• Molecular & Cellular Toxicology
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• 제2권1호
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• pp.15-20
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• 2006

Genistein is a potent, plant-derived isoflavone that displays estrogenic activity at low concentrations but inhibits proliferation at high amounts. However, the molecular mechanism of genistein is not completely understood. In the present study, the biphasic effects (estrogenic and antiestrogenic activity) of genistein on the growth of MCF-7 cells were identified. Genistein within a low range of concentration, $1-10\;{\mu}M$, stimulated proliferation, while $50-100\;{\mu}M$ caused apoptotic cell death. Additionally, genistein at a low concentration induced estrogen receptor (ER)-mediated gene expression and ER phosphorylation. When pre-treated with PD98059, an MEK inhibitor, ER-mediated gene expression and ER phosphorylation by genistein were noticeably increased. However, the increased gene expression and phosphorylation did not enhance cell proliferation. Moreover, it was observed that ER-mediated signaling performs an important role in the MAPK pathway. The proliferation and apoptosis in genistein-treated MCF-7 cells were partially dependent on the Bcl-2 level. The addition of IC1 182, 780, an estrogen receptor antagonist, inhibited Bcl-2 expression induced by genistein. This study suggests that there is a close relationship between Bcl-2 and the ER signaling pathways in MCF-7 cells.

• Biomolecules & Therapeutics
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• 제23권3호
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• pp.233-237
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• 2015

Shikonin, a natural flavonoid found in the roots of Lithospermum erythrorhizon, has been shown to possess many biological functions. The present study was undertaken to investigate the influence of shikonin on vascular smooth muscle contractility and to determine the mechanism involved. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Shikonin significantly relaxed fluoride-, thromboxane $A_2$- or phorbol ester-induced vascular contraction suggesting as a possible anti-hypertensive on the agonist-induced vascular contraction regardless of endothelial nitric oxide synthesis. Furthermore, shikonin significantly inhibited fluoride-induced increases in pMYPT1 levels and phorbol ester-induced increases in pERK1/2 levels suggesting the mechanism involving the inhibition of Rho-kinase activity and the subsequent phosphorylation of MYPT1 and the inhibition of MEK activity and the subsequent phosphorylation of ERK1/2. This study provides evidence regarding the mechanism underlying the relaxation effect of shikonin on agonist-induced vascular contraction regardless of endothelial function.

• Biomolecules & Therapeutics
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• 제22권4호
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• pp.282-287
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• 2014

We show that silymarin, a polyphenolic flavonoid isolated from milk thistle (Silybum marianum), inhibits cytokine mixture (CM: TNF-${\alpha}$, IFN-${\gamma}$, and IL-$1{\beta}$)-induced production of nitric oxide (NO) in the pancreatic beta cell line MIN6N8a. Immunostaining and Western blot analysis showed that silymarin inhibits iNOS gene expression. RT-PCR showed that silymarin inhibits iNOS gene expression in a dose-dependent manner. We also showed that silymarin inhibits extracellular signal-regulated protein kinase-1 and 2 (ERK1/2) phosphorylation. A MEK1 inhibitor abrogated CM-induced nitrite production, similar to silymarin. Treatment of MIN6N8a cells with silymarin also inhibited CM-stimulated activation of NF-${\kappa}B$, which is important for iNOS transcription. Collectively, we demonstrate that silymarin inhibits NO production in pancreatic beta cells, and silymarin may represent a useful anti-diabetic agent.

