• Natural Product Sciences
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• 제15권1호
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• pp.32-36
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• 2009

Glutamate causes neurotoxicity through formation of reactive oxygen species and activation of mitogen-activated protein kinase (MAPK) pathways. MAPK phosphatase-1 (MKP-1) is one of the phosphatases responsible for dephosphorylation/deactivation of three MAPK families: the extracellular signal-regulated kinase-1/2 (ERK-1/2), the c-Jun N-terminal kinase-1/2 (JNK-1/2), and the p38 MAPK. In this report, the potential involvement of MKP-1 in neuroprotective effects of curcumin, the active ingredient of turmeric (Curcuma longa), was examined using HT22 cells. Glutamate caused cell death and activation of ERK-1/2 but not p38 MAPK or JNK-1/2. Blockage of ERK-1/2 by its inhibitor protected HT22 cells against glutamate-induced toxicity. Curcumin attenuated glutamate-induced cell death and ERK-1/2 activation. Interestingly, curcumin induced MKP-1 activation. In HT22 cells transiently transfected with small interfering RNA against MKP-1, curcumin failed to inhibit glutamate-induced ERK-1/2 activation and to protect HT22 cells from glutamate-induced toxicity. These results suggest that curcumin can attenuate glutamate-induced neurotoxicity by activating MKP-1 which acts as the negative regulator of ERK-1/2. This novel pathway may contribute to and explain at least one of the neuroprotective actions of curcumin.

• BMB Reports
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• 제51권4호
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• pp.194-199
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• 2018

Mesenchymal stem cells (MSCs) have shown great potential in treating bone deficiency. Human adipose-derived stem cells (HASCs) are multipotent progenitor cells with multi-lineage differentiation potential. Human amnion-derived mesenchymal stem cells (HAMSCs) are capable of promoting osteogenic differentiation of MSCs. In this study, we investigated the effect of HAMSCs on HASCs by a transwell co-culture system. HAMSCs promoted proliferation, osteogenic differentiation, angiogenic potential and adiponectin (APN) secretion of HASCs. Moreover, the positive effect of HAMSCs was significantly inhibited by U0126, a highly selective inhibitor of extracellular signaling-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway. These observations suggested that HAMSCs induced bone regeneration in HASCs via ERK1/2 MAPK signaling pathway.

• 생명과학회지
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• 제21권2호
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• pp.242-250
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• 2011

본 연구에서는 C2C12 근육 세포에서 IGF-I이 리간드 비의존적으로 엔드로젠 수용체 coactivator 유전자 발현에 미치는 영향에 대해 알아보았다. 그 결과 IGF-I 이 리간드 비의존적으로 엔드로젠 수용체의 coactivator인 GRIP-1, SRC-1, ARA70 유전자들의 단백질과 mRNA 발현을 증가시켰으며, p38 MAPK와 ERK1/2 신호전달 경로 억제제인 SB203580과 PD98059를 IGF-I과 함께 처리한 결과 IGF-I에 의한 엔드로젠 수용체 coactivator 유전자 발현의 증가를 감소시켰음을 알 수 있었다. 엔드로젠 수용체 coactivator가 엔드로젠 물질이 없이도 IGF-I에 의해 발현이 증가하였다는 사실은 운동에 의해 근육에서 분비가 증가하는 IGF-I이 리간드 비의존적으로 근육 세포에서 엔드로젠 수용체 활성화 안정에 기여하는 엔드로젠 수용체 coactivator를 활성화 시킬 수 있다는 사실을 증명 하였다는데 의의가 있다고 사료된다. 또한, IGF-I의 하부신호전달 경로로 잘 알려진 p38 MAPK와 ERK1/2 신호전달 경로를 차단하였을 때는 발현이 억제되었는데 이를 통해 IGF-I이 근육세포 내에서 p38 MAPK, ERK1/2 경로를 통해 엔드로젠 수용체 coactivator 발현에 중요한 역할을 한다는 사실을 확인할 수 있었다. 이러한 결과는 근육에서 중요한 기능을 담당하는 IGF-I이 엔드로젠 수용체 coactivator 유전자 발현을 조절하는 기능이 있으며 이러한 IGF-I에 의한 리간드 비의존적인 엔드로젠 수용체 coactivator 유전자 발현 조절에 있어 p38 MAPK와 ERK1/2는 필수적인 신호전달 경로임을 확인하였다는 데서 그 의의가 있다고 할 수 있겠다. 향후 다양한 성장인자들에 의한 coactivator 발현에 관한 연구를 비롯하여, corepressor의 발현 억제 기능 및 신호전달 경로에 관한 연구가 추가적으로 이루어져야 할 것이다.

