Heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis suppresses RANKL-induced osteoclastic differentiation by inhibiting redox-sensitive NF-κB activation

( Sun-uk Bak ),( Suji Kim ),( Hae-jun Hwang ),( Jung-a Yun ),( Wan-sung Kim ),( Moo-ho Won ),( Ji-yoon Kim ),( Kwon-soo Ha ),( Young-guen Kwon ),( Young-myeong Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.2

Heme oxygenase (HO-1) catalyzes heme to carbon monoxide (CO), biliverdin/bilirubin, and iron and is known to prevent the pathogenesis of several human diseases. We assessed the beneficial effect of heme degradation products on osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL). Treatment of RAW264.7 cells with CORM-2 (a CO donor) and bilirubin, but not with iron, decreased RANKLinduced osteoclastogenesis, with CORM-2 having a more potent anti-osteogenic effect. CORM-2 also inhibited RANKLinduced osteoclastogenesis and osteoclastic resorption activity in marrow-derived macrophages. Treatment with hemin, a HO-1 inducer, strongly inhibited RANKL-induced osteoclastogenesis in wild-type macrophages, but was ineffective in HO-1^+/-cells. CORM-2 reduced RANKL-induced NFATc1 expression by inhibiting IKK-dependent NF-κB activation and reactive oxygen species production. These results suggest that CO potently inhibits RANKL-induced osteoclastogenesis by inhibiting redox-sensitive NF-κB-mediated NFATc1 expression. Our findings indicate that HO-1/CO can act as an antiresorption agent and reduce bone loss by blocking osteoclast differentiation. [BMB Reports 2017; 50(2): 103-108]

Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis

Choi, Seunghwan,Kim, Joohwan,Kim, Ji-Hee,Lee, Dong-Keon,Park, Wonjin,Park, Minsik,Kim, Suji,Hwang, Jong Yun,Won, Moo-Ho,Choi, Yoon Kyung,Ryoo, Sungwoo,Ha, Kwon-Soo,Kwon, Young-Guen,Kim, Young-Myeong Nature Publishing Group 2017 Experimental and molecular medicine Vol.49 No.11

<P>Heme oxygenase-1-derived carbon monoxide prevents inflammatory vascular disorders. To date, there is no clear evidence that HO-1/CO prevents endothelial dysfunction associated with the downregulation of endothelial NO synthesis in human endothelial cells stimulated with TNF-α. Here, we found that the CO-releasing compound CORM-2 prevented TNF-α-mediated decreases in eNOS expression and NO/cGMP production, without affecting eNOS promoter activity, by maintaining the functional activity of the <I>eNOS</I> mRNA 3′-untranslated region. By contrast, CORM-2 inhibited MIR155HG expression and miR-155-5p biogenesis in TNF-α-stimulated endothelial cells, resulting in recovery of the 3′-UTR activity of <I>eNOS</I> mRNA, a target of miR-155-5p. The beneficial effect of CORM-2 was blocked by an NF-κB inhibitor, a miR-155-5p mimic, a HO-1 inhibitor and siRNA against HO-1, indicating that CO rescues TNF-α-induced eNOS downregulation through NF-κB-responsive miR-155-5p expression via HO-1 induction; similar protective effects of ectopic HO-1 expression and bilirubin were observed in endothelial cells treated with TNF-α. Moreover, heme degradation products, except iron and <I>N</I>-acetylcysteine prevented H<SUB>2</SUB>O<SUB>2</SUB>-mediated miR-155-5p biogenesis and eNOS downregulation. These data demonstrate that CO prevents TNF-α-mediated eNOS downregulation by inhibiting redox-sensitive miR-155-5p biogenesis through a positive forward circuit between CO and HO-1 induction. This circuit may play an important preventive role in inflammatory endothelial dysfunction associated with human vascular diseases.</P>

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>

Ho-166 부착풍선도자를 이용한 방사선 조사의 돼지 관상동맥 스텐트 재협착 예방 효과

김원 ( Kim Won ),정명호 ( Jeong Myeong Ho ),박옥영 ( Park Og Yeong ),정우곤 ( Jeong U Gon ),박우석 ( Park U Seog ),김주한 ( Kim Ju Han ),안영근 ( An Yeong Geun ),조정관 ( Jo Jeong Gwan ),박종춘 ( Park Jong Chun ),강정채 ( Kang Je 한국지질동맥경화학회 ( 구 한국지질학회 ) 2002 韓國脂質學會誌 Vol.12 No.1

