Showing papers by "Thomas M. Badger published in 2006"
TL;DR: It is found that MCD feeding causes profound hepatic suppression of the gene encoding stearoyl-coenzyme A desaturase-1 (SCD-1) in the liver, which likely contributes to hypermetabolism and weight loss.
218 citations
TL;DR: There were significant interspecies differences in isoflavone metabolism, and the overall metabolic profile of pigs was closer to that of women than that of rats or monkeys.
Abstract: Various physiologic effects of soy food consumption have been attributed to the estrogenic actions of isoflavones. The order of estrogen receptor binding potency of soy-derived isoflavone aglycones is equol > genistein > daidzein, and their conjugates are less potent. Because the metabolic profile may be an important determinant of bioactivity after soy intake, we studied the serum and urine isoflavone concentrations in 3 animal models and compared them with isoflavone profiles in women. Female Sprague-Dawley rats, Hampshire/Duroc Cross pigs, cynomolgus monkeys, and women were fed diets containing soy protein isolate. Isoflavones and their metabolites were measured by LC-MS or electrochemical detection. Equol represented approximately 77 and 52% (molar ratio) of summed serum isoflavones (isoflavones plus metabolites) in rats and cynomolgus monkeys, respectively. Equol was undetectable in pig serum and human plasma, but daidzein and genistein contributed >88% of summed circulating isoflavones. Monkey and rat urine contained high levels of aglycones (>85% and >32%, respectively), whereas pigs and women excreted isoflavone mainly in the form of glucuronides (>80%), with <10% as aglycones. Isoflavones in human plasma were predominantly glucuronides (75%) with 24% as sulfates and <1% as aglycones; in monkey serum, however, 64% of isoflavones were sulfates, 30% glucuronides, and 6% aglycones. Equol was also a major serum metabolite of 6-mo-old rhesus monkeys (80% of summed isoflavones). Thus, there were significant interspecies differences in isoflavone metabolism, and the overall metabolic profile of pigs was closer to that of women than that of rats or monkeys.
187 citations
TL;DR: The results suggest that ethanol induces TRB3, which, through binding to the pleckstrin homology domain of Akt, prevents its plasma membrane association, Akt-Thr308 phosphorylation, and subsequentAkt-mediated signaling.
98 citations
TL;DR: Data suggest that inhibition of growth in tumor cells by "mycochemicals" in shiitake mushrooms may result from induction of apoptosis.
Abstract: Objective: Shiitake (Lentinus edodes) mushrooms have been reported to have cancer-preventing properties. However, little research has been conducted verifying the antitumor activities of "mycochemicals" in shiitake mushrooms. In this study, potential roles of an ethyl acetate fraction from shiitake mushrooms were investigated by in vitro bioassays. Design: The activities of an ethyl acetate fraction were evaluated by [3-(4,5-dimethylthiazol-yl)-2,5-diphenyltetrazolium bromide] (MTT), apoptosis bioassay, cell cycle analysis, and Western blot analysis using two human breast carcinoma cell lines (MDA-MB-453 and MCF-7), one human nonmalignant breast epithelial cell line (MCF-10F), and two myeloma cell lines (RPMI-8226 and IM-9). Results: Concentration-dependent antiproliferative effects of the fraction were observed in all cell lines using the MTT assay. Approximately 50 mg/L concentration of the fraction induced apoptosis in 50% of the population of four human tumor cell lines and the fraction-induced apopto...
57 citations
TL;DR: E2 prevents EtOH-induced bone loss by opposing the induction of RANKL mRNA in osteoblasts and ethanol-induced osteoclastogenesis, through opposing effects on sustained ERK signaling.
Abstract: To investigate the effects of sex hormones on ethanol (EtOH)-induced bone loss, female Sprague-Dawley rats were fed control or EtOH-containing diets (12 g/kg/day) by intragastric infusion. After 3 weeks, rats receiving EtOH had significant decreases in tibial trabecular and total bone mineral density, induction of receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA expression, and enhanced bone resorption, all of which were prevented by treatment with 17beta-estradiol (E(2)). The addition of progesterone did not enhance the beneficial effect of E(2) alone. Consistent with our in vivo findings, EtOH stimulated RANKL mRNA expression in cultured primary osteoblasts, and this expression was blocked by 4-methylpyrazole. Acetaldehyde also induced RANKL expression. Class 1 alcohol dehydrogenase was found to be expressed and EtOH-inducible in cultured osteoblasts, whereas CYP2E1 was undetectable. We found that EtOH induced phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducers and activators of transcription 3 (STAT3). E(2) and the mitogenactivated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059) blocked ERK and STAT3 phosphorylation and blocked RANKL induction. Moreover, E(2) completely blocked EtOH-induced osteoclastogenesis in a primary osteoblast and osteoclast precursor coculture system. The E(2) effects were estrogen receptor-mediated. Therefore, E(2) prevents EtOH-induced bone loss by opposing the induction of RANKL mRNA in osteoblasts and ethanol-induced osteoclastogenesis, through opposing effects on sustained ERK signaling.
