• 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.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.2
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• pp.163-172
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• 2018

PRF001 is a fragmented DNA polymer extracted from the testes of salmon. The purpose of this study was to assess the anti-inflammatory effect of PRF001 in vitro as well as the protective effect of PRF001 intake against arthritis in a rat model. In vitro, cell survival and inflammatory markers after $H_2O_2$ treatment to induce cell damage were investigated in CHON-001 cells treated with different concentrations of PRF001. In vivo, osteoarthritis was induced by intra-articular injection of monosodium iodoacetate (MIA) into the knee joints of rats. After consumption of PRF001 (10, 50, or 100 mg/kg) for 4 weeks, inflammatory mediators and cytokines in articular cartilage were investigated. In vitro, the levels of inflammatory markers, $IL-1{\beta}$, $TNF-{\alpha}$, COX-2, iNOS, and PGE2, were significantly suppressed by PRF001 treatment. In vivo, the inflammatory mediators and cytokines, $IL-1{\beta}$, p-Erk1/2, $NF-{\kappa}B$, $TNF-{\alpha}$, COX-2, and PGE2, as well as MMP3 and MMP7, which have catabolic activity in chondrocytes, were decreased in the MIA-induced osteoarthritic rats following intake of PRF001. Histological analysis revealed that PRF001 had a protective effect on the articular cartilage. Altogether, these results demonstrated that the anti-inflammatory property of PRF001 contributes to its protective effects in osteoarthritis through deregulating $IL-1{\beta}$, $TNF-{\alpha}$, and subsequent signals, such as p-Erk1/2, $NF-{\kappa}B$, COX-2, PGE2, and MMPs.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.6
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• pp.417-424
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• 2009

Osteoclasts, derived from multipotent myeloid progenitor cells, play homeostatic roles in skeletal modeling and remodeling, but may also destroy bone in pathological conditions such as osteoporosis and rheumatoid arthritis. Osteoclast development depends critically on a differentiation factor, the receptor activator of NF-${\kappa}B$ ligand (RANKL). In this study, we found that the hexane soluble fraction of the common fig Ficus carica (HF6-FC) is a potent inhibitor of osteoclastogenesis in RANKL-stimulated RAW264.7 cells and in bone marrow-derived macrophages (BMMs). HF6-FC exerts its inhibitory effects by suppression of p38 and NF-${\kappa}B$ but activation of ERK. In addition, HF6-FC significantly decreased the expression of NFATc1 and c-Fos, the master regulator of osteoclast differentiation. The data indicate that components of HF6-FC may have therapeutic effects on bone-destructive processes such as osteoporosis, rheumatoid arthritis, and periodontal bone resorption.

• Korean Journal of Microbiology
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• v.52 no.4
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• pp.421-427
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• 2016

Acne is known as the most common skin disease. It commonly occurs during adolescents, but it is also present in children and adults because of air pollution, drug abuse and so on. In addition to the hormonal, genetic and environmental factors, Propionibacterium acnes (P. acnes) have also critical roles in outbreak of acne by inducing inflammatory mediators. Increase of sebum production provides an ideal environment for P. acnes that induce inflammation on the skin by activation of monocytic cells and stimulation of inflammatory cytokines. In this study, natural extracts were investigated for anti-inflammatory effects against inflammatory acne by P. acnes infection in terms of reducing cytokine production. Eucalyptus globulus extracts effectively suppressed mRNA synthesis of inflammatory mediators such as $TNF-{\alpha}$, $IL-1{\beta}$, IL-2, and NLRP3 in P. acnes-activated macrophages. Moreover, Eucalyptus globulus extracts inhibit activation of transcription factors, $NF-{\kappa}B$ and NFAT, which are known as key regulators of inflammatory cytokine production. This study suggests the potential of using Eucalyptus globulus extracts as alternative agents for the treatment of acne.

