• Molecules and Cells
• /
• 제42권10호
• /
• pp.702-710
• /
• 2019

Neuroinflammation is an important contributor to the pathogenesis of neurodegenerative disorders including Parkinson's disease (PD). We previously reported that our novel synthetic compound KMS99220 has a good pharmacokinetic profile, enters the brain, exerts neuroprotective effect, and inhibits $NF{\kappa}B$ activation. To further assess the utility of KMS99220 as a potential therapeutic agent for PD, we tested whether KMS99220 exerts an anti-inflammatory effect in vivo and examined the molecular mechanism mediating this phenomenon. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, oral administration of KMS99220 attenuated microglial activation and decreased the levels of inducible nitric oxide synthase and interleukin 1 beta ($IL-1{\beta}$) in the nigrostriatal system. In lipopolysaccharide (LPS)-challenged BV-2 microglial cells, KMS99220 suppressed the production and expression of $IL-1{\beta}$. In the activated microglia, KMS99220 reduced the phosphorylation of $I{\kappa}B$ kinase, c-Jun N-terminal kinase, and p38 MAP kinase; this effect was mediated by heme oxygenase-1 (HO-1), as both gene silencing and pharmacological inhibition of HO-1 abolished the effect of KMS99220. KMS99220 induced nuclear translocation of the transcription factor Nrf2 and expression of the Nrf2 target genes including HO-1. Together with our earlier findings, our current results show that KMS99220 may be a potential therapeutic agent for neuroinflammation-related neurodegenerative diseases such as PD.

• 한국동물생명공학회지
• /
• 제36권4호
• /
• pp.285-291
• /
• 2021

Mesenchymal stem cells (MSCs) have been recognized as a therapeutic tool for various diseases due to its unique ability for tissue regeneration and immune regulation. However, poor survival during in vitro expansion and after being administrated in vivo limits its clinical uses. Accordingly, protocols for enhancing cell survivability is critical for establishing an efficient cell therapy is needed. CDDO-Me is a synthetic C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, which is known to stimulate nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. Herein, report that CDDO-Me promoted the proliferation of MSCs and increased colony forming units (CFU) numbers. No alteration in differentiation into tri-lineage mesodermal cells was found after CDDO-Me treatment. We observed that CDDO-Me treatment reduced the cell death induced by oxidative stress, demonstrated by the augment in the expression of Nrf2-downstream genes. Lastly, CDDO-Me led to the nuclear translocation of NRF2. Our data indicate that CDDO-Me can enhance the functionality of MSCs by stimulating cell survival and increasing viability under oxidative stress.

• Natural Product Sciences
• /
• 제23권3호
• /
• pp.183-191
• /
• 2017

Luteolin 5-O-glucoside is the major flavonoid from Korean thistle, Cirsium maackii. We previously reported the anti-inflammatory activities of luteolin 5-O-glucoside in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In this study, we determined the anti-inflammatory mechanisms of luteolin 5-O-glucoside through the inhibition of nitric oxide (NO) production in vitro and in vivo. Results revealed that luteolin 5-O-glucoside dose-dependently inhibited NO production and expression of iNOS and COX-2 in LPS-induced RAW 264.7 cells. Luteolin 5-O-glucoside also significantly inhibited the translocation of $NF-{\kappa}B$, the activation of MAPKs, and ROS generation in LPS-induced RAW 264.7 cells. In addition, protein expressions of Nrf-2 and HO-1 were also upregulated by luteolin 5-O-glucoside treatment. Moreover, luteolin 5-O-glucoside inhibited ${\lambda}-carrageenan-induced$ mouse paw edema by 65.34% and 48.31% at doses of 50 and 100 mg/kg body weight, respectively. These findings indicate potential anti-inflammatory effect of luteolin 5-O-glucoside particularly by downregulating $NF-{\kappa}B$ and upregulating HO-1/Nrf-2 pathway.

• 한국자원식물학회:학술대회논문집
• /
• 한국자원식물학회 2019년도 춘계학술대회
• /
• pp.94-94
• /
• 2019

In this study, we elucidated the anti-inflammatory mechanisms of leaves extracts from Rodgersia podophylla (RPL) in RAW264.7 cells. RP-L significantly inhibited the production of the proinflammatory mediators such as NO, iNOS, IL-$1{\beta}$ and IL-6 in LPS-stimulated RAW264.7 cells. RPL increased HO-1 expression in RAW264.7 cells, and the inhibition of HO-1 by ZnPP reduced the inhibitory effect of RPL against LPS-induced NO production in RAW264.7 cells. Inhibition of p38, ROS and $GSK3{\beta}$ attenuated RPL-mediated HO-1 expression. Inhibition of ROS inhibited p38 phosphorylation and $GSK3{\beta}$ expression induced by RPL. In addition, inhibition of $GSK3{\beta}$ blocked RPL-mediated p38 phosphorylation. RPL induced nuclear accumulation of Nrf2, and Inhibition of p38, ROS and $GSK3{\beta}$ abolished RPL-mediated nuclear accumulation of Nrf2. Furthermore, RPL blocked LPS-induced degradation of $I{\kappa}B-{\alpha}$ and nuclear accumulation of p65. RP-L also attenuated LPS-induced phosphorylation of ERK1/2 and p38. Our results suggest that RPL exerts potential antiinflammatory activity by activating ROS/$GSK3{\beta}$/p38/Nrf2/HO-1 signaling and inhibiting NF-${\kappa}B$ and MAPK signaling in RAW264.7 cells. These findings suggest that RPL may have great potential for the development of anti-inflammatory drug.

