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]

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>

<i>Prunella vulgaris</i> Suppresses HG-Induced Vascular Inflammation via Nrf2/HO-1/eNOS Activation

Hwang, Sun Mi,Lee, Yun Jung,Yoon, Jung Joo,Lee, So Min,Kim, Jin Sook,Kang, Dae Gill,Lee, Ho Sub Molecular Diversity Preservation International (MD 2012 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.13 No.1

<P>Vascular inflammation is an important factor which can promote diabetic complications. In this study, the inhibitory effects of aqueous extract from <I>Prunella vulgaris</I> (APV) on high glucose (HG)-induced expression of cell adhesion molecules in human umbilical vein endothelial cells (HUVEC) are reported. APV decreased HG-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. APV also dose-dependently inhibited HG-induced adhesion of HL-60 monocytic cells. APV suppressed p65 NF-κB activation in HG-treated cells. APV significantly inhibited the formation of intracellular reactive oxygen species (ROS). HG-stimulated HUVEC secreted gelatinases, however, APV inhibited it. APV induced Akt phosphorylation as well as activation of heme oxygenase-1 (HO-1), eNOS, and nuclear factor E2-related factor 2 (Nrf2), which may protect vascular inflammation caused by HG. In conclusion, APV exerts anti-inflammatory effect via inhibition of ROS/NF-κB pathway by inducing HO-1 and eNOS expression mediated by Nrf2, thereby suggesting that <I>Prunella vulgaris</I> may be a possible therapeutic approach to the inhibition of diabetic vascular diseases.</P>

Sulforaphane protects against acetaminophen-induced hepatotoxicity

Noh, Jung-Ran,Kim, Yong-Hoon,Hwang, Jung Hwan,Choi, Dong-Hee,Kim, Kyoung-Shim,Oh, Won-Keun,Lee, Chul-Ho Elsevier 2015 Food and chemical toxicology Vol.80 No.-

<P><B>Abstract</B></P> <P>Oxidative stress is closely associated with acetaminophen (APAP)-induced toxicity. Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced tissue injury. This study investigated whether sulforaphane (SFN), as a HO-1 inducer, plays a protective role against APAP hepatotoxicity <I>in vitro</I> and <I>in vivo</I>. Pretreatment of primary hepatocyte with SFN induced nuclear factor E2-factor related factor (Nrf2) target gene expression, especially HO-1 mRNA and protein expression, and suppressed APAP-induced glutathione (GSH) depletion and lipid peroxidation, which eventually leads to hepatocyte cell death. A comparable effect was observed in mice treated with APAP. Mice were treated with 300 mg/kg APAP 30 min after SFN (5 mg/kg) administration and were then sacrificed after 6 h. APAP alone caused severe liver injuries as characterized by increased plasma AST and ALT levels, GSH depletion, apoptosis, and 4-hydroxynonenal (4-HNE) formations. This APAP-induced liver damage was significantly attenuated by pretreatment with SFN. Furthermore, while hepatic reactive oxygen species (ROS) levels were increased by APAP exposure, pretreatment with SFN completely blocked ROS formation. These results suggest that SFN plays a protective role against APAP-mediated hepatotoxicity through antioxidant effects mediated by HO-1 induction. SFN has preventive action in oxidative stress-mediated liver injury.</P> <P><B>Highlights</B></P> <P> <UL> <LI> SFN pretreatment increases the cell viability against APAP-induced toxicity. </LI> <LI> SFN pretreatment protects depletion of cellular GSH after APAP treatment. </LI> <LI> SFN pretreatment enhances Nrf2 target gene expression, especially HO-1 after APAP treatment. </LI> <LI> SFN has protective effect against APAP overdose-induced liver injury <I>in vivo</I> model as well. </LI> </UL> </P>

Anti-Proliferative Effect of an Aqueous Extract of <i>Prunella vulgaris</i> in Vascular Smooth Muscle Cells

Hwang, Sun Mi,Lee, Yun Jung,Lee, Yong Pyo,Yoon, Jung Joo,Lee, So Min,Cha, Jeong Dan,Choi, Kyung Min,Kang, Dae Gill,Lee, Ho Sub Hindawi Publishing Corporation 2013 Evidence-based Complementary and Alternative Medic Vol.2013 No.-

