Heme oxygenase-1 induced by desoxo-narchinol-A attenuated the severity of acute pancreatitis via blockade of neutrophil infiltration

Bae, Gi-Sang,Kim, Dong-Goo,Jo, Il-Joo,Choi, Sun-Bok,Kim, Myoung-Jin,Shin, Joon Yeon,Kim, Dong-Uk,Song, Ho-Joon,Joo, Myungsoo,Park, Sung-Joo ELSEVIER 2019 INTERNATIONAL IMMUNOPHARMACOLOGY Vol.69 No.-

<P><B>Abstract</B></P> <P>Heme oxygenase-1 (HO-1) has an anti-inflammatory action in acute pancreatitis (AP). However, its mechanism of action and natural compounds/drugs to induce HO-1 in pancreas are not well understood. In this study, we investigated the regulatory mechanisms of HO-1 during AP using desoxo-narchinol-A (DN), the natural compound inducing HO-1 in the pancreas. Female C57/BL6 Mice were intraperitoneally injected with supramaximal concentrations of cerulein (50 μg/kg) hourly for 6 h to induce AP. DMSO or DN was administered intraperitoneally, then mice were sacrificed 6 h after the final cerulein injection. Administration of DN increased pancreatic HO-1 expression through activation of activating protein-1, mediated by mitogen-activated protein kinases. Furthermore, DN treatment reduced the pancreatic weight-to-body weight ratio as well as production of digestive enzymes and pro-inflammatory cytokines. Inhibition of HO-1 by tin protoporphyrin IX abolished the protective effects of DN on pancreatic damage. Additionally, DN treatment inhibited neutrophil infiltration into the pancreas via regulation of chemokine (C-X-C motif) ligand 2 (CXCL2) by HO-1. Our results suggest that DN is an effective inducer of HO-1 in the pancreas, and that HO-1 regulates neutrophil infiltration in AP via CXCL2 inhibition.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Desoxo-narchinol-A (DN) is a natural compound of HO-1 inducer in pancreas. </LI> <LI> Mechanism of DN-induced HO-1 is mediated by MAPK/Activator Protein-1/HO-1 signaling. </LI> <LI> DN-induced HO-1 blocks neutrophil infiltration into pancreas via inhibition of CXCL2. </LI> <LI> DN inhibits cerulein-induced acute pancreatitis (AP) and AP-associated lung injury. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

PGA2-induced expression of HO-1 is mediated by transcriptional upregulation of Nrf2

Sang-sun Lee,Yun-Jeong Choe,Hyein Lee,Sun-Young Lee,Ho-Shik Kim 대한독성 유전단백체 학회 2019 Molecular & cellular toxicology Vol.15 No.2

Backgrounds: Prostaglandin (PG) A2 reportedly stimulated expression of heme oxygenase (HO)-1 at the level of transcription via the activation of p38MAPK. Details of the mechanism, however, have not been provided, and this includes identification of the transcription factors responsible for PGA2-induced HO-1 expression. Herein is described an analysis of the role of nuclear factor erythroid 2 related factor 2 (Nrf2) and how PGA2 increases the activity of Nrf2 during PGA2-induced HO-1 expression. Methods: Expressions of HO-1 and Nrf2 were analyzed at the levels of both mRNA and protein. Nrf2 siRNA, SB203580, an inhibitor of p38MAPK, and scavengers of reactive oxygen species (ROS) were used to identify the effects of Nrf2, p38MAPK and ROS on PGA2-induced HO-1 expression. Results: Although SB203580 suppressed PGA2-induced HO-1 expression, genetic activation of p38MAPK could not stimulate the transcription of HO-1. Cycloheximide (CHX), an inhibitor of protein translation, almost completely prevented PGA2-induced increase of HO-1 transcription, but it did not prevent the phosphorylation of p38MAPK, which suggests that both de novo protein synthesis and p38MAPK activity are required to induce the transcription of HO-1 in response to PGA2 treatment. In addition, PGA2 increased the level of both Nrf2 mRNA and protein in a dose-dependent manner. Knockdown of Nrf2 using small interfering RNA (siRNA) suppressed PGA2-induced HO-1 expression. The PGA2-induced transcription of Nrf2 was prevented by ROS scavengers such as n-acetyl-l-cysteine and tempol but not CHX. Furthermore, siRNA against p38MAPK did not change the level of nuclear Nrf2 protein. Conclusion: These findings suggest that PGA2 induces HO-1 transcription via an increase in Nrf2 protein, the transcription of which is initiated by an accumulation of ROS that is independent of the p38MAPK activation pathway.

