Sánchez-González, C., Ciudad, C.J., Noé, V., Izquierdo-Pulido, M., 2014. Walnut polyphenol metabolites, urolithins A and B, inhibit the expression of the prostate-specific antigen and the androgen receptor in prostate cancer cells. Food Funct. 5(11):2922-30.
Walnuts have been gathering attention for their health-promoting properties. They are rich in polyphenols, mainly ellagitannins (ETs) that after consumption are hydrolyzed to release ellagic acid (EA). EA is further metabolized by microbiota to form urolithins, such as A and B, which are absorbed. ETs, EA and urolithins have shown to slow the proliferation and growth of different types of cancer cells but the mechanisms remain unclear. We investigate the role of urolithins in the regulatory mechanisms in prostate cancer, specifically those related to the androgen receptor (AR), which have been linked to the development of this type of cancer. In our study, urolithins down-regulated the mRNA and protein levels of both prostate specific antigen (PSA) and AR in LNCaP cells. The luciferase assay performed with a construct containing three androgen response elements (AREs) showed that urolithins inhibit AR-mediated PSA expression at the transcriptional level. Electrophoretic mobility shift assays revealed that urolithins decreased AR binding to its consensus response element. Additionally, urolithins induced apoptosis in LNCaP cells, and this effect correlated with a decrease in Bcl-2 protein levels. In summary, urolithins attenuate the function of the AR by repressing its expression, causing a down-regulation of PSA levels and inducing apoptosis. Our results suggest that a diet rich in ET-containing foods, such as walnuts, could contribute to the prevention of prostate cancer.
Toner, C.D, 2014. Communicating clinical research to reduce cancer risk through diet: Walnuts as a case example. Nutr Res Pract. 8(4):347-5.
Inflammation is one mechanism through which cancer is initiated and progresses, and is implicated in the etiology of other conditions that affect cancer risk and prognosis, such as type 2 diabetes, cardiovascular disease, and visceral obesity. Emerging human evidence, primarily epidemiological, suggests that walnuts impact risk of these chronic diseases via inflammation. The published literature documents associations between walnut consumption and reduced risk of cancer, and mortality from cancer, diabetes, and cardiovascular disease, particularly within the context of the Mediterranean Diet. While encouraging, follow-up in human intervention trials is needed to better elucidate any potential cancer prevention effect of walnuts, per se. In humans, the far-reaching positive effects of a plant-based diet that includes walnuts may be the most critical message for the public. Indeed, appropriate translation of nutrition research is essential for facilitating healthful consumer dietary behavior. This paper will explore the translation and application of human evidence regarding connections with cancer and biomarkers of inflammation to the development of dietary guidance for the public and individualized dietary advice. Strategies for encouraging dietary patterns that may reduce cancer risk will be explored.
Le, V., Esposito, D., Grace, M.H., Ha, D., Pham, A., Bortolazzo, A., Bevens, Z., Kim, J., Okuda, R., Komarnytsky, S., Lila, M.A., White, J.B., 2014. Cytotoxic effects of ellagitannins isolated from walnuts in human cancer cells. Nutr Cancer. 66(8):1304-14.
Walnuts contain many bioactive components that may slow cancer growth. A previous report showed that a diet supplemented with walnuts decreased the tumor size formed by MDA-MB-231 human cancer cells injected into nude mice. However, the mechanism of action was never determined. We characterized the effects of a methanol extract prepared from walnuts on human MDA-MB-231, MCF7, and HeLa cells. The extract was cytotoxic to all cancer cells. We identified compounds from the methanol extract that induced this cytotoxicity. The predominant compounds were Tellimagrandin I and Tellimagrandin II, members of the ellagitannin family. We also show a walnut extract decreases the intracellular pH, depolarizes the mitochondrial membrane with release of cytochrome c and phosphatidylserine flipping. The antimitogenic effects of walnut extract were associated with a twofold reduction of mitochondria respiration. These results suggest impairment of mitochondrial function and apoptosis as relevant mechanism of anticancer effects of the walnut extract.
