Effect of cinnamon spice on continuously monitored glycemic response in adults with prediabetes: a 4-week randomized controlled crossover trial.

BACKGROUND: Previous clinical studies showing that cinnamon spice lowers blood glucose concentrations had inconsistent results. OBJECTIVES: To determine the effect of daily cinnamon spice supplementation in an amount commonly used for seasoning on glucose concentrations in adults with obesity and prediabetes. METHODS: Following a 2-wk run-in period of maintaining a low polyphenol/fiber diet, 18 participants with obesity and prediabetes underwent a 10-wk randomized, controlled, double-blind, crossover trial (mean age 51.1 y; mean fasting plasma glucose 102.9 mg/dL). The participants were randomly assigned to take cinnamon (4 g/d) or placebo for 4-wk, followed by a 2-wk washout period, and then crossed over to the other intervention for an additional 4-wk. Glucose changes were measured with continuous glucose monitoring. Oral glucose tolerance testing immediately following ingestion of cinnamon or placebo was performed at 4-time points to assess their acute effects both at the baseline and end of each intervention phase. Digestive symptom logs were obtained daily. RESULTS: There were 694 follow-up days with 66,624 glucose observations. When compared with placebo, 24-h glucose concentrations were significantly lower when cinnamon was administered [mixed-models; effect size (ES) = 0.96; 95 % confidence interval (CI): -2.9, -1.5; P < 0.001]. Similarly, the mean net-area-under-the-curve (netAUC) for glucose was significantly lower than for placebo when cinnamon was given (over 24 h; ES = -0.66; 95 % CI: 2501.7, 5412.1, P = 0.01). Cinnamon supplementation resulted in lower glucose peaks compared with placebo (Δpeak 9.56 ± 9.1 mg/dL compared with 11.73 ± 8.0 mg/dL; ES = -0.57; 95 % CI: 0.8, 3.7, P = 0.027). Glucose-dependent-insulinotropic-polypeptide concentrations increased during oral glucose tolerance testing + cinnamon testing (mixed-models; ES = 0.51; 95 % CI: 1.56, 100.1, P = 0.04), whereas triglyceride concentrations decreased (mixed-models; ES = 0.55; 95 % CI: -16.0, -1.6, P = 0.02). Treatment adherence was excellent in both groups (cinnamon: 97.6 ± 3.4 % compared with placebo: 97.9 ± 3.7 %; ES = -0.15; 95 % CI: -1.8, 0.2, P = 0.5). No differences were found in digestive symptoms (abdominal pain, borborygmi, bloating, excess flatus, and stools/day) between cinnamon and placebo groups. CONCLUSIONS: Cinnamon, a widely available and low-cost supplement, may contribute to better glucose control when added to the diet in people who have obesity-related prediabetes. This trial was registered at clinicaltrials.gov as NCT04342624.

Enhanced Chemoprevention of Prostate Cancer by Combining Arctigenin with Green Tea and Quercetin in Prostate-Specific Phosphatase and Tensin Homolog Knockout Mice.

The low bioavailability of most phytochemicals limits their anticancer effects in humans. The present study was designed to test whether combining arctigenin (Arc), a lignan mainly from the seed of Arctium lappa, with green tea (GT) and quercetin (Q) enhances the chemopreventive effect on prostate cancer. We performed in vitro proliferation studies on different cell lines. We observed a strong synergistic anti-proliferative effect of GT+Q+Arc in exposing androgen-sensitive human prostate cancer LNCaP cells. The pre-malignant WPE1-NA22 cell line was more sensitive to this combination. No cytotoxicity was observed in normal prostate epithelial PrEC cells. For an in vivo study, 3-week-old, prostate-specific PTEN (phosphatase and tensin homolog) knockout mice were treated with GT+Q, Arc, GT+Q+Arc, or the control daily until 16 weeks of age. In vivo imaging using prostate-specific membrane antigen (PSMA) probes demonstrated that the prostate tumorigenesis was significantly inhibited by 40% (GT+Q), 60% (Arc at 30 mg/kg bw), and 90% (GT+Q+Arc) compared to the control. A pathological examination showed that all control mice developed invasive prostate adenocarcinoma. In contrast, the primary lesion in the GT+Q and Arc alone groups was high-grade prostatic intraepithelial neoplasia (PIN), with low-grade PIN in the GT+Q+Arc group. The combined effect of GT+Q+Arc was associated with an increased inhibition of the androgen receptor, the PI3K/Akt pathway, Ki67 expression, and angiogenesis. This study demonstrates that combining Arc with GT and Q was highly effective in prostate cancer chemoprevention. These results warrant clinical trials to confirm the efficacy of this combination in humans.

