Genistein Stimulates Jejunum Chloride Secretion via an Akt-Mediated Pathway in Intact Female Mice

Leung, Lana; Bhakta, Ashesh; Cotangco, Katherine; Al‐Nakkash, Layla

doi:10.1159/000373953

Cited by 6 publications

(5 citation statements)

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“…Interestingly, genistein diet rescued this in female ob/ob mice but not in males. We have previously noted sex-dependent mechanisms of action of genistein in ovariectomized mice [44]. The Na Our data is not consistent with Serhan et al [45], demonstrating that insulin increases glucose uptake with reductions in Na + /K + -ATPase expression, and increased expression of SGLT1 in Caco-2 cells and rat jejunum.…”

Section: +contrasting

confidence: 81%

Dietary Genistein Rescues Reduced Basal Chloride Secretion in Diabetic Jejunum via Sex-Dependent Mechanisms

Catmull¹,

Masood²,

Schacht³

et al. 2016

Cell Physiol Biochem

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Background/Aims: The goal of this study was to determine the effect of dietary genistein (naturally occurring phytoestrogen) on jejunal secretory function in a clinically relevant model of diabetes and obesity, the leptin-defIcient ob/ob mouse. Methods: We measured transepithelial short circuit current (I_sc), across freshly isolated segments of jejunum from 12-week old male and female ob/ob and lean C57Bl/6J mice fed a genistein diet (600 mg genistein/kg diet) for 4-weeks. Separate segments of jejunum were frozen for western blot determination of key proteins involved in secretory transport. Results: Basal I_sc was signifIcantly decreased (by 33%, P<0.05) in ob/ob females versus leans, and genistein-diet reversed this. Similarly, in males, basal I_sc was decreased (by 47%, P<0.05) in ob/ob mice versus leans, and genistein-diet reversed this. Inhibition with either clotrimazole (100 µM, bilateral) or ouabain (100 µM, basolateral) was signifIcantly reduced in ob/ob mice compared to leans (P<0.05), and genistein-diet reversed clotrimazole-sensitive inhibition in ob/ob females, and reversed the ouabain-sensitive inhibition in males (indicating sex-dependent mechanisms). Our data suggested that PDE3 levels were dysregulated in ob/ob females and genistein reversed this. Expression of total CFTR (normalized to actin) was signifIcantly decreased ∼80% (P<0.05) in all ob/ob mice compared to leans, and genistein-diet was without effect. Expression of total NKCC1 (normalized to actin) was signifIcantly decreased ∼80% (P<0.05) in ob/ob male mice versus leans, and genistein-diet reversed this. Conclusions: Our data suggests that the reduced basal jejunal I_sc in ob/ob female mice is a consequence of reduced CFTR expression, decreased activities of the basolateral K_Ca channel and Na⁺/K⁺-ATPase, and in male mice reduced basal jejunal I_sc is a consequence of reduced CFTR and NKCC1 expression, along with decreased activities of the basolateral K_Ca channel and Na⁺/K⁺-ATPase. Genistein-diet has beneficial effects on basal I_sc mediated by sex-dependent mechanisms in diabetic mice: in females via increased K_Ca-sensitive I_sc and in males via increased Na⁺/K⁺-ATPase activity and increased NKCC1 expression. Improved understanding of intestinal dysfunctions in the ob/ob jejunum, may allow for the development of novel drug targets to treat obesity and diabetes, and may also be of benefit in CF-related diabetes.

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Section: +contrasting

confidence: 81%

Dietary Genistein Rescues Reduced Basal Chloride Secretion in Diabetic Jejunum via Sex-Dependent Mechanisms

Catmull¹,

Masood²,

Schacht³

et al. 2016

Cell Physiol Biochem

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“…However, the role of sex hormones (mainly estrogen) on the enzymes involved in the intracellular signaling, i.e., kinases, is very controversial. Indeed, while some authors demonstrated that estrogen could modulates kinases proteins expression such as Akt (Bhuiyan et al, 2011; Turdi et al, 2015), PKG (Word and Cornwell, 1998) and PKC (Hunter and Korzick, 2005; Hunter et al, 2007), others suggest that there is no modulation by estrogen on these kinases (Teede et al, 2001; Cao et al, 2015; Leung et al, 2015). Taken together, these studies showed that the relationship between the expression of kinases and estrogen levels is very complex which becomes a limiting factor for the use of estrogen therapy in postmenopausal women.…”

