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Cooperative interaction of Angiopoietin-like proteins 1 and 2 in zebrafish vascular development.
Kubota, Yoshiaki,Oike, Yuichi,Satoh, Shinya,Tabata, Yoko,Niikura, Yuichi,Morisada, Tohru,Akao, Masaki,Urano, Takashi,Ito, Yasuhiro,Miyamoto, Takeshi,Nagai, Norihiro,Koh, Gou Young,Watanabe, Sumiko,Sud National Academy of Sciences 2005 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.102 No.38
<P>Angiopoietin-like protein (Angptl) 1 and Angptl2, which are considered orphan ligands, are highly homologous, particularly in the fibrinogen-like domain containing the putative receptor binding site. This similarity suggests potentially cooperative functions between the two proteins. In this report, the function of Angptl1 and Angptl2 is analyzed by using morpholino antisense technology in zebrafish. Knockdown of both Angptl1 and Angptl2 produced severe vascular defects due to increased apoptosis of endothelial cells at the sprouting stage. In vitro studies showed that Angptl1 and Angptl2 have antiapoptotic activities through the phosphatidylinositol 3-kinase/Akt pathway, and coinjection of constitutively active Akt/protein kinase B mRNA rescued impaired vascular development seen in double knockdown embryos. These results provide a physiological demonstration of the cooperative interaction of Angptl1 and Angptl2 in endothelial cells through phosphatidylinositol 3-kinase/Akt mediated antiapoptotic activities.</P>
Yoshiaki Kubota,Masaaki Miyamoto,Gen Takagi,Takeshi Ikeda,Sonoko Kirinoki-Ichikawa,Kotoko Tanaka,Kyoichi Mizuno 대한의학회 2012 Journal of Korean medical science Vol.27 No.11
The vascular endothelial function is impaired in the very early stage of atherosclerosis in diabetic patients. The goal of this study was to identify the mechanism underlying the improvement in vascular endothelial function by sitagliptin in type 2 diabetes mellitus patients. This study was an open-labeled prospective observational single arm trial. Forty patients were treated with 50 mg of sitagliptin once daily for 12-weeks. The flowmediated dilation (FMD) and plasma adiponectin were measured at baseline and 12 weeks after initiating treatment. The %FMD was significantly increased after treatment (4.13 ± 1.59 vs 5.12 ± 1.55, P < 0.001), whereas the nitroglycerin-mediated dilation (NMD) did not change. The plasma adiponectin levels significantly increased (13.0 ± 11.3vs 14.3 ± 12.8, P < 0.001). The changes in the FMD were significantly correlated with those of the plasma adiponectin (r = 0.322, P < 0.05). A multivariate linear regression analysis demonstrated that the improvement in the FMD is associated with the plasma adiponectin (P < 0.05). The treatment of type 2 diabetes mellitus patients with sitagliptin reverses vascular endothelial dysfunction, as evidenced by increase in the FMD, and improvement of the adiponectin levels (UMIN Clinical Trials Registry System as trial ID UMIN000004236).
Toyota Kazuhiro,Mori Masayuki,Hirahara Satoshi,Yoshioka Shoko,Kubota Haruna,Yano Raita,Kobayashi Hironori,Hashimoto Yasushi,Sakashita Yoshihiro,Yokoyama Yujiro,Murakami Yoshiaki,Miyamoto Katsunari 대한위암학회 2022 Journal of gastric cancer Vol.22 No.1
Purpose: Nutritional problems after gastrectomy affect continuation of postoperative chemotherapy. There have been no studies limited to total gastrectomy, which is particularly prone to nutritional problems. In this study, we aimed to investigate the factors that predict the continuation of postoperative chemotherapy. Materials and Methods: We included 101 patients who underwent curative total gastrectomy and postoperative chemotherapy at Hiroshima Memorial Hospital. The effects of 37 factors, including perioperative inflammatory, nutritional, and tumor status, on the persistence of postoperative chemotherapy were analyzed. Results: In univariate analysis of preoperative factors, age, carbohydrate antigen 19-9, platelet-to-neutrophil ratio, Onodera's prognostic nutritional index (PNI), controlling nutritional status score, and nutritional risk screening (NRS-2002) score were significantly associated with the duration of postoperative chemotherapy. In multivariate analysis of preoperative factors, age (≥74 years) was an independent factor for a shorter duration of postoperative chemotherapy (hazard ratio [HR], 5.24; 95% confidence interval [CI], 2.19–12.96; P<0.01). In univariate analysis of factors before postoperative chemotherapy, intraoperative blood loss, perioperative weight loss rate, postoperative performance status, PNI, albumin-to-bilirubin index, and NRS-2002 score were significantly associated with the duration of postoperative chemotherapy. In multivariate analysis of factors before postoperative therapy, age (≥74 years) (HR, 5.75; 95% CI, 1.90–19.49; P<0.01) and PNI (<39) (HR, 3.29; 95% CI, 1.26–8.56; P=0.02) were independent factors for a shorter duration of postoperative chemotherapy. Conclusions: Age and PNI are useful predictors of postoperative chemotherapy intolerance after total gastrectomy and may determine the treatment strategy and timing of chemotherapy initiation.
