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Effect of genistein on basal jejunal chloride secretion in R117H CF mice is sex and route specific.

Rayyan E, Polito S, Leung L, Bhakta A, Kang J, Willey J, Mansour W, Drumm ML, Al-Nakkash L - Clin Exp Gastroenterol (2015)

Bottom Line: Genistein, a naturally occurring phytoestrogen, is known to stimulate CFTR function in vitro.Isc was measured in response to the following: the adenylate cyclase activator forskolin (10 μM, bilateral), bumetanide (100 μM, basolateral) to indicate the Cl(-) secretory component, and acetazolamide (100 μM, bilateral) to indicate the HCO3 (-) secretory component; however, there was no effect of genistein (diet or injection) on any of these parameters.Serum levels of genistein were significantly elevated, compared to respective controls, by either 600Gd (equally elevated in males and females) or 600Gi (elevated more in females versus males).

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA.

ABSTRACT
Cystic fibrosis (CF) results from the loss or reduction in function of the CFTR (cystic fibrosis transmembrane conductance regulatory protein) chloride channel. The third most common CFTR mutation seen clinically is R117H. Genistein, a naturally occurring phytoestrogen, is known to stimulate CFTR function in vitro. We aimed to determine whether route of administration of genistein could mediate differential effects in R117H male and female CF mice. Mice were fed (4 weeks) or injected subcutaneously (1 week) with the following: genistein 600 mg/kg diet (600Gd); genistein-free diet (0Gd); genistein injection 600 mg/kg body weight (600Gi); dimethyl sulfoxide control (0Gi). In male R117H mice fed 600Gd, basal short circuit current (Isc) was unchanged. In 600Gd-fed female mice, there was a subgroup that demonstrated a significant increase in basal Isc (53.14±7.92 μA/cm(2), n=6, P<0.05) and a subgroup of nonresponders (12.05±6.59 μA/cm(2), n=4), compared to 0Gd controls (29.3±6.5 μA/cm(2), n=7). In R117H mice injected with 600Gi, basal Isc was unchanged in both male and female mice compared to 0Gi controls. Isc was measured in response to the following: the adenylate cyclase activator forskolin (10 μM, bilateral), bumetanide (100 μM, basolateral) to indicate the Cl(-) secretory component, and acetazolamide (100 μM, bilateral) to indicate the HCO3 (-) secretory component; however, there was no effect of genistein (diet or injection) on any of these parameters. Jejunal morphology (ie, villi length, number of goblet cells per villus, crypt depth, and number of goblet cells per crypt) in R117H mice suggested no genistein-mediated difference among the groups. Serum levels of genistein were significantly elevated, compared to respective controls, by either 600Gd (equally elevated in males and females) or 600Gi (elevated more in females versus males). These data suggest a sex-dependent increase in basal Isc of R117H mice and that the increase is also specific for route of administration.

No MeSH data available.


Related in: MedlinePlus

Effect of a 4 week genistein diet (600Gd) on average Isc in jejunum from R117H female mice.Notes: Average basal Isc and total Isc in the presence of forskolin (10 μM, bilateral), bumetanide (100 μM, serosal), acetazolamide (100 μM, bilateral), and glucose (10 mM, mucosal). Female R117H mice were fed 600Gd (closed triangle ▲, responders, n=6), 600Gd (open triangle ∆, nonresponders, n=4), or 0Gd (○, n=7) diet for 4 weeks. Values are mean ± SEM. *Significant difference from 0Gd, P<0.05.Abbreviations: Isc, short circuit current; 600Gd, 600 mg genistein/kg diet; 0Gd, genistein-free diet; SEM, standard error of the mean.
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f2-ceg-8-077: Effect of a 4 week genistein diet (600Gd) on average Isc in jejunum from R117H female mice.Notes: Average basal Isc and total Isc in the presence of forskolin (10 μM, bilateral), bumetanide (100 μM, serosal), acetazolamide (100 μM, bilateral), and glucose (10 mM, mucosal). Female R117H mice were fed 600Gd (closed triangle ▲, responders, n=6), 600Gd (open triangle ∆, nonresponders, n=4), or 0Gd (○, n=7) diet for 4 weeks. Values are mean ± SEM. *Significant difference from 0Gd, P<0.05.Abbreviations: Isc, short circuit current; 600Gd, 600 mg genistein/kg diet; 0Gd, genistein-free diet; SEM, standard error of the mean.

Mentions: Basal Isc was significantly increased in a subgroup of female mice fed 600Gd for 4 weeks (53.14±7.92 μA/cm2, n=6) compared to those fed 0Gd (29.30±6.47 μA/cm2, n=7, P<0.05; Figures 2 and 3A). Interestingly, another subgroup of female mice fed 600Gd for 4 weeks did not exhibit an increase in basal Isc (12.05±6.59 μA/cm2, n=4; Figure 2). Moreover, we found that basal anion secretion in jejuna removed from male mice fed 600Gd for 4 weeks (39.20±11.72 μA/cm2, n=9) was comparable to those from male mice fed 0Gd (34.89±7.67 μA/cm2, n=9; Figure 3A). The effect of bilateral application of 10 μM forskolin was determined, and steady-state forskolin-stimulated Isc was significantly increased only in the subgroup of females that had exhibited a significantly elevated basal Isc (Figure 3B). Addition of bumetanide (100 μM, serosal), to assess the Cl− secretory component, only resulted in a significant increase in the percentage inhibition with bumetanide in the subgroup of 600Gd females with elevated basal Isc (Figure 3C). There was no effect of acetazolamide (100 μM, bilateral) on the HCO3− contribution toward the Isc, in any of the groups (Figure 3D).


