Effects of a Group-Mediated Cognitive Behavioral Lifestyle Intervention on Select Social Cognitive Outcomes in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy.

Objective. To compare the effects of a group-mediated cognitive behavioral (GMCB) exercise and dietary (EX+D) intervention with those of standard-of-care (SC) treatment on select social cognitive outcomes in prostate cancer (PCa) patients undergoing androgen deprivation therapy (ADT). Methods. In the single-blind, 2-arm, randomized controlled Individualized Diet and Exercise Adherence-Pilot (IDEA-P) trial, 32 PCa patients (mean age = 66.2 years; SD = 7.8) undergoing ADT were randomly assigned to a 12-week EX+D intervention (n = 16) or SC treatment (n = 16). The exercise component of the personalized EX+D intervention integrated a combination of supervised resistance and aerobic exercise performed twice per week. The dietary component involved counseling and education to modify dietary intake and composition. Blinded assessments of social cognitive outcomes were obtained at baseline and 2-month and 3-month follow-up. Results. Intent-to-treat analysis of covariance demonstrated that the EX+D intervention resulted in significantly greater improvements in scheduling (P < .05), coping (P < .01), and exercise self-efficacy (P < .05), and satisfaction with function (P < .01) at 3 months relative to SC. Results of partial correlation analysis also demonstrated that select social cognitive outcomes were significantly correlated with primary trial outcomes of mobility performance and exercise participation (P < .05) at 3-month follow-up. Conclusions: The GMCB lifestyle intervention yielded more favorable improvements in relevant social cognitive outcomes relative to SC among PCa patients undergoing ADT. Additionally, more favorable social cognitive outcomes were associated with superior mobility performance and exercise participation following the independent maintenance phase of the EX+D intervention.

Green tea extract inhibits early oncogenic responses in mice with nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) increases hepatocellular carcinoma (HCC) risk. We hypothesized that the hepatoprotective anti-inflammatory benefits of catechin-rich green tea extract (GTE) would protect against HCC progression by inhibiting NASH-associated liver injury and pro-oncogenic responses. We used an HCC model in high-fat (HF)-fed mice that mimics early oncogenic events during NASH without inducing tumorigenesis and premature mortality. Male C57BL/6J mice (4-weeks old) were fed a HF diet containing GTE at 0% or 2%. Mice were administered saline or diethylnitrosamine (DEN; 60 mg kg-1, i.p.) at 5-weeks and 7-weeks of age. NASH, inflammation, fibrosis, and oncogenic responses were assessed at 25-weeks of age. Saline-treated mice showed prominent histopathological signs of steatosis and hepatocellular ballooning. Although DEN did not impact adiposity, steatosis, ballooning and hepatic lipid accumulation, these parameters were attenuated by GTE regardless of DEN. Hepatic lipid peroxidation and fibrosis that were increased by DEN were attenuated by GTE. Hepatic TLR4, MCP1 and TNFα mRNA levels were unaffected by DEN, whereas iNOS was increased by DEN. These transcripts were lowered by GTE. GTE attenuated the frequency of PCNA+ hepatocytes and mRNA expression of cyclin D1, MIB1 and Ki-67 that were otherwise increased by DEN. GTE increase APAF1 mRNA that was otherwise lowered by DEN. Relative to saline-treated mice, DEN increased mRNA levels of oncostatin M, gp130, c-Fos, c-Myc and survivin; each was lowered by GTE in DEN-treated mice. These findings indicate that GTE may protect against hepatic oncogenesis by limiting early steps in the carcinogenic cascade related to NASH-associated HCC.

Dietary Black Raspberries Impact the Colonic Microbiome and Phytochemical Metabolites in Mice.

