• 약학회지
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• 제56권6호
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• pp.347-351
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• 2012

5-Lipoxygenase (5-LO) catalyzes the formation of two major groups of leukotrienes, LTB4 and cysteinyl leukotrienes (CysLT), and it has been implicated as a promising drug target to treat various inflammatory diseases. Since its role in mature osteoclasts (mOCs) had not been reported, we investigated the effect of 5-LO inhibitors on mOCs. We showed that 5-LO inhibitors dose-dependently decreases the number of mOCs. The effects of 5-LO inhibitors were reversible, suggesting that they did not cause any cellular damages in mOCs. We further demonstrated that the suppression of mOCs by 5-LO inhibitors was caused mainly by disruption of the actin ring formation. Similar effects were shown with CysLT receptor (CysLTR)1 antagonist in mOCs. The mRNA expression of CysLTR1 and the production of CysLT were increased in mOCs. These results indicate that CysLTR1 mediates the suppression of mOCs by 5-LO inhibitors. Taken together, this study demonstrated that 5-LO plays important role in mOCs and possibly a novel therapeutic target for bone resorption diseases.

• 생약학회지
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• 제28권4호
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• pp.247-251
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• 1997

The effects of the extract of the root of Cynanchum wilfordi (Asclepiadaceae), the alkaloid fraction, and the isolated main constituent (gagaminine) on 5-lipoxygenase(5-LOEC 1.13.11.34) in bovine PMNL have been studied. The effect of the crude extracts of wildand cultivated plant was also compared each other. Furthermore, the inhibitory effect of gagaminine on 5-Lo was compared with those of the standard drugs. Gagaminine inhibited 5-Lo activity with an $IC_{50}$ value of $26\;{\mu}M$, this result indicates that gagaminine may be useful for in vivo experiments as 5-LO inhibitor.

• The Korean Journal of Physiology and Pharmacology
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• 제19권3호
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• pp.263-268
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• 2015

5-Lipoxygenase (5-LO) plays a pivotal role in the progression of atherosclerosis. Therefore, this study investigated the molecular mechanisms involved in 5-LO expression on monocytes induced by LPS. Stimulation of THP-1 monocytes with LPS ($0{\sim}3{\mu}g/ml$) increased 5-LO promoter activity and 5-LO protein expression in a concentration-dependent manner. LPS-induced 5-LO expression was blocked by pharmacological inhibition of the Akt pathway, but not by inhibitors of MAPK pathways including the ERK, JNK, and p38 MAPK pathways. In line with these results, LPS increased the phosphorylation of Akt, suggesting a role for the Akt pathway in LPS-induced 5-LO expression. In a promoter activity assay conducted to identify transcription factors, both Sp1 and NF-${\kappa}B$ were found to play central roles in 5-LO expression in LPS-treated monocytes. The LPS-enhanced activities of Sp1 and NF-${\kappa}B$ were attenuated by an Akt inhibitor. Moreover, the LPS-enhanced phosphorylation of Akt was significantly attenuated in cells pretreated with an anti-TLR4 antibody. Taken together, 5-LO expression in LPS-stimulated monocytes is regulated at the transcriptional level via TLR4/Akt-mediated activations of Sp1 and NF-${\kappa}B$ pathways in monocytes.

• The Korean Journal of Physiology and Pharmacology
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• 제13권5호
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• pp.385-392
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• 2009

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 ($AT_2$) receptor expression in SHR VSMCs. The inhibitory effect of CCL5 on Ang II-induced 12-LO mRNA expression was mediated through the $AT_2$ receptor. Although treatment of CCL5 alone induced SHR VSMCs proliferation, CCL5 inhibited Ang II-induced VSMCs proliferation and PD123,319, an $AT_2$ 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 $AT_2$ receptor via p38 inactivation, and CCL5 may play a beneficial role in Ang II-induced vascular hypertension.

