• YAKHAK HOEJI
• /
• v.59 no.5
• /
• pp.215-221
• /
• 2015

Glucocorticoids are known to have anti-inflammatory effect. To investigate whether corticosterone pretreatment enhances or not lipopolysaccharide (LPS)-induced production of inflammatory mediators, RAW 264.7 cells were pretreated with various concentrations of corticosterone for 24 h and then cultured without corticosterone in the presence or absence of LPS. Our results demonstrated that LPS remarkably increased production of TNF-${\alpha}$, IL-6, IL-$1{\beta}$, vascular endothelial growth factor (VEGF), and NO (nitric oxide). Corticosterone pretreatment significantly attenuated LPS-induced production of TNF-${\alpha}$, IL-$1{\beta}$, and VEGF, while significantly enhanced IL-6 and NO. These findings suggest that corticosterone pretreatment may contribute to LPS-induced inflammatory responses in macrophages via pro- and anti-inflammatory imbalance of inflammatory mediators.

• Bulletin of the Korean Chemical Society
• /
• v.30 no.9
• /
• pp.2083-2086
• /
• 2009

Human vascular endothelial growth factor receptor 2 (hVEGFR2) is an important signaling protein involved in angiogenesis and attractive drug target in cancer therapy. It has been reported that flavonols, a class of flavonoids, have anti-angiogenic activity in various cancer cell lines. We performed receptor-oriented pharmacophore based in silico screening for identification of hVEGFR2 inhibitors from flavonol database. By comparing with three X-ray complex structures of hVEGFR2 and its inhibitors, we evaluated the specific interactions between inhibitors and receptors and determined a single pharmacophore map. This map consisted of four features, a hydrogen bonding acceptor (HBA) on Cys917, two hydrogen bonding donors on Glu917 (HBD1) and Glu883 (HBD2), and one hydrophobic interaction (Lipo) with Val846, Ala864, Val897, Val914 and Phe1045 of hVEGFR2. Using this map, we searched a flavonol database including 9 typical flavonols and proposed that five flavonols, kaempferol, quercetin, fisetin, morin, and rhamnetin can be potent inhibitors of hVEGFR2. 3-OH of C-ring and 4’-OH of B-ring of flavonols are the essential features for hVEGFR2 inhibition. This study will be helpful for understanding the mechanism of inhibition of hVEGFR2 by natural products.

• Maxillofacial Plastic and Reconstructive Surgery
• /
• v.32 no.1
• /
• pp.1-8
• /
• 2010

Background and Purpose: Vascular endothelial growth factor (VEGF)-C and VEGF receptor (VEGFR)-3 are involved in tumor lymphangiogenesis. Oral mucosal squamous cell carcinoma (OMSCC) preferentially metastasizes to cervical lymph nodes, so we investigated the expression and distribution of VEGFR-3 signaling proteins in OMSCC. Materials and Methods: Tissue samples of 18 OMSCC, 10 oral mucosal leukoplakia, and 3 normal oral mucosa were evaluated for expression of VEGF-C, VEGF-D, and VEGFR-3 by immunohistochemical staining. The presence of lymphatic vessels was determined using D2-40 staining, by which we also measured lymphatic vessel density (LVD). Results: 72% (13/18) and 56% (10/18) of tissue samples showed VEGF-C and VEGF-D immunopositivity in tumor cells and tumor-associated endothelial cells. VEGFR-3 was also expressed in most of OMSCC, which was up-regulated when compared with normal mucosa or with leukoplakia. Furthermore, LVD was higher in OMSCC than in leukoplakia. Conclusion: Taken together, our results suggest that autocrine activation of lymphatic endothelial cell via VEGFR-3 by VEGF-C and/or VEGF-D could be involved in progression of OMSCC. Therefore, VEGF-C/VEGFR-3 signaling pathway can be a molecular target for anti-metastatic therapy in OMSCC.

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

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.26 no.4
• /
• pp.437-440
• /
• 2012

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that Cryptotanshione(CT), a tanshinone from oriental traditional medicinal herb Danshen (Salvia miltiorrhiza Bunge), had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells. CT inhibited the protein expression of hypoxia-inducible factor-1alpha (HIF-$1{\alpha}$) under hypoxic condition. Consistently, CT blocked hypoxia-induced phosphorylation and nuclear accumulation of STAT3. In addition, CT reduced cellular of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Of note, chromatin immunoprecipitation (ChiP) assay revealed that CT inhibited binding of STAT3 to VEGF promoter. Taken together, our results suggest that CT has anti-angiogenic activity by disturbing the binding STAT3 to the VEGF promoter in PC-3 cells.