Effect of omega-3 fatty acid diet on prostate cancer progression and cholesterol efflux in tumor-associated macrophages-dependence on GPR120.

BACKGROUND: Preclinical and clinical translational research supports the role of an ω-3 fatty acid diet for prostate cancer prevention and treatment. The anti-prostate cancer effects of an ω-3 diet require a functional host g-protein coupled receptor 120 (GPR120) but the underlying effects on the tumor microenvironment and host immune system are yet to be elucidated. METHODS: Friend leukemia virus B (FVB) mice received bone marrow from green fluorescent protein (GFP) labeled GPR120 wild-type (WT) or knockout (KO) mice followed by implanting Myc-driven mouse prostate cancer (MycCap) allografts and feeding an ω-3 or ω-6 diet. Tumor associated immune cells were characterized by flow cytometry, and CD206+ tumor infiltrating M2-like macrophages were isolated for gene expression studies. MycCap prostate cancer cell conditioned medium (CM) was used to stimulate murine macrophage cells (RAW264.7) and bone marrow-derived (BMD) macrophages to study the effects of docosahexanoic acid (DHA, fish-derived ω-3 fatty acid) on M2 macrophage function and cholesterol metabolism. RESULTS: The bone marrow transplantation study showed that an ω-3 as compared to an ω-6 diet inhibited MycCaP allograft tumor growth only in mice receiving GPR120 WT but not GPR120 KO bone marrow. In the ω-3 group, GPR120 WT BMD M2-like macrophages infiltrating the tumor were significantly reduced in number and gene expression of cholesterol transporters Abca1, Abca6, and Abcg1. RAW264.7 murine macrophages and BMDMs exposed to MycCaP cell CM had increased gene expression of cholesterol transporters, depleted cholesterol levels, and were converted to the M2 phenotype. These effects were inhibited by DHA through the GPR120 receptor. CONCLUSION: Host bone marrow cells with functional GPR120 are essential for the anticancer effects of dietary ω-3 fatty acids, and a key target of the ω-3 diet are the M2-like CD206+ macrophages. Our preclinical findings provide rationale for clinical trials evaluating ω-3 fatty acids as a potential therapy for prostate cancer through inhibition of GPR120 functional M2-like macrophages.

Concentrated Grape Powder Consumption Modulates Cholesterol Metabolism and Homeostasis in Healthy Subjects.

SCOPE: Four weeks' of concentrated grape powder (GP) consumption reduces circulating cholesterol in healthy free-living subjects consuming a low-fiber/low-polyphenol diet. Here, the study aims to investigate the underlying mechanisms for cholesterol reduction by evaluating biomarkers of cholesterol de novo biosynthesis, intestinal absorption, miRNA involved in transcriptional regulation of cholesterol metabolism, as well as cholesterol oxidation. METHODS AND RESULTS: Fasting plasma samples collected from 19 healthy free-living subjects at baseline and week 4 of GP consumption are used in this study. Gas chromatography-mass (GC-MS) analysis of plasma samples shows that lathosterol, a precursor of cholesterol synthesis, is significantly decreased after GP consumption indicating reduced cholesterol de novo biosynthesis. Markers of intestinal absorption, campesterol, and ß-sitosterol are not changed. Realtime PCR shows that plasma exosomal miRNA-1 is increased after GP consumption. GC-MS also shows that GP consumption reduces the plasma cholesterol oxidation product 27-hydroxycholesterol (27-HC). CONCLUSIONS: This study enhances the understanding of the mechanisms of the cholesterol lowering effects of GP, and provides new insights into the potential health benefits of grape consumption.

Pomegranate juice alters the microbiota in breast milk and infant stool: a pilot study.

