Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis <i>via</i> Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

Kim, Ji-Hee,Lee, Kwang-Soon,Lee, Dong-Keon,Kim, Joohwan,Kwak, Su-Nam,Ha, Kwon-Soo,Choe, Jongseon,Won, Moo-Ho,Cho, Byung-Ryul,Jeoung, Dooil,Lee, Hansoo,Kwon, Young-Guen,Kim, Young-Myeong Mary Ann Liebert 2014 Antioxidants & redox signaling Vol.21 No.18

<P>Aims: Hypoxia induces expression of various genes and microRNAs (miRs) that regulate angiogenesis and vascular function. In this study, we investigated a new functional role of new hypoxia-responsive miR-101 in angiogenesis and its underlying mechanism for regulating heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) expression. Results: We found that hypoxia induced miR-101, which binds to the 3 ' untranslated region of cullin 3 (Cul3) and stabilizes nuclear factor erythroid-derived 2-related factor 2 (Nrf2) via inhibition of the proteasomal degradation pathway. miR-101 overexpression promoted Nrf2 nuclear accumulation, which was accompanied with increases in HO-1 induction, VEGF expression, and endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production. The elevated NO-induced S-nitrosylation of Kelch-like ECH-associated protein 1 and subsequent induction of Nrf2-dependent HO-1 lead to further elevation of VEGF production via a positive feedback loop between the Nrf2/HO-1 and VEGF/eNOS axes. Moreover, miR-101 promoted angiogenic signals and angiogenesis both in vitro and in vivo, and these events were attenuated by inhibiting the biological activity of HO-1, VEGF, or eNOS. Moreover, these effects were also observed in aortic rings from HO-1(+/-) and eNOS(-/-) mice. Local overexpression of miR-101 improved therapeutic angiogenesis and perfusion recovery in the ischemic mouse hindlimb, whereas antagomiR-101 diminished regional blood flow. Innovation: Hypoxia-responsive miR-101 stimulates angiogenesis by activating the HO-1/VEGF/eNOS axis via Cul3 targeting. Thus, miR-101 is a novel angiomir. Conclusion: Our results provide new mechanistic insights into a functional role of miR-101 as a potential therapeutic target in angiogenesis and vascular remodeling. Antioxid. Redox Signal. 21, 2469-2482.</P>

간 세포암에서 VEGF, TGF-β1, b-FGF 발현의 의의

김성용,남충현,주종우,채만규,백무준,이문수,김형철,안현철,김홍수,김창진,김창호 순천향의학연구소 2001 Journal of Soonchunhyang Medical Science Vol.7 No.1

Purpose: Angiogenesis is important for the proliferation and the metastasis of solid tumors. The growth of a solid tumor is widely recognized to depend on the process of neovascularrozation. Without angiogenesis, tumors cease to grow beyond even a few milimeters in diameter. It has been shown that tumor vascular density is an independent prognostic marker in several types of human tumors and is known to correlate with poor prognosis. To date, many angiogenic factors have been identified, such as transforming growth factor-α(TGF-α), transforming growth factor-β(TGF-β), fibroblast growth factor family(FGF), vascular endothelial growth factor(VEGF), platelet derived endothelial cell growth factor(PD-ECGF), tumor necrosis factor-α(TNF-α), and angiogenin. Hepatocellular carcinoma(HCC) is the second most common tumor in Korean males and is known as a typical hypervascular tumor with frequent portal vein invastion. The authors identified the expreesion of VEGF, TGF-β1, and b-FGF in HCC specimens and evaluated the relationship between these growth factors and the clinicopathologic characteristics of HCC. Method: We reviewed the medical records of 30 patients who were diagnosed as hepatocellular carinoma treated with hepatic resection between January 1994 and December 1998 in Soonchunhyang University Chunan Hospital. The selection of the cases was decided according to the condition of paraffin block fixation. The prognostic factors such as age, sex, tumor size, concentration of serum α-fetoprotein, presence of liver cirrhosis, presence of tumor emboli in portal vein, TMN stage, amount of transfusion during the operation, hepatitis B virus(HBV) infection, and Edmonson-Steiner(E-S) grade were investigated. Relationship between the prognostic factors and the immunopathologic expression of the TGF-β1, b-FGF, and VEGF was examined. Result: Thirty patients (24 males, 6 females) were included in the current study. The patient's mean age was 50.6 years and the age ranged from 36 to 65 years. The mean size of the tumor was found to be 5.2cm. All the patients were follewed up for 7 to 63 months. Child's classification A patients were 23(76.7%)cases, B patients were 7(23.3%)cases, and C was none. Immunohistochemical staining of HCC tumor mass in VEGF expression patients were 17(56.7%), b-FGF expression patients were 10(33.3%), and TGF-β1 expression patients were 10(33.3%). VEGF expression or more than one positive expression among the three factors correlated with tumor size and the stage of HCC but did not correlated with other clinicopathological characteristics. TGF-β1 and b-FGF did not correlate with any clinicopathological characteristics. Conclusion: The results suggest that the expression of VEGF or more than one positive expression among the three factors in HCC cells may be a significant prognostic factor of HCC.

