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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 the loperamide-induced rat constipation model.(A) Frequency of feces excretion, (B) number, (C) water content (D) Thickness of fecal mucus of control (left bar in each column), loperamide-administered (middle bar in each column, 1.5 mg/kg, twice a day loperamide), and NAR-treated (150 mg/kg, twice a day) loperamide-administered rats (right bar in each column,) on experiment day. Each column represents the mean SE [***P<0.001].
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pone-0003348-g008: Effect of NAR on the loperamide-induced rat constipation model.(A) Frequency of feces excretion, (B) number, (C) water content (D) Thickness of fecal mucus of control (left bar in each column), loperamide-administered (middle bar in each column, 1.5 mg/kg, twice a day loperamide), and NAR-treated (150 mg/kg, twice a day) loperamide-administered rats (right bar in each column,) on experiment day. Each column represents the mean SE [***P<0.001].

Mentions: The body weight did not differ significantly between the experimental groups during the experiment. Compared with control group, loperamide markedly reduced the frequency of fecal output (Figure 8A), number of fecal pellet (Figure 8B), fecal water content (Figure 8C) and the average thickness of the mucus layer at the fecal surface (Figure 8D), while all of which were partially restored by NAR with no diarrhea observed.


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 the loperamide-induced rat constipation model.(A) Frequency of feces excretion, (B) number, (C) water content (D) Thickness of fecal mucus of control (left bar in each column), loperamide-administered (middle bar in each column, 1.5 mg/kg, twice a day loperamide), and NAR-treated (150 mg/kg, twice a day) loperamide-administered rats (right bar in each column,) on experiment day. Each column represents the mean SE [***P<0.001].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003348-g008: Effect of NAR on the loperamide-induced rat constipation model.(A) Frequency of feces excretion, (B) number, (C) water content (D) Thickness of fecal mucus of control (left bar in each column), loperamide-administered (middle bar in each column, 1.5 mg/kg, twice a day loperamide), and NAR-treated (150 mg/kg, twice a day) loperamide-administered rats (right bar in each column,) on experiment day. Each column represents the mean SE [***P<0.001].
Mentions: The body weight did not differ significantly between the experimental groups during the experiment. Compared with control group, loperamide markedly reduced the frequency of fecal output (Figure 8A), number of fecal pellet (Figure 8B), fecal water content (Figure 8C) and the average thickness of the mucus layer at the fecal surface (Figure 8D), while all of which were partially restored by NAR with no diarrhea observed.

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