• Biomolecules & Therapeutics
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• 제24권1호
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• pp.57-61
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• 2016

Fisetin, a natural flavonoid found in a variety of vegetables and fruits, has been shown to possess many biological functions. The present study was undertaken to investigate the influence of fisetin on vascular smooth muscle contractility and to determine the mechanism involved. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Fisetin significantly relaxed fluoride-, thromboxane $A_2$- or phorbol ester-induced vascular contraction suggesting as a possible anti-hypertensive on the agonist-induced vascular contraction regardless of endothelial nitric oxide synthesis. Furthermore, fisetin significantly inhibited fluoride-induced increases in pMYPT1 levels and phorbol ester-induced increases in pERK1/2 levels suggesting the mechanism involving the inhibition of Rho-kinase activity and the subsequent phosphorylation of MYPT1 and MEK activity and the subsequent phosphorylation of ERK1/2. This study provides evidence regarding the mechanism underlying the relaxation effect of fisetin on agonist-induced vascular contraction regardless of endothelial function.

• Journal of Electrical Engineering and Technology
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• 제9권5호
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• pp.1780-1787
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• 2014

Arterial oxygen saturation ($SpO_2$) monitoring for newborns requires special attention in neonatal intensive care units (NICUs). Newborns have very low photo-plethysmogram (PPG) amplitudes and their body movements are difficult to contain. Hardware design and its associated signal processing algorithms should be robust enough so that faulty measurements can be avoided. In this study, improved designs were implemented to deal with low perfusion, motion artifact, and the influence of ambient light. Dynamic range was increased by using different LED intensities and a feedback system. To minimize the effects of motion artifact and to discard other unqualified data, four additional algorithms were used, which were based on dual-trace detection, continuity of DC level, morphology of PPG, and simultaneity check of $SpO_2$. Our $SpO_2$ system was tested with newborns with normal respiration in the NICU. Our system provided fast, real-time responses and 100% artifact detection was accomplished under 84% of $SpO_2$.

• BMB Reports
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• 제40권2호
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• pp.196-204
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• 2007

Our previous study has shown that sodium selenite can cause apoptosis in acute promyelocytic leukemia-derived NB4 cells in a caspase-dependent manner, but the detailed mechanism is unknown. Here we demonstrate a requirement for extracellular signal-regulated protein kinase (ERK) in mediating sodium selenite -induced apoptosis in NB4 cell. Though no apparent elevation of ERK activity was observed during the apoptosis in NB4 cells caused by 20 μM sodium selenite treatment, PD98059 and U0126, specific chemical inhibitors of the MEK/ERK signaling pathway, were shown to strongly prevent the apoptosis process, while ERK activator TPA enhanced the process. It is also known that p38 MAPK inhibitor SB203580 and JNK inhibitor SP600125 had slight effects on apoptosis. Further study indicated that ERK exerted its proapoptotic effect only at the early stage of apoptosis and played an antiapoptotic role at the later stages. Taken together, our findings suggest that ERK plays an active role in mediating sodium seleniteinduced apoptosis in NB4 cells .

• 대한의생명과학회지
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• 제16권2호
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• pp.119-122
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• 2010

Interleukin-1${\beta}$ $(IL-1{\beta})$ is one of the key proinflammatory cytokines and it plays an important role for the antimycobacterial host defense mechanisms. In this study, we examined Mycobacterium tuberculosis (MTB)-stimulated induction of IL-1${\beta}$ and evaluated the associated signal transduction pathways. In PMA-differentiated THP-1 cells, MTB infection increased mRNA expression of IL-$1{\beta}$ in a dose-dependent manner. The expression of IL-1${\beta}$ mRNA began to be induced at 1.5 h after infection, and induced expression of IL-1${\beta}$ was retained for 48 h after MTB infection. The increase in expression of IL-1${\beta}$ caused by MTB was reduced in cells treated with Ro-31-8425 (an inhibitor of PK$C{\alpha}$, ${\beta}I$, ${\beta}II$, ${\gamma}$, ${\varepsilon}$) or PD98059 (an inhibitor of MEK1), meanwhile, pre-treatment with $G\ddot{o}6976$ (an inhibitor of $Ca^{2+}$ dependent PK$C{\alpha}$ and PK$C{\beta}I$) or Rottlerin (an inhibitor of PK$C{\delta}$) has no effect on MTB-induced expression of $IL-1{\beta}$ mRNA. These results show that the expression of $IL-1{\beta}$ mRNA caused by MTB may be mediated via MEK1 and PKC isoforms including PK$C{\beta}II$, $PKC{\gamma}$, or $PKC{\varepsilon}$. Further studies are required to determine whether other PKC isoforms $(PKC {\eta},\;{\theta},\;{\varepsilon},\;and\;{\lambda}/{\iota})$, except $PKC{\delta}$, $PKC{\alpha}$, and $PKC{\beta}I$, are also involved in $IL-1{\beta}$ mRNA expression after mycobacterial infection.