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.

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]

사례보고 : 하수오 복용 후 발생한 재발성 독성 간염 1예

배상훈 ( Sang Hoon Bae ),김동현 ( Dong Hyun Kim ),배영석 ( Young Seok Bae ),이광재 ( Kwang Jae Lee ),김동완 ( Dong Wan Kim ),윤정빈 ( Jeoung Bin Yoon ),홍준호 ( Joon Ho Hong ),김상현 ( Sang Hyun Kim ) 대한간학회 2010 Clinical and Molecular Hepatology(대한간학회지) Vol.16 No.2

Toxic hepatitis has been reported as a major cause of acute hepatitis, but its potential induction by herbal remedies and/or health foods is usually neglected. We experienced a case of toxic hepatitis associated with Polygoni multiflori, a Chinese herb commonly known as Ho-Shou-Wu. A 54-year-old woman consumed Ho-Shou-Wu for 1 month, after which she experienced fatigue and overall weakness. A diagnosis of toxic hepatitis was made based on her clinical history, the findings for viral markers and other laboratory data, and ultrasonography. Her condition improved considerably after she stopped taking Ho-Shou-Wu. However, she resumed taking Ho-Shou-Wu immediately after discharge from hospital, which aggravated her symptoms and liver function. She was immediately readmitted and stopped taking Ho-Shou-Wu. Her relapse into hepatitis immediate after resuming consumption of the herb is strongly indicative of the validity of Koch`s postulate in this case.

FK506이 T 림프구 사멸에서 활성산소 생성에 미치는 영향

이호균(Ho Kyun Lee),정상영(Sang Young Chung),최수진나(Soo Jin Na Choi) 대한외과학회 2009 Annals of Surgical Treatment and Research(ASRT) Vol.77 No.5

Purpose: Tacrolimus (FK506) has been widely used as an immunosuppressant in organ transplanted recipients to suppress organ rejection phenomenon. We investigated the role of oxidative stress and heme oxygense-1 by FK506 on human Jurkat T cells. Methods: The cells viability was examined by DAPI stain, enzyme activity of caspase family proteins, and western blotting for Baks, PUMA, iNOS, HO-1. Cells were cultured in the absence or presence of CoPPIX or ZnPPIX and the fluorescence intensity was analyzed using a flow cytometry. Results: Treatment with FK506 increased the generation of reactive oxygen species (ROS), including hydrogen peroxide and superoxide anion, and NO in Jurkat cells in a dose-dependent manner. Immunohistochemistry and Western blot analysis data revealed the hemoxygenase-1 (HO-1) was induced by the addition of FK506 in Jurkat cells. Induction of CoPP, HO-1 inducer, resulted in decreased intracellular H₂O₂ and NO concentrations. Instead ZnPP, an HO-1 competitive inhibitor did it reversely. In addition, ZnPP regulates iNOS protein synthesis by inhibition of HO-1. Conclusion: Increase of HO-1 expression would induce to decrease the intracellular H₂O₂ and NO concentrations. Also, HO-1 would regulate iNOS protein synthesis. Consequently, we can expect the regulation of HO-1 expression with concomitants use of FK506 to suppress organ rejection phenomenon by enhancing apoptosis.