SCOPE: Black raspberries (BRB) are a rich source of bioactive phytochemicals, including anthocyanins and ellagitannins. These phytochemicals are poorly absorbed and may be transformed by gut microbiota into various metabolites that may impact the colonic mucosa or upon absorption have systemic bioactivity. The objective of this study is to define the impact of a BRB-containing diet on the colon microbiome in mice and quantify the phytochemical metabolites in the colon contents and circulation. METHODS AND RESULTS: Male mice were fed 10% w/w freeze-dried BRB powder for 6 weeks. The colonic microbiota was evaluated by 16S rRNA gene sequencing. Anthocyanin and ellagitannin metabolites, protocatechuic acid, and urolithins were analyzed by HPLC-MS/MS. The BRB diet impacted colon mucosal microbial composition with a more robust effect observed on the luminal microflora. BRB-derived protocatechuic acid and urolithins were quantified in the colon, luminal contents, plasma, liver, and prostate with protocatechuic acid present in higher concentrations compared to urolithins. CONCLUSION: This study highlights the complex interactions between dietary phytochemicals, the host microbiome, and metabolism. It is demonstrated that microbially produced phytochemical metabolites are present in the colon and systemic circulation where they may exert biological activity.

Plasma Metabolomics Reveals Steroidal Alkaloids as Novel Biomarkers of Tomato Intake in Mice.

SCOPE: Diets rich in tomato products are associated with a reduced risk of various chronic disease processes. The carotenoid lycopene is most intensely studied as the bioactive mediating health effects, yet tomatoes contain an array of phytochemicals. An untargeted metabolomics study is conducted on blood plasma to identify novel markers of tomato consumption absorbed from the diet and released into the bloodstream in mice. METHODS AND RESULTS: Male mice are fed a control AIN-93G diet or the same diet supplemented with 0.25 % lycopene beadlets, or 10 % freeze-dried red tomato, tangerine tomato, or low-carotenoid tomato for 4 weeks. Untargeted UHPLC-QTOF-MS data acquisition and differential analysis of plasma metabolites reveals several structurally related deglycosylated tomato steroidal alkaloids, including tomatidine and hydroxylated/desaturated derivatives, in plasma after the consumption of all three tomato varieties. Additionally, plasma metabolite profiles reflect glycoalkaloid forms found in the tomato diets. CONCLUSION: Dietary tomato glycoalkaloids are cleaved during digestion to aglycones and further metabolized post-absorption. Steroidal alkaloids in plasma may serve as novel and specific biomarkers of tomato consumption and represent a class of phytochemical metabolites that could potentially have in vivo bioactivity impacting health and disease processes.

Intestinal microbial dysbiosis and colonic epithelial cell hyperproliferation by dietary α-mangostin is independent of mouse strain.

Beverages and supplements prepared from mangosteen fruit are claimed to support gut health and immunity, despite the absence of supporting evidence from clinical trials. We recently reported that α-mangostin (α-MG), the most abundant xanthone in mangosteen fruit, altered the intestinal microbiome, promoted dysbiosis, and exacerbated colitis in C57BL/6J mice. The objective of this study was to determine whether induction of dysbiosis by dietary α-MG is limited to the C57BL/6J strain or represents a more generic response to chronic intake of the xanthone on the gut microbiota of mice. C3H, Balb/c, Nude FoxN1nu, and C57BL/6J mice, each demonstrating unique microbiomes, were fed standard diet or diet containing 0.1% α-MG for four weeks. Dietary α-MG significantly altered the cecal and colonic microbiota in all four strains of mice, promoting a reduction in generally assumed beneficial bacterial groups while increasing the abundance of pathogenic bacteria. Consumption of α-MG was associated with reduced abundance of Firmicutes and increased abundance of Proteobacteria. The abundance of Lachnospiraceae, Ruminococcaceae, and Lactobacillaceae was reduced in α-MG-fed mice, while that of Enterobacteriaceae and Enterococcaceae was increased. Dietary α-MG also was associated with increased proliferation of colonic epithelial cells, infiltration of immune cells, infiltration of immune cells and increased fluid content in stool. These results suggest that ingestion of pharmacologic doses of xanthones in mangosteen-containing supplements may adversely alter the gut microbiota and should be used with caution.

