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Saucerneol F, a New Lignan Isolated from Saururus chinensis, Attenuates Degranulation via Phospholipase Cγ1 Inhibition and Eicosanoid Generation by Suppressing MAP Kinases in Mast Cells

  • Lu, Yue;Son, Jong-Keun;Chang, Hyeun Wook
    • Biomolecules & Therapeutics
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    • v.20 no.6
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    • pp.526-531
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    • 2012
  • During our on-going studies to identify bioactive compounds in medicinal herbs, we found that saucerneol F (SF), a naturally occurring sesquilignan isolated from Saururus chinensis (S. chinensis), showed in vitro anti-inflammatory activity. In this study, we examined the effects of SF on the generation of 5-lipoxygenase (5-LO) dependent leukotriene $C_4$ ($LTC_4$), cyclooxygenase-2 (COX-2) dependent prostaglandin $D_2$ ($PGD_2$), and on phospholipase $C{\gamma}1$ ($PLC{\gamma}1$)-mediated degranulation in SCF-induced mouse bone marrow-derived mast cells (BMMCs). SF inhibited eicosanoid ($PGD_2$ and $LTC_4$) generation and degranulation dose-dependently. To identify the molecular mechanisms underlying the inhibition of eicosanoid generation and degranulation by SF, we examined the effects of SF on the phosphorylation of $PLC{\gamma}1$, intracellular $Ca^{2+}$ influx, the translocation of cytosolic phospholipase $A_2$ ($cPLA_2$) and 5-LO, and on the phosphorylation of MAP kinases (MAPKs). SF was found to reduce intracellular $Ca^{2+}$ influx by inhibiting $PLC{\gamma}1$ phosphorylation and suppressing the nuclear translocations of $cPLA_2$ and 5-LO via the phosphorylations of MAPKs, including extracellular signal-regulated protein kinase-1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Taken together, these results suggest that SF may be useful for regulating mast cell-mediated inflammatory responses by inhibiting degranulation and eicosanoid generation.

Effects of Triclosan on Neural Stem Cell Viability and Survival

  • Park, Bo Kyung;Gonzales, Edson Luck T.;Yang, Sung Min;Bang, Minji;Choi, Chang Soon;Shin, Chan Young
    • Biomolecules & Therapeutics
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    • v.24 no.1
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    • pp.99-107
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    • 2016
  • Triclosan is an antimicrobial or sanitizing agent used in personal care and household products such as toothpaste, soaps, mouthwashes and kitchen utensils. There are increasing evidence of the potentially harmful effects of triclosan in many systemic and cellular processes of the body. In this study, we investigated the effects of triclosan in the survivability of cultured rat neural stem cells (NSCs). Cortical cells from embryonic day 14 rat embryos were isolated and cultured in vitro. After stabilizing the culture, triclosan was introduced to the cells with concentrations ranging from $1{\mu}M$ to $50{\mu}M$ and in varied time periods. Thereafter, cell viability parameters were measured using MTT assay and PI staining. TCS decreased the cell viability of treated NSC in a concentration-dependent manner along with increased expressions of apoptotic markers, cleaved caspase-3 and Bax, while reduced expression of Bcl2. To explore the mechanisms underlying the effects of TCS in NSC, we measured the activation of MAPKs and intracellular ROS. TCS at $50{\mu}M$ induced the activations of both p38 and JNK, which may adversely affect cell survival. In contrast, the activities of ERK, Akt and PI3K, which are positively correlated with cell survival, were inhibited. Moreover, TCS at this concentration augmented the ROS generation in treated NSC and depleted the glutathione activity. Taken together, these results suggest that TCS can induce neurodegenerative effects in developing rat brains through mechanisms involving ROS activation and apoptosis initiation.

