UDP-α-D-Glucose (sodium), as a preferential agonist, activates the P2Y14 receptor, functions as an extracellular signaling molecule under conditions of cell injury and apoptosis[1-2]. P2Y14 is a neuroimmune system G protein-coupled receptor (GPCR). As a potent endogenous agonist with the highest affinity for the P2Y14 receptor, UDP-α-D-Glucose establishes an exclusive relationship between P2Y14 receptors in regulating inflammation via cyclic adenosine monophosphate (cAMP), nod-like receptor protein 3 (NLRP3) inflammasome, mitogen-activated protein kinases (MAPKs), and signal transducer and activator of transcription 1 (STAT1) pathways [1-2]. Moreover, UDP-α-D-Glucose serves as the precursor for glucose-containing oligosaccharides, polysaccharides, glycoproteins, and glycolipids in animal tissues and certain microorganisms[3].
In vitro, treating hepatic stellate cells (HSCs) with 10μM UDP-α-D-Glucose for 24 hours increased extracellular signal–regulated kinase (ERK) phosphorylation, upregulated α-smooth muscle actin (αSMA) and Acta2 mRNA, elevated Yes-associated protein (YAP), and increased expression of fibrogenic genes Lox, Col4a1, and Col8a1[4]. Treating GL261 cells with 300µM UDP-α-D-Glucose for 24 hours further reduced IL-6 levels in the transwell supernatants and decreased the proliferation of glioma cells by about 75%[5].
In vivo, eight-week-old wild-type mice treated with endotoxin-free PBS (2μl/g; intratracheal instillation) containing 10mM UDP-α-D-Glucose significantly increased the number of neutrophils in bronchoalveolar lavage (BAL) after dissection[6]. After tail vein injection of mice with 100μM UDP-α-D-Glucose (corresponding to 200mg/kg of body weight) for 4 hours, the recruitment of neutrophils to the renal medulla was induced[7].
References:
[1] Zhang JZ, Shi NR, Wu JS, Wang X, Illes P, Tang Y. UDP-glucose sensing P2Y14R: A novel target for inflammation. Neuropharmacology. 2023;238:109655.
[2] Das A, Ko H, Burianek LE, Barrett MO, Harden TK, Jacobson KA. Human P2Y(14) receptor agonists: truncation of the hexose moiety of uridine-5'-diphosphoglucose and its replacement with alkyl and aryl groups. J Med Chem. 2010;53(1):471-480.
[3] DietrichKeppler, et al. Uridine-5’-diphosphoglucose. Methods of Enzymatic Analysis (Second English Edition). 1974;4:2225-2228.
[4] Mederacke I, Filliol A, Affo S, et al. The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver. Sci Transl Med. 2022;14(639):eabe5795.
[5] Curet MA, Watters JJ. P2Y14 receptor activation decreases interleukin-6 production and glioma GL261 cell proliferation in microglial transwell cultures. J Neurooncol. 2018;137(1):23-31.
[6] Sesma JI, Weitzer CD, Livraghi-Butrico A, et al. UDP-glucose promotes neutrophil recruitment in the lung. Purinergic Signal. 2016;12(4):627-635.
[7] Azroyan A, Cortez-Retamozo V, Bouley R, et al. Renal intercalated cells sense and mediate inflammation via the P2Y14 receptor. PLoS One. 2015;10(3):e0121419.
UDP-α-D-Glucose (sodium)作为一种优先激动剂，能够激活 P2Y14 受体，并在细胞损伤和凋亡条件下作为细胞外信号分子发挥作用[1-2]。P2Y14 是神经系统和免疫系统中的一种 G 蛋白偶联受体（GPCR）。UDP-α-D-Glucose作为一种对 P2Y14 受体亲和力最高的强效内源性激动剂，通过环磷酸腺苷（cAMP）、NOD 样受体蛋白 3（NLRP3）炎症体、丝裂原活化蛋白激酶（MAPKs）和信号转导与转录激活因子 1（STAT1）途径调节炎症，从而确立了其与 P2Y14 受体之间的独特关系[1-2]。此外，UDP-α-D-Glucose还是动物组织及某些微生物中含葡萄糖的寡糖、多糖、糖蛋白和糖脂的前体物质[3]。
在体外，用 10µM 的 UDP-α-D-Glucose处理肝星状细胞（HSCs）24 小时，可以增加细胞外信号调节激酶（ERK）的磷酸化水平，上调 α-平滑肌肌动蛋白（αSMA）和 Acta2 mRNA 的表达，提高 Yes 相关蛋白（YAP）的水平，并增加纤维化相关基因 Lox、Col4a1 和 Col8a1 的表达[4]。用 300µM 的UDP-α-D-Glucose处理 GL261 细胞 24 小时，可进一步降低Transwell上清液中的白细胞介素-6（IL-6）水平，并使胶质瘤细胞的增殖减少约 75%[5]。
在体内，8 周龄野生型小鼠通过气管内灌注接受无内毒含有 10mM UDP-α-D-Glucose的磷酸盐缓冲液（PBS，2µl/g）处理后，支气管肺泡灌洗液（BAL）中的中性粒细胞数量显著增加[6]。通过尾静脉注射给予小鼠 100µM 的 UDP-α-D-Glucose（相当于 200mg/kg 体重）4 小时后，诱导中性粒细胞向肾髓质募集[7]。