• 대한의생명과학회지
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• 제20권4호
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• pp.209-220
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• 2014

Vascular endothelial growth factor (VEGF) is a key factor involved in the induction of angiogenesis and has become an attractive target for anti-angiogenesis therapies. The purpose of this study was to elucidate the anti-angiogenic activity of Rubus coreanus Miquel water extract (RCME). Rubus coreanus Miquel has long been employed as a traditional medicine, and recent studies have demonstrated that it has measureable biological activities. Thus, we investigated for the first time the effect of RCME on angiogenesis and its underlying signaling pathways. The effects of RCME were tested on in vitro models of angiogenesis, namely, proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells as well as an ex vivo model of vessel sprouting from the rat aorta in response to VEGF. We observed that VEGF-induced angiogenesis was strongly suppressed by RCME treatment compared to that of the control group. Moreover, we found that RCME inhibited VEGF-induced activation of matrix metalloproteinases and phosphorylation of extracellular signal-regulated kinase and p38, and also effectively inhibited phosphorylation of VEGF receptor 2. These results indicated that RCME inhibits angiogenesis by suppressing phosphorylation of the VEGF receptor and may be useful for the treatment of angiogenesis-dependent diseases such as cancer and diabetic retinopathy.

• 대한안과학회지
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• 제59권12호
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• pp.1142-1151
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• 2018

목적: 삼출 나이관련황반변성에 대한 유리체내 항혈관내피성장인자 주사 치료의 장기 결과를 알아보고자 한다. 대상과 방법: 삼출 나이관련황반변성 진단 후 treat-and-extend 또는 as needed 방법으로 7년 이상 유리체내 항혈관내피성장인자 주사 치료를 시행 받은 환자들에 대한 후향적 의무기록 분석을 시행하였다. 주사 횟수, 최대교정시력 및 중심망막두께 등을 평가하였으며, 장기간 주사 치료에 따른 부작용 여부를 같이 조사하였다. 결과: 총 196명의 196안을 분석하였다(평균 나이 $68.6{\pm}9.6$세, 여성 77명). 평균 $78.0{\pm}16.5$개월 경과관찰하였고, 해당 기간 동안 평균 $17.3{\pm}13.5$회의 유리체내주사가 시행되었다. 치료 전 측정한 최대교정시력은 평균 $0.75{\pm}0.58$ logMAR, 중심망막두께는 $349.7{\pm}152.6{\mu}m$였고, 6개월째 두 수치 모두 최대 호전을 보였으나(p<0.05), 이후 점차 악화 소견을 보이며 7년째 최대교정시력 $0.91{\pm}0.78$ logMAR, 중심망막두께 $284.5{\pm}105.8{\mu}m$로 확인되었다. 주사 후 7년째 시력은 치료 전 시력과 강한 양의 상관관계를 보였다. 장기간 주사 동안 총 11회의 안압상승 및 3회의 전방 내 염증 증가 소견이 있었으나 안내염 등의 심각한 부작용은 관찰되지 않았다. 결론: 삼출 나이관련황반변성에서 유리체내 항혈관내피성장인자 주사 치료 후 초기 6개월간의 최대 시력 호전이 있었으나 5년 이상 경과 시 지속적인 시력 저하를 막지 못하였다. 진단 당시 시력이 장기 시력예후와 관련된 중요 예측 인자로 판단되며 적극적인 유리체 내주사 치료를 통해 더 나은 장기 시력 결과를 기대해 볼 수 있다.

• Asian Pacific Journal of Cancer Prevention
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• 제14권1호
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• pp.429-433
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• 2013

