• Biomolecules & Therapeutics
• /
• 제29권5호
• /
• pp.506-518
• /
• 2021

The imprinted tumour suppressor NOEY2 is downregulated in various cancer types, including ovarian cancers. Recent data suggest that NOEY2 plays an essential role in regulating the cell cycle, angiogenesis and autophagy in tumorigenesis. However, its detailed molecular function and mechanisms in ovarian tumours remain unclear. In this report, we initially demonstrated the inhibitory effect of NOEY2 on tumour growth by utilising a xenograft tumour model. NOEY2 attenuated the cell growth approximately fourfold and significantly reduced tumour vascularity. NOEY2 inhibited the phosphorylation of the signalling components downstream of phosphatidylinositol-3'-kinase (PI3K), including phosphoinositide-dependent protein kinase 1 (PDK-1), tuberous sclerosis complex 2 (TSC-2) and p70 ribosomal protein S6 kinase (p70S6K), during ovarian tumour progression via direct binding to vascular endothelial growth factor receptor-2 (VEGFR-2). Particularly, the N-terminal domain of NOEY2 (NOEY2-N) had a potent anti-angiogenic activity and dramatically downregulated VEGF and hypoxia-inducible factor-1α (HIF-1α), key regulators of angiogenesis. Since no X-ray or nuclear magnetic resonance structures is available for NOEY2, we constructed the three-dimensional structure of this protein via molecular modelling methods, such as homology modelling and molecular dynamic simulations. Thereby, Lys15 and Arg16 appeared as key residues in the N-terminal domain. We also found that NOEY2-N acts as a potent inhibitor of tumorigenesis and angiogenesis. These findings provide convincing evidence that NOEY2-N regulates endothelial cell function and angiogenesis by interrupting the VEGFR-2/PDK-1/GSK-3β signal transduction and thus strongly suggest that NOEY2-N might serve as a novel anti-tumour and anti-angiogenic agent against many diseases, including ovarian cancer.

• Clinical and Experimental Pediatrics
• /
• 제46권8호
• /
• pp.811-816
• /
• 2003

목 적 : 저자들은 가와사끼병의 혈관염 발생 및 관상동맥 질환 합병증 발생에 있어서 VEGF의 역할을 알아보고자 가와사끼병에서 혈청 VEGF 농도를 측정 후 관상동맥류 등 심혈관계 합병증 발생과 다른 임상적 위험 인자들과의 상관관계를 조사하여 그 임상적 의의를 밝히고자 하였다. 방 법: 2001년 11월부터 2002년 3월까지 강북삼성병원 소아과에서 가와사끼병으로 입원 치료를 받은 11례의 환자와 건강 검진을 위해 소아과 외래를 방문하였던 건강한 어린이 11명을 대상으로 ELISA 방법으로 혈청 VEGF 농도를 측정하여 두 군 사이를 비교하였으며, 관상동맥 내경, 발열 기간, 혈색소치, 백혈구 수, 혈소판 수, ESR, CRP, LDH치와의 상관관계를 조사하였다. 결 과 : 1) 평균 혈청 VEGF 농도는 정상 대조군에서 $279.9{\pm}150.6pg/mL$, 가와사끼병 환자군에서 $847.9{\pm}495.7pg/mL$으로 대조군에 비해 가와사끼병 환자군에서 유의하게 높았다(P<0.05). 2) 환자군 중 두 번 채혈이 가능하였던 5명의 급성기 VEGF 농도는 $913.1{\pm}662.6pg/mL$이었고, 발열이 회복된 아급성기 VEGF 농도는 $1,086.2{\pm}624.7pg/mL$로서 급성기와 아급성기 두 시기에서 모두 높게 측정되었다. 3) 환자군 중 관상동맥류(CAL)가 있었던 5명의 평균 VEGF 농도는 $1,059.2{\pm}573.8pg/mL$이었고, CAL이 없었던 6명의 평균 VEGF 농도는 $671.9{\pm}382.5pg/mL$이었으나, 통계적으로 유의한 차이는 없었다. 4) 혈청 VEGF 농도와 관상 동맥의 내경 간에 유의한 상관관계를 보였다(P<0.05, $r_s=0.75$). 5) 혈청 VEGF 농도와 발열기간, 혈색소치, 백혈구 수, 혈소판 수, ESR, CRP, LDH치 사이에 의의있는 상관관계는 관찰되지 않았다. 결 론 : 가와사끼병에서 혈청 VEGF 농도의 측정은 가와사끼병의 진단과 관상동맥류 합병증 발생 예측에 유용한 지표로 사용될 수 있으리라 생각되었다.

