• Korean Chemical Engineering Research
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• 제51권6호
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• pp.727-732
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• 2013

본 연구는 역오팔 지지체를 이용하여 인간지방유래 줄기세포의 연골 분화를 촉진하는 내용을 담고 있다. 비 다공성 구조를 가진 지지체에서 세포를 분화 시도하였을 경우 분화가 잘 촉진되지 않는 것에 비해 200 nm 정도의 균일한 구멍을 가지는 poly(D,L-lactide-co-glycolide)로 구성된 역오팔 지지체는 그 다공성 구조로 인하여 지지체의 내부까지 산소와 유기물의 수송을 가능하게 하여 지지체 내에서 어떤 유전적, 약물적 처리 없이 인간지방유래 줄기세포가 분화가 잘 되게 하는 것을 확인하였다.

• Molecules and Cells
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• 제45권7호
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• pp.454-464
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• 2022

DJ-1 is one of the causative genes of early-onset familial Parkinson's disease (PD). As a result, DJ-1 influences the pathogenesis of sporadic PD. DJ-1 has various physiological functions that converge to control the levels of intracellular reactive oxygen species (ROS). Based on genetic analyses that sought to investigate novel antioxidant DJ-1 downstream genes, pyruvate dehydrogenase (PDH) kinase (PDK) was demonstrated to increase survival rates and decrease dopaminergic (DA) neuron loss in DJ-1 mutant flies under oxidative stress. PDK phosphorylates and inhibits the PDH complex (PDC), subsequently downregulating glucose metabolism in the mitochondria, which is a major source of intracellular ROS. A loss-of-function mutation in PDK was not found to have a significant effect on fly development and reproduction, but severely ameliorated oxidative stress resistance. Thus, PDK plays a critical role in the protection against oxidative stress. Loss of PDH phosphatase (PDP), which dephosphorylates and activates PDH, was also shown to protect DJ-1 mutants from oxidative stress, ultimately supporting our findings. Further genetic analyses suggested that DJ-1 controls PDK expression through hypoxia-inducible factor 1 (HIF-1), a transcriptional regulator of the adaptive response to hypoxia and oxidative stress. Furthermore, CPI-613, an inhibitor of PDH, protected DJ-1 null flies from oxidative stress, suggesting that the genetic and pharmacological inhibition of PDH may be a novel treatment strategy for PD associated with DJ-1 dysfunction.

• Journal of Gastric Cancer
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• 제21권4호
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• pp.439-456
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• 2021

Purpose: Gastric cancer (GC) has high morbidity and mortality and is a serious threat to public health. The flavonoid compound vitexin is known to exhibit anti-tumor activity. In this study, we explored the therapeutic potential of vitexin in GC and its underlying mechanism. Materials and Methods: The viability, migration, and invasion of GC cells were determined using MTT, scratch wound healing, and transwell assays, respectively. Target molecule expression was determined by western blotting. Tumor growth and liver metastasis were evaluated in vivo using nude mice. Protein expression in the tumor tissues was examined by immunohistochemistry. Results: Vitexin inhibited GC cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT) in a dose-dependent manner. Vitexin treatment led to the inactivation of phosphatidylinositol-3-kinase (PI3K)/AKT/hypoxia-inducible factor-1α (HIF-1α) pathway by repressing HMGB1 expression. Vitexin-mediated inhibition in proliferation, migration, invasion and EMT of GC cells were counteracted by hyper-activation of PI3K/AKT/HIF-1α pathway or HMGB1 overexpression. Finally, vitexin inhibited the xenograft tumor growth and liver metastasis in vivo by suppressing HMGB1 expression. Conclusions: Vitexin inhibited the malignant progression of GC in vitro and in vivo by suppressing HMGB1-mediated activation of PI3K/Akt/HIF-1α signaling pathway. Thus, vitexin may serve as a promising therapeutic agent for the treatment of GC.

