Protective Effect of Heme Oxygenase-1 on High Glucose-Induced Pancreatic β-Cell Injury

Lee, Eun-Mi,Lee, Young-Eun,Lee, Esder,Ryu, Gyeong Ryul,Ko, Seung-Hyun,Moon, Sung-Dae,Song, Ki-Ho,Ahn, Yu-Bae Korean Diabetes Association 2011 Diabetes and Metabolism Journal Vol.35 No.5

<P><B>Background</B></P><P>Glucose toxicity that is caused by chronic exposure to a high glucose concentration leads to islet dysfunction and induces apoptosis in pancreatic β-cells. Heme oxygenase-1 (HO-1) has been identified as an anti-apoptotic and cytoprotective gene. The purpose of this study is to investigate whether HO-1 up-regulation when using metalloprotophyrin (cobalt protoporphyrin, CoPP) could protect pancreatic β-cells from high glucose-induced apoptosis.</P><P><B>Methods</B></P><P>Reverse transcription-polymerase chain reaction was performed to analyze the CoPP-induced mRNA expression of HO-1. Cell viability of INS-1 cells cultured in the presence of CoPP was examined by acridine orange/propidium iodide staining. The generation of intracellular reactive oxygen species (ROS) was measured using flow cytometry. Glucose stimulated insulin secretion (GSIS) was determined following incubation with CoPP in different glucose concentrations.</P><P><B>Results</B></P><P>CoPP increased HO-1 mRNA expression in both a dose- and time-dependent manner. Overexpression of HO-1 inhibited caspase-3, and the number of dead cells in the presence of CoPP was significantly decreased when exposed to high glucose conditions (HG). CoPP also decreased the generation of intracellular ROS by 50% during 72 hours of culture with HG. However, decreased GSIS was not recovered even in the presence of CoPP.</P><P><B>Conclusion</B></P><P>Our data suggest that CoPP-induced HO-1 up-regulation results in protection from high glucose-induced apoptosis in INS-1 cells; however, glucose stimulated insulin secretion is not restored.</P>

Ethanol Extract of Ganoderma lucidum Augments Cellular Anti-oxidant Defense through Activation of Nrf2/HO-1

Lee, Yoo-hwan,Kim, Jung-hee,Song, Choon-ho,Jang, Kyung-jeon,kim, Cheol-hong,Kang, Ji-Sook,Choi, Yung-hyun,Yoon, Hyun-Min KOREAN PHARMACOPUNCTURE INSTITUTE 2016 Journal of pharmacopuncture Vol.19 No.1

Objectives: The mushroom Ganoderma lucidum has been widely used as a traditional herbal medicine for many years. Although several studies have focused on the anti-oxidative activity of this mushroom, the molecular mechanisms underlying its activity have not yet been clearly established. The present study investigated the cytoprotective effect of ethanol extract of Ganoderma lucidum (EGL) against oxidative stress (hydrogen peroxide, $H_2O_2$) and elucidated the underlying mechanisms in a C2C12 myoblast cell line. Methods: Oxidative stress markers were determined by using the comet assay to measure reactive oxygen species (ROS) generation and deoxyribonucleic acid (DNA) damage. Cell viability and Western blotting analyses were employed to evaluate the cellular response to EGL and $H_2O_2$ in C2C12 cells. Transfection with nuclear factor erythroid 2-related factor 2 (Nrf2)-specific small interfering ribonucleic acid (siRNA) was conducted to understand the relationship between Nrf2 expression and $H_2O_2$-induced growth inhibition. Results: The results showed that EGL effectively inhibited $H_2O_2$-induced growth and the generation of ROS. EGL markedly suppressed $H_2O_2$-induced comet-like DNA formation and phosphorylation of histone H2AX at serine 139 ($p-{\gamma}H2AX$), a widely used marker of DNA damage, suggesting that EGL prevented $H_2O_2$-induced DNA damage. Furthermore, the EGL treatment effectively induced the expression of Nrf2, as well as heme oxygenase-1 (HO-1), with parallel phosphorylation and nuclear translocation of Nrf2 in the C2C12 myoblasts. However, zinc protoporphyrin IX, a HO-1 inhibitor, significantly abolished the protective effects of EGL against $H_2O_2$-induced accumulation of ROS and reduced cell growth. Notably, transient transfection with Nrf2-specific siRNA attenuated the cytoprotective effects and HO-1 induction by EGL, indicating that EGL induced the expression of HO-1 in an Nrf2-dependent manner. Conclusion: Collectively, these results demonstrate that EGL augments the cellular anti-oxidant defense capacity through activation of Nrf2/HO-1, thereby protecting C2C12 myoblasts from $H_2O_2$-induced oxidative cytotoxicity.

