• Molecules and Cells
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• v.28 no.1
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• pp.1-5
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• 2009

Vascular endothelial growth factor (VEGF) is essential for many angiogenic processes both in normal and pathological conditions. However, the signaling pathways involved in VEGF-induced angiogenesis are incompletely understood. The protein kinase D1 (PKD1), a newly described calcium/calmodulin-dependent serine/threonine kinase, has been implicated in cell migration, proliferation and membrane trafficking. Increasing evidence suggests critical roles for PKD1-mediated signaling pathways in endothelial cells, particularly in the regulation of VEGF-induced angiogenesis. Recent studies show that class IIa histone deacetylases (HDACs) are PKD1 substrates and VEGF signal-responsive repressors of myocyte enhancer factor-2 (MEF2) transcriptional activation in endothelial cells. This review provides a guide to PKD1 signaling pathways and the direct downstream targets of PKD1 in VEGF signaling, and suggests important functions of PKD1 in angiogenesis.

• Journal of Life Science
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• v.34 no.2
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• pp.128-137
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• 2024

This review discusses the pivotal role of vascular endothelial growth factors (VEGF) in angiogenesis and lymphangiogenesis, vital processes influencing vascular permeability, endothelial cell recruitment, and the maintenance of tumor-associated blood and lymphatic vessels. VEGF exerts its effects through tyrosine-kinase receptors, VEGFR-1, VEGFR-2, and VEGFR-3. This VEGF-VEGFR system is central not only to cancer but also to diseases arising from abnormal blood vessel and lymphatic vessel formation. In the context of cancer, VEGF and its receptors are essential for the development of tumor-associated vessels, making them attractive targets for therapeutic intervention. Various approaches, such as anti-VEGF antibodies, receptor antagonists, and VEGF receptor function inhibitors, are being explored to interfere with tumor growth. However, the clinical efficacy of anti-angiogenic agents remains uncertain and necessitates further refinement. The article also highlights the physiological role of VEGFs, emphasizing their involvement in endothelial cell functions, survival, and vascular permeability. The identification of five distinct VEGFs in humans (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PLGF) is discussed, along with the classification of VEGFRs as typical receptor tyrosine kinases with distinct signaling systems. The family includes VEGFR-1 and VEGFR-2, crucial in tumor biology and angiogenesis, and VEGFR-3, specifically involved in lymphangiogenesis. Overall, this review has provided a comprehensive overview of VEGF and VEGFR, detailing their roles in various diseases, including cancer. This is expected to further facilitate the utilization of VEGF and VEGFR as therapeutic targets.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.2009-2014
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• 2012

Objective: Taspine, isolated from Radix et Rhizoma Leonticis has demosntrated potential proctiective effects against cancer. Tas13D, a novel taspine derivative synthetized by structure-based drug design, have been shown to possess interesting biological and pharmacological activities. The current study was designed to evaluate its antiproliferative activity and underlying mechanisms. Methods: Antiproliferative activity of tas13D was evaluated by xenograft in athymic mice in vivo, and by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and cell migration assays with human liver cancer (SMMC-7721) cell lines in vitro. Docking between tas13D and VEGFR and EGFR was studied by with a Sybyl/Surflex module. VEGF and EGF and their receptor expression was determined by ELISA and real-time PCR methods, respectively. Results: Our present study showed that tas13D inhibited SMMC-7721 xenograft tumor growth, bound tightly with the active site of kinase domains of EGFR and VEGFR, and reduced SMMC-7721 cell proliferation (IC=34.7 ${\mu}mol/L$) and migration compared to negative controls. VEGF and EGF mRNAs were significantly reduced by tas13D treatment in a dose-dependent manner, along with VEGF and EGF production. Conclusion: The obtained results suggest that tas13D inhibits tumor growth and cell proliferation by inhibiting cell migration, downregulating mRNA expression of VEGF and EGF, and decreasing angiogenic factor production. Tas13D deserves further consideration as a chemotherapeutic agent.

