• The Korean Journal of Pain
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• 제34권2호
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• pp.176-184
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• 2021

Background: Diabetes-related neuropathic pain frequently occurs, and the underpinning mechanism remains elusive. The periaqueductal gray (PAG) exhibits descending inhibitory effects on central pain transmission. The current work aimed to examine whether inflammatory cytokines regulate mechanical allodynia and thermal hyperalgesia induced by diabetes through the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway in the PAG. Methods: Streptozotocin (STZ) was administered intraperitoneally to mimic allodynia and hyperalgesia evoked by diabetes in rats. Behavioral assays were carried out for determining mechanical pain and thermal hypersensitivity. Immunoblot and ELISA were performed to examine PAG protein amounts of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), as well as their corresponding receptors in STZ rats, and the expression of PI3K/protein kinase B (Akt)/mTOR signaling effectors. Results: Increased PAG p-PI3K/p-Akt/p-mTOR protein amounts were observed in STZ-induced animals, a PI3K-mTOR pathway inhibition in the PAG attenuated neuropathic pain responses. Moreover, the PAG concentrations of IL-1β, IL-6, and TNF-α and their receptors (namely, IL-1R, IL-6R, and tumor necrosis factor receptor [TNFR] subtype TNFR1, respectively) were increased in the STZ rats. Additionally, inhibiting IL-1R, IL-6R, and TNFR1 ameliorated mechanical allodynia and thermal hyperalgesia in STZ rats, alongside the downregulation of PI3K-mTOR signaling. Conclusions: Overall, the current study suggests that upregulated proinflammatory cytokines and their receptors in the PAG activate PI3K-mTOR signaling, thereby producing a de-inhibition effect on descending pathways in modulating pain transmission, and eventually contributing to neuropathic pain.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.79.1-79.1
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• 2003

Aster scaber T. (Asteraceae) has been used in traditional Korean and Chinese medicine to treat bruises, snakebites, headaches and dizziness. (-) 3,5-Dicaffeoyl-muco-quinic acid (DQ) isolated from Aster scaber induced neurite outgrowth in PC12 cells. It has been reported that the activation of the extracellular signal regulated kinase1/2 (Erk 1/2) and phosphoinositide 3 (P13) kinase plays a crucial role in the NGF-induced differentiation of PC12 cells. This study showed that the effect of DQ on neurite outgrowth is mediated via the Erk 1/2 and PI3 kinase-dependent pathways like NGF. (omitted)

• Journal of Applied Biological Chemistry
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• 제64권3호
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• pp.317-322
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• 2021

Among the different cardiovascular disorders (CVDs), the activation of platelets is a necessary step. Based on this knowledge, therapeutic treatments for CVDs that target the disruption of platelet activation are proving to be worthwhile. One such substance, a bioactive 6,7-dihydroxy derived from coumarin, is 6,7-Dihydroxy-2H-1-benzopyran-2-one (esculetin). This compound has demonstrated several pharmacological effects on CVDS as well as various other disorders including diabetes, obesity, and renal failure. In various reports, esculetin and its effect has been explored in experimental mouse models, human platelet activation, esculetin-inhibited collagen, and washed human platelets exhibiting aggregation via arachidonic acid. Yet, esculetin affected aggregation with agonists like U46619 or thrombin in no way. This study investigated esculetin and how it affected human platelet aggregation activated through U46619. Ultimately, we confirmed that esculetin had an effect on the aggregation of human platelets when induced from U46619 and clarified the mechanism. Esculetin interacts with the downregulation of both phosphoinositide 3-kinase/Akt and mitogen-activated protein kinases, important phosphoproteins that are involved in activating platelets and their signaling process. The effects of esculetin reduced TXA₂ production, phospholipase A₂ activation, and platelet secretion of intracellular granules (ATP/serotonin), ultimately causing inhibition of overall platelet aggregation. These results clearly define the effect of esculetin in inhibiting platelet activity and thrombus formation in humans.

• KSBB Journal
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• 제25권1호
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• pp.11-17
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• 2010

본 논문에서는 혈관내피세포에서 저농도의 트롬빈이 TNF-$\alpha$가 NF-kB의 활성화를 통해 생성되는 IL-6의 생성량에 미치는 영향을 관찰하였다. TNF-$\alpha$는 혈관내피세포에서 NF-kB의 활성화를 통해 염증을 유발시킨다는 것은 잘 알려진 사실이다. 이 논문에서는 TNF-$\alpha$가 매개하는 염증작용에서 저농도의 트롬빈은 TNF-$\alpha$가 생성시키는 IL-6의 생성량을 감소시켰고, 여기에는 트롬빈의 수용체인 PAR-1이 작용하다는 것을 확인하였다. 뿐만 아니라, 세포내의 PI3-Kinase 역시 저농도 트롬빈이 관여한다는 것을 확인하였다. 이것은 저농도의 트롬빈이 수용체인 PAR-1을 활성화시키고, 활성화된 PAR-1 은 PI3-Kinase의 활성화을 통해 항염증작용을 보여준디는 것을 의미한다. 이 결과는 향후 중증 패혈증 및 각종 염증질환을 치료할 수 있는 신약개발에 있어 중요한 단서를 제공하고 혈관내피세포에서 아직 명확하게 밝혀지지 않은 트롬빈의 염증작용 및 항염증작용의 기전을 밝히는데 좋은 정보를 제공할 것이다.