Induction of heme oxygenase-1 protects against podocyte apoptosis under diabetic conditions

Lee, Sang Choel,Han, Seung Hyeok,Li, Jin Ji,Lee, Sun Ha,Jung, Dong-Sub,Kwak, Seung-Jae,Kim, Seung Hye,Kim, Dong Ki,Yoo, Tae-Hyun,Kim, Jin Hyun,Chang, Se-Ho,Han, Dae Suk,Kang, Shin-Wook International Society of Nephrology 2009 Kidney international Vol.76 No.8

Heme oxygenase-1 (HO-1) is an anti-oxidant enzyme normally upregulated in response to oxidant injury. Here we determined the role of HO-1 in podocyte apoptosis in glomeruli of streptozotocin-treated rats and in immortalized mouse podocytes cultured in media containing normal or high glucose. HO-1 expression, its activity, the ratio of Bax/Bcl-2 protein, and active caspase-3 fragments were all significantly higher in isolated glomeruli of diabetic rats and in high glucose–treated podocytes. These increases were inhibited by zinc protoporphyrin treatment of the rats or by HO-1 siRNA treatment of the podocytes in culture. The number of apoptotic cells was also significantly increased in the glomeruli of diabetic rats and in high glucose–treated podocytes. Inhibition of HO-1 accentuated the increase in apoptotic cells both in vivo and in vitro. Our findings suggest that HO-1 expression protects against podocyte apoptosis under diabetic conditions.

