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>

PGA2 induces the expression of HO-1 by activating p53 in HCT116 cells

Hyein Lee,Sang-Sun Lee,Ji-Young Park,Yun-Jeong Choe,이선영,Ho-Shik Kim,H.-S. Kim 대한독성 유전단백체 학회 2017 Molecular & cellular toxicology Vol.13 No.2

Prostaglandin (PG) A2 which is a cytotoxic PG, was reported to induce the expression of heme oxygenase (HO)-1 via activation of p38MAPK to keep U2OS cells from cell cycle arrest in G2M phase. The expression of HO-1 is primarily regulated at the level of transcription. But the transcription factors that are responsible for PGA2-induced HO-1 expression were not clarified yet. Here, we report that PGA2-induced transcription of HO-1 is mediated by p53, a tumor suppressive transcription factor. In HCT116 cells, PGA2 treatment led to the phosphorylation of p53 and an increase of p21WAF1 transcription as well as the activation of HO-1 transcription. Knocking p53 down via RNA interference or inhibiting the p53’s transcriptional activity by pifithrin-α treatment led to suppression of the increase in the level of both HO-1 expression and activity of HO-1 promoter. Pretreatment of NU- 7441, a chemical inhibitor of DNA-activated protein kinase (DNA-PK), prevented both the PGA2-induced phosphorylation of p53 and an increase of HO-1 transcription. In addition, N-acetyl-l-cysteine, a scavenger of reactive oxygen species (ROS), also mimicked the effect of NU-7441 on the PGA2-induced activation of p53 and HO-1 transcription. Collectively, these results suggest that PGA2 induces the expression of HO-1 via activation of p53, which is mediated by the ROSDNA- PK pathway.

Prostaglandin A₂-induced Apoptosis is Not Inhibited by Heme Oygenase-1 in U2OS Cells

Kyoung-Won Ko(고경원),Sun-Young Lee(이선영),Ji-Hyun Ahn(안지현),Jaetaek Kim(김재택),In-Kyung Kim(김인경),Ho-Shik Kim(김호식) 한국생명과학회 2008 생명과학회지 Vol.18 No.11

Prostaglandin A₂ (PGA₂)는 사람 골육종 세포인 U2OS 세포주에서 apoptosis와 heme oxygenase (HO)-1의 발현을 함께 유도하였다. PGA₂에 의한 apoptosis는 HO-1의 과도한 발현이나 HO-1에 대한 small interfering RNA에 의한 발현저하에 의하여 변동되지 않았으나 H₂O₂에 의한 세포사망은 HO-1의 발현 수준에 반비례하여 변동되었다. 또한 thiol antioxidant인 N-acetyl-L-cysteine (NAC)은 PGA₂에 의한 세포사망과 HO-1의 발현 증가를 모두 차단하였지만, non-thiol antioxidant인 butylated hydroxyanisole (BHA)과 ascorbic acid는 세포사망과 HO-1의 발현 유도를 차단하지 않았다. 이와 같은 결과들은 PGA₂는 산화성 손상에 의해서가 아니라 PGA₂의 thiol-reactivity에 의하여 apoptosis와 HO-1의 발현을 유도하며, HO-1의 발현은 PGA₂에 의한 apoptosis와는 독립적인 현상이거나 기능적으로 apoptosis 유도의 하부에 위치하고 apoptosis의 진행에는 기여하지 않을 것이라는 것을 시사해 준다. Prostaglandin A₂ (PGA₂), one of cyclopentenone PGs, induced both apoptosis and heme oxygenase (HO)-1 expression in U2OS cells. PGA₂-induced apoptosis was not perturbed by either over-expression or knock-down of HO-1, whereas H₂O₂-induced cell death was inversely modulated by the expression level of HO-1. In addition, N-acetyl-L-cysteine (NAC), a thiol antioxidant, blocked both apoptosis and HO-1 expression induced by PGA₂. But, non-thiol antioxidants like butylated hydorxyanisole (BHA) and ascorbic acid did not block either apoptosis or HO-1-induction. Taken together, these results suggest that PGA₂ induces both apoptosis and HO-1 expression, which are critically related to the thiol-reactivity of PGA₂, but not oxidative stress, and HO-1 expression may be independent or functionally located downstream of apoptosis by PGA₂ without contribution to apoptosis progression.