Dietary α-mangostin, a xanthone from mangosteen fruit, exacerbates experimental colitis and promotes dysbiosis in mice.

SCOPE: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. α-Mangostin (α-MG), the most abundant xanthone in mangosteen fruit, exerts anti-inflammatory and antibacterial activities in vitro. We evaluated the impact of dietary α-MG on murine experimental colitis and on the gut microbiota of healthy mice. METHODS AND RESULTS: Colitis was induced in C57BL/6J mice by administration of dextran sulfate sodium (DSS). Mice were fed control diet or diet with α-MG (0.1%). α-MG exacerbated the pathology of DSS-induced colitis. Mice fed diet with α-MG had greater colonic inflammation and injury, as well as greater infiltration of CD3(+) and F4/80(+) cells, and colonic myeloperoxidase, than controls. Serum levels of granulocyte colony-stimulating factor, IL-6, and serum amyloid A were also greater in α-MG-fed animals than in controls. The colonic and cecal microbiota of healthy mice fed α-MG but no DSS shifted to an increased abundance of Proteobacteria and decreased abundance of Firmicutes and Bacteroidetes, a profile similar to that found in human UC. CONCLUSION: α-MG exacerbated colonic pathology during DSS-induced colitis. These effects may be associated with an induction of intestinal dysbiosis by α-MG. Our results suggest that the use of α-MG-containing supplements by patients with UC may have unintentional risk.

ß-Carotene-9',10'-oxygenase status modulates the impact of dietary tomato and lycopene on hepatic nuclear receptor-, stress-, and metabolism-related gene expression in mice.

Tomato and lycopene (ψ,ψ-carotene) consumption is hypothesized to protect against nonalcoholic steatohepatitis and hepatocarcinogenesis, processes that may depend upon diet and gene interactions. To investigate the interaction of tomato or lycopene feeding with ß-carotene-9',10'-monooxygenase (Bco2) on hepatic metabolic and signaling pathways, male wild-type (WT) and Bco2(-/-) mice (3-wk-old; n = 36) were fed semi-purified control, 10% tomato powder-containing, or 0.25% lycopene beadlet-containing diets for 3 wk. Serum lycopene concentrations were higher in lycopene- and tomato-fed Bco2(-/-) mice compared with WT (P = 0.03). Tomato- and lycopene-fed mice had detectable hepatic apolipoprotein (apo)-6'-, apo-8'-, and apo-12'-lycopenal concentrations. Hepatic expression of ß-carotene-15,15'-monooxygenase was increased in Bco2(-/-) mice compared with WT (P = 0.02), but not affected by diet. Evaluation of hepatic gene expression by focused quantitative reverse transcriptase-polymerase chain reaction arrays for nuclear receptors and coregulators (84 genes) and stress and metabolism (82 genes) genes indicates that tomato feeding affected 31 genes (≥1.5-fold, P < 0.05) and lycopene feeding affected 19 genes, 16 of which were affected by both diets. Lycopene down-regulation of 7 nuclear receptors and coregulators, estrogen-related receptor-α, histone deacetylase 3, nuclear receptor coactivator 4, RevErbA-ß, glucocorticoid receptor, peroxisome proliferator-activated receptor (PPAR)-α, and PPAR-γ, coactivator 1 ß was dependent upon interaction with Bco2 status. Lycopene and tomato feeding induced gene expression patterns consistent with decreased lipid uptake, decreased cell proliferation and mitosis, down-regulated aryl hydrocarbon receptor signaling, and decreased expression of genes involved in retinoid X receptor heterodimer activation. Tomato feeding also caused expression changes consistent with down-regulation of DNA synthesis and terpenoid metabolism. These data suggest tomato components, particularly lycopene, affect hepatic gene expression, potentially affecting hepatic responses to metabolic, infectious, or chemical stress.

Anti-tumorigenicity of dietary α-mangostin in an HT-29 colon cell xenograft model and the tissue distribution of xanthones and their phase II metabolites.