腫瘍의 화학요법과 放射線療法의 副作用에 대한 韓方藥物療法

곽계호,김성훈,임낙철 대한동의병리학회 1995 동의생리병리학회지 Vol.9 No.2

연구배경 : 국내 질병에 의한 사망률중 암에 의한 것이 최상위를 차지하고 있으며 또한 그 비율이 점차 증가추세에 있다. 지금까지 국내외에서 암의 예방과 치료법에 대하여 대규모 연구가 진행되어 많은 함암제가 개발되었으나 여러 부작용이 나타나면서 최근에는 암의 치료를 극대화하면서 여러 항암치료의 부작용을 감소시키기 위한 생약 및 한약에 대한 연 구가 활발히 진행되고 있어, 저자는 향후한약을 이용한 실험연구와 임상에 기여하고자 제 관련 문헌을 정리 조사하여 보고하게 되었다. 방법 : 한의학에서의 연구동향과 암치료에 널리 활용되고 있는 화학료법 및 방사선료법의 부작용감소를 위한 한방약물료법에 관해 한의학의 중요서적과 잡지를 중심으로 정리하고 비교 고찰하였다. 결과 : 종양치료에 활용된 치법으로는 부정법(扶正法)과 거사법(祛邪法)으로 크게 나눌수 있는데 부정법에 활용된 약물로는 삼류와 백출, 황기, 복령, 감초, 자감초, 당귀, 백작약, 생지황, 숙지황 등의 약물이 선용되었으며, 거사약물로는 백화사설초, 반지련, 석상백외 18종 이 주로사용되었고, 종양치료에 실험 및 임상에서 유효하였던 처방은 화류탕등을 비롯 다 양한 처방이 면역 기능을 증강시켜 부작용감소 및 병용투여에서 상승효과를 나타냈다. To be helpful to the treatment of cancer with oriental medicine, we got clinical report together and analyzed the data. The results were obtained as follows; 1. The treating methods could be summarized as two methods that were reinforcing vital energy and eliminating harmful Qi; The methods of reinforcing vital energy were reinforcing spleen and increasing Qi; reinforcing spleen and harmonize stomach, aid virility and nourishing blood, nourishing stomach and incresing body fluid, reinforcing kidney and strength the basic energy, warmth kidney and aid virility. The other methods of eliminating poison were transforming pathological fluid and softening activating blood, transforming pathological blood, guiding Qi, take off and harmonize harmful body fluid, disperse Qi and dry the dampness, transforming pathological blood and harmonize moisture. 2. The oriental herbs used for reinforcing vital energy were Radix Ginseng, Codonops is Pilosulae Radix, Radix Pseudostellariae, Adenophorae Radix, Scrophulariae Radix, Astractylodis Macrocephalae Rhizoma, Astragali Radix, Poria, Gylcyrrhizae Radix, Angelicae Gigantis Radix, Paeonilae Radix Alba, Rehmanniae Radix and used for eliminating harmful Qi were Oldenlindiae Diffusae Herba, Herba Scutellariae Barbatae, Paridis Rhizoma, Verbenae Herba, Smilacis Chlnae Rhizoma, Radix Semiaquilegiae, Houttuynae Herba et. 3.The useful prescriptions used for cancer therapy were Hwalyutang Yukmijihwangtang, Yonghosinchonghwan, Bokbangkyokolamtang, Yikki-sojeungbang, Samchobujeonhangamchungjye and Bokbangkyokolamtang, Yikksojeungbang were reported to be effective in immunodulatory reaction and Bokbangsamsahapjye, Sibjeondaeboang, Gagyulpijukyeotang, Hwayebokwontang showed the combined treatment with anticancer drug was effective and Hangamlyeong(抗癌靈) was effective for pain caused by cancer. 