부산·울산·경남지역 직업병 감시체계

김정일,김병권,김정원,채창호,이철호,강동묵,김지홍,김진하,김영욱,이영하,이지호,김정호,윤형렬,유철인,정백근,장태원,김운규,윤동영,강진욱,김종은,안진홍,이동준,장준호,이광영,송혜란,최영희,이용환,조병만,최홍렬,고상백,김은아,이유진,홍영습,정갑열,김정만,김준연 大韓産業醫學會 2004 대한직업환경의학회지 Vol.16 No.1

Objective: Occupational medicine specialists in the Busan, Ulsan and Kyung-Nam areas established an area-based occupational disease surveillance system and used this system to collected case information for the purpose of preventing occupational diseases Methods: l l hospital participated in this system. The authors selected five main diseases, which were hand-arm vibration syndrome (HAVS), work-related musculoskeletal disorder (WRMSD), occupational asthma, occupational skin disease and occupational and occupational lung cancer and established their case definitions. All cases were reported on the web, and real time analysis was conducted. Results: Between April 2001 and April 2003, 192 cases of HAVS, 118 cases of WRMSD, 33 cases of occupational asthma, 17 cases of occupational skin disease and 17 cases of occupational lung cancer (for a total of 377 cases of these five main diseases) were reported. most of the HAVS cases came from shipbuilding, and 172 of them (92.7%) were associated with grinding. Of the four main types of WRMSD, carpal tunnel syndrome (CTS) was the most prevalent with 46 cases and shipbuilding was also the main industry involved (83.9%). The ergonomic risk factors involved mainly associated with the hand. In 19 (57.6%) and 4 (12.1%) cases of occupational asthma, the agents involved. The causative agents of occupational lung cancer included Cr, welding fume, PAH, Ni, etc. 10(58.8%) of the cases were diagnosed as squamous cell carcinoma and 5(29.4%) as adenoma. Conclusion: This result showed that an area-based occupational disease surveillance system might provide an effective method of evaluating the prevalence of such diseases, however the Busan, Ulsan and Kyung-Nam provinces are too large to be treated as individual areas. Therefore, the authors suggest that each province should establish its own surveillance system.

Hepatocellular Carcinoma in the Elderly: Clinical Characteristics, Outcomes and Treatment Efficacy, Safety in Older than 75 Years

