• The Korean Journal of Physiology and Pharmacology
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• 제22권2호
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• pp.127-134
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• 2018

Myofibrillogenesis regulator-1 (MR-1) is a novel protein involved in cellular proliferation, migration, inflammatory reaction and signal transduction. However, little information is available on the relationship between MR-1 expression and the progression of atherosclerosis. Here we report atheroprotective effects of silencing MR-1 in a model of Ang II-accelerated atherosclerosis, characterized by suppression focal adhesion kinase (FAK) and nuclear factor kappaB ($NF-{\kappa}B$) signaling pathway, and atherosclerotic lesion macrophage content. In this model, administration of the siRNA-MR-1 substantially attenuated Ang II-accelerated atherosclerosis with stabilization of atherosclerotic plaques and inhibited FAK, Akt, mammalian target of rapamycin (mTOR) and NF-kB activation, which was associated with suppression of inflammatory factor and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in Ang II-treated vascular smooth muscle cells (VSMCs) and macrophages: siRNA-MR-1 inhibited the expression levels of proinflammatory factor. These studies uncover crucial proinflammatory mechanisms of Ang II and highlight actions of silencing MR-1 to inhibit Ang II signaling, which is atheroprotective.

• Mycobiology
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• 제38권4호
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• pp.302-309
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• 2010

Formic acid is a representative carboxylic acid that inhibits bacterial cell growth, and thus it is generally considered to constitute an obstacle to the reuse of renewable biomass. In this study, Saccharomyces cerevisiae was used to elucidate changes in protein levels in response to formic acid. Fifty-seven differentially expressed proteins in response to formic acid toxicity in S. cerevisiae were identified by 1D-PAGE and nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) analyses. Among the 28 proteins increased in expression, four were involved in the MAP kinase signal transduction pathway and one in the oxidative stress-induced pathway. A dramatic increase was observed in the number of ion transporters related to maintenance of acid-base balance. Regarding the 29 proteins decreased in expression, they were found to participate in transcription during cell division. Heat shock protein 70, glutathione reductase, and cytochrome c oxidase were measured by LC-MS/MS analysis. Taken together, the inhibitory action of formic acid on S. cerevisiae cells might disrupt the acidbase balance across the cell membrane and generate oxidative stress, leading to repressed cell division and death. S. cerevisiae also induced expression of ion transporters, which may be required to maintain the acid-base balance when yeast cells are exposed to high concentrations of formic acid in growth medium.

• BMB Reports
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• 제40권6호
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• pp.966-972
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• 2007

Pituitary tumor transforming gene (PTTG1) is widely detected in many tumors. Increasing evidence reveals that PTTG1 is associated with cell proliferation, cellular transformation and apoptosis. However, the functions of PTTG1, especially its role in DNA damage-induced apoptosis, remain largely unclear. In this report, we used UV irradiation to induce apoptosis in HeLa cells to examine the role of PTTG1 in UV-induced apoptosis by RNAi-mediated knockdown and overexpression of PTTG1. RNAi-mediated knockdown of PTTG1 expression increased and overexpression of PTTG1 decreased the UV-induced apoptosis. Furthermore, UV irradiation decreased PTTG1 mRNA and protein expression. These effects were found to be mediated by JNK pathway. Therefore, PTTG1 had an important anti-apoptotic role in UV-induced apoptosis and this role was mediated by JNK pathway. These results may provide important information for understanding the exact role and the regulation mechanism of PTTG1 in UV-induced apoptosis.

• Molecules and Cells
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• 제37권7호
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• pp.503-510
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• 2014

Lymphatic vessels provide essential roles in maintaining fluid homeostasis and lipid absorption. Dysfunctions of the lymphatic vessels lead to debilitating pathological conditions, collectively known as lymphedema. In addition, lymphatic vessels are a critical moderator for the onset and progression of diverse human diseases including metastatic cancer and obesity. Despite their clinical importance, there is no currently effective pharmacological therapy to regulate functions of lymphatic vessels. Recent efforts to manipulate the Vascular Endothelial Growth Factor-C (VEGFC) pathway, which is arguably the most important signaling pathway regulating lymphatic endothelial cells, to alleviate lymphedema yielded largely mixed results, necessitating identification of new targetable signaling pathways for therapeutic intervention for lymphedema. Zebrafish, a relatively new model system to investigate lymphatic biology, appears to be an ideal model to identify novel therapeutic targets for lymphatic biology. In this review, we will provide an overview of our current understanding of the lymphatic vessels in vertebrates, and discuss zebrafish as a promising in vivo model to study lymphatic vessels.

• Molecules and Cells
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• 제41권1호
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• pp.55-64
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• 2018

Autophagy is an intracellular degradation pathway for large protein aggregates and damaged organelles. Recent studies have indicated that autophagy targets cargoes through a selective degradation pathway called selective autophagy. Peroxisomes are dynamic organelles that are crucial for health and development. Pexophagy is selective autophagy that targets peroxisomes and is essential for the maintenance of homeostasis of peroxisomes, which is necessary in the prevention of various peroxisome-related disorders. However, the mechanisms by which pexophagy is regulated and the key players that induce and modulate pexophagy are largely unknown. In this review, we focus on our current understanding of how pexophagy is induced and regulated, and the selective adaptors involved in mediating pexophagy. Furthermore, we discuss current findings on the roles of pexophagy in physiological and pathological responses, which provide insight into the clinical relevance of pexophagy regulation. Understanding how pexophagy interacts with various biological functions will provide fundamental insights into the function of pexophagy and facilitate the development of novel therapeutics against peroxisomal dysfunction-related diseases.

