A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity.

Autor:	Zachos NC; Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: n.zachos@vumc.org., Vaughan H; Translational Tissue Engineering Center, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland., Sarker R; Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Est-Witte S; Translational Tissue Engineering Center, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland., Chakraborty M; Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Baetz NW; Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Yu H; Translational Tissue Engineering Center, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland., Yarov-Yarovoy V; Department of Physiology and Membrane Biology, University of California Davis, Davis, California; Department of Anesthesiology and Pain Medicine, University of California Davis, Davis, California., McNamara G; Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Green JJ; Translational Tissue Engineering Center, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland., Tse CM; Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Donowitz M; Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: mdonowit@jhmi.edu.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2023 Oct; Vol. 165 (4), pp. 986-998.e11. Date of Electronic Publication: 2023 Jul 08.
DOI:	10.1053/j.gastro.2023.06.028
Abstrakt:	Background & Aims: Acute 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. Methods: A 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. Results: N3SP 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 Ca 2+ 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 coli heat-stable enterotoxin-, and cluster of differentiation 3 inflammation-induced fluid secretion in a live mouse intestinal loop model. Conclusions: These findings suggest pharmacologic stimulation of NHE3 activity as an efficacious approach for the treatment of moderate/severe diarrheal diseases. (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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