• 생명과학회지
• /
• 제21권7호
• /
• pp.1046-1051
• /
• 2011

Dially disulfide (DADS)는 마늘의 주요한 유기 황화합물 성분으로서 다양한 약리 작용을 나타낸다. 최근 DADS가 항염증과 항동맥경화 작용뿐만 아니라 암세포의 증식을 억제하고 사멸을 유도한다는 보고가 이어지고 있고, 이에 관련된 연구가 활발히 진행되고 있는 실정이다. 한편, DADS가 세포 내 항산화 인자인 glutathione을 증가시킨다는 연구결과와 세포 내 항산화 효소의 일종인 HO-1의 발현을 직접 유도한다는 결과가 보고되었다. 그래서, 본 연구에서는 논란이 되고 있는 DADS의 세포 내 항산화 효소인 HO-1의 발현에서의 효과 및 그 전사인자들의 작용에 관여하는지를 인간 간암세포주 HepG2에서 조사하였다. 배양 중인 HepG2 세포에서 DADS는 독성이 없는 농도에서 세포의 증식을 크게 억제하였고, 전사인자 Nrf2의 발현을 약하게 유도하였으나 HO-1의 발현에는 영향을 미치지 못하는 것으로 나타났다. 또한, DADS는 HO-1 유도제인 CoPP와 hemin에 의해 자극된 HepG2 세포의 HO-1 발현의 증가를 단백질 수준에서 강력하게 억제시키는 것으로 나타났다. 그러나 DADS는 CoPP에 의한 HO-1 유전자의 mRNA 수준의 전사에는 억제 효과를 보이지 않았으며, 또한 Nrf2와 small Maf의 발현을 증가시키고 핵 내에 축적시키는 것으로 나타났다. 이를 종합해 볼 때 DADS는 단독으로 HO-1 발현을 유도하지 못하고, HO-1 유도제에 의한 HO-1 유전자의 발현과정에서는 전사단계가 아닌 번역단계에서 역할을 함으로써 HO-1의 단백질 합성을 억제하는 것으로 보인다. 결론적으로, 항산화 효소인 HO-1의 활성은 외부 자극으로부터 세포를 보호하고 사멸에 저항하게 하는데, DADS는 인간 간암세포주 HepG2에서 이 효소의 발현을 억제함으로써 항암제 및 redox 변화에 따른 암세포주의 성장을 억제하고 세포사멸을 촉진시킬 수 있다고 여겨진다.

• Nonlinear Functional Analysis and Applications
• /
• 제26권2호
• /
• pp.303-322
• /
• 2021

The concepts of new classes of mappings are introduced in the spaces which are more general space than the usual metric spaces. The existence and uniqueness of common fixed points and fixed point results are established in the setting of complete complex valued b-metric spaces. An illustration is given by establishing the existence of solution of periodic differential equations in the framework of a complete complex valued b-metric spaces.

• 생명과학회지
• /
• 제29권9호
• /
• pp.977-985
• /
• 2019

쑥부쟁이는 국화과에 속하는 다년생 식물로서 다양한 질병의 예방 및 치료에 오랫동안 사용되어 왔다. 최근 연구에서 쑥부쟁이 잎 추출물이 항산화 및 항염증 효과가 있는 것으로 알려져 있지만, 정확한 효능 평가에 관한 연구는 여전히 미비한 실정이다. 본 연구에서는 RAW 264.7 대식세포에서 쑥부쟁이 잎 에탄올 추출물(EEAY)의 항산화 효능이 항염증 효능과 연관이 있는지의 여부를 조사하였다. 본 연구의 결과에 의하면, EEAY는 $H_2O_2$ 처리에 의한 RAW 264.7 세포의 세포 독성을 유의적으로 억제시켰으며, 이는 Nrf2 및 HO-1의 발현 증가와 관련이 있음을 보여 주었다. 또한 EEAY는 $H_2O_2$에 의한 apoptosis를 유의적으로 억제하였으며, 이는 caspase-3의 활성 억제에 따른 PARP의 분해 차단과 연관성이 있었다. 그리고 EEAY는 대표적인 항 염증성 사이토카인인 IL-10의 발현 및 생산을 증가시켰으며, 이는 전사 및 번역 수준에서의 TLR-4 및 Myd88 발현 증가와 관련이 있었다. 아울러 EEAY는 LPS에 의한 염증성 매개인자인 NO의 생성 증가를 현저히 억제하였으며, EEAY에 의한 NO 생성의 억제 효과는 HO-1 유도제인 hemin에 의해 더욱 증가되었다. 따라서 본 연구의 결과는 EEAY에 의한 산화적 및 염증성 스트레스에 대한 RAW 264.7 대식세포의 보호 효과에 최소한 Nrf2/HO-1 신호 경로의 활성화가 관여할 가능성을 보여주었다.

