Combined Gene Therapy with Hypoxia-Inducible Factor-1α and Heme Oxygenase-1 for Therapeutic Angiogenesis

Bhang, Suk Ho,Kim, Ju Hee,Yang, Hee Seok,La, Wan-Geun,Lee, Tae-Jin,Kim, Ga Hee,Kim, Hyun Ah,Lee, Minhyung,Kim, Byung-Soo Mary Ann Liebert 2011 Tissue engineering. Part A Vol.17 No.7

<P>Transfection with either hypoxia-inducible factor-1α (HIF-1α) or heme oxygenase-1 (HO-1) gene can induce neovascularization in ischemic tissues. Although expression of transfected HIF-1α gene occurs rapidly, the expressed HIF-1α protein degrades quickly, limiting its therapeutic efficacy. Meanwhile, expressed HO-1 protein does not rapidly undergo degradation, but gene expression occurs a couple of days after transfection, resulting in apoptosis and a delay in angiogenesis in ischemic tissues at the incipient period of HO-1 gene transfection. We hypothesize that combined delivery of HIF-1α and HO-1 gene will enhance antiapoptosis and neovascularization in ischemic tissue compared with HIF-1α or HO-1 single-gene therapy. To test this hypothesis, ischemic mouse hindlimbs were treated with HIF-1α and/or HO-1 gene therapy. The combined gene therapy proved superior to both single-gene therapies, resulting in rapid expression of HIF-1α gene and long-term maintenance of expressed HO-1 protein. The apoptosis in the ischemic region was significantly less, and angiogenic growth factor secretion and angiogenesis were greater in the combined gene therapy than in either of the single-gene therapies. Our results suggest that a combined gene therapy of HIF-1α and HO-1 enhances the transfection of both genes and improves angiogenesis compared with either single-gene therapy.</P>

크론병에 대한 CoPPLX의 방어효과에 대한 연구

이호학,김유림,문창기,이재일,양병윤,김종수,이정민,정재혁,안석진,박상준,김윤권,김소연,김영중,조민구,최영자,장성조 圓光大學校 醫科學硏究所 2005 圓光醫科學 Vol.20 No.1

Up-regulation of Heme Oxygenase-1 by Korean Red Ginseng Water Extract as a Cytoprotective Effect in Human Endothelial Cells

Yang, Ha-Na,Lee, Seung-Eun,Jeong, Seong-Il,Park, Cheung-Seog,Jin, Young-Ho,Park, Yong-Seek The Korean Society of Ginseng 2011 Journal of Ginseng Research Vol.35 No.3

Korean red ginseng (KRG) is used worldwide as a popular traditional herbal medicine. KRG has shown beneficial effects on cardiovascular diseases, such as atherosclerosis, diabetes, and hypertension. Up-regulation of a cytoprotective protein, heme oxygenase (HO)-1, is considered to augment the cellular defense against various agents that may induce cytotoxic injury. In the present study, we demonstrate that KRG water extract induces HO-1 expression in human umbilical vein endothelial cells (HUVECs) and possible involvement of the anti-oxidant transcription factor nuclear factor-eythroid 2-related factor 2 (Nrf2). KRG-induced HO-1 expression was examined by western blots, reverse transcriptase polymerase chain reaction and immunofluorescence staining. Specific silencing of Nrf2 genes with Nrf2-siRNA in HUVECs abolished HO-1 expression. In addition, the HO inhibitor zinc protoporphyrin blunted the preventive effect of KRG on $H_2O_2$-induced cell death, as demonstrated by terminal transferase dUTP nick end labeling assay. Taken together, these results suggest that KRG may exert a vasculoprotective effect through Nrf2-mediated HO-1 induction in human endothelial cell by inhibition of cell death.