Objectives: To explore the correlation between multi-slice spiral CT (MSCT) perfusion parameters and the expression of vascular endothelial growth factor (VEGF) as well as matrix metalloproteinase-2 (MMP-2) in breast cancer. Methods: Forty five breast cancer patients and 16 patients with benign breast tumor, both confirmed by pathology examination, were enrolled. All underwent MSCT perfusion imaging to obtain perfusion maps and data for parameters including blood flow (BF), blood volume (BV) and permeability surface (PS). Cancer patients did not receive treatment prior to surgery. The expression of VEGF and MMP-2 were examined with both immunohistochemistry and Western blotting. Results: The levels of VEGF and MMP-2 by immunohistochemistry were significantly higher in the breast cancer group (P < 0.01) than the benign tumor group. Relative OD values from Western blotting were also higher in cancer cases (P < 0.05). Similarly, the mean MSCT perfusion parameters (BF, BV, PS) were significantly higher in the breast cancer group (P < 0.01), BF and BV positively correlating with VEGF expression (r = 0.878 and 0.809 respectively, P < 0.01); PS and VEGF and MMP-2 expression were also positively correlated (r= 0.860, 0.786 respectively, P < 0.01). Conclusion: There is a correlation between breast cancer MSCT perfusion parameters and VEGF andMMP-2 expression, which might be useful for detection of breast lesions, qualitative diagnosis of breast cancer, and evaluation of breast cancer treatment.

• Journal of Ginseng Research
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• 제40권2호
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• pp.151-159
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• 2016

Background: Ginsenoside-Rg3, the pharmacologically active component of red ginseng, has been found to inhibit tumor growth, invasion, metastasis, and angiogenesis in various cancer models. Previously, we found that 20(R)-ginsenoside-Rg3 (Rg3) could inhibit angiogenesis. Since microRNAs (miRNAs) have been shown to affect many biological processes, they might play an important role in ginsenoside-mediated angiomodulation. Methods: In this study, we examined the underlying mechanisms of Rg3-induced angiosuppression through modulating the miRNA expression. In the miRNA-expression profiling analysis, six miRNAs and three miRNAs were found to be up- or down-regulated in vascular-endothelial-growth-factor-induced human-umbilical-vein endothelial cells (HUVECs) after Rg3 treatment, respectively. Results: A computational prediction suggested that mature hsa-miR-520h (miR-520h) targets ephrin receptor (Eph) B2 and EphB4, and hence, affecting angiogenesis. The up-regulation of miR-520h after Rg3 treatment was validated by quantitative real-time polymerase chain reaction, while the protein expressions of EphB2 and EphB4 were found to decrease, respectively. The mimics and inhibitors of miR- 520h were transfected into HUVECs and injected into zebra-fish embryos. The results showed that overexpression of miR-520h could significantly suppress the EphB2 and EphB4 protein expression, proliferation, and tubulogenesis of HUVECs, and the subintestinal-vessel formation of the zebra fish. Conclusion: These results might provide further information on the mechanism of Rg3-induced angiosuppression and the involvement of miRNAs in angiogenesis.

• 생물정신의학
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• 제14권4호
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• pp.232-240
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• 2007

목 적: Cytokine 중의 하나인 vascular endothelial growth factor(VEGF)와 VEGF 수용체들은 다양한 생체내 조절 및 질병 상태와 연관이 있음이 알려져 있다. 본 연구는 정신분열병 환자에서 항정신병약물 치료에 따른 혈청내 자유(free) VEGF와 가용성 VEGFR-1, 가용성 VEGFR-2의 변화를 보기 위한 것이었다. 방 법: 각 환자들은 DSM-IV 진단기준에 의해 정신분열병으로 진단을 받았고, 약물투여 시작일을 기준으로 4주째 및 8주째에 추적 관찰하였다. 모두 13명이 환자군에 포함되었으며 항정신병약물 투여전과 투여후 4주째, 8주째에 각각 PANSS에 의한 상태 평가와 함께 자유 VEGF, sVEGFR-1, sVEGFR-2의 농도를 측정하였다. 13명의 정상 대조군을 환자군의 나이와 성별에 맞춰 선정하였다. 결 과: 정신분열병 환자군의 혈청 자유 VEGF($295.2{\pm}43.7$pg/ml)와 sVEGFR-2($8259{\pm}336.7$)의 농도는 정상 대조군($199.0{\pm}28.8$ 및 $8481{\pm}371.9$)과 비교하였을 때 의미있는 차이를 보이지 않았다. 그러나 sVEGFR-1의 농도($86.2{\pm}10.3$, p<0.05)는 정신분열병 환자군에서 대조군($59.0{\pm}6.4$)에 비해 의미있게 상승하였다. 정신분열병 환자군에서 항정신병약물 투여 후 자유 VEGF 농도는 4주째($338.9{\pm}56.5$)와 8주째($309.5{\pm}58.7$) 모두 투여 전과 비교하여 차이가 없었다. 그러나 sVEGFR-1 농도는 약물 치료후 8주째($57.3{\pm}6.3$, p<0.05)에 측정한 결과에서 유의하게 감소하였다. sVEGFR-2의 농도도 치료전과 비교하였을때 약물 치료후 4주째($7761{\pm}403.0$, p<0.05)와 8주째($7435{\pm}333.5$, p<0.05) 모두 유의하게 감소하였다. 결 론: sVEGFR-1과 sVEGFR-2 농도의 감소는 항정신병약물이 작용하는 도파민 신경계와 관련된 것으로 추정된다.