Section: Introductionmentioning

confidence: 99%

Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats

et al. 2017

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Decline in estrogen levels promotes endothelial dysfunction and, consequently, the most prevalent cardiovascular diseases in menopausal women. The use of natural therapies such as pomegranate can change these results. Pomegranate [Punica granatum L. (Punicaceae)] is widely used as a phytotherapeutic agent worldwide, including in Brazil. We hypothesized that treatment with pomegranate hydroalcoholic extract (PHE) would improve coronary vascular reactivity and cardiovascular parameters. At the beginning of treatment, spontaneously hypertensive female rats were divided into Sham and ovariectomized (OVX) groups, which received pomegranate extract (PHE) (250 mg/kg) or filtered water (V) for 30 days by gavage. Systolic blood pressure was measured by tail plethysmography. After euthanasia, the heart was removed and coronary vascular reactivity was assessed by Langendorff retrograde perfusion technique. A dose-response curve for bradykinin was performed, followed by L-NAME inhibition. The protein expression of p-eNOS Ser1177, p-eNOS Thr495, total eNOS, p-AKT Ser473, total AKT, SOD-2, and catalase was quantified by Western blotting. The detection of coronary superoxide was performed using the protocol of dihydroethidium (DHE) staining Plasma nitrite measurement was analyzed by Griess method. Systolic blood pressure increased in both Sham-V and OVX-V groups, whereas it was reduced after treatment in Sham-PHE and OVX-PHE groups. The baseline coronary perfusion pressure was reduced in the Sham-PHE group. The relaxation was significantly higher in the treated group, and L-NAME attenuated the relaxation in all groups. The treatment has not changed p-eNOS (Ser1177), total eNOS, p-AKT (Ser473) and total AKT in any groups. However, in Sham and OVX group the treatment reduced the p-eNOS (Thr495) and SOD-2. The ovariectomy promoted an increasing in the superoxide anion levels and the treatment was able to prevent this elevation and reducing oxidative stress. Moreover, the treatment prevented the decreasing in plasmatic nitrite. We observed a reduction in total cholesterol and LDL in the Sham-PHE group. The treatment with PHE enhances the endothelium-dependent coronary relaxation and improves cardiovascular parameters, which suggests a therapeutic role of PHE.

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Section: Bioelectric Measurement Of Intestinal Secretionmentioning

confidence: 99%

“…Assessments of transepithelial short circuit current (I sc , μA/cm 2 ) were obtained as described previously [11,18], with 0.3 cm 2 exposed surface area of freshly excised jejunum. Short circuit current was measured via an automatic voltage clamp (VCC-600, Physiologic Instruments, San Diego, CA) [11,18]. All tissue segments were maintained in 1 μM indomethacin which served to reduce the tissue exposure to endogenously generated prostanoids due to tissue handling [19].…”

Section: Bioelectric Measurement Of Intestinal Secretionmentioning

confidence: 99%

“…Freshly isolated jejunum was embedded and flash frozen in Optimal Cutting Temperature compound (OCT, Tissue-Tek, Torrance, CA). Frozen sliced sections (10 µm) of jejunum were stained with a standard protocol for hematoxylin and eosin (H & E) staining, as previously published, [11,18,22]. Measures of villi length, crypt depth, and wall thickness were taken using Image J (NIH), from images taken at 10x magnification.…”

Section: Histology and Morphology With H And E Stainingmentioning

confidence: 99%

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High Fat High Sugar Diet Reduces Small Intestinal Secretion by Sex-Dependent Mechanisms

Miller

2023

Cell Physiol Biochem

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Background/Aims: The goal of this study was to determine the influence of high-fat high-sugar diet (Western diet) on intestinal function and subsequently to determine if there were any beneficial effects of exercise, genistein (a naturally occurring phytoestrogen) or both, on the intestine. Methods: We measured transepithelial short circuit current (Isc), across freshly isolated segments of jejunum from male and female C57Bl/6J mice randomly assigned to one of the following groups for the 12-week study duration: high-fat high-sugar diet (HFS), HFS with genistein (Gen), HFS with exercise (Ex), or HFS with both genistein and exercise (Gen+Ex) and compared them to lean controls. Genistein concentration was 600 mg genistein/kg diet. Exercise comprised of moderate intensity treadmill running (150 min per week). At the completion of the study, segments of jejunum were frozen for western blot determination of key proteins involved in secretory and absorptive functions, as well as senescence. Intestinal morphology was assessed. Serum cytokine assays were performed. Results: Basal Isc was significantly decreased (by 70%, P <0.05) in HFS females and males versus leans. This decrease was partially mitigated by exercise in both sexes. In females, the HFS-induced decrease in Isc was attributed to a significant loss of CLC2, NKCC1 and CFTR expression whereas in males this was due to a significant loss of Na/K-ATPase, KCa and NKCC1 expression (indicating sex-dependent mechanisms). Exercise mitigated most of the loss of Isc in both sexes. Our data suggested that A2BR levels were dysregulated in HFS fed mice and that concomitant treatment with Gen or Gen+Ex prevented this disruption in females only. Inflammatory state was associated with body weight changes. Conclusion: Our data suggests that the reduced basal jejunal Isc in HFS mice is attributed to sex-dependent mechanisms and while exercise partially mitigated this, it’s mechanism of action was unclear. Improved understanding of Western diet induced intestinal dysfunctions may allow for the development of novel drug targets to treat gastrointestinal disturbances in diabetic obesity.

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Genistein Stimulates Jejunum Chloride Secretion via an Akt-Mediated Pathway in Intact Female Mice

Cited by 6 publications

References 38 publications

Dietary Genistein Rescues Reduced Basal Chloride Secretion in Diabetic Jejunum via Sex-Dependent Mechanisms

Dietary Genistein Rescues Reduced Basal Chloride Secretion in Diabetic Jejunum via Sex-Dependent Mechanisms

Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats

High Fat High Sugar Diet Reduces Small Intestinal Secretion by Sex-Dependent Mechanisms

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