Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.030
Suppression of Lipopolysaccharide-Induced Inflammatory and Oxidative Response by 5-Aminolevulinic Acid in RAW 264.7 Macrophages and Zebrafish Larvae
Seon Yeong Ji1,2,†, Hee-Jae Cha3,†, Ilandarage Menu Neelaka Molagoda4, Min Yeong Kim1,2, So Young Kim1,2, Hyun Hwangbo1,2, Hyesook Lee1,2, Gi-Young Kim4, Do-Hyung Kim5, Jin Won Hyun6, Heui-Soo Kim7, Suhkmann Kim8, Cheng-Yun Jin9 and Yung Hyun Choi1,2,*
1Anti-Aging Research Center, Dong-eui University, Busan 47340,
2Department of Biochemistry, College of Korean Medicine, Dong-eui University, Busan 47227,
3Department of Parasitology and Genetics, College of Medicine, Kosin University, Busan 49104,
4Department of Marine Life Sciences, Jeju National University, Jeju 63243,
5Department of Aquatic Life Medicine, Pukyong National University, Busan 48513,
6Department of Biochemistry, College of Medicine, Jeju National University, Jeju 63243,
7Department of Biological Sciences, Pusan National University, Busan 46241,
8Department of Chemistry, Pusan National University, Busan 46241, Republic of Korea
9School of Pharmaceutical Sciences, Zhengzhou University, Henan 450001, China
*E-mail: choiyh@deu.ac.kr
Tel: +82-51-890-3319, Fax: +82-51-890-3333
The first two authors contributed equally to this work.
Received: February 5, 2021; Revised: March 11, 2021; Accepted: March 15, 2021; Published online: April 6, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
In this study, we investigated the inhibitory effect of 5-aminolevulinic acid (ALA), a heme precursor, on inflammatory and oxidative stress activated by lipopolysaccharide (LPS) in RAW 264.7 macrophages by estimating nitric oxide (NO), prostaglandin E2 (PGE2), cytokines, and reactive oxygen species (ROS). We also evaluated the molecular mechanisms through analysis of the expression of their regulatory genes, and further evaluated the anti-inflammatory and antioxidant efficacy of ALA against LPS in the zebrafish model. Our results indicated that ALA treatment significantly attenuated the LPS-induced release of pro-inflammatory mediators including NO and PGE2, which was associated with decreased inducible NO synthase and cyclooxygenase-2 expression. ALA also inhibited the LPS-induced expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, reducing their extracellular secretion. Additionally, ALA abolished ROS generation, improved the mitochondrial mass, and enhanced the expression of heme oxygenase-1 (HO-1) and the activation of nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) in LPS-stimulated RAW 264.7 macrophages. However, zinc protoporphyrin, a specific inhibitor of HO-1, reversed the ALA-mediated inhibition of pro-inflammatory cytokines production and activation of mitochondrial function in LPS-treated RAW 264.7 macrophages. Furthermore, ALA significantly abolished the expression of LPS-induced pro-inflammatory mediators and cytokines, and showed strong protective effects against NO and ROS production in zebrafish larvae. In conclusion, our findings suggest that ALA exerts LPS-induced anti-inflammatory and antioxidant effects by upregulating the Nrf2/HO-1 signaling pathway, and that ALA can be a potential functional agent to prevent inflammatory and oxidative damage.
Keywords: 5-Aminolevulinic acid, Inflammation, ROS, Nrf2/HO-1


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