• Toxicological Research
• /
• 제29권4호
• /
• pp.241-247
• /
• 2013

This study was carried out to examine the action mechanism of Chamaecyparis obtusa oil (CO) on hair growth in C57BL/6 mice. For alkaline phosphatase (ALP) and ${\gamma}$-glutamyl transpeptidase (${\gamma}$-GT) activities in the skin tissue, at week 4, the 3% minoxidil (MXD) and 3% CO treatment groups showed an ALP activity that was significantly higher by 85% (p < 0.001) and 48% (p < 0.05) and an ${\gamma}$-GT activity that was significantly higher by 294% (p < 0.01) and 254% (p < 0.05) respectively, as compared to the saline (SA) treatment group. For insulin-like growth factor-1 (IGF-1) mRNA expression in the skin tissue, at week 4, the MXD and CO groups showed a significantly higher expression by 204% (p < 0.05) and 426% (p < 0.01) respectively, as compared to the SA group. At week 4, vascular endothelial growth factor (VEGF) expression in the MXD and CO groups showed a significantly higher expression by 74% and 96% (p < 0.05) respectively, however, epidermal growth factor (EGF) expression in the MXD and CO groups showed a significantly lower expression by 66% and 61% (p < 0.05) respectively, as compared to the SA group. Stem cell factor (SCF) expression in the MXD and CO groups was observed by immunohis-tochemistry as significant in a part of the bulge around the hair follicle and in a part of the basal layer of the epidermis. Taking all the results together, on the basis of effects on ALP and ${\gamma}$-GT activity, and the expression of IGF-1, VEGF and SCF, which are related to the promotion of hair growth, it can be concluded that CO induced a proliferation and division of hair follicle cells and maintained the anagen phase. Because EGF expression was decreased significantly, CO could delay the transition to the catagen phase.

• Archives of Plastic Surgery
• /
• 제43권6호
• /
• pp.498-505
• /
• 2016

Background Algae have traditionally been used for promotion of hair growth. Use of hair regrowth drugs, such as minoxidil, is limited due to side effects. The aim of this study was to examine a mixture of Saccharina japonica and Undaria pinnatifida (L-U mixture) on hair growth and to compare the promoting effect of hair growth by a 3% minoxidil and a L-U mixture. Methods To evaluate the hair growth-promoting activity, saline, 50% ethanol, 3% minoxidil, and the L-U mixture were applied 2 times a day for a total of 14 days on the dorsal skin of C57BL/6 mice after depilation. Analysis was determined by using a high-resolution hair analysis system, real-time polymerase chain reaction, and H&E staining. Results On day 14, the hair growth effect of the L-U mixture was the same as that of the 3% minoxidil treatment. The L-U mixture significantly (P<0.05) stimulated hair growth-promoting genes, as vascular endothelial growth factor (VEGF) and insulin-like growth factor -1. Increase of VEGF was observed in the L-U mixture group compared with minoxidil and the negative control. In contrast, the L-U mixture suppressed the expression of transforming growth factor-${\beta}1$, which is the hair loss-related gene. In histological examination in the L-U mixture and minoxidil groups, the induction of an anagen stage of hair follicles was faster than that of control groups. Conclusions This study provides evidence that the L-U mixture can promote hair growth in mice, similar to the effect from minoxidil, and suggests that there is potential application for hair loss treatments.

