• BMB Reports
• /
• v.53 no.4
• /
• pp.218-222
• /
• 2020

Excessive and hyperactive osteoclast activity causes bone diseases such as osteoporosis and periodontitis. Thus, the regulation of osteoclast differentiation has clinical implications. We recently reported that dehydrocostus lactone (DL) inhibits osteoclast differentiation by regulating a nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), but the underlying mechanism remains to be elucidated. Here we demonstrated that DL inhibits NFATc1 by regulating nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and nuclear factor-erythroid 2-related factor 2 (Nrf2). DL attenuated IκBα phosphorylation and p65 nuclear translocation as well as decreased the expression of NF-κB target genes and c-Fos. It also inhibited c-Jun N-terminal kinase (JNK) but not p38 or extracellular signal-regulated kinase. The reporter assay revealed that DL inhibits NF-κB and AP-1 activation. In addition, DL reduced reactive oxygen species either by scavenging them or by activating Nrf2. The DL inhibition of NFATc1 expression and osteoclast differentiation was less effective in Nrf2-deficient cells. Collectively, these results suggest that DL regulates NFATc1 by inhibiting NF-κB and AP-1 via down-regulation of IκB kinase and JNK as well as by activating Nrf2, and thereby attenuates osteoclast differentiation.

• Proceedings of the Korean Society of Toxicology Conference
• /
• 2002.05a
• /
• pp.78-78
• /
• 2002

Microsomal epoxide hydrolase (mEH), an epoxide detoxifying enzyme and putative cell surface autoantigen, is inducible by xenobiotics and by certain pathophysiological conditions. The present study was designed to determine mEH expression in H4IIE cells during cell death initiated by sulfur amino acid deprivation (SAAD) and to identify the signaling pathway for the enzyme induction.(omitted)

• Tuberculosis and Respiratory Diseases
• /
• v.53 no.6
• /
• pp.595-611
• /
• 2002

Akt/PKB protein kinase B, ALI acute lung injury, ARDS acute respiratory distress syndrome, CREB C-AMP response element binding protein, ERK extracelluar signal-related kinase, fMLP fMet-Leu-Phe, G-CSF granulocyte colony-stimulating factor, IL interleukin, ILK integrin-linked kinase, JNK Jun N-terminal kinase, LPS lipopolysaccharide, MAP mitogen-activated protein, MEK MAP/ERK kinase, MIP-2 macrophage inflammatory protein-2, MMP matrix metalloproteinase, MPO myeloperoxidase, NADPH nicotinamide adenine dinucleotide phosphate, NE neutrophil elastase, NF-kB nuclear factor-kappa B, NOS nitric oxide synthase, p38 MAPK p38 mitogen activated protein kinase, PAF platelet activating factor, PAKs P21-activated kinases, PMN polymorphonuclear leukocytes, PI3-K phosphatidylinositol 3-kinase, PyK proline-rich tyrosine kinase, ROS reactive oxygen species, TNF-${\alpha}$ tumor necrosis factor-a.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.19 no.5
• /
• pp.1363-1369
• /
• 2005

Previously we have shown that shikonin has strong anti-tumor activities via inducing apoptosis and suppressing metastasis on LLC cells in vivo and in vitro. Here we have investigated anti-angiogenic potential of shikonin and its possible mechanism of action in HSE cells. Shikonin inhibited the proliferation of HSE cells in a concentration-dependent manner. It was shown that this proliferation inhibition was caused by apoptosis induced by shikonin via BrdU incorporation and Western blotting analysis. Shikonin treatment was caused that decrease of activation of caspases and cleavage of PARP. And shikonin induced that the activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38. Moreover, shikonin showed anti-angiogenic activities inhibiting tube-like formation of HSE cells in vitro and vascular formation of LLC cells in vivo. These findings suggest that shikonin may a possible candidate not only anti-metastatic agent but also anti-angiogenic agent.

• Proceedings of the PSK Conference
• /
• 2003.10b
• /
• pp.96.1-96.1
• /
• 2003

Lysophosphatidic acid (LPA) is a well-known mitogen in various cell types. However, we were surprised to find that LPA inhibits melanocyte proliferation. Thus, we further investigated the possible signaling pathways involved in melanocyte growth inhibition. We first examined the regulation of the three major subfamilies of mitogen-activated protein (MAP) kinases and of the Akt pathway by LPA. The activations of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) were observed in concert with the inhibition of melanocyte proliferation by LPA, whereas p38 MAP kinase and Akt were not influenced by LPA. (omitted)

• BMB Reports
• /
• v.42 no.3
• /
• pp.148-153
• /
• 2009

Pyrrolidine dithiocarbamate (PDTC) is a stable anti-oxidant or pro-oxidant, depending on the situation, and it is widely used to inhibit the activation of NF-${\kappa}B$. We recently reported that PDTC activates the MIP-2 gene in a NF-${\kappa}B$-independent and c-Jun-dependent manner in macrophage cells. In this work, we found that PDTC activates signal transduction pathways in mouse ES cells. Among the three different mitogen-activated protein kinase (MAPK) pathways, including the extracellular-signal-regulated kinase (ERK), p38 MAP kinase, and stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) pathways, only the ERK pathway was significantly activated in mouse ES cells after stimulation with PDTC. Additionally, we observed a synergistic activation of ERK and induction of c-Fos after stimulation with PDTC in the presence of mouse embryonic fibroblast (MEF) conditioned medium. In contrast, another NF-${\kappa}B$ inhibitor, BMS-345541, did not activate the MAP kinase pathways or induce expression of c-Fos. These results suggest that changes in the presence of the NF-${\kappa}B$ inhibitor PDTC should be carefully considered when it used with mouse ES cells.