배경 : 국내에서 개발된 방사선 동위원소 Holmium-166 (166Ho)은 주로 베타선을 방출하며, 166Ho을 부착한 풍선도자를 이용하여 돼지 관상동맥 재협착 모형에서 풍선확장술 후 신생내막 증식을 전신적 부작용 없이 안전하고 효과적으로 억제하였음을 보고한 바 있다. 본 연구에서는 돼지 관상동맥 스텐트 재협착 모형에서 스텐트 시술 후 신생내막 증식에 의한 재협착 병변을 166Ho 부착 풍선도자를 이용하여 치료하여 그 효과를 관찰하고자 하였다. 방법

Comparison of the community structure and changes of ground beetle (Coleoptera: Carabidae) as indicator species in forest genetic resource reserve

Myeong–Ho Kim,Min-Chul Kim,Seung-Gyu Lee,Il-Kwon Kim 한국응용곤충학회 2018 한국응용곤충학회 학술대회논문집 Vol.2018 No.04

2016년도에 조사를 수행한 경상북도 내 위치한 산림유전자원보호구역 3개 지역(봉화・영주・울진)의 곤충 군집 변화를 확인하기 위하여 5월에서 9월까지 함정 트랩(pitfall trap)을 이용하여 5회씩 3반복하여 각각 상대적으로 비교 하였다. 채집된 딱정벌레류는 딱정벌레과 등 22과 141종 2,415개체가 확인 되었으며, MRPP (Multi-response Permutation procedures)분석 결과 서식지간의 군집구조차이가 있음을 확인 하였고(p < 0.001), Bray-cutis 분석결과 군집간의 차이와 함께 신갈나무 군락이 보행성 딱정벌레류의 종 풍부도에 큰 영향을 주는 것으로 나타났고 소나무군락 은 비교적 낮은 영향을 받았다. 식생유형에 대한 지표종 분석결과 신갈나무 군락에서 붉은칠납작먼지벌레(Synuchus cycloderus Bates, 1873)를 포함한 4종, 자작나무 군락에서는 노랑털검정반날개(Ocypus weisei Harold, 1877)를 포함한 3종, 소나무 군락에서는 홍딱지반날개(Platydracus brevicornis Motschulsky, 1862)를 포함한 3종의 지표종 변화를 확인 하였다.

Antioxidant and hepatoprotective effects of Korean ginseng extract GS-KG9 in a D-galactosamine-induced liver damage animal model

Yun Ho Jo,Hwan Lee,Myeong Hwan Oh,Gyeong Hee Lee,You Jin Lee,Ji Sun Lee,Min Jung Kim,Won Yong Kim,Jin Seong Kim,Dae Seok Yoo,Sang Won Cho,Seon Woo Cha,Mi Kyung Pyo 한국영양학회 2020 Nutrition Research and Practice Vol.14 No.4

BACKGROUND/OBJECTIVES: This study was designed to investigate the improvement effect of white ginseng extract (GS-KG9) on D-galactosamine (Ga1N)-induced oxidative stress and liver injury. SUBJECTS/METHODS: Sixty Sprague-Dawley rats were divided into 6 groups. Rats were orally administrated with GS-KG9 (300, 500, or 700 mg/kg) or silymarin (25 mg/kg) for 2 weeks. The rats of the GS-KG9- and silymarin-treated groups and a control group were then intraperitoneally injected Ga1N at a concentration of 650 mg/kg for 4 days. To investigate the protective effect of GS-KG9 against GalN-induced liver injury, blood liver function indicators, anti-oxidative stress indicators, and histopathological features were analyzed. RESULTS: Serum biochemical analysis indicated that GS-KG9 ameliorated the elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in GalN-treated rats. The hepatoprotective effects of GS-KG9 involved enhancing components of the hepatic antioxidant defense system, including glutathione, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT). In addition, GS-KG9 treatment inhibited reactive oxygen species (ROS) production induced by GalN treatment in hepatocytes and significantly increased the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins, which are antioxidant proteins. In particular, by histological analyses bases on hematoxylin and eosin, Masson"s trichrome, α-smooth muscle actin, and transforming growth factor-β1 staining, we determined that the administration of 500 mg/kg GS-KG9 inhibited hepatic inflammation and fibrosis due to the excessive accumulation of collagen. CONCLUSIONS: These findings demonstrate that GS-KG9 improves GalN-induced liver inflammation, necrosis, and fibrosis by attenuating oxidative stress. Therefore, GS-KG9 may be considered a useful candidate in the development of a natural preventive agent against liver injury.