• Tuberculosis and Respiratory Diseases
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• v.55 no.5
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• pp.467-477
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• 2003

Background : Pleural effusions are generally divided into transudates and exudates. If it is exudative, more diagnostic tests are required in order to determine the cause of the local disease. A malignancy is a common and important cause of exudative pleural effusions. Because the pleural fluid cytology and pleural biopsy specimens do not provide a diagnosis in a high percentage of malignant effusions, several tumor markers have been examined. In order to overcome this limitation, this study hypothesized that C-reactive protein(CRP) and vascular endothelial growth factor(VEGF) measurements would be useful for differentiating trasudates from exudates and determining the differences between a benign and malignant effusion. Methods : Eighty consecutive patients with a pleural effusion (tuberculous 20, parapneumonic 20, malignant 20, transudative 20) were examined prospectively: 60 of them were classified according to Light's criteria as having an exudative fluid and 20 had a transudative fluid. The standard parameters of a pleural effusion were examined and the serum and pleural effusion VEGF levels were measured using enzyme linked immunosorbent assay(ELISA). CRP in the serum and pleural fluid was determined by a turbidimetric immunoassay. Results : The pleural CRP levels in the exudates were significantly higher than those in the transudates, $4.19{\pm}4.22mg/d{\ell}$ and $1.29{\pm}1.45mg/d{\ell}$, respectively. The VEGF levels in the pleural effusions were significantly elevated in the exudates compared to the transudate, $1,011{\pm}1,055pg/m{\ell}$ and $389{\pm}325pg/m{\ell}$, respectively. The VEGF ratio in the exudative effusion is significantly higher than a transudative effusions, $3.9{\pm}4.7$ and $1.6{\pm}0.9$, respectively. The pleural CRP levels in the patients with a benign effusion($4.15{\pm}4.20mg/d{\ell}$) were significantly higher than those in the malignant effusion($1.43{\pm}1.91mg/d{\ell}$). The VEGF ratio is significantly higher in malignant effusions($4.9{\pm}5.5$) than in benign effusions($2.8{\pm}3.6$). Conclusion : In conclusion, the CRP and VEGF levels in the serum and pleural effusion can distinguish between transudates and exudates. Moreover it can differentiate between benign and malignant pleural effusions.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.6001-6005
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• 2013

Our aim was to explore anti-cell proliferative and anti-angiogenic potential of andrographolide by analyzing the expression pattern of cell proliferative (PCNA, Cyclin D1) and angiogenic (VEGF) markers during 7, 12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch carcinogenesis. DMBA painting three times a week for 14 weeks in the buccal pouch of golden Syrian hamsters resulted in oral tumors which were histopathologically diagnosed as well differentiated squamous cell carcinoma. Immunohistochemical (PCNA, VEGF) and RT-PCR (Cyclin D1) studies revealed over expression of PCNA, VEGF and Cyclin D1 in the buccal mucosa of hamsters treated with DMBA alone. Oral administration of andrographolide at a dose of 50 mg/kg bw to hamsters treated with DMBA not only suppressed the histological abnormalities but also down regulated the expression of PCNA, VEGF and Cyclin D1. The results of the present study suggest that andrographolide suppressed tumor formation in the buccal mucosa of hamsters treated with DMBA through its anti-cell proliferative and anti-angiogenic potential.

• Korean Journal of Head & Neck Oncology
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• v.27 no.1
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• pp.32-37
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• 2011