Pomegranate juice (PomJ) contains ellagitannins (ETs) that are metabolized to ellagic acid (EA). Intestinal bacteria convert EA further to urolithins that are absorbed into the circulation and may provide health benefits. PomJ consumption by pregnant women was reported to be neuroprotective for their infants. In order to determine whether EA and metabolites are transferred from breast milk of mothers consuming PomJ to nursing infants, we performed an interventional pilot study and enrolled ten healthy women with full-term, exclusively breast-fed infants, consuming 8 oz. of PomJ daily for two weeks. Breast milk, plasma, urine and stool samples were collected from the mothers and the urine and stool samples from the infants before and after two weeks of PomJ consumption. Samples were analyzed using liquid chromatography-mass spectrometry to identify EA metabolites and 16S rRNA sequencing to determine changes in the microbiota. EA metabolite conjugates (dimethyl EA-glucuronide DMEAG and urolithin A-glucuronide UAG) were found in breast milk, plasma and urine from mothers and in urine of infants after 14 days of PomJ consumption. In addition, urolithin B-glucuronide (UBG) was found in breast milk, plasma and urine from two participants and urine from their infants. PomJ consumption was associated with a significant decrease in breast milk of Lactococcus, Subdoligranulum, and Acinetobacter, while the abundance of Firmicutes/Faecalibacterium increased significantly. In breast milk Escherichia/Shigella was inversely correlated to breast milk UAG. In infant stools, the abundance of Lachnoclostridium and Staphylococcus was increased. Infant stool Blautia was positively correlated to breast milk and mother plasma UBG. This pilot study demonstrates that EA and its metabolites are absorbed by the nursing infant from breast milk, excreted in urine and impact the infant gut microbiome. The concentration of EA metabolites in breast milk increased over time. Phenolic compounds in breast milk could be a way to promote neuroprotective, antioxidant and anti-inflammatory health benefits in infants.

Microbial and Chemical Profiles of Commercial Kombucha Products.

Kombucha is an increasingly popular functional beverage that has gained attention for its unique combination of phytochemicals, metabolites, and microbes. Previous chemical and microbial composition analyses of kombucha have mainly focused on understanding their changes during fermentation. Very limited information is available regarding nutrient profiles of final kombucha products in the market. In this study, we compared the major chemicals (tea polyphenols, caffeine), antioxidant properties, microbial and metabolomic profiles of nine commercial kombucha products using shotgun metagenomics, internal transcribed spacer sequencing, untargeted metabolomics, and targeted chemical assays. All of the nine kombucha products showed similar acidity but great differences in chemicals, metabolites, microbes, and antioxidant activities. Most kombucha products are dominated by the probiotic Bacillus coagulans or bacteria capable of fermentation including Lactobacillus nagelii, Gluconacetobacter, Gluconobacter, and Komagataeibacter species. We found that all nine kombuchas also contained varying levels of enteric bacteria including Bacteroides thetaiotamicron, Escherischia coli, Enterococcus faecalis, Bacteroides fragilis, Enterobacter cloacae complex, and Akkermansia muciniphila. The fungal composition of kombucha products was characterized by predominance of fermenting yeast including Brettanomyces species and Cyberlindnera jadinii. Kombucha varied widely in chemical content assessed by global untargeted metabolomics, with metabolomic variation being significantly associated with metagenomic profiles. Variation in tea bases, bacteria/yeast starter cultures, and duration of fermentation may all contribute to the observed large differences in the microbial and chemical profiles of final kombucha products.

Effects of dietary omega-3 fatty acids on orthotopic prostate cancer progression, tumor associated macrophages, angiogenesis and T-cell activation-dependence on GPR120.

BACKGROUND: The antiprostate cancer effects of dietary ω-3 fatty acids (FAs) were previously found to be dependent on host G-protein coupled receptor 120 (GPR120). Using an orthotopic tumor model and an ex-vivo model of bone marrow derived M2-like macrophages, we sought to determine if ω-3 FAs inhibit angiogenesis and activate T-cells, and if these effects are dependent on GPR120. METHODS: Gausia luciferase labeled MycCaP prostate cancer cells (MycCaP-Gluc) were injected into the anterior prostate lobe of FVB mice. After established tumors were confirmed by blood luminescence, mice were fed an ω-3 or ω-6 diet. Five weeks after tumor injection, tumor weight, immune cell infiltration and markers of angiogenesis were determined. An ex-vivo co-culture model of bone marrow derived M2-like macrophages from wild-type or GPR120 knockout mice with MycCap prostate cancer cells was used to determine if docosahexanoic acid (DHA, ω-3 FA) inhibition of angiogenesis and T-cell activation is dependent on macrophage GPR120. RESULTS: Feeding an ω-3 diet significantly reduced orthotopic MycCaP-Gluc tumor growth relative to an ω-6 diet. Tumors from the ω-3 group had decreased M2-like macrophage infiltration and decreased expression of angiogenesis factors. DHA significantly inhibited M2 macrophage-induced endothelial tube formation and reversed M2 macrophage-induced T-cell suppression, and these DHA effects were mediated, in part, by M2 macrophage GPR120. CONCLUSION: Omega-3 FAs delayed orthotopic tumor growth, inhibited M2-like macrophage tumor infiltration, and inhibited M2-like macrophage-induced angiogenesis and T-cell suppression. Given the central role of M2-like macrophages in prostate cancer progression, GPR120-dependent ω-3 FA inhibition of M2-like macrophages may play an important role in prostate cancer therapeutics.

