• The Korean Journal of Physiology and Pharmacology
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• 제18권1호
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• pp.61-66
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• 2014

Lung cancer is still the number one cause of death from cancer worldwide. The clinical effect of platinum-based chemotherapy for non-small cell lung cancer is constrained by the resistance to drug. To overcome chemo-resistance, various modified treatment including combination therapy has been used, but overall survival has not been improved yet. In this study, chemo-resistant lung cancer cells, A549/Cis and H460/Cis, were developed by long-term exposure of cells to cisplatin and the proliferative capability of these resistant cells was verified to be reduced. We found cytotoxic effect of epigallocatechin gallate (EGCG), a major catechin derived from green tea, on both the parental lung cancer cells, A549 and H460, and their cisplatin resistant cells, A549/Cis and H460/Cis. ELISA and Western blot analysis revealed that EGCG was able to increase interlukine-6 (IL-6) production per cell, whereas its downstream effector Signal transducers and activators of transcription 3 (STAT3) phosphorylation was not changed by EGCG, indicating that IL-6/STAT3 axis is not the critical signaling to be inhibited by EGCG. We next found that EGCG suppresses the expression of both Axl and Tyro 3 receptor tyrosine kinases at mRNA and protein level, explaining the cytotoxic effect of EGCG on lung cancer cells, especially, regardless of cisplatin resistance. Taken together, these data suggest that EGCG impedes proliferation of lung cancer cells including their chemo-resistant variants through downregulation of Axl and Tyro 3 expression.

• Natural Product Sciences
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• 제26권2호
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• pp.136-143
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• 2020

Psoriasis is one of the most common inflammatory skin disorders, with a global prevalence of 2% - 3%. It is an autoimmune skin disorder characterized by excessive generation of plaques on the skin with typical long-lasting red, itchy, and scaly lesions. In this study, we aimed to elucidate the anti-psoriatic effect of the methanolic extract of Persicaria senticosa (PS), a bioactive edible plant extract used in traditional medicine, using a mouse model of imiquimod (IMQ)-induced psoriasis. The daily topical application of IMQ could induce human psoriasis-like lesion. The extract ameliorated IMQ-induced psoriasis. Furthermore, hematoxylin and eosin staining and the Psoriasis Area and Severity Index (PASI) scores indicated that topical application of PS led to an improvement in erythema, scaling, and thickness scores of the mouse dorsal skin and a considerable decrease in the epidermal thickness of the ear and dorsal skin in the IMQ-induced psoriatic mouse model. We also studied the effect of PS on the proliferation of keratinocytes using HaCaT cells. The extract inhibited cell proliferation and IL-6 and pSTAT3 expression induced by M5 cocktail (comprising interleukin [IL]-1α, IL-17A, IL-22, oncostatin M, and tumor necrosis factor-α) in HaCaT cells. Thus, PS might serve as a potential therapeutic agent for the treatment of psoriasis.

• 대한한방소아과학회지
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• 제32권2호
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• pp.1-10
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• 2018

Objectives This study investigated the effects of Hataedock treatment with Douchi on induction of allergic rhinitis in obese induced NC/Nga mice. Methods NC/Nga mice were divided into control group (Ctrl), allergic rhinitis induced obese mice group (ARE), and allergic rhinitis induced obese mice group with Douchi Hataedock treatment (FGT). The 3-week-old mice of the FGT group were given one 10 mg/kg dose of Douchi Hataedock extract and sensitized with allergic antigens at weeks 4, 5, and 6. After 1 week of final sensitization, allergic rhinitis was induced primarily in mice nasal cavities for five days. After one week of the completion with the first induction, the second induction was introduced by the same method. After 1 week, few samples of the nasal mucosal tissues of each group were prepared. The factor of Th2 differentiation and inflammation control such that IL-4, STAT6, CD40, $Fc{\varepsilon}RI$, substance P, MMP-9, $NF-{\kappa}B$ p65, p-IkB, iNOS and COX-2 were observed by immunohistochemistry. Also, the difference in nasal mucosal injury was observed by histochemical method (PAS staining). Results The FGT group showed that reduced IL-4 production, STAT6 expression and CD40 expression by regulating excessive Th2 differentiation. Also, production of substance P and MMP-9 and activity of $Fc{\varepsilon}RI$ in mast cells were decreased. Inhibition of $NF-{\kappa}B$ p65 activity was induced by inhibition of p-IkB, and the production of inflammatory enzymes iNOS and COX-2 were decreased. In addition, the damage of intramural respiratory epithelium was low and excessive mucin secretion in goblet cells was low. Conclusions This study confirmed the possibility of controlling the allergic rhinitis in obese children who are expected to have an overactive inflammation.

