한국인 비용 환자들에서 5-Lipoxygenase 촉진자의유전적 다형성에 관한 연구

박성국,최정배,정현,예성수 대한이비인후과학회 2007 대한이비인후과학회지 두경부외과학 Vol.50 No.4

Background and Objectives: the nasal cavity and occur on both infectious and noninfectious basis, and genetic etiology is suspected in the development of nasal polyps. 5-Lipoxygenase is the first enzyme committed in the metabolic pathway leading to the intracellular synthesis of leukotrienes. Some studies have shown that leuko-trienes were significantly higher in nasal polyps from aspirin-sensitive asthmatics than in nasal polyps from aspirin-tolerant asthmatics and normal nasal mucosa. The purpose of the present study is to evaluate whether genetic polymorphism of the core promoter region of the 5-lipoxygenase gene contributes to the development of nasal polyps. Subjects and Method:This study was conducted in 97 nasal polyp patients associated with chronic sinusitis and 92 healthy controls. Genetic polymorphisms of 5-lipoxygenase gene promoter were genot Results:There were no significant differences between the 5-lipoxygenase gene promoter polymorphisms in nasal polyp patients with chronic sinusitis and those in healthy controls (p= 0.76). In the nasal polyp patients associated with chronic sinusitis, the frequencies of 6-bp deletion were lower than those of healthy controls (OR, 0.88 95% CI, 0.48- 1.60), but there was no statistical significance (p= 0.67). The frequencies of 6-bp addition were higher than those of healthy controls (OR, 1.96; 95% CI, 0.33- 10.6), but no significant diference was found (p= 0.68). Conclusion:We concluded that 5-lipoxygenase gene promoter polymorphism did not show genetic predisposition with regard to nasal polyps in the Korean population. (Korean J Otolaryngol 2007 ;50 :310-3)

두경부암종에서의 Cyclooxygenase-2와 5-Lipoxygenase 병합 억제의 향상된 항암 효과

박석우,성명훈 대한이비인후과학회 2010 대한이비인후과학회지 두경부외과학 Vol.53 No.7

Background and Objectives It has recently been found that arachidonate 5-lipoxygenase (5-lipoxygenase, 5-LO or ALOX5), another molecule capable of arachidonic acid (AA) metabolism,might promote cancer cell viability through unique mechanisms. Interestingly, 5-LO appears to have similar mechanisms to prostaglandin-endoperoxide synthase 2 (cyclooxygenase-2,COX-2) in the regulation of cell viability, although it often utilizes different signaling pathways. We found that not only COX-2 expression but also the expression of 5-LO is up-regulated in some of head and neck squamous cell carcinoma (HNSCC) cell lines. From these findings, we hypothesized that the combined inhibition of these pathways would be likely to be a more effective anti-cancer modality with less side-effect in HNSCC. Materials and Method In HNSCC cell lines, we investigated the expression of COX-2 and 5-LO by western blotting and checked the levels of prostaglandin E2, leukotrien B4 and vascular endothelial growth factor (VEGF) by enzyme-linked immunosorbent assay. We performed MTT assay to analyze the growth-inhibitory effect of COX-2 and 5-LO inhibition. Results Actually, combined knock-down of COX-2 and 5-LO resulted in an enhanced inhibitory effect in cell proliferation of HNSCC than a single inhibition of COX-2. Furthermore, we observed that VEGF production was blocked more effectively by combined treatment of COX-2and 5-LO small interfering RNA (siRNA) in all tested cell lines. Conclusion Therefore, the combined inhibition of COX-2 and 5-LO may be one way to overcome low efficacy of single inhibition of COX-2 in cancer cells with both COX-2 and 5-LO overexpression. Korean J Otorhinolaryngol-Head Neck Surg 2010;53:430-5

The Protective Effect of Eupatilin against Hydrogen Peroxide-Induced Injury Involving 5-Lipoxygenase in Feline Esophageal Epithelial Cells

Lim, Jae-Chun,Park, Sun-Young,Nam, Yoon-Jin,Nguyen, Thanh Thao,Sohn, Uy-Dong The Korean Society of Pharmacology 2012 The Korean Journal of Physiology & Pharmacology Vol.16 No.5