• 대한안과학회지
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• 제59권11호
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• pp.1039-1048
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• 2018

목적: 연령관련황반변성 환자에 대해 항혈관내피성장인자의 가능한 치료 방법에 따라 건강보험 재정에 미치는 영향을 분석하였다. 대상과 방법: 여러 치료 방법에 따른 건강보험 재정의 변화를 향후 5년(2018-2022년) 동안 추정하였다. 새로운 급여기준 이외 바이오시밀러 등장, 허가초과 비급여약제 사용 등을 고려한 시나리오에 대해서도 재정 영향을 분석하였다. 국민건강보험공단 청구자료 및 의료기관 자료를 기준으로 각 시나리오별로 향후 5년 동안 예상 진료환자 수, 치료 횟수를 추정하였으며, 재정부담을 추계하였다. 결과: 연령관련황반변성에서 현행의 사용형태로 기존 급여기준(평생 14회)이 유지되는 경우(시나리오 1) 2018년 기준 향후 5년간 보험소요재정은 약 4,403억 원으로 추정되었다. 2017년 12월에 변경된 급여기준하에서 5년간 보험소요재정은 약 5,601억 원으로 추정되었다. 2020년 이후 바이오시밀러 급여(시나리오 3), 현재 허가초과 비급여약제인 베바시주맙(시나리오 4)을 급여전환하는 경우에 각각 5,210억 원, 4,197억 원으로 예상되었다. 결론: 본 평생 14회라는 급여기준 삭제로 인해 건강보험 재정이 크게 증가할 것이 예상되었으나 실제 0.1 이하 그리고 반흔화/위축성 병변일 경우 급여 중단 등의 새로운 기준으로 중간폭으로 증가하는 것으로 나타났다. 또한 고령화로 인한 연령관련황반변성 유병환자의 증가를 고려할 때 바이오시밀러 및 베바시주맙 도입 등의 정책적 대안도 고려할 수 있다.

• Journal of Genetic Medicine
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• 제7권2호
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• pp.138-144
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• 2010

목 적: 자궁내막의 신혈관 형성을 조정하는 혈관내피전구세포는 자궁-태반 순환에서의 신혈관 형성에 관여하는 것으로 알려져 있다. 혈관내피전구세포의 정량적 지표로 사용되는 집락생성단위(CFU)의 감소는 혈관질환의 예측 표지자로서 보고되고 있다. 본 연구에서는 정상 산모와 자간전증 산모 간에 CFU의 수적인 차이를 비교해 보고자 하였다. 대상 및 방법: 임신말기의 단태 정상 산모 26명과 자간전증산모 20명을 대상으로 혈관내피전구세포의 수를 CFU로 정량화하였다. 효소면역분석법을 이용하여 혈장내의 VEGF와 sFlt-1, PlGF 농도를 분석하였다. 결 과: CFU의 수는 정상 산모에 비해 자간전증 산모에서 매우 감소하였다[median value: 3 (range: 1-12) vs median value: 31(range:3-81) CFU/ well, P<0.001). 집락을 구성하는 대부분의 세포는 혈관내피세포의 특징적인 성질을 보였다(Ulex europaeus lectin의 발현 및 acetylated lowdensity lipoprotein의 섭취). 혈장내의 sFlt-1 농도는 정상 산모에 비해 자간전증 산모에서 매우 높은 반면(P<0.001), PlGF의 농도는 매우 낮았으며(P=0.004), sFlt-1과 PlGF의 농도는 CFU의 수와 연관성이 없었다. 결 론: 산모 말초혈액내의 CFU의 수적 감소가 자간전증 발생에 기여할 것으로 생각된다.