冠岳樹木園地域內 荒廢山地土壤의 肥沃化를 통한 綠化促進에 關한 硏究

李宗學,麻鎬燮,權台鎬,李憲浩,禹保命 서울大學校農業生命科學大學附屬樹木園 1984 서울大學校 樹木園 硏究報告 Vol.- No.5

冠岳樹木園地域의 山腹斜面은 地質的으로 대보화강암에서 풍화생성된 거친 돌부수러기가 많은 粗砂質壤土로 구성되었으므로 表土層의 土壤流失이 심하여 土深이 대단히 얕거나 岩盤露出이 심하여 林木生長이 심히 不良한 地帶로서,山地의 地力恢復 및 現存하는 散生樹木의 生長力恢復을 通한 山地綠化保全이 시급히 요청되고 있다. 이와같은 요청에 부응하여 荒廢地斜面에 自生하고있는 주요한 4樹種(소나무, 리기다소나무, 노간주나무, 철쭉)에 대하여 山地施肥效果 試驗을 春期와 秋期로 나누어 실시한 결과 樹高 및 直徑生長量에 있어서 無施肥區에 比하여 현저한 施肥效果가 인정되었다. 따라서 冠岳山地帶의 荒廢地를 조속히 復舊綠化하기 위해서는 砂防土木的 工事方法 및 砂防造林的 播植方法이외에도 현존 수목의 保全 및 生長力恢復을 통한 速成綠化方法도 채용되어야 할 것이다. Hillsides in the Kwanak arboretum area were composed mainly of coarse sandy loam having relatively high proportion of rough weathered debris derived from the Daebo granite geologically. Owing to heavy soil erosion resulted to shallow soil depth and heavy rock exposures, the growing trees in this type of surface soil are very poor in their growth. For woody plant vegetation establishment in this montain area, it is urgent to recover the fertility of soil and the growth of existing trees. For this purpose, in spring and autumn season in 1983∼84 the fertilization experiment was conducted with the 4 principal native species(Pinus densiflora, Pinus rigida, Juniperus rigida, Rhododendron schlippenbachii) growing in this denuded forest land, and the effects of fertilized tree plots were more prominent than the control plot in both height and root-collar diameter growth. Therefore, the accelerating measures of vegetation rehabilitation through conservation of existing trees and recovery of tree growth by forest fertilization practices, besides forest engineering measur es and soil erosion control afforestation measures, could be acceptable as the measures for the recovery of denuded forest land in Mt. Kwanak area.

冠岳樹木園地域內 荒廢山地土壤의 肥沃化를 통한 綠化促進에 關한 硏究

李宗學,麻鎬燮,李憲浩,權台鎬,禹保命 서울大學校 農科大學 1984 서울대농학연구지 Vol.9 No.2

冠岳樹木園地域의 山復斜面은 地質的으로 대보화강암에서 풍화생성된 거친 돌부수러기가 많은 粗砂質壤土로 구성되었으므로 表土層의 土壤流矢이 심하여 土深이 대단히 얕거나 岩盤露出이 심하여 林木生長이 심히 不良한 地帶로서, 山地의 地力恢復 및 現存하는 散生樹木의 生長力恢復을 通한 山地綠化保全이 시급히 요청되고 있다. 이와같은 요청에 부응하여 荒廢地斜面에 自生하고 있는 주요한 4樹種(소나무, 리기다소나무, 노간주나무, 철쭉)에 대하여 山地施肥效果 試驗을 春期와 秋期로 나누어 실시한 결과 樹高 및 直徑生長量에 있어서 無施肥區에 比하여 현저한 施肥效果가 인정되었다. 따라서 冠岳山地帶의 荒廢地를 조속히 復舊綠化하기 위해서는 砂防土木的 工事方法 및 砂方造林的 播植方法이외에도 현존 수목의 保全 및 生長力恢復을 통한 速成綠化方法도 채용되어야 할 것이다. Hillsides in the Kwanak arboretum area were composed mainly of coarse sandy loam having relatively high proportion of rough weathered debris derived from the Daebo granite geologically. Owing to heavy soil erosion resulted to shallow soil depth and heavy rock exposures, the growing trees in this type of surface soil are very poor in their growth. For woody plant vegetation establishment in this montain area, it is urgent to recover the fertility of soil and the growth of existing trees. For this purpose, in spring and autumn season in 1983~84 the fertilization experiment was conducted with the 4 principal native species(Pinus densifltora, Pinus rigida, Juniperus rigida, Rhododendron schlippenbachii) growing in this denuded forest land, and the effects of fertilized tree plots were more prominent than the control plot in both height and root-collar diameter growth. Therefore, the accelerating measures of vegetation rehabilitation through conservation of existing trees and recovery of tree growth by forest fertilization practices, besides forest engineering measur es and soil erosion control afforestation measures, could be acceptable as the measures for the recovery of denuded forest land in Mt. Kwanak area.

