• Asian Pacific Journal of Cancer Prevention
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• 제15권23호
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• pp.10463-10468
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• 2015

Opisthorchis viverrini (Ov) infection is the major etiological factor for cholangiocarcinoma (CCA), especially in northeast Thailand. We have previously reported significant involvement of PI3K/AKT/PTEN and $Wnt/{\beta}$-catenin in human CCA tissues. The present study, therefore, examined the expression and activation of PI3K/AKT/PTEN and $Wnt/{\beta}$-catenin signaling components during Ov-induced cholangiocarcinogenesis in a hamster animal model. Hamsters were divided into two groups; non-treated and Ov plus NDMA treated. The results of immunohistochemical staining showed an upregulation of PI3K/AKT signaling as determined by elevated expression of the $p85{\alpha}$-regulatory and $p110{\alpha}$-catalytic subunits of PI3K as well as increased expression and activation of AKT during cholangiocarcinogenesis. Interestingly, the staining intensity of activated AKT (p-AKT) increased in the apical regions of the bile ducts and strong staining was detected where the liver fluke resides. Moreover, PTEN, a negative regulator of PI3K/AKT, was suppressed by decreased expression and increased phosphorylation during cholangiocarcinogenesis. We also detected upregulation of $Wnt/{\beta}$-catenin signaling as determined by increased positive staining of Wnt3, Wnt3a, Wnt5a, Wnt7b and ${\beta}$-catenin, corresponded with the period of cholangiocarcinogenesis. Furthermore, nuclear staining of ${\beta}$-catenin was observed in CCA tissues. Our results suggest the liver fluke infection causes chronic inflammatory conditions which lead to upregulation of the PI3K/AKT and $Wnt/{\beta}$-catenin signaling pathways which may drive CCA carcinogenesis. These results provide useful information for drug development, prevention and treatment of CCA.

• Molecules and Cells
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• 제38권6호
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• pp.535-539
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• 2015

Olfactory stimulation activates multiple signaling cascades in order to mediate activity-driven changes in gene expression that promote neuronal survival. To date, the mechanisms involved in activity-dependent olfactory neuronal survival have yet to be fully elucidated. In the current study, we observed that olfactory sensory stimulation, which caused neuronal activation, promoted activation of the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway and the expression of Bcl-2, which were responsible for olfactory receptor neuron (ORN) survival. We demonstrated that Bcl-2 expression increased after odorant stimulation both in vivo and in vitro. We also showed that odorant stimulation activated Akt, and that Akt activation was completely blocked by incubation with both a PI3K inhibitor (LY294002) and Akt1 small interfering RNA. Moreover, blocking the PI3K/Akt pathway diminished the odorantinduced Bcl-2 expression, as well as the effects on odorant-induced ORN survival. A temporal difference was noted between the activation of Akt1 and the expression of Bcl-2 following odorant stimulation. Blocking the PI3K/Akt pathway did not affect ORN survival in the time range prior to the increase in Bcl-2 expression, implying that these two events, activation of the PI3K pathway and Bcl-2 induction, were tightly connected to promote post-translational ORN survival. Collectively, our results indicated that olfactory activity activated PI3K/Akt, induced Bcl-2, and promoted long term ORN survival as a result.

• Asian Pacific Journal of Cancer Prevention
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• 제14권4호
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• pp.2201-2205
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• 2013

Colorectal cancer (CRC) is one of the most common cancers in many parts of the world. Its development is a multi-step process involving three distinct stages, initiation that alters the molecular message of a normal cell, followed by promotion and progression that ultimately generates a phenotypically altered transformed malignant cell. Reports have suggested an association of the phosphoinositide-3-kinase (PI3K)/Akt pathway with colon tumorigenesis. Activation of Akt signaling and impaired expression of phosphatase and tensin homolog (PTEN) (a negative regulator of Akt) has been reported in 60-70% of human colon cancers and inhibitors of PI3K/Akt signaling have been suggested as potential therapeutic agents. Around 80% of human colon tumors possess mutations in the APC gene and half of the remainder feature ${\beta}$-catenin gene mutations which affect downstream signaling of the PI3K/Akt pathway. In recent years, there has been a great focus in targeting these signaling pathways, with natural and synthetic drugs reducing the tumor burden in different experiment models. In this review we survey the role of PI3K/Akt/mTOR and Wnt signaling in CRC.

