Loureirin C extracted from Dracaena cochinchinensis S.C. Chen prevents rotaviral diarrhea in mice by inhibiting the intestinal Ca2+-activated Cl− channels

Resina Draconis (RD) is the red resin of Dracaena cochinchinensis (Lour.) S.C. Chen and most used as a hemostatic drug in traditional Chinese medicine. Recent studies have reported that RD has a therapeutic effect on gastrointestinal diseases. Loureirin A, B, and C (LA, LB, and LC) are dihydrochalcone compounds isolated from RD.Dehydration is the primary cause of death in rotaviral diarrhea. Inhibition of Ca2+-activated Cl- channels (CaCCs)-mediated Cl- secretion significantly reduced fluid secretion in rotaviral diarrhea. RD was used to treat digestive diseases such as diarrhea and abdominal pain; however, the pharmacological mechanism remains unclear. This study investigated the effects of RD and loureirin on intestinal Cl- channels and their therapeutic effects on rotavirus-induced diarrhea, aiming to reveal RD's molecular basis, targets, and mechanisms for treating rotaviral diarrhea.Cell-based fluorescence quenching assays were used to examine the effect of RD and loureirin on Cl- channels activity. Electrophysiological properties were tested using short-circuit current experiments in epithelial cells or freshly isolated mouse intestinal tissue. Fecal water content, intestinal peristalsis rate, and smooth muscle contraction were measured in neonatal mice infected with SA-11 rotavirus before and after LC treatment or adult mice.RD, LA, LB, and LC inhibited CaCCs-mediated Cl- current in HT-29 cells and colonic epithelium. The inhibitory effect of LC on CaCCs was primarily on the apical side in epithelial cells, which may be partially produced by affecting cytoplasmic Ca2+ levels. LC significantly inhibited TMEM16A-mediated Cl- current. Characterization studies revealed that LC inhibited basolateral K+ channel activity without affecting Na+/K+-ATPase activity in the colonic epithelium. Although LC activated the cystic fibrosis transmembrane regulator in epithelial cells, its effect was not apparent in colonic epithelium. In vivo, LC significantly reduced the fecal water content, intestinal peristalsis rate, and smooth muscle contraction of mice infected with rotavirus.RD and its active compound LC inhibit intestinal CaCCs activity, which might mediate the anti-rotaviral diarrheal effect of RD.