• Proceedings of the Korean Society of Applied Pharmacology
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• 2003.11a
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• pp.84-84
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• 2003

Lead has long been considered as a toxic environmental pollutant, which severely damages central nervous system. Lead can cause hypo- and de-myelination, and glial cells are closely related with myelination or demyelination. Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in the remodelling of the extracellular matrix in a variety of physiological and pathological processes. MMPs also seem to be important in the pathogenesis of inflammatory demyelinating diseases of the central and peripheral nervous system. In this study, we investigated whether lead affects MMP-9 expression in rat primary glial cells. Treatment of 0.1-5 ${\mu}$M lead dose- and time-dependently increased MMP-9 expression in rat primary glial cells. The activity of MMPs was determined using zymography. Lead activated Erk(1/2) but neither of the other endogenous MAP kinases, p38 or JNK. Inhibition of Erk(1/2) activation by PD98059, a MEK inihibitor, prevented lead-induced expression of MMP-9. The results of the present study suggest that lead intoxication may adversely affect brain function at least in part by inducing MMP-9 expression through Erk(1/2) activation in primary glial cells.

• BMB Reports
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• v.40 no.1
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• pp.1-6
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• 2007

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogenactivated protein kinase (MAPK) kinase kinase that activates JNK and p38 kinases. ASK1 is activated by various stresses, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, lipopolysaccharide (LPS) and calcium influx which are thought to be responsible for the pathogenesis or exacerbations of various human diseases. Recent studies revealed the involvement of ASK1 in ROS- or ER stressrelated diseases, suggesting that ASK1 may be a potential therapeutic target of various human diseases. In this review, we focus on the current findings for the relationship between pathogenesis and ASK1-MAPK pathways.

• YAKHAK HOEJI
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• v.57 no.6
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• pp.394-399
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• 2013

In this study we demonstrated whether the extract of Polygonum aviculare L. (PAE) can be applied to the immune-stimulating responses in macrophages (Raw 264.7 cells). Cell viability was determined by WST-8 assay, and all four doses of PAE (5, 10, 20, and 40 ${\mu}g/ml$) had no significant cytotoxicity during the entire experimental period. PAE increased the production of inducible nitric oxide synthase (iNOS) and nitric oxide (NO), and mRNA expressions and protein levels of pro-inflammatory cytokines(tumor necrotic factor (TNF)-${\alpha}$, interleukin (IL)-$1{\beta}$ and IL-6) in the same cells. These immune-stimulating activities of PAE were found to be caused by the stimulation of $NF{\kappa}B$ signal and phosphorylation of MAP kinases (p38, ERK and JNK).

• Journal of Physiology & Pathology in Korean Medicine
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• v.19 no.2
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• pp.501-507
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• 2005

Shikonin is a chemically characterized component of traditional herbal medicine, the root of Lithospermum erythrorhizon and has been shown to possess antitumor activities. Here we investigated anticancer potential of shikonin and its possible mechanism of action in LLC cells. Shikonin inhibited the proliferation of LLC cells in a concentration-dependent manner. It was also demonstrated that shikonin induced apoptosis in LLC cells by Annexin V staining and TUNEL staining analysis. Shikonin treatment was caused that decrease of Bcl-2, activation of caspases and cleavage of PARP. And shikonin also 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. Interestingly, the cell proliferation inhibition induced by shikonin was recovered by specific inhibitors of JNK and p38 but the inhibitor of MEK, the upstream kinase of ERK, did not recover. Additionally, shikonin administration at doses of 5 mg/kg in C57BL/6 mice strongly inhibited the primary tumor growth of LLC. Taken together, these results suggest that shikonin may suppress LLC cell proliferation by inducing an apoptotic process via activation of caspases and MAPKs

• Molecules and Cells
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• v.40 no.5
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• pp.371-377
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• 2017