• Asian Pacific Journal of Cancer Prevention
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• 제15권20호
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• pp.8539-8548
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• 2014

Mitogen-activated protein kinase (MAPK) is an important signaling pathway in living beings in response to extracellular stimuli. There are 5 main subgroups manipulating by a set of sequential actions: ERK(ERK1/ERK2), c-Jun N(JNK/SAPK), p38 MAPK($p38{\alpha}$, $p38{\beta}$, $p38{\gamma}$ and $p38{\delta}$), and ERK3/ERK4/ERK5. When stimulated, factors of upstream or downstream change, and by interacting with each other, these groups have long been recognized to be related to multiple biologic processes such as cell proliferation, differentiation, death, migration, invasion and inflammation. However, once abnormally activated, cancer may occur. Several components of the MAPK network have already been proposed as targets in cancer therapy, such as p38, JNK, ERK, MEK, RAF, RAS, and DUSP1. Among them, alteration of the RAS-RAF-MEK-ERK-MAPK(RAS-MAPK) pathway has frequently been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations in genes. The reported roles of MAPK signaling in apoptotic cell death are controversial, so that further in-depth investigations are needed to address these controversies. Based on an extensive analysis of published data, the goal of this review is to provide an overview on recent studies about the mechanism of MAP kinases, and how it generates certain tumors, as well as related treatments.

• BMB Reports
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• 제41권3호
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• pp.242-247
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• 2008

MSS, a comprising mixture of maesil (Prunus mume Sieb. et Zucc) concentrate, disodium succinate and Span80 (3.6 : 4.6 : 1 ratio) showed a significant improvement of memory when daily administered (460 mg/kg day, p.o.) into the normal rats for 3 weeks. During the spatial learning of 4 days in Morris water maze test, both working memory and short-term working memory index were significantly increased when compared to untreated controls. We investigated a molecular signal transduction mechanism of MSS on the behaviors of spatial learning and memory. MSS treatment increased hippocampal mRNA levels of NR2B and TrkB without changes of NR1, NR2A, ERK1, ERK2 and CREB. However, the protein levels of pERK/ERK and pCREB/CREB were all significantly increased to $1.5{\pm}0.17$ times. These results suggest that the improving effect of spatial memory for MSS is linked to MAPK/ERK signaling pathway that ends up in the phosphorylation of CREB through TrkB and/or NR2B of NMDA receptor.

• 생명과학회지
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• 제29권1호
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• pp.129-134
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• 2019

이전 연구에서 전통주 주박 ethyl acetate 분획물로부터 11개의 순수물질을 분리 동정하였다. 11개의 순수물질은 caffeic acid, coumaric acid, D-mannitol, ferulic acid, hesperetin, hesperidin, naringenin, naringin, sinapic acid, syringic acid, 그리고 vanilic acid로 동정되었다. 이번 연구에서는 그들의 항염증 활성을 연구하기 위하여 LPS로 활성화된 RAW 264.7 세포에서 nitric oxide (NO) 생산을 측정하였다. 11개의 순수물질 중 hesperetin과 naringenin이 가장 높은 NO 생성 억제를 보여주었다. 또한, hesperetin은 세포 생존율에 영향 없이 농도의존적으로 NO 생산을 저해하였다. 그리고, hesperetin은 농도의존적으로 염증유전자인 iNOS의 발현을 농도의존적으로 억제한 반면, COX-2 단백질의 발현에는 영향을 주지 않았다. 게다가, hesperetin은 p38 MAPK와 ERK1/2의 인산화를 억제한 반면 JNK의 인산화에는 영향을 주지 못했다. 이러한 결과는 hesperetin은 항염증 활성을 가지며, 이러한 항염증 활성은 p38 MAPK와 ERK1/2 경로를 억제함으로써 일어난다는 것을 나타낸다.

• Molecules and Cells
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• 제39권3호
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• pp.186-194
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• 2016

Epidemiological evidence suggests that bone is especially sensitive to oxidative stress, causing bone loss in the elderly. Previous studies indicated that human amnion-derived mesenchymal stem cells (HAMSCs), obtained from human amniotic membranes, exerted osteoprotective effects in vivo. However, the potential of HAMSCs as seed cells against oxidative stress-mediated dysfunction is unknown. In this study, we systemically investigated their antioxidative and osteogenic effects in vitro. Here, we demonstrated that HAMSCs significantly promoted the proliferation and osteoblastic differentiation of $H_2O_2$-induced human bone marrow mesenchymal stem cells (HBMSCs), and down-regulated the reactive oxygen species (ROS) level. Further, our results suggest that activation of the ERK1/2 MAPK signal transduction pathway is essential for both HAMSCs-mediated osteogenic and protective effects against oxidative stress-induced dysfunction in HBMSCs. U0126, a highly selective inhibitor of extracellular ERK1/2 MAPK signaling, significantly suppressed the antioxidative and osteogenic effects in HAMSCs. In conclusion, by modulating HBMSCs, HAMSCs show a strong potential in treating oxidative stress- mediated bone deficiency.