서 론 : 미세갑상선유두상암종 환자에서 불필요한 예방적 중앙 림프절절제술을 피하기 위해서 림프절 전이를 수술 전에 예측하는 수단이 필요하다. 림프관 생성 및 성장의 조절에 VEGF-C/D, VEGFR-3 pathway, podoplain이 관여된다는 사실이 밝혀져 있다. 림프관 생성 및 성장과 관련된 인자인 VEGF-C/D, podoplanin에 대한 면역조직화학염색과 반정량적 분석을 통해 미세갑상선유두상암종에서 림프절전이와의 관련성을 확인하고자 하였다. 대상 및 방법 : 2006년 9월부터 2008년 6월까지 본원에서 미세갑상선유두상암종으로 진단받고 1인 술자에 의해 갑상선 전 절제술 및 예방적 중앙 림프절절제술을 받은 104명의 환자 중 중앙 림프절 전이가 있었던 환자와 없었던 환자를 각각 25명씩 무작위로 선별하여 종양부위에 면역화학염색을 실시하여 림프관생성인자의 발현 정도를 비교하였다. 결 과 : 대상군 50예 중 VEGF-C/D는 50예(100%) 모두 발현이 되었고 podoplanin은 33예(66%)에서 발현이 되었다. 그 중 VEGF-C는 10예(20%)에서 약한 양성, 37예(74%)에서 중등도 양성, 3예(6%)에서 강한 양성소견을 보였고 VEGF-D는 9예(18%)에서 약한 양성, 37예(74%)에서 중등도 양성, 4예(8%)에서 강한 양성소견을 보였다. 중앙 림프절 전이 음성 환자 군과 양성 환자 군으로 분류하였을 때 VEGF-C/D의 발현율의 차이는 p-value가 각각 0.48, 1.00으로 통계적으로 유의한 차이를 보이지 않았다. 50예 전체를 대상으로 하여 종양의 개수, 최대크기, 검출된 전체 림프절의 수, 양성 림프절의 수, 주변조직 침범여부에 따른 VEGF-C/D의 발현도 통계적으로 유의한 차이를 보이지 않았다. Podoplanin의 경우 염색 여부에 따라 양성군과 음성군으로 나누어 분석하였을 때 종양의 개수, 최대크기, 검출된 림프절의 수, 양성 림프절의 수, 주변조직 침범여부도 통계적으로 유의한 차이를 보이지 않았다. 결 론 : VEGF-C/D는 대상군 전체(100%)에서 발현이 되었고 podoplanin은 66%에서 발현이 되었다. 림프관 생성인자로 알려진 VEGF-C/D및 podoplanin이 미세갑상선유두상암종에서 많이 발현이 되는 것으로 보아 위 인자들이 림프절 전이를 일으키는 인자 중 하나로 생각된다. 하지만 미세갑상선유두상암종에서 중앙 림프절 전이를 예측할 수 있는 인자로 부적합 한 것으로 생각되며 향후 더 많은 증례를 통해 관련성 여부에 대한 연구가 필요하고 또 다른 인자의 관련성에 대해서 연구가 필요하겠다.

• Asian-Australasian Journal of Animal Sciences
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• v.27 no.9
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• pp.1355-1359
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• 2014

To detect goat vascular endothelial growth factor (VEGF)-mediated regrowth of hair, full-length VEGF164 cDNA was cloned from Inner Mongolia cashmere goat (Capra hircus) into the pET-his prokaryotic expression vector, and the recombinant plasmid was transferred into E. coli BL21 cells. The expression of recombinant $6{\times}his-gVEGF164$ protein was induced by 0.5 mM isopropyl thio-${\beta}$-D-galactoside at $32^{\circ}C$. Recombinant goat VEGF164 (rgVEGF164) was purified and identified by western blot using monoclonal anti-his and anti-VEGF antibodies. The rgVEGF164 was smeared onto the dorsal area of a shaved mouse, and we noted that hair regrowth in this area was faster than in the control group. Thus, rgVEGF164 increases hair growth in mice.