• 생명과학회지
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• 제32권2호
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• pp.86-93
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• 2022

Lupeol은 pentacyclic triterpene의 일종으로 다양한 질병에 약리 효과가 있는 것으로 보고되어 있으나, lupeol이 포도당 흡수에 미치는 영향은 아직 보고된 바 없다. 본 연구에서 3T3-L1 지방세포에서 포도당 흡수에 대한 lupeol의 효과를 조사하였다. 그 결과, Lupeol은 3T3-L1 지방세포에서 GLUT4를 원형질막으로 이동시켜 포도당 흡수를 촉진하였으며, 이는 PI3K/AKT 및 AMPK 경로의 활성화와 관련되어 있었다. PI3K/AKT 경로에서 lupeol은 PI3K를 활성화시키는 insulin receptor substrate 1의 인산화와 AKT의 인산화를 촉진하지만 비정형 단백질 키나아제 C isoforms ζ 및 λ의 인산화는 촉진하지 않았다. 반면, lupeol은 5 'AMP-activated protein kinase의 인산화를 촉진하였고, Lupeol의 의한 AMPK의 활성화는 원형질막-GLUT4의 발현과 세포내 포도당 흡수를 증가시키는 것으로 확인되었다. 3T3-L1 지방세포에서 lupeol에 의한 포도당 흡수 효과는 PI3K 억제제인 wortmannin 및 AMPK 억제제인 Compound C에 의해 억제됨을 통해 확인하였다. 본 연구 결과는 lupeol이 3T3-L1 지방세포에서 PI3K/AKT 및 AMPK 경로를 통해 원형질막 GLUT4의 발현을 자극함으로써 인슐린 감수성을 증가시켜 포도당 흡수를 촉진할 수 있음을 제시하고 있다.

• 한국식품영양과학회지
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• 제45권6호
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• pp.835-842
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• 2016

PI3K/Akt 신호계는 세포 생존의 조절에 필수적인 경로로 대부분 암세포에서 활성이 증대되어 있다. 본 연구에서는 동충하초의 주요 생리활성 물질인 cordycepin에 의한 AGS 인체 위암 세포의 apoptosis 유도에 미치는 PI3K/Akt 신호계의 역할을 조사하였다. 본 연구의 결과에 의하면 cordycepin의 처리 농도의 증가에 따라 AGS 세포의 생존율은 억제되었으며, 이는 apoptosis 유도와 밀접한 관계가 있음을 핵의 형태적 변화와 flow cytometry 분석을 통하여 확인 하였다. 이러한 cordycepin의 apoptosis 유도 효과는 PI3K/Akt 신호계의 활성 저하와 연관성이 있었으며, 세포독성을 나타내지 않는 범위의 PI3K/Akt 신호계 저해제인 LY294002를 cordycepin과 동시 처리하였을 경우, cordycepin에 의한 apoptosis 유발을 더욱 증대시켰다. 그리고 cordycepin에 대한 LY294002의 apoptosis 유발 증대는 caspases (caspase-3, -8 및 -9)의 활성 증가와 poly(ADP-ribose) polymerase 단백질의 분해 증가를 촉진했다. 또한 cordycepin이 처리된 AGS 세포에서 LY294002는 apoptosis 유도에 관여하는 Bax의 발현을 증가시켰고 apoptosis 억제에 관여하는 Bcl-2의 발현은 감소시켰으며, 이는 미토콘드리아 기능 손상과 미토콘드리아에서 세포질로의 cytochrome c 유리를 증대시켰다. 따라서 PI3K/Akt 신호계의 활성 차단은 cordycepin의 항암 활성을 더욱 상승시켰으며, 이는 미토콘드리아 기능 손상과 caspase의 활성 증대를 통하여 이루어짐을 알 수 있었다.

