• Journal of Microbiology and Biotechnology
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• v.25 no.7
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• pp.1047-1055
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• 2015

For the search of a potent first-in-class compound to inactivate macrophages responsible for inflammatory responses, in the present study, we investigated the anti-nflammatory effects of YH-1118, a novel synthetic compound, in a lipopolysaccharide (LPS)-stimulated mouse macrophage cell line, Raw 264.7. YH-1118 inhibited LPS-induced nitric oxide (NO) production and inducible NO synthase (iNOS) expression at both the protein and mRNA levels. The suppression of LPS-induced iNOS expression by YH-1118 was mediated via nuclear factor kappa B (NF-κB), but not activator protein-1 (AP-1) transcription factor. This was supported by the finding that YH-1118 attenuated the phosphorylation of inhibitor of κBα (IκBα) and nuclear translocation and DNA binding activity of NF-κB. Through the mechanisms that YH-1118 inhibited the activation of IκB kinases (IKKs), upstream activators of NF-κB, or p38 MAPK, YH-1118 significantly suppressed LPS-induced production of pro-inflammatory cytokines, tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6 (p < 0.05). In conclusion, our results suggest that YH-1118 inhibits LPS-induced inflammatory responses by blocking IKK and NF-κB activation in macrophages, and may be a therapeutic candidate for the treatment of various inflammatory diseases.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.2
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• pp.157-163
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• 2020

Chronic inflammatory airway diseases, such as chronic rhinosinusitis, chronic obstructive pulmonary disease, and asthma, are associated with excessive mucus production. Hence, the regulation of mucus production is important for the treatment of upper and lower airway diseases. Eupatilin is a pharmacologically active ingredient obtained from Artemisia asiatica Nakai (Asteraceae) and exerts potent anti-inflammatory, anti-allergic, and anti-tumor activities. In the present study, we investigated the effect of eupatilin on phorbol 12-myristate 13-acetate (PMA)-induced MUC5AC and MUC5B expression in human airway epithelial cells. We found that eupatilin treatment significantly inhibited PMA-induced mucus secretion in PAS staining. In addition, qRT-PCR results showed that eupatilin dose-dependently decreased the mRNA expression of MUC5AC in human airway epithelial cells. Western blot and immunofluorescence assay also showed that PMA-induced protein expression of MUC5AC was inhibited by eupatilin treatment. Finally, we investigated MAPKs activity after stimulation with PMA using western blot analysis in human airway epithelial cells. The results showed that eupatilin downregulated the levels of phosphorylated p38, ERK, and JNK. In summary, the anti-inflammatory activities of eupatilin, characterized as the suppression of MUC5AC expression and secretion in human airway epithelial cells, were found to be associated with the inhibition of p38/ERK/JNK MAPKs signaling pathway of MUC5AC secretion.

• Journal of Acupuncture Research
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• v.18 no.1
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• pp.129-145
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• 2001

Objectives : To characterize the antitumorigenic potential of three representative bee venom components, Melittin, Apamin, and Phospholipase A2, their effects on cell proliferation and apotosis of the human melanoma cell line SK-MEL-2 were analyzed using molecular biological approaches. Methodes & Results : To determine the doses of the drugs that do not induce cytotoxic damage to this cell line, cell viability was examined by MTT assay. While SK-MEL-2 cells treated with 0.5 - 2.0㎍/㎖ of each drug showed no recognizable cytotoxic effect, marked reductions of cell viability were detected at concentrations over 5.0㎍/㎖. [3H]thymidine incorporation assay for cell proliferation demonstrated that DNA replication of SK-MEL-2 cells is inhibited by Apamin and Phospholipase A2 in a dose-dependent manner. Consistent with this result, the cells were accumulated at the G1 phase of the cell cycle after treatment with Apamin and Phospholipase A2, whereas no detectable change in cell proliferation was identified by Melittin treatment. In addition, tryphan blue exclusion and flow cytometric analyses showed that all of these drugs can trigger apoptotic cell death of SK-MEL-2, suggesting that Melittin, Apamin, and Phospholipase A2 have antitumorigenic potential through the suppression of cell growth and/or induction of apoptosis. Qantitative RT-PCR analysis revealed that Apamin and Phospholipase A2 inhibit expression of growth-promoting genes such as c-Jun, c-Fos, and Cyciin D1. Furthermore, Phospholipase A2 induced tumor suppressors p53 and p21/Wafl. In addition, all three drugs were found to activate expression of a representative apoptosis-inducing gene Bax while expression of apoptosis-suppressing Bcl-2 and Bcl-XL genes was not changed. Taken together, this study strongly suggests that Metittin, Apamin, and Phosphalipase A2 may have antitumorigenic activities, which are associated with its growth-inhibiting and/or apoptosis-inducing potentials.