Korean Red ginseng prevents endothelial senescence by downregulating the HO-1/NF-κB/miRNA-155-5p/eNOS pathway

Tae-Hoon Kim,Ji-Yoon Kim,Jieun Bae,Young-Mi Kim,Moo-Ho Won,Kwon-Soo Ha,Young-Guen Kwon,Young-Myeong Kim 고려인삼학회 2021 Journal of Ginseng Research Vol.45 No.2

Background: Korean Red ginseng extract (KRGE) has beneficial effects on the cardiovascular system by improving endothelial cell function. However, its pharmacological effect on endothelial cell senescence has not been clearly elucidated. Therefore, we examined the effect and molecular mechanism of KRGE on the senescence of human umbilical vein endothelial cells (HUVECs). Methods: HUVECs were grown in normal or KRGE-supplemented medium. Furthermore, they were transfected with heme oxygenase-1 (HO-1) gene or treated with its inhibitor, a NF-κB inhibitor, and a miR-155-5p mimic or inhibitor. Senescence-associated characteristics of endothelial cells were determined by biochemical and immunohistochemical analyses. Results: Treatment of HUVECs with KRGE resulted in delayed onset and progression of senescence-associated characteristics, such as increased lysosomal acidic β-galactosidase and decreased telomerase activity, angiogenic dysfunction, and abnormal cell morphology. KRGE preserved the levels of anti-senescent factors, such as eNOS-derived NO, MnSOD, and cyclins D and A: however, it decreased the levels of senescence-promoting factors, such as ROS, activated NF-κB, endothelial cell inflammation, and p21 expression. The beneficial effects of KRGE were due to the induction of HO-1 and the inhibition of NF-κB-dependent biogenesis of miR-155-5p that led to the downregulation of eNOS. Moreover, treatment with inhibitors of HO-1, NF-κB, and miR-155-5p abolished the anti-senescence effects of KRGE. Conclusion: KRGE delayed or prevented HUVEC senescence through a signaling cascade involving the induction of HO-1, the inhibition of NF-κB-dependent miR-155-5p biogenesis, and the maintenance of the eNOS/NO axis activity, suggesting that it may protect against vascular diseases associated with endothelial senescence.

IMT-2000서비스가 國內 經濟에 미치는 影響

李明豪, 金銀美, 全孝悧 서울대학교 경제연구소 2000 經濟論集 Vol.39 No.1

정보통신산업은 우리나라 총수출의 27.6%, 전체 무역흑자의 60.0%를 차지(1999년)하고 있는 등 국민경제에서 큰 비중을 차지하고 있다. 특히 차세대이동통신으로 알려진 IMT-2000서비스는 관련사업자의 직접적인 이해관계 및 경제적 파급효과 측면에서 세간의 큰 주목을 받고 있다. 본 논문에서는 이러한 IMT-2000서비스 도입의 파급효과를 통신서비스산업에 미치는 영향, 관련산업에 미치는 영향, 국민경제에 미치는 영향, 국민생활에 미치는 영향 등으로 나누어 살펴보고 있다. IMT-2000서비스 도입에 따른 긍정적 효과를 극대화하기 위해서는 첫째, 해외의 사업자 허가 추세에 비추어 볼 때 IMT-2000사업자를 조속히 선정하여 경쟁력을 확보하는 것이 중요하며, 둘째, 특히 멀티미디어 컨텐츠 관련산업의 보다 적극적인 지원 육성이 필요하고, 셋째, 기술표준의 결정이 국내 기술력과 시장성에 대한 정확한 분석과 예측을 바탕으로 이루어지는 한편 이에 대한 연구개발의 지원 및 단말기나 시스템부품의 기술력을 보유한 벤처기업 육성 등의 대책이 필요하다.