Inhibitory effects of decursin derivative against lipopolysaccharide-induced inflammation : 리포폴리사카라이드 유도 염증에 대한 데쿠르신 유도체의 억제 효과

다국어 초록 (Multilingual Abstract)

Background: This study aims to explore the protective role of JB-V-60—a novel synthetic derivative of decur-sin—against lipopolysaccharide (LPS)-induced inflammation. Methods: We examined the effects of JB-V-60 on heme oxygenase (HO)-1, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) in LPS-activated human pulmonary artery endothelial cells (HPAECs). Additionally, we assessed its effects on iNOS, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β in LPS-exposed mice. Results: JB-V-60 enhanced HO-1 levels, inhibited NF-κB activation, reduced COX-2/PGE2 and iNOS/NO concentra-tions, and lowered phosphorylation of signal transducer and activator of transcription 1. It also promoted the translocation of Nrf2 into the nucleus, allowing its binding to antioxidant response elements and resulting in reduced IL-1β in LPS-stimulated HPAECs. The reduction in iNOS/NO levels by JB-V-60 was reversed when HO-1 was inhibited via RNAi. In the animal model, JB-V-60 sig-nificantly decreased iNOS expression in lung tissues and TNF-α levels in bronchoalveolar lavage fluid. Conclusions: These findings highlight the anti-inflammatory effects of JB-V-60 and its potential as a treat-ment for inflammatory disorders.

국문 초록 (Abstract)

이 연구는 LPS(lipopolysaccharide)로 유도된 염증에 대한 새로운 합성 데커신 유도체인 JB-V-60의 보호 역할을 탐색하는 것을 목표로 합니다. 우리는 LPS로 활성화된 인간 폐동맥 내피세포(HPAECs)에서 헴 산소화효소(HO)-1, 사이클로옥시게나제(COX)-2, 그리고 유도성 산화질소 합성효소(iNOS)에 대한 JB-V-60의 효과를 조사했습니다. 또한, LPS에 노출된 쥐에서 iNOS, 종양 괴사 인자(TNF)-α, 및 인터루킨(IL)-1β에 대한 그 효과를 평가했습니다. JB-V-60은 HO-1 수치를 높이고, NF-κB 활성화를 억제하며, COX-2/PGE2 및 iNOS/NO 농도를 감소시키고, 신호 변환기 및 전사 활성인자 1의 인산화를 낮췄습니다. 또한 Nrf2의 핵 내 이동을 촉진하여 항산화 반응 요소에 결합하게 하고, 그 결과 LPS로 자극된 HPAECs에서 IL-1β를 감소시켰습니다. JB-V-60에 의한 iNOS/NO 수치 감소는 HO-1이 RNAi를 통해 억제되었을 때 역전되었습니다. 동물 모델에서 JB-V-60은 폐 조직의 iNOS 발현과 기관지폐포 세척액의 TNF-α 수치를 유의하게 감소시켰습니다. 이러한 발견들은 JB-V-60의 항염증 효과와 염증성 질환 치료제로서의 잠재력을 강조합니다.

목차 (Table of Contents)

• I. INTRODUCTION 1
• II. EXPERIMENTAL 4
• 1. Cell culture and substances 4
• 2. General information of JB-V-60 4
• 2.1 Method for the synthesis of N-(8,8-dimethyl-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl)cinnamamide (JB-V-60) 5
• 3. In vitro studies 8
• 3.1 Cell viability assay 8
• 3.2 Enzyme-linked immunosorbent assays (ELISA) 9
• 3.3 Nitrite levels 9
• 3.4 Intracellular fractionation, co-immunoprecipitation (Co-IP), and immunoblotting 10
• 3.5 Quantitative real-time polymerase chain reaction 10
• 3.6 Transfection 11
• 3.7 ARE luciferase reporter assay 11
• 4. In vivo studies 12
• 4.1 Mouse model of LPS-induced lung injury 12
• 4.2 Histopathological analysis 12
• 4.3 Evaluation of oxidative stress markers 13
• 5. Statistical Analysis 13
• III. RESULTS 14
• 1. Effect of JB-V-60 on iNOS and COX-2 expression in LPS-stimulated HPAECs 14
• 2. Effect of JB-V-60 on NF-κB activity, STAT-1 phosphorylation, and HO-1 protein levels in LPS-stimulated HPAECs 16
• 3. Effects of JB-V-60 on Nrf2 nuclear translocation, ARE reporter activity, and anti-inflammatory mechanismsin LPS-stimulated HPAECs 18
• 4. Effects of JB-V-60 on TNF-α and iNOS protein expression in a mouse model of LPS-induced lung injury 20
• IV. DISCUSSION 23
• V. REFERENCES 26
• Abstract in Engilsh 32
• Abstract in Korean 33