Water soluble tomato concentrate regulates platelet function via the mitogen-activated protein kinase pathway

  • Jeong, Dahye;Irfan, Muhammad;Saba, Evelyn;Kim, Sung-Dae;Kim, Seung-Hyung;Rhee, Man Hee
    • Korean Journal of Veterinary Research
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    • v.56 no.2
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    • pp.67-74
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    • 2016
  • Tomato extract has been shown to exert antiplatelet activity in vitro and to change platelet function ex vivo, but with limitations. In this study, antiplatelet activity of water soluble tomato concentrate (Fruitflow I) and dry water soluble tomato concentrate (Fruitflow II) was investigated using rat platelets. Aggregation was induced by collagen and adenosine diphosphate and granule-secretion, $[Ca^{2+}]_i$, thromboxane B2, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels were examined. The activation of integrin ${\alpha}_{IIb}{\beta}_3$ and phosphorylation of signaling molecules, including mitogen-activated protein kinase (MAPK) and PI3K/Akt, were investigated by flow cytometry and immunoblotting, respectively. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were examined. Moreover, in vivo thrombus weight was tested by an arteriovenous shunt model. Fruitflow I and Fruitflow II significantly inhibited agonist induced platelet aggregation, adenosine triphosphate and serotonin release, $[Ca^{2+}]_i$, and thromboxane B2 concentration, while having no effect on cAMP and cGMP levels. Integrin ${\alpha}_{IIb}{\beta}_3$ activation was also significantly decreased. Moreover, both concentrates reduced phosphorylation of MAPK pathway factors such as ERK, JNK, P38, and PI3K/Akt. In vivo thrombus formation was also inhibited. Taken together, these concentrates have the potential for ethnomedicinal applications to prevent cardiovascular ailments and can be used as functional foods.

Anti-inflammatory Effect of Dangyuja (Citrus grandis Osbeck) Leaves in LPS-stimulated RAW 264.7 Cells

  • Yang, Eun-Jin;Lee, Hye-Ja;Kang, Gyeoung-Jin;Park, Sun-Soon;Yoon, Weon-Jong;Kang, Hee-Kyoung;Cho, So-Mi Kim;Yoo, Eun-Sook
    • Food Science and Biotechnology
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    • v.18 no.5
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    • pp.1063-1070
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    • 2009
  • Dangyuja (Citrus grandis Osbeck) is a native plant growing only on Jeju Island in Korea. In this study, antiinflammatory effect of dangyuja leaves on a murine macrophage cell line was investigated. RAW 264.7 murine macrophage cells were stimulated with lipopolysaccharide (LPS, $1{\mu}g/mL$) to induce expression of pro-inflammatory markers [interleukin (IL)-6 and inducible nitric oxide synthase (iNOS)]. The crude extract (80% MeOH Ex.) and solvent fractions (hexane, $CHCl_3$, EtOAc, BuOH, and $H_2O$ Ex.) were obtained from dangyuja leaves. The $CHCl_3$ fraction inhibited the nitric oxide (NO) and IL-6 production in a dose-dependent manner. Also, the $CHCl_3$ fraction inhibited mRNA expression and protein levels of iNOS in a dose-dependent manner. Furthermore, the $CHCl_3$ fraction inhibited LPS-induced nuclear factor (NF)-${\kappa}B$ activation and phosphorylation of mitogen-activated protein kinases (MAPKs: ERK, JNK, and p38). These results suggest that dangyuja leaves may inhibit LPS-induced production of inflammatory markers by blocking NF-${\kappa}B$ and MAPKs signaling in RAW 264.7 cells.

Inhibitory Effects of Achyranthis Bidentatae Radix on Osteoclast Differentiation and Bone Resorption (우슬의 파골세포 분화 억제와 골 흡수 억제효과)

  • Kim, Ju-Ho;Ki, Ji-Ye;Ann, Ji-Young;Park, Hye-Jung;Kim, Hyun-Ju;Kwak, Han-Bok;Oh, Jae-Min;Kim, Yun-Kyung
    • The Korea Journal of Herbology
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    • v.25 no.1
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    • pp.65-74
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    • 2010
  • Objectives : Achyranthis Bidentatae Radix (ABR) has been used for treating of many symptoms especially osteoporosis and rheumatoid arthritis. In this study, we determined the effects of water extract of ABR in RANKL (Receptor Activator for Nuclear Factor $\kappa$ B Ligand)-induced osteoclast differentiation culture system. Methods : We assayed mRNA expression levels of NFATc1, c-Fos, TRAP, OSCAR, $FcR{\gamma}$, DAP12 and GAPDH in bone marrow macrophages (BMMs) treated with ABR. The protein expression levels of NFATc1, c-Fos, MAPKs and $\beta$-actin in cell lysates treated with ABR were analysed by Western blotting. In addition we determined the effects of water extract of ABR on LPS-induced bone-loss mouse. Results : Water extract of ABR showed remarkable inhibition on RANKL-treated osteoclast differentiation without cytotoxicity. ABR down-regulated the induction of c-Fos and NFATc1 by RANKL. ABR suppressed phosphorylation of JNK, p38 and I-${\kappa}B$. ABR rescued bone erosion by LPS induction in vivo study. Conclusions : These results demonstrate that ABR may be a useful remedy for curing of bone-loss disease such as osteoporosis.