• Molecules and Cells
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• 제27권4호
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• pp.417-422
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• 2009

Lipoxygenase (LO) metabolites are generated in inflamed tissues. However, it is unclear whether the inhibition of the LO activity regulates the expression of c-Fos protein, a pain marker in the spinal cord. Here we used a carrageenan-induced inflammation model to examine the role of LO in the development of c-Fos expression. Intradermally injected carrageenan caused elevated number of cells exhibiting Fos-like immunoreactivity (Fos-LI) in the spinal dorsal horn, and decreased the thermal and mechanical threshold in Hargreaves and von Frey tests. Pretreatment with an inhibitor of phospholipase A2, that generates the LO substrate, prior to the carrageenan injection significantly reduced the number of Fos-(+) cells. A general LO inhibitor NDGA, a 5-LO inhibitor AA-861 and a 12-LO inhibitor baicalein also exhibited the similar effects. Moreover, the LO inhibitors suppressed carrageenan-induced thermal and mechanical hyperalgesic behaviors, which inidcates that the changes in Fos expression correlates with those in the nociceptive behaviors in the inflamed rats. LO products are endogenous TRPV1 activators and pretreatment with BCTC, a TRPV1 antagonist inhibited the thermal but not the mechanical hypersensitivity. Overall, our results from the Fos-LI and behavior tests suggest that LO products released from inflamed tissues contribute to nociception during carrageenan-induced inflammation, indicating that the LO pathway is a possible target for modulating inflammatory pain.

• Bulletin of the Korean Chemical Society
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• 제32권10호
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• pp.3752-3755
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• 2011

• BMB Reports
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• 제54권3호
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• pp.182-187
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• 2021

Leukotriene B4 (LTB4) is a lipid mediator of inflammation that is generated from arachidonic acid via the 5-lipoxygenase pathway. Previous studies have reported that the receptors of LTB4, BLT1, and BLT2 play mediatory roles in the allergic airway inflammation induced by ovalbumin (OVA). However, considering that house dust mites (HDMs) are the most prevalent allergen and well-known risk factor for asthmatic allergies, we are interested in elucidating the contributory roles of BLT1/2 in HDM-induced allergic airway inflammation. Our aim in this study was to investigate whether BLT1/2 play any roles in HDM-induced allergic airway inflammation. In this study, we observed that the levels of ligands for BLT1/2 [LTB4 and 12(S)-HETE (12(S)-hydroxyeicosatetraenoic acid)] were significantly increased in bronchoalveolar lavage fluid (BALF) after HDM challenge. Blockade of BLT1 or BLT2 as well as of 5-lipoxygenase (5-LO) or 12-lipoxygenase (12-LO) markedly suppressed the production of TH2 cytokines (IL-4, IL-5, and IL-13) and alleviated lung inflammation and mucus secretion in an HDM-induced eosinophilic airway-inflammation mouse model. Together, these results indicate that the 5-/12-LO-BLT1/2 cascade plays a role in HDM-induced airway inflammation by mediating the production of TH2 cytokines. Our findings suggest that BLT1/2 may be a potential therapeutic target for patients with HDM-induced allergic asthma.

• 한국식품영양과학회지
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• 제37권9호
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• pp.1109-1113
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• 2008

본 연구에서는 아로니아 추출물의 항산화제와 항알레르기 치료제로써의 유효성을 알아보기 위해 페놀성 화합물 및 플라보노이드 함량과 DPPH 라디칼 포착효능, superoxide 음이온 라디칼 포착효능, 5-LO억제 효능 및 COX억제효능을 측정하였다. 측정결과 아로니아는 유효성분으로 예상되는 페놀성 화합물과 플라보노이드가 각각 $745.4{\pm}3.7\;mg/g$, $74.63{\pm}2.2\;mg/g$으로 상당량 함유되어 있으며, 상당히 낮은 농도($6.15{\pm}0.343\;ppm$, $6.99{\pm}1.26\;ppm$)에서 DPPH 라디칼과 superoxide 음이온 라디칼을 50% 소거하는 것으로 나타났다. 아로니아의 항알레르기 효능에 관하여 5-LO의 $IC_{50}$값이 $47.07{\pm}0.15\;ppm$으로, EGCG의 $IC_{50}(15.83{\pm}0.98\;ppm)$보다는 높았지만 아로니아가 EGCG와 같은 단일물질이 아니라 천연혼합물임을 감안하여 다른 천연물들의 $IC_{50}$값과 비교하였을 때 5-LO를 비교적 낮은 농도에서 억제하고 있다고 볼 수 있다. 또한, COX-1과 COX-2의 저해 비율 비교를 통해 양성대조군으로 사용한 EGCG만큼 COX-2를 선택적으로 저해하고 있음을 확인하였다. 이상의 결과에 따르면 아로니아 추출물은 항산화 및 항알레르기 효능을 갖고 있으며, 따라서 알레르기성 비염이나 아토피와 같은 알레르기 관련 질병 치료에 유효하게 사용될 것이라 생각된다.

