• Journal of Physiology & Pathology in Korean Medicine
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• v.22 no.4
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• pp.871-877
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• 2008

Heme oxygenase-1 (HO-1), an inducible heme-degrading enzyme, is expressed by macrophages and endothelial cells in response to various stresses and mediators of inflammation. HO-1 has been recently implicated in regulation of angiogenesis via expression of VEGF. The purpose of this study was to determine the effects of HO-1 modulation on the collagen-induced arthritis (CIA) model and on angiogenesis via up- regulation of VEGF expression in human synovial fibroblast. DBA/1J mice were treated with an inhibitor of HO-1, tin protoporphyrin IX (SnPP), or with an inducer of HO-1, cobalt protoporphyrin IX (CoPP), from day 1 to day 35 after CIA induction. The clinical evolution of disease was monitored visually. At the end of the experiment, histopathologic changes were examined on the joints. VEGF expression in paws were measured by immunohistochemical stain. mRNA expression of HO-1 and VEGF stimulated with various concentration of $TNF-{\alpha}$, CoPP accessed on human synovial fibroblast by RT-PCR. Effects of pretreatment with SnPP on mRNA expression of HO-1 and VEGF in the presence of CoPP and $TNF-{\alpha}$ in synovial fibroblast was accessed by Real-time RT-PCR. Administration of cobalt protoporphyrin IX significantly induced the inflammatory response, with increased arthritis index and expression of VEGF in the paws of the arthritis models. Treatment with SnPP significantly reduced the severity of CIA through inhibition of joint inflammation and cartilage destruction. The expression of VEGF were also significantly reduced by SnPP treatment in the paw. CoPPIX as inducer of HO-1, increased HO-1 and VEGF expression dose dependently in synovial fibroblast. In contrast, inhibition of HO-1 activity by SnPPIX abrogated CoPPIX-induced HO-1 and VEGF production in synovial fibroblast. Stimulation with $TNF-{\alpha}$ increased HO-1 and VEGF expression itself and showed additive effect on HO-1 and VEGF expression when it treated with CoPP. When SnPP was treated with CoPP and $TNF-{\alpha}$, it abrogated the CoPP induced HO-1 and VEGF expression and also abrogated $TNF-{\alpha}$ induced HO-1 and VEGF expression in synovial fibroblast. The effects of HO-1 induction in rheumatoid arthritis results in aggravation of arthritis via up-regulation of VEGF. I concluded that inhibition of the expression or activity of HO-1 could be a therapeutic target of rheumatoid arthritis.

• Journal of Life Science
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• v.21 no.11
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• pp.1625-1630
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• 2011

Heme oxygenase-1 (HO-1) is a stress-responsive protein that is known to regulate cellular functions such as cell proliferation, inflammation, and apoptosis. In this study, we investigated the role of NADPH oxidase on the expression of HO-1 in human liver hepatoma cell line HepG2. Diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, markedly inhibited HO-1 expression and the nuclear translocation of transcription factor Nrf2 in cobalt protoporphyrin (CoPP) or hemin-treated HepG2 cells. Similarly, the knockdown of $p47^{phox}$, a cytosolic factor for NADPH oxidase activity, by siRNA inhibited the CoPP-induced expression of HO-1. In addition, GSHmee, an intracellular antioxidant, blocked the expression of HO-1 in CoPP-treated cells. Based on these results, we conclude that the blockage of NADPH oxidase with DPI or $p47^{phox}$ siRNA inhibits CoPP-induced HO-1 expression in HepG2 cells, and also suggest that the expression of HO-1 in CoPP-induced HepG2 cells is associated with increase of intracellular ROS by NADPH oxidase activity.

• Biomolecules & Therapeutics
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• v.29 no.2
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• pp.175-183
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• 2021

The mitogen-activated protein kinase (MAPK) pathway controls intestinal epithelial barrier permeability by regulating tight junctions (TJs) and epithelial cells damage. Heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal epithelial barrier function, but the molecular mechanism is not yet clarified. MAPK activation and barrier permeability were studied using monolayers of Caco-2 cells treated with tissue necrosis factor α (TNF-α) transfected with FUGW-HO-1 or pLKO.1-sh-HO-1 plasmid. Intestinal mucosal barrier permeability and MAPK activation were also investigated using carbon tetrachloride (CCl4) administration with CoPP (a HO-1 inducer), ZnPP (a HO-1 inhibitor), CO releasing molecule 2 (CORM-2), or inactived-CORM-2-treated wild-type mice and mice with HO-1 deficiency in intestinal epithelial cells. TNF-α increased epithelial TJ disruption and cleaved caspase-3 expression, induced ERK, p38, and JNK phosphorylation. In addition, HO-1 blocked TNF-α-induced increase in epithelial TJs disruption, cleaved caspase-3 expression, as well as ERK, p38, and JNK phosphorylation in an HO-1-dependent manner. CoPP and CORM-2 directly ameliorated intestinal mucosal injury, attenuated TJ disruption and cleaved caspase-3 expression, and inhibited epithelial ERK, p38, and JNK phosphorylation after chronic CCl4 injection. Conversely, ZnPP completely reversed these effects. Furthermore, mice with intestinal epithelial HO-1 deficient exhibited a robust increase in mucosal TJs disruption, cleaved caspase-3 expression, and MAPKs activation as compared to the control group mice. These data demonstrated that HO-1-dependent MAPK signaling inhibition preserves the intestinal mucosal barrier integrity by abrogating TJ dysregulation and epithelial cell damage. The differential targeting of gut HO-1-MAPK axis leads to improved intestinal disease therapy.