• IMMUNE NETWORK
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• v.9 no.2
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• pp.64-73
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• 2009

Background: 15d-$PGJ_2$ has been known to act as an anti-inflammatory agent and has anti-hypertensive effects. As a result of these properties, we examined the effect of 15d-$PGJ_2$ on the LPS-induced IL-8/CXCL8 mRNA expression in VSMCs from SHR. Methods: Effect and action mechanism of 15d-$PGJ_2$ on the expression of LPS-induced IL-8/CXCL8 mRNA in VSMCs from SHR and WKY were examined by using real-time polymerase chain reaction, electrophoretic mobility shift assay for NF-${\kappa}B$ avtivity, Western blotting analysis for ERK and p38 phosphorylation and flow cytometry for NAD(P)H oxidase activity. Results: 15d-$PGJ_2$ decreased the expression of LPS-induced IL-8/CXCL8 mRNA in WKY VSMCs, but increased the expression of LPS-induced IL-8/CXCL8 mRNA in SHR VSMCs. The upregulatory effect of 15d-$PGJ_2$ in SHR VSMCs was mediated through PPAR${\gamma}$, and dependent on NF-${\kappa}B$ activation and ERK phosphorylation. However, inhibition of the p38 signaling pathway augmented the upregulatory effect of 15d-$PGJ_2$ on LPS-induced IL-8/CXCL8 mRNA. A NAD(P)H oxidase inhibitor inhibited the upregulatory effect of 15d-$PGJ_2$ on LPS-induced IL-8/CXCL8 mRNA expression in SHR VSMCs, and an increase in NAD(P)H oxidase activity was detected in SHR VSMCs treated with 15d-$PGJ_2$/LPS. Conclusion: Our results indicate that the upregulatory effect of 15d-$PGJ_2$ on LPS-induced IL-8/CXCL8 expression in SHR VSMCs is mediated through the PPAR${\gamma}$ and ERK pathway, and may be related to NAD(P)H oxidase activity. However, p38 inactivation may also play an important role in 15d-$PGJ_2$/LPS-induced IL-8/CXCL8 expression in SHR VSMCs.

• Journal of Acupuncture Research
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• v.24 no.4
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• pp.167-181
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• 2007

Objectives: To evaluate expression of MIF mRNA, MIF, $TNF-{\alpha}$, $IL-6R-{\alpha}$, STAT-3, $NF-{\kappa}B$ p65, COX-2 and iNOS, MMP-9mRNA after injecting deer antler herbal acupuncture solution in a LPS rat model. Methods: The experiment was divided in category of the control group, RA group, and NA group. RA was induced in the mice via injecting 300ug/kg LPS. The deer antler herbal acupuncture solution 50ug/kg was applied on $ST_{35}$(犢鼻) and EX-LE201(內膝眼) for 19days from $3^{rd}$ day of RA inducement. Results: 1. In the deer antler herbal acupuncture solution treated RAW 264.7cell, the mRNA expression of cytokines, RA related inflammation factors, such as the MIF, COX- 2, iNOS, and MMP-g reduced concentration dependently. 2. In the deer antler herbal acupuncture treated mice's synovial membrane, decrease in the cell replication of synovial joint cells, regeneration of blood vessel, fibrosis and fibroblastic cells expansion were observed. 3. Positive reaction of RA-related cytokines MIF, $TNF-{\alpha}$, $IL-6R-{\alpha}$, STAT3, COX-2, iNOS, $NF-\;{\kappa}B$ p65, MMP-9 was reduced. Conclusion : On the basis of the results, it was concluded that deer antler herbal acupuncture extract has significant protecting ability against acute progressive RA by inhibiting the production of MIF, as a top in cytokines related to inflammation.

• Biomedical Science Letters
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• v.14 no.3
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• pp.147-155
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• 2008