• Biomedical Science Letters
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• v.20 no.1
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• pp.39-42
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• 2014

Asthma is an allergic inflammation and house dust mite (HDM) is a major allergen to induce asthma pathogenesis. Regulation of eosinophil apoptosis is an essential immune process and its dysregulation is implicated in asthma. In the present study, we examined the effects of HDM on spontaneous apoptosis of asthmatic eosinophils and on cytokine secretion in eosinophils of normal subjects including non-atopic and atopic normal. Extract of Dermatophagoides pteronissinus (DP) inhibited eosinophil apoptosis in a time-dependent manner. DP increased the secretion of G-CSF, GM-SCF, and IL-4, which is involved in suppression of eosinophil apoptosis, but IL-5 expression was not altered after DP stimulation. DP also elevated the release of IL-6, IL-8, tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and CCL2, which are anti-apoptotic or survival factors. The secretion of G-CSF, GM-CSF, IL-6, IL-8, and TNF-${\alpha}$ due to DP is higher in atopic normal than that in non-atopic normal. In conclusion, DP increases the survival of eosinophils and its mechanism may be associated with cytokine release. These findings may enable elucidation of asthma pathogenesis induced by HDM.

• BMB Reports
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• v.39 no.5
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• pp.469-478
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• 2006

Vascular endothelial growth factor (VEGF)-A, a major regulator for angiogenesis, binds and activates two tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). These receptors regulate physiological as well as pathological angiogenesis. VEGFR2 has strong tyrosine kinase activity, and transduces the major signals for angiogenesis. However, unlike other representative tyrosine kinase receptors which use the Ras pathway, VEGFR2 mostly uses the Phospholipase-$C{\gamma}$-Protein kinase-C pathway to activate MAP-kinase and DNA synthesis. VEGFR2 is a direct signal transducer for pathological angiogenesis including cancer and diabetic retinopathy, thus, VEGFR2 itself and the signaling appear to be critical targets for the suppression of these diseases. VEGFR1 plays dual role, a negative role in angiogenesis in the embryo most likely by trapping VEGF-A, and a positive role in adulthood in a tyrosine kinase-dependent manner. VEGFR1 is expressed not only in endothelial cells but also in macrophage-lineage cells, and promotes tumor growth, metastasis, and inflammation. Furthermore, a soluble form of VEGFR1 was found to be present at abnormally high levels in the serum of preeclampsia patients, and induces proteinurea and renal dysfunction. Therefore, VEGFR1 is also an important target in the treatment of human diseases. Recently, the VEGFR2-specific ligand VEGF-E (Orf-VEGF) was extensively characterized. Interestingly, the activation of VEGFR2 via VEGF-E in vivo results in a strong angiogenic response in mice with minor side effects such as inflammation compared with VEGF-A, suggesting VEGF-E to be a novel material for pro-angiogenic therapy.

• Journal of Life Science
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• v.21 no.8
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• pp.1100-1108
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• 2011

The immunomodulating effects of moxifloxacin seem to be effective in downregulating inflammatory reactions. This presumed effect was tested in endotoxin (ETX)-induced acute lung injury (ALI) in rats. After moxifloxacin treatment (10 mg/kg) of ETX-given rats, lung myeloperoxidase (MPO) activity, bronchoalveolar-lavage (BAL) protein, and the number of neutrophils in the BAL cells were measured. Light and electron microscopic structures were also examined. Electron microscopic $CeCl_3$ histochemistry for the detection of hydrogen peroxide in the lungs and immunohistochemistry of cytosolic phospholipase A2 (cPLA2) in the lung tissues and BAL cells were performed. To examine the expression of TNF${\alpha}$ in the lungs, western blotting was carried out with the lung tissues. ETX had accumulated neutrophils in the lungs, which was followed by lung leak. Oxidative stress occurred, and increased expression of cPLA2 in the lung tissues and BAL cells was observed in the ETX-given rats. Simultaneously, the expression of TNF${\alpha}$ was enhanced by ETX. Moxifloxacin, however, decreased all these parameters, indicating that ALI may have been ameliorated. Moxifloxacin appears to ameliorate ETX-induced ALI partially through the suppression of cPLA2 in the lungs of rats.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3653-3656
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• 2012

