A molecular cascade showing nitric oxide-heme oxygenase-1-vascular endothelial growth factor-interleukin-8 sequence in human endothelial cells.

Pae, Hyun-Ock,Oh, Gi-Su,Choi, Byung-Min,Kim, Young-Myeong,Chung, Hun-Taeg Association for the Study of Internal Secretions 2005 Endocrinology Vol.146 No.5

<P>Heme oxygenase (HO)-1 has been shown to be an important biological target of nitric oxide (NO). NO can induce HO-1 expression and IL-8 production, particularly, in endothelial cells. Interestingly, HO-1 tends to induce the production of vascular endothelial growth factor (VEGF) that is involved in endothelial IL-8 syntheses. Whether HO-1 expression by NO may provide a link with IL-8 or VEGF synthesis was investigated in human umbilical vein endothelial cells (HUVECs). The NO donor S-nitroso-N-acetyl-penicillamine (SNAP) dose-dependently increased IL-8 and VEGF productions and HO-1 expression in HUVECs. Transfection with either HO-1 small interfering RNA or HO-1 antisense oligodeoxynucleotide abrogated the ability of SNAP to induce HO-1 expression and IL-8 and VEGF productions. Both pharmacological induction and gene transfer of HO-1 directly induced IL-8 and VEGF productions. Anti-VEGF neutralizing antibody blocked SNAP-mediated IL-8 production and VEGF itself induced IL-8 production, whereas anti-IL-8 neutralizing antibody had no effect on VEGF production in SNAP-treated HUVECs. Neither anti-VEGF nor anti-IL-8 antibodies influenced SNAP-induced HO-1 expression. Moreover, neither VEGF nor IL-8 showed an additive effect on SNAP-induced HO-1 expression. HO-1 transfection had no significant effect on productions of other CXC chemokines, such as growth-related oncogen-alpha and epithelial neutrophil activation peptide-78. Taken together, these results provide a molecular cascade showing NO-HO-1-VEGF-IL-8 sequence in human endothelial cells.</P>

Subtle Interplay of Endogenous Bioactive Gases (NO, CO and H2S) in Inflammation

Hyun-Ock Pae,이용철,Eun-Kyeong Jo,정헌택 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.8

Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) constitute a unique class of mediators which play important roles in maintaining the homeostasis of biological systems. They have many common features: they 1) are small gaseous molecules; 2) freely penetrate the cell membranes to produce cell signaling in a receptor-independent manner; 3) are synthesized endogenously on demand; 4) are rapidly degraded after their release; 5) have specific cellular and molecular targets; 6) work together with each other at many levels. The common roles of NO, CO and H2S appear to include the regulation of vascular homeostasis and central nervous system function, but they also play additional roles in inflammation. This review will focus on the nature of possible interaction of NO with CO or H2S in inflammatory states, with a brief description of roles of each of these gaseous molecules in inflammation.

Heme oxygenase-1 attenuates contact hypersensitivity induced by 2,4-dinitrofluorobenzene in mice.

Pae, Hyun-Ock,Ae Ha, Young,Chai, Kyu-Yun,Chung, Hun-Taeg Marcel Dekker 2008 IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY Vol.30 No.2

<P>Heme oxygenase (HO)-1 may have an important role in the resolution of T cell-mediated inflammation. The authors elucidated the role of the anti-inflammatory HO-1 in the pathogenesis of skin inflammation, using a mouse contact hypersensitivity (CHS) induced by 2,4-dinitrofluorobenzene (DNFB). Ear swelling was induced by challenge with DNFB, accompanied by infiltration of inflammatory cells in the challenged ear skin. DNFB challenge induced low levels of HO-1 mRNA and protein expression. Ear swelling induced by DNFB challenge was significantly reduced by topical treatment with cobalt protoporphyrin IX (CoPP), a HO-1 inducer, but exaggerated by blockage of HO-1 activity with tin protoporphyrin IX (SnPP), a HO-1 inhibitor. Similarly, the number of infiltrated cells in DNFB-challenged ear skin were reduced by CoPP but increased by SnPP. Our findings suggest that HO-1 plays an important role in CHS and is an important pharmacological target for the treatment of CHS.</P>

Heme Oxygenase-1 : Its Therapeutic Roles in Inflammatory Diseases

Pae, Hyun-Ock,Chung, Hun-Taeg The Korean Association of Immunobiologists 2009 Immune Network Vol.9 No.1