한국형출혈열 병원체 Hantaan virus에 대한 뇨의 살균작용

이호왕,백낙주,양상기 대한감염학회 1981 감염 Vol.13 No.1

Korean hemorrhagic fever(KHF) reported for the first time in Korea in 1951, althought it had previously been known from both Manchuria and Russia. Since that time it has been known as Korean hemorrhagic fever and has remained endemic near the Demilitarized Zone between North and South Korea. In 1976 and 1978, Lee et al reported the isolation of Hantaan virus, the etiologic agent of KHF, from the patients and Apodemus agrarius coreae collected in the endemic areas of KHF and developed Lee's method of serological diagnosis of KHF. Very recently, Lee et al demonstrated virus excretion in the urine of infected Apodemus agrarius for a long time. The urine from both Apodemus agrarius and susceptible human were examined its effect on the infectivity of Hantaan virus to Apodemus mice. The results are summarized as follows: 1) The urine from Apodemus agrarius rodent, the natural reservoir of Hantaan virus, had higher activity to inactivate the infectivity of Hantaan virus than that of human. 2) The urine from Apodemus agrarius just after sampling was pH 8.3 and it had stronger antiviral activity than the urine adjusted to pH 7.2. 3) pH of human urine just after sampling was 6.1 and this urine decreased 10~100 10? of the virus after 3 hours in room temperature, but the urine with pH 7.2 had no change to infectivity of the virus.

Eriodictyol Protects Endothelial Cells against Oxidative Stress-Induced Cell Death through Modulating ERK/Nrf2/ARE-Dependent Heme Oxygenase-1 Expression

Lee, Seung Eun,Yang, Hana,Son, Gun Woo,Park, Hye Rim,Park, Cheung-Seog,Jin, Young-Ho,Park, Yong Seek MDPI 2015 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.16 No.7

<P>The pathophysiology of cardiovascular diseases is complex and may involve oxidative stress-related pathways. Eriodictyol is a flavonoid present in citrus fruits that demonstrates anti-inflammatory, anti-cancer, neurotrophic, and antioxidant effects in a range of pathophysiological conditions including vascular diseases. Because oxidative stress plays a key role in the pathogenesis of cardiovascular disease, the present study was designed to verify whether eriodictyol has therapeutic potential. Upregulation of heme oxygenase-1 (HO-1), a phase II detoxifying enzyme, in endothelial cells is considered to be helpful in cardiovascular disease. In this study, human umbilical vein endothelial cells (HUVECs) treated with eriodictyol showed the upregulation of HO-1 through extracellular-regulated kinase (ERK)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathways. Further, eriodictyol treatment provided protection against hydrogen peroxide-provoked cell death. This protective effect was eliminated by treatment with a specific inhibitor of HO-1 and RNA interference-mediated knockdown of HO-1 expression. These data demonstrate that eriodictyol induces ERK/Nrf2/ARE-mediated HO-1 upregulation in human endothelial cells, which is directly associated with its vascular protection against oxidative stress-related endothelial injury, and propose that targeting the upregulation of HO-1 is a promising approach for therapeutic intervention in cardiovascular disease.</P>