• Asian Pacific Journal of Cancer Prevention
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• 제16권7호
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• pp.2645-2651
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• 2015

Background: The phosphatidylinositol 3'-kinase/Akt (PI3K/Akt) pathway is a key regulator for HER2-overexpressing breast cancer, but data about whether activation of PI3K/Akt is associated with poor prognosis and resistance to trastuzumab therapy is controversial. In this study we investigated predictive and prognostic significance of expression of p27, Akt, PTEN and PI3K, which are components of the PI3K/Akt signaling pathway, in HER2-positive metastatic breast cancer (MBC), retrospectively. Materials and Methods: Fifty-four HER2-positive MBC patients who had received first-line trastuzumab-based therapy were recruited for the study group. All of the patient's breast tissue samples were examined for p27 and Akt expression. In addition, twenty-five patients with sufficient amount of tumor tissue were also examined for PTEN and PI3K expression. p27, Akt, PTEN and PI3K were evaluated by immunohistochemistry and their relationship with patient demographic features, tumor characteristics, response to trastuzumab-based treatment and survival outcomes were analyzed. Results: p27, Akt, PTEN and PI3K were positive in 25.9%, 70.4%, 24% and 96% of the cases, respectively. Nomne were significantly associated with response to trastuzumab and time to progression (TTP). A trend toward statistical significance for longer overall survival (OS) was found for PTEN-positive patients (p=0.058); there was no significant relationship between the other immunohistochemical variables and OS. When we analyzed groups regarding co-expression, the PTEN-negative/Akt-negative group had a significantly lower objective response rate (ORR) (20% vs 80%, p=0.023) and the PTEN-negative/p27-negative and PTEN-negative/Akt-negative groups had significantly lower median OS compared to other patients (26.4 months vs 76.1 months, p=0.005 and 25.6 months vs 52.0 months, p=0.007, respectively). Conclusions: p27, Akt, PTEN and PI3K expression is not statistically significantly associated with ORR, TTP and OS, individually. However, the combined evaluation of p27, Akt and PTEN could be helpful to predict the response to trastuzumab-based therapy and prognosis in HER2-positive MBC.

• The Korean Journal of Physiology and Pharmacology
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• 제24권5호
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• pp.423-431
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• 2020

This study aimed to evaluate the effect of curcumin on brain hypoxic-ischemic (HI) damage in neonatal rats and whether the phosphoinositide 3-kinase (PI3K)/Akt/vascular endothelial growth factor (VEGF) signaling pathway is involved. Brain HI damage models were established in neonatal rats, which received the following treatments: curcumin by intraperitoneal injection before injury, insulin-like growth factor 1 (IGF-1) by subcutaneous injection after injury, and VEGF by intracerebroventricular injection after injury. This was followed by neurological evaluation, hemodynamic measurements, histopathological assessment, TUNEL assay, flow cytometry, and western blotting to assess the expression of p-PI3K, PI3K, p-Akt, Akt, and VEGF. Compared with rats that underwent sham operation, rats with brain HI damage showed remarkably increased neurological deficits, reduced right blood flow volume, elevated blood viscosity and haematocrit, and aggravated cell damage and apoptosis; these injuries were significantly improved by curcumin pretreatment. Meanwhile, brain HI damage induced the overexpression of p-PI3K, p-Akt, and VEGF, while curcumin pretreatment inhibited the expression of these proteins. In addition, IGF-1 treatment rescued the curcumin-induced down-regulated expression of p-PI3K, p-Akt, and VEGF, and VEGF overexpression counteracted the inhibitory effect of curcumin on brain HI damage. Overall, pretreatment with curcumin protected against brain HI damage by targeting VEGF via the PI3K/Akt signaling pathway in neonatal rats.