• Journal of Oral Medicine and Pain
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• 제32권4호
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• pp.357-364
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• 2007

고농도 포도당이 뼈모세포와 치주인대세포의 세포자멸사에 미치는 영향과 그 경로를 알아보기 위하여 뼈모세포주인 MC3T3-E1 (E1) 세포와 사람 치주인대로부터 일차배양을 통해 얻은 치주인대세포를 1,000 mg/L 농도의 포도당이 포함된 배양액 (대조군)과 4,500 mg/L 농도의 포도당이 포함된 배양액 (실험군)으로 나누어 24시간과 48시간 배양하였다. 그 후, ELISA assay를 통해 p38 MAPK와 caspase-3의 발현을 평가하고 Western blot을 통해 JNK-1과 ERK-1의 발현을 평가하여 다음과 같은 결론을 얻었다. 1. 뼈모세포와 치주인대세포 모두 대조군에 비해 실험군에서 caspase-3와 p38 MAPK 발현이 증가하였다. 2. 실험군에서의 caspase-3와 p38 MAPK 발현은 뼈모세포에 비해 치주인대세포에서 더욱 크게 증가하였다. 3. 뼈모세포와 치주인대세포 모두 대조군에 비해 실험군에서 JNK-1 발현이 증가하였다. 4. 뼈모세포와 치주인대세포 모두 ERK-1 발현에는 변화가 없었다. 이상의 결과로 보아, 고혈당 조건에 의해 뼈모세포와 치주인대세포의 세포자멸사가 증가하며, 치주인대세포가 고혈당 조건에 더욱 민감하게 반응하여 세포자멸사가 크게 증가하는 것으로 생각된다. 또한 이들 세포의 세포자멸사 과정은 p38 MAPK와 JNK-1 경로가 관여하며 ERK-1 경로는 관여하지 않는 것으로 추정된다.

• International Journal of Oral Biology
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• 제34권2호
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• pp.115-121
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• 2009

Bone morphogenetic protein (BMP) 2 is a potent osteogenic factor. Although both Smad1/5 and mitogenactivated protein kinases (MAPKs) are activated by BMP2, the hierarchical relationship between them is unclear. In this study, we examined if BMP2-stimulated MAPK activation is regulated by Smad1/5 or vice versa. When C2C12 cells were treated with BMP2, the activation of extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun-N-terminal kinase was evident within 5 min. The knockdown of both Smad1 and Smad5 by small interfering RNA did not affect the activation of these MAPKs. In addition, neither the overexpression of Smad1 nor Smad5 induced ERK activation. When ERK activation was induced by constitutively active MEK1 expression, the protein level and activation of Smad1 increased. Furthermore, the inhibition of constitutively active BMP receptor type IB-induced ERK activation significantly suppressed Smad1 activation. These results indicate that Smad1/5 activation is not necessary for BMP2-induced MAPK activation and also that ERK positively regulates Smad1 activation.

• Asian Pacific Journal of Cancer Prevention
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• 제13권4호
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• pp.1183-1186
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• 2012

Objective: To observe the effect of insulin-like growth factor-1 (IGF-1) on bone morphogenetic protein (BMP)-2 expression in hepatocellular carcinoma SMMC7721 cells. Methods: Cells were divided into blank control, IGF-1, IGF-1 + SB203580, and SB203580 groups. SB203580 was used to block the p38 MAPK signaling pathway. Changes in the expression of BMP-2, p38 MAPK, and phosphorylated p38, MERK, ERK and JNK were determined using reverse transcription polymerase chain reactions (RT-PCR) and Western blot analysis. Results: Protein expression of phosphorylated BMP-2, MERK, ERK, and JNK was significantly up-regulated by IGF-1 compared with the control group ($1.138{\pm}0.065$ vs. $0.606{\pm}0.013$, $0.292{\pm}0.005$ vs. $0.150{\pm}0.081$, $0.378{\pm}0.006$ vs. $0.606{\pm}0.013$, and $0.299{\pm}0.015$ vs. $0.196{\pm}0.017$, respectively; P<0.05). Levels of BMP-2 and phosphorylated MERK and JNK were significantly reduced after blocking of the p38MAPK signaling pathway ($0.494{\pm}0.052$ vs. $0.165{\pm}0.017$, $0.073{\pm}0.07$ vs. $0.150{\pm}0.081$, and $0.018{\pm}0.008$ vs. $0.196{\pm}0.017$, respectively; P<0.05), but such a significant difference was not observed for phosphorylated ERK protein expression ($0.173{\pm}0.07$ vs. $0.150{\pm}0.081$, P>0.05). Conclusion: IGF-1 can up-regulate BMP-2 expression, and p38 MAPK signaling pathway blockage can noticeably reduce the up-regulated expression. We can conclude that the up-regulatory effect of IGF-1 on BMP-2 expression is realized through the p38 MAPK signaling pathway.