title: Mechanism of surface charge triggered intestinal epithelial tight junction opening upon chitosan nanoparticles for insulin oral delivery.
abstract: Intestinal epithelium is a major barrier limiting the absorption of oral insulin owing to the presence of intercellular tight junctions (TJs). Previous studies proved that carboxymethyl chitosan/chitosan-nanoparticles (CMCS/CS-NPs) exhibited surface charge depending promotion of intestinal absorption. This study further confirmed the better performances of insulin:CMCS/CS-NPs(-) in enhancing epithelial permeation, increasing bioavailability and extending blood duration of insulin than insulin:CMCS/CS-NPs(+). Immunohistochemistry sections found that TJs on jejunum epithelium completely disappeared in insulin:CMCS/CS-NPs(-) group, partially existed in insulin:CMCS/CS-NPs(+) group and appeared no change in control. Surface charges of CMCS/CS-NPs triggered intestinal epithelial TJs opening through different mechanisms. Although a down-regulation of TJs protein claudin-4 was detected in both nanoparticles groups, for phosphorylated claudin-4, the activating form, whose down-regulation occurred only in insulin:CMCS/CS-NPs(-) group. Counting upon synergetic effects of Ca2+deprivation from adherens junctions and claudin-4 dephosphorylation and degradation, CMCS/CS-NPs(-) triggered more extensive disintegration of TJs and stronger paracellular permeability than the positive.
authors.affiliation: College of Marine Life Science, Ocean University of China, Qingdao, 266003, PR China; College of Life Science, Linyi University, Shandong, 276005, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Marine Life Science, Ocean University of China, Qingdao, 266003, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Kong
authors.affiliation: Shandong Linyi Guolong Eco-Tech Co., Ltd., Lin'yi, 276034, PR China.
authors.forename: Zhenjin
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: College of Marine Life Science, Ocean University of China, Qingdao, 266003, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yan
authors.affiliation: College of Marine Life Science, Ocean University of China, Qingdao, 266003, PR China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yu
authors.affiliation: College of Marine Life Science, Ocean University of China, Qingdao, 266003, PR China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Cheng
authors.affiliation: College of Marine Life Science, Ocean University of China, Qingdao, 266003, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Feng
authors.affiliation: College of Marine Life Science, Ocean University of China, Qingdao, 266003, PR China. Electronic address: yaliu@ouc.edu.cn.
authors.forename: Ya
authors.initials: Y
authors.lastname: Liu
authors.affiliation: College of Marine Life Science, Ocean University of China, Qingdao, 266003, PR China. Electronic address: xgchen@ouc.edu.cn.
authors.forename: Xiguang
authors.initials: X
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D048271:Chitosan; D062506:Claudin-4 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004337:Drug Carriers; D065546:Drug Liberation; D007328:Insulin / Q000008:administration & dosage*; D007408:Intestinal Absorption; D053758:Nanoparticles; D051381:Rats; D019108:Tight Junctions / Q000187:drug effects*; D014018:Tissue Distribution
chemical_list: D062506:Claudin-4; D004337:Drug Carriers; D007328:Insulin; D048271:Chitosan
keywords: CMCS/CS nanoparticles; Claudin-4; Insulin oral; Surface charge; Tight junction