• 동의생리병리학회지
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• 제38권1호
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• pp.32-37
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• 2024

The aim of this study was to investigate the role of Daesiho-tang (Da Chai Hu-Tang) water extract (DSTE) in regulating chronic stress-induced cancer progression, focusing on its activity in modulating tumor-associated macrophages (TAMs). Different stimuli can polarize TAMs into immune-stimulating M1 macrophages or immunosuppressive M2 macrophages. During cancer progression, M2 phenotype increases and supports tumor growth, angiogenesis and metastasis. Notably, chronic stress-induced catecholamines promote M2 macrophage polarization. In this study, we investigated whether DSTE regulates norepinephrine (NE)-induced M2 macrophage polarization in RAW 264.7 mouse macrophage cells. Even though NE itself did not increase the expression of M2 markers, the conditioned media of NE-treated 4T1 mouse breast cancer cells (NE CM) significantly up-regulated M2 markers in RAW 264.7 cells, suggesting that NE-regulated cancer cell secretome stimulated M2 polarization. However, such increase was abrogated by DSTE. NE CM also induced phosphorylation of signal transducer and activator of transcription 6 (STAT6) in RAW 264.7 cells, which was clearly reversed by pretreatment with DSTE, demonstrating that DSTE inhibited M2 polarization by inactivating STAT6. Finally, M2-polarized RAW264.7 cells by NE CM markedly increased the migration of 4T1 cells. However, such increase was completely reversed by co-treating RAW264.7 cells with NE CM and DSTE, indicating that DSTE attenuated cancer cell migration by blocking M2 polarization. Taken together, our results suggest a probable use of DSTE for cancer patients under chronic stress by regulating M2 macrophage polarization.

• Asian Pacific Journal of Cancer Prevention
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• 제16권6호
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• pp.2219-2225
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• 2015

SHP1 negatively regulates the Janus kinase 2/signal transducer and activator of transcription (JAK2/STAT) signaling pathway, which is constitutively activated in myeloproliferative neoplasms (MPNs) and leukemia. Promoter hypermethylation resulting in epigenetic inactivation of SHP1 has been reported in myelomas, leukemias and other cancers. However, whether SHP1 hypermethylation occurs in MPNs, especially in Chinese patients, has remained unclear. Here, we report that aberrant hypermethylation of SHP1 was observed in several leukemic cell lines and bone marrow mononuclear cells from MPN patients. About 51 of 118 (43.2%) MPN patients including 23 of 50 (46%) polycythaemia vera patients, 20 of 50 (40%) essential thrombocythaemia and 8 of 18 (44.4%) idiopathic myelofibrosis showed hypermethylation by methylation-specific polymerase chain reaction. However, SHP1 methylation was not measured in 20 healthy volunteers. Hypermethylation of SHP1 was found in MPN patients with both positive (34/81, 42%) and negative (17/37, 45.9%) JAK2V617F mutation. The levels of SHP1 mRNA were significantly lower in hypermethylated samples than unmethylated samples, suggesting SHP1 may be epigenetically inactivated in MPN patients. Furthermore, treatment with 5-aza-2'-deoxycytidine (AZA) in K562 cells showing hypermethylation of SHP1 led to progressive demethylation of SHP1, with consequently increased reexpression of SHP1. Meanwhile, phosphorylated JAK2 and STAT3 were progressively reduced. Finally, AZA increased the expression of SHP1 in primary MPN cells with hypermethylation of SHP1. Therefore, our data suggest that epigenetic inactivation of SHP1 contributes to the constitutive activation of JAK2/STAT signaling. Restoration of SHP1 expression by AZA may contribute to clinical treatment for MPN patients.