• Biomolecules & Therapeutics
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• v.23 no.1
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• pp.19-25
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• 2015

Vascular endothelial growth factor (VEGF) is an important regulator of neovascularization. Hypoxia inducible nitric oxide (NO) enhanced the expression of VEGF and thymosin beta-4 ($T{\beta}4$), actin sequestering protein. Here, we investigated whether NO-mediated VEGF expression could be regulated by $T{\beta}4$ expression in HeLa cervical cancer cells. Hypoxia inducible NO production and VEGF expression were reduced by small interference (si) RNA of $T{\beta}4$. Hypoxia response element (HRE)-luciferase activity and VEGF expression were increased by the treatment with N-(${\beta}$-D-Glucopyranosyl)-N2-acetyl-S-nitroso-D, L-penicillaminamide (SNAP-1), to generate NO, which was inhibited by the inhibition of $T{\beta}4$ expression with $T{\beta}4$-siRNA. In hypoxic condition, HRE-luciferase activity and VEGF expression were inhibited by the treatment with $N^G$-monomethyl-L-arginine (L-NMMA), an inhibitor to nitric oxide synthase (NOS), which is accompanied with a decrease in $T{\beta}4$ expression. VEGF expression inhibited by L-NMMA treatment was restored by the transfection with pCMV-$T{\beta}4$ plasmids for $T{\beta}4$ overexpression. Taken together, these results suggest that $T{\beta}4$ could be a regulator for the expression of VEGF via the maintenance of NOS activity.

• Genomics & Informatics
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• v.19 no.1
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• pp.6.1-6.10
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• 2021

Vascular endothelial growth factor (VEGF) is expressed at elevated levels by most cancer cells, which can stimulate vascular endothelial cell growth, survival, proliferation as well as trigger angiogenesis modulated by VEGF and VEGFR (a tyrosine kinase receptor) signaling. The angiogenic effects of the VEGF family are thought to be primarily mediated through the interaction of VEGF with VEGFR-2. Targeting this signaling molecule and its receptor is a novel approach for blocking angiogenesis. In recent years virtual high throughput screening has emerged as a widely accepted powerful technique in the identification of novel and diverse leads. The high resolution X-ray structure of VEGF has paved the way to introduce new small molecular inhibitors by structure-based virtual screening. In this study using different alkaloid molecules as potential novel inhibitors of VEGF, we proposed three alkaloid candidates for inhibiting VEGF and VEGFR mediated angiogenesis. As these three alkaloid compounds exhibited high scoring functions, which also highlights their high binding ability, it is evident that these alkaloids can be taken to further drug development pipelines for use as novel lead compounds to design new and effective drugs against cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.6
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• pp.2823-2828
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• 2012

Objective: To explore a new model of in-situ xenograft lymphangiogenesis of human colonic adenocarcinomas in nude mice. Method: On the basis of establishing subcutaneous xenograft lymphangiogenesis model of human colonic adenocarcinoms, in-situ xenografts were established through the in situ growth of the HT-29 human colonic adenocarcinoma cell line in nude mice. The numbers of lymphangiogenic microvessels, the expression of lymphatic endothelial cell markers lymphatic vessel endothelial hyaloronic acid receptor-1 (LYVE-1), D2-40 and the lymphatic endothelial growth factors vascular endothelial growth factor-C (VEGF-C), -D (VEGF-D) and receptor-3 (VEGFR-3) were compared by immunohistochemical staining, Western bolt and quantitative RT-PCR in xenograft in-situ models. Results: Some microlymphatics with thin walls, large and irregular or collapsed cavities and increased LMVD, with strong positive of LYVE-1, D2-40 in immunohistochemistry, were observed, identical with the morphological characteristics of lymphatic vessels and capillaries. Expression of LYVE-1 and D2-40 proteins and mRNAs were significantly higher in xenograpfts in-situ than in the negative control group(both P<0.01). Moreover, the expression of VEGF-C, VEGF-D and VEGFR-3 proteins and mRNAs were significantly higher in xenografts in-situ (both P<0.01), in conformity with the signal regulation of the VEGF-C,-D/VEGFR-3 axis of tumor lymphangiogenesis. Conclusions: In-situ xenografts of a human colonic adenocarcinoma cell line demonstrate tumor lymphangiogenesis. This novel in-situ animal model should be useful for further studying mechanisms of lymph node metastasis, drug intervention and anti-metastasis therapy in colorectal cancer.