• 공업화학
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• 제32권6호
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• pp.647-652
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• 2021

본 연구에서는 에탄올과 노말헥산을 이용하여 당목향 뿌리 추출물을 제조하고, 인체 모유두세포의 세포증식 및 모발성장 관련 신호전달에 미치는 영향을 평가하였다. 당목향 뿌리 추출물의 세포증식 효과는 MTT assay를 실시하였으며, ERK, Akt, Wnt/𝛽-catenin 신호 경로, 5𝛼-reductase의 발현을 western blot 분석을 통해 측정하였다. 당목향 뿌리 추출물은 인체 모유두세포의 증식을 유의하게 증가시켰고, 세포증식에 관여하는 ERK와 Akt의 인산화를 촉진하였으며, 당목향 뿌리 추출물에 의해 증가된 ERK, Akt 인산화 촉진과 세포증식은 MEK/ERK 억제제 PD98059와 PI3K/Akt 억제제 LY294002에 의해 유의하게 감소되었다. 또한 당목향 뿌리 추출물은 GSK-3𝛽 (Ser9)의 인산화를 통한 𝛽-catenin(Ser552, 675)의 인산화를 촉진함으로써 핵 내의 𝛽-catenin 축적을 유도하였고, 5𝛼-reductase type I, II의 활성을 억제하였다. 종합적으로 당목향 뿌리 추출물은 모유두세포의 ERK, Akt 경로의 활성화를 통해 세포의 증식을 유도하며, 𝛽-catenin 신호 경로 활성화 및 5𝛼-reductase 활성 억제를 통해 탈모 예방 및 모발 성장 효과를 나타냄으로써 헤어케어제품의 소재로 응용가능성이 있음을 시사한다.

• Food Science and Biotechnology
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• 제17권5호
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• pp.1079-1085
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• 2008

The chemopreventive activity of sulforaphane (SFN) occurs through its inhibition of carcinogen-activating enzymes and its induction of detoxification enzymes. However, the exact mechanisms by which SFN exerts its anti-carcinogenic effects are not fully understood. Therefore, the mechanisms underlying the cytoprotective effects of SFN were examined in MCF-7 breast cancer cells. Exposure of cells to SFN (10 ${\mu}M$) induced a transcriptional change in the AKR1C3 gene, which is one of aldo-keto reductases (AKRs) family that is associated with detoxification and antioxidant response. Further analysis revealed that SFN elicited a dose- and time-dependent increase in the expression of both the NRF2 and AKR1C3 proteins. Moreover, this up-regulation of AKR1C3 was inhibited by pretreatment with antioxidant, N-acetyl-L-cysteine (NAC), which suggests that the up-regulation of AKR1C3 expression induced by SFN involves reactive oxygen species (ROS) signaling. Furthermore, pretreatment of cells with LY294002, a pharmacologic inhibitor of phosphatidylinositol 3-kinase (PI3K), suppressed the SFN-augmented Nrf2 activation and AKR1C3 expression; however, inhibition of PKC or MEK1/2 signaling with $G\ddot{o}6976$ or PD98059, respectively, did not alter SFN-induced AKR1C3 expression. Collectively, these data suggest that SFN can modulate the expression of the AKR1C3 in MCF-7 cells by activation of PI3K via the generation of ROS.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2003년도 Annual Meeting of KSAP : International Symposium on Pharmaceutical and Biomedical Sciences on Obesity
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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.