• Journal of Korean Traditional Oncology
• /
• v.13 no.1
• /
• pp.13-24
• /
• 2008

Objective: To evaluate the effects of Bikihaun (BKH) on angiogenesis. Method: We examined the anti-angiogenic effect of BKH in invasion assay model. We performed proliferation assay, migration assay, tube formation assay and Chicken Chorioallantoic Membrane (CAM) assay. Results: In proliferation assay, at lower dose under 125 ${\mu}g/m{\ell}$ anti-angiogenesis effect of the group treated BKH made no difference with the control group. But, at the dose of 250 ${\mu}g/m{\ell}$ or more anti-angiogenesis effect of the group treated BKH showed more effective as compared to the control group. In migration assay, BKH did not affect migration of vascular endothelial cell. In tube formation assay, at lower dose under 100 ${\mu}g/m{\ell}$ showed mild effect of anti-tube formation. But, at the dose of 1000 ${\mu}g/m{\ell}$ showed more effective anti-tube formation. In CAM assay, BKH showed anti-angiogenesis effect at the dose of 10 ${\mu}g/m{\ell}$. Conclusion: BKH has antiangiogenetic properties in vitro.

• Biomolecules & Therapeutics
• /
• v.24 no.6
• /
• pp.572-580
• /
• 2016

3-Deoxysappanchalcone (3-DSC) has been reported to possess anti-allergic, antiviral, anti-inflammatory and antioxidant activities. In the present study, we investigated the effects of 3-DSC on the proliferation of human hair follicle dermal papilla cells (HDPCs) and mouse hair growth in vivo. A real-time cell analyzer system, luciferase assay, Western blot and real-time polymerase chain reaction (PCR) were employed to measure the biochemical changes occurring in HDPCs in response to 3-DSC treatment. The effect of 3-DSC on hair growth in C57BL/6 mice was also examined. 3-DSC promoted the proliferation of HDPCs, similar to Tofacitinib, an inhibitor of janus-activated kinase (JAK). 3-DSC promoted phosphorylation of ${\beta}$-catenin and transcriptional activation of the T-cell factor. In addition, 3-DSC potentiated interleukin-6 (IL-6)-induced phosphorylation and subsequent transactivation of signal transducer and activator of transcription-3 (STAT3), thereby increasing the expression of cyclin-dependent kinase-4 (Cdk4), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). On the contrary, 3-DSC attenuated STAT6 mRNA expression and IL4-induced STAT6 phosphorylation in HDPCs. Finally, we observed that topical application of 3-DSC promoted the anagen phase of hair growth in C57BL/6 mice. 3-DSC stimulates hair growth possibly by inducing proliferation of follicular dermal papilla cells via modulation of $WNT/{\beta}$-catenin and STAT signaling.

• Journal of The Korean Ophthalmological Society
• /
• v.59 no.11
• /
• pp.1030-1038
• /
• 2018

Purpose: To evaluate whether early visual acuity response at 4 weeks after the first intravitreal anti-vascular endothelial growth factor (VEGF) injection or 4 weeks after the third injection in neovascular age-related macular degeneration (nAMD) is associated with 12-month follow-up outcome. Methods: Thirty treatment-naive patients (30 eyes) with nAMD, treated with intravitreal anti-VEGF, were retrospectively included. Initially, all patients were injected at least three times for three consecutive months and followed up with a pro re nata regimen for at least 12 months. The relationship between 4 weeks after the first and third anti-VEGF injections in visual acuity response was explored, including the mean change from baseline in best-corrected visual acuity (BCVA). The mean change in BCVA was classified into three groups according to visual improvement: <1, 1-<3, or ${\geq}3$ logMAR line(s) in BCVA. The associations among baseline characteristics (gender, age, duration of symptoms, initial BCVA, central macular thickness, and intraocular pressure) and visual acuity responses 4 weeks after the first and third anti-VEGF injections were also assessed. Results: The proportions of eyes with <1, 1-<3, and ${\geq}3-line(s)$ improvement at 4 weeks after the first injection were 6 eyes (20%), 7 eyes (23.3%), and 17 eyes (56.6%), respectively. The proportions of eyes with <1, 1-<3, and ${\geq}3-line(s)$ improvement at 4 weeks after the third injection were 9 eyes (30%), 9 eyes (30%), and 12 eyes (40%), respectively. A BCVA response ${\geq}3-lines$ improvement at 4 weeks after the third injection showed significant associations with ${\geq}3-line(s)$ improvement and BCVA response at 12 months in multiple logistic and linear regression analyses (p = 0.04). Conclusions: In this study, BCVA response ${\geq}3-lines$ improvement at 4 weeks after the third injection showed a significant association with ${\geq}3-line(s)$ improvement and BCVA response at 12 months.