• 대한본초학회지
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• 제27권1호
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• pp.59-64
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• 2012

Objective : This study was performed to evaluate the effect of Forsythiae Fructus (FF) ethanol extract on inflammatory cytokine production and its underlying mechanisms in mouse macrophages. Methods : Peritoneal macrophages from thioglycollate medium-injected mice were cultured and stimulated with lipopolysaccharide(LPS) or LPS/interferon(IFN)-${\gamma}$ for cytokine measurement and cellular signaling molecule analysis. Results : FF ethanol extract decreased the levels of secreted tumor necrosis factor(TNF)-${\alpha}$ and interleukin(IL)-6 in IFN-${\gamma}$/LPS-stimulated cells in a concentration-dependent manner. FF extract reduced IFN-${\gamma}$/LPS-induced STAT1 phosphorylation and LPS-induced p38 and JNK activation, but not ERK1/2 activity. The extract also inhibited LPS-induced $I{\kappa}B{\alpha}$ degradation through suppression of $I{\kappa}B{\alpha}$ kinase. Conclusions : These results suggest that FF ethanol extract affects the production of TNF-${\alpha}$ and IL-6 through inhibition of activation of STAT-1, $I{\kappa}B{\alpha}$, p38, and JNK.

• 대한한방내과학회지
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• 제27권1호
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• pp.72-83
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• 2006

Objective : This study was designed to identify lipid protection formation in stratum corneum and anti-inflammatory effects of Sopungdojeok-tang(SD) on atopic dermatitis(AD). Materials and Methods : In Vivo, SD extract was orally administered to BALB/c mice at $2.5m{\ell}/kg/day$ for 2 days after 5% sodium dodecyl sulfate evoked atopic dermatitis in abdominal skin. Morphological changes were observed by immunohistochemical stain using monoclonal antibodies(BrdU, ceramide, MIP-2, $NF-{\kappa}B$ p50, IL-4, and STAT6) and TUNEL method. In vitro, the alterations of IL-4 mRNA expression were detected by RT-PCT in SD extract treated EL4 cells after phorbol-12-myristate-13-acetate and 4-tert-Octylphenol induce Th2 skewed condition. Results : SD is used in Oriental Medicine for its potential curative for atopic dermatitis. In this study, we have investigated the anti-inflammatory and lipid lamella repair effects of SD were investigated. SD decreased the number of eosinophil in atopic dermatitis induced mice. In the histological properties, the hyperplasia, edema, infiltration of lymphocytes, damage of intercellular space of stratum corneum, BrdU positive reacted cells in stratum basal, and degranulated mast cells and capillaries in dermal papillae decreased in mice with SD. Treatment of SD also decreased MIP-2, STAT6 and IL-4 in dermal papillae. The IL-4 mRNA expression decreased in a dose-dependant manner in SD treated EL4 cells. In addition, decrease of $NF-{\kappa}B$ p50 and increase of apoptotic cells in dermis were observed in SD treated mice. These data suggest that SD may beneficial for atopic dermatitis. Conclusions : These data suggest that SD is beneficial in treatment of atopic dermatitis, and that SD provides lipid protection in stratum corneum and anti-inflammatory effects on atopic dermatitis.

• 대한한방내과학회지
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• 제38권4호
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• pp.468-478
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• 2017

