Direct inhibition of the first PDZ domain of ZO-1 by glycyrrhizin is a possible mechanism of tight junction opening of Caco-2 cells

Hibino, Emi; Goda, Nobuhito; Hisada, Misaki; Tenno, Takeshi; Hiroaki, Hidekazu

doi:10.1039/d1fo03062k

Cited by 3 publications

(4 citation statements)

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“…We previously succeeded in determining the solution structure of mouse ZO-1(PDZ1) using solution NMR experiments found that the C-terminal peptide of CLD-3 and phosphatidylinositol phosphate competitively bound to the canonical peptide binding site of ZO-1(PDZ1) [ 16 ]. In a recent study, ZO-1(PDZ1) was directly inhibited by glycyrrhizin, which prolongs TJ-opening induced by deoxycholate in the Caco-2 cell monolayer [ 33 ]. These results suggest that the direct binding of a small molecule ligand to the CLD binding site of ZO-1(PDZ1) may inhibit the physiologically important interaction between ZO-1(PDZ1) and CLDs, which may result in the malformation of TJ or at least disturb TJ integrity in epithelial cells.…”

Section: Resultsmentioning

confidence: 99%

“…We previously succeeded in determining the solution structure of mous 1(PDZ1) using solution NMR experiments found that the C-terminal peptide of and phosphatidylinositol phosphate competitively bound to the canonical peptide ing site of ZO-1(PDZ1) [16]. In a recent study, ZO-1(PDZ1) was directly inhibi glycyrrhizin, which prolongs TJ-opening induced by deoxycholate in the Caco-2 cel olayer [33]. These results suggest that the direct binding of a small molecule ligand…”

Section: Nmr Evidence Of Direct Binding Of Hst But Not Que To Zo-1(pdz1)mentioning

confidence: 99%

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Pharmacologic Comparison of High-Dose Hesperetin and Quercetin on MDCK II Cell Viability, Tight Junction Integrity, and Cell Shape

et al. 2023

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The modulation of tight junction (TJ) integrity with small molecules is important for drug delivery. High-dose baicalin (BLI), baicalein (BLE), quercetin (QUE), and hesperetin (HST) have been shown to open TJs in Madin-Darby canine kidney (MDCK) II cells, but the mechanisms for HST and QUE remain unclear. In this study, we compared the effects of HST and QUE on cell proliferation, morphological changes, and TJ integrity. HST and QUE were found to have opposing effects on the MDCK II cell viability, promotion, and suppression, respectively. Only QUE, but not HST, induced a morphological change in MDCK II into a slenderer cell shape. Both HST and QUE downregulated the subcellular localization of claudin (CLD)-2. However, only QUE, but not HST, downregulated CLD-2 expression. Conversely, only HST was shown to directly bind to the first PDZ domain of ZO-1, a key molecule to promote TJ biogenesis. The TGFβ pathway partially contributed to the HST-induced cell proliferation, since SB431541 ameliorated the effect. In contrast, the MEK pathway was not involved by both the flavonoids, since U0126 did not revert their TJ-opening effect. The results offer insight for using HST or QUE as naturally occurring absorption enhancers through the paracellular route.

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Section: Resultsmentioning

confidence: 99%

Section: Nmr Evidence Of Direct Binding Of Hst But Not Que To Zo-1(pdz1)mentioning

confidence: 99%

Pharmacologic Comparison of High-Dose Hesperetin and Quercetin on MDCK II Cell Viability, Tight Junction Integrity, and Cell Shape

et al. 2023

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“…Sodium deoxycholate can open the TJs of the Caco-2 monolayer model, activate the paracellular pathway, reduce the TEER value, and increase the amount of the hydrophilic substance in the paracellular pathway; therefore, we selected sodium deoxycholate as the paracellular absorption promoter. The tolerance concentrations of QMDDQ and sodium deoxycholate in Caco-2 cells were determined by the MTT assay.…”

Section: Resultsmentioning

confidence: 99%

“…Liang et al used a Caco-2 cell model to study the effects of total coumarins and volatile oils in radix Angelica dahurica on cell permeability by inhibiting the expression of ZO-1 and actin and opening TJs. Hibino et al used NMR experiments and Haddock construction to study the combination of glycyrrhizin and the first PDZ domain of ZO-1 (ZO-1 (PDZ1)), which directly inhibits the expression of ZO-1, regulates the integrity of TJs, and enhances absorption. Claudin-2 is an important selective pore-forming TJ protein in the intestinal epithelium, which can form small cations and water paracellular channels; the expression of claudin-2 was contrary to that of ZO-1 and occludin.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Intestinal Epithelial Absorption and Electrophysiological Regulation of the Shrimp Peptide QMDDQ

Li,

Song

et al. 2023

J. Agric. Food Chem.

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We investigated the absorption mechanism of the shrimp peptide QMDDQ in small intestines, explored its physiological function in inhibiting neuronal hyperactivity, and verified its entry into the brain in vivo to display functional activity. The everted rat sac model and a Caco-2 paracellular absorption monolayer model were used, indicating that QMDDQ has a good absorption capacity with an apparent permeability coefficient (P app ) > 1 × 10 −6 cm/s and the absorption of QMDDQ was concentration-dependent. When the concentration of QMDDQ was 1 mM and the transport time was 180 min, the highest absorption concentration of QMDDQ was 41.17 ± 3.48 μM (P < 0.05). The myosin light-chain kinase (MLCK)-specific inhibitor ML-7 and activator MPA, Western blotting, and immunofluorescence results showed that QMDDQ absorption takes place by mediating the MLCK-p-MLCK-MLC signaling pathway, reversibly opening the zonula occludens-1 (ZO-1), occludin in tight junctions (TJs), upregulating claudin-2 expression, and reaching targets through blood to inhibit neuronal overactivity. Results of fluorescence imaging in vivo verified that QMDDQ could enter the brain 4 h after oral administration. The results provide a theoretical foundation for the mechanism of paracellular absorption of active peptides and a starting point for the development of functional foods for Alzheimer's disease intervention.

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Tremella aurantialba polysaccharides alleviate ulcerative colitis in mice by improving intestinal barrier via modulating gut microbiota and inhibiting ferroptosis

Peng,

Wang,

Zhang

et al. 2024

International Journal of Biological Macromolecules

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Direct inhibition of the first PDZ domain of ZO-1 by glycyrrhizin is a possible mechanism of tight junction opening of Caco-2 cells

Abstract: Glycyrrhizin (GL) is known to exhibit a variety of useful pharmacological activities, including anti-inflammation, anti-hepatotoxicity, and enhancement of intestinal drug absorption. GL has been reported to modify the assembly of...

Cited by 3 publications

References 37 publications

Pharmacologic Comparison of High-Dose Hesperetin and Quercetin on MDCK II Cell Viability, Tight Junction Integrity, and Cell Shape

Pharmacologic Comparison of High-Dose Hesperetin and Quercetin on MDCK II Cell Viability, Tight Junction Integrity, and Cell Shape

Mechanism of Intestinal Epithelial Absorption and Electrophysiological Regulation of the Shrimp Peptide QMDDQ

Tremella aurantialba polysaccharides alleviate ulcerative colitis in mice by improving intestinal barrier via modulating gut microbiota and inhibiting ferroptosis

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