• Archives of Pharmacal Research
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• 제25권6호
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• pp.747-758
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• 2002

The skin displays a highly active metabolism of polyunsaturated fatty acids (PUFA). Dietary deficiency of linoleic acid (LA), an 18-carbon (n-6) PUFA, results in characteristic scaly skin disorder and excessive epidermal water loss. Although arachidonic acid (AA), a 20-carbon (n6) PUFA, is metabolized via cyclooxygenase pathway into predominantly prostaglandin $E_2(PGE_2)$ and $PGF_{2{\alpha}}$, the metabolism of AA via the 15-lipoxygenase (15-LOX) pathway, which is very active in skin epidermis and catalyzes the transformation of M into predominantly 15S-hydroxyeicosatetraenoic acid (15S-HETE). Additionally, the 15-LOX also metabolizes the 18-carbon LA into 13S-hydroxyoctadecadienoic acid (13S-HODE), respectively. Interestingly, 15-LOX catalyzes the transformation of $dihomo-{\gamma}-linolenic$ acid (DGLA), derived from dietary gamma-linolenic acid, to 15S-hydroxyeicosatrienoic acid (15S-HETrE). These monohydroxy fatty acids are incorporated into the membrane inositol phospholipids which undergo hydrolytic cleavage to yield substituted-diacylglycerols such as 13S-HODE-DAG from 13S-HODE and 15S-HETrE-DAG from 15S-HETrE. These substituted-monohydroxy fatty acids seemingly exert anti-inflammatory/antiproliferative effects via the modulation of selective protein kinase C as well as on the upstream/down-stream nuclear MAP-kinase/AP-1/apoptotic signaling events.

• BMB Reports
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• 제48권2호
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• pp.109-114
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• 2015

The COX-2/$PGE_2$ pathway has been implicated in the occurrence and progression of cancer. The underlying mechanisms facilitating the production of COX-2 and its mediator, $PGE_2$, in cancer survival remain unknown. Herein, we investigated $PGE_2$-induced COX-2 expression and signaling in HL-60 cells following menadione treatment. Treatment with $PGE_2$ activated anti-apoptotic proteins such as Bcl-2 and Bcl-xL while reducing pro-apoptotic proteins, thereby enhancing cell survival. $PGE_2$ not only induced COX-2 expression, but also prevented casapse-3, PARP, and lamin B cleavage. Silencing and inhibition of COX-2 with siRNA transfection or treatment with indomethacin led to a pronounced reduction of the extracellular levels of $PGE_2$, and restored the menadione- induced cell death. In addition, pretreatment of cells with the MEK inhibitor PD98059 and the PKA inhibitor H89 abrogated the $PGE_2$-induced expression of COX-2, suggesting involvement of the MAPK and PKA pathways. These results demonstrate that $PGE_2$ signaling acts in an autocrine manner, and specific inhibition of $PGE_2$ will provide a novel approach for the treatment of leukemia.

• IMMUNE NETWORK
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• 제6권3호
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• pp.123-127
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• 2006

Background: Caveolin-1 is a principal component of caveolae membranes in vivo. Although expression of caveolae structure and expression of caveolin family, caveolin-1, -2 and -3, was known in chondrocytes, the functional role of caveolae and caveolins in chondrocytes remains unknown. In this study, we investigated the role of caveolin-1 in articular chondrocytes. Methods: Rabbit articular chondrocytes were prepared from cartilage slices of 2-week-old New Zealand white rabbits by enzymatic digestion. Caveolin-1 cDNA was transfected to articular chondrocytes using LipofectaminePLUS. The cyclooxygenase-2 (COX-2) expression levels were determined by immunoblot analysis, immunostaining, immunohistochemistry, and prostaglandin $E_2\;(PGE_2)$ assay was used to measure the COX-2 activity. Results: Ectopic expression of caveolin-1 induced COX-2 expression and activity, as indicated by immunoblot analysis and $PGE_2$ assay. And also, overexpression of caveolin-1 stimulated activation of p38 kinase and ERK-1/-2. Inhibition of p38 kinase and ERK-1/-2 with SB203580 and PD98059, respectively, led to a dose-dependent decrease COX-2 expression and $PGE_2$ production in caveolin-1-transfected cells. Conclusion: Taken together, our data suggest that ectopic expression of caveolin-1 contributes to the expression and activity of COX-2 in articular chondrocytes through MAP kinase pathway.