54 citations
TL;DR: The data suggest that undernutrition potentiates the fetal toxicity of EtOH in part by disrupting maternal GH-IGF-1, signaling thereby decreasing maternal uterine capacity and placental growth.
Abstract: Nutrition-ethanol (EtOH) interactions during gestation remain unclear primarily due to the lack of appropriate rodent models. In the present report we utilize total enteral nutrition (TEN) to speci...
53 citations
TL;DR: Metabolism in the human GI tract has an important role in the generation of potentially bioactive isoflavone sulfates and a major role for the human phenolic sulfotransferase SULT1A family in metabolism of genistein in the gut is suggested.
Abstract: Phytoestrogens, in particular the isoflavone aglycones genistein and daidzein, are thought to be the bioactive components of soy. Like estrogens, isoflavones can be sulfur-conjugated. However, although isoflavones in the serum are found largely in the form of glucuronide and sulfur conjugates following soy consumption, little is known regarding the relative contributions of sulfotransferases in the liver and small intestine to isoflavone sulfation. Since the sulfates may be deconjugated in target tissues, circulating isoflavone sulfates may act as a source of tissue aglycones. In the current study genistein and daidzein sulfotransferase activities were measured in cytosol from human and rat liver and gastrointestinal tract. Isoflavone sulfation in the human gastrointestinal (GI) tract was correlated with activities towards substrates for previously characterized human sulfotransferases. Western blots of human cytosols were also conducted using antisera towards human sulfotransferases SULT1E1 and SULT2A1. Whereas rat liver was almost fourfold more active than small intestine in sulfation of genistein, in the human, activities in the two tissues were comparable. In contrast, intestinal sulfation of daidzein was comparable to hepatic sulfation in the rat and significantly greater in the human. Genistein and daidzein sulfation occurred throughout the human GI tract, but with a different distribution and different interindividual variability. Whereas genistein sulfation in the human GI tract correlated significantly with sulfation of the prototypical human phenolic sulfotransferase SULT1A family substrate 2-naphthol (r2 = 0.71), daidzein sulfotransferase activity did not correlate with activities towards any prototypical sulfotransferase substrate or with genistein sulfation. Our results suggest that metabolism in the human GI tract has an important role in the generation of potentially bioactive isoflavone sulfates and a major role for the human phenolic sulfotransferase SULT1A family in metabolism of genistein in the gut. However, human intestinal daidzein sulfation appears to be catalyzed by a separate enzyme.
44 citations
TL;DR: Limited exposure during gestation to SPI can positively influence resistance to chemically induced mammary tumorigenesis later in life, and preventative strategies against mammary and other types of cancer might be uncovered by refinement of the developmental window for dietary factor exposure.
Abstract: The linkage of nutrition and cancer prevention is an intriguing concept that is gaining widespread support. Here, we investigated the influence of developmental context on dietary protection against tumorigenesis initiated by the direct-acting carcinogen N-methyl-N-nitrosourea (NMU), and examined potential mechanisms underlying these effects. Rats were exposed only in utero or for lifetime to American Institute of Nutrition-93G diets made with casein (CAS), soy protein isolate (SPI) or CAS supplemented with genistein (GEN). Mammary glands of post-natal day (PND) 50 rats prior to NMU administration were examined for apoptotic status, pro-apoptotic gene expression and immunoreactive phosphatase and tensin homolog deleted on chromosome ten (PTEN) and epithelial cadherin (E-cadherin) levels, whereas mammary tumor parameters were evaluated 99 days post-NMU. Animals exposed only in utero to SPI had increased tumor latency, decreased tumor multiplicity and lower higher grade tumors, than those fed CAS. In utero exposure to GEN resulted in similar tumor parameters as the CAS group, whereas lifetime SPI exposure decreased tumor incidence that was not mimicked by in utero exposure alone. Mammary glands of PND50 rats fed lifetime SPI had increased terminal end bud apoptotic status and PTEN expression, than the other diet groups. Rats exposed only in utero to SPI or GEN had higher membrane E-cadherin in mammary structures than those lifetime-fed CAS or SPI. Thus, limited exposure during gestation to SPI can positively influence resistance to chemically induced mammary tumorigenesis later in life. Preventative strategies against mammary and other types of cancer might be uncovered by refinement of the developmental window for dietary factor exposure.
