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首页> 外文期刊>The FEBS journal >Novel synthetic gluco-disaccharide RSCL-0409 - a lipopolysaccharide-induced Toll-like receptor-mediated signalling antagonist
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Novel synthetic gluco-disaccharide RSCL-0409 - a lipopolysaccharide-induced Toll-like receptor-mediated signalling antagonist

机译：新型合成葡萄糖二糖RSCL-0409-脂多糖诱导的Toll样受体介导的信号传导拮抗剂

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摘要

The regulation of cytokines and pro-inflammatory genes is an absolute essentiality to combat inflammatory diseases. The present study investigated the effects of 4-O-chloroacetyl-2,3-di-O-acetyl-6-O-levulinoyl-o- d-glucopyranosyl]-(1-3)-1-O-(p-methoxyphenyl)-2-deoxy-2-N-trichloroacetyl-4,6-O-benzylidene-l- d-glucopyranoside (RSCL-0409), a novel small molecule Toll-like receptor (TLR) signalling antagonist, and its mechanism of action in human monocytic (THP-1) cells stimulated with lipopolysaccharide (LPS). In THP-1 and RAW264.7 cells, RSCL-0409 suppressed LPS-induced production of tumour necrosis factor-l (TNF-l) with a 50% inhibitory concentration of 10.6 o m and mRNA expression of ICAM-1, Cox-2 and interleukin-8 with no evidence of cytotoxicity. RSCL-0409 also suppressed TNF-l production from LPS-stimulated human peripheral blood mononuclear cells. Similar results were obtained in vivo in a murine model of LPS-induced inflammation, where pretreatment with RSCL-0409 resulted in significant inhibition of TNF-l. It is also noteworthy that RSCL-0409 suppressed the cytokine production induced by TLR2 and -4 ligands and not for any other TLR ligands. RSCL-0409 significantly inhibited p65 nuclear translocation induced by LPS. In conclusion, RSCL-0409, a novel small molecule, is the first of its kind in the category of carbohydrate-derived TLR signalling antagonists and could definitely be a promising therapeutic agent for inflammatory diseases whose pathogenesis involves TLR2- or TLR4-mediated signalling processes.
机译：细胞因子和促炎基因的调节是抵抗炎性疾病的绝对必要条件。本研究调查了4-O-氯乙酰基-2,3-二-O-乙酰基-6-O-乙酰丙酰基-o-d-吡喃葡萄糖基]-（1-3）-1-O-（对甲氧基苯基）的作用新型小分子Toll样受体（TLR）信号拮抗剂）-2-脱氧-2-N-三氯乙酰基-4,6-O-亚苄基-1-d-吡喃葡萄糖苷（RSCL-0409）及其作用机理脂多糖（LPS）刺激的人单核细胞（THP-1）细胞中的作用。在THP-1和RAW264.7细胞中，RSCL-0409抑制LPS诱导的肿瘤坏死因子-1（TNF-1）的产生，其50％抑制浓度为10.6 om，ICAM-1，Cox-2和ICAM的mRNA表达。白细胞介素8，无细胞毒性证据。 RSCL-0409还抑制了LPS刺激的人外周血单核细胞产生TNF-1。在LPS诱导的炎症的鼠模型中，在体内获得了相似的结果，其中用RSCL-0409的预处理导致对TNF-1的显着抑制。还值得注意的是，RSCL-0409抑制了由TLR2和-4配体诱导的细胞因子产生，而不是任何其他TLR配体。 RSCL-0409显着抑制LPS诱导的p65核易位。总之，新型的小分子RSCL-0409在碳水化合物衍生的TLR信号拮抗剂中是首个此类药物，并且绝对可以作为炎症性疾病的理想治疗剂，其发病机理涉及TLR2或TLR4介导的信号传导过程。

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