• Journal of Life Science
• /
• v.23 no.5
• /
• pp.650-656
• /
• 2013

Endothelial protein C receptor (EPCR) plays a pivotal role in augmenting Protein C activation through the thrombin-thrombomodulin complex. EPCR activity is markedly changed by ectodomain cleavage and released as the soluble protein (sEPCR). EPCR shedding is mediated by tumor necrosis factor-${\alpha}$ converting enzyme (TACE). Lycopene found in tomatoes and tomato products has anti-oxidant, anti- cancer and anti-inflammatory effects. However, little is known about the effects of lycopene on EPCR shedding. We investigated this issue by monitoring the effects of lycopene on the phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-$1{\beta}$ and on the cecal ligation and puncture (CLP)-mediated EPCR shedding. Data showed that lycopene potently inhibited the PMA, TNF-${\alpha}$, IL-$1{\beta}$ and CLP-induced EPCR shedding by suppressing TACE expression. Furthermore, lycopene reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2 and c-Jun N-terminal kinase (JNK). Given these results, lycopene should be viewed as a candidate therapeutic agent for the treatment of various severe vascular inflammatory diseases via inhibition of the EPCR shedding.

• BMB Reports
• /
• v.47 no.6
• /
• pp.336-341
• /
• 2014

Endothelial cell protein C receptor (EPCR) plays important roles in blood coagulation and inflammation. EPCR activity is markedly changed by ectodomain cleavage and release as the soluble EPCR. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-${\alpha}$ converting enzyme (TACE). Oroxylin A (OroA), a major component of Scutellaria baicalensis Georgi, is known to exhibit anti-angiogenic, antiinflammation, and anti-invasive activities. However, little is known about the effects of OroA on EPCR shedding. Data showed that OroA induced potent inhibition of phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-$1{\beta}$ and on cecal ligation and puncture (CLP)-induced EPCR shedding through suppression of TACE expression and activity. In addition, treatment with OroA resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate the potential of OroA as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.22 no.5
• /
• pp.1299-1303
• /
• 2008

Since exercise training induces mechanical stress to the heart, we examined the activation pattern of mitogen-activated protein kinase(MAPK)s signaling pathway by immunohistochemistry. The immunoreactions of MAPKs signaling with c-fos and Schiff's reaction were increased in the cardiac muscle of exercised rat compared to normal one except immunoreaction for MEK1/2 and ERK1/2 and p38. However, the immunoreaction of phospho-JNK and phospho-p38 with early gene c-fos were arrested markedly in water extract of Alliium sativum (WEAS) treated rat compared to exercised one. Since MAPKs signaling does play a protective role in response to pathological stimulus in the heart, results in the present study suggest that WEAS may act as a alleviating agent for exercise-induced stress to. heart through regulating MAPKs signaling activation.

• Journal of Life Science
• /
• v.24 no.6
• /
• pp.664-670
• /
• 2014

In the present study, we investigate the role of V. vulnificus in promoting the inflammation of mouse ileal ephitelium and its related signaling pathways. ICR mice were infected orally with V. vulnificus ($1{\times}10^9CFU$) for 16 h as a representative model of food-borne infection. To find the major portal of entry of V. vulnificus in mouse intestine, we have measured the levels of bacterial colonization in small intestine, colon, spleen, and liver. V. vulnificus appeared to colonize in intestine and colon in the order of ileum >> jejunum> colon, but lack in the duodenum, spleen, and liver. V. vulnificus in ileum caused severe necrotizing enteritis and showed shortened villi heights accompanied by an expanded width and inflammation, compared with the control mice. V. vulnificus induced ileal epithelium inflammation by activating phosphorylation of PKC and membrane translocation of $PKC{\alpha}$. V. vulnificus induced the phosphorylation of ERK and JNK, but did not affect p38 MAPK phosphorylation. Notably, V. vulnificus stimulated the I-${\kappa}B$-dependent phosphorylation of NF-${\kappa}B$ in mouse ileal epithelium. Finally, the ileal infection of V. vulnificus resulted in a significant increase in expression of proinflammatory cytokines and Toll-like receptors, respectively, compared to the control. Collectively, our results indicate that V. vulnificus induces ileal epithelium inflammation by increasing NF-${\kappa}B$ phosphorylation via activation of PKC, ERK, and JNK, which is critical for host defense mechanism in food-borne infection by V. vulnificus.