• Molecules and Cells
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• 제41권6호
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• pp.532-544
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• 2018

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. In order to investigate a new treatment fot GIST, we hypothesized the effect of miR-374b targeting PTEN gene-mediated PI3K/Akt signal transduction pathway on proliferation and apoptosis of human gastrointestinal stromal tumor (GIST) cells. We obtained GIST tissues and adjacent normal tissues from 143 patients with GIST to measure the levels of miR-374b, PTEN, PI3K, Akt, caspase9, Bax, MMP2, MMP9, ki67, PCNA, P53 and cyclinD1. Finally, cell viability, cell cycle and apoptosis were detected. According to the KFGG analysis of DEGs, PTEN was involved in a variety of signaling pathways and miRs were associated with cancer development. The results showed that MiR-374b was highly expressed, while PTEN was downregulated in the GIST tissues. The levels of miR-374b, PI3K, AKT and PTEN were related to tumor diameter and pathological stage. Additionally, miR-374b increased the mRNA and protein levels of PI3K, Akt, MMP2, MMP9, P53 and cyclinD1, suggesting that miR-374b activates PI3K/Akt signaling pathway in GIST-T1 cells. Moreover, MiR374b promoted cell viability, migration, invasion, and cell cycle entry, and inhibited apoptosis in GIST cells. Taken together, the results indicated that miR-374b promotes viability and inhibits apoptosis of human GIST cells by targeting PTEN gene through the PI3K/Akt signaling pathway. Thus, this study provides a new potential target for GIST treatment.

• 생약학회지
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• 제53권2호
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• pp.64-69
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• 2022

When blood vessels are damaged, a rapid hemostatic response should occur in order to lower blood loss and keep normal circulation, and platelet activation and aggregation are essential. Nevertheless, abnormal or excessive platelet aggregation can be a reason of cardiovascular diseases including thrombosis, atherosclerosis, and stroke. Therefore, the screening for a substance which can regulate platelet activation and suppress aggregation reaction is very important for treatment and prevention of cardiovascular diseases. Artemether is a methyl ether derivative of artemisinin, which is isolated from the antimalarial plant Artemisia annua, but research on platelet aggregation or its mechanisms is still insufficient. This study identified the effects of artemether on U46619-induced human platelet aggregation and their granule secretion (ATP and serotonin release). In addition, the effects of artemether on the phosphorylation of PI3K/Akt or MAPK, which are related to signal transduction in platelet aggregation, were studied. As the results, artemether significantly lowered PI3K/Akt and MAPK phosphorylation, which inhibited platelet aggregation through granule secretion (ATP and serotonin release) dose-dependently. Therefore, we suggest that artemether is an antiplatelet substance that regulates PI3K/Akt and MAPK pathway and is of value as a therapeutic and preventive agent for platelet-derived cardiovascular diseases.

• 대한임상검사과학회지
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• 제49권2호
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• pp.99-107
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• 2017

진균 속에 속하는 종인 Cordyceps는 중국의 전통약제로서, 그 유효성분인 cordycepin이 혈소판 응집에 관여한다는 보고가 있지만 phosphoprotein 조절에 관련된 연구는 미흡하다. 본 연구에서는, cordycepin이 fibrinogen binding에 관여한다고 알려진 PI3k/Akt와 $TXA_2$ 분비 및 과립방출에 관여한다고 알려진 p38와 같은 phosphoprotein의 인산화를 어떻게 조절하며 혈소판응집을 억제시키는지 규명하고자 하였다. 그 결과, cordycepin가 $261.1{\mu}M$의 $IC_{50}$으로 collagen이 유도한 혈소판 응집을 강력하게 억제하였고, PI3K와 Akt의 인산화를 감소시키며 ${\alpha}IIb/{\beta}_3$에 대한 fibrinogen 결합을 농도의존적으로 억제하였다. 또한, cordycepin은 collagen이 촉진시킨 p38의 인산화를 억제함으로써, 과립방출의 지표인 ATP 과 serotonin의 방출을 억제하였고 COX-1과 TXAS의 활성 및 $PLC-{\gamma}_2$ 인산화에 대한 영향없이 $TXA_2$ 생성량을 감소시켰다. 따라서, cordycepin은 PI3K/Akt, p38와 같은 phosphoprotein의 인산화를 억제함으로써 혈소판 응집억제를 나타내는 항혈전 치료 및 예방약물로서 유용한 가치가 있다고 여겨진다.