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Cellular mechanisms underlying the laxative effect of flavonol naringenin on rat constipation model.

Yang ZH, Yu HJ, Pan A, Du JY, Ruan YC, Ko WH, Chan HC, Zhou WL - PLoS ONE (2008)

Bottom Line: Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC).In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion.Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model.

View Article: PubMed Central - PubMed

Affiliation: The School of Life Science, Sun Yat-sen University, Guangzhou, China.

ABSTRACT

Background & aims: Symptoms of constipation are extremely common, especially in the elderly. The present study aim to identify an efficacious treatment strategy for constipation by evaluating the secretion-promoting and laxative effect of a herbal compound, naringenin, on intestinal epithelial anion secretion and a rat constipation model, respectively.

Methods/principal findings: In isolated rat colonic crypts, mucosal addition of naringenin (100 microM) elicited a concentration-dependent and sustained increase in the short-circuit current (I(SC)), which could be inhibited in Cl- free solution or by bumetanide and DPC (diphenylamine-2-carboxylic acid), but not by DIDS (4, 4'- diisothiocyanatostilbene-2, 2'-disulfonic acid). Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC). In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion. Naringenin-evoked whole cell current which exhibited a linear I-V relationship and time-and voltage- independent characteristics was inhibited by DPC, indicating that the cAMP activated Cl- conductance most likely CFTR (cystic fibrosis transmembrane conductance regulator) was involved. In rat constipation model, administration of naringenin restored the level of fecal output, water content and mucus secretion compared to loperamide-administrated group.

Conclusions: Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model. Naringenin appears to be a novel alternative treatment strategy for constipation.

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Effect of naringenin on the PKA activity.A, colonic mucosa was treated with DMSO alone (control) or 100 µM naringenin for 5, 10 and 15 min. The positive and negative controls provided by the assay kit are shown in lanes 5 and 6. B, summarized data showing the relative grey value as compared with control. Each column represents the mean±S.E. (*p<0.05).
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pone-0003348-g006: Effect of naringenin on the PKA activity.A, colonic mucosa was treated with DMSO alone (control) or 100 µM naringenin for 5, 10 and 15 min. The positive and negative controls provided by the assay kit are shown in lanes 5 and 6. B, summarized data showing the relative grey value as compared with control. Each column represents the mean±S.E. (*p<0.05).

Mentions: PKA activity was also measured, as shown in Figure 6, NAR incubation for 5, 10 and especially 15min could increase the PKA activity by 14.63%,15.12% and 32.89%, respectively, compared with which was pretreated with DMSO alone. These results unequivocally demonstrate that NAR could stimulate an increase in cytosolic cAMP content maybe through activating the adenyl cyclase rather than inhibiting the activity of phosphodiesterase, which in turn activate PKA, hence promote Cl− secretion across rat colonic mucosa.


Cellular mechanisms underlying the laxative effect of flavonol naringenin on rat constipation model.

Yang ZH, Yu HJ, Pan A, Du JY, Ruan YC, Ko WH, Chan HC, Zhou WL - PLoS ONE (2008)

Effect of naringenin on the PKA activity.A, colonic mucosa was treated with DMSO alone (control) or 100 µM naringenin for 5, 10 and 15 min. The positive and negative controls provided by the assay kit are shown in lanes 5 and 6. B, summarized data showing the relative grey value as compared with control. Each column represents the mean±S.E. (*p<0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553183&req=5

pone-0003348-g006: Effect of naringenin on the PKA activity.A, colonic mucosa was treated with DMSO alone (control) or 100 µM naringenin for 5, 10 and 15 min. The positive and negative controls provided by the assay kit are shown in lanes 5 and 6. B, summarized data showing the relative grey value as compared with control. Each column represents the mean±S.E. (*p<0.05).
Mentions: PKA activity was also measured, as shown in Figure 6, NAR incubation for 5, 10 and especially 15min could increase the PKA activity by 14.63%,15.12% and 32.89%, respectively, compared with which was pretreated with DMSO alone. These results unequivocally demonstrate that NAR could stimulate an increase in cytosolic cAMP content maybe through activating the adenyl cyclase rather than inhibiting the activity of phosphodiesterase, which in turn activate PKA, hence promote Cl− secretion across rat colonic mucosa.

Bottom Line: Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC).In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion.Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model.

View Article: PubMed Central - PubMed

Affiliation: The School of Life Science, Sun Yat-sen University, Guangzhou, China.

ABSTRACT

Background & aims: Symptoms of constipation are extremely common, especially in the elderly. The present study aim to identify an efficacious treatment strategy for constipation by evaluating the secretion-promoting and laxative effect of a herbal compound, naringenin, on intestinal epithelial anion secretion and a rat constipation model, respectively.

Methods/principal findings: In isolated rat colonic crypts, mucosal addition of naringenin (100 microM) elicited a concentration-dependent and sustained increase in the short-circuit current (I(SC)), which could be inhibited in Cl- free solution or by bumetanide and DPC (diphenylamine-2-carboxylic acid), but not by DIDS (4, 4'- diisothiocyanatostilbene-2, 2'-disulfonic acid). Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC). In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion. Naringenin-evoked whole cell current which exhibited a linear I-V relationship and time-and voltage- independent characteristics was inhibited by DPC, indicating that the cAMP activated Cl- conductance most likely CFTR (cystic fibrosis transmembrane conductance regulator) was involved. In rat constipation model, administration of naringenin restored the level of fecal output, water content and mucus secretion compared to loperamide-administrated group.

Conclusions: Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model. Naringenin appears to be a novel alternative treatment strategy for constipation.

Show MeSH
Related in: MedlinePlus