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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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Related in: MedlinePlus

Effect of NAR on intracellular cAMP level of rat colonic mucosa.Comparison of the cAMP generation induced by IBMX (100 µM, both sides), NAR (NAR; 100 µM, mucosal), forskolin (Fors; 0.3 µM, mucosal), each column represents the mean±SE [*P<0.05 vs. control].
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pone-0003348-g005: Effect of NAR on intracellular cAMP level of rat colonic mucosa.Comparison of the cAMP generation induced by IBMX (100 µM, both sides), NAR (NAR; 100 µM, mucosal), forskolin (Fors; 0.3 µM, mucosal), each column represents the mean±SE [*P<0.05 vs. control].

Mentions: ELISAs (enzyme linked immunosorbent assay) data presented in Figure 5 confirm that the cAMP dependent pathway was involved in mediating the NAR-induced response. The intracellular cAMP content under basal condition (0.1% dimethyl sulfoxide (DMSO), both sides) was 108.80±10.60 pmol/mg protein (n = 3), while after incubation with serosal NAR (100 µM), the cAMP level was 181.34±8.79 pmol/mg protein (n = 3). Effect of phosphodiesterase inhibitor IBMX (3-isobutyl-1-methylxanthine, 100 µM) was detected to test whether cAMP degradation contributed to increased cAMP levels, IBMX alone caused an increase in cAMP levels to 159.60±19.68 pmol/mg protein (n = 3), whereas incubation with 100 µM NAR in the presence of IBMX (100 µM) led a significant increase in cAMP levels to 214.18±5.00 pmol/mg protein.


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 NAR on intracellular cAMP level of rat colonic mucosa.Comparison of the cAMP generation induced by IBMX (100 µM, both sides), NAR (NAR; 100 µM, mucosal), forskolin (Fors; 0.3 µM, mucosal), each column represents the mean±SE [*P<0.05 vs. control].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003348-g005: Effect of NAR on intracellular cAMP level of rat colonic mucosa.Comparison of the cAMP generation induced by IBMX (100 µM, both sides), NAR (NAR; 100 µM, mucosal), forskolin (Fors; 0.3 µM, mucosal), each column represents the mean±SE [*P<0.05 vs. control].
Mentions: ELISAs (enzyme linked immunosorbent assay) data presented in Figure 5 confirm that the cAMP dependent pathway was involved in mediating the NAR-induced response. The intracellular cAMP content under basal condition (0.1% dimethyl sulfoxide (DMSO), both sides) was 108.80±10.60 pmol/mg protein (n = 3), while after incubation with serosal NAR (100 µM), the cAMP level was 181.34±8.79 pmol/mg protein (n = 3). Effect of phosphodiesterase inhibitor IBMX (3-isobutyl-1-methylxanthine, 100 µM) was detected to test whether cAMP degradation contributed to increased cAMP levels, IBMX alone caused an increase in cAMP levels to 159.60±19.68 pmol/mg protein (n = 3), whereas incubation with 100 µM NAR in the presence of IBMX (100 µM) led a significant increase in cAMP levels to 214.18±5.00 pmol/mg protein.

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