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]

서울의 Penicillinase Producing Neisseria Gonorrhoeae 발생빈도(1996)

김재홍,황동규,전재홍,김윤석,김중환,김용준,이창균,임동진,김현수,조창근,김경문,박상훈,전우형,김희성,이호정,차명수,김갑형,김형석,김석우,황지환,박병순,권오상,이민수,송기훈,성소영,이인섭,부태성 대한화학요법학회 1999 대한화학요법학회지 Vol.17 No.2

Background : In recent years, gonorrhea has been panedemic and remains one of the most commom STDs in the world, especially in developing countries. Objective & Methods: For the detection of a more effective therapeutic regimen and assessing the prevalence of PPNG, we have been trying to study the patients who have visited the VD Clinic of Choong-Ku Public Health Center in Seoul since 1980 by means of the chromogenic cephalosporin method. Results: In 1996, 139 strains of N. gonorrhoeae were isolated, among which 53(39.0%) were PPNG. Conclusion: Our results suggests that after a peak of 74.3% in 1993, the prevalence of PPNG in Seoul is gradually declining.

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>

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>

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>

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.

한국인 직무 스트레스 측정도구의 개발 및 표준화

장세진,고상백,강동묵,김성아,강명근,이철갑,정진주,조정진,손미아,채창호,김정원,김정일,김형수,노상철,박재범,우종민,김수영,김정연,하미나,박정선,이경용,김형렬,공정옥,김인아,김정수,박준호,현숙정,손동국 大韓産業醫學會 2005 대한직업환경의학회지 Vol.17 No.4

Background and Purposes: Over the past three decades, numerous studies performed in Korea have reported that job stress is a determinant risk factor for chronic diseases and work disability. Every society has its own culture and occupational climate particular to their organizations, and hence experiences different occupational stress. An occupational stress measurement tool therefore needs to be developed to estimate it objectively. The purpose of this study is to develop and standardize the Korean Occupational Stress Scale (KOSS) which is considered to be unique and specific occupational stressors in Korean employees. Subjects and Methods: Data were obtained from the National Study for Development and Standardization of Occupational Stress (NSDSOS Project: 2002-2004). A total of 12,631 employees from a nationwide sample proportional to the Korean Standard Industrial Classification and the Korean Standard Occupational Classification were administered. The KOSS was developed for 2 years (2002-2004). In the first year, we collected 255 items from the most popular job stress measurement tools such as JCQ, ERI, NIOSH and OSI, and 44 items derived from the a qualitative study (depth interview). Forty-three items of KOSS, in the second year, were retained for use in the final version of the KOSS by using Delphi and factor analysis. Items were scored using conventional 1-2-3-4 Likert scores for the response categories. Results: We developed eight subscales by using factor analysis and validation process: physical environment (3 items), job demand (8 items), insufficient job control (5 items), interpersonal conflict (4 items), job insecurity (6 items), organizational system (7 items), lack of reward (6 items), and occupational climate (4 items). Together they explained 50.0% of total variance. Internal consistency alpha scores were ranged from 0.51 to 0.82. Twenty-four items of the short form of the KOSS (KOSS-SF) were also developed to estimate job stress in the work setting. Because the levels of the subscales of occupational stress were gender dependent, gender-specific standard norms for both the 43-item full version and the 24-item short form using a quartile for the subscales of KOSS were presented. Conclusion: The results of this study suggest that KOSS might be an appropriate measurement scale to estimate occupational stress of Korean employees. Further and more detailed study needs to be conducted to improve the validity of this scale.