Heme oxygenase (HO)-1 is an inducible enzyme that catalyzes the first and rate-limiting step in the oxidative degradation of free heme into ferrous iron, carbon monoxide (CO), and biliverdin (BV), the latter being subsequently converted into bilirubin (BR). HO-1, once expressed during inflammation, forms high concentrations of its enzymatic by-products that can influence various biological events, and this expression is proven to be associated with the resolution of inflammation. The degradation of heme by HO-1 itself, the signaling actions of CO, the antioxidant properties of BV/BR, and the sequestration of ferrous iron by ferritin all concertedly contribute to the anti-inflammatory effects of HO-1. This review focuses on the anti-inflammatory mechanisms of HO-1 actions and its roles in inflammatory diseases.

Integrative Survival Response Evoked by Heme Oxygenase-1 and Heme Metabolites

Pae, Hyun-Ock,Kim, Eun-Cheol,Chung, Hun-Taeg the Society for Free Radical Research Japan 2008 Journal of clinical biochemistry and nutrition Vol.42 No.3

<P>Heme oxygenase (HO) catalyzes the rate-limiting step in heme degradation to produce carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently converted to bilirubin by its reductase, and iron is recycled for heme synthesis. The inducible HO isoform, HO-1, is involved in the protection of multiple tissues and organs. The mechanism of protective actions of HO-1 has not been completely elucidated, but recent evidence suggests that one or more of heme metabolites can mediate the protective effects of HO-1. Particularly, CO mimics the antioxidant, anti-inflammatory, anti-apoptotic and antiproliferative actions of HO-1. Many of these effects of CO depend on the production of cyclic guanosine monophosphate (cGMP), and the modulation of mitogen-activated protein kinase (MAPK) pathways. The transcription factors, including nuclear factor E2-related factor-2 (Nrf2), and their upstream kinases, including MAPK pathway, play an important regulatory role in HO-1 expression by dietary antioxidants and drugs. This review attempts to concisely summarize the molecular and biochemical characteristics of HO-1, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by dietary antioxidants and drugs. In addition, the cytoprotective roles of HO-1 shall be discussed from the perspective of each of the metabolic by-products.</P>

Heme Oxygenase-1 : Its Therapeutic Roles in Inflammatory Diseases

Pae, Hyun-Ock,Chung, Hun-Taeg 대한면역학회 2009 Immune Network Vol.9 No.1

Heme oxygenase (HO)-1 is an inducible enzyme that catalyzes the first and rate-limiting step in the oxidative degradation of free heme into ferrous iron, carbon monoxide (CO), and biliverdin (BV), the latter being subsequently converted into bilirubin (BR). HO-1, once expressed during inflammation, forms high concentrations of its enzymatic by-products that can influence various biological events, and this expression is proven to be associated with the resolution of inflammation. The degradation of heme by HO-1 itself, the signaling actions of CO, the antioxidant properties of BV/BR, and the sequestration of ferrous iron by ferritin all concertedly contribute to the anti-inflammatory effects of HO-1. This review focuses on the anti-inflammatory mechanisms of HO-1 actions and its roles in inflammatory diseases.

1,2,3,4,6-penta-O-galloyl-beta-D-glucose up-regulates heme oxygenase-1 expression by stimulating Nrf2 nuclear translocation in an extracellular signal-regulated kinase-dependent manner in HepG2 cells.

Pae, Hyun-Ock,Oh, Gi-Su,Jeong, Sun-Oh,Jeong, Gil-Saeng,Lee, Bok-Soo,Choi, Byung-Min,Lee, Ho-Sub,Chung, Hun-Taeg WJG Press 2006 WORLD JOURNAL OF GASTROENTEROLOGY Vol.12 No.2

<P>To examine the potency of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) as a hepatic heme oxygenase-1 (HO-1) inducer and its regulation in HepG2 cells.</P>