In previous works, we found that solvent extract of Opuntia humifusa Raf., a member of the lactaceae family, displayed potent anti-oxidative and anti-inflammatory activities. Thus, all solvent fractions, except for the water layer, showed potent scavenging effects. According to activity-guided fractionation, one of active radical scavenging principles in the ethyl acetate fraction was found to be taxifolin. In this study, we investigated whether taxifolin showed anti-oxidative activity. In addition, taxifolin modulated nitric oxide (NO) release and the expression of pro-inflammatory cytokine mRNA such as interleukin-$1{\beta}$ (IL-$1{\beta}$), IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and TNF-${\alpha}$. Taxifolin showed potent anti-oxidant activity with the $IC_{50}\;of\;8.5{\pm}1.4\;and\;9.3{\pm}1.0{\mu}M$ using xanthine/xanthine oxidase (XO) assay and 2,2-Diphenyl-lpicrylhydrazyl radical (DPPH) assay, respectively. We next determined the role of taxifolin on the immunomodulating activity using murine macrophage cell line RAW264.7 cells. Taxifolin dose-dependently inhibited NO production in lipopolysaccharide (LPS)-activated RAW264.7. It also significantly blocked the expression of inducible NO synthase (iNOS) mRNA in the LPS-stimulated RAW264.7 cells. In addition, taxifolin potently suppressed the expression of IL-$1{\beta}$, IL-6 and GM-CSF mRNA in LPS-activated RAW264.7 cells, but not that of TNF-${\alpha}$ Moreover, taxifolin significantly inhibited the transcriptional activity of nuclear factor-${\kappa}B$ (NF-${\kappa}B$) and activator protein -1 (AP-1). These results suggest that taxifolin may downregulate inflammatory iNOS, IL-$1{\beta}$, IL-6 and GM-CSF gene expressions through inhibition of NF-K and AP-1 activation in LPS-stimulated RAW264.7 cells.

• The Journal of Korean Medicine
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• v.24 no.2
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• pp.166-178
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• 2003

Objectives : Nitric oxide (NO) plays an important role in normal and pathophysiological cells as a messenger molecule, neurotransmitter, microbiological agent, or dilator of blood vessels and arteriosclerosis, respectively. This study was undertaken to understand the mechanism of NO production and effect of Hyeolbuchukeo-tang (Xiefuzhuyu-tang) on NO production in cultured vascular smooth muscle cell (VSMC). Methods and Results : VSMC was isolated from aorta and cultured. Cultured primary cells were identified as VSMC with anti--smooth muscle actin antibody. A large amount of NO was produced in cultured VSMC treated with $IFN-{\gamma}$ plus TNF in a time- and dose-dependent manner. $TNF-{\alpha}$ was a more efficient stimulator than $IFN-{\gamma}$ in NO production of cultured VSMC. iNOS protein wasdetected within 3 hrs and it increased up to 12 hrs in a time-dependent manner. However, accumulated NO in cytokine-treated VSMC was not detected within 3 hrs. NO production in cytokine-treated VSMC showed the dose- and time-dependent manner, and increased up to 48 hrs. The activated VSMC produced a large amount of NO (about 60 uM). Hyeolbuchukeo-tang (Xiefuzhuyu-tang) alone did not induceNO production, but it potentiated the effect of $TNF-{\alpha}$ on NO production and increased NO production by about 20%. Hyeolbuchukeo-tang (Xiefuzhuyu-tang) did not affect the transcriptional activity of iNOS gene, but increased the accumulation of iNOS. These results indicate that Hyeolbuchukeo-tang (Xiefuzhuyu-tang) could modulate the translational level of iNOS. PKC did not modulate NO production, but calcium ionophore A23187 decreased NO production. However, Hyeolbuchukeo-tang (Xiefuzhuyu-tang) elevated the decreased NO production in A23187-treated VSMC by modulating the stability of iNOS transcripts. Half-life of the synthesized transcripts appeared to have about 6 hrs. PDTC, an $NF-{\kappa}B$ inhibitor, blocked the accumulation of iNOS mRNA, indicating that $NF-{\kappa}B$ served as an important modulator in the transcriptional regulation of iNOS. As Hyeolbuchukeo-tang (Xiefuzhuyu-tang) potentiated the effect of the $TNF-{\alpha}$ on NO production but had no additional effect on PDTC-modulated NO production, it is suggested that Hyeolbuchukeo-tang (Xiefuzhuyu-tang) enhances the $TNF-{\alpha}-mediated$ NO production of VSMC by modulating the iNOS activity and the stability of iNOS transcripts in activated VSMC having the elevated intracellular calcium ion. Conclusions : This study suggests that Hyeolbuchukeo-tang (Xiefuzhuyu-tang) has a potential capacity for preventing and treating diseases of the circulation system, including arteriosclerosis.

