• Title/Summary/Keyword: MAPK/ERK pathway

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Screening of the Bufonis Venenum on Hep G2 Cells (섬여가 간암(肝癌) 세포주 Hep G2에 미치는 효과)

  • Kang, A-my;Kim, Bo-Ram;Kim, Sung-Uk;Lim, Seong-Woo
    • The Journal of Korean Medicine
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    • v.29 no.4
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    • pp.171-179
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    • 2008
  • Objective: Bufonis Venenum is the traditional Korean medicine Chan Su, which is obtained from the skin and parotid venom gland of the toads. It has been used for myocardial diseases, inflammation diseases, pain relief, cancer and others. The main components of BV are cinobufotoxin, cinobufalin, bufalin and others. Of these, bufalin, the major active ingredient of BV, has been reported to induce apoptosis and to possess anti-tumor effects. There was no report of anti-tumor screening of BV on hepatic cancer and which signaling pathway can be involved. In order to examine the effect of BV on hepatic cancer and the related signaling pathway with BV-induced apoptosis, human Hep G2 cells were used. Methods: Analysis of apoptosis was confirmed by MTT assay. BV decreased cell viability in a dose and duration dependent manner. To observe which signaling molecules will be activated by BV, phosphorylation of MAPK (p38, ERK, JNK), caspase 8 and caspase 9 were examined by Western blot analysis. Results: The phosphorylation levels of p38 started to increase at 5 min after addition of 5 ${\mu}g$/ml of BV and sustained to increase until 48 hours. The phosphorylation levels of other MAPK (ERK and JNK), caspase 8 and caspase 9 increased in a time-dependent manner. These imply that BV may activate different signaling pathways, MAPK, caspase 8 and caspase 9. These results propose that BV may induce apoptosis on Hep G2 cells through the activation of MAPK, caspase 8 and caspase 9.

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Protective Role of Fucoidan in Cerebral Ischemia-Reperfusion Injury through Inhibition of MAPK Signaling Pathway

  • Che, Nan;Ma, Yijie;Xin, Yinhu
    • Biomolecules & Therapeutics
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    • v.25 no.3
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    • pp.272-278
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    • 2017
  • Fucoidan has been reported to exhibit various beneficial activities ranging from to antivirus and anticancer properties. However, little information is available about the effects of fucoidan on cerebral ischemia-reperfusion injury (IRI). Our study aimed to explore the effects of fucoidan on cerebral IRI, as well as the underlying mechanisms. Sprague-Dawley (SD) rats were randomly subjected to four groups: Sham, IRI+saline (IRI+S), IRI+80 mg/kg fucoidan (IRI+F80), and IRI+160 mg/kg fucoidan (IRI+F160). Fucoidan (80 mg/kg or 160 mg/kg) was intraperitoneally injected from 7 days before the rats were induced to cerebral IRI model with middle cerebral artery occlusion (MCAO) method. At 24 h after reperfusion, neurological deficits and the total infarct volume were determined. The levels of inflammation-associated cytokines (interleukin (IL)-$1{\beta}$, IL-6, myeloperoxidase (MPO), and tumor necrosis factor (TNF)-${\alpha}$), oxidative stress-related proteins (malondialdehyde (MDA) and superoxide dismutase (SOD)) in the ischemic brain were measured by enzyme-linked immunosorbent assay (ELISA). Besides, the levels of apoptosis-related proteins (p-53, Bax, and B-cell lymphoma (Bcl)-2) and mitogen-activated protein kinase (MAPK) pathway (phosphorylation-extracellular signal-regulated kinase (p-ERK), p-c-Jun N-terminal kinase (JNK), and p-p38) were measured. Results showed that administration of fucoidan significantly reduced the neurological deficits and infarct volume compared to the IRI+S group in a dose-dependent manner. Also, fucoidan statistically decreased the levels of inflammation-associated cytokines, and oxidative stress-related proteins, inhibited apoptosis, and suppressed the MAPK pathway. So, Fucoidan plays a protective role in cerebral IRI might be by inhibition of MAPK pathway.

Paraquat Induces Apoptosis through Cytochrome C Release and ERK Activation

  • Seo, Hong Joo;Choi, Sang Joon;Lee, Jung-Hee
    • Biomolecules & Therapeutics
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    • v.22 no.6
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    • pp.503-509
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    • 2014
  • Paraquat has been suggested to induce apoptosis by generation of reactive oxygen species (ROS). However, little is known about the mechanism of paraquat-induced apoptosis. Here, we demonstrate that extracellular signal-regulated protein kinase (ERK) is required for paraquat-induced apoptosis in NIH3T3 cells. Paraquat treatment resulted in activation of ERK, and U0126, inhibitors of the MEK/ERK signaling pathway, prevented apoptosis. Moreover, paraquat-induced apoptosis was associated with cytochrome C release, which could be prevented by treatment with the MEK inhibitors. Taken together, our findings suggest that ERK activation plays an active role in mediating paraquat-induced apoptosis of NIH3T3 cells.

