title: A novel perspective and approach to intestinal octreotide absorption: sinomenine-mediated reversible tight junction opening and its molecular mechanism.
abstract: In this work, we assessed the effects of sinomenine (SN) on intestinal octreotide (OCT) absorption both in Caco-2 cell monolayers and in rats. We also investigated the molecular mechanisms of tight junction (TJ) disruption and recovery by SN-mediated changes in the claudin-1 and protein kinase C (PKC) signaling pathway. The data showed that exposure to SN resulted in a signiﬁcant decrease in the expression of claudin-1, which represented TJ weakening and paracellular permeability enhancement. Then, the recovery of TJ after SN removal required an increase in claudin-1, which demonstrated the transient and reversible opening for TJ. Meanwhile, the SN-mediated translocation of PKC-α from the cytosol to the membrane was found to prove PKC activation. Finally, SN significantly improved the absolute OCT bioavailability in rats and the transport rate in Caco-2 cell monolayers. We conclude that SN has the ability to enhance intestinal OCT absorption and that these mechanisms are related at least in part to the important role of claudin-1 in SN-mediated, reversible TJ opening via PKC activation.
authors.affiliation: Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China. cathydoctor@sina.com.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Li
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Duan
authors.forename: Yan
authors.initials: Y
authors.lastname: Tian
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Qiuming
authors.initials: Q
authors.lastname: Wang
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism; D017097:Electric Impedance; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D009019:Morphinans / Q000494:pharmacology*; D015282:Octreotide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*
chemical_list: D062445:Claudin-1; D009019:Morphinans; D012333:RNA, Messenger; C009271:sinomenine; D051571:Protein Kinase C-alpha; D015282:Octreotide