항 백혈병작용에 관련된 천연물의 자료조사

배현옥,임창경,장선일,한동민,안원근,윤유식,전병훈,김원신,윤용갑 대한동의병리학회 2003 동의생리병리학회지 Vol.17 No.3

人蔘, 虎杖根, 常山 등에서 분리한 성분들이 HL60, HL-60, Jurkat, Molt-4에 대한 억제작용이 있는 것으로 조사되었고, 益母草의 Leonunrine, 大靑葉의 Indirubin, 天門冬의 Aspargus polysaccharide A.B.C.D, 百合의 Colchicnamile, 益母草의 Leonunrine, 山豆根, 紫草根 추출물이 여러유형의 백혈병 환자에 대한 백혈병 억제효과가 있는 것으로 조사되었으며, mouse의 P388, L1210, L615, L120, S-180 등에 항 백혈병 효과가 있는 것으로는 莞花, 노회, 遠志, 吳茱萸, 巴豆, 雷公藤, 石蒜, 白朮, 丹蔘, 山藥, 牧丹皮, 靑黛, 甘草, 當歸에서 분리한 성분들이 있으며 白屈菜, 馬錢子, 가시오가피, ??草 축출물들이 동물실험에서 항암작용이 있는 것으로 조사되었다. 또 천연물에서 분리한 성분이 항백혈병 작용이 있는것으로는 ginsenoside Ro, ginsenoside Rh2, Emodin, Yuanhuacine, Aleemodin, phorbocdiester, Triptolide, Homolycorine, Atractylol, Colchicnamile, Paeonol, 당귀다당체, Aspargus, polysaccharideABCD, Indirubin, Leonunrine, Acinosohic acid, Trichosanthin, Ge 132, Schizandrin, allicin, Indirubin, cmdiumlactone chuanxiongol, 18A glycyrrhetic acid, Kansuiphorin A, 13 oxyingenol Kansuiphorin B 등이 조사되었고 추출물이 항 백혈병 작용이 있는 것으로는 遠志, 吳茱萸, 白屈菜, 大黃, 山豆根, 馬錢子, 가시오가피, 천초 등이 조사되었다. According to the Leukemia and Lymphoma Society, leukemia is a malignant disease (cancer) that originates in a cell in the marrow. It is characterized by the uncontrolled growth of developing marrow cells. These are two major classifications of leukemia: myelogenous or lymphocytic, which can each be acute or chronic. The terms myelogenous or lymphocytic denote the cell type involved. Thus, four major types of leukemia are: acute or chronic myelogenous leukemia and acute or chronic lymphocytic leukemia. Leukemia, lymphoma and myeloma are considered to be related cancers because they involve the uncontrolled growth of cells with similar function and origins. The diseases result from an acquired (not inherited) genetic injury to the DNA of a single cell, which becomes abnormal (malignant) and multiplies continuously. In the United States, about 2,000 children and 27,000 adults are diagnosed each year with leukemia. Treatment for cancer may include one or more of the following: chemotherapy, radiation therapy, biological therapy, surgery and bone marrow transplantation. The most effective treatment for leukemia is chemotherapy, which may involve one or a combination of anticancer drugs that destroy cancer cells. Specific types of leukemia are sometimes treated with radiation therapy or biological therapy. Common side effects of most chemotherapy drugs include hair loss, nausea and vomiting, decreased blood counts and infections. Each type of leukemia is sensitive to different combinations of chemotherapy. Medications and length of treatment vary from person to person. Treatment time is usually from one to two years. During this time, your care is managed on an outpatient basis at M. D. Anderson Cancer Center or through your local doctor. Once your protocol is determined, you will receive more specific information about the drug(s) that will be used to treat your leukemia. There are many factors that will determine the course of treatment, including age, general health, the specific type of leukemia, and also whether there has been previous treatment, there is considerable interest among basic and clinical researchers in novel drugs with activity against leukemia, the vast history of experience of traditional oriental medicine with medicinal plants may facilitate the identification of novel anti leukemic compounds. In the present investigation, we studied 31 kinds of anti leukemic medicinal plants, which its pharmacological action was already reported through many experimental articles and oriental medical book: 「pharmacological action and application of anticancer traditional chinese medicine」 In summary : Used leukemia cellline are HL60, HL-60, Jurkat, Molt-4 of human, and P388, L-1210, L615, L-210, EL-4 of mouse. 31 kinds of anti leukemic medicinal plants are Panax ginseng C.A Mey; Polygonum cuspidatum Sieb, et Zucc; Daphne genkwa Sieb, et Zucc; Aloe ferox Mill; Phorboc diester; Tripterygium wilfordii Hook .f.; Lycoris radiata(L Her)Herb; Atractylodes macrocephala Koidz; Lilium brownii F.E. Brown Var; Paeonia suffruticosa Andr; Angelica sinensis (Oliv.) Diels; Asparagus cochinensis (Lour.)Merr; Isatia tinctoria L; Leonurus heterophyllus Sweet; Phytolacca Roxb; Trichosanthes kirilowii Maxim; Dioscorea opposita Thumb; Schisandra chinensis (Rurcz.)Baill; Auium Sativum L; Isatis tinctoria, L; Ligustisum Chvanxiong Hort;Glycyrrhiza uralensis Fisch; Euphorbia Kansui Liou; Polygala tenuifolia Wild; Evodia rutaecarpa (Juss.) Benth; Chelidonium majus L; Rumax madaeo Mak; Sophora Subprostmousea Chunet T.ehen; Strychnos mux-vomical; Acanthopanax senticosus (Rupr.et Maxim.)Harms; Rubia cordifolia L. Anti leukemic compounds, which were isolated from medicinal plants are ginsenoside Ro, ginsenoside Rh2, Emodin, Yuanhuacine, Aleemodin, phorbocdiester, Triptolide, Homolycorine, Atractylol, Colchicnamile, Paeonol, Aspargus polysaccharide A.B.C.D, Indirubin Leonunrine, Acinosohic acid, Trichosanthin, Ge 132, Schizandrin, allicin, Indirubin, cmdiumlactone chuanxiongol, 18A glycyrrhetic acid, Kansuiphorin A 13 oxyingenol Kansuiphorin B. These investigation suggest that it may be very useful for developing more effective anti leukemic new dregs from medicinal plants.