SCOPE: This study investigated the in vivo and in vitro activity of α-mangostin (α-MG), the most abundant xanthone in mangosteen pericarp, on HT-29 cell tumorigenicity, proliferation, and several markers of tumor cell activity, as well as the profile and amounts of xanthones in serum, tumor, liver, and feces. METHODS AND RESULTS: Balb/c nu/nu mice were fed either control diet or diet containing 900 mg α-MG/kg. After 1 week of acclimation to diet, mice were injected subcutaneously with HT-29 cells and fed the same diets ad libitum for an additional 2 or 4 weeks. After 2 and 4 weeks, tumor mass and the concentrations of BcL-2 and ß-catenin in tumors of mice fed diet with α-MG were significantly less than in mice fed control diet. Xanthones and their metabolites were identified in serum, tumor, liver, and feces. In vitro treatment of HT-29 cells with α-MG also inhibited cell proliferation and decreased expression of BcL-2 and ß-catenin. CONCLUSION: Our data demonstrate that the anti-neoplastic effect of dietary α-MG is associated with the presence of xanthones in the tumor tissue. Further investigation of the impact of beverages and food products containing xanthones on the prevention of colon cancer or as complementary therapy is merited.

Inhibition of bladder cancer by broccoli isothiocyanates sulforaphane and erucin: characterization, metabolism, and interconversion.

SCOPE: Epidemiologic evidence suggests diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk. Our objectives are to investigate these observations and determine the role of isothiocyanates in primary or secondary bladder cancer prevention. METHODS AND RESULTS: We initially investigate the mechanisms whereby broccoli and broccoli sprout extracts and pure isothiocyanates inhibit normal, noninvasive (RT4), and invasive (J82, UMUC3) human urothelial cell viability. Sulforaphane (IC(50) = 5.66 ± 1.2 µM) and erucin (IC(50) = 8.79 ± 1.3 µM) are found to be the most potent inhibitors and normal cells are least sensitive. This observation is associated with downregulation of survivin, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/neu), G(2) /M cell cycle accumulation, and apoptosis. In a murine UMUC3 xenograft model, we fed semipurified diets containing 4% broccoli sprouts, or 2% broccoli sprout isothiocyanate extract; or gavaged pure sulforaphane or erucin (each at 295 µmol/kg, similar to dietary exposure); and report tumor weight reduction of 42% (p = 0.02), 42% (p = 0.04), 33% (p = 0.04), and 58% (p < 0.0001), respectively. Sulforaphane and erucin metabolites are present in mouse plasma (micromolar range) and tumor tissue, with N-acetylcysteine conjugates as the most abundant. Interconversion of sulforaphane and erucin metabolites was observed. CONCLUSION: This work supports development of fully characterized, novel food products containing broccoli components for phase I/II human studies targeting bladder cancer prevention.

Tomato-based food products for prostate cancer prevention: what have we learned?

Evidence derived from a vast array of laboratory studies and epidemiological investigations have implicated diets rich in fruits and vegetables with a reduced risk of certain cancers. However, these approaches cannot demonstrate causal relationships and there is a paucity of randomized, controlled trials due to the difficulties involved with executing studies of food and behavioral change. Rather than pursuing the definitive intervention trials that are necessary, the thrust of research in recent decades has been driven by a reductionist approach focusing upon the identification of bioactive components in fruits and vegetables with the subsequent development of single agents using a pharmacologic approach. At this point in time, there are no chemopreventive strategies that are standard of care in medical practice that have resulted from this approach. This review describes an alternative approach focusing upon development of tomato-based food products for human clinical trials targeting cancer prevention and as an adjunct to therapy. Tomatoes are a source of bioactive phytochemicals and are widely consumed. The phytochemical pattern of tomato products can be manipulated to optimize anticancer activity through genetics, horticultural techniques, and food processing. The opportunity to develop a highly consistent tomato-based food product rich in anticancer phytochemicals for clinical trials targeting specific cancers, particularly the prostate, necessitates the interactive transdisciplinary research efforts of horticulturalists, food technologists, cancer biologists, and clinical translational investigators.