• 약학회지
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• 제48권2호
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• pp.105-110
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• 2004

Akt (or Protein Kinase B; PKB) is a serine/threonine kinase and is activated by phosphoinositide 3-kinase (PI3K) pathway. Recent evidence indicates that the abnormal activities or expression of Akt is closely associated with cancer, diabetes and neuro-degenerative diseases. These findings mean that Akt is likely to be a new therapeutic target for the treatment of disease. Here, we screened the effects of dithiolo-dithione derivatives such as SWU-20004, SWU-20009 and SWU-20025 on Akt activities. Among these compounds, only SWU-20009 (2-Thioxo-[1,3]dithiolo[4,5- $\beta$][1,4]dithiine-5,6-dicarboxylic acid dimethyl ester) inhibited the growth of KATOIII cell at micromolar range of concentration. Further investigation also revealed that SWU-20009 inhibited cellular Akt activity and induced apoptotic cell death.

• 대한약리학회:학술대회논문집
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• 대한약리학회 2006년도 The 6th Congress of the Federation of Asian and Oceanian Physiological Societies
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• pp.113.1-113.1
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• 2006

• 대한약학회:학술대회논문집
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• 대한약학회 2001년도 Proceedings of International Convention of the Pharmaceutical Society of Korea
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• pp.156.2-157
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• 2001

• 대한의생명과학회지
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• 제12권3호
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• pp.201-208
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• 2006

PI3-kinase activity through p85, the regulatory subunit of class IA PI3-kinase, is indispensable for the growth, differentiation, and survival of skeletal muscle cells, but little is known about the function of other regulatory subunits such as p55 and p50. We examined the subcellular localization and the expression of the regulatory subunits of class IA PI3-kinase in L6 myoblasts. Both p55 and p50 as well as p85 were expressed in L6 myoblasts. Whereas p85 was localized at both cytosolic and nuclear tractions, p55 and p50 were localized at only the nuclear traction. During the differentiation of L6 myoblasts, the protein concentrations of both p55 and p50 were decreased but that of p85 was not significantly changed. Menadione-induced oxidative stress induced the translocation of p85 from cytosol to nucleus and the increase of p55 expression. These results suggest that the regulatory subunits of class IA PI3-kinase play an important role in L6 myoblasts.

• 대한의생명과학회지
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• 제15권4호
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• pp.349-353
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• 2009

Lysophosphatidic Acid (LPA) is a bioactive lysophospholipid that is a potent signaling molecule able to provoke a variety of cellular responses in many cell types such as differentiation, inflammation and apoptosis. In this study, we have investigated the effect of LPA on Nitric oxide (NO)-induced apoptosis in rabbit articular chondrocytes. LPA dramatically reduced NO induced apoptosis of chondrocytes determined by phase contrast microscope and MTT assay. When chondrocytes alone treated with LPA, LPA induced phosphorylation of p70S6kinase, a serine/threonine kinase that acts downstream of phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphoinositide-dependent kinase-1 (PDK-1) in the PI3 kinase pathway, dose-dependently detected by Western blot analysis. Phosphorylation of p70S6k with LPA was reduced expression of p53 in NO-induced apoptosis of chondrocytes. Also, inhibition of p70S6kinase with rapamycin was enhanced expression of p53 in chondrocytes. Our findings collectively suggest that LPA regulates NO induced apoptosis through p70S6kinase pathway in rabbit articular chondrocytes.

• 생명과학회지
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• 제28권1호
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• pp.43-49
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• 2018

Chrysoeriol은 alfalfa에서 주로 발견되는, 식물계에 많이 분포하고 있는 flavone으로 전통의학에서 소화불량, 천식, 비뇨기계 이상의 치료에 사용되어 왔다. 최근의 연구에서는 항염증 효과가 있는 것으로 밝혀졌으나 항산화 효과에 대한 분석은 없었다. 본 연구에서는 chrysoeriol의 항산화 효과와 그 분자적 기전을 RAW 264.7 cell에서 세포생존율, reactive oxygen species (ROS)와 Western blot분석을 통해 알아보고자 하였다. Chrysoeriol은 lipopolysaccharide(LPS)에 의해 발생한 ROS를 세포독성없이 농도의존적으로 제거하였다. 그리고 항산화효과를 보이는 2상 효소 중 하나인 heme oxygenase (HO)-1의 발현을 강하게 유도하였고, 그와 동시에 전사인자인 Nrf2의 핵내 이동도 촉진하는 것으로 밝혀졌다. 특히, 산화스트레스에 대한 세포내 산화환원항상성 유지에 중요한 역할을 하고 있는 것으로 알려진 mitogen activated protein kinase (MAPK)와 phosphoinositide 3-kinase (PI3K)의 분석결과, chrysoeriol은 extracellular signal regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK)와 p38의 인산화를 통해 HO-1의 발현을 유도하는 것으로 나타났다. HO-1에 의한 항산화 효과를 확인하기 위하여 chrysoeriol을 전처리한 후 t-BHP에 의한 산화 스트레스에 세포를 노출시킨 결과, chrysoeriol 처리에 의해 세포사멸이 줄어드는 것을 확인하였고, HO-1의 유도제와 억제제의 처리에 따라 세포생존율 또한 조절되는 것을 확인할 수 있었다. 따라서, chrysoeriol은 HO-1의 발현을 유도하여 항산화 효과를 높이고 이것은 Nrf2/MAPK 신호전달 체계에 의한다는 것을 알 수 있었다.