4.The useful antitumor effective prescriptions in experimental investi-sation were Yikikeonbihabjye, Keon biiksinchungjye, Bisinbang, Sankyeol pyeolpyeon, Hangamdanhyeokkeombokbang, Janglyupyeong, HangamIIho, Keonbiyikitang, Yikkiisojingbang, Sakunjatang, Bokbanggyongkyejusayek, Bujeonghangambang, Bokbangjungyakjusayek, Yukmijihwangtang, Samchobujeonghangamchungjae, Samkijusayek, Yikkiyanghyeolbowonkyonang, Samyongtang-Bojungikkitang, Soyinibo-jungikang among them Bisinbang, keonbiiksinchungjye, Janglyup-yeong, Keonbiyikitang, Yikkisojingbang, Yukmijihwangtang, Keumku-esinkihwan were showed antitumor effect by regulate immunity function. 5. The main treatment for the side effect by chemotheraphy was reinforcing Qi, spleen and harmonize stomach and Omisodokyeum, Hyangsaynkkunjatang, Yijintang, Kamlosodokdan, Silbiyeum, Hageojye-johwan, Sibjeondaebotang, Olyeongsan, Sobanhakaboklyeongtang, seung-baektang, Bisinbang, Keonbiyiksinbang, Sambaekdangjang, Bokbang-samsahabjye, Keonbiyikitang, Janganseungbaekchungjye, Kobonkeoe I ho, Bokihwawejikubang, Bokbangsaenghyeolyeng, Keonbiyikkibosinbang, Hwangbaekhabjye, Yukkunjatang, Seonbokdaejatang, Bangdoktang, Hwangjeongomibang, seunghyeoltang, Kilpijukyetang, Sakunjatang, Yikkibohy-eolkeonbitang, Kangyeoktang,Samkijusayaek, Bujeongseungbaektang, Yukmijihwanghwan, were suggested for the side effect by chemotheraphy. 6. The main treatment for the side effect by radiotheraphy was increasing Yin and clarifying heat, Sasammaekmundongtang, Boyeum-jeon, Maekmundongyeum, Dangkwibohyeltang, Paljintang, Bowontang, Yukkunjatang, Pyeongwesan, samintang, Kwakrakhalywongtang, Cheon-keumwekyeongtang, Sohamhamhyungtang, Paljeongsan, Sokyeoyeumja, Kalkeunkeumlyeongtang, Yeonlitang, Yilkwanjeon Oklyeojeon, Yukmijihwangtang, Hwangiyeontang, Hwanglyeonhaedoktang, Yangyeumcheongpyeoko, Yidongko, Chuliko, Cheongpyeotang, Jayeumkanghwatang, Hangbiyinam I ho, Hangbiyinam II ho, Hangbiyinam III ho, Hangbyinam IV ho, Jukyeoseokkotang, Samsatang I ho, Samsatang II ho, Samsatang, Bokbanggsaenghyeollyeng, Bujeongsaengjintang, Yikkiyangyeumbang, Sinlibpyeon, Sakunjatang, Sakunjatang, Kobonyik-kitang, keoehaedoktang, Bujeongjeunghyohabjye, were suggested for the side effect by radiotheraphy. 7. The useful prescription for the side effect by chemotheraphy and radiotherapy in experimental investigation were Hwangbaekhabjye, Sakunjatang, Yikkibohyeolkeonbitang, Bujeongsaengjintang, Samchobu

