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Gut:靶向FXR蛋白药物治疗肠道腹泻

来源:生物谷 2013-12-11 20:28

2013年12月12日讯 /生物谷BIOON/--近日,都柏林三一学院和约翰斯霍普金斯大学一起进行的一项消化病学研究,有望帮助开发出一类新的抗腹泻药物。新的抗腹泻药物将直接靶向肠道中细胞和分子过程(控制水运动进入小肠的过程)。

研究发现,药物作用于肠道组织中一个叫做法尼酯X受体(Farnesoid X Receptor,FXR)的蛋白质,药物能阻止水移动到肠道中。通过“关闭”水运动到肠道中,这样可以防止腹泻发生。首席研究员Stephen Keely说,腹泻病是常见的,但其安全且有效的治疗药物仍然缺乏。

研究发现,FXR是肠功能的重要调节剂,具有潜能成为一类新抗腹泻药物的作用位点。在爱尔兰,腹泻是每年消化内科诊所约40,000例门诊中的主要病例。急性感染性腹泻疫情是非常常见的,许多疾病如发炎性肠道疾病,消化系统疾病和肠易激综合症干扰肠道的正常功能,导致腹泻。

研究发现,针对FXR蛋白的药物,通过靶向肠道里的细胞,也正因为如此,这些药物将可以产生更广泛的疗效和较少的副作用(与市场上许多抗腹泻药物相比而言)。相关研究论文发表在国际期刊Gut上。(生物谷Bioon.com)


 

Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo

Magdalena S Mroz, Niamh Keating, Joseph B Ward, Rafiquel Sarker, Silvie Amu, Gabriella Aviello, Mark Donowitz, Padraic G Fallon, Stephen J Keely

Objective Bile acids are important regulators of intestinal physiology, and the nuclear bile acid receptor, farnesoid X receptor (FXR), is emerging as a promising therapeutic target for several intestinal disorders. Here, we investigated a role for FXR in regulating intestinal fluid and electrolyte transport and the potential for FXR agonists in treating diarrhoeal diseases.

Design Electrogenic ion transport was measured as changes in short-circuit current across voltage-clamped T84 cell monolayers or mouse tissues in Ussing chambers. NHE3 activity was measured as BCECF fluorescence in Caco-2 cells. Protein expression was measured by immunoblotting and cell surface biotinylation. Antidiarrhoeal efficacy of GW4064 was assessed using two in vivo mouse models: the ovalbumin-induced diarrhoea model and cholera toxin (CTX)-induced intestinal fluid accumulation.

Results GW4064 (5μmol/L; 24h), a specific FXR agonist, induced nuclear translocation of the receptor in T84 cells and attenuated Cl? secretory responses to both Ca2+ and cAMP-dependent agonists. GW4064 also prevented agonist-induced inhibition of NHE3 in Caco-2 cells. In mice, intraperitoneal administration of GW4064 (50 mg/mL) also inhibited Ca2+ and cAMP-dependent secretory responses across ex vivo colonic tissues and prevented ovalbumin-induced diarrhoea and CTX-induced intestinal fluid accumulation in vivo. At the molecular level, FXR activation attenuated apical Cl? currents by inhibiting expression of cystic fibrosis transmembrane conductance regulator channels and inhibited basolateral Na+/K+-ATPase activity without altering expression of the protein.

Conclusions These data reveal a novel antisecretory role for the FXR in colonic epithelial cells and suggest that FXR agonists have excellent potential for development as a new class of antidiarrheal drugs.

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