In this study, we focused to identify whether eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone), an extract from Artemisia argyi folium, prevents $H_2O_2$-induced injury of cultured feline esophageal epithelial cells. Cell viability was measured by the conventional MTT reduction assay. Western blot analysis was performed to investigate the expression of 5-lipoxygenase by $H_2O_2$ treatment in the absence and presence of inhibitors. When cells were exposed to 600 ${\mu}M$ $H_2O_2$ for 24 hours, cell viability was decreased to 40%. However, when cells were pretreated with 25~150 ${\mu}M$ eupatilin for 12 hours, viability was significantly restored in a concentration-dependent manner. $H_2O_2$-treated cells were shown to express 5-lipoxygenase, whereas the cells pretreated with eupatilin exhibited reduction in the expression of 5-lipoxygenase. The $H_2O_2$-induced increase of 5-lipoxygenase expression was prevented by SB202190, SP600125, or NAC. We further demonstrated that the level of leukotriene $B_4$ ($LTB_4$) was also reduced by eupatilin, SB202190, SP600125, NAC, or nordihydroguaiaretic acid (a lipoxygenase inhibitor) pretreatment. $H_2O_2$ induced the activation of p38MAPK and JNK, this activation was inhibited by eupatilin. These results indicate that eupatilin may reduce $H_2O_2$-induced cytotoxicity, and 5-lipoxygenase expression and $LTB_4$ production by controlling the p38 MAPK and JNK signaling pathways through antioxidative action in feline esophageal epithelial cells.

5-Lipoxygenase in monocytes emerges as a therapeutic target for intimal hyperplasia in a murine wire-injured femoral artery

Baek, S.E.,Jang, M.A.,Lee, S.J.,Park, S.Y.,Bae, S.S.,Kim, C.D. Elsevier/North Holland [etc.] 2017 Biochimica et biophysica acta Vol.1863 No.9

Given the importance of leukotrienes in vascular inflammation induced by local tissue injury, this study investigated the role for 5-lipoxygenase (5-LO) in monocytes in the development of intimal hyperplasia. As a mechanistic study, the importance of monocyte 5-LO in monocyte-macrophage differentiation with subsequent infiltration in neointima was evaluated. In a mouse model of wire-injured femoral artery, intimal hyperplasia started as early as 2wks after injury, and luminal area and blood flow were reduced due to increased neointima formation. Time-dependent increases in macrophage infiltration were observed in neointima and showed a positive relationship with neointima volume. In 5-LO-deficient (KO) mice or wild-type (WT) mice treated with an inhibitor of 5-LO activating protein (MK886, 1 and 10mg/kg), intimal hyperplasia and macrophage infiltration into neointima were reduced, but monocyte adhesion to injured luminal surface was not inhibited, which suggested 5-LO participates in monocyte-macrophage differentiation. In an in vitro study, monocyte-macrophage differentiation was found to be increased by high mobility group box 1 protein (HMGB1), but this effect was attenuated in cells isolated from 5-LO-KO mice. Furthermore, macrophage infiltration and intimal hyperplasia were more prominent in 5-LO-KO mice transplanted with monocytes from WT mice than in 5-LO-KO mice transplanted with monocytes from 5-LO-KO mice. Taken together, it was suggested that 5-LO in monocytes played a pivotal role in monocyte-macrophage differentiation and subsequent infiltration of macrophage in neointima, leading to vascular remodeling after vascular injury.

Downregulation of Angiotensin II-Induced 12-Lipoxygenase Expression and Cell Proliferation in Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats by CCL5

Jung Hae Kim,Hee Sun Kim 대한생리학회-대한약리학회 2009 The Korean Journal of Physiology & Pharmacology Vol.13 No.5

Angiotensin II (Ang II) plays an important role in vascular hypertension. The role of the chemokine CCL5 on Ang II-induced activities in vascular smooth muscle cells (VSMCs) has not been studied. In this study, we elucidated the effect of CCL5 on Ang II-induced 12-lipoxygenase (LO) expression and cell proliferation in spontaneously hypertensive rats (SHR) VSMCs. CCL5 decreased Ang II-induced 12-LO mRNA expression and protein production, and it increased Ang II type 2 (AT2) receptor expression in SHR VSMCs. The inhibitory effect of CCL5 on Ang II-induced 12-LO mRNA expression was mediated through the AT2 receptor. Although treatment of CCL5 alone induced SHR VSMCs proliferation, CCL5 inhibited Ang II-induced VSMCs proliferation and PD123,319, an AT2 receptor antagonist, blocked the inhibitory effect of CCL5 on Ang II-induced VSMCs proliferation. Phosphorylation of p38 was detected in VSMCs treated with Ang II or CCL5 alone. But, decrease of p38 phosphorylation was detected in VSMCs treated with Ang II and CCL5 simultaneously (Ang II/CCL5) and PD123,319 increased p38 phosphorylation in VSMCs treated with Ang II/CCL5. Therefore, these results suggest that the inhibitory effect of CCL5 on Ang II-induced VSMCs proliferation is mediated by the AT2 receptor via p38 inactivation, and CCL5 may play a beneficial role in Ang II-induced vascular hypertension.

