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author:("Lin, chifeng")
1.  Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis 
There is compelling evidence that oligodendrocyte apoptosis, in response to CNS inflammation, contributes significantly to the development of the demyelinating disorder multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Therefore, approaches designed to protect oligodendrocytes would likely have therapeutic value. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum (ER) stress increases cell survival under various cytotoxic conditions. Moreover, there is evidence that PERK signaling is activated in oligodendrocytes within demyelinating lesions in MS and EAE. Our previous study demonstrated that CNS delivery of the inflammatory cytokine interferon-γ before EAE onset protected mice against EAE, and this protection was dependent on PERK signaling. In our current study, we sought to elucidate the role of PERK signaling in oligodendrocytes during EAE. We generated transgenic mice that allow for temporally-controlled activation of PERK signaling, in the absence of ER stress, specifically in oligodendrocytes. We demonstrated that persistent activation of PERK signaling was not deleterious to oligodendrocyte viability or the myelin of adult animals. Importantly, we found that enhanced activation of PERK signaling specifically in oligodendrocytes significantly attenuated EAE disease severity, which was associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration. This effect was not the result of an altered degree of the inflammatory response in EAE mice. Our results provide direct evidence that activation of PERK signaling in oligodendrocytes is cytoprotective, protecting mice against EAE.
doi:10.1523/JNEUROSCI.1636-12.2013
PMCID: PMC3654380  PMID: 23554479
2.  Overcoming Trastuzumab Resistance in Breast Cancer by Targeting Dysregulated Glucose Metabolism 
Cancer research  2011;71(13):4585-4597.
Trastuzumab shows remarkable efficacy in treatment of ErbB2-positive breast cancers when used alone or in combination with other chemotherapeutics. However, acquired resistance develops in most treated patients, necessitating alternate treatment strategies. Increased aerobic glycolysis is a hallmark of cancer and inhibition of glycolysis may offer a promising strategy to preferentially kill cancer cells. In this study, we investigated the antitumor effects of trastuzumab in combination with glycolysis inhibitors in ErbB2-positive breast cancer. We found that trastuzumab inhibits glycolysis via downregulation of heat shock factor 1 (HSF1) and lactate dehydrogenase A (LDH-A) in ErbB2-positive cancer cells, resulting in tumor growth inhibition. Moreover, increased glycolysis via HSF1 and LDH-A contributes to trastuzumab resistance. Importantly, we found that combining trastuzumab with glycolysis inhibition synergistically inhibited trastuzumab-sensitive and -resistant breast cancers in vitro and in vivo, due to more efficient inhibition of glycolysis. Taken together, our findings show how glycolysis inhibition can dramatically enhance the therapeutic efficacy of trastuzumab in ErbB2-positive breast cancers, potentially useful as a strategy to overcome trastuzumab resistance.
doi:10.1158/0008-5472.CAN-11-0127
PMCID: PMC3129363  PMID: 21498634
Warburg effect; glycolysis; HSF1; LDH-A; trastuzumab; ErbB2; resistance
3.  Interferon-γ Activates Nuclear Factor-κ B in Oligodendrocytes through a Process Mediated by the Unfolded Protein Response 
PLoS ONE  2012;7(5):e36408.
Our previous studies have demonstrated that the effects of the immune cytokine interferon-γ (IFN-γ) in immune-mediated demyelinating diseases are mediated, at least in part, by the unfolded protein response (UPR) in oligodendrocytes. Data indicate that some biological effects of IFN-γ are elicited through activation of the transcription factor nuclear factor-κB (NF-κB). Interestingly, it has been shown that activation of the pancreatic endoplasmic reticulum kinase (PERK) branch of the UPR triggers NF-κB activation. In this study, we showed that IFN-γ-induced NF-κB activation was associated with activation of PERK signaling in the oligodendroglial cell line Oli-neu. We further demonstrated that blockage of PERK signaling diminished IFN-γ-induced NF-κB activation in Oli-neu cells. Importantly, we showed that NF-κB activation in oligodendrocytes correlated with activation of PERK signaling in transgenic mice that ectopically express IFN-γ in the central nervous system (CNS), and that enhancing IFN-γ-induced activation of PERK signaling further increased NF-κB activation in oligodendrocytes. Additionally, we showed that suppression of the NF-κB pathway rendered Oli-neu cells susceptible to the cytotoxicity of IFN-γ, reactive oxygen species, and reactive nitrogen species. Our results indicate that the UPR is involved in IFN-γ-induced NF-κB activation in oligodendrocytes and suggest that NF-κB activation by IFN-γ represents one mechanism by which IFN-γ exerts its effects on oligodendrocytes in immune-mediated demyelinating diseases.
doi:10.1371/journal.pone.0036408
PMCID: PMC3344863  PMID: 22574154
4.  IFN-γ inhibits central nervous system myelination through both STAT1-dependent and STAT1-independent pathways 
Journal of neuroscience research  2010;88(12):2569-2577.