Characterization and multicolor upconversion emission properties of BaMoO₄: Yb³⁺, Ln³⁺ (Ln = Tm, Ho, Tm/Ho) microcrystals

Ray, Schindra Kumar,Kshetri, Yuwaraj K.,Yamaguchi, Tokutaro,Kim, Tae-Ho,Lee, Soo Wohn Elsevier 2019 Journal of solid state chemistry Vol.272 No.-

<P><B>Abstract</B></P> <P>Hydrothermal process was employed to synthesize the Yb<SUP>3+</SUP>/Tm<SUP>3+</SUP>, Yb<SUP>3+</SUP>/Ho<SUP>3+</SUP> and Yb<SUP>3+</SUP>/Tm<SUP>3+</SUP>/Ho<SUP>3+</SUP> doped BaMoO<SUB>4</SUB> octahedron microcrystals (0.50–5.0 µm). The synthesized phosphors have scheelite tetragonal structure. The elemental mapping suggests the uniform distribution of elements in the samples. The oxidation state of samples were investigated by X-ray photoelectron spectroscopy (XPS) which indicates the existence of Ba<SUP>2+</SUP>, Mo<SUP>6+</SUP>, O, Yb<SUP>3+</SUP>, Tm<SUP>3+</SUP> and Ho<SUP>3+</SUP> in samples. The presence of rare earth ions was also verified by observation of specific absorption peaks in diffuse reflectance spectra (DRS). The tunable multicolor upconversion (UC) emissions were successfully obtained under 980 nm NIR excitation by precisely adjusting the concentration of rare earth ions. The as prepared sample exhibits blue, green and red emission as a result of energy transfer from the Yb<SUP>3+</SUP> to Tm<SUP>3+</SUP> and Ho<SUP>3+</SUP> ions. The power dependent UC emission spectra show the two photonic processes. The energy transfer mechanism from Yb<SUP>3+</SUP> to Tm<SUP>3+</SUP> and Ho<SUP>3+</SUP> was explained <I>via</I> an energy level analysis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Synthesis of BaMoO<SUB>4</SUB>: Yb<SUP>3+</SUP>, Ln<SUP>3+</SUP> (Ln = Tm, Ho, Tm/Ho) by hydrothermal process. </LI> <LI> Investigation of upconversion luminescence of phosphors under 980 nm excitation. </LI> <LI> Obtaining the multicolor emission by adjusting doped rare-earth ions concentration. </LI> <LI> Explanation of photonic process and energy transfer mechanism. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>Multicolor upconversion emission properties of BaMoO<SUB>4</SUB>: Yb<SUP>3+</SUP>, Ln<SUP>3+</SUP> (Ln = Tm, Ho, Tm/Ho) octahedrons</P> <P>[DISPLAY OMISSION]</P>

HMG-CoA 환원효소 억제제에 의한 ICAM-1 유전자의 발현조절

김현진,정효균,홍우정,김군순,조영석,김도희,채수흥,구본정,송민호,노흥규,김영건 충남대학교 의과대학 지역사회의학연구소 2001 충남의대잡지 Vol.28 No.1

Background : ICAM-1 act as one of major adhesion molecules in the atherosclerotic lesion. ICAM-1 expression is mainly regulated at the level of transcription and depend on IFN-γ signal transduction pathway in which the STAT1 transcrption factor is a critical intermediate. IFN-γreceptor not only initiates tyrosine 701 phosphorylation of STAT1 by Jak1 and Jak2, but also phosphorylates serine 727 through the activation of Raf-1/MAP kinases. HMG-CoA reductase inhibitors have anti-atherosclertic effects, beyond normalization of hypercholesterolemia, by directly acting on endothelial cells, macrophages and vascular smooth muscle cells. HMG-CoA reductase inhibitors suppress the synthesis of isoprenoid intermediates such as geranylgeranyl-pyrophosphate or farnesylpyrophosphate. These effects results inhibitors suppress the synthesis of isoprenoid intermediates such as geranylgeranyl-pyrophosphate or farnesylpyrophosphate. These effects results inhibition posttranslational farnesylation and geranyl-geranylation processing of small GTP-binding preoteins and inhibition of normal signaling activities. Method : We made several 5'-deletion constructs of rat ICAM-1 promoter and analyzed the promoter activities by measuring the luciferase activity after transfection into ECV304 cells and smooth muscle cells. We checked the level of total and phosphorylated STAT1 protein by immunoblot analysis using specific antibodies. Results : Lovastatin inhibits IFN-γ-induced ICAM-1 gene expression in the ECV304cell. The cells pretreated with PD98059, MEKK inhibitor showed significantly low ICAM-1 RNA induction with IFN-γ stimulatio. IFN-γ induced phosphorylation of tyrosine 701 was not significantly changed by the pretreatment of lovastatin. But lovastatin suppresses IFN-γ-induced phosphorylation of ERK1/ERK2 which are responsible for the seine 727 phosphorylation in STAT1. Conclusion : We showed that HMG-CoA reductase inhibitors, lovastatin, suppresses IFN-γ mediated ICAM-1 gene expression through the inhibition of transcription. HMG-CoA reductase inhibitor suppresses IFN-γ-induced phosphorylation of serine 727 in STAT1 through the modulation of MAP kinases.