Despite the importance of the receptor activator of nuclear factor (NF)-kappaB ligand (RANKL)-RANK signaling mechanisms on osteoclast differentiation, little has been studied on how RANK expression is regulated or what regulates its expression during osteoclastogenesis. We show here that insulin signaling increases RANK expression, thus enhancing osteoclast differentiation by RANKL. Insulin stimulation induced RANK gene expression in time- and dose-dependent manners and insulin receptor shRNA completely abolished RANK expression induced by insulin in bone marrow-derived monocyte/macrophage cells (BMMs). Moreover, the addition of insulin in the presence of RANKL promoted RANK expression. The ability of insulin to regulate RANK expression depends on extracellular signal-regulated kinase 1/2 (ERK1/2) since only PD98059, an ERK1/2 inhibitor, specifically inhibited its expression by insulin. However, the RANK expression by RANKL was blocked by all three mitogen-activated protein (MAP) kinases inhibitors. The activation of RANK increased differentiation of BMMs into tartrate-resistant acid phosphatase-positive ($TRAP^+$) osteoclasts as well as the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and d2 isoform of vacuolar ($H^+$) ATPase (v-ATPase) Vo domain (Atp6v0d2), genes critical for osteoclastic cell-cell fusion. Collectively, these results suggest that insulin induces RANK expression via ERK1/2, which contributes to the enhancement of osteoclast differentiation.

• Journal of Food Hygiene and Safety
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• v.29 no.4
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• pp.356-362
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• 2014

Allergic diseases have increased rapidly over the past decades, affecting an estimated 20~30% of the population in developed countries. In this study, we investigated whether or not a typical costal sand dune plant Carex pumila (CPE) suppresses the activation of mast cells and IgE-mediated allergic response in vitro and in vivo. As the results, the extract of Carex pumila inhibited antigen-stimulated degranulation in RBL-2H3 cells and Bone marrow-derived mast cells (BMMCs), and IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. CPE also suppressed the production of pro-inflammatory cytokines, TNF-${\alpha}$ and IL-4, in antigen-stimulated mast cells. As its mechanism of action, CPE inhibited the activation of Syk in $Fc{\varepsilon}RI$-mediated signalling pathway, and that of LAT, a downstream adaptor molecule of Syk, in a dose-dependent manner. CPE also suppressed the activation of mitogen-activated protein (MAP) kinases, p38, ERK1/2, JNK, and Akt. Altogether, CPE inhibited mast cell activation and IgE-mediated allergic response by antigen through suppressing the activation of Syk. These results suggest that CPE may be useful for the treatment of allergic diseases.

• Korean Journal of Pharmacognosy
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• v.51 no.4
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• pp.317-324
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• 2020

Mast cells play a key role in IgE-mediated allergic response. We investigated whether Swertia pseudochinensis Hara extract (SPE) inhibits IgE-mediated allergic response in mast cells and an allergic animal model. Additionally, we explored SPE's mechanism of action in mast cells. Our results showed that SPE inhibited both antigen-stimulated degranulation and the production of TNF-α and IL-4 in bone marrow-derived mast cells (BMMCs) and rat basophilic leukemia (RBL)-2H3 cells. SPE also suppressed allergic response in IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. As for the mechanism of action of SPE in mast cells, it inhibited the activation of Syk kinase, a critical signaling protein in the FcεRI-mediated signaling pathway, and also the activation of LAT, a downstream adaptor protein of Syk. We further observed the reduced activation of mitogen-activated protein (MAP) kinases (P38, ERK1/2, and JNK) and Akt in mast cells. Our results described for the first time that SPE has an anti-allergic effect by suppressing mast cells through the inhibition of Syk kinase. Therefore, SPE may be useful for the treatment of type I allergic diseases.

• Tuberculosis and Respiratory Diseases
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• v.73 no.5
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• pp.258-265
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• 2012

Background: Vitamin D can translocate a vitamin D receptor (VDR) from the nucleus to the cell membranes. The meaning of this translocation is not elucidated in terms of a role in pathogenesis of chronic obstructive pulmonary disease (COPD) till now. VDR deficient mice are prone to develop emphysema, suggesting that abnormal function of VDR might influence a generation of COPD. The blood levels of vitamin D have known to be well correlated with that of lung function in patients with COPD, and smoking is the most important risk factor in development of COPD. This study was performed to investigate whether cigarette smoke extracts (CSE) can inhibit the translocation of VDR and whether mitogen activated protein kinases (MAPKs) are involved in this inhibition. Methods: Human alveolar basal epithelial cell line (A549) was used in this study. 1,25-$(OH_2)D_3$ and/or MAPKs inhibitors and antioxidants were pre-incubated before stimulation with 10% CSE, and then nucleus and microsomal proteins were extracted for a Western blot of VDR. Results: Five minutes treatment of 1,25-(OH2)D3 induced translocation of VDR from nucleus to microsomes by a dose-dependent manner. CSE inhibited 1,25-$(OH_2)D_3$-induced translocation of VDR in both concentrations of 10% and 20%. All MAPKs inhibitors did not suppress the inhibitory effects of CSE on the 1,25-$(OH_2)D_3$-induced translocation of VDR. Quercetin suppressed the inhibitory effects of CSE on the 1,25-$(OH_2)D_3$-induced translocation of VDR, but not in n-acetylcysteine. Conclusion: CSE has an ability to inhibit vitamin D-induced VDR translocation, but MAPKs are not involved in this inhibition.