The Protective Effect of Eupatilin against Hydrogen Peroxide-Induced Injury Involving 5-Lipoxygenase in Feline Esophageal Epithelial Cells

Jae Chun Lim,Sun Young Park,Yoonjin Nam,Thanh Thao Nguyen,Uy Dong Sohn 대한생리학회-대한약리학회 2012 The Korean Journal of Physiology & Pharmacology Vol.15 No.5

In this study, we focused to identify whether eupatilin (5,7-dihydroxy-3 ,4 ,6-trimethoxyflavone), an extract from Artemisia argyi folium, prevents H₂O₂-induced injury of cultured feline esophageal epithelial cells. Cell viability was measured by the conventional MTT reduction assay. Western blot analysis was performed to investigate the expression of 5-lipoxygenase by H₂O₂ treatment in the absence and presence of inhibitors. When cells were exposed to 600 ՌM H₂O₂ for 24 hours, cell viability was decreased to 40%. However, when cells were pretreated with 25∼150 ՌM eupatilin for 12 hours, viability was significantly restored in a concentration-dependent manner. H₂O₂-treated cells were shown to express 5-lipoxygenase, whereas the cells pretreated with eupatilin exhibited reduction in the expression of 5-lipoxygenase. The H₂O₂-induced increase of 5-lipoxygenase expression was prevented by SB202190, SP600125, or NAC. We further demonstrated that the level of leukotriene B₄ (LTB₄) was also reduced by eupatilin, SB202190, SP600125, NAC, or nordihydroguaiaretic acid (a lipoxygenase inhibitor) pretreatment. H₂O₂ induced the activation of p38MAPK and JNK, this activation was inhibited by eupatilin. These results indicate that eupatilin may reduce H₂O₂-induced cytotoxicity, and 5-lipoxygenase expression and LTB₄ production by controlling the p38 MAPK and JNK signaling pathways through antioxidative action in feline esophageal epithelial cells.

The Protective Effect of Eupatilin against Hydrogen Peroxide-Induced Injury Involving 5-Lipoxygenase in Feline Esophageal Epithelial Cells

Jae Chun Lim,Sun Young Park,Yoonjin Nam,Thanh Thao Nguyen,손의동 대한약리학회 2012 The Korean Journal of Physiology & Pharmacology Vol.16 No.5

In this study, we focused to identify whether eupatilin (5,7-dihydroxy-3’,4’,6-trimethoxyflavone), an extract from Artemisia argyi folium, prevents H2O2-induced injury of cultured feline esophageal epithelial cells. Cell viability was measured by the conventional MTT reduction assay. Western blot analysis was performed to investigate the expression of 5-lipoxygenase by H2O2 treatment in the absence and presence of inhibitors. When cells were exposed to 600 μM H2O2 for 24 hours, cell viability was decreased to 40%. However, when cells were pretreated with 25∼150 μM eupatilin for 12 hours, viability was significantly restored in a concentration-dependent manner. H2O2-treated cells were shown to express 5-lipoxygenase, whereas the cells pretreated with eupatilin exhibited reduction in the expression of 5-lipoxygenase. The H2O2-induced increase of 5-lipoxygenase expression was prevented by SB202190, SP600125, or NAC. We further demonstrated that the level of leukotriene B4 (LTB4) was also reduced by eupatilin, SB202190, SP600125, NAC, or nordihydroguaiaretic acid (a lipoxygenase inhibitor) pretreatment. H2O2 induced the activation of p38MAPK and JNK, this activation was inhibited by eupatilin. These results indicate that eupatilin may reduce H2O2-induced cytotoxicity, and 5-lipoxygenase expression and LTB4 production by controlling the p38 MAPK and JNK signaling pathways through antioxidative action in feline esophageal epithelial cells.