• 한국조경학회지
• /
• 제29권4호
• /
• pp.24-33
• /
• 2001

The purpose of this paper is to examine the differences of user´s satisfaction of development elements of natural recreation forest(NFR) developed by public and private bodies in order to answer the research question: What is the differences of user´s satisfaction of development elements of NFR\ulcorner After reviewing the literature, mechanism of outdoor recreation, and development elements in NRF, we constructed the conceptual framework and have formulated the hypothesis of this research. We had obtained data through a questionnaire, which surveyed 584 visitors at 10 of the 72 natural recreation forests in Korea in 1999. We have analyzed the data using he descriptive statistical method, the mean difference test, and logistic regression method. We have found that 1) all the development elements have turned out to be significantly different from the mean difference test, 2) the two elements of atmosphere and activity have turned out to be statistically significant in determining the difference of NFR developed by public and private body in logistic regression analysis while user´s satisfaction in recreational resources, facilities and service make no differences between public and private NRF, 3) the higher the degree of user´s satisfaction in atmosphere and activity at NFR, the more the NFR developed by private body, and 4) their relative contribution of atmosphere and activities on whether the NFR is developed by public or private body have been turned out to have 0.258 and 0.242 respectively, which have a similar importance. The research results suggest that a guideline for the creation of marketable NFR by public and private developer, and development of use-programs and recreational atmosphere be recommended in the planning and development process of NRF. The approach and anlaysis method adopted by this research is highly useful for an evaluation of NRF developed by the tow bodies and development of devices for increasing user´s satisfaction and marketing positioning of NRF by the tow developers. It is recommended that more empirical study on individual development elements affecting user´s satisfaction be performed in the future.

• Molecular & Cellular Toxicology
• /
• 제5권2호
• /
• pp.120-125
• /
• 2009

Alaria esculenta is a brown seaweed found in the Arctic. This study investigated the protective effect of A. esculenta extract (AEE) against oxidant-mediated injury and its mode of action in RAW264.7 macrophages. The methyl thiazolyl tetrazolium (MTT) assay showed that $H_2O_2$ treatment reduced cell viability, whereas AEE protected cells from $H_2O_2$-mediated cytotoxicity in a dose-dependent manner. Because heme oxygenase-1 (HO-1) is known to protect cells against oxidative damage, we investigated the effect of AEE on HO-1 gene expression and HO enzyme activity. The protective effect of AEE against $H_2O_2$-induced injury was correlated with increased HO enzyme activity. AEE also induced HO-1 mRNA and protein expression, as determined RT-PCR and Western blotting, respectively. To characterize the mechanisms by which AEE induces HO-1 gene expression, we examined the effect of AEE on the nuclear translocation of NF-E2-related factor-2 (Nrf2) and Akt phosphorylation. AEE treatment activated upstream signaling for HO-1 gene expression, including the nuclear translocation of Nrf2 and Akt phosphorylation. Collectively, these results suggest that AEE has anti-oxidant activity that is mediated, at least in part, via the activation of Nrf2 and Akt and the subsequent induction of HO-1 gene expression.

• Food Science and Biotechnology
• /
• 제18권5호
• /
• pp.1204-1211
• /
• 2009

Hericium erinaceus is an edible mushroom used as a medicinal food in Asian countries. In this study, the chemopreventive effects of H. erinaceus mycelia hot water extract (HEW) were evaluated. HEW remarkably induced the luciferase activity of the antioxidant response element (ARE), located in the promoter region of phase 2 and antioxidant genes and regulated by nuclear factor E2-related factor 2 (Nrf2). The up-regulation of ARE activity by HEW corresponded with the induction of Nrf2 and the antioxidant enzyme, hemeoxygenase-1. The inhibition of cyclooxygenase-2 (COX-2) activity is a promising effective approach in cancer chemoprevention, and HEW prominently suppressed COX-2 protein expression in HepG2 cells. Furthermore, HEW showed anti-inflammatory activity by modulating inflammatory mediators such as nitric oxide (NO), inducible NO synthase, tumor necrosis factor-${\alpha}$, interleukin-$1{\beta}$, and the transcription factor, nuclear factor-${\kappa}B$, in lipopolysaccharide-stimulated RAW 264.7 cells. These results suggest that H. erinaceus possessed anti-tumor and anti-inflammatory effects via the modulation of Nrf2/ARE and inflammatory signaling pathways, and may therefore have potential use as a natural chemopreventive agent.