• Journal of Applied Biological Chemistry
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• 제65권1호
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• pp.23-31
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• 2022

Oxidative stress and neuroinflammation play important roles in the pathogenesis of Alzheimer's disease (AD). This study investigated the protective effects of paeoniflorin (PF) against neuronal oxidative stress and neuroinflammation in lipopolysaccharide (LPS)-induced mice. The brains of LPS-injected control group showed significantly increased neuroinflammation by activating the nuclear factor kappa B (NF-κB) pathway and increasing inflammatory mediators. However, administration of PF significantly attenuated oxidative stress by inhibiting lipid peroxidation, nitric oxide levels, and reactive oxygen species production in the brain; PF at doses of 5 and 10 mg/kg/day downregulated the expression of NF-κB pathway-related proteins and significantly decreased inflammatory mediators including inducible nitric oxide synthase and cyclooxygenase-2. Moreover, the levels of brain-derived neurotrophic factor and its receptor, tropomycin receptor kinase B, were significantly increased in PF-treated mice. Furthermore, acetylcholinesterase activity and the ration of B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X were significantly reduced by PF in the brains of LPS-induced mice, resulting in the inhibition of cholinergic dysfunction and neuronal apoptosis. Thus, we can conclude that administration of PF to mice prevents the development of LPS-induced AD pathology through the inhibition of neuronal oxidative stress and neuroinflammation, suggesting that PF has a therapeutic potential for AD.

• Journal of Microbiology and Biotechnology
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• 제34권7호
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• pp.1491-1500
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• 2024

Inflammation is a biodefense mechanism that provides protection against painful conditions such as inflammatory bowel disease, other gastrointestinal problems, and irritable bowel syndrome. Paraprobiotics have probiotic characteristics of intestinal modulation along with merits of safety and stability. In this study, heat-killed Lactiplantibacillus plantarum KU15122 (KU15122) was investigated for its anti-inflammatory properties. KU15122 was subjected to heat-killed treatment for enhancement of its safety, and its concentration was set at 8 log CFU/mL for conducting different experiments. Nitric oxide production was most remarkably reduced in the KU15122 group, whereas it was increased in the LPS-treated group. In RAW 264.7 cells, KU15122 inhibited the expression of inducible nitric oxide synthase, cyclooxygenase-2, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. ELISA revealed that among the tested strains, KU15122 exhibited the most significant reduction in PGE2, IL-1β, and IL-6. Moreover, KU15122 inhibited various factors involved in the nuclear factor-kappa B, activator protein-1, and mitogen-activated protein kinase pathways. In addition, KU15122 reduced the generation of reactive oxygen species. The anti-inflammatory effect of KU15122 was likely attributable to the bacterial exopolysaccharides. Conclusively, KU15122 exhibits anti-inflammatory potential against inflammatory diseases.

• Tuberculosis and Respiratory Diseases
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• 제66권4호
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• pp.274-279
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• 2009

연구배경: Uteroglobin (UG)은 폐를 비롯한 우리 몸의 대부분의 표피세포에서 생성되는 면역조절능을 가진 분비단백이다. UG의 과발현은 cyclooxygenase (COX)-2의 발현의 감소 및 암세포의 성장억제와 관련이 있다. Indoleamine 2,3-dioxygenase (IDO)는 kynurenine pathway를 통해 tryptophan을 이화시키는 효소로서, 국소적으로 tryptopha을 고갈시키고 tryptophan 대사물을 생성 함으로써 T 세포의 면역반응을 억제시키는 데 기여한다. 방 법: 본 연구에서는 여러 비소세포폐암 세포주, 특히 A549에서 COX-2와 IDO의 발현양상 및 UG transduction 이 COX-2 및 IDO의 발현에 미치는 영향을 살펴보았다. 결 과: A549와 H460에서 구조적으로 COX-2와 IDO가 모두 발현되었고, COX-2 및 IDO의 발현은 UG transduction에 의해 감소되었다. A549에 IFN-$\gamma$를 투여했을때 COX-2 및 IDO의 발현이 약간 증가하였고, 이는 UGtransduction 시행 후 다시 감소하였다. 그러나, A549에 UG transduction 시행하여 감소된 COX-2, IDO의 발현은 IFN-$\gamma$ 투여 후에도 증가하지 않았다. A549 COX-2 sense와 A549 COX-2 anti-sense (siRNA 감염) 세포주 모두에서 COX-2의 발현여부와 상관없이 IDO가 발현되었고, UG transduction으로 인해 IDO의 발현이 감소하였다. 결 론: 이러한 결과는 UG의 세포성장억제 기능이 COX-2를 통한 기전과는 독립적으로 IDO의 면역관용 기전과 관련될 가능성이 있음을 시사한다.