Induction of 5-lipoxygenase by 4-hydroxynonenal via Nitric Oxide Generation in Vascular Smooth Muscle Cells

이지영 한국안광학회 2023 한국안광학회지 Vol.28 No.3

Purpose: The induction of 5-lipoxygenase (5-LO) by 4-hydroxynonenal (HNE) is of significant interest for understanding the mechanisms underlying the homeostasis of the cellular redox balance, leading to retinal dysfunction. However, the roles of these mediators in vascular smooth muscle cells (VSMC) remain unclear. This study investigated whether the induction of 5-LO by HNE was mediated by nitric oxide (NO) generation in VSMC. Methods: A10 cells were preincubated in DMEM containing HNE after preincubation with NO inhibitors. The gene expression levels of 5- LO were analyzed by western blotting and reverse transcriptase-polymerase chain reaction. Intracellular NO formation was measured by fluorescence using 4,5-diaminofluorescein as a specific NO indicator using flow cytometry. Results: The fluorescence profiles increased in a time-dependent manner in cells treated with 1mM HNE. These data indicate that HNE induced NO generation in VSMC. NO inhibitors prevent HNE-induced NO generation and 5-LO expression. In addition, the results showed the upregulation of 5-LO mRNA levels by HNE. This suggests that HNE plays a role in regulating 5-LO at the transcriptional level without the possibility of post-translational modification. Conclusions: These findings suggest that HNE-induced oxidative stress, including NO generation, is an important risk factor for retinopathy development via 5-LO gene expression in VSMC. The induction of 5-LO by HNE in VSMC is mediated by NO generation, leading to the deterioration of vasculature homeostasis and subsequent retinal dysfunction, such as retinopathy.

아스피린 과민성 천식에서 류코트리엔의 생합성에 관여하는 효소들과 그 수용체의 단일염기다형 및 5-lipoxygenase 일배체형 분석

최정희 ( Choe Jeong Hui ),박해심 ( Park Hae Sim ),신승수 ( Sin Seung Su ),오흥범 ( O Heung Beom ),이준혁 ( Lee Jun Hyeog ),서유진 ( Seo Yu Jin ),박춘식 ( Park Chun Sig ),신형두 ( Sin Hyeong Du ) 대한천식알레르기학회 2003 천식 및 알레르기 Vol.23 No.4

5-Lipoxygenase plays a pivotal role in endothelial adhesion of monocytes via an increased expression of Mac-1

Lee, Seung Jin,Choi, Eun Kyoung,Seo, Kyo Won,Bae, Jin Ung,Kim, Yun Hak,Park, So Youn,Oh, Sae Ock,Kim, Chi Dae Oxford University Press 2013 Cardiovascular research Vol.99 No.4

<P><B>Aims</B></P><P>5-Lipoxygenase (5-LO) is known to participate in the pathogenesis of atherosclerosis; however, the underlying mechanisms are unclear. Thus, this study investigated the molecular mechanisms responsible for 5-LO expression in monocytes as well as the role of 5-LO in monocyte adhesion to the vascular endothelium, which is a key early event in macrophage foam cell formation.</P><P><B>Methods and results</B></P><P>An <I>en face</I> immunohistochemistry of endothelial surfaces revealed a marked increase in monocyte adhesion to the aortic endothelium in wild-type (WT) mice treated with lipopolysaccharide (LPS), which was significantly attenuated in 5-LO<SUP>(−/−)</SUP> mice. Likewise, the adhesion capacity of primary monocytes isolated from LPS-treated WT mice was higher than those of monocytes from 5-LO<SUP>(−/−)</SUP> mice. In <I>in vitro</I> study, LPS increased monocyte adhesion to endothelial cells with an enhanced Mac-1 expression. These were attenuated by a 5-LO inhibitor, MK886, as well as by molecular depletion of 5-LO in monocytes. Furthermore, LPS-induced Mac-1 expression on monocytes was significantly inhibited by pre-treatment with U-75302, a BLT<SUB>1</SUB>-receptor antagonist, suggesting a pivotal role of 5-LO-derived leukotrienes. In promoter activity analysis and chromatin immunoprecipitation assays to identify transcription factors involved in 5-LO expression, both NF-κB and Sp1 played central roles to increase 5-LO expression in LPS-treated monocytes.</P><P><B>Conclusion</B></P><P>5-LO expression in monocytes is modulated via NF-κB and Sp1 signalling pathways, and 5-LO plays a pivotal role in LPS-mediated monocyte adhesion to the vascular endothelium through an increased expression of Mac-1 on monocytes.</P>