CIGB-258和载脂蛋白A-I联合增强斑马鱼伤口愈合和抗炎作用,对抗羧甲基赖氨酸毒性:洞察结构稳定和抗氧化特性

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Antioxidants Pub Date : 2024-08-28 DOI:10.3390/antiox13091049
Kyung-Hyun Cho, Yunki Lee, Sang Hyuk Lee, Ji-Eun Kim, Ashutosh Bahuguna, Maria del Carmen Dominguez-Horta, Gillian Martinez-Donato
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引用次数: 0

摘要

众所周知,CIGB-258 可通过在结构上稳定载脂蛋白 A-I(apoA-I)和在功能上增强高密度脂蛋白(HDL)抵抗羧甲基甘氨酸(CML)急性毒性的能力来发挥抗炎活性。在重组高密度脂蛋白(rHDL)中共存 CIGB-258 会形成较大的 rHDL 颗粒,并以载脂蛋白 A-I:CIGB-258(摩尔比为 1:0、1:0.1、1:0.5 和 1:1)的剂量依赖性方式增强 rHDL 合成过程中的抗炎活性。然而,还没有研究评估过无脂载脂蛋白 A-I 和 CIGB-258 共存对 HDL 功能的增强作用。因此,本研究旨在比较 HDL2 和 HDL3 中不含脂质的 apoA-I 和 CIGB-258 以 1:0、1:0.1、1:0.5 和 1:1 的摩尔比存在时 HDL 的结构稳定和功能改善情况。随着 CIGB-258 浓度的增加,它能有效抑制铜离子诱导的 HDL 氧化,从而保护载脂蛋白 A-I 免受蛋白水解。此外,在 CML 存在的情况下,apoA-I:CIGB-258(1:1)比单独的 apoA-I(1:0)能显著提高斑马鱼的伤口愈合活性(p < 0.01),最高可达 1.6 倍。ApoA-I:CIGB-258 (1:1) 处理对 CML 诱导的伤口部位损伤的凋亡和活性氧产生的影响最小。此外,在治疗后的 48 小时内,随着 CIGB-258 浓度的增加,伤口组织肉芽和表皮厚度也会随着愈合过程而增加。腹腔注射apoA-I:CIGB-258混合物可显著改善斑马鱼的急性瘫痪症状,并恢复其因CML急性毒性而受损的游泳能力。CIGB-258含量的增加,特别是apoA-I:CIGB-258(1:1)的联合注射,使斑马鱼的存活率和游泳能力的恢复分别比CML对照组显著高出2.3倍(p < 0.001)和4.1倍(p < 0.001)。在apoA-I:CIGB-258(1:1)组中,细胞损伤和凋亡最少的肝组织中的中性粒细胞浸润和白细胞介素(IL)-6的产生最少。此外,接受载脂蛋白A-I:CIGB-258(1:1)治疗组的血浆总胆固醇(TC)和甘油三酯(TG)水平最低,肾脏、卵巢和睾丸细胞的损伤也最小。CIGB-258与载脂蛋白A-I的联合治疗可有效缓解斑马鱼的急性炎症,保护重要器官,稳定载脂蛋白A-I的结构,并增强高密度脂蛋白的功能。
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Enhancing Wound Healing and Anti-Inflammatory Effects by Combination of CIGB-258 and Apolipoprotein A-I against Carboxymethyllysine Toxicity in Zebrafish: Insights into Structural Stabilization and Antioxidant Properties
CIGB-258 is known to exert anti-inflammatory activity via structural stabilization of apolipoprotein A-I (apoA-I) and functional enhancement of high-density lipoproteins (HDL) against acute toxicity of carboxymethyllysine (CML). The co-presence of CIGB-258 in reconstituted HDL (rHDL) formed larger rHDL particles and enhanced anti-inflammatory activity in a dose-dependent manner of apoA-I:CIGB-258, 1:0, 1:0.1, 1:0.5, and 1:1 of molar ratio, in the synthesis of the rHDL. However, no study has evaluated the enhancement of HDL functionality by the co-presence of lipid-free apoA-I and CIGB-258. The present study was therefore designed to compare the structural stabilization and functional improvement of HDL in the presence of lipid-free apoA-I and CIGB-258 in molar ratios of 1:0, 1:0.1, 1:0.5, and 1:1 within both HDL2 and HDL3. As the concentration of CIGB-258 increased, it effectively inhibited the cupric-ion-induced oxidation of HDL, thereby safeguarding apoA-I from proteolytic degradation. Additionally, the wound-healing activity of zebrafish was significantly (p < 0.01) enhanced by the co-addition of apoA-I:CIGB-258 (1:1) up to 1.6-fold higher than apoA-I alone (1:0) under the presence of CML. ApoA-I:CIGB-258 (1:1) treatment exhibited the lowest apoptosis and production of reactive oxygen species against CML-induced damage in the wound site. Also, an increase in wounded tissue granulation and epidermis thickness was observed with increasing concentration of CIGB-258 during 48 h post-treatment via the healing process. Intraperitoneal injection of apoA-I:CIGB-258 mixture remarkably ameliorated the acute paralysis and restored zebrafish swimming ability impaired by the acute toxicity of CML. The increase of CIGB-258 content, especially co-injection of apoA-I:CIGB-258 (1:1), leads to a significant 2.3-fold (p < 0.001) and 4.1-fold (p < 0.001) higher zebrafish survivability and recovery of swimming ability, respectively, than those of CML-control. In the apoA-I:CIGB-258 (1:1) group, neutrophil infiltration and interleukin (IL)-6 production was lowest in the hepatic tissue with the least cellular damage and apoptosis. Additionally, the group treated with apoA-I:CIGB-258 (1:1) demonstrated the lowest plasma levels of total cholesterol (TC) and triglycerides (TG), along with minimal damage to the kidney, ovary, and testicular cells. Conclusively, co-treatment of CIGB-258 with apoA-I effectively mitigated acute inflammation in zebrafish, safeguarded vital organs, structurally stabilized apoA-I, and enhanced HDL functionality.
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来源期刊
Antioxidants
Antioxidants Biochemistry, Genetics and Molecular Biology-Physiology
CiteScore
10.60
自引率
11.40%
发文量
2123
审稿时长
16.3 days
期刊介绍: Antioxidants (ISSN 2076-3921), provides an advanced forum for studies related to the science and technology of antioxidants. It publishes research papers, reviews and communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files and software regarding the full details of the calculation or experimental procedure, if unable to be published in a normal way, can be deposited as supplementary electronic material.
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