원격 영상 정보 시스템의 개발

김선호,유선국,김용구,박성욱,김성림,김남현 대한의료정보학회 1996 Healthcare Informatics Research Vol.2 No.1

심근 허혈-재관류 백서 모델에서 mitogen-activated protein kinase 활성화에 대한 α-lipoic acid의 효과

김연경,박은미,최준호,윤경호,유남진,이은미,김남호,정진원,김민선,박병림,오석규 圓光大學校 醫科學硏究所 2006 圓光醫科學 Vol.21 No.1

혈액암환자에서 조혈모세포 이식 후 따르는 헤르페스 바이러스 감영 양상

이호섭,탁희상,신성훈,김양수,남성진,김혜수,박진희,정수현,김성빈,김예나 고신대학교 의과대학 2010 고신대학교 의과대학 학술지 Vol.25 No.1

배경 : 헤르페스바이러스과에는 단순포진 바이러스(HERPES SIMPLEX VIRUS, HSV), 수두대상포진 바이러스 (VARICELLA-ZOSTER VIRUS, VZV), 엡스타인-바 바이러스 (EPSTEIN-BARR VIRUS, EBV), 그리고 거대세포 바이러스 (CYTOMEGALOVIRUS, CMV) 등이 있다. 헤르페스바이러스 감염은 혈액암환자에서 조혈모세포 이식 환자에서 전파 (dissemination), 이차감염, 세균 중복 감염의 심각한 합병증을 일으킬 수 있다. 하지만 항암약물치료를 받는 림파종 환자에서 항 바이러스 약제의 사용 용량과 기간에 대한 concensus는 없다. 헤르페스바이러스 감염에 대한 발생율과 위험인자를 후향성으로 분석하였다. 방법 : 고신대학교 복음 병원에서 1995년 6월부터 2009 년 2월 사이에 새롭게 진단되어 조혈모세포 이식을 받은 전체 58명의 환자들이 후향적으로 현 연구에 등록했다. 헤르페스 바이러스 감염은 임상적 진단, 혈청학적 검사 또는 병리학적 진단에 기초하여 확진한다. 환자들의 특성은 다음과 같다: 평균 연령은 44세 (범위 19-62세)였고 남녀비는 30:28이었다. 등록된 질환은 백혈병 (n=9, 15.5%), 림프종 (n=30, 51.7%), 다발성 골수종 (n=12, 20.7%), 재생불량성 빈혈 (n=6, 10.3%) 그리고 골수이형성증후군 (n=1, 1.7%)이 포함되었다. 결과는 chi-squre test나 independent samples T test를 사용하여 분석되었다. Multivariate analysises에 대해 logistic regression test를 사용하였다. 결과 : 15명의 환자들 (25.9%)에서 조혈모세포 이식후 헤르페스 바이러스 감염이 발생하였다. 조혈모세포 이식 5년간 누적 발생율은 53.9%였다. Univariate analyses에서 헤르페스 바이러스 감염에 대한 유의한 위험 인자는 없었다. 하지만 조혈모세포 이식후 생존 기간(40.18 ± 30.14 months vs 20.06 ± 26.67 months, p=0.018)은 헤르페스 바이러스 감염의 낮은 발병율과 유의한 관련성이 있었다. 이식 편대 숙주질환 (GVHD)의 존재 (37.5% in developed GVHD vs 0% in no GVHD, p=0.200), 동종조혈 모세포 이식에서 면역억제요법의 기간 (15.98 ± 14.02 months vs 6.78 ± 3.67 months, p = 0.374)은 헤르페스 바이러스 감염에 대한 위험인자가 아니었다. 결론 : 조혈모세포 이식 후 생존 기간은 어사이클로비어 예방을 받은 혈액암 환자에서 헤르페스 바이러스 감염의 낮은 발병율과 연관성이 있는 것으로 보인다. 저용량의 어사이클로비어 예방은 헤르페스 바이러스 감염의 고위험군인 조혈모세포 이식을 받은 혈액암 환자에 필요하리라 생각된다. Background : Herpesviridae family includes herpes simplex virus, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus, etc. Herpesviridae viral infection (HVI) can lead to serious complications including dissemination, secondary infection, bacterial superinfection in patients with hematologic malignancy following hematopoietic stem cell transplantation (HSCT). But there was no consensus on the dose and duration of antiviral agents prophylaxis in patients undergoing chemotherapy. We retrospectively analyzed the incidence and the risk factors for HVI. Method : A total of 58 patients who newly diagnosed and received HSCT with prophylaxis of acyclovir at the Kosin University Gospel Hospital, Busan, Korea