The Phospholipase-Protein Kinase C-MEK-ERK Pathway is Essential in Mycobacteria-induced CCL3 and CCL4 Expression in Human Monocytes (사람 단핵구에서 결핵균에 의해 유도되는 CCL3 및 CCL4 발현에 대한 Phospholipase-Protein Kinase C-MEK-ERK 경로의 역할 분석)

  • Yang, Chul-Su;Song, Chang-Hwa;Jung, Saet-Byel;Lee, Kil-Soo;Kim, Su-Young;Lee, Ji-Sook;Shin, A-Rum;Oh, Jae-Hee;Kwon, Yu-Mi;Kim, Hwa-Jung;Park, Jeong-Kyu;Paik, Tae-Hyun;Jo, Eun-Kyeong
    • IMMUNE NETWORK
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    • v.5 no.4
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    • pp.237-246
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    • 2005
  • Background: Little information is available on the identification and characterization of the upstream regulators of the signal transduction cascades for Mycobacterium tuberculosis (M. tbc)-induced ERK 1/2 activation and chemokine expression. We investigated the signaling mechanisms involved in expression of CCL3 /MIP-1 and CCL4/MIP-1 in human primary monocytes infected with M. tbc. Methods: MAP kinase phosphorylation was determined using western blot analysis with specific primary antibodies (ERK 1/2, and phospho-ERK1/2), and the upstream signaling pathways were further investigated using specific inhibitors. Results: An avirulent strain, M. tbc H37Ra, induced greater and more sustained ERK 1/2 phosphorylation, and higher CCL3 and CCL4 production, than did M. tbc H37Rv. Specific inhibitors for mitogen-activated protein kinase (MAPK) kinase (MEK; U0126 and PD98059) significantly inhibited the expression of CCL3 and CCL4 in human monocytes. Mycobactetia-mediated expression of CCL3 and CCL4 was not inhibited by the Ras inhibitor manumycin A or the Raf-1 inhibitor GW 5074. On the other hand, phospholipase C (PLC) inhibitor (U73122) and protein kinase C (PKC)specific inhibitors ($G\ddot{o}6976$ and Ro31-8220) significantly reduced M. tbc-induced activation of ERK 1/2 and chemokine synthesis. Conclusion: These results are the first to demonstrate that the PLC-PKC-MEK-ERK, not the Ras-Raf-MEK-ERK, pathway is the major signaling pathway inducing M. tbc-mediated CCL3 and CCL4 expression in human primary monocytes.

Modulation of Activator Protein-1 (AP-1) and MAPK Pathway by Flavonoids in Human Prostate Cancer PC3 Cells

  • Gopalakrishnan, Avanthika;Xu, Chang-Jiang;Nair, Sujit S.;Chen, Chi;Hebbar, Vidya;Kong, Ah-Ng Tony
    • Archives of Pharmacal Research
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    • v.29 no.8
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    • pp.633-644
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    • 2006
  • In last couple of decades the use of natural compounds like flavonoids as chemopreventive agents has gained much attention. Our current study focuses on identifying chemopreventive flavonoids and their mechanism of action on human prostate cancer cells. Human prostate cancer cells (PC3), stably transfected with activator protein 1 (AP-1) luciferase reporter gene were treated with four main classes of flavonoids namely flavonols, flavones, flavonones, and isoflavones. The maximum AP-1 luciferase induction of about 3 fold over control was observed with $20\;{\mu}M$ concentrations of quercetin, chrysin and genistein and $50\;{\mu}M$ concentration of kaempferol. At higher concentrations, most of the flavonoids demonstrated inhibition of AP-1 activity. The MTS assay for cell viability at 24 h showed that even at a very high concentration $(500\;{\mu}M)$, cell death was minimal for most of the flavonoids. To determine the role of MAPK pathway in the induction of AP-1 by flavonoids, Western blot of phospho MAPK proteins was performed. Four out of the eight flavonoids namely kaempferol, apigenin, genistein and naringenin were used for the Western Blot analysis. Induction of phospho-JNK and phospho-ERK activity was observed after two hour incubation of PC3-AP1 cells with flavonoids. However no induction of phospho-p38 activity was observed. Furthermore, pretreating the cells with specific inhibitors of JNK reduced the AP-1 luciferase activity that was induced by genistein while pretreatment with MEK inhibitor reduced the AP-1 luciferase activity induced by kaempferol. The pharmacological inhibitors did not affect the AP-1 luciferase activity induced by apigenin and naringenin. These results suggest the possible involvement of JNK pathway in genistein induced AP-1 activity while the ERK pathway seems to play an important role in kaempferol induced AP-1 activity.