Pomegranate Extract Improves Colitis in IL-10 Knockout Mice Fed a High Fat High Sucrose Diet.

SCOPE: The study tests the hypothesis that dietary pomegranate extract (PomX) supplementation attenuates colitis in a Western diet feed IL-10 deficient (IL-10-/-) murine model. METHODS AND RESULTS: Four-week-old male IL-10-/- mice are randomly assigned to a high fat high sucrose (HFHS) diet or a HFHS diet supplement with 0.25% PomX for 8 weeks. PomX supplementation lead to significantly lower histological score for colitis (2.6 ± 0.5 vs 3.9 ± 1.0), lower spleen weight (0.11 ± 0.01 vs 0.15 ± 0.02), and lower circulating Interleukin 6(IL-6) levels (15.8±2.2 vs 29.5±5.5) compared with HFHS fed controls. RNAseq analysis of colonic tissues showed 483 downregulated and 263 upregulated genes with PomX supplementation, which are mainly associated with inflammatory responses, defenses, and neutrophil degranulation. In addition, PomX treatment affects the cecal microbiome with increased alpha diversity, altered microbial composition, and increased levels of the tryptophan-related microbial metabolite indole propionate. CONCLUSION: The data demonstrate that dietary PomX supplementation ameliorated colitis and lowered inflammatory markers in HFHS fed IL-10-/- mice. These data support the anti-inflammatory effects of dietary PomX supplementation for IBD and a potential mediating role of gut microbiome, suggesting the need for future clinical studies to explore the use of PomX dietary supplementation in IBD patients.

Effect of Standardized Grape Powder Consumption on the Gut Microbiome of Healthy Subjects: A Pilot Study.

Grapes provide a rich source of polyphenols and fibers. This study aimed to evaluate the effect of the daily consumption of 46 g of whole grape powder, providing the equivalent of two servings of California table grapes, on the gut microbiome and cholesterol/bile acid metabolism in healthy adults. This study included a 4-week standardization to a low-polyphenol diet, followed by 4 weeks of 46 g of grape powder consumption while continuing the low-polyphenol diet. Compared to the baseline, 4 weeks of grape powder consumption significantly increased the alpha diversity index of the gut microbiome. There was a trend of increasing Verrucomicrobia (p = 0.052) at the phylum level, and a significant increase in Akkermansia was noted. In addition, there was an increase in Flavonifractor and Lachnospiraceae_UCG-010, but a decrease in Bifidobacterium and Dialister at the genus level. Grape powder consumption significantly decreased the total cholesterol by 6.1% and HDL cholesterol by 7.6%. There was also a trend of decreasing LDL cholesterol by 5.9%, and decreasing total bile acid by 40.9%. Blood triglyceride levels and body composition were not changed by grape powder consumption. In conclusion, grape powder consumption significantly modified the gut microbiome and cholesterol/bile acid metabolism.

California strawberry consumption increased the abundance of gut microorganisms related to lean body weight, health and longevity in healthy subjects.

