A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity.
A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity.
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一种新型肽通过刺激钠氢交换器 3 活性来防止肠毒素和炎症引起的肠液分泌。
DOI：
10.1053/j.gastro.2023.06.028
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发表时间：
2023
期刊：
影响因子：
29.4
通讯作者：
Donowitz,Mark
中科院分区：
文献类型：
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作者：
Zachos,NicholasC;Vaughan,Hannah;Sarker,Rafiquel;Est-Witte,Savannah;Chakraborty,Molee;Baetz,NicholasW;Yu,Hongzhe;Yarov-Yarovoy,Vladimir;McNamara,George;Green,JordanJ;Tse,Chung-Ming;Donowitz,Mark
背景与目的急性腹泻病是发展中国家婴儿死亡的第二大常见原因。这是由于缺乏有效的药物治疗来缩短持续时间或减少腹泻量。上皮刷状边界钠(Na+)/氢（H+）交换剂3 （NHE3）是肠道钠+吸收的主要组成部分，在大多数腹泻中被抑制。由于肠道Na+吸收增加可使腹泻患者补水，NHE3已被认为是腹泻药物治疗的潜在药物靶点。方法合成一种肽（钠氢交换3刺激肽[N3SP]），模拟NHE3 c端部分，形成抑制NHE3活性的多蛋白复合物。N3SP对NHE3转染成纤维细胞NHE3活性的影响被评估为与其他质膜NHEs(人类结肠癌细胞系，模拟肠道吸收肠细胞（Caco-2/BBe），人肠和小鼠肠道在体外和体内的作用。N3SP通过疏水荧光马来酰亚胺或纳米颗粒递送到细胞中。结果在基础条件下，sn3sp摄取刺激了nmol/L浓度的NHE3活性，部分逆转了细胞系和体外小鼠肠道中3′、5′-环单磷酸腺苷、3′、5′-环单磷酸鸟苷和Ca2+升高引起的NHE3活性降低。在活体小鼠肠环模型中，N3SP还能刺激小鼠小肠内的肠液吸收，阻止霍乱毒素-、大肠杆菌-稳定型肠毒素-和分化簇3炎症诱导的液体分泌。结论药物刺激NHE3活性是治疗中、重度腹泻的有效方法。
Background & AimsAcute diarrheal diseases are the second most common cause of infant mortality in developing countries. This is contributed to by lack of effective drug therapy that shortens the duration or lessens the volume of diarrhea. The epithelial brush border sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) accounts for a major component of intestinal Na+absorption and is inhibited in most diarrheas. Because increased intestinal Na+absorption can rehydrate patients with diarrhea, NHE3 has been suggested as a potential druggable target for drug therapy for diarrhea.MethodsA peptide (sodium-hydrogen exchanger 3 stimulatory peptide [N3SP]) was synthesized to mimic the part of the NHE3 C-terminus that forms a multiprotein complex that inhibits NHE3 activity. The effect of N3SP on NHE3 activity was evaluated in NHE3-transfected fibroblasts null for other plasma membrane NHEs, a human colon cancer cell line that models intestinal absorptive enterocytes (Caco-2/BBe), human enteroids, and mouse intestine in vitro and in vivo. N3SP was delivered into cells via a hydrophobic fluorescent maleimide or nanoparticles.ResultsN3SP uptake stimulated NHE3 activity at nmol/L concentrations under basal conditions and partially reversed the reduced NHE3 activity caused by elevated adenosine 3′,5′-cyclic monophosphate, guanosine 3′,5′-cyclic monophosphate, and Ca2+in cell lines and in in vitro mouse intestine. N3SP also stimulated intestinal fluid absorption in the mouse small intestine in vivo and prevented cholera toxin–,Escherichia coliheat-stable enterotoxin–, and cluster of differentiation 3 inflammation–induced fluid secretion in a live mouse intestinal loop model.ConclusionsThese findings suggest pharmacologic stimulation of NHE3 activity as an efficacious approach for the treatment of moderate/severe diarrheal diseases.