Kim, H., Yokoyama, W., Davis, P.A., 2014. TRAMP prostate tumor growth is slowed by walnut diets through altered IGF-1 levels, energy pathways, and cholesterol metabolism. J Med Food. Oct 29. [Epub ahead of print]
Dietary changes could potentially reduce prostate cancer morbidity and mortality. Transgenic adenocarcinoma of the mouse prostate (TRAMP) prostate tumor responses to a 100 g of fat/kg diet (whole walnuts, walnut oil, and other oils; balanced for macronutrients, tocopherols [α-and γ]) for 18 weeks ad libitum were assessed. TRAMP mice (n=17 per group) were fed diets with 100 g fat from either whole walnuts (diet group WW), walnut-like fat (diet group WLF, oils blended to match walnut’s fatty acid profile), or as walnut oil (diet group WO, pressed from the same walnuts as WW). Fasted plasma glucose was from tail vein blood, blood was obtained by cardiac puncture, and plasma stored frozen until analysis. Prostate (genitourinary intact [GUI]) was weighed and stored frozen at −80°C. Plasma triglyceride, lipoprotein cholesterol, plasma multianalyte levels (Myriad RBM Rat Metabolic MAP), prostate (GUI), tissue metabolites (Metabolon, Inc., Durham, NC, USA), and mRNA (by Illumina NGS) were determined. The prostate tumor size, plasma insulin-like growth factor-1 (IGF-1), high density lipoprotein, and total cholesterol all decreased significantly (P<.05) in both WW and WO compared to WLF. Both WW and WO versus WLF showed increased insulin sensitivity (Homeostasis Model Assessment [HOMA]), and tissue metabolomics found reduced glucose-6-phosphate, succinylcarnitine, and 4-hydroxybutyrate in these groups suggesting effects on cellular energy status. Tissue mRNA levels also showed changes suggestive of altered glucose metabolism with WW and WO diet groups having increased PCK1 and CIDEC mRNA expression, known for their roles in gluconeogenesis and increased insulin sensitivity, respectively. WW and WO group tissues also had increased MSMB mRNa a tumor suppressor and decreased COX-2 mRNA, both reported to inhibit prostate tumor growth. Walnuts reduced prostate tumor growth by affecting energy metabolism along with decreased plasma IGF-1 and cholesterol. These effects are not due to the walnut’s N-3 fatty acids, but due to component(s) found in the walnut’s fat component.
Hardman, W.E., 2014. Diet components can suppress inflammation and reduce cancer risk. Nutr Res Pract. 8(3):233-40.
Epidemiology studies indicate that diet or specific dietary components can reduce the risk for cancer, cardiovascular disease and diabetes. An underlying cause of these diseases is chronic inflammation. Dietary components that are beneficial against disease seem to have multiple mechanisms of action and many also have a common mechanism of reducing inflammation, often via the NFκB pathway. Thus, a plant based diet can contain many components that reduce inflammation and can reduce the risk for developing all three of these chronic diseases. We summarize dietary components that have been shown to reduce cancer risk and two studies that show that dietary walnut can reduce cancer growth and development. Part of the mechanism for the anticancer benefit of walnut was by suppressing the activation of NFκB. In this brief review, we focus on reduction of cancer risk by dietary components and the relationship to suppression of inflammation. However, it should be remembered that most dietary components have multiple beneficial mechanisms of action that can be additive and that suppression of chronic inflammation should reduce the risk for all three chronic diseases.
Grace, M.H., Warlick, C.W., Neff, S.A., Lila, M.A. 2014. Efficient preparative isolation and identification of walnut bioactive components using high-speed counter-current chromatography and LC-ESI-IT-TOF-MS. Food Chem. 158:229-38.
Preparative isolation of complex mixtures of compounds from walnut polar extracts was established by a combination of high-speed counter-current chromatography (HSCCC) and electrospray ionization-ion trap-time of flight mass spectrometry (ESI-IT-TOF-MS). Compounds were isolated after a solvent optimization selection based on solute distribution in a biphasic solvent system. Isolation was achieved through one or two successive HSCCC runs, and final purification on Sephadex LH-20. Isolated compounds included ellagitannins, gallic acid, dicarboxylic acid glucosides, hydrojuglone glucoside, catechin, procyanidin B2, and megasterone glucosides. Praecoxin D was isolated for the first time from walnut, while praecoxin A methyl ester (5) and glansreginin A n-butyl ester (14) are newly identified compounds. The purity and identity of isolated compounds were confirmed by NMR and HPLC-ESI-MS/MS. These results provided a foundation for in depth characterization of walnut compounds and offered an efficient strategy for isolation of potentially health-relevant phytochemicals from walnuts.
Fleming, J.A., Kris-Etherton, P.M., 2014. The evidence for α-linolenic acid and cardiovascular disease benefits: comparisons with eicosapentaenoic acid and docosahexaenoic acid. Adv Nutr. 5(6):863S-76S.
Our understanding of the cardiovascular disease (CVD) benefits of a-linolenic acid (ALA, 18:3n–3) has advanced markedly during the past decade. It is now evident that ALA benefits CVD risk. The expansion of the ALA evidence base has occurred in parallel with ongoing research on eicosapentaenoic acid (EPA, 20:5n–3) and docosahexaenoic acid (DHA, 22:6n–3) and CVD. The available evidence enables comparisons to be made for ALA vs. EPA + DHA for CVD risk reduction. The epidemiologic evidence suggests comparable benefits of plant-based and marinederived n–3 (omega-3) PUFAs. The clinical trial evidence for ALA is not as extensive; however, there have been CVD event benefits reported. Those that have been reported for EPA + DHA are stronger because only EPA + DHA differed between the treatment and control groups, whereas in the ALA studies there were diet differences beyond ALA between the treatment and control groups. Despite this, the evidence suggests many comparable CVD benefits of ALA vs. EPA + DHA. Thus, we believe that it is time to revisit what the contemporary dietary recommendation should be for ALA to decrease the risk of CVD. Our perspective is that increasing dietary ALA will decrease CVD risk; however, randomized controlled clinical trials are necessary to confirm this and to determine what the recommendation should be. With a stronger evidence base, the nutrition community will be better positioned to revise the dietary recommendation for ALA for CVD risk reduction.
