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Lipoxin A4 and its analog suppress inflammation by modulating HMGB1 translocation and expression in psoriasis.
Scientific Reports ( IF 3.8 ) Pub Date : 2017-Aug-02 , DOI: 10.1038/s41598-017-07485-1
Xinxin Liu , Xin Wang , Xiaoru Duan , Devesh Poorun , Juntao Xu , Song Zhang , Lu Gan , Mengwen He , Ke Zhu , Zhangyin Ming , Feng Hu , Hongxiang Chen

Psoriasis is a chronic inflammatory skin disease that affects 2-3% of the global population, and there is still no known possibility of a cure. Lipoxin A4 (LXA4), an endogenous lipoxygenase-derived eicosanoid mediator, has potent dual pro-resolving and anti-inflammatory properties. BML-111 (5(S)-6(R)-7-trihydroxyheptanoic acid methyl ester), a lipoxin receptor agonist, has been previously confirmed to be equivalent to LXA4 in the anti-inflammatory processes. High mobility group box 1 (HMGB1) serves as an inflammatory cytokine when secreted extracellularly in psoriatic lesions and is involved in the development of psoriasis. Therefore, we investigated the effects of LXA4 and BML-111 on the HMGB1 signaling cascade and inflammation in lipopolysaccharide (LPS)-induced keratinocytes and imiquimod (IMQ)-induced psoriasiform dermatitis in mice. In the present study, we found that treatment with BML-111 attenuated the development of IMQ-induced psoriasiform dermatitis. Furthermore, treatment with BML-111 and LXA4 inhibited HMGB1 translocation from the nucleus to cytoplasm and downregulated the expression of toll-like receptor 4 (TLR4), receptor for advanced glycation end products (RAGE), p-ERK1/2, nuclear NF-κB p65, and proinflammatory cytokines in vivo and in vitro. Our findings indicate that LXA4 and its analog may be potential therapeutic candidates for psoriasis because of their ability to modulate the translocation and expression of HMGB1.

中文翻译:

Lipoxin A4及其类似物可通过调节HMGB1易位和在牛皮癣中的表达来抑制炎症。

银屑病是一种慢性炎症性皮肤病,影响了全球2-3%的人口,目前尚无治愈的可能。脂氧合蛋白A4(LXA4)是一种内源性脂氧合酶衍生的类二十烷酸介质,具有强大的双重促分解和抗炎特性。BML-111(5(S)-6(R)-7-三羟基庚酸甲酯),一种脂蛋白受体激动剂,先前已被证实在抗炎过程中等同于LXA4。高迁移率族盒1(HMGB1)在牛皮癣病变的细胞外分泌时起炎症细胞因子的作用,并参与牛皮癣的发展。因此,我们调查了LXA4和BML-111对HMGB1信号级联和脂多糖(LPS)诱导的角质形成细胞和咪喹莫特(IMQ)诱导的银屑病皮炎的炎症的影响。在本研究中,我们发现用BML-111进行治疗可减轻IMQ诱导的牛皮癣性皮炎的发展。此外,用BML-111和LXA4处理可抑制HMGB1从细胞核转移至细胞质,并下调Toll样受体4(TLR4),晚期糖基化终产物的受体(RAGE),p-ERK1 / 2,核NF- κBp65和体内和体外促炎细胞因子。我们的发现表明,由于LXA4及其类似物调节HMGB1的转运和表达的能力,它们可能是牛皮癣的潜在治疗候选物。BML-111和LXA4处理可抑制HMGB1从细胞核转移至细胞质,并下调Toll样受体4(TLR4),晚期糖基化终产物受体(RAGE),p-ERK1 / 2,核NF-κBp65的表达,以及体内和体外促炎细胞因子。我们的发现表明,由于LXA4及其类似物调节HMGB1的转运和表达的能力,它们可能是牛皮癣的潜在治疗候选物。BML-111和LXA4处理可抑制HMGB1从细胞核转移至细胞质,并下调Toll样受体4(TLR4),晚期糖基化终末产物受体(RAGE),p-ERK1 / 2,核NF-κBp65的表达,以及体内和体外促炎细胞因子。我们的发现表明,由于LXA4及其类似物调节HMGB1的转运和表达的能力,它们可能是牛皮癣的潜在治疗候选物。
更新日期:2017-08-02
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