Inhibitory effects of Nardostachys Jatamansi on the maturation of dendritic cells (감송향이 수지상세포 성숙에 미치는 영향)

  • O, Kwang-Woo;Jeong, Ji-Hye;Cheong, Hyun-Cheol;Cho, Han-Baek;Kim, Song-Baeg;Choe, Chang-Min
    • The Journal of Korean Obstetrics and Gynecology
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    • v.23 no.3
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    • pp.14-25
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    • 2010
  • Purpose: The purpose of this study is to investigate inhibitory effect on the maturation of dendritic cells from aqueous extract from Nardostachys Jatamansi(NJ). Methods: I examined the phenotypic maturation(class II MHC, CD40, CD86), expression of pro-inflammatory cytokine(TNF-$\alpha$, IL-6, IL-12) and endocytosis of FITC-Dextran in the LPS-induced bone marrow-derived dendritic cells(BMDCs) of mice. Furthermore, the Western-blot analysis reveals the mechanism of inhibitory effect. Results: 1. The NJ extract inhibited the phenotypic maturation of BMDCs in a dose-dependent manner. 2. The NJ extract inhibited the LPS induced cytokine production of BMDCs in a dose-dependent manner. 3. The NJ extract enhanced the endocytosis of Dex-FITC in LPS treated DC. 4. The NJ extract inhibited the activation of JNK and p38 phosphorylation, but not ERK phosphorylation of MAPK family and doesn't inhibit Ik-Ba degradation in LPS-stimulated BMDCs. Conclusion: These results suggest that NJ extract is able to attenuate the inflammation and maturation in BMDCs and may inhibit proliferation of T cells. In conclusion, this experiment suggests that NJ extract may be useful in hypersensitivity disease including autoimmune disease.

LPS Increases 5-LO Expression on Monocytes via an Activation of Akt-Sp1/NF-${\kappa}B$ Pathways

  • Lee, Seung Jin;Seo, Kyo Won;Kim, Chi Dae
    • The Korean Journal of Physiology and Pharmacology
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    • v.19 no.3
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    • pp.263-268
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    • 2015
  • 5-Lipoxygenase (5-LO) plays a pivotal role in the progression of atherosclerosis. Therefore, this study investigated the molecular mechanisms involved in 5-LO expression on monocytes induced by LPS. Stimulation of THP-1 monocytes with LPS ($0{\sim}3{\mu}g/ml$) increased 5-LO promoter activity and 5-LO protein expression in a concentration-dependent manner. LPS-induced 5-LO expression was blocked by pharmacological inhibition of the Akt pathway, but not by inhibitors of MAPK pathways including the ERK, JNK, and p38 MAPK pathways. In line with these results, LPS increased the phosphorylation of Akt, suggesting a role for the Akt pathway in LPS-induced 5-LO expression. In a promoter activity assay conducted to identify transcription factors, both Sp1 and NF-${\kappa}B$ were found to play central roles in 5-LO expression in LPS-treated monocytes. The LPS-enhanced activities of Sp1 and NF-${\kappa}B$ were attenuated by an Akt inhibitor. Moreover, the LPS-enhanced phosphorylation of Akt was significantly attenuated in cells pretreated with an anti-TLR4 antibody. Taken together, 5-LO expression in LPS-stimulated monocytes is regulated at the transcriptional level via TLR4/Akt-mediated activations of Sp1 and NF-${\kappa}B$ pathways in monocytes.