It was our hypothesis that foods high in polyphenols and fiber have prebiotic activity. This human intervention study aimed to determine if daily consumption of freeze-dried California strawberry powder (SBP) leads to changes in the intestinal microbiota, fecal cholesterol and bile acid (BA) microbial metabolites. Fifteen healthy adults consumed a beige diet+26 g of SBP for 4 weeks, followed by 2 weeks of beige diet only. Stool samples were collected at 0, 4, and 6 weeks. Fecal microbiota was analyzed by 16S rRNA sequencing; fecal cholesterol, BA, and microbial metabolites by gas chromatography. Confirming compliance, urine concentration of pelargonidin, urolithin A glucuronide and dimethylellagic acid glucuronide were present after 4 weeks of SBP consumption. Daily SBP altered the abundance of 24 operational taxonomic units (OTUs). Comparing week 4 to baseline the most significant increases were observed for one OTU from Firmicutes\Clostridia\ Christensenellaceae\NA, one OTU from Firmicutes\ Clostridia\Mogibacteriacea\NA, one OTU from Verrucomicrobia\ Verrucomicrobiaceae\Akkermansia\Muciniphila, one OTU from Actinobacteria\ Bifidobacteriaceae\Bifidobacterium\NA, and one OTU from Bacteroidetes\Bacteroidia\ Bacteroidaceae\Bacteroides and decrease of one OTU from Proteobacteria\ Betaproteobacteria\Alcaligenaceae\Sutterella. Comparing week 4 to 6, we observed a reversal of the same OTUs from C Christensenellaceae, V muciniphilia and C Mogibacteriaceae. Fecal short chain fatty acids and most of the fecal markers including cholesterol, coprostanol, primary and secondary BAs were not changed significantly except for lithocholic acid, which was increased significantly at week 6 compared to baseline. In summary, SBP consumption increased the abundance of gut microorganisms related to lean body weight, health and longevity, and increased fecal lithocholic acid at week 6 in healthy study participants.

Almond consumption increased UVB resistance in healthy Asian women.

BACKGROUND: Almonds are a rich source of phenolic and polyphenolic compounds, which have antioxidant activity. In vitro and in vivo studies have demonstrated that topical application of almond oil and almond skin extract reduces UVB-induced photoaging. Ultraviolet-B (UVB) protection by oral almond consumption has not been previously studied in humans. OBJECTIVES: To investigate whether oral almond consumption can increase resistance to UVB radiation and reduce skin aging in healthy Asian women. METHODS: Thirty-nine female participants (18-45 years) with Fitzpatrick skin type II-IV were randomly assigned to consume either 1.5 oz of almonds or 1.8 oz of pretzels daily for 12 weeks. Minimal erythema dose (MED) was determined using a standardized protocol, which determined the minimal radiation needed to induce erythema on the inner arm following UVB exposure. Facial skin texture was evaluated by two dermatologists using the Clinician's Erythema Assessment scale and Allergan Roughness scale. Facial melanin index, hydration, sebum, and erythema were determined using a cutometer. RESULTS: The MED was increased in the subjects consuming almonds compared to the control group consuming pretzels. There were no differences noted between the groups consuming almonds versus pretzels in Allergan roughness, melanin, hydration, or sebum on facial skin. CONCLUSIONS: Our findings suggest that daily oral almond consumption may lead to enhanced protection from UV photodamage by increasing the MED.

Nutritional supplements in combination with chemotherapy or targeted therapy reduces tumor progression in mice bearing triple-negative breast cancer.

The potential anti-cancer properties of selenium (Se) and eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) have been documented. However, few studies have been conducted examining anti-tumor effects of nutritional supplements (NS) containing Se and EPA/DHA in combination with anti-cancer agents, such as taxol (Tax), adriamycin (Adr), and avastin (Ava). Compared with triple-negative breast cancer (TNBC)-bearing positive control (TB) mice, a low dose of Tax, Adr, and Ava decreased tumor size and the incidence of metastasis in TB-Tax, TB-Adr, and TB-Ava groups. Combination treatment with anti-cancer agent and NS (2.7 µg Se and 5.1 mg EPA/3.7 mg DHA/g) induced additional decreases in TB-Tax-NS, TB-Adr-NS, and TB-Ava-NS groups. Th1-associated cytokines were increased, and Th2-type cytokines were decreased significantly in TB mice with combination treatment than that of anti-cancer agent treatment alone. Combination treatment with anti-cancer agents and NS has also been shown to further increased tumor malondialdehyde (MDA) levels, lowered hypoxia-inducible factor (HIF)-1α, angiogenic markers (vascular endothelial growth factor [VEGF] and CD31) and metastatic potential, as well as reduced heat shock proteins, receptor tyrosine kinase AXL, and surface markers of cancer stem cells, and increased apoptotic proteins. For immune checkpoint molecules, combination treatment was associated with a greater decrease in programmed cell death ligand-1 (PD-L1) in both tumors and mammary glands, but PD-1 level in primary tumors was increased. Our results suggest that combination treatment with low-dose anti-cancer agents (Tax, Adr, and Ava) and oral supplementation of Se/ EPA/DHA significantly decreased tumor growth and metastatic progression in TNBC mice through multiple anti-tumor mechanisms.