울산 석유화학공단 인근 어린이들의 혈액상변화 및 면역기능

이충렬,유철인,이지호,이헌,김양호 대한산업의학회 2001 대한직업환경의학회지 Vol.13 No.2

목적 : 지역 특성상 휘발성 유기화합물, 분진, 악취 등 환경오염의 영향을 많이 받는 것으로 추정되는 울산석유화학공단 인근 어린이들의 혈액상 변화, 계절 차이에 의한 혈액상 변화와 면역기능에 미치는 영향을 평가하기 위하여 본 연구를 실시하였다. 방법 : 2000년 4월, 7월, 10월 3회에 걸쳐 석유화학공단 인근 A 초등학생 46명(남자 32명, 여자 14명), B 초등학생 97명(남자 49명, 여자 48명)과 교외지역의 A 초등학생 95명(남자 47명, 여자 48명)을 대상으로 일반혈액검사, 백혈구 백분율 검사를 실시하였으며 7월 조사 때는 B 및 C 초등학생 11세 남자 각각 25명을 대상으로 면역학적 기능검사를 실시하였다. 결과 : 3차례에 걸쳐 진행된 검사결과는 계절별로 다른 양상을 보여 주었다. 즉, 총백혈구수, 호중구수, 림프구수는 A와 C 초등학생은 7월 조사에서는 감소되었다 다시 10월 조사 때는 다시 증가하는 경향을 보여주며, B초등학생은 계절별 변화가 거의 없는 것으로 나타났다. 적혈구수는 B와 C 초등학생은 7월 조사시 감소되었다가 10월 조사 때는 다시 증가하는 양상을 보여주나 A 초등학생은 갈수록 감소하는 경향을 보여주었다. 혈색소량의 변화는 적혈구수의 변화와 유사하였다 혈소판수는 모두 7월 조사 때는 감 소되었다가 10월 조사 때는 다시 증가하는 양상을 보여주었다. 조사시기에 따라 각 학교 어린이들간에 혈구세포수의 차이가 있음을 구명하기 위하여 generalized linear model의 repeated measures ANOVA를 시도한 결과 연령과 성을 공변인으로 보정한 후의 P 값에서 조사시기의 차이와 학교간 차이의 교호작용변수(interaction variable)는 모든 혈구세포에서 유의한 것으로 나타났다(P<0.05). 이는 조사시기에 따라 각 학교어린이들간에 혈구세포수의 차이가 유의하게 다르다는 것을 의미한다. 면역기능 평가를 위하여 혈중 immunoglobulin 측정 및 림프구 아형 분포분석을 B 및 C 초등학생 6학년 남학생 각 25명, 총 50명을 대상으로 실시하였으나 모두 정상범위이었고 학교간 차이도 없었다. 결론 : 휘발성 유기화합물 같은 물질에 쉽게 영향을 받을 수 있는 백혈구와 적혈구 등의 혈구세포는 조사시기에 따라 각 학교어린이들간에 혈구세포수의 차이가 유의하게 나타남은 각 학교 어린이들간에 조사시기에 따라 혈구세포수에 영향을 주는 휘발성 유기화합물의 노출량의 차이가 중요한 원인 중 하나일 것으로 추정된다. 향후 혈구세포의 변화의 원인이라 추정되는 휘발성 유기화합물의 기중 농도측정이나 체내 생체지표검사를 통한 노출원 조사를 병행하는 추가적 조사가 필요한 것으로 사료된다. Objectives : To evaluate the hematological changes and the immunological function of children living near the petrochemical estate in Ulsan. Methods : The study subjects comprised of 238 children who consisted of 143 children living near the petrochemical estate and 95 children living in a suburban area. We conducted the hematological examination 3 times, in April, July and October. Also we evaluated the immunological function of some children in July. To confirm differences between schools repeated measures ANOVA of generalized linear model was done controlling age and sex as covariates. Results : The blood cell counts of children showed differences between schools in accordance with the survey month. The total WBC, neutrophil, and lymphocyte counts of children living in a suburban area decreased in July and increased in October again, but those of some children living near the petrochemical estate did not changed distinctly. The RBC counts of children living in a suburban area decreased in July and increased in October again, but those of some children living near the petrochemical estate decreased as time passed. The changes of the amount of hemoglobin of all study subjects were similar with those of RBC. The platelet counts of all study subjects decreased in July and increased in October again. In the generalized linear model, school was a significant independent variable for the total WBC, RBC, and platelet counts, and sex was a significant independent variable for the RBC counts. Age was a significant independent variable for the iymphocyte and platelet counts. P values of all blood cell were statistically significant in interaction variable between the survey month and school, and those of the total WBC, neutrophil, and iymphocyte counts were statistically significant in interaction variable between the survey month and age. The immunological function showed no significant difference between study groups. Conclusions : The total WBC and RBC counts which would be easily affected by volatile organic compounds (VOCs) in the atmosphere showed differences between schools in accordance with the survey month. This suggests that the amounts of exposure to VOCs are different among each school children in different months. To ascertain the hematological changes by VOCs, an additional study evaluating the concentrations of atmosphere of VOCs and biological monitoring of some VOCs is needed.