41 citations
TL;DR: The data suggest that EtOH-induced bone loss in pregnant rats is mainly due to inhibited bone formation, whereas in nonpregnant rats, the data are consistent with increased osteoclast activation and bone resorption concomitant with decreased estradiol levels.
Abstract: Chronic ethanol (EtOH) consumption can result in osteopenia. In the current study, we examined the modulation of EtOH-induced bone loss during pregnancy. Nonpregnant and pregnant dams were intragastrically infused either control or EtOH-containing diets throughout gestation (gestation d 5 through 20 or an equivalent period of 15 d) by total enteral nutrition. The effects of EtOH (8.5 to 14 g/kg/d) on tibial bone mineral density (BMD), mineral content (BMC), and bone mineral area were assessed at gestation d 20 via peripheral quantitative computerized tomography. EtOH caused a dose-dependent decrease in BMD and BMC without affecting bone mineral area. Trabecular BMD and BMC were significantly lower in EtOH-treated, nonpregnant dams, compared with pregnant cohorts at the same infused dose of EtOH and urinary ethanol concentrations. Static histomorphometric analysis of tibiae from pregnant rats after EtOH treatment showed decreased osteoblast and osteoid surface, indicating inhibited bone formation, whereas EtOH-treated cycling rats showed higher osteoclast and eroded surface, indicative of increased bone resorption. Circulating osteocalcin and 1,25-dihydroxyvitamin D3 were lower in both EtOH-fed nonpregnant and pregnant rats. Gene expression of osteoclast markers, 70 kDa v-ATPase, and tartrate-resistant acid phosphatase were increased selectively in nonpregnant EtOH-treated rats but not pregnant rats. Moreover, only nonpregnant EtOH-fed rats showed induction in bone marrow receptor activator of nuclear factor-kappaB ligand mRNA and decreased circulating 17beta-estradiol levels. Our data suggest that EtOH-induced bone loss in pregnant rats is mainly due to inhibited bone formation, whereas in nonpregnant rats, the data are consistent with increased osteoclast activation and bone resorption concomitant with decreased estradiol levels.
30 citations
TL;DR: Results indicate potential physiological linkages of dietary protein type with circulating C-peptide (and by inference insulin), local expression of SREBP-1c gene and propensity for small intestine tumorigenesis.
Abstract: We evaluated partially hydrolyzed whey protein (WPH) for inhibitory effects on the development of colon aberrant crypt foci (ACF) and intestinal tumors in azoxymethane (AOM)-treated rats. Pregnant Sprague-Dawley rats and their progeny were fed AIN-93G diets containing casein (CAS, control diet) or WPH as the sole protein source. Colons and small intestines from the male progeny were obtained at 6, 12, 20 and 23 weeks after AOM treatment. At 6 and 23 weeks, post-AOM, WPH-fed rats had fewer ACF than did CAS-fed rats. Intestinal tumors were most frequent at 23 weeks, post-AOM. At this time point, differences in colon tumor incidence with diet were not observed; however, WPH-fed rats had fewer tumors in the small intestine (7.6% vs. 26% incidence, P=.004). Partially hydrolized whey protein suppressed circulating C-peptide concentration (a stable indicator of steady-state insulin secretion) at all four time points relative to the corresponding CAS-fed animals. The relative mRNA abundance for the insulin-responsive, transcription factor gene, SREBP-1c, was reduced by WPH in the duodenum but not colon. Results indicate potential physiological linkages of dietary protein type with circulating C-peptide (and by inference insulin), local expression of SREBP-1c gene and propensity for small intestine tumorigenesis.
29 citations
TL;DR: Results indicate that mammary glands of rats fed a WPH diet are more protected from endogenous DNA damage than are those of CAS-fed rats, and identify MCP-1 as a potential serum biomarker for the positive effects of healthy diets.