Immune cytokine interferon-γ (IFN-γ) plays a crucial role in immune-mediated demyelination diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Our previous studies have shown that enforced expression of IFN-γ in the central nervous system (CNS) inhibits developmental myelination or remyelination in EAE demyelinated lesions. While many of the cellular actions of IFN-γ result from its activation of the signal transducer and activator of transcription 1 (STAT1) pathway, recent studies have shown that STAT1-independent pathways regulate some facets of IFN-γ biology. In this study, we dissected the role of STAT1-dependent and STAT1-independent pathways in IFN-γ-induced hypomyelination using a genetic approach. We found that the induction of the STAT1-dependent, IFN-γ responsive genes in response to this cytokine was abolished in the CNS of STAT1 null mice. Moreover, STAT1 deletion diminished oligodendrocyte loss, the reduction of myelinated axons and inflammatory response in the CNS of transgenic mice that ectopically express IFN-γ in the CNS. Nevertheless, IFN-γ-induced reduction of myelin sheath thickness in the CNS of these mice was not altered by STAT1 deletion. Collectively, these data demonstrated that both STAT1-dependent and STAT1-independent pathways are involved in the detrimental effects of IFN-γ on the myelination process.
doi:10.1002/jnr.22425
PMCID: PMC2911948  PMID: 20648647
oligodendrocyte; myelin; multiple sclerosis; cytokine; signal transduction
5.  The Protective Role of Nrf2 in Streptozotocin-Induced Diabetic Nephropathy 
Diabetes  2010;59(4):850-860.
OBJECTIVE
Diabetic nephropathy is one of the major causes of renal failure, which is accompanied by the production of reactive oxygen species (ROS). Nrf2 is the primary transcription factor that controls the antioxidant response essential for maintaining cellular redox homeostasis. Here, we report our findings demonstrating a protective role of Nrf2 against diabetic nephropathy.
RESEARCH DESIGN AND METHODS
We explore the protective role of Nrf2 against diabetic nephropathy using human kidney biopsy tissues from diabetic nephropathy patients, a streptozotocin-induced diabetic nephropathy model in Nrf2−/− mice, and cultured human mesangial cells.
RESULTS
The glomeruli of human diabetic nephropathy patients were under oxidative stress and had elevated Nrf2 levels. In the animal study, Nrf2 was demonstrated to be crucial in ameliorating streptozotocin-induced renal damage. This is evident by Nrf2−/− mice having higher ROS production and suffering from greater oxidative DNA damage and renal injury compared with Nrf2+/+ mice. Mechanistic studies in both in vivo and in vitro systems showed that the Nrf2-mediated protection against diabetic nephropathy is, at least, partially through inhibition of transforming growth factor-β1 (TGF-β1) and reduction of extracellular matrix production. In human renal mesangial cells, high glucose induced ROS production and activated expression of Nrf2 and its downstream genes. Furthermore, activation or overexpression of Nrf2 inhibited the promoter activity of TGF-β1 in a dose-dependent manner, whereas knockdown of Nrf2 by siRNA enhanced TGF-β1 transcription and fibronectin production.
CONCLUSIONS
This work clearly indicates a protective role of Nrf2 in diabetic nephropathy, suggesting that dietary or therapeutic activation of Nrf2 could be used as a strategy to prevent or slow down the progression of diabetic nephropathy.
doi:10.2337/db09-1342
PMCID: PMC2844833  PMID: 20103708
6.  Tissue factor pathway inhibitor-2 was repressed by CpG hypermethylation through inhibition of KLF6 binding in highly invasive breast cancer cells 
BMC Molecular Biology  2007;8:110.
Background
Tissue factor pathway inhibitor-2 (TFPI-2) is a matrix-associated Kunitz inhibitor that inhibits plasmin and trypsin-mediated activation of zymogen matrix metalloproteinases involved in tumor progression, invasion and metastasis. Here, we have investigated the mechanism of DNA methylation on the repression of TFPI-2 in breast cancer cell lines.
Results
We found that both protein and mRNA of TFPI-2 could not be detected in highly invasive breast cancer cell line MDA-MB-435. To further investigate the mechanism of TFPI-2 repression in breast cancer cells, 1.5 Kb TFPI-2 promoter was cloned, and several genetic variations were detected, but the promoter luciferase activities were not affected by the point mutation in the promoter region and the phenomena was further supported by deleted mutation. Scan mutation and informatics analysis identified a potential KLF6 binding site in TFPI-2 promoter. It was revealed, by bisulfite modified sequence, that the CpG island in TFPI-2 promoter region was hypermethylated in MDA-MB-435. Finally, using EMSA and ChIP assay, we demonstrated that the CpG methylation in the binding site of KLF-6 diminished the binding of KLF6 to TFPI-2 promoter.
Conclusion
In this study, we found that the CpG islands in TFPI-2 promoter was hypermethylated in highly invasive breast cancer cell line, and DNA methylation in the entire promoter region caused TFPI-2 repression by inducing inactive chromatin structure and decreasing KLF6 binding to its DNA binding sequence.
doi:10.1186/1471-2199-8-110
PMCID: PMC2233638  PMID: 18053161

Results 1-6 (6)