• BMB Reports
• /
• 제53권10호
• /
• pp.533-538
• /
• 2020

Notch signaling has been identified as a critical pathway in gastric cancer (GC) progression and metastasis, and inhibition of Delta-like ligand 4 (DLL4), a Notch ligand, is suggested as a potent therapeutic approach for GC. Expression of both DLL4 and vascular endothelial growth factor receptor 2 (VEGFR2) was similar in the malignant tissues of GC patients. We focused on vascular endothelial growth factor (VEGF), a known angiogenesis regulator and activator of DLL4. Here, we used ABL001, a DLL4/VEGF bispecific therapeutic antibody, and investigated its therapeutic effect in GC. Treatment with human DLL4 therapeutic antibody (anti-hDLL4) or ABL001 slightly reduced GC cell growth in monolayer culture; however, they significantly inhibited cell growth in 3D-culture, suggesting a reduction in the cancer stem cell population. Treatment with anti-hDLL4 or ABL001 also decreased GC cell migration and invasion. Moreover, the combined treatment of irinotecan with anti-hDLL4 or ABL001 showed synergistic antitumor activity. Both combination treatments further reduced cell growth in 3D-culture as well as cell invasion. Interestingly, the combination treatment of ABL001 with irinotecan synergistically reduced the GC burden in both xenograft and orthotopic mouse models. Collectively, DLL4 inhibition significantly decreased cell motility and stem-like phenotype and the combination treatment of DLL4/VEGF bispecific therapeutic antibody with irinotecan synergistically reduced the GC burden in mouse models. Our data suggest that ABL001 potentially represents a potent agent in GC therapy. Further biochemical and pre-clinical studies are needed for its application in the clinic.

• 한국식품영양학회지
• /
• 제22권4호
• /
• pp.542-547
• /
• 2009

Brine mineral water(BMW) has recently gained attention as a new water resource due to its biological activities. In this study, BMW from the Geumjin area(Gangneung-city, Korea) was evaluated for its growth inhibition, anti-metastasis and anti-angiogenesis activity against cancer cells. The in vitro cytotoxicity was measured by CCK assay, and the anti-metastasis activity was estimated by lung metastasis in vivo. The in vitro incubation of mouse splenic cells with BMW that had been diluted more than 4-fold showed no effect on the cell growth when compared to a control group. Additionally, BMW inhibited the growth of the EL-4, L5178Y-R and colon26-M3.1 cancer cell lines in a dose-dependent manner. In vivo evaluation of the anti-metastasis activity of BMW in BALB/c mice inoculated with the colon26-M3.1 cell line revealed dose-dependent inhibition in response to treatment with samples that were diluted by up to 9 times. Finally, treatment with BMW effectively suppressed the growth of vascular endothelial growth factor(VEGF) added human umbilical vein endothelial cells. Overall, these results suggest that BMW has anti-cancer activity.

• 한국축산식품학회지
• /
• 제44권1호
• /
• pp.204-215
• /
• 2024

This study was designed to examine the effect of Lactilactobacillus curvatus LB-P9 on hair regeneration. The treatment of LB-P9 conditioned medium increased the proliferation of both hair follicle dermal papilla cells and hair germinal matrix cells (hGMCs). Moreover, the expression levels of hair growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor 7 were significantly elevated in hGMCs co-cultured with LB-P9. After time-synchronized depilation, mice were orally administered with either 4×10⁷ colony forming unit (CFU) of LB-P9 (low dose) or 4×10⁸ CFU of LB-P9 (high dose), once daily for 4 weeks. Compared with the vehicle (phosphate-buffered saline)-administrated group, the LB-P9-treated groups exhibited accelerated hair regrowth rate and enhanced hair thickness in a dose-dependent manner. Supporting this observation, both hair follicle numbers and the dermal thickness in skin tissues of the LB-P9-treated groups were increased, compared to those of the vehicle-treated group. These results might be explained by the increased level of β-catenin and number of hair follicle stem cells (CD34⁺ CD49f⁺ cells) in the skin tissues of mice administered with LB-P9, compared to the vehicle-treated mice. Also, increased serum levels of hair growth factors such as VEGF and insulin-like growth factor-1, and superoxide dismutase were found in the LB-P9-treated groups, compared to those of the vehicle-treated group. Taken together, these results might demonstrate that the oral administration of LB-P9 promotes hair regeneration by the enhancement of dermal papilla proliferation through the stimulation of hair growth factor production.