• Journal of Ginseng Research
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• 제13권2호
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• pp.202-210
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• 1989

인삼 성분이 prostaglandin 등 arachidonic acid 대사산물 생성에 미치는 영향을 실험함으로써 인삼의 약리학적 작용기전을 간접적으로 모색하였다. 즉, [$^3H$]-arachidonic acid를 기질로 넣어주고 토끼 신장 micorsome, 소의 대동맥 microsome, 정상 성인의 혈소판 homogenate 등을 효소원으로 한 in vitro 생합성 과정에 변화를 주는 수종 인삼 saponin 성분의 효과를 검정하였다. 실험에 사용한 인삼 saponin 성분은 panaxadiol, panaxatriol 및 protopanaxadiol계 soponin류인 Ginsenoside $Rb_2$(G-$Rb_2$), Ginsenoside Rc(G-Rc) 및 protopanaxatriol계 saponi류인 Ginsenoside (G-$Rb_2$)이었다. 1. Arachidonic acid로부터 생성된 총 cycoloxygenase 반응생성물 및 malondialdehyde의 양은 실험에 사용한 인삼 saponin 성분의 전 농도 범위에서 유의적인 변화를 보이지 않았는데 이는 인삼 saponin 성분들은 cyclooxygenase에 직접 작용하지 않는다는 것을 설명해 준다. 2. Panaxdiol($500{\mu}g$/ml)은 $PGE_2$ 생성에는 영향이 없으나 $PGF_2$ 및 $TXB_2$의 생성을 감소시켰으며 동시에 6-keto-$PGF_{1{\alpha}}$의 생성은 증가시켰다. Panaxatriol도 유사한 양상을 보였다. 3. G-$Rb_2$, Rc, Re에 의해 $TXB_2$의 생성은 농도 의존적으로 감소하였으나 6-keto-$PGF_{1{\alpha}}$의 생성은 유의적으로 증가하였다. 또한 arachidonic acid와 $TXA_2$ 유사제인 U46619(9,11-methanoepoxy $PGH_2$)로 유도한 혈소판 응집 현상은 세 ginsenoside에 의해 억제되었다. G-Re의 6-keto-$PGF_{1{\alpha}}$생성증가 효과는 prostacyclin 합성효소억제제에 의해 길항하였다. 이상의 결과와 같이 인삼saponin 성분들은 arachidonic acid로부터 cyclooxygenase를 통해 일단 생성된 endoperoxide에서 각각의 prostaglandin을 생성하는 효소, 특히 G-$Rb_2$는 $TXA_2$ synthetase에 강력한 억제제로, G-Re는 prostacyclin 생합성에 촉진데로 심혈관계 균형에 기여하리라 생각된다.

• 대한약리학회지
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• 제26권1호
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• pp.51-54
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• 1990