<P>The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenic factor of vascular disorders such as diabetic atherosclerosis. We have reported the anti-inflammatory effect of an aqueous extract from <I>Prunella vulgaris</I> (APV) in vascular endothelial cell. In the present study, APV exhibited inhibitory effects on high glucose-stimulated VSMC proliferation, migration, and invasion activities, inducing G<SUB>1</SUB> cell cycle arrest with downregulation of cyclins and CDKs and upregulation of the CKIs, p21<SUP>waf1/cip1</SUP> and p27<SUP>kip1</SUP>. Furthermore, APV dose dependently suppressed the high glucose-induced matrix metalloproteinase activity. High glucose-induced phosphorylation of ERK, p38 MAPK, was decreased by the pretreatment of APV. NF-<I><I>κ</I></I>B activation by high glucose was attenuated by APV, as an antioxidant. APV attenuated the high glucose-induced decrease of nuclear factor E2-related factor-2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression. Intracellular cGMP level was also increased by APV treatment. These results demonstrate that APV may inhibit VSMC proliferation via downregulating ROS/NF-<I><I>κ</I></I>B /ERK/p38 MAPK pathways. In addition, APV has a beneficial effect by the interaction of Nrf2-mediated NO/cGMP with HO-1, suggesting that <I>Prunella vulgaris</I> may be useful in preventing diabetic atherosclerosis.</P>

A Decision Model for Advertising Expense: From the Perspective of the Blockholder's Private Benefits

Hwang,Joon-Ho,Chun,Se-Hak 한국상품학회 2009 商品學硏究 Vol.27 No.2

This paper examines how the size of private benefits of large owners, measured using block premium, affects changes in advertising expense of the company. If large owners enjoy private benefits through engaging in pet projects, it will result in increased advertising expense. On a sample of 130 firms whose blocks of shares are traded in the U.S., we show that the magnitude of private benefits is not associated with changes in advertising expense.

황토 기포콘크리트를 이용한 식생용 인공토양골재의 이화학적 특성 평가

황인혁(Hwang, In-Hyuk),이경호(Lee, Kyung-Ho),양근혁(Yang, Keun-Hyeok) 대한건축학회 2016 大韓建築學會論文集 : 構造系 Vol.32 No.10

This study examined the practical application of cement foamed concrete with natural hwang-toh to develop artificial soil aggregates for vegetation. The soil aggregates with the particle size between 1 and 10 mm were produced from the fragmentation of the foamed concrete. The physiochemical properties, including apparent density, pH value, particle distribution, coefficient of permeability, EC, CEC, C/N and total amount of organic matter, of the produced soil aggregates were tested and compared with the requirements for vegetation recommended in the landscape specification. The produced artificial soil aggregates achieved the apparent density, coefficient of permeability, and CEC value satisfying the requirements of the landscape specification, whereas pH, EC, C/N values, and total amount of organic matter of the soil aggregates did not satisfy the specification requirements. To utilize the foamed concrete as soil aggregates for vegetation, the additional approaches such as compulsory neutralization and the addition of organic fertilizers would be required for appropriate values of EC, CEC, and C/N.

Platycodon grandiflorum root-derived saponins attenuate atopic dermatitis-like skin lesions via suppression of NF-kB and STAT1 and activation of Nrf2/ARE-mediated heme oxygenase-1

( Jae Ho Choi ),( Sun Woo Jin ),( Eun Hee Han ),( Bong Hwan Park ),( Hyung Gyun Kim ),( Tilak Khanal ),( Yong Pil Hwang ),( Minh Truong Do ),( Hyun Sun Lee ),( Young Chul Chung ),( Hee Suk Kim ),( Tae 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0