Anti-inflammatory Effects of Hemistepta lyrata Bunge in LPS-stimulated RAW 264.7 Cells through Regulation of MAPK Signaling Pathway (LPS로 유도된 RAW 264.7 대식세포의 염증반응에서 MAPK 신호경로 조절을 통한 지칭개 에탄올 추출물의 항염증 효과)

  • Kim, Chul Hwan;Lee, Young-Kyung;Jeong, Jin-Woo;Hwang, Buyng Su;Jeong, Yong Tae;Oh, Yong Taek;Cho, Pyo Yun;Kang, Chang-Hee
    • Korean Journal of Plant Resources
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    • v.34 no.1
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    • pp.23-30
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    • 2021
  • Hemistepta lyrata Bunge (HL) has been used as a folk remedy to treat cancer, inflammation, bleeding, hemorrhoids and fever, and leaves and young shoots have been used as famine food. Nevertheless, the biological activities and underlying mechanisms of the anti-inflammatory effects remain unclear. In this study, it was undertaken to explore the functions of the aerial part of HL as a suppressor of inflammation by using RAW 264.7 cells. As immune response parameters, the productions of as nitric oxide (NO) and prostaglandin E2 (PGE2), cytokines such tumor necrotic factor (TNF)-α and interleukin (IL)-6 were evaluated. Although the release of TNF-α remained unchanged in HL-treated RAW 264.7 cells, the productions of NO, PGE2 and IL-6 were significantly increased at concentrations with no cytotoxicity. Furthermore, HL significantly attenuated the mitogen-activated protein kinases (MAPK) pathway including decreasing the phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein kinases. Collectively, this study provides evidence that HL inhibits the production of major pro-inflammatory molecules in LPS-stimulated RAW 264.7 cells via suppression of ERK and P38 MAPK signaling pathways. These findings suggest that the beneficial therapeutic effects of HL may be attributed partly to its ability to modulate immune functions in macrophages.

IL-12 and IL-23 Production in Toxoplasma gondii- or LPS-Treated Jurkat T Cells via PI3K and MAPK Signaling Pathways

  • Ismail, Hassan Ahmed Hassan Ahmed;Kang, Byung-Hun;Kim, Jae-Su;Lee, Jae-Hyung;Choi, In-Wook;Cha, Guang-Ho;Yuk, Jae-Min;Lee, Young-Ha
    • Parasites, Hosts and Diseases
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    • v.55 no.6
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    • pp.613-622
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    • 2017
  • IL-12 and IL-23 are closely related in structure, and have been shown to play crucial roles in regulation of immune responses. However, little is known about the regulation of these cytokines in T cells. Here, we investigated the roles of PI3K and MAPK pathways in IL-12 and IL-23 production in human Jurkat T cells in response to Toxoplasma gondii and LPS. IL-12 and IL-23 production was significantly increased in T cells after stimulation with T. gondii or LPS. T. gondii and LPS increased the phosphorylation of AKT, ERK1/2, p38 MAPK, and JNK1/2 in T cells from 10 min post-stimulation, and peaked at 30-60 min. Inhibition of the PI3K pathway reduced IL-12 and IL-23 production in T. gondii-infected cells, but increased in LPS-stimulated cells. IL-12 and IL-23 production was significantly reduced by ERK1/2 and p38 MAPK inhibitors in T. gondii- and LPS-stimulated cells, but not in cells treated with a JNK1/2 inhibitor. Collectively, IL-12 and IL-23 production was positively regulated by PI3K and JNK1/2 in T. gondii-infected Jurkat cells, but negatively regulated in LPS-stimulated cells. And ERK1/2 and p38 MAPK positively regulated IL-12 and IL-23 production in Jurkat T cells. These data indicate that T. gondii and LPS induced IL-12 and IL-23 production in Jurkat T cells through the regulation of the PI3K and MAPK pathways; however, the mechanism underlying the stimulation of IL-12 and IL-23 production by T. gondii in Jurkat T cells is different from that of LPS.