Objectives: This study investigated the effects of Douchi Hataedock on Th2-skewed conditions to control allergic rhinitis. Methods: NC/Nga mice were divided into three groups: 10 mice were assigned to the control group (CTRL; no treatment), 10 mice to allergic rhinitis-induced (ARE) without treatment group, and 10 mice to the allergic rhinitis-induced (FGT) after Douchi Hataedock treatment group. The 3-week-old mice of the FGT group were given one 10 mg/kg dose of Douchi Hataedock extract and resensitized to allergic antigens at weeks four, five, and six. Allergic rhinitis was induced primarily in mice nasal cavities for five days after one week of final sensitization. The second induction used the same method one week after the first induction was completed. After one week, the nasal mucosal tissues of each group were observed. Immunohistochemical staining for IL-4, STAT6, CD40, $Fc{\varepsilon}RI$, substance P, MMP-9, $NF-{\kappa}B$ p65, p-IkB, and iNOS in the nasal mucosa was also performed. Results: The FGT group had less respiratory epithelial damage and less mucin secretion in goblet cells than the ARE group and showed a 62% decrease in IL-4, 85% decrease in STAT6, 71% decrease in CD40, 69% decrease in $Fc{\varepsilon}RI$, 43% decrease in substance P, 49% decrease in MMP-9, 43% decrease in NF-kB p65, 38% decrease in p-IkB, and 73% decrease in iNOS compared to the ARE group. Conclusions: Douchi Hataedock lessens inflammation in epithelial and goblet cells and reduces inflammatory mediator secretion in a mouse allergic rhinitis model.

• Biomolecules & Therapeutics
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• 제20권6호
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• pp.513-519
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• 2012

Although the immense efforts have been made for cancer prevention, early diagnosis, and treatment, cancer morbidity and mortality has not been decreased during last forty years. Especially, lung cancer is top-ranked in cancer-associated human death. Therefore, effective strategy is strongly required for the management of lung cancer. In the present study, we found that novel daphnane diterpenoids, yuanhualine (YL), yuanhuahine (YH) and yuanhuagine (YG) isolated from the flower of Daphne genkwa (Thymelaeaceae), exhibited potent anti-proliferative activities against human lung A549 cells with the $IC_{50}$ values of 7.0, 15.2 and 24.7 nM, respectively. Flow cytometric analysis revealed that the daphnane diterpenoids induced cell-cycle arrest in the G0/G1 as well as G2/M phase in A549 cells. The cell-cycle arrests were well correlated with the expression of checkpoint proteins including the up-regulation of cyclin-dependent kinase inhibitor p21 and p53 and down-regulation of cyclin A, cyclin B1, cyclin E, cyclin dependent kinase 4, cdc2, phosphorylation of Rb and cMyc expression. In the analysis of signal transduction molecules, the daphnane diterpenoids suppressed the activation of Akt, STAT3 and Src in human lung cancer cells. The daphnane diterpenoids also exerted the potent anti-proliferative activity against anticancer-drug resistant cancer cells including gemcitabine-resistant A549, gefitinib-, erlotinib-resistant H292 cells. Synergistic effects in the growth inhibition were also observed when yuanhualine was combined with gemcitabine, gefitinib or erlotinib in A549 cells. Taken together, these findings suggest that the novel daphnane diterpenoids might provide lead candidates for the development of therapeutic agents for human lung cancers.

• KSBB Journal
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• 제18권3호
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• pp.197-201
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• 2003

알콜증류 폐액에 빵효모를 배양하는 중에 포도당, 암모늄 및 인산을 자동 첨가하여 균체량을 효율적으로 증가시킴으로써 폐액의 재이용성을 향상시키고자 하였다. 포도당은 DO를 제어파라미터로 하는 제어방법을 사용하여 자동 첨가함으로서 그 농도를 300 mg/L 이하로 유지하였다. 암모늄은 pH-stat 방법을 사용하여 N $H_4$OH로서 자동 첨가함으로서 12.6~17.4mM의 낮은 농도범위로 유지하였다. 인산의 경우에는 분석방법으로써 ascorbic acid법을 채택한 자동화 FIA sysetm을 제작하여 사용하였다. 이 system으로 배양 19.4 시간 후부터 배양액을 자동분석하고 제어한 결과 배양액의 P $O_4$-P 농도를 23.3~43.4 mg/L 의 낮은 농도범위로 유지할 수 있었다. 세가지 영양성분을 자동첨가하면서 배양한 결과 증식의 정체없이 균체량을 33.0배 더 증가시킬 수 있었다. 비증식속도는 0.19 $hr^{－l}$였다.