Purpose: The consequences of precipitously rising allergic skin inflammation rates worldwide have accelerated the risk of atopic dermatitis (AD). Natural product-based agents with good efficacy and low risk of side effects offer promising prevention and treatment strategies for inflammation-related diseases. We have already reported that Platycodon grandiflorum root-derived saponins (Changkil saponins, CKS) have many pharmacological effects, including anti-inflammatory and anti-allergic effects, but its influence on AD remains unclear. Therefore, we evaluated the inhibitory effect of CKS, mainly platycodin D, on AD-like skin symptoms in mice and the possible mechanisms in cells. Methods: Mice were sensitized and challenged with 2,4-dinitrochlorobenzene (DNCB). Four weeks after challenge, mice were treated with oral administration of CKS for 4 weeks. In addition, cells were used to evaluate the effect of CKS, mainly platycodin D, on the TARC expression regulated mechanism. Results: CKS attenuated DNCB-induced dermatitis severity, serum levels of IgE and TARC, and mRNA expression of TARC, TNF-α, IFN-γ, IL-4, IL-5, and IL-13 in mice. Histopathological examination showed reduced thickness of the epidermis/dermis and dermal infiltration of inflammatory cells and mast cells in the ears. Moreover, CKS and platycodin D inhibited TNF-α/IFN-γ-induced TARC expression through the suppression of NF-κB and STAT1 and induction of Nrf2/ARE-mediated hemeoxygenase-1 (HO-1) expression in cells. Conclusion: We suggest that CKS and platycodin D inhibited the development of AD-like skin symptoms by regulating cytokine mediators and may be an effective alternative therapy for AD-like skin symptoms.ⓒ2014 Elsevler Gmbh. All rights reserved.

머리염색이 인체에 미치는 영향

윤형식,황성호,이현륭,김수호,박연석,권낙현,정호진,김동훈,노현주,홍성호,박병찬,이관,정해관 東國大學校醫學硏究所 2002 東國醫學 Vol.9 No.1

일상생활에서 모발염색은 흔히 접할 수 있는 미용의 한 종류로 특히 젊은층을 중심으로 폭발적으로 유행하고 있다. 염색을 위항 사용하는 약제는 표백제와 발색제 등 각종 화학약품이 사용되고 있으나 이로 인한 건강장해에 대한 연구는 그리 많지 않다. 저자들은 염색이 인체의 모발건강에 미치는 영향을 파악하기 위하여 염색과 관련된 주관적 증상과 모발의 변화에 대한 실험적 연구를 시행하였다. 동국대학교 경주 캠퍼스 재학생 80명을 대상으로 설문조사를 시행하여 염색 유 ·무 및 염색 후에 경험한 증상에 대해 설문 조사하였고, 의과대학 재학생 46명을 대상으로 피부 반응 테스트를 실시하였다. 또한 염색 전후의 모발 탄성도를 측정하였고 모발의 상태를 파악하기 위해 전자 현미경검사를 실시하였다. 설문조사 결과 염색 전에 비하여 염색 후 안구혼탁, 안구건조, 시력저하, 발진 및 접촉성 피부염, 모발손상, 모근손상 등의 증상을 더 많이 경험한다고 호소하였다(p<0.05). 모발손상과 모근손상은 헤어드라이어 사용 빈도에 따라 증가하는 것으로 조사되었다(p<0.05). 피부반응검사에서 가려움증이 가장 많은 증상이었으며 이는 여성보다는 남성에서 높은 것으로 조사되었다. 염색 전후의 모발장력은 염색 전 134.5±10.37g, 염색 128.0±30.69g, 염색 이틀 후 112.5±19.69g으로 나타났다. 염색 전후의 모발의 전자현미경 케라틴 층이 현저히 감소하고 모발이 가늘어지는 차이를 보였다. 염색은 모발손상, 모발 케라틴 손상 및 모근 손상, 발진 및 접촉성 피부반응, 안구혼탁, 안구건조, 시력 저하를 유발한다. 따라서 염색약으로 인한 손상에 대한 주의와 예방이 필요하다고 생각한다. 예방대책으로 염색 전 피부테스트를 통한 적합성 여부를 판단하는 것이 필요하며 가급적 염색을 피하는 것이 좋을 것이다. 염색약에 발암물질이 포함되어있다는 보고도 있어 염색 제조사의 철저한 실험과 염색 물질의 선별이 염색으로 인한 부작용을 최소화하는데 중요한 역할을 할 것이다. Hair coloring has became one of the most popular cosmetic activities to younger generations during last decade. However, there are few studies on the health effect of widespread use of chemical dyes. This study was conducted to study the effects of hair coloring dye on hair and other systems. We conducted a questionnaire survey of 80 persons in Kyongju campus, Dongguk University. We have done open patch skin test on 46 medical students. We also conducted scanning electron microscopy to examine the hair strength and structure before and after hair coloring process. Injury of hair and hair bulb, contact dermatitis, turbid eyes, xerophthalmia, and poor visual acuity were the main symptoms complained after hair coloring (p<0.05). Injury of hair and hair bulb were increased by frequency of hair-dryer use(p<0.05). In open patch test, pruritus was complanined by more than half of the subjects. Mean strength of hairs before and after hair coloring was as follows; 134.5 (SD 10.37)g before hair coloring, 128.0 (SD 30.69)g immediately after hair coloring, and 112.5 (SD 19.69)g after two days. The scanning electron microscopic findings of hair surface before and after hair coloring showed decreased keratin layer and thinning of the hair. Hair coloring induces injury to hair, its keratin layer, and hair bulb as well as contact dermatitis, turbid eyes, xerophthalmia, and poor visual acuity. Therefore, we think that precaution is needed in use of hair coloring dye. To prevent complications induced by hair coloring dye, it is necessary, especially to those with allergy or skin disorders, to perform skin test before action and avoid hair coloring whenever possible. Longterm health effects of hairdye should be studied and manufacturing companies should try to minimize complications induced by hair coloring dye.