between June 1995 and February 2009 were enrolled retrospectively in the current study. HVI was confirmed based on clinical diagnosis, serologic test or pathologic diagnosis. The characteristics of the patients were as follows: the median age was 44 years (range 19-62 years) with a female-to-male ratio of 30:28. The enrolled diseases included leukemia (n=9, 15.5%), lymphoma (n=30, 51.7%), multiple myeloma (n=12, 20.7%), aplastic anemia (n=6, 10.3%) and myelodysplastic syndrome (n=1, 1.7%). The results were analyzed using a chi-square test and independent samples T test. For the multivariate analysis, we used logistic regression test. Results : Fifteen patients (25.9%) developed HVI after HSCT. The cumulative incidence of HVI was 53.8% at 5 years after HSCT. In univariate analysis, there was no significant risk factor for HVI. The presence of graft-versus-host disease (GVHD) (37.5% in developed GVHD vs. 0% in no GVHD, p=0.200), duration of immunosuppressive therapy (IST) in allo-SCT (15.98 ± 14.02 months vs. 6.78 ± 3.67 months, p = 0.374) were not risk factors for HVI. Conclusion : The incidence of HVI was similar to that in historical other studies. There was no risk factor associated with development of HVI. Most of the HVI occurred within the first 24 months after transplantation. So long term use of antiviral prophylaxis may be needed to prevention of HVI after HSCT.

백서 척수후근절로부터 슈반세포의 효과적인 체외 배양법

김성민,이종호,김남열,안강민,최원재,최시호,차미주,이주영,황순정,장정원,명훈,최진영,서병무,정필훈,김명진 大韓顎顔面成形再建外科學會 2003 Maxillofacial Plastic Reconstructive Surgery Vol.25 No.4

Schwann cells(SCs), an important component of the peripheral nervous system, intract with nerous to mutually support growth and replication for the peripheral nerve regentation. Recently, ading SCs to the lumen of guidance channel is widely tried to improve regeneration or to make regeneration possible over otherwise irreparable gaps. however, it is not easy to isolate and multiplicate SCs as much as enough to help the axonal regeneration. For the allogeneic SCs source for tubular nerve guidance, we developed a little bit improved technique of harvesting and multiplicating SCs. by culturing dispersed dorsal root ganglia in specially designed medium with growth factors and serial processing, we repeatedlly generate relatively homogenous SC cultures. Our technique was compared with other methods of literature using immunostaining methods such as GFAP, S100, BDNF and the total SC count assessment at different time interval after primary culture.