• Biomolecules & Therapeutics
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• 제29권5호
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• pp.545-550
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• 2021

Chemotherapy-induced alopecia and hair loss can be stressful in patients with cancer. The hair grows back, but sometimes the hair tends to stay thin. Therefore, understanding mechanisms regulating hair regeneration may improve the management of chemotherapy-induced alopecia. Previous studies have revealed that chemotherapeutic agents induce a hair follicle vascular injury. As hair growth is associated with micro-vessel regeneration, we postulated that the stimulation of angiogenesis might enhance hair regeneration. In particular, mice treated with 5-fluorouracil (5-FU) showed delayed anagen initiation and reduced capillary density when compared with untreated controls, suggesting that the retardation of anagen initiation by 5-FU treatment may be attributed to the loss of perifollicular micro-vessels. We investigated whether the ETS transcription factor ETV2 (aka ER71), critical for vascular development and regeneration, can promote angiogenesis and hair regrowth in a 5-FU-induced alopecia mouse model. Tie2-Cre; Etv2 conditional knockout (CKO) mice, which lack Etv2 in endothelial cells, presented similar hair regrowth rates as the control mice after depilation. Following 5-FU treatment, Tie2-Cre; Etv2 CKO mice revealed a significant reduction in capillary density, anagen induction, and hair restoration when compared with controls. Mice receiving lentiviral Etv2 injection after 5-FU treatment showed significantly improved anagen induction and hair regrowth. Two-photon laser scanning microscopy revealed that enforced Etv2 expression restored normal vessel morphology after 5-FU mediated vessel injury. Our data suggest that vessel regeneration strategies may improve hair regrowth after chemotherapeutic treatment.

• Asian Pacific Journal of Cancer Prevention
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• 제16권16호
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• pp.6813-6823
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• 2015

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive of human brain tumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cell proliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficient curative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiple genetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. The transforming growth factor ${\beta}$ ($TGF{\beta}$) superfamily is a large group of structurally related proteins including $TGF{\beta}$ subfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiation factor (GDF). It is involved in important biological functions including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. This superfamily is also considered to impact on cancer biology including that of GBM, with various effects depending on the member. The $TGF{\beta}$ subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. This subfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and major histocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenic factors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulinlike growth factor-binding protein 7 (IGFBP7), contributes to GBM progression by inducing metalloproteinases (MMPs), "pro-neoplastic" integrins (${\alpha}v{\beta}3$, ${\alpha}5{\beta}1$) and GBM initiating cells (GICs) as well as inducing a GBM mesenchymal phenotype. Equally, Nodal promotes GICs, induces cancer metabolic switch and supports GBM cell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDF yields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivity to chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategies in anti-cancer therapy. While suppressing the $TGF{\beta}$ subfamily yields advantageous results, enhancing BMPs production is also beneficial.

• Archives of Plastic Surgery
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• 제32권3호
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• pp.347-356
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• 2005

The wound healing process in fetus is quite different form that of adult. Regeneration plays an important role and scarless wound healing is possible in early gestational fetal period. Recently, the various effects of the hypoxia and reoxygenation in the wound healing process have been investigated by many researchers. The hypoxic state is known to alter protein synthesis and gene expression of TGF-${\beta}$, VEGF. The authors hypothesize there may be differences between fetal and adult fibroblast and this difference may play a possible role in the mechanism of scarless fetal wound healing. In this study, we investigated the growth of fibroblast, the amount of collagen deposition, the amount of protein synthesis and gene expression in TGF-${\beta}$(transforming growth factor-${\beta}$), VEGF(vascular endothelial growth factor) under the various hypoxic and reoxygenation conditions. Through these processes, we tried to determine the relationships between scarless fetal wound healing and hypoxic condition. In control group, fetal and adult fibroblasts were cultured under normoxic condition. The experimental groups were allocated into four different groups. The differences in TGF-beta, VEGF under 24, 48, 72 hours were statistically investigated. Compared to adult fibroblast group, there was a statistically significant increase (p<0.01) in the rates of protein synthesis in TGF-beta and VEGF of fetal fibroblast. In this study, these results may reflect the possibility that fetal fibroblast are more susceptible to change in oxygen and has a superior rate of angiogenesis through increased VEGF expression. The possible superiority of angiogenesis in fetal fibroblast may play an important role in scarless wound healing.