Abstract: Dietary protection from mammary cancer is likely coordinated through multiple signaling pathways, based on the known heterogeneity of the disease and the distinct origins of mammary tumor cells. The present study examined the modulatory effects of dietary intake of whey protein hydrolysate (WPH) relative to casein (CAS), on mammary epithelial cell resistance to endogenous DNA damage using Tp53 gene expression and signaling as a read-out, and on systemic proapoptotic and immune surveillance activity, in young adult female Sprague-Dawley rats. Rats were fed AIN-93G diets made with CAS or WPH as the sole protein source beginning at gestation d 4. At postnatal day (PND) 50, mammary glands of rats fed WPH had lower levels of activated Tp53 and p38 mitogen-activated protein kinase proteins, and reduced transcript levels for Tp53-associated DNA damage repair, growth arrest, and proapoptotic genes than those of CAS-fed rats. Serum from WPH-fed rats had greater apoptotic activity in MCF-7 tumor cells than that from rats fed CAS. Serum levels of monocyte chemoattractant protein (MCP)-1 were higher in WPH- than in CAS-fed rats. MCF-7 cells treated with CAS serum + recombinant rat MCP-1 had apoptotic activity and Tp53 and p21 gene expression levels comparable to those treated with WPH serum or recombinant MCP-1. Results indicate that mammary glands of rats fed a WPH diet are more protected from endogenous DNA damage than are those of CAS-fed rats, and identify MCP-1 as a potential serum biomarker for the positive effects of healthy diets.
TL;DR: This model can be used to study the mechanisms underlying inhibition of bone formation by chronic ethanol exposure and to test preclinical interventions and is supported by radiographic and histologic analyses of the % new bone formation in the DO gaps.
TL;DR: The data suggest that the athero-protective effect of soy diets may be mediated by blocking monocyte-endothelial cell interaction, and suggest that inhibition of CD54-dependent monocyte adhesion by soy isoflavones is mediated in part by affinity regulation of CD11a.
Abstract: Soy-based diets have been shown to protect against the development of atherosclerosis; however, the underlying mechanism(s) remain unknown. Interaction between activated monocytes and inflamed endothelial cells is an early event in atherogenesis. Therefore, we examined whether treatment of monocytes with soy phytochemicals could inhibit their adhesion to the endothelial cell-specific protein, CD54, a key factor in monocyte adhesion. Female Sprague-Dawley rats were fed AIN-93G diets containing soy protein isolate or casein. Sera from soy-fed rats inhibited CD54-dependent monocyte adhesion, whereas sera from casein-fed rats did not. To determine whether isoflavones in the sera of soy-fed rats were involved in this inhibition, monocytes were preincubated with soy isoflavones. Isoflavone treatment inhibited monocyte adhesion to CD54 protein, as well as to endothelial cells expressing CD54. Monocyte expression of CD11a, the cognate receptor for CD54, was unaffected by isoflavones. However, binding of the activation epitope-specific antibody mAb24, which binds specifically to the active form of CD11a, was significantly lower in soy isoflavone-treated monocytes than in media-treated cells. These findings suggest that inhibition of CD54-dependent monocyte adhesion by soy isoflavones is mediated in part by affinity regulation of CD11a. Inhibition of monocyte adhesion to endothelial cells by isoflavones resulted in reduced expression of the inflammatory cytokines IL-6 and IL-8. Collectively, these data suggest that the athero-protective effect of soy diets may be mediated by blocking monocyte-endothelial cell interaction.
TL;DR: In vitro antitumor activities of an ether fraction from RPI was studied using human tumor cell lines, including two human breast carcinoma cell lines (MDA-MB-453 and MCF-7) and two myeloma cell Lines (RPMI-8226 and IM-9).
Abstract: Rice protein isolate (RPI) has been reported to reduce the incidence of 7,12-dimethylbenz[a]anthracene-induced mammary tumors in rats. To determine the potential role of phytochemicals associated with the RPI, we studied in vitro antitumor activities of an ether fraction from RPI using human tumor cell lines, including two human breast carcinoma cell lines (MDA-MB-453 and MCF-7) and two myeloma cell lines (RPMI-8226 and IM-9). Concentration-dependent antiproliferative effects of the ether fraction were observed in all cell lines using the standard 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Fraction-induced apoptosis (P < 0.05) was detected in all cell lines, and this was associated with the induction of proapoptotic bax protein and cdk inhibitors (p21) and the suppression of cdk4 and cyclin D1 activity. Liquid chromatography−mass spectrometry/mass spectrometry (LC-MS/MS) with both positive and negative modes was used to analyze the phytochemicals in the ether fraction from RPI. Fi...
TL;DR: It is suggested that early soy consumption may increase the metabolism of a wide variety of CYP3A substrates, but that soy does not imprint the expression of CYp3A enzymes.