관상동맥 스텐트 삽입술을 시행한 환자에서 안지오텐신 전환효소 억제제와 안지오텐신 수용체 차단제가 재협착에 미치는 영향

김연경,정진원,윤경호,박은미,송미진,최준호,이은미,유남진,김남호,오석규 圓光大學校 醫科學硏究所 2006 圓光醫科學 Vol.21 No.1

소에서 盲腸擴張을 동반한 第4胃食滯 手術 1例

김명철,김덕환,신상태,임준호,김남중,김종만 충남대학교 수의과대학 동물의과학연구소 1998 動物醫科學硏究誌 Vol.6 No.-

Abomasal impaction with cecal dilatation was diagnosed in a 3 years old holstein cow. The clinical signs were loss of appetite, scant feces and moderate distension of the abdomen. Ping sound was revealed in the right 11th intercostal space by auscultation. Cecal dilatation and abomasal impaction were ascertained by right flank laparotomy and abdominal exploration, and intestinal content and gas were removed from the cecal apex incised. One day later, 2.5㎏ of sand was removed by ventral paramedian abomasotomy.

Sheehan 증후군 발생한 Torsades de Pointes

김승환,김남호,김용철,최준호,박은미,이상재,이은미,유남진,윤경호,오석규,정진원 圓光大學校 醫科學硏究所 2008 圓光醫科學 Vol.23 No.1

재발하는 심실 빈맥으로 내원한 환자에서 Sheehan 증후군을 진단하였고, 적절한 호르몬 보충 치료 후 심전도 이상이 정상으로 회복된 예를 경험하였기에 문헌고찰과 함께 보고하는 바이다. Torsades de Pointes is a form of polymorphic ventricular tachycardia that is associated with prolongation of QT intervals, characterized by QRS complexes of progressively changing ampulitude and cyclic length, giving the appearance of oscillations around the baseline. A 77 years-old woman was presented with hypotention and arrhythmia. Twenty four-hour ECG showed typical episodes of torsades de pointes with QT prolongation. This arrhythmia was controlled by isoproterenol and magnesium infusion, but it was not disappeared. She was diagnosed as Sheehan's syndrome by past history, anterior pituitary stimulation test and empty sella on CT scan. After hormone replacement treatment, Prolonged QT interval was normalized and polymorphic ventricular tachycardia has not recurred. We report a case of torsades de pointes associated with Sheehan's syndrome

치내치에 관한 치험례 : A CASE REPORT

김혜영,조호진,김은정,김현정,김영진,남순현 大韓小兒齒科學會 2004 大韓小兒齒科學會誌 Vol.31 No.4

치내치는 치아 발육 중에 석회화되기 전, 치아의 법랑상피가 일부 함입되어 설측에 깊은 소와를 형성하는 발생학적 변이이다. 주로, 상악 측절치에 호발한다. 치내치는 형태학적으로 다양하며, 종종 초기에 치수괴사에 이르기도 한다. 치내치는 복잡한 해부학적 구조로 인해 치수 치료시 많은 어려움이 따른다. 따라서, 치내치는 초기 진단이 중요하고, 예방적 치료가 추천된다. 이에 본 증례는 치내치를 가진 환아에서의 치료에 관해 보고하고자 한다. Dens invaginatus is a developmental variation resulting from invasination of the tooth crown of root before calcification. Teeth most affected are maxillary lateral incisors. The malformation shows a broad spectrum of morphologic variations and frequently results in early pulp necrosis. Root canal therapy may present severe problems because of the complex anatomy of the teeth. So, the early diagnosis of such malformation is crucial and a preventive approach has been recommended. This report describes three cases of dens invaginatus treatment.