Hong, Ki Yong,Bae, Hosung,Park, Intae,Park, Dae-Young,Kim, Kyun Hoo,Kubota, Yoshiaki,Cho, Eui-Sic,Kim, Hail,Adams, Ralf H.,Yoo, Ook-Joon,Koh, Gou Young The Company of Biologists Limited 2015 Development (Cambridge) Vol.142 No.15
<P>Despite the growing interest in adipose tissue as a therapeutic target of metabolic diseases, the identity of adipocyte precursor cells (preadipocytes) and the formation of adipose tissue during embryonic development are still poorly understood. Here, we clarified the identity and dynamic processes of preadipocytes in mouse white adipose tissue during embryogenesis through direct examination, lineage tracing and culture systems. Surprisingly, we found that lipid-lacking but perilipin(+) or adiponectin(+) proliferating preadipocytes started to emerge at embryonic day 16.5, and these cells underwent active proliferation until birth. Moreover, these preadipocytes resided as clusters and were distributed along growing adipose vasculatures. Importantly, the embryonic preadipocytes exhibited considerable coexpression of stem cell markers, such as CD24, CD29 and PDGFR alpha, and a small portion of preadipocytes were derived from PDGFR beta(+) mural cells, in contrast to the adult preadipocytes present in the stromal vascular fraction. Further analyses with in vitro and ex vivo culture systems revealed a stepwise but dynamic regulation of preadipocyte formation and differentiation during prenatal adipogenesis. To conclude, we unraveled the identity and characteristics of embryonic preadipocytes, which are crucial for the formation and expansion of adipose tissue during embryogenesis.</P>
YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation
Kim, Jongshin,Kim, Yoo Hyung,Kim, Jaeryung,Park, Do Young,Bae, Hosung,Lee, Da-Hye,Kim, Kyun Hoo,Hong, Seon Pyo,Jang, Seung Pil,Kubota, Yoshiaki American Society for Clinical Investigation 2017 The Journal of clinical investigation Vol.127 No.9
SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling
Kim, Kangsan,Kim, Il-Kug,Yang, Jee Myung,Lee, Eunhyeong,Koh, Bong Ihn,Song, Sukhyun,Park, Junseong,Lee, Sungsu,Choi, Chulhee,Kim, Jin Woo,Kubota, Yoshiaki,Koh, Gou Young,Kim, Injune Grune & Stratton 2016 Circulation research Vol.119 No.7
<P>Rationale: Vascular endothelial growth factor (VEGF) signaling is a key pathway for angiogenesis and requires highly coordinated regulation. Although the Notch pathway-mediated suppression of excessive VEGF activity via negative feedback is well known, the positive feedback control for augmenting VEGF signaling remains poorly understood. Transcription factor Sox17 is indispensable for angiogenesis, but its association with VEGF signaling is largely unknown. The contribution of other Sox members to angiogenesis also remains to be determined. Objective: To reveal the genetic interaction of Sox7, another Sox member, with Sox17 in developmental angiogenesis and their functional relationship with VEGF signaling. Methods and Results: Sox7 is expressed specifically in endothelial cells and its global and endothelial-specific deletion resulted in embryonic lethality with severely impaired angiogenesis in mice, substantially overlapping with Sox17 in both expression and function. Interestingly, compound heterozygosity for Sox7 and Sox17 phenocopied vascular defects of Sox7 or Sox17 homozygous knockout, indicating that the genetic cooperation of Sox7 and Sox17 is sensitive to their combined gene dosage. VEGF signaling upregulated both Sox7 and Sox17 expression in angiogenesis via mTOR pathway. Furthermore, Sox7 and Sox17 promoted VEGFR2 (VEGF receptor 2) expression in angiogenic vessels, suggesting a positive feedback loop between VEGF signaling and SoxF. Conclusions: Our findings demonstrate that SoxF transcription factors are indispensable players in developmental angiogenesis by acting as positive feedback regulators of VEGF signaling.</P>
Jang, Jeon Yeob,Choi, Sung Yong,Park, Intae,Park, Do Young,Choe, Kibaek,Kim, Pilhan,Kim, Young Keum,Lee, Byung‐,Joo,Hirashima, Masanori,Kubota, Yoshiaki,Park, Jeong‐,Won,Cheng, Sheueȁ John Wiley and Sons Inc. 2017 EMBO molecular medicine Vol.9 No.6
<P><B>Abstract</B></P><P>Thyroid gland vasculature has a distinguishable characteristic of endothelial fenestrae, a critical component for proper molecular transport. However, the signaling pathway that critically governs the maintenance of thyroid vascular integrity, including endothelial fenestrae, is poorly understood. Here, we found profound and distinct expression of follicular epithelial VEGF‐A and vascular VEGFR2 that were precisely regulated by circulating thyrotropin, while there were no meaningful expression of angiopoietin–Tie2 system in the thyroid gland. Our genetic depletion experiments revealed that VEGFR2, but not VEGFR3, is indispensable for maintenance of thyroid vascular integrity. Notably, blockade of VEGF‐A or VEGFR2 not only abrogated vascular remodeling but also inhibited follicular hypertrophy, which led to the reduction of thyroid weights during goitrogenesis. Importantly, VEGFR2 blockade alone was sufficient to cause a reduction of endothelial fenestrae with decreases in thyrotropin‐responsive genes in goitrogen‐fed thyroids. Collectively, these findings establish follicular VEGF‐A–vascular VEGFR2 axis as a main regulator for thyrotropin‐dependent thyroid angiofollicular remodeling and goitrogenesis.</P>