Immuno-Modulatory Activities of Polysaccharides Separated from Jubak in Macrophage Cells (주박(酒粕)에서 분리된 다당류의 대식세포 면역조절 활성)

  • Park, Woo-Young;Sung, Nak-Yun;Byun, Eui-Hong;Oh, Kwang-Hoon;Byun, Myung-Woo;Yoo, Yung Choon
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.44 no.7
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    • pp.1079-1083
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    • 2015
  • Activating macrophage cells play an important role in the host immune defense system. In this paper, immuno-modulatory activities of polysaccharides separated from Jubak (JPS) in macrophage cells were investigated. Immuno-modulatory activities were estimated based on cell proliferation, nitric oxide (NO) and cytokine production, degree of mitogen-activated protein kinases (MAPKs), and nuclear factor (NF)-${\kappa}B$ phosphorylation in RAW264.7 macrophage cells. JPS (62.5 to $250{\mu}g/mL$) did not induce a cytotoxic event. Additionally, NO and proinflammatory cytokines (tumor necrosis factor-${\alpha}$ and interleukin-6) production significantly increased in a dose-dependent manner. Similarly, phosphorylation of MAPKs and NF-${\kappa}B$ increased upon JPS treatment. Therefore, our results suggest that polysaccharides separated from Jubak can induce macrophage activation through MAPK and NF-${\kappa}B$ signaling and induction of Th1 polarization.

Mycobacterial Heparin-binding Hemagglutinin Antigen Activates Inflammatory Responses through PI3-K/Akt, NF-${\kappa}B$, and MAPK Pathways

  • Kim, Ki-Hye;Yang, Chul-Su;Shin, A-Rum;Jeon, So-Ra;Park, Jeong-Kyu;Kim, Hwa-Jung;Jo, Eun-Kyeong
    • IMMUNE NETWORK
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    • v.11 no.2
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    • pp.123-133
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    • 2011
  • Background: Mycobacterium tuberculosis (Mtb) heparin binding hemagglutinin (HBHA) is an Ag known to evoke effective host immune responses during tuberculosis infection. However, the molecular basis of the host immune response to HBHA has not been fully characterized. In this study, we examined the molecular mechanisms by which HBHA can induce the expression of proinflammatory cytokines in macrophages. Methods: HBHA-induced mRNA and protein levels of proinflammatory cytokines were determined in bone marrow-derived macrophages (BMDMs) using RT-PCR and ELISA analysis. The roles of intracellular signaling pathways for NF-${\kappa}B$, PI3-K/Akt, and MAPKs were investigated in macrophage proinflammatory responses after stimulation with HBHA. Results: HBHA robustly activated the expression of mRNA and protein of both TNF-${\alpha}$ and IL-6, and induced phosphorylation of NF-${\kappa}B$, Akt, and MAPKs in BMDMs. Both TNF-${\alpha}$ and IL-6 production by HBHA was regulated by the NF-${\kappa}B$, PI3-K, and MAPK pathways. Furthermore, PI3-K activity was required for the HBHA-induced activation of ERK1/2 and p38 MAPK, but not JNK, pathways. Conclusion: These data suggest that mycobacterial HBHA significantly induces proinflammatory responses through crosstalk between the PI3-K and MAPK pathways in macrophages.

Anti-inflammatory Effect of Zostera marina Ethanolic Extract on LPS-induced RAW264.7 Cells and Mouse Model (LPS로 유도된 RAW264.7 Cell과 마우스모델에 대한 잘피 에탄올 추출물의 항염증 효과)

  • Kim, Min-Ji;Bae, Nan-Young;Kim, Koth-Bong-Woo-Ri;Park, Ji-Hye;Park, Sun-Hee;Cho, Young-Je;Ahn, Dong-Hyun
    • KSBB Journal
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    • v.30 no.4
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    • pp.182-190
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    • 2015
  • The Zostera marina ethanolic extract (ZMEE) was tested in this study to investigate the anti-inflammatory activity in LPS-induced RAW 264.7 cells and mouse model. Nitric oxide production and inducible nitiric oxide synthase expression in cells treated with ZMEE was reduced significantly in a dose-dependent manner. Similarly, the secretion of pro-inflammatory cytokines such as interleukin (IL)-6, IL-$1{\beta}$, and TNF-${\alpha}$ was inhibited markedly. In addition, the expression of nuclear factor kappa B (NF-${\kappa}B$) and the phosphorylation of JNK, ERK, and p38 MAPKs was suppressed by ZMEE as well. In vivo test, ZMEE attenuated the croton oil-induced mouse ear edema and there were no mortalities in mice administered 5,000 mg/kg body weight of ZMEE during the observation periods. The results in photomicrograph of mice ear tissue showed the reduction of dermal thickness and the number of infiltrated mast cells. These results indicate that ZMEE inhibits the production of LPS-induced pro-inflammatory mediators, suggesting that ZMEE may be a potential material for anti-inflammatory therapies.