• Journal of The Korean Ophthalmological Society
• /
• v.59 no.11
• /
• pp.1039-1048
• /
• 2018

Purpose: To evaluate the effects of anti-vascular endothelial growth factor (VEGF) treatment on the healthcare-related finances of patients with age-related macular degeneration. Methods: Changes in health care financing due to newly introduced benefit standards were predicted over the coming 5-year period (2018-2022). We also analyzed the financial impact of scenarios in which agents similar to anti-VEGF, such as the over-licensed drug bevacizumab, were introduced. For this purpose, the future number of patients receiving anti-VEGF treatments was estimated for various scenarios based on National Health Insurance Corporation claims data followed by an estimate of the financial burden. Results: In the case of age-related macular degeneration, the current standard of care (14 times in a lifetime) was maintained in scenario 1. In 2018, the insurance budget for the coming 5-year period was estimated at approximately 440.3 billion won. The insurance cost for that period was estimated at approximately 560.1 billion won under the revised standard of December 2017 (scenario 2). For scenarios wherein, after 2020, similar treatments (scenario 3) and bevacizumab (scenario 4) were introduced, the estimated health insurance costs were 521 billion won and 419.7 billion won, respectively. Conclusions: Health insurance costs are projected to increase substantially due to the elimination of the 14 time pay standard; however, the actual budget will only moderately increase, due to new limitations of visual acuity ${\leq}0.1$ or in case of scarring/atrophic lesions. Clinically similar agents and bevacizumab could be considered as alternatives to anti-VEGF treatment for age-related macular degeneration.

• Korean Journal of Ophthalmology
• /
• v.32 no.6
• /
• pp.451-458
• /
• 2018

Purpose: To investigate the efficacy, safety, and anatomical outcomes associated with intravitreal anti-vascular endothelial growth factor (VEGF) treatment of retinopathy of prematurity (ROP). Methods: We performed a retrospective review of intravitreal anti-VEGF (bevacizumab or ranibizumab) treatment of 153 eyes (83 infants) diagnosed with ROP at two tertiary hospitals from June 2011 to January 2017. The primary outcome was the rate of recurrence requiring additional treatment; secondary outcomes included incidence of major complications and final refractive error. Results: A total of 101 eyes were treated with bevacizumab, and 52 with ranibizumab. The bevacizumab and ranibizumab groups were characterized by mean birthweights of $941.8{\pm}296.1$ and $1,257.7{\pm}514.5g$, gestational ages at birth of $26.9{\pm}1.9$ and $28.1{\pm}3.2$ weeks, and postmenstrual ages at treatment of $40.4{\pm}2.4$ and $39.2{\pm}2.3$ weeks, respectively. The two groups differed significantly in birthweights and gestational ages at birth, but not in postmenstrual ages at treatment. The mean follow-up duration was $30.9{\pm}18.4$ months for the bevacizumab group, and $13.9{\pm}12.5$ months for ranibizumab. More cases were classified as zone 1 ROP in the ranibizumab group (44.2% vs. 11.9%, p < 0.001). Major surgical interventions included scleral encircling and vitrectomy (one and two eyes, respectively, both in the bevacizumab group). Retinal detachment was noted in one eye treated with bevacizumab. There was no significant difference in the most recent spherical equivalence for the two groups ($+0.10{\pm}3.66$ and $+0.22{\pm}3.00$ diopters for bevacizumab and ranibizumab, respectively). Univariable analysis revealed that only ROP stage influenced the occurrence of major complications (odds ratio, 9.046; p = 0.012). Conclusions: Intravitreal anti-VEGF treatment of ROP with both bevacizumab and ranibizumab achieved stable retinal vascularization with a low rate of complications and recurrence. Ranibizumab achieved similar anatomical outcomes as bevacizumab, without additional risk for major complications.