( Ji Ho Seo ),( Sunmin Kim ),( Eunae Cho ),( Chung Hwan Jun ),( Sun Young Park ),( Sung Bum Cho ),( Chang Hwan Park ),( Hyun Soo Kim ),( Sung Kyu Choi ),( Jong Sun Rew ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) has been increasing because the increase in the longevity of the general population. But there is no proper management based on age stratification in elderly patients. We compared clinical characteristics, outcomes and treatment efficacy, safety between oldest-old (aged more than 85 years), middle-old (aged between 80 and 85 years) and young-old (aged between 75 and 80 years) patients with HCC. Methods: We conducted a retrospective cohort study, from January 2010 to December 2016, at Chonnam National University Hospital. A total of 550 elderly patients whose data included demographics, co-morbidity, etiology of liver disease, presence of cirrhosis, staging of HCC, treatment modality and treatment related adverse event were evaluated retrospectively. Also overall survival was assessed in enrolled patient. Results: Fifty one patients (oldest-old; median 87 years old), 153 patients (middle-old; median 82 years old) and 346 patients (young-old; median 77 years old) were diagnosed with HCC. Both oldest- and middle-old patients, compared to young-old patients had significantly lower rate of alcohol-related disease (13.7% vs 20.9% vs 34.1%, P = 0.001). There were no significant difference in underlying sex, body mass index, presence of co-morbidity, hepatitis C-related disease and stage of HCC. The Child-Pugh class (CPT class A 88.9% vs 84.1% vs 83.6%, CPT class B 11.1% vs 15.9% vs 15.0% and CPT class C 0.0% vs 0.0% vs 1.3%, respectively, P = 0.912) and Model for End Stage Liver Disease score (mean MELD score 7.22±3.34 vs 5.88±3.01 vs 5.77±3.14, P = 0.166) were no significant difference between the patients with active treatment. The modified UICC staging (stage I 5.6% vs 17.1% vs 18.6%, stage II 55.6% vs 46.3% vs 47.3%, Stage III 22.2% vs 24.4% vs 24.8%, Stage IV-A 11.1% vs 6.1% vs 4.9% and Stage IV-B 5.6% vs 6.1% vs 4.4%, respectively, P = 0.826) and Barcelona Clinic Liver Cancer staging (stage 0 5.6% vs 9.8% vs 9.3%, stage A 16.7% vs 17.1% vs 22.1%, stage B 27.8% vs 29.3% vs 24.8%, stage C 50.0% vs 43.9% vs 41.2% and stage D 0.0% vs 0.0% vs 2.7%, respectively, P = 0.878) were no significant difference between the patients with active treatment. Furthermore, there were no difference between the age groups in treatment modality (Surgical resection 0.0% vs 3.3% vs 5.2%, P = 0.166; Radiofrequency ablation 2.0% vs 8.5% vs 11.0%, P=0.113; Transcatheter arterial chemoembolization 21.6% vs 34.6% vs 41.6%, P=0.014; Best supportive care 62.7% vs 40.5% vs 29.2%, P < 0.001), adverse event related treatment (P = 0.731) and disease-free survival days (329 .3±309.1 days vs 271.7 ± 414.2 days vs 357.2 ± 511.6 days, P = 0.336). Multivariate analysis showed that age, performance status, CTP class, MELD score, modified UICC staging, presence of portal vein thrombosis and ruptured HCC are risk factors for mortality. Conclusions: Clinician should make an active treatment in elderly patients with HCC not a age but performance status, liver function and disease status of cancer.

Young-Ki Kim

Sun-young Park,Youngjae Lee,Jinyoung Song,Seok-ho Jeon,Ji-yoon Jeong,강병택,강지훈,장진화,장동우 한국임상수의학회 2016 한국임상수의학회지 Vol.33 No.3

Signalment: An 8-month-old female Alaskan malamute was presented for progressive cluster seizure disorder. Results: There were no abnormalities on neurological examination, survey radiographs, or blood analysis. Magnetic resonance (MR) imaging and computed tomography revealed extension of the olfactory bulb and frontal lobe into the nasal cavity. They also confirmed abnormal anatomy of the nasal turbinates within the rostral part of the nasal cavity and the absence of a cribriform plate. On T2-weighted and fluid-attenuated inversion recovery images, the herniated brain showed heterogeneous and hyperintense signals consistent with intraparenchymal edema. Transverse MR images showed brain herniation into the right frontal cavity and an asymmetrical lateral ventricle because of a left midline shift. On contrast-enhanced MR images, the protruding brain parenchyma was mildly enhanced. Ethmoidal encephalocele was suspected as the final diagnosis. Despite symptomatic treatment, the dog continued to exhibit seizures and was euthanized. Clinical relevance: Ethmoidal encephalocele is a rare disease in dogs. However, it could be considered as a cause of seizure in young dogs.

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]

영골(靈骨).강압혈(降壓穴) 자극(刺鍼)이 혈압(血壓)에 미치는 영향(影向)

임영남,심성용,한지완,고호연,박종형,한양희,전찬용,김동우,Yim, Young-Nam,Sim, Sung-Yong,Han, Ji-Wan,Ko, Ho-Yeon,Park, Chong-Hyeong,Han, Yang-Hee,Chun, Chan-Yong,Kim, Dong-Woo 대한한방내과학회 2004 大韓韓方內科學會誌 Vol.25 No.2