峿堂 李象秀의 『史記』 評述에 대하여

이현호(Lee Hyun-Ho) 동양한문학회(구 부산한문학회) 2010 동양한문학연구 Vol.31 No.-

본고는 峿堂李象秀(1820-1882)가 『사기』에 대해서 남긴 비평적 저술을 살핀 논문이다. 이상수는 텍스트의 선택이나텍스트의 선본에 관심을 갖지않고 독서하는 방법에 주목하였다. 그리하여 대부분의 사람들의 독서법이 잘못되었기에 글을 잘 짓는 자가 드물다 하면서, 맹목적 독서가 아닌 能思의 독서를 해야함을 강조하였다. 이러한 이상수의 독서론은 ‘虛讀’이 아닌 ‘實讀’이라 명명할 수 있는데, 독서에 潛心해야 志向이 정해지고 見識이 분명해져 결국에는 작자의 本心을 파악하며 글 전체의 大義를 구명할 수 있게 된다 하였다. 또한 이상수는 독서를 작문의 기초단계로 파악하지 않고, 오히려 작문 이후에 더 독서를 잘 할 수 있다는 의견을 피력한다. 곧 작문법을 독서론에 적용하여 체계적이고도 분석적으로 글을 읽어야 글에 나타난 작자의 묘처를 알 수 있게 된다고 하였다. 이러한 독서작문론을 『사기』에 적용하여 비평적 언술을 남기게 된다. 혹리열전 에서는 저작의도를 후세의 경계가 아닌 한무제의 어리석고 현명하지 못함을 기롱하고 풍자하는 것이라 하였고, ‘脈理’에 입각하여 입전 순서가 단절되지 않고 연속되어 있음을 논증하고 있다. 화식열전 에서는 작자의 本心과 宗旨를 글의 표면에서 찾지 않고 글에 드러나 있지 않은 곳에서 찾고 있으며, 사람들이 재화의 증식만 추구하여 올바른 가치를 망각하는 모습을 안타까워한 것이 이 傳을 創立한 사마천의 본심이라 하였다. 또한 문장의 ‘摺’과 ‘承’이라는 段落구성에서 접속 기법의 차원으로 화식전 에대하여 수사학적 분석을 하고 있다. 이러한 것들에서 이상수의 독서작문론의 의의와 『사기』에 대한 평술의 실상을 확인할 수 있다. The present study analyzes a critical review by Lee Sang-Soo (pseudonym: eh-dang, 1820-1882) on the Records of the Great Historian (Shiji or 史記, Sima Qian;109 BC - 91 BC). Lee focused on the mode of reading, rather than on the choice and content of text. He pointed that most people employ an improper mode of reading and hence good writers are rare, thereby he urged to exercise truthful and proper reading instead of pointless reading. Such a theory of reading by Lee can be defined as true reading (實讀), as opposed to a vain reading (實讀), where he asserted that being engrossed in reading is what offers the inclination of messages and firmly sets the insight of reader; only then, one can eventually recite the true intention of the writer and be able to define the ultimate message of the whole text. Further, Lee did not identify reading as a prerequisite step for writing but instead expressed that reading can be improved with writing exercise. In other words, applying writing skills to the reading theory that one should read text in an orderly and analytic manner in order to appreciate the writer's merit from the text. He applied this theory of reading-by-writing in his critical review on the Records of the Great Historian. He stated that the Biographies of Cruel Officials (Kuli liezhuan, 酷吏列傳) of the Records is not intended as a discipline for succeeding generations but to deride and satire the Emperor Wu of Han for his folly and poor wisdom, arguing that the contents are connected by the thread of logic in consecutive manner, without disruption. While discussing on the Biographies of Usurers (Huozhi liezhuan, 貨殖列傳), he finds the writer's true intention and ultimate message from the unmentioned context instead of the textual contents, that frustration was the real intention behind Sima Qian's establishment of the Records, for people becoming obsessed with material wealth and in turn oblivious to the value of morals. He also conducted rhetoric analysis on the Biographies of Usurers in terms of conjunctive method on the paragraph composition characterized by remit and receiving. Such are the particulars that present the significance of Lee's reading-bywriting theory, as well as the insight to his critical assessment on the Records of the Great Historian.

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>

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.

편두통 환자의 임상 양상 및 생체전기 자율반응과의 상관성 고찰

이현종,정인태,김수영,이두익,김건식,이재동,이윤호,최도영 WHO COLLABORATING CENTRE FOR TRADITIONAL MEDICINE 2004 東西醫學硏究所 論文集 Vol.2004 No.-

Objective : We had a clinical report in headache but didn't in migraine. We have planned this study in order to get the basic data of migraine in oriental medicine. Methods : The patient of 36 in migraine checked sec, age, onset, family history, severity of pain, influences of life, induced cause, clinical pain characteristics, associated symptom, treatment style, and paescription, frequency, using period of analgesics by a questionnaire and differentiated syndromes in migraine and evaluated autonomic bioelectric response recorder(ABR-2000). Results : There are 23.4% in prevalence rate of migraine. The ratio of sex is M: F=1:17. The age of an attack is the highest in thirties. The patient are the most in forties. The mean duration of illness is 12.0±9.9 years. 83.4% had a family history. 61.1% had a moderate grade in severity of pain. 77.8% selected fatigue in induced cause of migraine. 69.4% had tingling sense, nausea and vomiting in the associated symptoms. 91.7% used analgesics for treatment and 51.5% of them used analgesics voluntarily. 61.9% of them take analgesics less than once in a week. 33.6% had the phlegm syncope headache in differentiation of syndrome. In ABR-2000 results, item of graph showed low tendency mostly. Conclusions : We expected that this re port of clinical progress, differentiation of syndromes and ABR-2000 results in migraine would be used basic data by oriental medicine to treat migraine.