사람 중성구내의 azurophil granule 내에 존재하는 serine protease인 cathepsin G는 정상 반응에서는 항 박테리아 작용을 나타내는데 관여하지만, 이들의 효소활성이 비정상적으로 증가되었을 때는 오히려 인체 정상 조직을 파괴함으로써 rheumatoid arthritis를 비롯한 여러가지 염증성 질환을 야기시킨다고 알려져 있다. 항염증제로 작용하는데 있어서 prostaglandin 합성을 억제하는 작용 이외에 다른 작용 기전이 있는가 하는것은 대단히 흥미있는 연구 과제이었으므로 neutral protease 중의 하나인 cathepsin G와 이 염증반응에 직접적으로 관여하는지 알아보기 위하여 본 연구에서는 두 단계의 크로마토그라피를 거쳐 순수한 cathepsin G를 분리하고, 여러가지 비스테로이드성 항염증제를 이용하여 cathepsin G에 대한 억제 정도를 관찰하였다. 이중 sulindac, salicylate, phenylbutazone, oxyphenbutazone 그리고 salicyluric acid가 각각 4.3mM, 14.3mM, 6.5mM, 11mM, 15mM의 $IC_{50}$로써 cathepsin G의 활성도를 억제하였다. 따라서 NSAIDs의 항염증 작용 기전은 기존에 알려지고 있는 cyclooxygenase 억제에 따른 prostaglanndin 합성, 분비 억제 기전이외에 rheumatoid arthritis 부위에 직접적 원인으로 작용할 가능성이 있는 cathepsin G를 억제 함으로써 조직 파괴를 막는 역할을 하고 있을 가능성이 있는 것으로 사료된다.

• Biomolecules & Therapeutics
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• 제23권6호
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• pp.539-548
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• 2015

Prostaglandin $E_2$ ($PGE_2$), a major product of cyclooxygenase, binds to four different prostaglandin $E_2$ receptors (EP1, EP2, EP3, and EP4) which are G-protein coupled transmembrane receptors (GPCRs). Although GPCRs including EP receptors have been shown to be associated with their specific G proteins, recent evidences suggest that GPCRs can regulate MAPK signaling via non-G protein coupled pathways including Src. EP2 is differentially expressed in various tissues and the expression of EP2 is induced by extracellular stimuli. We hypothesized that an increased level of EP2 expression may affect MAPK signaling. The overexpression of EP2 in HEK 293 cells resulted in significant increase in intracellular cAMP levels response to treatment with butaprost, a specific EP2 agonist, while overexpression of EP2 alone did not increase intracellular cAMP levels. However, EP2 overexpression in the absence of $PGE_2$ induced an increase in the level of p38 phosphorylation as well as the kinase activity of p38, suggesting that up-regulation of EP2 may promote p38 activation via non-G protein coupled pathway. Inhibition of Src completely blocked EP2-induced p38 phosphorylation and overexpression of Src increased the level of p38 phosphorylation, indicating that Src is upstream kinase for EP2-induced p38 phosphorylation. EP2 overexpression also increased the Src activity and EP2 protein was co-immunoprecipitated with Src. Furthermore, sequential co-immunoprecipitation studies showed that EP2, Src, and ${\beta}$-arrestin can form a complex. Our study found a novel pathway in which EP2 is associated with Src, regulating p38 pathway.

• Journal of Gastric Cancer
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• 제14권3호
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• pp.147-155
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• 2014

Homeostatic imbalance between cell proliferation and death in gastric mucosal epithelia may lead to gastritis and gastric cancer. Despite abundant gastrokine 1 (GKN1) expression in the normal stomach, the loss of GKN1 expression is frequently detected in gastric mucosa infected with Helicobacter pylori, as well as in intestinal metaplasia and gastric cancer tissues, suggesting that GKN1 plays an important role in gastric mucosal defense, and the gene functions as a gastric tumor suppressor. In the stomach, GKN1 is involved in gastric mucosal inflammation by regulating cytokine production, the nuclear factor-${\kappa}B$ signaling pathway, and cyclooxygenase-2 expression. GKN1 also inhibits the carcinogenic potential of H. pylori protein CagA by binding to it, and up-regulates antioxidant enzymes. In addition, GKN1 reduces cell viability, proliferation, and colony formation by inhibiting cell cycle progression and epigenetic modification by down-regulating the expression levels of DNMT1 and EZH2, and DNMT1 activity, and inducing apoptosis through the death receptor-dependent pathway. Furthermore, GKN1 also inhibits gastric cancer cell invasion and metastasis via coordinated regulation of epithelial mesenchymal transition-related protein expression, reactive oxygen species production, and PI3K/Akt signaling pathway activation. Although the modes of action of GKN1 have not been clearly described, recent limited evidence suggests that GKN1 acts as a gastricspecific tumor suppressor. This review aims to discuss, comment, and summarize the recent progress in the understanding of the role of GKN1 in gastric cancer development and progression.