• Molecules and Cells
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• 제38권4호
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• pp.373-379
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• 2015

Pyruvate kinase M2 isoform (PKM2), a rate-limiting enzyme in the final step of glycolysis, is known to be associated with the metabolic rewiring of cancer cells, and considered an important cancer therapeutic target. Herein, we report a novel PKM2 activator, PA-12, which was identified via the molecular docking-based virtual screening. We demonstrate that PA-12 stimulates the pyruvate kinase activity of recombinant PKM2 in vitro, with a half-maximal activity concentration of $4.92{\mu}M$, and effectively suppresses both anchorage-dependent and -independent growth of lung cancer cells in non-essential amino acid-depleted medium. In addition, PA-12 blocked the nuclear translocalization of PKM2 in lung cancer cells, resulting in the inhibition of hypoxia response element (HRE)-mediated reporter activity as well as hypoxia-inducible factor 1 (HIF-1) target gene expression, eventually leading to the suppression of cell viability under hypoxia. We also verified that the effects of PA-12 were dependent on PKM2 expression in cancer cells, demonstrating the specificity of PA-12 for PKM2 protein. Taken together, our data suggest that PA-12 is a novel and potent PKM2 activator that has therapeutic implications for lung cancer.

• BMB Reports
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• 제52권6호
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• pp.379-384
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• 2019

Epithelial-mesenchymal transition (EMT) is widely-considered to be a modulating factor of anoikis and cancer metastasis. We found that, in MDA-MB-231 cells, TP53I11 (tumor protein P53 inducible protein 11) suppressed EMT and migration in vitro, and inhibited metastasis in vivo. Our findings showed that hypoxic treatment upregulated the expression of $HIF1{\alpha}$, but reduced TP53I11 protein levels and TP53I11 overexpression reduced $HIF1{\alpha}$ expression under normal culture and hypoxicconditions, and in xenografts of MDA-MB-231 cells. Considering $HIF1{\alpha}$ is a master regulator of the hypoxic response and that hypoxia is a crucial trigger of cancer metastasis, our study suggests that TP53I11 may suppress EMT and metastasis by reducing $HIF1{\alpha}$ protein levels in breast cancer cells.

• Journal of Gastric Cancer
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• 제20권1호
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• pp.95-105
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• 2020

Purpose: Gastric cancer is a highly metastatic malignant tumor, often characterized by chemoresistance and high mortality. In the present study, we aimed to investigate the role of B-cell lymphoma 3 (Bcl-3) protein on cell migration and chemosensitivity of gastric cancer. Materials and Methods: The gastric cancer cell lines, AGS and NCI-N87, were used for the in vitro studies and the in vivo studies were performed using BALB/c nude mice. Western blotting, wound healing assay, Cell Counting Kit-8 assay, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay were used to evaluate the role of Bcl-3 in gastric cancer. Results: We found that the protein expression of hypoxia (HYP)-inducible factor-1α and Bcl-3 were markedly upregulated under hypoxic conditions in both AGS and NCI-N87 cells in a time-dependent manner. Interestingly, small interfering RNA-mediated knockdown of Bcl-3 expression affected the migration and chemosensitivity of the gastric cancer cells. AGS and NCI-N87 cells transfected with si-RNA-Bcl-3 (si-Bcl-3) showed significantly reduced migratory ability and increased chemosensitivity to oxaliplatin, 5-fluorouracil, and irinotecan. In addition, si-Bcl-3 restored the autophagy induced by HYP. Further, the protective role of si-Bcl-3 on the gastric cancer cells could be reversed by the autophagy inducer, rapamycin. Importantly, the in vivo xenograft tumor experiments showed similar results. Conclusions: Our present study reveals that Bcl-3 knockdown inhibits cell migration and chemoresistance of gastric cancer cells through restoring HYP-induced autophagy.

• Molecules and Cells
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• 제28권6호
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• pp.537-543
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• 2009

Keratinocyte overgrowth after UVB exposure is believed to contribute to skin photoageing and cancer development. However, little is known about the transcription factors that epigenetically regulate keratinocyte response to UVB. Recently, $HIF-1{\alpha}$ was found to play a role in epidermal homeostasis by controlling the keratinocyte cell cycle, and thus, we hypothesized that $HIF-1{\alpha}$ is involved in UVB-induced keratinocyte growth. In cultured keratinocytes, $HIF-1{\alpha}$ was found to be down-regulated shortly after UVB exposure and to be involved in UVB-induced proliferation. In mice repeatedly treated with UVB, the epidermis became hyperplasic and keratinocytes lacked $HIF-1{\alpha}$ in nuclei. Based on these results, we suggest that the deregulation of $HIF-1{\alpha}$ is associated with UVB-induced hyperplasia of the epidermis. This work provides insight of the molecular mechanism underlying UV-induced photoageing and skin cancer development.