CHEMILUMINESCENCE STUDIES ON THE BIOLOGICAl, INTERACTION BETWEEN SUPEROXIDE ANION RADICAL AND NITRIC OXIDE PRODUCED BY PHORBOI, ESTER-STIMULATED RAW264.7 MACROPHAGES

Lee, Hong,Pae, Hyun-Ock,Jun, Chang-Duk,Kwak, Hyun-Jeong,Park, Rae-Kil,Yoo, Ji-Chang,Lee, Seog-Jae,Kim, Myung-Sun,Kim, Hae-Song,Choi, Byung-Min,Chung, Hun-Taeg Korean Society of Photoscience 1997 Journal of Photosciences Vol.4 No.2

The rapid and spontaneous interaction between superoxide anion radical and nitric oxide to yield the potent oxidants. peroxynitrite artion and peroxynitrous acid, was investigated in phorbol myristate acetate(PMA)-stimulated RAW264.7 macrophases by means of lucigenin- or luminol-enhanced chemiluminescence method. When RAW264.7 macrophages were stimulated by PMA. peroxynitrite-induced chemiluminescence was clearly observed. To prove observed chemiluminescencc due to the reaction between superoxide anion radical and nitric oxide produced by RAW264.7 macrophases, N-nitrosoglutathione (GSNO), a nitric oxide-releasing compound. superoxide dismutase(SOD), an enzyme removing superoxide anion radical by dismutating superoxide artion radical to hydrogen peroxide, and N-acethyl cysteine(NAC), a scarvenging reagent both superoxide artion radical and nitric oxide, were added in the cell system. Peroxynitrite- induced chemilumincscence was increased by exogenous addition of GSNO. whereas observed chemiluminescence was decreased by SOD and NAC. These results suggest that PMA-stimulated RAW264.7 macrophages produce both superoxide anion radical and nitric oxide to form peroxynitrite.

Kinetic Studies of the Aggregation of 3,3-Dihexyl Oxacarbocyanine onto Poly(styrenesulfonate)

Lee, Hong,Pae, Hyun-Ock 圓光大學校 基礎自然科學硏究所 1996 基礎科學硏究誌 Vol.15 No.1

Poly(styrenesulfonate)(PSS)에서 3,3―Dihexyl oxacarbocyanine(dihexyl―OXA)의 회합에 대한 속도론적 연구를 정지흐름법으로 연구하였다. Dihexyl―OXA의 metachromatic band의 특성적 변화를 stacking 이론으로 설명하였으며, 가능한 stacking mechanism을 제안하였다. 이 mechanism에서 색소분자는 빠르게 고분자의 음이온 잔기와 결합하고, 이어서 결합된 색소분자들이 재분포하여 stacking을 형성한다. The kinetic studies of the aggregation of 3,3'―dialkyl oxacarbocyanine(dihexyl―OXA) onto Poly(styrenesulfonate)(PSS)were studied with stopped―flow measurements. The characteristic changes of metachromatic bands of dihexl―OXA were discussed in view of stacking theory. A mechanism of the stacking was proposed by which a dye molecule binds very rapidly to a site on polyanion, followed by a slow rearrangement of bound dye molecules.