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Pharmacol Res. 2018 Mar;129:453-461. doi: 10.1016/j.phrs.2017.11.016. Epub 2017 Nov 14.

Resveratrol dimer trans-ε-viniferin prevents rotaviral diarrhea in mice by inhibition of the intestinal calcium-activated chloride channel.

Author information

1
School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, PR China.
2
School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, PR China; College of Life Science, Jilin Agricultural University, Changchun, PR China.
3
Institute of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, PR China.
4
School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, PR China. Electronic address: hyanglnnu@126.com.
5
Institute of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, PR China. Electronic address: tonghuima@dlmedu.edu.cn.

Abstract

We previously identified, by a natural-product screen, resveratrol oligomers as inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Here, we report the resveratrol dimer trans-ε-viniferin (TV) and tetramer r-2-viniferin (RV) as inhibitors of the intestinal calcium-activated chloride channel (CaCC) and demonstrate their antisecretory efficacy in a neonatal mouse model of rotaviral diarrhea. Short-circuit measurements show inhibition of CaCC current in the human colonic cell line HT-29 by TV and RV with IC50∼1 and 20μM, respectively. TV primarily inhibited the physiologically relevant, long-term CaCC current following agonist stimulation, without effect on cytoplasmic Ca2+ signaling. TV and RV inhibited short-circuit current in mouse colon as well. In a neonatal mouse model of rotaviral secretory diarrhea produced by oral inoculation with rotavirus, 2μg TV or 11μg RV inhibited secretory diarrhea by >50%, without effect on the rotaviral infection. Our results support the antisecretory efficacy of non-toxic, natural-product resveratrol oligomers for diarrheas produced by CaCC activation. Because these compounds also inhibit the CFTR chloride channel, they may be useful for antisecretory therapy of a wide range of diarrheas.

KEYWORDS:

Amiloride (PubChem CID: 16231); CFTR; CFTR(inh)-172 (PubChem CID: 1554208); CaCC; CaCC(inh)-A01 (PubChem CID: 747219); Clotrimazole (PubChem CID: 2812); Forskolin (PubChem CID: 47936); Ionomycin (PubChem CID: 6912226); R-2-viniferin (PubChem CID: 44251742); Rotavirus; Secretory diarrhea; T16A(inh)-A01 (PubChem CID: 3193184); Tannic acid (PubChem CID: 16129778); Thapsigargin (PubChem CID: 446378); Trans-ε-viniferin (PubChem CID: 5315232); trans-ε-Viniferin

PMID:
29155014
DOI:
10.1016/j.phrs.2017.11.016
[Indexed for MEDLINE]

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