Prospective randomized trial evaluating blood and prostate tissue concentrations of green tea polyphenols and quercetin in men with prostate cancer.

We evaluated if chronic consumption of quercetin (Q) with green tea extract (GTE) enhances the bioavailability of GT polyphenols (GTPs) and reduces methylation activity as previously observed in mouse xenograft tumors. In this prospective, randomized, parallel design, placebo controlled study, thirty-one men with prostate cancer consumed daily 1 gram of GTE (830 mg of GTP) with 800 mg of Q (GT + Q) or placebo (GT + PL) for four weeks before prostatectomy. First morning voided urine was collected at baseline, 3 weeks and the day of surgery, and prostate tissue on the day of surgery. In week 3, plasma concentration of GTPs and Q was measured in blood collected before and 2 hours after the morning dose. Prostate tissue epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) were detected in 67 and 93% of participants in the GT + Q group and 75 and 94% of participants in the GT + PL group. Q was increased 14-fold, 12-fold and 4.5-fold in plasma, urine, and prostate tissue, respectively, in the GT + Q compared to the GT + PL-group. There was a trend for decreased EGC levels in urine collected prior to prostatectomy in the GT + Q compared to GT + PL-group (p = 0.053). Plasma epigallocatechin (EGC) showed a trend to increase (p = 0.066) two hours after capsule intake in the GT + Q vs. the GT + PL-group. There was no significant difference between the groups in GTP content or methylation activity in prostate tissue or RBCs. No liver toxicity was observed. Although our findings are suggestive, further studies are warranted evaluating if Q alters GTP metabolism.

Arctigenin inhibits prostate tumor growth in high-fat diet fed mice through dual actions on adipose tissue and tumor.

This study investigated the inhibitory effect of arctigenin, a novel anti-inflammatory lignan, on prostate cancer in obese conditions both in vitro and in vivo. In vitro obese models were established by co-culture of mouse adipocytes 3T3-L1 with androgen-sensitive LNCaP human prostate cancer cells, or by culturing LNCaP cells in adipocytes-conditioned medium. Arctigenin significantly inhibited LNCaP proliferation, along with decreased androgen receptor (AR) and increased Nkx3.1 cellular expression. Male severe combined immunodeficiency mice were subcutaneously implanted with human prostate cancer LAPC-4 xenograft tumors for in vivo study. Mice were fed high-fat (HF) diet and orally given arctigenin at 50 mg/kg body weight daily or vehicle control for 6 weeks. Tumor bearing HF control mice showed a significant increase in serum free fatty acids (FFAs) and decrease in subcutaneous/peritoneal fat depots compared to non-tumor bearing control mice. Arctigenin intervention significantly reduced tumor growth by 45%, associated with decreased circulating FFAs and adipokines/cytokines including IGF-1, VEGF, and MCP-1, along with decreased AR, Ki67, and microvessel density and increased Nkx3.1 expression in tumors. These results indicate the strong ability of arctigenin to co-target obesity and tumor itself in inhibition of prostate tumor growth at a lower concentration compared to most phytochemicals.

Effect of dietary omega-3 fatty acids on castrate-resistant prostate cancer and tumor-associated macrophages.

