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Biomed Res Int
2014 Jan 01;2014:902735. doi: 10.1155/2014/902735.
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Distinct action of flavonoids, myricetin and quercetin, on epithelial Cl⁻ secretion: useful tools as regulators of Cl⁻ secretion.
Sun H
,
Niisato N
,
Nishio K
,
Hamilton KL
,
Marunaka Y
.
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Epithelial Cl(-) secretion plays important roles in water secretion preventing bacterial/viral infection and regulation of body fluid. We previously suggested that quercetin would be a useful compound for maintaining epithelial Cl(-) secretion at a moderate level irrespective of cAMP-induced stimulation. However, we need a compound that stimulates epithelial Cl(-) secretion even under cAMP-stimulated conditions, since in some cases epithelial Cl(-) secretion is not large enough even under cAMP-stimulated conditions. We demonstrated that quercetin and myricetin, flavonoids, stimulated epithelial Cl(-) secretion under basal conditions in epithelial A6 cells. We used forskolin, which activates adenylyl cyclase increasing cytosolic cAMP concentrations, to study the effects of quercetin and myricetin on cAMP-stimulated epithelial Cl(-) secretion. In the presence of forskolin, quercetin diminished epithelial Cl(-) secretion to a level similar to that with quercetin alone without forskolin. Conversely, myricetin further stimulated epithelial Cl(-) secretion even under forskolin-stimulated conditions. This suggests that the action of myricetin is via a cAMP-independent pathway. Therefore, myricetin may be a potentially useful compound to increase epithelial Cl(-) secretion under cAMP-stimulated conditions. In conclusion, myricetin would be a useful compound for prevention from bacterial/viral infection even under conditions that the amount of water secretion driven by cAMP-stimulated epithelial Cl(-) secretion is insufficient.
Figure 2. Effects of quercetin and myricetin on Isc under basal (a) and forskolin-stimulated conditions (b). (a) Benzamil (BNZ, a blocker of epithelial Na+ channel: ENaC; 10âμM) was applied to the apical solution at â10âmin. DMSO (dimethyl sulfoxide; a solvent for forskolin; 0.1% as the final concentration in Isc measuring solutions) was added to both apical and basolateral solutions at 0âmin (open circles, closed squares, and closed triangles). Quercetin (100âμM; open circles), myricetin (100âμM; closed squares), or DMSO (a solvent for quercetin and myricetin; 0.1%; closed triangles) was applied to both apical and basolateral solutions at 60âmin. NPPB (a nonspecific blocker of Clâ channels; 100âμM) was applied to the apical solution at 120âmin (open circles, closed squares, and closed triangles). n = 5 for DMSO, n = 6 for quercetin, and n = 7 for myricetin. (b) Benzamil (BNZ, 10âμM) was applied to the apical solution at â10âmin. Forskolin (10âμM) was added to both apical and basolateral solutions at 0âmin (open circles, closed squares, and closed triangles). Quercetin (100âμM; open circles), myricetin (100âμM; closed squares), or DMSO (a solvent for quercetin and myricetin; 0.1%; closed triangles) was applied to both apical and basolateral solutions at 60âmin. NPPB (100 μM) was applied to the apical solution at 120âmin (open circles, closed squares and closed triangles). n = 6 for DMSO, n = 5 for quercetin, and n = 8 for myricetin. The values marked with â (open circles and closed squares) are significantly larger than DMSO (closed triangles; P < 0.05). The values marked with # (closed squares) are significantly smaller than DMSO (closed triangles; P < 0.05).
Figure 3. NPPB-sensitive Isc. The NPPB-sensitive Isc was measured as the difference of Isc just before and 30âmin after addition of 100âμM NPPB to the apical solution. n = 5 for DMSO, n = 6 for quercetin, and n = 7 for myricetin without forskolin ((â) FK). n = 6 for DMSO, n = 5 for quercetin, and n = 8 for myricetin with forskolin ((+) FK). Under basal conditions ((â) FK), the values of quercetin-stimulated Isc (â) and myricetin-stimulated NPPB-sensitive Isc (ââ) were significantly larger than the NPPB-sensitive Isc with DMSO alone (solvent control; P < 0.001). The value of Isc with DMSO alone under forskolin-stimulated conditions (DMSO marked with § in (+) FK) was significantly larger than that with DMSO alone under basal conditions (DMSO in (â) FK; P < 0.001). Under forskolin-stimulated conditions ((+) FK), the value of quercetin-stimulated Isc (Quercetin in (+) FK marked with #) was significantly smaller than that with DMSO alone (DMSO in (+) FK; P < 0.001). On the one hand, under forskolin-stimulated conditions ((+) FK), the value of myricetin-stimulated Isc (##) was significantly larger than that with DMSO alone (DMSO in (+) FK; P < 0.001). The value of quercetin-stimulated Isc was identical irrespective of forskolin stimulation (Quercetin in (â) FK versus Quercetin in (+) FK; NS, no significant difference), while the value of myricetin-stimulated Isc under forskolin-stimulated conditions (Myricetin in (+) FK) was significantly larger than that under basal condition (Myricetin in (â) FK; P < 0.001).
Figure 4. NPPB-sensitive conductance. The NPPB-sensitive conductance was measured as the difference of Isc just before and 30âmin after addition of 100âμM NPPB to the apical solution. n = 4 for DMSO, n = 7 for quercetin, and n = 11 for myricetin without forskolin ((â) FK). n = 11 for DMSO, n = 7 for quercetin, and n = 10 for myricetin with forskolin ((+) FK). Under basal conditions ((â) FK), the values of quercetin-stimulated conductance (â) and myricetin-stimulated NPPB-sensitive conductance (ââ) were significantly larger than the NPPB-sensitive conductance with DMSO alone (solvent control; P < 0.001). The value of Isc with DMSO alone under forskolin-stimulated conditions (DMSO marked with § in (+) FK) was significantly larger than that with DMSO alone under basal conditions (DMSO in (â) FK; P < 0.005). Under forskolin-stimulated conditions ((+) FK), the value of quercetin-stimulated Isc (Quercetin in (+) FK marked with #) was slightly but significantly larger than that with DMSO alone (DMSO in (+) FK; P < 0.05). Further, under forskolin-stimulated conditions ((+) FK), the value of myricetin-stimulated Isc (##) was significantly larger than that with DMSO alone (DMSO in (+) FK; P < 0.001). The quercetin-stimulated NPPB-sensitive conductance under forskolin-stimulated conditions (Quercetin in (+) FK) was significantly larger than that under basal condition (Quercetin in (â) FK; P < 0.001). The myricetin-stimulated NPPB-sensitive conductance under forskolin-stimulated conditions (Myricetin in (+) FK) was significantly larger than that under basal condition (Myricetin in (â) FK; P < 0.001).
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