Objective : The purpose of this study is to evaluate the clinical effect of the non-pharmacological anti-hypertension method, acupuncture, for hypertensive patients. Methods : 26 patients diagnosed with hypertension were each treated by one of three methods: an anti-hypertension drug(adalat soft capsule), venepuncture, and acupuncture. In cases of rising blood pressure, patients were treated by their one of the three methods, and blood pressure was measured at regular intervals. Result : As for the group of acupuncture treated patients on Young-gol(ling-gu) and Gang-ap-hyul(jiang-ya-xue), readings dropped 18.0mmHg in systolic blood pressure and 6.50mmHg in diastolic blood pressure. This was a greater effect than that seen in the venepuncture treated patients. Blood pressure checked one hour after acupuncture treatment showed a greater difference than blood pressure checked after thirty minutes. Conclusion : Safe reductions in blood pressure were observed through the non-pharmacological method of acupuncture on Young-gol(ling-gu) and Gang-ap-hyul(Jiang-ya-xue).

무청시래기를 첨가한 추어 떡갈비의 개발 및 품질특성

유지영 ( Ji Young You ),진금용 ( Jinlong Chen ),임종준 ( Jong Jun Lim ),박지인 ( Ji In Park ),백서준 ( Seo Jun Baek ),최준호 ( Joon Ho Choi ) 한국산업식품공학회 2021 산업 식품공학 Vol.25 No.4

이번 연구는 남원식 추어탕의 주재료인 추어와 무청시래기에 대한 인식개선과 이를 이용하여 젊은 연령층의 기호도에 적합한 분쇄육 제품을 개발하고자 추진되었다. 떡갈비 주원료인 돈육과 우지의 15%를 추어 페이스트로 대체한 추어 떡갈비를 대조구로 사용하였으며, 대파의 일정비율(25%, 50%, 75%, 100%)을 무청시래기로 대체하여 추어와 무청시래기가 첨가된 떡갈비 시료를 제조하였다. 무청시래기를 첨가한 떡갈비는 가열·조리 후 pH와 당도는 각각 6.07-6.28과 9.94-10.9로 시중에서 유통되는 떡갈비의 개별 특성에 적합하였다. 가열·조리에 따른 가열감량은 대파를 사용한 대조구에 비하여 대파를 무청시래기로 대체한 떡갈비 시료에서 유의적으로 낮았지만 무청시래기의 첨가량에 따른 유의적인 차이는 없었다. 가열 전과 가열·조리 후 무청시래기를 첨가한 떡갈비의 수분함량은 모두 대조구 보다 높았으며 이는 무청시래기의 식이섬유가 육가공품의 보수성을 높여 가열감량을 감소시킨 것으로 판단되었다. 대파를 무청시래기로 대체한 떡갈비 시료의 명도(44.5-47.8)는 시료 간의 유의적인 차이를 보이지 않은 반면 적색도(0.77-4.97)와 황색도(6.92-12.8)는 무청시래기의 첨가량에 따라 유의적으로 감소하였다. 떡갈비 시료에 대한 TPA 결과, 부착성은 대파를 무청시래기로 대체한 떡갈비 시료에서 대조구보다 유의적으로 낮아졌으나 경도, 응집성, 검성, 씹힘성에서는 대조구와 무청시래기를 첨가한 시료 간에 유의적인 차이를 확인할 수 없었다. 무청시래기가 첨가된 떡갈비 시료에 대한 관능적인 평가에서 색, 연도, 다즙성에서 대조구보다 낮은 점수를 받았다. 전반적인 기호도 역시 무청시래기가 첨가되지 않은 대조구에서 가장 높은 점수를 받았으나 무청시래기를 첨가한 시료에서는 대파의 50%를 대체한 시료에서 높은 점수를 받았다. 무청시래기 자체가 지닌 특유의 향미는 관능적인 평가에서 확인되지 않았으며 전자코를 이용한 향기패턴 분석에서도 낮은 분별지수(-90)로 시료 간의 향기패턴 차이를 확인하기 어려운 수준이었다. 이번 연구를 통해 떡갈비의 제조에서 대파를 대체하는 무청시래기의 함량은 25-50%가 적절하였으며 무청시래기와 추어가 지닌 특유의 맛과 냄새로 인한 영향을 받지 않는 떡갈비를 개발함으로써 향후 남원지역의 향토음식과 연계되는 새로운 메뉴개발이 가능하게 되었다. This study was performed to develop tteokgalbi suitable for young-aged individuals by using mudfish and radish greens, major ingredients of Chueo-tang. Mudfish-tteokgalbi (control), in which 15% of the meat and tallow was replaced with mudfish paste, was used while substituting 25 to 100% of the green onions with radish greens. The pHs and sugar contents of the tteokgalbi developed in this study were 6.07-6.28 and 9.94-10.9, respectively, and it was suitable for tteokgalbi sold in the market. Replacing green onions with radish greens while manufacturing tteokgalbi significantly reduced the color (a and b values) and weight loss during cooking compared to the control. Replacing green onions with increasing quantities of radish greens also significantly reduced the adhesiveness of the samples in the texture profile analysis. Although the overall acceptability of the control was the best, the ideal quantity of radish greens as a substitution for green onions appears to be 25-50%. The unique flavor of the supplemented radish greens was indistinguishable in the sensory evaluation and the principal component analysis with an electronic nose. Finally, radish greens were confirmed as a good ingredient for manufacturing tteokgalbi together with mudfish paste.