• Fisheries and Aquatic Sciences
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• 제17권3호
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• pp.305-311
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• 2014

Dieckol is a polyphenol compound isolated from brown algae that has anti-oxidant, anti-inflammatory, and anti-tumor activity. We examined the anti-angiogenic effects of dieckol in endothelial cells under hypoxic conditions. Treatment with $CoCl_2$, a hypoxic mimetic agent, increased proliferation, adhesion, migration, and tube formation in HUVECs, as well as vessel sprouting in rat aortic rings, which correlated well with increased expression of hypoxia-inducible factor 1-alpha ($HIF1{\alpha}$) and ${\beta}1$-integrin. Dieckol suppressed $CoCl_2$-induced adhesion, migration, and tube formation in HUVECs and vessel sprouting in rat aortic rings. Dieckol treatment decreased $CoCl_2$-induced overexpression of $HIF1{\alpha}$ and its downstream signaling molecules, including ${\beta}1$-integrin/Fak, Akt/eNOS, and p38 MAPK. These results suggest that dieckol is a novel angiogenesis inhibitor and a potential treatment for angiogenesis-dependent diseases in humans, such as malignant tumors.

• 대한한방내과학회지
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• 제34권2호
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• pp.178-191
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• 2013

Objectives : In this study, we made an effort to investigate the protective mechanism of Ukgan-san (UGS) extracts on hypoxia-induced C6 glial cell death. Methods : The cell viability was assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MMT) assay and cell morphological changes were analysed with microscope after staining with crystal violet (CV). Reactive oxygen species (ROS) formation was assessed by flow cytometer after staining with 2'7'-dichlorofluorescein diacetate (DCF-DA). We also analyzed expression of hypoxia-inducible factor-1 alpha (HIF-$1{\alpha}$) and p53, processing of procaspase-3 and procyclic acidic repetitive protein (PARP) by western blot method. Results : We estimated the elevated cell viability by UGS extract on $CoCl_2$-induced C6 glial cells. UGS attenuated $CoCl_2$-induced ROS formation in C6 glial cells and also showed a protective activity compared to antioxidants and exhibited abrogation of LDH-released by $CoCl_2$. UGS suppressed the typical apoptotic cell death markers, caspase-3 and PARP activation. UGS inhibited $CoCl_2$-induced HIF-1${\alpha}$ expression which is known as a major regulator for hypoxia-induced cell death, and suppressed p53 expression. Conclusions : These results suggest that UGS extract contains protective constituents for hypoxia-induced C6 glial cell death.

• Tuberculosis and Respiratory Diseases
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• 제66권3호
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• pp.178-185
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• 2009

연구배경: 암세포는 빠른 증식 속도로 인하여 상대적인 저산소증에 노출되면서 비정상적인 종양 혈관을 형성하여 치명적인 병인을 형성한다. EGCG는 녹차의 추출물로 간세포암주 및 전립선암주에서 HIF-1$\alpha$의 발현을 억제하는 것으로 알려져 있다. 그러나 EGCG의 비혈관 증식성 효과에 대해서는 아직 정확히 규명되어 있지 않다. 본 연구에서는 EGCG가 비소세포폐암주에서 HIF-1$\alpha$ 및 VEGF의 발현에 대한 억제 가능성을 확인하여 보고자 하였다. 방 법: 비소세포폐암주인 A549를 RPMI배지에서 계대 배양하였다. 저산소 유사 상태는 Modular Incubator Chamber (MIC-101)을 이용하였고 5% 이산화탄소와 95% 질소 혼합 가스를 5분 동안 공급하여 저산소 상태를 만들었으며 세포 배양액을 채취하여 혈액가스분석기(Blood Gas Analyzer ABL725)로 세포 배양 상태를 측정하였다. 세포의 증식 상태는 MTT 방법을 실시하였다. EGCG는 0, 12.5, 25, 50,100 ${\mu}mol/L$로 농도 변화를 주어 실험을 시행하였으며 16시간 동안 저산소 상태를 만든 뒤 HIF-1$\alpha$, VEGF, $\beta$-actin mRNA에 대해 Real time PCR을 시행하였다. 결 과: 48시간과 72시간에서 저산소 상태에 놓인 A549 세포의 증식능력은 대조군에 비하여 억제되었다. EGCG 는 저산소화에 의해 유도된 HIF-1$\alpha$의 mRNA의 전사를 유의하게 억제하였다. 그러나 이러한 억제 효과는 VRGF mRNA 발현에는 미치지 못하였다. 결 론: EGCG는 HIF-1$\alpha$의 발현을 억제함으로써 비소세포암주에서의 예방적 항암요법이나 항암 치료요법 시의 주요 작용 목표로 사용될 수 있을 것으로 보인다.