Effect of genistein on basal jejunal chloride secretion in R117H CF mice is sex and route specific.

Rayyan E, Polito S, Leung L, Bhakta A, Kang J, Willey J, Mansour W, Drumm ML, Al-Nakkash L - Clin Exp Gastroenterol (2015)

Effect of a 4 week genistein diet (600Gd) on average Isc in jejunum from R117H female mice.Notes: Average basal Isc and total Isc in the presence of forskolin (10 μM, bilateral), bumetanide (100 μM, serosal), acetazolamide (100 μM, bilateral), and glucose (10 mM, mucosal). Female R117H mice were fed 600Gd (closed triangle ▲, responders, n=6), 600Gd (open triangle ∆, nonresponders, n=4), or 0Gd (○, n=7) diet for 4 weeks. Values are mean ± SEM. *Significant difference from 0Gd, P<0.05.Abbreviations: Isc, short circuit current; 600Gd, 600 mg genistein/kg diet; 0Gd, genistein-free diet; SEM, standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4321419&req=5

f2-ceg-8-077: Effect of a 4 week genistein diet (600Gd) on average Isc in jejunum from R117H female mice.Notes: Average basal Isc and total Isc in the presence of forskolin (10 μM, bilateral), bumetanide (100 μM, serosal), acetazolamide (100 μM, bilateral), and glucose (10 mM, mucosal). Female R117H mice were fed 600Gd (closed triangle ▲, responders, n=6), 600Gd (open triangle ∆, nonresponders, n=4), or 0Gd (○, n=7) diet for 4 weeks. Values are mean ± SEM. *Significant difference from 0Gd, P<0.05.Abbreviations: Isc, short circuit current; 600Gd, 600 mg genistein/kg diet; 0Gd, genistein-free diet; SEM, standard error of the mean.
Mentions: Basal Isc was significantly increased in a subgroup of female mice fed 600Gd for 4 weeks (53.14±7.92 μA/cm2, n=6) compared to those fed 0Gd (29.30±6.47 μA/cm2, n=7, P<0.05; Figures 2 and 3A). Interestingly, another subgroup of female mice fed 600Gd for 4 weeks did not exhibit an increase in basal Isc (12.05±6.59 μA/cm2, n=4; Figure 2). Moreover, we found that basal anion secretion in jejuna removed from male mice fed 600Gd for 4 weeks (39.20±11.72 μA/cm2, n=9) was comparable to those from male mice fed 0Gd (34.89±7.67 μA/cm2, n=9; Figure 3A). The effect of bilateral application of 10 μM forskolin was determined, and steady-state forskolin-stimulated Isc was significantly increased only in the subgroup of females that had exhibited a significantly elevated basal Isc (Figure 3B). Addition of bumetanide (100 μM, serosal), to assess the Cl− secretory component, only resulted in a significant increase in the percentage inhibition with bumetanide in the subgroup of 600Gd females with elevated basal Isc (Figure 3C). There was no effect of acetazolamide (100 μM, bilateral) on the HCO3− contribution toward the Isc, in any of the groups (Figure 3D).

Bottom Line: Genistein, a naturally occurring phytoestrogen, is known to stimulate CFTR function in vitro.Isc was measured in response to the following: the adenylate cyclase activator forskolin (10 μM, bilateral), bumetanide (100 μM, basolateral) to indicate the Cl(-) secretory component, and acetazolamide (100 μM, bilateral) to indicate the HCO3 (-) secretory component; however, there was no effect of genistein (diet or injection) on any of these parameters.Serum levels of genistein were significantly elevated, compared to respective controls, by either 600Gd (equally elevated in males and females) or 600Gi (elevated more in females versus males).

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA.

ABSTRACT
Cystic fibrosis (CF) results from the loss or reduction in function of the CFTR (cystic fibrosis transmembrane conductance regulatory protein) chloride channel. The third most common CFTR mutation seen clinically is R117H. Genistein, a naturally occurring phytoestrogen, is known to stimulate CFTR function in vitro. We aimed to determine whether route of administration of genistein could mediate differential effects in R117H male and female CF mice. Mice were fed (4 weeks) or injected subcutaneously (1 week) with the following: genistein 600 mg/kg diet (600Gd); genistein-free diet (0Gd); genistein injection 600 mg/kg body weight (600Gi); dimethyl sulfoxide control (0Gi). In male R117H mice fed 600Gd, basal short circuit current (Isc) was unchanged. In 600Gd-fed female mice, there was a subgroup that demonstrated a significant increase in basal Isc (53.14±7.92 μA/cm(2), n=6, P<0.05) and a subgroup of nonresponders (12.05±6.59 μA/cm(2), n=4), compared to 0Gd controls (29.3±6.5 μA/cm(2), n=7). In R117H mice injected with 600Gi, basal Isc was unchanged in both male and female mice compared to 0Gi controls. Isc was measured in response to the following: the adenylate cyclase activator forskolin (10 μM, bilateral), bumetanide (100 μM, basolateral) to indicate the Cl(-) secretory component, and acetazolamide (100 μM, bilateral) to indicate the HCO3 (-) secretory component; however, there was no effect of genistein (diet or injection) on any of these parameters. Jejunal morphology (ie, villi length, number of goblet cells per villus, crypt depth, and number of goblet cells per crypt) in R117H mice suggested no genistein-mediated difference among the groups. Serum levels of genistein were significantly elevated, compared to respective controls, by either 600Gd (equally elevated in males and females) or 600Gi (elevated more in females versus males). These data suggest a sex-dependent increase in basal Isc of R117H mice and that the increase is also specific for route of administration.

No MeSH data available.


Related in: MedlinePlus