BACKGROUND: M2-like macrophages are associated with the pathogenesis of castrate-resistant prostate cancer (CRPC). We sought to determine if dietary omega-3 fatty acids (ω-3 FAs) delay the development and progression of CRPC and inhibit tumor-associated M2-like macrophages. METHODS: MycCap cells were grown subcutaneously in immunocompetent FVB mice. Mice were castrated when tumors reached 300 mm2. To study effects of dietary ω-3 FAs on development of CRPC, ω-3 or ω-6 diets were started 2 days after castration and mice sacrificed after early regrowth of tumors. To study ω-3 FA effects on progression of CRPC, tumors were allowed to regrow after castration before starting the diets. M2 (CD206+) macrophages were isolated from allografts to examine ω-3 FA effects on macrophage function. Omega-3 fatty acid effects on androgen-deprived RAW264.7 M2 macrophages were studied by RT-qPCR and a migration/ invasion assay. RESULTS: The ω-3 diet combined with castration lead to greater MycCap tumor regression (tumor volume reduction: 182.2 ± 33.6 mm3) than the ω-6 diet (tumor volume reduction: 148.3 ± 35.2; p = 0.003) and significantly delayed the time to CRPC (p = 0.006). Likewise, the ω-3 diet significantly delayed progression of established castrate-resistant MycCaP tumors (p = 0.003). The ω-3 diet (as compared to the ω-6 diet) significantly reduced tumor-associated M2-like macrophage expression of CSF-1R in the CRPC development model, and matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the CRPC progression model. Migration of androgen-depleted RAW264.7 M2 macrophages towards MycCaP cells was reversed by addition of docosahexaenoic acid (ω-3). CONCLUSIONS: Dietary omega-3 FAs (as compared to omega-6 FAs) decreased the development and progression of CRPC in an immunocompetent mouse model, and had inhibitory effects on M2-like macrophage function. Clinical trials are warranted evaluating if a fish oil-based diet can delay the time to castration resistance in men on androgen deprivation therapy, whereas further preclinical studies are warranted evaluating fish oil for more advanced CRPC.

Randomized placebo-controlled study of the memory effects of pomegranate juice in middle-aged and older adults.

BACKGROUND: Antioxidant nutrients such as the polyphenols in pomegranate juice may prevent neuronal damage from the free radicals produced during normal metabolism. Previous research in animals and a short-term clinical trial in middle-aged and older adults support the potential memory benefits of pomegranate juice; however, the long-term effects of pomegranate juice consumption on cognition have not been studied. OBJECTIVE: In this study, we investigated the long-term effect of pomegranate juice on memory in nondemented middle-aged and older adults. METHODS: We performed a 12-month, randomized, double-blind, placebo-controlled trial of pomegranate juice in middle-aged and older adults. Two hundred and sixty-one subjects (aged 50-75 y) were randomly assigned to consume pomegranate juice [8 oz (236.5 mL) per day] or a placebo drink (8 oz, matched constituents of pomegranate juice except for pomegranate polyphenols). Memory measures [Brief Visuospatial Memory Test-Revised (BVMT-R) and Buschke Selective Reminding Test (SRT)] were assessed at 6 and 12 mo and analyzed using a mixed-effects general linear model. RESULTS: Twenty-eight subjects in the pomegranate juice group and 33 subjects in the placebo group dropped out before completing the study. Baseline variables in the 98 pomegranate juice and 102 placebo group subjects who completed the study did not differ significantly. Group by time interaction was statistically significant for BVMT-R Learning (F[2, 257]= 5.90, P = 0.003; between-group effect size [ES] = 0.45): the change within the pomegranate group was not significant (ES = 0.15), whereas the placebo group showed a significant decline (ES = -0.35). Changes in the other BVMT-R scores as well as the SRT measures were not significantly different between groups. CONCLUSIONS: Daily consumption of pomegranate juice may stabilize the ability to learn visual information over a 12-mo period. This trial was registered at clinicaltrials.gov as NCT02093130.

Pomegranate Juice and Extract Consumption Increases the Resistance to UVB-induced Erythema and Changes the Skin Microbiome in Healthy Women: a Randomized Controlled Trial.

In vitro and animal studies have demonstrated that topical application and oral consumption of pomegranate reduces UVB-induced skin damage. We therefore investigated if oral pomegranate consumption will reduce photodamage from UVB irradiation and alter the composition of the skin microbiota in a randomized controlled, parallel, three-arm, open label study. Seventy-four female participants (30-45 years) with Fitzpatrick skin type II-IV were randomly assigned (1:1:1) to 1000 mg of pomegranate extract (PomX), 8 oz of pomegranate juice (PomJ) or placebo for 12 weeks. Minimal erythema dose (MED) and melanin index were determined using a cutometer (mexameter probe). Skin microbiota was determined using 16S rRNA sequencing. The MED was significantly increased in the PomX and PomJ group compared to placebo. There was no significant difference on phylum, but on family and genus level bacterial composition of skin samples collected at baseline and after 12 week intervention showed significant differences between PomJ, PomX and placebo. Members of the Methylobacteriaceae family contain pigments absorbing UV irradiation and might contribute to UVB skin protection. However, we were not able to establish a direct correlation between increased MED and bacterial abundance. In summary daily oral pomegranate consumption may lead to enhanced protection from UV photodamage.

