Penta-o-galloyl-beta-d-Glucose (PGG) inhibits inflammation in human rheumatoid arthritis synovial fibroblasts and rat adjuvant-induced arthritis model.
Penta-o-galloyl-beta-d-Glucose (PGG) inhibits inflammation in human rheumatoid arthritis synovial fibroblasts and rat adjuvant-induced arthritis model.
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DOI：
10.3389/fimmu.2022.928436
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发表时间：
2022
影响因子：
7.3
通讯作者：
Ahmed, Salahuddin
中科院分区：
文献类型：
--
作者：
Umar, Sadiq;Singh, Anil K.;Chourasia, Mukesh;Rasmussen, Stephanie M.;Ruth, Jeffrey H.;Ahmed, Salahuddin
关键词：
o - glcn酰化是一种可逆的翻译后修饰，调节许多细胞过程，包括胚胎发育和免疫反应。然而，它在炎症中的作用仍然不明确。本研究旨在研究o - glcn酰化在类风湿关节炎（RA）中的作用，并利用人RA患者衍生的滑膜成纤维细胞（rasf）来研究其调控作用。五- o -没食子酰- β - d -葡萄糖（PGG），一种有效的抗炎分子，在调节人类rasf炎症过程中的功效也被评估。与未患病的滑膜组织和rasf相比，人类滑膜组织和rasf表现出更高的o - glcn酰化表达。用O-GlcNAcase抑制剂Thiamet G预处理rasf，可显著增加o - glcnac修饰的蛋白，同时抑制il -1β诱导的体外人rasf中IL-6和IL-8的产生。用PGG（0.5-10µM）预处理人rasf， il -1β诱导的IL-6和IL-8的产生呈剂量依赖性。免疫沉淀分析显示，PGG抑制TAB1的o - glcn酰化，减少其与TGF β-活化激酶1 （TAK1）的关联及其自磷酸化，这是il -1β诱导的信号通路中必不可少的信号步骤。分子对接的计算机研究表明，PGG占据了激酶结构域的C174位点，这是一个抑制TAK1激酶活性的atp结合位点。发病后10天口服PGG （25 mg/kg/天）可显著改善大鼠佐剂诱导（AIA）。与AIA关节相比，PGG治疗降低了治疗关节中TAK1的磷酸化，这与疾病严重程度降低和血清IL-1β、GM-CSF、TNF-α和RANKL水平的抑制相关。这些发现提示o - glcn酰化是一个潜在的治疗靶点，并为检测PGG或结构类似分子的治疗效果提供了依据。
O-GlcNAcylation is a reversible post-translational modification that regulates numerous cellular processes, including embryonic development as well as immune responses. However, its role in inflammation remains ambiguous. This study was designed to examine the role of O-GlcNAcylation in rheumatoid arthritis (RA) and its regulation using human RA patient-derived synovial fibroblasts (RASFs). The efficacy of penta-O-galloyl-beta-D-glucose (PGG), a potent anti-inflammatory molecule, in regulating inflammatory processes in human RASFs was also evaluated. Human synovial tissues and RASFs exhibited higher expression of O-GlcNAcylation compared to their non-diseased counterparts. Pretreatment of RASFs with Thiamet G, an inhibitor of O-GlcNAcase, markedly increased the O-GlcNAc-modified proteins and concomitantly inhibited the IL-1β-induced IL-6 and IL-8 production in human RASFs in vitro. Pretreatment of human RASFs with PGG (0.5-10 µM) abrogated IL-1β-induced IL-6 and IL-8 production in a dose-dependent manner. Immunoprecipitation analysis showed that PGG inhibited O-GlcNAcylation of TAB1 to reduce its association with TGF β-activated kinase 1 (TAK1) and its autophosphorylation, an essential signaling step in IL-1β-induced signaling pathways. Molecular docking in silico studies shows that PGG occupies the C174 position, an ATP-binding site in the kinase domain to inhibit TAK1 kinase activity. Oral administration of PGG (25 mg/kg/day) for 10 days from disease onset significantly ameliorated rat adjuvant-induced (AIA) in rats. PGG treatment reduced the phosphorylation of TAK1 in the treated joints compared to AIA joints, which correlated with the reduced disease severity and suppressed levels of serum IL-1β, GM-CSF, TNF-α, and RANKL. These findings suggest O-GlcNAcylation as a potential therapeutic target and provide the rationale for testing PGG or structurally similar molecule for their therapeutic efficacy.
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p65的O连接N-乙酰葡萄糖糖基化加剧了肿瘤坏死因子-α刺激的成纤维细胞样的滑膜细胞和胶原蛋白诱导的关节炎刺激的炎症。
影响因子：
4.9
作者：
Kim HB;Lee SW;Mun CH;Yoon JY;Pai J;Shin I;Park YB;Lee SK;Cho JW
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Cho JW
DOI：
10.1073/pnas.0510802103
发表时间：
2006-02-21
影响因子：
11.1
作者：
Davis, CN;Mann, E;Bartfai, T
通讯作者：
Bartfai, T
结合化学酶标记、无铜点击化学、还原裂解和电子转移解离质谱进行 O-GlcNAc 位点定位
影响因子：
7.4
作者：
Ma, Junfeng;Wang, Wei-Han;Hart, Gerald W.
通讯作者：
Hart, Gerald W.
DOI：
10.1016/j.biocel.2009.12.023
发表时间：
2010-05-01
影响因子：
4
作者：
Landstrom, Marene
通讯作者：
Landstrom, Marene
影响因子：
7.3
作者：
Jang, Se-Eun;Hyam, Supriya R.;Kim, Dong-Hyun
通讯作者：
Kim, Dong-Hyun