Abstract: Feeding soy diets has been shown to induce cytochrome P450s in gene family CYP3A in Sprague-Dawley rat liver. We compared expression of CYP3A enzymes on postnatal Day 33 (PND33) rats fed casein or soy protein isolate (SPI+)-based AIN-93G diets continuously from gestational Day 4 through PND33 or the diets were switched on PND15 (n = 3-6 litters) to examine the potential imprinting effects of soy on drug metabolism. In addition rats were fed casein, SPI+, SPI+ stripped of phytochemicals (SPI-), or casein diets supplemented with the soy-associated isoflavones genistein or daidzein from weaning through PND33 to examine the hypothesis that the isoflavones are responsible for CYP3A induction by soy feeding. Feeding SPI either continuously or from weaning induced hepatic CYP3A1 and CYP3A2 mRNA, apoprotein, and CYP3A-dependent testosterone 6beta-hydroxylase activity in liver microsomes 2- to 5-fold (P < 0.05). CYP3A mRNA expression was also elevated 2- to 3-fold in the jejunum of SPI-fed rats (P < 0.05). CYP3A was not induced in livers of rats switched to casein from soy at weaning. Induction of CYP3A1 also did not occur in rats fed SPI-, but CYP3A2 mRNA and apoprotein were induced (P < 0.05) in females fed SPI-. Offspring weaned onto genistein-supplemented diets had no elevation of CYP3A mRNAs or apoproteins. Weaning onto daidzein diets increased CYP3A2 mRNA and apoprotein expression in male rats (P < 0.05). These data suggest that early soy consumption may increase the metabolism of a wide variety of CYP3A substrates, but that soy does not imprint the expression of CYP3A enzymes. Effects on CYP3A1 expression appear to be primarily due to phytochemical components of SPI other than isoflavones. In contrast, consumption of soy protein and daidzein appear to be associated with the induction of CYP3A2.
TL;DR: Results demonstrate stimulatory actions of 1% and inhibitory actions of 4% Shiitake mushroom on indices of rat colon tumorigenesis, which may be associated with altered metabolism.
TL;DR: It is found that lifetime exposure to WPH, relative to CAS, decreased mammary tumor incidence and prolonged the appearance of tumors in NMU-treated female rats, with no corresponding effects on tumor multiplicity.
Abstract: The mammary tumor-protective effects of dietary factors are considered to be mediated by multiple signaling pathways, consistent with the heterogeneous nature of the disease and the distinct genetic profiles of tumors arising from diverse mammary cell populations. In a 7,12-dimethylbenz(a)anthracene-induced model of carcinogenesis, we showed previously that female Sprague-Dawley rats exposed to AIN-93G diet containing whey protein hydrolysate (WPH) beginning at gestation Day 4 had reduced tumor incidence than those exposed to diet containing casein (CAS), due partly to increased mammary differentiation and reduced activity of phase I metabolic enzymes. Here, we evaluated the tumor-protective effects of these same dietary proteins to the direct-acting carcinogen N-methyl-N-nitrosourea (NMU). We found that lifetime exposure to WPH, relative to CAS, decreased mammary tumor incidence and prolonged the appearance of tumors in NMU-treated female rats, with no corresponding effects on tumor multiplicit...
01 Jan 2006
TL;DR: In this article, the influence of developmental context on dietary protection against tumorigenesis initiated by the direct-acting carcinogen N-methyl-N-nitrosourea (NMU) was examined.
Abstract: The linkage of nutrition and cancer prevention is an intriguing concept that is gaining widespread support. Here, we investigated the influence of developmental context on dietary protection against tumorigenesis initiated by the direct-acting carcinogen N-methyl-N-nitrosourea (NMU), and examined potential mechanisms underlying these effects. Rats were exposed only in utero or for lifetime to American Institute of Nutrition-93G diets made with casein (CAS), soy protein isolate (SPI) or CAS supplemented with genistein (GEN). Mammary glands of post-natal day (PND) 50 rats prior to NMU administration were examined for apoptotic status, pro-apoptotic gene expression and immunoreactive phosphatase and tensin homolog deleted on chromosome ten (PTEN) and epithelial cadherin (E-cadherin) levels, whereas mammary tumor parameters were evaluated 99 days post-NMU. Animals exposed only in utero to SPI had increased tumor latency, decreased tumor multiplicity and lower higher grade tumors, than those fed CAS. In utero exposure to GEN resulted in similar tumor parameters as the CAS group, whereas lifetime SPI exposure decreased tumor incidence that was not mimicked by in utero exposure alone. Mammary glands of PND50 rats fed lifetime SPI had increased terminal end bud apoptotic status and PTEN expression, than the other diet groups. Rats exposed only in utero to SPI or GEN had higher membrane E-cadherin in mammary structures than those lifetime-fed CAS or SPI. Thus, limited exposure during gestation to SPI can positively influence resistance to chemically induced mammary tumorigenesis later in life. Preventative strategies against mammary and other types of cancer might be uncovered by refinement of the developmental window for dietary factor exposure.