• Toxicological Research
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• v.29 no.3
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• pp.181-185
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• 2013

Aluminum nanoparticles (Al-NPs) are one of the most widely used nanomaterial in cosmetics and medical materials. For this reason, Al-NP exposure is very likely to occur via inhalation in the environment and the workplace. Nevertheless, little is known about the mechanism of Al-NP neurotoxicity via inhalation exposure. In this study, we investigated the effect AL-NPs on the brain. Rats were exposed to Al-NPs by nasal instillation at 1 mg/kg body weight (low exposure group), 20 mg/kg body weight (moderate exposure group), and 40 mg/kg body weight (high exposure group), for a total of 3 times, with a 24-hr interval after each exposure. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated that the presence of aluminum was increased in a dose-dependent manner in the olfactory bulb (OFB) and the brain. In microarray analysis, the regulation of mitogen-activated protein kinases (MAPK) activity (GO: 0043405), including Ptprc, P2rx7, Map2k4, Trib3, Trib1, and Fgd4 was significantly over-expressed in the treated mice than in the controls (p = 0.0027). Moreover, Al-NPs induced the activation of ERK1 and p38 MAPK protein expression in the brain, but did not alter the protein expression of JNK, when compared to the control. These data demonstrate that the nasal exposure of Al-NPs can permeate the brain via the olfactory bulb and modulate the gene and protein expression of MAPK and its activity.

• Journal of Microbiology and Biotechnology
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• v.18 no.6
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• pp.1170-1178
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• 2008

The cyclopentenone prostaglandins (cyPGs) prostaglandin $A_1$ ($PGA_1$) and 15-deoxy-${\Delta}^{12,14}$-prostaglandin $J_2$ (15d-$PGJ_2$) have been reported to exhibit antiinflammatory activity in activated monocytes/macrophages. However, the effects of these two cyPGs on the expression of cytokine genes may differ. In this study, we investigated the mechanism of action of $PGA_1$ in lipopolysaccharide (LPS)-induced expression of inter leu kin (IL)-10 mRNA in mouse peritoneal macrophages. 15d-$PGJ_2$ inhibited expression of LPS-induced IL-10, whereas $PGA_1$ increased LPS-induced IL-10 expression. This synergistic effect of $PGA_1$ on LPS-induced IL-10 expression reached a maximum as early as 2 h after simultaneous $PGA_1$ and LPS treatment ($PGA_1$/LPS), and did not require new protein synthesis. The synergistic effect of $PGA_1$ was inhibited by GW9662, a specific peroxisome proliferator-activated receptor ${\gamma}(PPAR{\gamma})$ antagonist, and Bay-11-7082, a NF-${\kappa}B$ inhibitor. The extracellular signal-regulated kinases (ERK) inhibitor PD98059 increased the expression of $PGA_1$/LPS-induced IL-10 mRNA, rather than inhibiting the IL-10 expression. Moreover, $PGA_1$ inhibited LPS-induced ERK phosphorylation. The synergistic effect of $PGA_1$ on LPS-induced IL-10 mRNA and protein production was inhibited by p38 inhibitor PD169316, and $PGA_1$ increased LPS-induced p38 phosphorylation. In the case of stress-activated protein kinase/c-Jun $NH_2$-terminal kinase (SAPK/JNK), the SAPK/JNK inhibitor SP600125 did not inhibit IL-10 mRNA synthesis but inhibited the production of IL-10 protein remarkably. These results suggest that the synergistic effect of $PGA_1$ on LPS-induced IL-10 expression is NF-${\kappa}B$-dependent and mediated by mitogen-activated protein (MAP) kinases, p38, and SAPK/JNK signaling pathways, and also associated with the $PPAR{\gamma}$ pathway. Our data may provide more insight into the diverse mechanisms of $PGA_1$ effects on the expression of cytokine genes.