부산, 울산, 경남지역 직업병감시체계에서 나타난 수지진동증후근의 역학적 특성

최영희,유철인,이지호,이충렬,이헌,김영욱,채창호,고상백,김은아,이유진,김양호 大韓産業醫學會 2003 대한직업환경의학회지 Vol.15 No.3

목적: 국내에서도 국소진동에 의한 수지진동증후군이 다수 있을 것으로 추정하나 최근에 이에 대한 보고가 적어 부·울·경 직업병감시체계를 통하여 수지진동증후군에 대한 환례를 수집하여 이의 역학적 특성을 밝히고자 본 연구를 실시하였다. 방법: 2001년 44월부터 2002년 12월까지 부산, 울산, 경남지역에 있는 종합병원 9곳을 통하여 특수 건강진단과 산업의학과 외래를 방문한 근로자를 대상으로 진동폭로에 대한 설문조사를 실시하고 이들중에서 수지진동으로 인한 증상을 호소하는 근로자는 이학적 검사와 Stockholm workshop scale을 이용하여 수지진동증후군이 있는지 평가하였다. 결과: 남자 188명, 여자 4명 등 총 192례의 수진진동증후군이 의심되는 환례를 수집하였으며, 업종별로는 조선업에 종사하는 근로자들이 가장 많았다. 국소진동의 주된 폭로원은 그라인더가 가장 많았으며, 혈관장해로 인한 증상보다 감각신경성 장해로 인한 증상을 많이 호소하였다. 결론: 전국적으로 조선업종의 그라인더 사용자를 중심으로 많은 수의 수지진동증후군의 환자가 있을 것으로 추정되며, 이들에 대한 예방대책을 마련하기 위하여 전국규모의 정확한 유병률 조사 및 실태파악이 필요한 것으로 판단된다. Objects: The objectives of this study were to estimate the epidemiologic characteristics of hand-arm vibration syndrome (HAVS) due to occupational exposure of hand transmitted vibration and to identify the occupations and industries where such exposures arises, and the main sources of exposure. Methods: In April 2001 the Busan, Ulsan, and Kyung-Nam Province occupational disease surveillance system was established to measure the incidence and prevalence of work-relatd HAVS and other occipational diseases in these Korean provinces. Occupational physicians of nine hospitals in Busan, Ulsan, and Kyung-nam Province were involved in this project between April 2001 and November 2002. Physicians collected information through questionnaires and interviews. Information gathered included age, occupation, types of vibration tools used and presence of subkective symptoms such as vibration-induced white finger (VWF), numbness and tingling. Results: A total 192 cases were reported with 188 males and 4 females. The shipbuilding industry was the most common type of industry and grinders were the most common source of exposire. Symptoms of neurological disorder were more common than those of vascular disprder. Conclusions: The authors concluded that exposure to hand transmitted vibration is common and that HAVS is one of the most common occupational diseases in Korea. However, the range and extent of hand transmitted vibration and the overall prevalence of HAVS in Korea is still unknown. More extensive research on this syndrome in order to priorite necessary preventive measures is required.