• BMB Reports
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• v.50 no.2
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• pp.103-108
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• 2017

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-${\kappa}B$ ligand (RANKL). Treatment of RAW264.7 cells with CORM-2 (a CO donor) and bilirubin, but not with iron, decreased RANKL-induced osteoclastogenesis, with CORM-2 having a more potent anti-osteogenic effect. CORM-2 also inhibited RANKL-induced 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-${\kappa}B$ activation and reactive oxygen species production. These results suggest that CO potently inhibits RANKL-induced osteoclastogenesis by inhibiting redox-sensitive NF-${\kappa}B$-mediated NFATc1 expression. Our findings indicate that HO-1/CO can act as an anti-resorption agent and reduce bone loss by blocking osteoclast differentiation.

• Journal of Life Science
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• v.21 no.7
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• pp.1046-1051
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• 2011

Diallyl disulfide (DADS), the most prevalent oil-soluble organosulfur compound in garlic, is known to have diverse biological activities, including anticarcinogenic, antiatherosclerotic, antiinflammatory, and antioxidant actions. In this study, we investigated the effect of DADS on the expression of heme oxygenase-1 (HO-1) in human liver hepatoma cell line HepG2. Treatment of HepG2 cells by DADS evoked a dose-dependent growth inhibition without significant toxicity to the cells, and also induced the expression of transcription factor Nrf2. However, DADS did not have any enhancing effect on transcription and translation of HO-1 expression in HepG2 cells. In addition, DADS efficiently blocked protein synthesis of HO-1 in HepG2 cells stimulated by CoPP or hemin. But, DADS did not decrease the content of transcripts of HO-1 gene stimulated by CoPP, with accumulation of Nrf2 and small Maf in the nucleus. Based on these results, we conclude that DADS inhibits HO-1 expression by modulation of translational level of CoPP or hemin-induced HO-1 expression in HepG2 cells.

• 한국정보디스플레이학회:학술대회논문집
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• 2006.08a
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• pp.198-201
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• 2006

The optimization of poly-Si TFT process on metal foil for UTL AMOLED was systematically investigated. The improvement in device performance of poly-Si TFT on metal foil was achieved by optimizing the dopant activation condition and gate dielectric structure. Hence, the world first flexible full color 5.6-inch AMOLED with top emission mode on poly-Si TFT stainless steel foil is demonstrated.

• Journal of the Korean Institute of Oriental Medical Informatics
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• v.21 no.1
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• pp.14-22
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• 2015

Flavonoids show diverse bioactivities, such as anti-oxidant, anti-cancer, anti-allergic, anti-inflammatory, and anti-viral. Quercetin is one of the flavonoids present in a wide range of plants, especially onions and consumed all over the world. Recently, it is known that quercetin induces mitochondrial biogenesis in vivo and in vitro. However, detail mechanism of these actions remains unknown. We investigated quercetin's effects on mitochondrial biogenesis in HepG2 cells, and determined the mechanisms involved. We found that quercetin treatment induced the expression of mitochondrial biogenesis activators, $PGC-1{\alpha}$, NRF-1, TFAM, and mitochondrial proteins, cytochorome c and complex IV (COXIV). Moreover, amount of mitochondrial DNA was also increased by quercetin. Quercetin has been known to induce heme oxygenase (HO)-1 in several types of cells. Here, we found quercetin induces HO-1, and inhibition of HO-1 or CO, which is product of HO-1, decreased quercetin-induced mitochondrial biogenesis such as induction of $PGC-1{\alpha}$, NRF-1, TFAM, cytochorome c, COXIV, and mitochondrial DNA. These findings imply that quercetin can increase mitochondrial biogenesis via HO-1/CO system. High glucose results in dysfunction of mitochondria biogenesis. In the present study, 25 mM glucose decreased mitochondrial biogenesis and this damage was restored by quercetin. Conversely, inhibition of HO-1 or CO inhibited quercetin-induced mitochondrial biogenesis rescue. These results suggest that quercetin enhances mitochondrial biogenesis via HO-1/CO system and hence, can rescue mitochondria from damage by high glucose.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.1
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• pp.87-92
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• 2001

Carbon monoxide (CO) binds to soluble guanylate cyclase to lead its activation and elicits smooth muscle relaxation. The vascular tissues have a high capacity to produce CO, since heme oxygenase-2 (HO-2) is constitutively expressed in endothelial and smooth muscle cells, and HO-1 can be greatly up-regulated by oxidative stress. Moreover, the substrate of HO, heme, is readily available for catalysis in vascular tissue. Although the activation of heme oxygenase pathway under various stress conditions may provide a defence mechanism in compromised tissues, the specific role of HO-1-derived CO in the control of aortic contractility still remains to be elucidated. The present study was done to determine the effect of HO-1 induction on the aortic contractility. Thus, the effects of incubation of aortic tissue with S-nitroso-N-acetylpenicillamine (SNAP) for 1 hr on the aortic contractile response to phenylephrine were studied. The preincubation with SNAP resulted in depression of the vasoconstrictor response to phenylephrine. This effect was restored by HO inhibitor or methylene blue but not by NOS inhibitor. The attenuation of vascular reactivity by preincubation with SNAP was also revealed in endothelium-free rings. $AlF4^--evoked$ contraction in control did not differ from that in SNP-treated group. These results suggest that increased production of CO was responsible for the reduction of the contractile response to phenylephrine in aortic ring preincubated with SNAP and this effect of SNAP was independent on endothelium.

• Proceedings of the PSK Conference
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• 2001.10a
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• pp.236.1-236.1
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• 2001

• Archives of Pharmacal Research
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• v.23 no.4
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• pp.332-337
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• 2000

This study describes the synthesis, in vitro evaluation and molecular modeling study of novel compounds for the inhibition of TNF-$\alpha$production, Among these compounds, 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-isoindolinone (9) was selected as a lead compound and its pyridine derivative 10 was more potent in activity and safer than rolipram.