유기용제노출이 직업적 청력손실에 미치는 영향

이지호,고영주,이헌,강정학,유철인,이충렬,김양호 大韓産業醫學會 2000 대한직업환경의학회지 Vol.12 No.4

목적 : 산업 장에서 노출되는 유기용제가 청력역치에 어떠한 영향을 미치는가를 5년 동안의 추적조사를 통하여 파악하고자 하였다. 방 법 : 유기용제와 소음에 동시에 노출된 근로자 43명과 소음노출수준, 연령, 근무경력을 짝짓기 한소음노출군을 대상으로 문진과 이경검사, 소음노출 수준, 유기용제노출수준을 조사하였다. 결과 : 1. 전체 근로자의 각 주파수별 청력역치 변화양상에서 500Hz∼2000Hz에서는 추적기간 동 소음동안 현저한 변화가 없었고, 4000Hz 및 8000Hz에서는 역치가 증가하는 경향을 나타내었다. 2.유기용제와 소음에 동시에 노출된군에서 소음 노출군에 비해 4000Hz 이상에서 청력역치가 높게 나타났으나, 통계적인 유의성은 없었다(p(0.05). 3.반복측정 분산분석 법으로 각 주파수별 평균청력 역치의 연차적 변화에 미치는 영향을 분석한 결과 유기용제 노출은 통계적으로 유의한 영향이 없었으나(p)0.05), 소음노출수준은 250Hz, 2000Hz 및 4000Hz에서, 연령은 250Hz와 500Hz에서 통계학적으로 유의한 영향을 미치는 것으로 나타났다(p(0.05). 4.소음노출군파 동시노출군 각각에서의 청력역치 변화량을 paired t-test로 비교한 결과 250Hz∼4000Hz에서는 통계학적 유의성이 없었으며(p(0.1), 8000Hz에서만 경계치 (p=0.0884)의 유의성을 나타내었다. 5.요인들의 영향을 보정한 상태에서 관찰하기 위해 관찰기간동안의 청력역치변화량을 종속변수로 두고 일반선형모형을 이용하여 주파수별로 관찰한 결과 8000Hz에서만 모델에 통계학적 유의성이 있었으며 (p(0.05), 여기서 소음노출수준이 통계학적으로 유의한 영향을 미치는 것으로 나타났고(p(0.05), 유기용제노출은 경 계수준이 었다(p=0.087). 결론 : 청력에 대한 유기용제의 영향이 소음과 연령에 비해 상대적으로 미미하여 명확한 결론에 이르지는 못하였으나, 다소 영향이 있는 것으로 생각되어 유기용제의 영향에 대한 추가연구가 필요할 것으로 판단된다. 또한 보다 효과적인 근로자들의 청력관리를 위해서는 소음 외 산업 장에서 동시에 노출되는 여러 유해물질들을 고려하여야 할 것이다. Objectives : This study was to evaluate the impacts of simultaneous exposure to noise and mixed solvents on workers'hearing threshold level (HTL) over five-year period. Methods : The study was conducted by interview and annual audiometric test on workers in ship building industry from 1994 to 1998. The cases(workers who exposed to noise and mixed solvent simultaneously) were 43 male workers and controls (workers who exposed to nolle) were selected by matching method with regard to age, sex, carrier, and noise exposure level. To assess the impacts of solvent exposure on hearing threshold level, with considering other factors, general liner model was used. Results : 1. The audiogram of all subjects showed typical sensorineural hearing loss pattern. The mean HTLe were increased at high frequency (4000HB and 8000Hz) for study period. 2. The HTLs of cases were more increased than those of controls at high frequencies (4000Hz and 8000Hz), but there was not statlstical significance. 3. The impact of age on the HTL was statistically significant at 250Hz and 500Hz (p(0.05), and the impact of noise on the HTL was statistically significant at 250Hz, 2000Hz and 4000Hz (p(0.05), but the impact solvent exposure on the HTL was not significant. 4. The changes in HTLs of cases were higher than those of controls at high frequency, there were not statistical significance at 4000Hz, but only at 8000Hz (p=0.087). 5. Statistical analysis of the general linear model implicated that the changes in HTL was impacted by noise exposure bevel significantly (p=0.031) and Impacted by solvent exposure weakly (p=0.087) at 8000Hz. Conclusions : The results of this study suggest that workers who simultaneously exposed to noise and mixed solvent were at risk for more affected HTL than those exposed to noise exposure only, but we could not find definitive evidence. Further detailed studies must be made in large number of workers.

