gastric cancer tissues compared with their adjacent non-cancerous tissues, whereas moderate protein expression were noted in intestinal metaplasia. Knockdown of RAMP in gastric cancer cells significantly reduced cell proliferation (Po0.01) and soft agar colony formation (Po0.001), but induced apoptosis and G2/M arrest. In additional, knockdown RAMP induced cell apoptosis is dependent on functional accumulation of p53 and p21 and induction of cleaved caspases-9, caspases-3 and PARP. Strikingly, overexpression of RAMP promoted anchorage-independent cell growth in soft agar. CONCLUSION: Our findings demonstrate that RAMP plays an oncogenic role in gastric carcinogenesis. Inhibition of RAMP may be a promising approach for gastric cancer therapy.

Differential and Synergistic Effect of Nerve Growth Factor and cAMP on the Regulation of Early Response Genes during Neuronal Differentiation

Abstract: Neurotrophin (NT)-driven differentiation is a process involving activation of multiple signalling events. Treatment of PC12 cells with the prototypic NT nerve growth factor (NGF) induces PC12 cell differentiation characterized by neurite outgrowth and expression of differentiation genes. Cyclic AMP (cAMP), one of the second messengers of NGF stimulation, has also been observed to induce neuronal differentiation in PC12 cells. Interestingly, co-treatment of NGF and dibutyryl cAMP (DBcAMP) exhibits a synergistic effect on neurite outgrowth in PC12 cells, but the mechanisms underlying this synergism remain unknown. In the current study, we compared the gene expression profiles of PC12 cells treated with NGF, DBcAMP or both for 12 h to identify differentially regulated genes during the early stage of differentiation. We found that the genes that were differentially regulated by NGF, DBcAMP or both include genes for acquiring neuronal phenotypes, cytoskeleton-binding proteins and cell cycle proteins. Importantly, we identified a subset of genes that was specifically regulated during co-treatment of NGF and cAMP, suggesting that the synergistic effect of NGF and DBcAMP on neurite outgrowth is possibly mediated through transcription regulation. Our observations provide novel insights on the signalling mechanisms underlying the regulation of neuronal differentiation by NGF and cAMP.

Endophilin B1. Guarding the gate to destruction

Abstract: Endophilin B1 is a member of the endophilin family that is localized predominantly to intracellular membranes. Also known as Bax-interacting factor-1 (Bif-1), this protein has been observed to regulate the membrane dynamics of various intracellular compartments, such as the control of mitochondrial morphology and autophagosome formation in fibroblast. Endophilin B1 is expressed in the brain, but its functions in neurons had remained unknown. Recently, we have observed a novel role of endophilin B1 in neurons where it controls the trafficking of TrkA, cognate receptor for the prototypic neurotrophin nerve growth factor (NGF). Knock-down of endophilin B1 expression induces precocious targeting of NGF/TrkA to late endosomes and lysosomes, thereby leading to reduced TrkA levels. This is accompanied by marked attenuation of NGF-induced gene transcription and neurite outgrowth. Our observations suggest that endophilin B1 regulates TrkA level and downstream functions by controlling the movement of TrkA to late endosomes/lysosomes, possibly acting at the level of early endosomes.

Multiple Gi proteins participate in nerve growth factor-induced activation of c-Jun N-terminal kinases in PC12 cells.

Abstract: Nerve growth factor (NGF)-mediated activation of mitogen-activated protein kinases (MAPK) is critical for differentiation and apoptosis of PC12 cells. Since NGF employs stress-activated c-Jun N-terminal kinase (JNK) to regulate both programmed cell death and neurite outgrowth of PC12 cells, we examined NGF-regulated JNK activity and the role of Gi/o proteins. Induction of JNK phosphorylation by NGF occurred in a time- and dose-dependent manner and was partially inhibited by pertussis toxin (PTX). To discern the participation of various signaling intermediates, PC12 cells were treated with specific inhibitors prior to NGF challenge. NGF-elevated JNK activity was abolished by inhibitors of JNK, p38 MAPK, Src, JAK3 and MEK1/2. NGF-dependent JNK phosphorylation became insensitive to PTX treatment upon transient expressions of Gαz or the PTX-resistant mutants of Gαi1–3 and GαoA. Collectively, these studies indicate that NGF-dependent JNK activity may be mediated via Gi1–3 proteins, JAK3, Src, p38 MAPK and the MEK/ERK cascade.

Oxazolidine derivatives as nmda antagonists

Abstract: The present invention provides therapeutically active oxazolidine derivatives and compositions as NMDA antagonists, which are useful in preventing and treating central nervous system disorders by inhibiting over-activation of NMDA receptors. In one aspect, the present invention provides methods of treating and/or preventing neurodegenerative diseases and neuropathological disorders, methods of providing neuroprotection under stress conditions such as a stroke, and methods of enhancing the brain's cognitive functions in mammals and humans. For example, the compounds can prevent glutamate-induced neuro-toxicity by inhibiting the activities of the NMDA receptor in the presence of toxic doses of NMDA. In addition, the compounds can potentiate the calcium current in the presence of low dose of NMDA.

Triterpenoid compounds and methods of use thereof

Abstract: The present invention provides therapeutically active compounds and compositions as receptor antagonists and methods of use thereof. In one aspect, the compounds are useful in modulating pain, inflammation and acute phase reactions by inhibiting the PGE2 receptors including PGE2 EP1, EP2 and EP4 receptors.