Protective Effects of Pyropia yezoensis Glycoprotein against Ethanol-induced Chronic Gastric Injury in the Rat (만성적인 에탄올 섭취로 인한 쥐의 위 조직 손상에서 방사무늬 김(Pyropia yezoensis)의 보호효과)

  • Soma, Saeidi;Choi, Jeong Wook;Lee, Min Kyeong;Kim, Young Min;Kim, In Hye;Nam, Taek Jeong
    • Korean Journal of Fisheries and Aquatic Sciences
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    • v.47 no.6
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    • pp.765-769
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    • 2014
  • We examined the protective effects of Pyropia yezoensis glycoprotein (PYGP) against ethanol-induced gastric damage. The experimental animals were divided into four groups. They were treated with distilled water (control), ethanol alone (EtOH), ethanol + PYGP 150 mg/kg BW (EtOH+150), or ethanol + PYGP 300 mg/kg BW (EtOH+300). The groups were treated for 4 weeks. We measured mitogen-activated protein kinase (MAPK), the apoptotic signaling pathway, and PARP activity in gastric tissues obtained from the rats. Ethanol consumption increased apoptotic signal activity and ERK, JNK, and p38 phosphorylation. PYGP reduced the apoptotic signaling pathway activity and ERK, JNK, and p38 phosphorylation. Furthermore, PYGP regulated Bcl-2 family expression. In light of these findings, PYGP appears to prevent ethanol-induced gastric injury and oxidative stress.

Effect of Achyrantis Radixs on Rat Chondrocyte Oxidative Stress and Its Signal Transduction (우슬이 산화적 스트레스와 관련한 세포내 신호전달계에 미치는 영향)

  • Kim, Eun-Jung;Chung, Hun-Woo;Kim, Gye-Yeop
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.22 no.4
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    • pp.841-848
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    • 2008
  • Archyranthes radix has had extensive therapeutic application, and there has been increasing interest in its biological effects. However, the biochemical effects of Archyranthes radix on chondrocyte oxidative stress have never been systematically investigated. Therefore, we investigated the effects of Acyranthes radix on role of MAPK signal transduction pathway on oxidative stress induced by hydrogen peroxide in rat articular chondrocytes. The statistically significant inhibitory action of Archyranthes radix on cell proliferation was observed at above $5{\mu}g/m{\ell}$. Next, we examined the time-dependent effect of $5{\mu}g/m{\ell}$ Archyranthes radix on cell proliferaion. Archyranthes radix significantly inhibited cell proliferation from 12 hr after treatment (P<0.05). $H_2O_2$, resulted in a time- and dose-dependent cell proliferation, which was largely attributed to oxidative damage. Acyranthes radix and $H_2O_2$ treatment caused marked sustained activation of phosphorylation of ERK1/2. Moreover, the synergistic phosphorylation of p44/42 MAPK by $H_2O_2$ and Archyranthes radix was selectively inhibited by PD 98059, a p44/42 MAPK inhibitor. In conclusion, these results are consistent with the hypothesis that under conditions of oxidative stress, the $H_2O_2$-induced inhibition of cell proliferation in the rat chondrocyte is mediated through a modulation of the Archyranthes radix signaling pathway, promoting further phosphorylation of p44/42 MAPK, indicating a potentially important role in cartilage repair and in the treatment of osteoarthritic cartilage.

Critical role of protein L-isoaspartyl methyltransferase in basic fibroblast growth factor-mediated neuronal cell differentiation

  • Dung, To Thi Mai;Yi, Young-Su;Heo, Jieun;Yang, Woo Seok;Kim, Ji Hye;Kim, Han Gyung;Park, Jae Gwang;Yoo, Byong Chul;Cho, Jae Youl;Hong, Sungyoul
    • BMB Reports
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    • v.49 no.8
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    • pp.437-442
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    • 2016
  • We aimed to study the role of protein L-isoaspartyl methyltransferase (PIMT) in neuronal differentiation using basic fibroblast growth factor (bFGF)-induced neuronal differentiation, characterized by cell-body shrinkage, long neurite outgrowth, and expression of neuronal differentiation markers light and medium neurofilaments (NF). The bFGF-mediated neuronal differentiation of PC12 cells was induced through activation of mitogen-activated protein kinase (MAPK) signaling molecules [MAPK kinase 1/2 (MEK1/2), extracellular signal-regulated kinase 1/2 (ERK1/2), and p90RSK], and phosphatidylinositide 3-kinase (PI3K)/Akt signaling molecules PI3Kp110β, PI3Kp110γ, Akt, and mTOR. Inhibitors (adenosine dialdehyde and S-adenosylhomocysteine) of protein methylation suppressed bFGF-mediated neuronal differentiation of PC12 cells. PIMT-eficiency caused by PIMT-specific siRNA inhibited neuronal differentiation of PC12 cells by suppressing phosphorylation of MEK1/2 and ERK1/2 in the MAPK signaling pathway and Akt and mTOR in the PI3K/Akt signaling pathway. Therefore, these results suggested that PIMT was critical for bFGF-mediated neuronal differentiation of PC12 cells and regulated the MAPK and Akt signaling pathways.