조구등(釣鉤藤)의 4-VO로 유발한 흰쥐뇌허혈에 대한 신경방어효과

李仁煥,林康鉉,李鍾錫,石庚浩,安德均,朴虎君,김頀哲 대한본초학회 1999 大韓本草學會誌 Vol.14 No.2

Uncariae Ramulus et Uncus(UR, ???) has sweet in flavour and slightly cold in property, acting on the liver and pericardium channels. This drug was described in a medical classic as having the ability to remove "heat", check hyperfunction of the liver and relieve dizziness, tremors, and convulsion, and subdue "endogenous wind". So this study was planned to check the neuroprotective effect of UR on the global ischemia induced by 4-vessel occlusion in Wistar rats. and UR extract was lyophilized after extraction with 70% methanol. We induced 4-vessel occlusion for 10 minutes and reperfused again. The number of CA1 pyramidal neurons were counted after 7 days of reperfusion under the cresyl violet staining. In 4-VO ischemia model, UR showed significantly neuroprotective effects(1,000 and 500 ㎎/㎏ of UR extracts, p<0.05) compared with control group. Each neuroprotective ratio was about 23.0%, 19.0% respectively. Consequently, Uncariae Ramulus et Uncus has neuroprotective effects on the global ischermia induced by 4-vessel occlusion in Wistar rats. So we expect that Uncariae Ramulus et Uncus can be used as a drug for neurodegenerative disease.

봉독약침이 류마티스 관절염 환자의 관절 통증, 종창 및 급성 염증 반응에 미치는 영향

이상훈,이현종,백용현,김수영,박재경,홍승재,양형인,김건식,이재동,최도영,이두익,이윤호 WHO COLLABORATING CENTRE FOR TRADITIONAL MEDICINE 2003 東西醫學硏究所 論文集 Vol.2003 No.-

Objective In order to study the effects of bee venom(BV) on the pain, edema, and acute inflammatory reactant of rheumatoid arthritis(RA) patients. Methods Patients with RA who met the ACR(American College of Rheumatology) 1987 revised criteria for the diagnosis of RA were treated with the BV therapy twice a week for 3 months. Tender Joint counts, swollen joint counts, Visual analog scale(VAS), morning stiffness, ESR. C-reactive protein(CRP) were analyzed before and after BV therapy. Results The results as follows. 1. Tender joint counts in patients after BV therapy were significantly lower than those before BV therapy(9.0±7.9 vs 15± 11.4, p=0.002). 2. Swollen joint counts of the patients after BV therapy were significantly lower than those before BV therapy(50±61 vs 15±23, p=0.001). 3. VAS in patients after BV therapy was significantly lower than those before BV therapy(608± 17.6 vs 380± 159, p=0.000). 4. Duration of morning stiffness in patients after BV therapy was significantly reduced compared with that before BV therapy(119.1± 112.6 min vs 59.0±89.7 min, p=0.009). 5. ESR and CRP were not significantly changed before and after BV therapy, suggesting BV itself could make inflammatory reaction as well as therapeutic effect. Conclusions BV therapy improved tender joint counts, swollen joint counts and duration of morning stiffness in this study, and further study is needed on long-term effect of BV therapy.

KAERI 부지 주변의 환경선량 측정을 위한 온라인 감마선량 감시시스템

이정호,박두원,이원윤,이현덕,최용호,김삼랑,홍광희,이창우 대한방사선 방어학회 1994 방사선방어학회지 Vol.19 No.2

환경감마선량 변동을 감시하기 위해 한국원자력연구소 부지 주변에 온라인 감마선량 감시망을 구성하였다. 모니터링 포스트에 설치된 전리함 검출기에 의해 측정된 자료는 무선전송방식으로 중앙통제소에 전송되어 실시간으로 감시된다. 무선전송 방식은 자료의 전송, 처리 및 자자에 신뢰도가 높고 경제적이었다. 감시시스템은 급격한 선량증가시 조기경보체제와 연결할 수 있게 하였다. On-line gamma monitoring system around KSERI-site was set up to monitor the radiation fluctuations in environment. Data on gamma exposure rates measured by the ionication chamber in the monitoring posts are transmitted to a computer of central control station with radio telemetry transmission and reliable on handing and storing of data. This monitroing system can triger an early warning system in the event of abnormal radiation levels.