• The Journal of Korean Medicine
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• v.32 no.2
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• pp.102-117
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• 2011

Objectives: This study was performed to investigate the protective and treating efficacy of Pyeongwi-san, Ijin-tang, and Pyeongjin-tang extracts to the mice with gastric mucosal lesions induced from indomethacin. Methods: In order to verify protective and treating efficacy of Pyeongwi-san, Ijin-tang, and Pyeongjin-tang extracts to the mice with gastric mucosal lesions induced from indomethacin, I administered the extracts of these prescriptions to three group, and induced gastric mucosal lesion by indomethacin, and then I observed the gastric mucosal morphology of stomach, changes from stress resulting from HSP70, changes of gastro-protection (mucous barrier, COX-1). After I observed the anti-oxidant effect, and anti-inflammation effect (IKK mRNA, iNOS mRNA, COX-2 mRNA) in vitro, I induced gastric mucosal lesion by indomethacin, and administered the extracts of each prescriptions to three group, and then I observed the gastric mucosal morphology, anti-inflammation effect to mucosa (NF-${\kappa}$B, iNOS, COX-2) in vivo. Results & Conclusions: 1. Hemorrhagic erosion and damaged mucus secreting cell, positive responses to HSP70 were decreased in all the before-gastric-mucosal-lesion-induced groups, compared to non-extract administered group. The effects were good in the order of Pyeongwi-san extracts administered group, Pyeongjin-tang extracts administered group and Ijin-tang extracts administered group. 2. In all the before-gastric-mucosal-lesion-induced groups, gastro- protection functions (mucous barrier, COX-1) were significant. The effects were good in the order of Pyeongwi-san extracts administered group, Pyeongjin-tang extracts administered group and Ijin-tang extracts administered group. 3. Anti-oxidant effect was significant in Pyeongwi-san extracts, Ijin-tang extracts and Pyeongjin-tang extracts. The effects were good in the order of Pyeongjin-tang extracts, Pyeongwi-san extracts and Ijin-tang extracts. 4. The anti-inflammation effects in vitro were good in Pyeongwi-san extracts, Ijin-tang extracts and Pyeongjin-tang extracts. Especially Pyeongjin-tang extracts showed the most prominent results. Damaged mucus secreting cells and the positive reactions of NF-${\kappa}$B, iNOS, COX-2 in vivo were decreased in after-gastric-mucosal-lesion-induced groups compared to non-extract administered group. The effects were good in the order of Pyeongjin-tang extracts administered group, Pyeongwi-san extracts administered group and Ijin-tang extracts administered group. These results show that Pyeongwi-san, Ijin-tang and Pyeongjin-tang are effective on both in protecting and treating the gastric mucosal membrane. Pyeongwi-san is more effective than other prescriptions, in protecting gastric mucosal membrane, and Pyeongjin-tang is more effective in treating gastric mucosal lesion.

• Journal of Life Science
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• v.21 no.6
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• pp.893-900
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• 2011

Prostatic acid phosphatase (PAP) is one of the widely used biomarkers in the diagnosis of prostate cancer. It was initially identified in 1935 and is the most abundant phosphatase in the human prostate. PAP is a prostate-specific enzyme that is synthesized in prostate epithelial cells. It belongs to the acid phosphatase group that shows enzymatic activity in acidic conditions. PAP is abundant in prostatic fluid and is thought to have a role in fertilization and oligospermia. It also has a potential role in reducing chronic pain. But one of the most apparent functions of PAP is the dephosphorylation of macromolecules such as HER-2 and PI3P that are involved in the ERK1/2 and MAPK pathways, which in turn leads to inhibition of cell growth and tumorigenesis. Currently, clinical trials using PAP DNA vaccine are underway and FDA-approved immunotherapy using PAP is commercially available. Despite these clinically important aspects, molecular mechanisms underlying PAP regulation are not fully understood. The promoter region of PAP was reported to be regulated by NF-${\kappa}B$, TNF-${\alpha}$, IL-1, androgen and androgen receptors. Here, the features of PAP gene and protein structures together with the function, regulation and roles of PAP in prostate cancer are discussed.