Up-regulation of Heme Oxygenase-1 by Korean Red Ginseng Water Extract as a Cytoprotective Effect in Human Endothelial Cells

Hana Yang,Seung Eun Lee,Seong Il Jeong,Cheung-Seog Park,Young-Ho Jin,Yong Seek Park 고려인삼학회 2011 Journal of Ginseng Research Vol.35 No.3

Korean red ginseng (KRG) is used worldwide as a popular traditional herbal medicine. KRG has shown beneficial effects on cardiovascular diseases, such as atherosclerosis, diabetes, and hypertension. Up-regulation of a cytoprotective protein, heme oxygenase (HO)-1, is considered to augment the cellular defense against various agents that may induce cytotoxic injury. In the present study, we demonstrate that KRG water extract induces HO-1 expression in human umbilical vein endothelial cells (HUVECs) and possible involvement of the anti-oxidant transcription factor nuclear factor-eythroid 2-related factor 2 (Nrf2). KRG-induced HO-1 expression was examined by western blots, reverse transcriptase polymerase chain reaction and immunofluorescence staining. Specific silencing of Nrf2 genes with Nrf2-siRNA in HUVECs abolished HO-1 expression. In addition, the HO inhibitor zinc protoporphyrin blunted the preventive effect of KRG on H₂O₂-induced cell death, as demonstrated by terminal transferase dUTP nick end labeling assay. Taken together, these results suggest that KRG may exert a vasculoprotective effect through Nrf2-mediated HO-1 induction in human endothelial cell by inhibition of cell death.

Bortezomib과 Dexamthasone으로 치료한 골수외 형질세포종 4예

백종현,이은영,장리라,손창배,신은경,서정아,이지숙,이호섭,이상민,신성훈,김양수 고신대학교의과대학 2007 고신대학교 의과대학 학술지 Vol.22 No.2

Despite the use of aggressive local and systemic treatment including autologous stem cell transplantation in multiple myeloma, extramedullary recurrences are common and the prognosis of these patients is poor. Many novel drugs such as thalidomide, lenalidomide and bortezomib improve the response of treatment of multiple myeloma, but some reports failed to describe thalidomide has effect in extramedullary plasmacytoma. Recent data report on the successful treatment plasmacytomas with bortezomib in patients with advanced multiple myeloma. We treated 4 relapsed or refractory extramedullary plasmacytomas with bortezomib at our institution. We recognized all these extramedullary plasmacytomas decreased and showed more than partial response. This report lends support to the efficacy of bortezomib in the treatment of plasmacytoma and describes the safe use of bortezomib. Responses may, however, be of short duration. Therefore, despite our limited experience, we propose that bortezomib may be considered a therapeutic option for such patients who have risk of radiation therapy

Crotonaldehyde-exposed macrophages induce heme oxygenase-1 expression as an adaptive mechanism

Seung Eun Lee,Hana Yang,Gun Woo Son,Hye Rim Park,Young-Ho Jin,Cheung-Seog Park,Yong Seek Park 대한독성 유전단백체 학회 2015 Molecular & cellular toxicology Vol.11 No.2

Cigarette smoke represents one of the most significant risk factors for the progression of vascular disease. Exposure to cigarette smoke induces oxidative stress in the vascular system and results in vascular dysfunction. Crotonaldehyde, a highly reactive α,β-unsaturated aldehyde, is a foremost compound of cigarette smoke and a product of endogenous lipid peroxidation. Heme oxygenase-1 (HO-1) expression plays an essential role in cellular defense against environmental insults and represents an adaptive response. Here, we showed the effects of crotonaldehyde on the induction of HO-1 expression in RAW 264.7 macrophages. Crotonaldehyde treatment resulted in significantly increased phosphorylation of p38 mitogenactivated protein kinase (MAPK) and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, treatment with zinc protoporphyrin (ZnPP; the specific HO-1 inhibitor) markedly augmented the death of crotonaldehyde-treated macrophages. In summary, these results highlight the role of the HO-1 upregulation through p38 MAPK-Nrf2 activation in the adaptive response to crotonaldehyde in macrophages.