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.

류건휴의 『溪湖學的』과 『異學集辨』에 나타난 후기 영남학파의 ‘도통’과 ‘벽이단’ 의식

이상호(Lee Sang-ho) 한국동양철학회 2009 동양철학 Vol.0 No.32

이 논문은 19세기 초 호파계열에서 병호시비를 주도했던 류건휴의 『계호학적』과 『이학집변』을 중심으로, 후기 영남학인들의 도통과 이단에 대한 인식을 살펴보고 있다. 특히 이 두 책은 이황의 적통이 누구에게 이어졌는지를 중심으로 진행된 병호시비의 중요한 이론적 근거가 되었던 것으로, 향후 정재학파의 이론적 토대에 중요한 영향을 끼쳤다. 『계호학적』은 이황의 도통이 이상정에게 있다는 사실을 밝히기 위해 이상정의 어록과 문집 내용을 발췌하여 이황의 입장과 비교할 수 있도록 편집한 책이다. 『근사록』과 같은 편집체계를 통해 이상정의 철학이 이황과 완전하게 일치한다는 사실을 드러내려고 했던 것이다. 이에 비해 『이학집변』은 퇴계학의 정통성을 공고히 하기 위한 작업으로서의 성격을 가지고 있다. 이단에 대한 강한 비판을 통해 주자학 내에서의 퇴계학 정통성을 공고히 하려고 했던 것이다. 이와 같은 류건휴의 작업은 당시의 시대적 상황 속에서 ‘도통 확립의 필요성’과 이단 비판을 통한 ‘정학正學 보존의 노력’에 따른 것으로, 이를 통해 우리는 후기 영남학파의 인물들이 무엇을 중심으로 생각하면서 살아갔는지를 잘 알 수 있다. 정치적으로 이미 중앙으로부터 소외된 상태에서 그들 스스로의 자긍심과 자부심을 만들어 내고 있으면, 동시에 스스로 주자학적 정통에서 있음을 밝힘으로써 학문적인 우위성을 확보하려는 노력의 일환인 것이다. 더불어 기호학파로부터 받을 수 있는 조금의 의심에 대해서도 철저하게 불식시켜 나감으로써, 자신들 학문의 정통성을 드러내려고 했던 것이다. The purpose of this essay is to examine cognizance of 'taotung(道統: Legitimate Transmission of the Orthodoxy)' and heresy of late Yeungnam School, focused on Ryu, Geon-Hyu's "Gyeho-hakjeok(溪湖學的)" and "Yihak-jipbyeon(異學集辨)", which took the lead in Byungho Dispute(屛虎是非) in Ho faction of the early 19th century. Specially, for the next, these books affected theoretical foundation of Jeongjae School, become theoretical foundation of ByungHo Dispute which is gone on problem of whom the main line of descent of Lee Hwang is continued. Geyho-hakjeok is the book which we can compare to standpoint of Lee Hwang extracting contents of collection of works and quotations of Lee, Sang-Jeong by the book, to define the fact there is the main line of descent of Lee Hwang in Lee, Sang-Jeong. Through a system of edit like Keunsarok(『近思錄』), we can see that philosophy of Lee, Sang-Jeong perfectly correspond with it of Lee Hwang. In comparison, Yihak-jipbyeon has character as work for solidifying legitimate of Toegye's Philosophy. It is to solidify legitimate of Toegye's Philosophy in Zhuxi Studies through strong criticism about heresy. These works of Ryu, Geon-Hyu is caused by 'effort of preservation of Righteousness Philosophy(正學)' through 'necessity of establishing Taotung' and criticism of heresy, on this wise, we can see about what persons of Yeungnam School thought and lived. They make own self-esteem and pride in politically a shunned situation from the central government, at the same time, this is part of effort to secure scientific superiority, by defining that which is on legitimacy of Zhuxi Studies; besides, they was going to reveal legitimacy of own science, by eliminating a little suspicion from kiho School(畿湖學派).

N-acetyl cysteine inhibits H2O2-mediated reduction in the mineralization of MC3T3-E1 cells by down-regulating Nrf2/HO-1 pathway

( Daewoo Lee ),( Sung Ho Kook ),( Hyeok Ji ),( Seung Ah Lee ),( Ki Choon Choi ),( Kyung Yeol Lee ),( Jeong Chae Lee ) 생화학분자생물학회(구 한국생화학분자생물학회) 2015 BMB Reports Vol.48 No.11

There are controversial findings regarding the roles of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway on bone metabolism under oxidative stress. We investigated how Nrf2/HO-1 pathway affects osteoblast differentiation of MC3T3-E1 cells in response to hydrogen peroxide (H2O2), N-acetyl cysteine (NAC), or both. Exposing the cells to H2O2 decreased the alkaline phosphatase activity, calcium accumulation, and expression of osteoblast markers, such as osteocalcin and runt-related transcription factor-2. In contrast, H2O2 treatment increased the expression of Nrf2 and HO-1 in the cells. Treatment with hemin, a chemical HO-1 inducer, mimicked the inhibitory effect of H2O2 on osteoblast differentiation by increasing the HO-1 expression and decreasing the osteogenic marker genes. Pretreatment with NAC restored all changes induced by H2O2 to near normal levels in the cells. Collectively, our findings suggest that H2O2-mediated activation of Nrf2/HO-1 pathway negatively regulates the osteoblast differentiation, which is inhibited by NAC. [BMB Reports 2015; 48(11): 636-641]