염증성 피부질환 개선 기능 소재로서 둥근전복(Haliotis discus) 유래 항균펩타이드 Ab4-7의 항염증 효과

최수철 ( Soo-cheol Choi ),서정길 ( Jung-kil Seo ),황준호 ( Joon-ho Hwang ),이기영 ( Ki-young Lee ),이인아 ( In-ah Lee ) 대한화장품학회 2020 대한화장품학회지 Vol.46 No.2

서해안에 서식하는 해양생물인 전복은 항산화 및 항염증 효과가 있으며, 항생제 개발 및 화장품 원료 등 다양한 산업에 활용될 수 있는 잠재력을 가진 자원이다. 본 연구에서 우리는 서해안의 다양한 해양 생물중에서 전복을 선택하였으며, 전복에서 분리한 항균펩타이드(AMP)를 이용하여 항균펩타이드 유도체인 Ab4-7를 규명하고 생리활성을 연구하였다. Ab4-7의 항염증 효능을 확인하기 위해 염증이 유도된 RAW 264.7에 Ab4-7을 처리한 결과, 염증성 사이토카인, TLR4, TNF-α, IL-1β, COX-2, iNOS 등을 억제하고 항산화와 관련된 유전인자인 HO-1의 mRNA 발현을 증가시켰다. Ab4-7의 강력한 항산화 및 항염증 효과를 바탕으로, 염증이 유도된 RAW 264.7 세포에서 Ab4-7이 extrocellular matrix metalloproteinase (ECM) 분해에 관여하여 다양한 염증성 피부질환을 유도하는 유전자인 matrix metalloproteinase (MMPs)를 조절하는 효과를 RT-PCR을 통해 확인하였다. Ab4-7은 강력한 항염증 및 항산화 효과를 가지고 있으며, 항염증 및 항산화 효과를 통한 MMPs 관련 유전인자 조절을 통해 다양한 염증성 피부질환 치료제의 기능성 재료로 활용될 수 있다고 사료된다. Abalone, a marine organism inhabiting the west coast of Korea, has antioxidant and anti-inflammatory effects, and is a resource with potential to be used in various industries such as antibiotic development and cosmetic raw materials. In this study, we chose abalone among various marine lives on the west coast. Antibacterial peptide (AMP) was separated from abalone and its derivative Ab4-7 was identified and its physiological activity was studied. The treatment of Ab4-7 in inflammatory RAW 264.7 to check the anti-inflammatory efficacy nhibited inflammatory cytokines, TLR4, TNF-α, IL-1β, COX-2, and iNOS and increased mRNA manifestation of HO-1, genes related to antioxidants. Based on the strong antioxidant and anti-inflammatory effects of Ab4-7, the effects of Ab4-7 in the inflammatory RAW 264.7 cells were identified through RT-PCR, which regulates the gene Matrix Metalloproteinase (MMPs) that induces a variety of inflammatory skin diseases by engaging in the decomposition of the extrocellular matrix metalloproteinase (ECM). Taken together, it is concluded that Ab4-7 has a powerful anti-inflammatory and antioxidant effect and can be used as a functional material for various inflammatory skin disease treatments by controlling the genes associated with matrix metalloproteinase (MMPs).