Mechanism and consequence of chitosan-mediated reversible epithelial tight junction opening

Yeh, Tzyy-Harn; Hsu, Li-Wen; Tseng, Michael T.; Lee, Pei-Ling; Sonjae, Kiran; Ho, Yi Cheng; Sung, Hsing‐Wen

doi:10.1016/j.biomaterials.2011.03.056

Cited by 306 publications

(189 citation statements)

References 38 publications

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“…Recently, β-arrestin1 and β-arrestin2 have been found to mediate internalization of proteins that are not GPCRs, such as transient receptor potential vanilloid subtype 4 and vascular endothelial cadherin (Shukla et al, 2010;Yeh et al, 2011). Here, we revealed that mAChR activation promoted the interaction between claudin-4 and β-arrestin2, but not β-arrestin1.…”

Section: Discussionsupporting

confidence: 47%

“…The well-balanced amounts of tight junction proteins in the apical cell membranes guarantee their function as regulators for paracellular transport (Schulzke et al, 2012). Previous studies have shown that the impact on paracellular permeability induced by different stimulators can be either reversible or irreversible due to their effects on the content and distribution of tight junctions Yeh et al, 2011). Here, we found that carbachol removal caused a partial TER recovery at 5 min, but was followed by irreversible TER responses at both 10 and 30 min, which implies that mAChR activation modulates paracellular permeability by influencing the content and distribution of tight junctions.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have reported that the internalized proteins can be either recycled to the membrane or degraded in the cytoplasm through the ubiquitin-proteasome pathway (Gavard and Gutkind, 2006;Yeh et al, 2011). Accordingly, we decided to determine whether the carbachol-induced intracellular claudin-4 was degraded by ubiquitylation.…”

Section: Carbachol Downregulates Claudin-4 Protein Through Ubiquitylamentioning

confidence: 98%

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Claudin-4 is required for modulation of paracellular permeability by muscarinic acetylcholine receptor in epithelial cells

Cong

Zhang

et al. 2015

Journal of Cell Science

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The epithelial cholinergic system plays an important role in water, ion and solute transport. Previous studies have shown that activation of muscarinic acetylcholine receptors (mAChRs) regulates paracellular transport of epithelial cells; however, the underlying mechanism is still largely unknown. Here, we found that mAChR activation by carbachol and cevimeline reduced the transepithelial electrical resistance (TER) and increased the permeability of paracellular tracers in rat salivary epithelial SMG-C6 cells. Carbachol induced downregulation and redistribution of claudin-4, but not occludin or ZO-1 (also known as TJP1). Small hairpin RNA (shRNA)-mediated claudin-4 knockdown suppressed, whereas claudin-4 overexpression retained, the TER response to carbachol. Mechanistically, the mAChR-modulated claudin-4 properties and paracellular permeability were triggered by claudin-4 phosphorylation through ERK1/2 (also known as MAPK3 and MAPK1, respectively). Mutagenesis assay demonstrated that S195, but not S199, S203 or S207, of claudin-4, was the target for carbachol. Subsequently, the phosphorylated claudin-4 interacted with β-arrestin2 and triggered claudin-4 internalization through the clathrin-dependent pathway. The internalized claudin-4 was further degraded by ubiquitylation. Taken together, these findings suggested that claudin-4 is required for mAChR-modulated paracellular permeability of epithelial cells through an ERK1/2, β-arrestin2, clathrin and ubiquitin-dependent signaling pathway.

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Section: Discussionsupporting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Section: Carbachol Downregulates Claudin-4 Protein Through Ubiquitylamentioning

confidence: 98%

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Claudin-4 is required for modulation of paracellular permeability by muscarinic acetylcholine receptor in epithelial cells

Cong

Zhang

et al. 2015

Journal of Cell Science

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“…14) In the case of exendin-4, there was no observable effect on either cell viability or cell monolayer permeability. These results clearly showed that both exendin-4 and exendin-4-loaded chitosan nanoparticles were safe and biocompatible.…”

Section: Formulation and Characterization Of Nanoparticlesmentioning

confidence: 96%

“…13) Recently, it was found that chitosan treatment of Caco-2 cell monolayers at pH 6.4 could still lead to a redistribution of claudin-4 from the cell membrane to the cytosol followed by lysosomal degradation, ultimately resulting in a decrease in tight junction integrity and an increase in paracellular permeability. 14) These new insights suggest that the disruption of tight junctions probably occurs through multiple mechanisms. Besides increasing permeability, chitosan exhibits its mucoadhesive property via interacting with negatively charged sialic acid residues on mucin at physiological pH.…”

Section: )mentioning

confidence: 99%

Permeability of Exendin-4-Loaded Chitosan Nanoparticles across MDCK Cell Monolayers and Rat Small Intestine

Wang

Zhang

Sun

et al. 2014

Biological & Pharmaceutical Bulletin

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The purpose of this study was to investigate the permeability of exendin-4-loaded chitosan nanoparticles using the Madin Darby canine kidney (MDCK) cell monolayer as an in vitro model and the rat intestine as an ex vivo model of the human intestinal barrier. A series of formulations of sodium tripolyphosphate (TPP) and chitosan with different molecular weights and degrees of deacetylation was evaluated. The formulation consisting of 0.1% TPP and 0.2% chitosan (400 kDa, 95% degree of deacetylation), which gave optimized monodispersed particle size (303.1 10.36 nm), zeta potential (18.37 1.15 mV) and encapsulation efficiency (38.0 2.6%), was used for further analysis. After determining their biocompatibility, the transport potential of drug-loaded chitosan nanoparticles was evaluated and compared with free exendin-4 using both MDCK cell monolayers and different rat intestinal segments. Mechanisms underlying enhanced transport of exendin-4 in the cell model were also explored. Compared with free exendin-4, the absorption of optimized chitosan nanoparticles was enhanced by 4.7-fold in MDCK cell monolayers and by 2.0-2.78-fold in different rat intestinal segments, with no significant difference between the duodenum, jejunum and ileum. As supported by confocal laser scanning microscopic analysis, the lower enhancement of absorption in the intestine compared to the cell monolayer likely resulted from the chitosan nanoparticle-mediated opening of cellular tight junctions and not through intracellular transport. These findings suggest that the potential application of chitosan nanoparticles as delivery carriers of exendin-4 is limited and may need further modifications.

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Chitosan and Trimethyl Chitosan (TMC) as Drug Absorption Enhancers

Benediktsdóttir

2020

Encyclopedia of Marine Biotechnology

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Mechanism and consequence of chitosan-mediated reversible epithelial tight junction opening

Cited by 306 publications

References 38 publications

Claudin-4 is required for modulation of paracellular permeability by muscarinic acetylcholine receptor in epithelial cells

Claudin-4 is required for modulation of paracellular permeability by muscarinic acetylcholine receptor in epithelial cells

Permeability of Exendin-4-Loaded Chitosan Nanoparticles across MDCK Cell Monolayers and Rat Small Intestine

Chitosan and Trimethyl Chitosan (TMC) as Drug Absorption Enhancers

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