Satitsri Saravut, Khumjiang Rungtiwa, Tansakul Chittreeya, Chiangjong Wararat, Apichaiyarat Nuttapon, Kitiyakara Taya, Purintrapibal Yanisa, Rukachaisirikul Vatcharin, Muanprasat Chatchai
Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakarn, Thailand.
Division of Physical Science and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Songkhla, Thailand.
Pharm Biol. 2025 Dec;63(1):645-662. doi: 10.1080/13880209.2025.2544930. Epub 2025 Aug 22.
cAMP-induced intestinal chloride secretion plays a pivotal role in the pathogenesis of secretory diarrheas.
In this study, we investigated the antisecretory effects of α,β-dehydromonacolin K, a derivative of lovastatin from , on cAMP-induced chloride secretion in human T84 cells and fluid secretion in human colonoids.
Short-circuit current analyses and swelling assays were used to investigate the effects of α,β-dehydromonacolin K on chloride transport and fluid secretion, respectively. Proteomic analyses were performed to determine the potential anti-diarrheal mechanisms of α,β-dehydromonacolin K.
In T84 cells, α,β-dehydromonacolin K inhibited cAMP-induced chloride secretion with an IC of ∼ 6.32 μM. Apical chloride current analyses demonstrated that α,β-dehydromonacolin K inhibited CFTR chloride channels stimulated by cAMP agonists with an IC of ∼ 1 μM. Basolateral potassium current analyses indicated that α,β-dehydromonacolin K had no effect on basolateral potassium channel activities. In a three-dimensional (3D) model of human colonoids, α,β-dehydromonacolin K (20 µM) suppressed both cAMP-induced and calcium-induced fluid secretion by ∼ 70%. Proteomic analyses of human colonoids revealed that α,β-dehydromonacolin K interacted with 33 proteins, including those associated with non-sense-mediated mRNA decay (NMD). Notably, the inhibitory effects of α,β-dehydromonacolin K on cAMP-induced chloride and fluid secretion were significantly diminished in the presence of SMG1i, an inhibitor of serine/threonine-protein kinase SMG1 involved in NMD, suggesting that α,β-dehydromonacolin K inhibits cAMP-induced chloride-driven fluid secretion in human intestinal epithelial cells by mechanisms involving SMG1-dependent NMD pathways.
α, β-Dehydromonacolin K represents a promising class of natural compounds that exert antisecretory effects in human intestinal epithelia a novel mechanism of action involving SMG1 in NMD pathways.
环磷酸腺苷（cAMP）诱导的肠道氯化物分泌在分泌性腹泻的发病机制中起关键作用。
在本研究中，我们研究了洛伐他汀衍生物α,β-脱氢莫纳可林K对人T84细胞中cAMP诱导的氯化物分泌以及人结肠类器官中液体分泌的抗分泌作用。
分别采用短路电流分析和肿胀试验来研究α,β-脱氢莫纳可林K对氯化物转运和液体分泌的影响。进行蛋白质组学分析以确定α,β-脱氢莫纳可林K潜在的抗腹泻机制。
在T84细胞中，α,β-脱氢莫纳可林K抑制cAMP诱导的氯化物分泌，半数抑制浓度（IC）约为6.32 μM。顶端氯化物电流分析表明，α,β-脱氢莫纳可林K抑制cAMP激动剂刺激的囊性纤维化跨膜传导调节因子（CFTR）氯化物通道，IC约为1 μM。基底外侧钾电流分析表明，α,β-脱氢莫纳可林K对基底外侧钾通道活性没有影响。在人结肠类器官的三维（3D）模型中，α,β-脱氢莫纳可林K（20 μM）将cAMP诱导的和钙诱导的液体分泌均抑制了约70%。人结肠类器官的蛋白质组学分析显示，α,β-脱氢莫纳可林K与33种蛋白质相互作用，包括那些与无义介导的mRNA降解（NMD）相关的蛋白质。值得注意的是，在存在丝氨酸/苏氨酸蛋白激酶SMG1（参与NMD）的抑制剂SMG1i的情况下，α,β-脱氢莫纳可林K对cAMP诱导的氯化物和液体分泌的抑制作用显著减弱，这表明α,β-脱氢莫纳可林K通过涉及SMG1依赖性NMD途径的机制抑制人肠上皮细胞中cAMP诱导的氯化物驱动的液体分泌。
α,β-脱氢莫纳可林K代表了一类有前景的天然化合物，它们在人肠上皮细胞中发挥抗分泌作用 这是一种涉及NMD途径中SMG1的新作用机制。