Role of Host GPR120 in Mediating Dietary Omega-3 Fatty Acid Inhibition of Prostate Cancer.

Background: GPR120, a G protein-coupled receptor for long-chain polyunsaturated fatty acids (FAs), mediates the anti-inflammatory effects of omega-3 (ω-3) FAs. We investigated whether host or tumor GPR120 plays a role in the anti-prostate cancer effects of ω-3 FAs. Methods: MycCap prostate cancer allografts were grown in immunocompetent wild-type (WT) and GPR120 knockout (KO) mice fed ω-3 (fish oil) or ω-6 (corn oil) diets. Immune cell infiltration was quantified by flow cytometry, and gene expression of immune cell markers in isolated tumor-associated macrophages (TAMs) was quantified by quantitative real-time polymerase chain reaction. Archived tissue from a fish oil intervention trial was used to correlate gene expression of GPR120 with cell cycle progression (CCP) genes and Ki67 index (n = 11-15 per group). All statistical tests were two-sided. Results: In WT mice (n = 7 per group), dietary ω-3 FAs decreased MycCap allograft tumor growth (mean [SD] final tumor volume ω-6 = 491 [437] mm3 vs ω-3 = 127 [77] mm3, P = .04), whereas in global GPR120KO mice (n = 7 per group) ω-3 FAs had no anticancer effects. Dietary ω-3 FAs inhibited GPR120KO-MycCaP allografts grown in WT mice (n = 8 per group; mean [SD] final tumor volume ω-6 = 776 [767] mm3 vs ω-3 = 36 [34] mm3, P = .02). Omega-3 FA treatment decreased the number of M2-like TAMs in tumor tissue and gene expression of M2 markers in isolated TAMs compared with ω-6 controls in WT (n = 7 per group) but not in GPR120KO mice (n = 7 per group). In human tissue, higher expression of stromal GPR120 correlated with greater reduction in expression of CCP genes in men with prostate cancer on a high-ω-3 diet (r = -.57, P = .04). Conclusions: Host GPR120 plays a central role in the anti-prostate cancer effects of dietary ω-3 FAs. Future studies are required to determine if the anticancer effects of ω-3 FAs are mediated through inhibition of M2-like macrophages and if host GPR120 status predicts anticancer effects of dietary ω-3 FAs in men with prostate cancer.

Intravenous Fish Oil and Pediatric Intestinal Failure-Associated Liver Disease: Changes in Plasma Phytosterols, Cytokines, and Bile Acids and Erythrocyte Fatty Acids.

BACKGROUND: Soybean oil (SO) emulsions are associated with intestinal failure-associated liver disease (IFALD); fish oil (FO) emulsions are used to treat IFALD. SO and FO differ with respect to their fatty acid and phytosterol content. In children with IFALD whose SO was replaced with FO, we aimed to (1) quantify changes in erythrocyte fatty acids and plasma phytosterols, cytokines, and bile acids and (2) correlate these changes with direct bilirubin (DB). DESIGN: This study enrolled IFALD children who received 6 months of FO. Blood samples were collected prior to FO, and after 2 weeks and 3 and 6 months of FO. The primary outcome was 3-month vs baseline biomarker concentrations. RESULTS: At study initiation, the median patient age was 3 months (interquartile range, 3-17 months), and mean ± standard deviation DB was 5.6 ± 0.7 mg/dL (n = 14). Cholestasis reversed in 79% of subjects. Eicosapentaenoic and docosahexaenoic acid was greater than baseline (P < .001, all time points). Linoleic and arachidonic acid and sitosterol and stigmasterol were less than baseline (P < .05, all time points). Three- and 6-month interleukin-8 (IL-8) and total and conjugated bile acids were less than baseline (P < .05). Baseline IL-8 was correlated with baseline DB (r = 0.71, P < .01). Early changes in stigmasterol and IL-8 were correlated with later DB changes (r = 0.68 and 0.75, P < .05). CONCLUSION: Specific fat emulsion components may play a role in IFALD. Stigmasterol and IL-8 may predict FO treatment response.