• 한국식품과학회지
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• 제43권2호
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• pp.200-205
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• 2011

본 연구에서는 문헌을 통하여 항산화 혹은 항염증 활성을 가지는 6종의 생약재와 이들 생약재를 혼합하여 제조한 생약복합제의 항산화 및 항염증 활성을 측정하였다. 총 폴리페놀 함량은 어성초, 홍화, MIX-2 에탄올추출물이 각각 58.98, 60.79, 57.74 mg/g의 함량으로 다른 시료들 보다 높게 측정되었다. 또한 플라보노이드 함량도 어성초(HC), 홍화(CT), MIX-2에탄올추출물이 각각 36.86, 19.42, 14.74 mg/g으로 높게 측정되었다. 단일 생약재와 생약복합제 에탄올추출물의 라디칼 소거능을 측정한 결과 DPPH 라디칼의 RC50 값은 어성초, 홍화, MIX-2 에탄올추출물에서 각각 69.64, 50.70, $63.49{\mu}g/mL$로 추출물 가운데 우수한 DPPH 라디칼 소거능을 보였고, ABTS 라디칼의 $RC_{50}$ 값도 어성초, 홍화, MIX-2가 각각 24.06, 18.91, $41.61{\mu}g/mL$로 DPPH 라디칼 소거능과 유사한 경향을 보였다. 시료들의 항염증 효능을 측정하기 위해 5-LO 및 COX-2 효소 저해활성을 측정한 결과 단일 생약재 에탄올추출물보다 생약복합제 에탄올추출물이 5-LO와 COX-2 효소를 동시에 저해하는 효과가 증가되는 것으로 나타났다. 염증유발 효소 저해활성이 우수했던 생약복합제 에탄올추출물들의 NO 소거활성을 비교한 결과, MIX-2 에탄올추출물이 $50{\mu}g/mL$의 농도에서부터 유의적으로 NO의 생성을 저해하는 것을 확인하였다. 따라서 단일 생약재 보다는 생약복합제가 서로 혼합되면서 시너지 효과가 나타나는 것으로 생각되며 앞으로 명확한 기전에 대한 연구들이 지속된다면 기능성 식품 소재로서의 이용이 가능할 것으로 생각된다.

• Molecules and Cells
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• 제44권12호
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• pp.893-899
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• 2021

BLT2 is a low-affinity receptor for leukotriene B₄, a potent lipid mediator of inflammation generated from arachidonic acid via the 5-lipoxygenase pathway. The aim of this study was to investigate whether BLT2 plays any role in sepsis, a systemic inflammatory response syndrome caused by infection. A murine model of cecal ligation and puncture (CLP)-induced sepsis was used to evaluate the role of BLT2 in septic inflammation. In the present study, we observed that the levels of ligands for BLT2 (LTB₄ [leukotriene B₄] and 12(S)-HETE [12(S)-hydroxyeicosatetraenoic acid]) were significantly increased in the peritoneal lavage fluid and serum from mice with CLP-induced sepsis. We also observed that the levels of BLT2 as well as 5-lipoxygenase (5-LO) and 12-LO, which are synthesizing enzymes for LTB₄ and 12(S)-HETE, were significantly increased in lung and liver tissues in the CLP mouse model. Blockade of BLT2 markedly suppressed the production of sepsis-associated cytokines (IL-6 [interleukin-6], TNF-α [tumor necrosis factor alpha], and IL-1β [interleukin-β] as well as IL-17 [interleukin-17]) and alleviated lung inflammation in the CLP group. Taken together, our results suggest that BLT2 cascade contributes to lung inflammation in CLP-induced sepsis by mediating the production of inflammatory cytokines. These findings suggest that BLT2 may be a potential therapeutic target for sepsis patients.