Background: A number of effective prevention measures have been introduced in attempts to substantially reduce both the incidence and mortality due to many kinds of cancer. The search for new anti-cancer compounds in foods or in plant medicines is one realistic and promising approach to prevention. Chinese medicines provide a rich pool of novel and efficacious agents for cancer prevention and treatment. Previously it was demonstratrated that hyperin extracted from the Manchurian rhododendron leaf reduces the proliferation of many cancer cells. The present study was carried out to evaluate its effects on human endometrial cancer cell viability and apoptosis and to investigate its mechanisms of action in RL952 cells. Methods: Cell viability was measured using the MTT assay. Intracellular calcium ions were detected using laser-scanning confocal microscopy. The effects of hyperin on apoptosis related proteins in RL952 cells were examined using Western blot analysis. Results: The growth of RL952 cells was inhibited by treatment with hyperin. OD values of caspase-3 and caspase-9 were increased and expression of bcl-2 was increased and bax was decreased in protein levels in RL952 cells after 24 h of hyperin treatment, Moreover, intracellular calcium accumulation occurred in hyperin-treated cells. Conclusion: These results suggest that hyperin may play an important role in tumor growth suppression by inducing apoptosis in human endometrial cells via a $Ca^{2+}$-related mitochondrion apoptotic pathway in RL952 cells.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6233-6239
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• 2013

Diabetes represents a serious health problem. In the diabetic state, alterations in metabolism, increased susceptibility to infections and immunological changes occur. The suppression of the immune response has been identified as a relevant factor that contributes to the increase in the rate of infections in these patients. At the same time, breast cancer is the most frequent malignant tumor in women. The molecular and cellular mechanisms underlying cancer development have revealed that immune cells functionally regulate epithelial cancer development and progression. Breastfeeding has been hypothesized to reduce the risk of breast cancer. However, early systematic reviews have not yielded consistent findings for this association. The demand for human milk is increasing due to the promotion and consumer acceptance of the health benefits of consuming a natural product rich in bioactive components. However, due to changes in glucose metabolism, the components of the milk from diabetic women are modified depending on the time of evaluation. In this literature review, we summarize important new findings revealing the paradoxical role of breastfeeding in preventing the onset of breast cancer in diabetic mothers. We hypothesized that the milk component production in diabetic mothers is affected by changes in glucose metabolism. Therefore, adequate maternal glycemic control and an adequate duration of breastfeeding for diabetic mothers are crucial to ensure that the immunity components are able to confer protection against breast cancer.

• Advances in Traditional Medicine
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• v.6 no.3
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• pp.237-244
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• 2006

Samultang has been believed for prevention and remedy various blood diseases such as menstrual irregularity, anemia, and metrorrhagia. However, the mechanism that accounts for anti-inflammatory effects of the Samultang is still not fully understood. This study was designed to evaluate whether and how the Samultang could modulate the production of pro-inflammatory cytokines in phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187 treated-human mast cell line, HMC-1. Samultang inhibited the production of tumor necrosis factor $(TNF)-\alpha$, interleukin (IL)-6, granulocyte macrophage colony stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) in HMC-1. Maximal inhibition rate of $TNF-\alpha$, IL-6, GM-CSF, and VEGF by 0.1 mg/ml Samultang was about $70.73{\pm}3.0%,\;51.49{\pm}4.14%,\;54.03{\pm}2.09%$, and $47.95{\pm}7.86%$, respectively. Samultang partially blocked PMA plus A23187-induced cyclooxygenase (COX)-2 expression. In addition, Samultang inhibited activation of nuclear factor (NF)-kB, and extracellular signal-regulated kinase (ERK) activation. These results suggest that anti-inflammatory effect of Samulatng may be mediated by the suppression of cytokine production and COX-2 activation via down-regulation of NF-kB and ERK activation.

• Animal cells and systems
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• v.13 no.2
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• pp.133-139
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• 2009

Green tea seed was extracted with absolute ethanol,and the green tea seed extract(GTSE)was subjected to assays for toxicity, antioxidant ability, angiogenesis inhibitory effects and cell adhesion, as well as western blotting, and an in vivo experiment against 4 high-ranking adult cancers in Korea. Our series of experimental data demonstrated that GTSE has an antioxidant ability superior to that of EGCG in the green tea leaf, and also exhibits a profound high tumor growth inhibitory activity on a variety of cancer cell lines, as well as nude mice infected with cancer cells. GTSE was identified as a natural anticancer compound showing excellent angiogenesis inhibition and cancer cell suppression abilities. Our preliminary observations also indicate that GTSE may be another potential source of natural dietary antioxidants and also may be applicable as a novel natural anticancer agent.