• The Korean Journal of Physiology and Pharmacology
• /
• 제20권5호
• /
• pp.459-466
• /
• 2016

Adipogenic differentiation of mesenchymal stem cells (MSCs) is critical for metabolic homeostasis and nutrient signaling during development. However, limited information is available on the pivotal modulators of adipogenic differentiation of MSCs. Adaptor protein Lnk (Src homology 2B3 [SH2B3]), which belongs to a family of SH2-containing proteins, modulates the bioactivities of different stem cells, including hematopoietic stem cells and endothelial progenitor cells. In this study, we investigated whether an interaction between insulin-like growth factor-1 receptor (IGF-1R) and Lnk regulated IGF-1-induced adipogenic differentiation of MSCs. We found that wild-type MSCs showed greater adipogenic differentiation potential than $Lnk^{-/-}$ MSCs. An ex vivo adipogenic differentiation assay showed that $Lnk^{-/-}$ MSCs had decreased adipogenic differentiation potential compared with wild-type MSCs. Interestingly, we found that Lnk formed a complex with IGF-1R and that IGF-1 induced the dissociation of this complex. In addition, we observed that IGF-1-induced increase in the phosphorylation of Akt and mammalian target of rapamycin was triggered by the dissociation of the IGF-1R-Lnk complex. Expression levels of a pivotal transcription factor peroxisome proliferator-activated receptor gamma ($PPAR-{\gamma}$) and its adipogenic target genes (LPL and FABP4) significantly decreased in $Lnk^{-/-}$ MSCs. These results suggested that Lnk adaptor protein regulated the adipogenesis of MSCs through the $IGF-1/Akt/PPAR-{\gamma}$ pathway.

• The Korean Journal of Physiology and Pharmacology
• /
• 제22권5호
• /
• pp.555-566
• /
• 2018

Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) are used in tissue repair and regeneration; however, the mechanisms involved are not well understood. We investigated the hair growth-promoting effects of hUCB-MSCs treatment to determine whether hUCB-MSCs enhance the promotion of hair growth. Furthermore, we attempted to identify the factors responsible for hair growth. The effects of hUCB-MSCs on hair growth were investigated in vivo, and hUCB-MSCs advanced anagen onset and hair follicle neogeneration. We found that hUCB-MSCs co-culture increased the viability and up-regulated hair induction-related proteins of human dermal papilla cells (hDPCs) in vitro. A growth factor antibody array revealed that secretory factors from hUCB-MSCs are related to hair growth. Insulin-like growth factor binding protein-1 (IGFBP-1) and vascular endothelial growth factor (VEGF) were increased in co-culture medium. Finally, we found that IGFBP-1, through the co-localization of an IGF-1 and IGFBP-1, had positive effects on cell viability; VEGF secretion; expression of alkaline phosphatase (ALP), CD133, and ${\beta}-catenin$; and formation of hDPCs 3D spheroids. Taken together, these data suggest that hUCB-MSCs promote hair growth via a paracrine mechanism.

• Biomolecules & Therapeutics
• /
• 제24권3호
• /
• pp.260-267
• /
• 2016

Mesenchymal stem cells (MSCs) offer significant therapeutic promise for various regenerative therapies. However, MSC-based therapy for injury exhibits low efficacy due to the pathological environment in target tissues and the differences between in vitro and in vivo conditions. To address this issue, we developed adipose-derived MSC spheroids as a novel delivery method to preserve the stem cell microenvironment. MSC spheroids were generated by suspension culture for 3 days, and their sizes increased in a time-dependent manner. After re-attachment of MSC spheroids to the plastic dish, their adhesion capacity and morphology were not altered. MSC spheroids showed enhanced production of hypoxia-induced angiogenic cytokines such as vascular endothelial growth factor (VEGF), stromal cell derived factor (SDF), and hepatocyte growth factor (HGF). In addition, spheroid culture promoted the preservation of extracellular matrix (ECM) components, such as laminin and fibronectin, in a culture time- and spheroid size-dependent manner. Furthermore, phosphorylation of AKT, a cell survival signal, was significantly higher and the expression of pro-apoptotic molecules, poly (ADP ribose) polymerase-1 (PARP-1) and cleaved caspase-3, was markedly lower in the spheroids than in MSCs in monolayers. In the murine hindlimb ischemia model, transplanted MSC spheroids showed better proliferation than MSCs in monolayer. These findings suggest that MSC spheroids promote MSC bioactivities via secretion of angiogenic cytokines, preservation of ECM components, and regulation of apoptotic signals. Therefore, MSC spheroid-based cell therapy may serve as a simple and effective strategy for regenerative medicine.