만성 경막하혈종의 단순 천공 배액술후 재발 및 두개강내 합병증 발생과 관련된 요인

김영규,민경수,이무섭,김동호,복원길,홍석기,김호재 충북대학교 의학연구소 2001 忠北醫大學術誌 Vol.11 No.2

연구목적: 만성 경막하혈종은 두개골 천두술및 혈종배액으로 쉽게 치료될 수 있는 예후가 양호한 질환으로 알려져 있으나, 혈종의 재발 및 합병증이 드물지 않게 발생하기도 한다. 본 연구는 두개골 천두술 및 혈종배액으로 치료받은 102예의 만성 경막하혈종 환자들을 분석하여 혈종의 재발 및 수술후 합병증과 관련된 요인들을 분석하고자 하였다. 대상 및 방법: 만성 경막하혈종으로 진단되어 두개골 천두술 및 혈종배액술법으로 본원 신경외과에서 수술치료받은 102명의 환자를 대상으로 하였고, 입원진료기록 및 방사선소견을 후향적으로 분석하였다. 재발 및 합병증의 발생과 관련된 요인으로는 수술전 환자의 나이, 의식상태, 양측성여부, 뇌실질의 위축정도, 수술후 기뇌의 양, 전신질환여부에 대하여 분석하였다. 결과: 재발의 빈도는 9.8% 였으며 재발과 관련된 요인으로는 양측성, 고령, 수술후 뇌실질재팽창정도(뇌 실질위축, 잔여수액, 기뇌)가 관계가 있었으나 환자의 예후에는 영향이 없었다. 합병증의 종류에는 수술후 급성출혈 5예 및 경막하 농양 1예가 있었으나 이는 모두 출혈성전신질환 또는 면역결핍증이 동반된 환자에서 발생하였고 예후가 불량하였으며, 긴장성 기뇌가 1예발생 하였다. 결론: 전신질환의 동반여부가 합병증의 발생 및 환자의 예후에 가장 중요한 영향을 미쳤으며, 비록 예후에는 영향이 적으나 혈종의 재발의 빈도가 드물지 않으며 기뇌의 방지 및 배액방법의 개선으로 재발의 빈도를 줄일 수 있을 것으로 생각된다. Purpose : Most of chronic subdural hematomas(SOH) are amenable disease with simple cranoistomy drainage, but the recurrence of SDH or development of complications after surgery is not uncommon. To see the prognostic factors related to outcome the recurrence of chronic subdural hematoma and development of complication were analysed in 102 cases of chronic SDH after craniostomy drainage. Materials and Methods: We studied 102 chronic SDH patients treated with craniostomy drainage. Clinical and radiological records were reviewed retrospectively. We analysed the recurrence and complication rate, factors related to the development of recurrence and complications. Results: The rate of recurrence of chronic SDH was 9.8% and factors related to recurrence were bilaterality, old age, and postoperative intracranial environments for brain reexpansion(degree of brain atrophy, amount of residual fluid, amount of intracranial air). Intracranial complications after surgery were developed in 7 cases(6.9%), 5 postoperative bleedings, 1 tension pneumocephalus, 1 subdural empyema. Conclusion : Preoperative clinical condition and association of serious sytemic disease were of major importance in prognosis. The recurrence of chronc SDH was not uncommon, Even though the recurrence was not related to the outcome, great care should be paid on the patients with high risk group.