• Molecular & Cellular Toxicology
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• 제5권1호
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• pp.23-31
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• 2009

To compare the effects of nanometer-sized silver ions and support materials (nano-silver coating material, NM-silver) and silver ions, we exposed zebrafish embryos to both types of nano-silver ions and compared the acute responses during embryogenesis. The amount of silver in the NM-silver (17.16%) was greater than that in the silver ion (4.56%). Both of these materials have different atomic compositions. The silver ion-exposed groups (10 and 20 ppt) showed lower survival rates than the NM-silver-exposed groups (10 and 20 ppt). NM-silver penetrated the skin and blood tube of zebrafish larvae as aggregated particles, whereas, silver ions penetrated the organelles, nucleus and yolk in a spread-out pattern. Micro-array analysis of RNA from zebrafish larvae (72 hours post-fertilization) that were treated with either NM-silver or silver ions, showed alteration in expression of the BMP, activin, TGF-$\beta$, and $GSK3{\beta}$ genes pathway. Additionally, $GSK3{\beta}$ gene pathway for apoptosis that was related with left-right asymmetry. Gene expression changes in the NM-silver or silver ions-treated zebrafish embryo led to phenotypic changes in the hatched larvae, reflecting increased apoptosis and incomplete formation of an axis.

• Molecular & Cellular Toxicology
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• 제5권1호
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• pp.1-6
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• 2009

Microglial cells constitute the first line of defense against infection and injury in the brain. This study was conducted to evaluate the protective mechanisms of Agrimonia pilosa (AP) on LPS-induced activation of BV-2 microglial cells. The effects of AP on gene expression profiles in activated BV-2 microglial cells were evaluated using microarray analysis. BV-2 microglial cells were cultured in a 100 mm dish ($1{\times}10^7/mL$) for 24 hr and then pretreated with 1 g/mL AP or left untreated for 30 min. Next, 1 g/mL LPS was added to the samples and the cells were reincubated at $37^{\circ}C$ for 30 min, 3 hr and 6 hr. The gene expression profiles of the BV-2 microglial cells varied depending on the AP. The microarray analysis revealed that MAPK signaling pathway-related genes were down-regulated and IL10 gene was up-regulated in AP-treated BV-2 microglial cells. AP can affect the inflammatory response and MAPK pathway in BV-2 microglial cells.

• IMMUNE NETWORK
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• 제8권3호
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• pp.75-81
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• 2008

Background: Platelets take part in repairing the lesions of endothelial damage. To understand the molecular mechanism of this process, we tested the hypothesis that CD154 expressed on activated platelets stimulates proliferation of human endothelial cells. Methods: The expression levels of CD154 and CD40 on platelets and endothelial cells, respectively, were measured by flow cytometry and confocal microscopy. Function-blocking monoclonal antibody against CD154 was developed after immunization with CD154-transfected L cells. Results: An anti-CD40 agonist antibody and soluble CD154 both induced significant proliferation of endothelial cells. In addition, a function-blocking anti-CD154 antibody inhibited the platelet-induced proliferation of endothelial cells, indicating that the CD154-CD40 pathway is involved in these cellular interactions. An anti-VEGF antibody failed to inhibit the proliferation. This, in addition to the fact that very small amounts of VEGF are released from platelets or endothelial cells, suggests that VEGF does not play an important role in the platelet-stimulated proliferation of endothelial cells. Conclusion: Our results indicate that platelets induce proliferation of endothelial cells by CD154-CD40 interactions independently of VEGF.

• Biomolecules & Therapeutics
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• 제19권1호
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• pp.21-26
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• 2011

Ceramide is an important lipid mediator of extracellular signals that control various cellular functions, including apoptosis. In this study, we showed that ceramide induced apoptosis in U373MG human glioblastoma cells associated with G1 cell cycle arrest. Treatment of cells with ceramide increased proapoptotic Bax expression and inhibited the expression of antiapoptotic Bcl-2 and Bcl-xL Ceramide also downregulated cyclin E, cyclin D1, cdk 2, and cdk4 which are involved in regulating cell cycle. In addition, ceramide suppressed phosphorylation of Akt, Bad, p70 S6 kinase, and 4E-BP1, suggesting the involvement of Akt/mTOR signaling pathway. Additionally, okadaic acid, an inhibitor of protein phosphatase 2A, partially blocked the ceramide mediated inhibition of phosphorylation of Akt and 4E-BP1. These results suggest that ceramide induces apoptosis in U373MG glioblastoma cells by regulating multiple signaling pathways that involve cell cycle arrest associated with Akt signaling pathway.

• Molecules and Cells
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• 제28권1호
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• pp.49-55
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• 2009

Hepatitis delta virus (HDV) infection causes fulminant hepatitis and liver cirrhosis. To elucidate the molecular mechanism of HDV pathogenesis, we examined the effects of HDV viral proteins, the small hepatitis delta antigen (SHDAg) and the large hepatitis delta antigen (LHDAg), on $NF-{\kappa}B$ signaling pathway. In this study, we demonstrated that $TNF-{\alpha}-induced$ $NF-{\kappa}B$ transcriptional activation was increased by LHDAg but not by SHDAg in both HEK293 and Huh7 cells. Furthermore, LHDAg promoted TRAF2-induced $NF-{\kappa}B$ activation. Using coimmunoprecipitation assays, we demonstrated that both SHDAg and LHDAg interacted with TRAF2 protein. We showed that isoprenylation of LHDAg was not required for the increase of $NF-{\kappa}B$ activity. We further showed that only LHDAg but not SHDAg increased the $TNF-{\alpha}-mediated$ nuclear translocation of p65. This was accomplished by activation of $I{\kappa}B_{\alpha}$ degradation by LHDAg. Finally, we demonstrated that LHDAg augmented the COX-2 expression level in Huh7 cells. These data suggest that LHDAg modulates $NF-{\kappa}B$ signaling pathway and may contribute to HDV pathogenesis.