Farvid, M.S., M. Ding, A. Pan, Q. Sun, S.E. Chiuve, L.M. Steffen, W.C. Willett, F.B. Hu, 2014. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation. 130(18):1568-1578.
Background: Prior studies on intake of linoleic acid (LA), the predominant n-6 fatty acid, and coronary heart disease (CHD) risk have generated inconsistent results. We performed a systematic review and meta-analysis of prospective cohort studies to summarize the evidence regarding the relation of dietary LA intake and CHD risk. Methods and Results: We searched MEDLINE and EMBASE databases through June, 2013 for prospective cohort studies that reported the association between dietary LA and CHD events. In addition, we utilized unpublished data from cohort studies in a previous pooling project. We pooled the multivariate-adjusted relative risk (RR) comparing the highest with the lowest categories of LA intake using fixed-effect meta-analysis. We identified 13 published and unpublished cohort studies with a total of 310,602 individuals and 12,479 total CHD events including 5,882 CHD deaths. Comparing the highest to the lowest category, dietary LA was associated with a 15% lower risk of CHD events (pooled RR, 0.85; 95% confidence intervals (95% CI): 0.78-0.92; I²=35.5%) and a 21% lower risk of CHD deaths (pooled RR, 0.79; 95% CI, 0.71-0.89; I²=0.0%). A 5% of energy increment in LA intake replacing energy from saturated fat intake was associated with a 9% lower risk of CHD events (RR, 0.91; 95% CI, 0.86-0.96) and a 13% lower risk of CHD deaths (RR, 0.87; 95% CI, 0.82-0.94). Conclusions: In prospective observational studies, dietary LA intake is inversely associated with CHD risk in a dose-response manner. These data provide support for current recommendations to replace saturated fat with polyunsaturated fat for primary prevention of CHD.
Burns-Whitmore, B., E. Haddad, J. Sabaté, S. Rajaram, 2014. Effects of supplementing n-3 fatty acid enriched eggs and walnuts on cardiovascular disease risk markers in healthy free-living lacto-ovo-vegetarians: a randomized, crossover, free-living intervention study. Nutr J. 13(1):29.
Background: Plant and marine n-3 fatty acids (FA) may favorably modify select markers of cardiovascular disease risk. Whether supplementing the habitual diet of lacto-ovo-vegetarians (LOV) with walnuts (containing α-linolenic acid, ALA) and n-3 FA enriched eggs (containing primarily docosahexaenoic acid, DHA and ALA) would have equivalent effects on CVD risk factors is explored in this study. Methods: In this study, 20 healthy free-living LOVs following their habitual diet were randomly assigned in a crossover design to receive one of three supplements: n-3 FA enriched egg (6/week), walnuts (28.4 g, 6/week) or a standard egg, 6/week (control) for 8 weeks each with 4-wk washout between treatments. Erythrocyte membrane fatty acids, serum lipids and inflammatory markers were measured at the end of each treatment. Results: Dietary compliance was observed by an expected increase in erythrocyte membrane ALA following the walnut treatment and in DHA following the n-3 FA enriched egg treatment. Walnut treatment lowered serum triacylglycerol, total cholesterol and Apo B (p < 0.05) compared to the standard egg but not the n-3 FA enriched egg treatment. However, walnut treatment significantly reduced total: HDL cholesterol ratio compared to both egg treatments. There were no differences between treatments for any of the inflammatory markers. Conclusions: For LOV, a direct source of DHA such as n-3 FA enriched eggs seems necessary to increase membrane levels of DHA. However for producing an overall favorable blood lipid profile, daily consumption of a handful of walnuts rich in ALA may be a preferred option for lacto-ovo vegetarians.
Farvid, M.S., Ding, M., Pan, A., Sun, Q., Chiuve, S.E., Steffen, L.M., Willett, W.C., Hu, F.B, 2014. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation. 130(18):1568-1578.
BACKGROUND: Prior studies on intake of linoleic acid (LA), the predominant n-6 fatty acid, and coronary heart disease (CHD) risk have generated inconsistent results. We performed a systematic review and meta-analysis of prospective cohort studies to summarize the evidence regarding the relation of dietary LA intake and CHD risk. METHODS AND RESULTS: We searched MEDLINE and EMBASE databases through June, 2013 for prospective cohort studies that reported the association between dietary LA and CHD events. In addition, we utilized unpublished data from cohort studies in a previous pooling project. We pooled the multivariate-adjusted relative risk (RR) comparing the highest with the lowest categories of LA intake using fixed-effect meta-analysis. We identified 13 published and unpublished cohort studies with a total of 310,602 individuals and 12,479 total CHD events including 5,882 CHD deaths. Comparing the highest to the lowest category, dietary LA was associated with a 15% lower risk of CHD events (pooled RR, 0.85; 95% confidence intervals (95% CI): 0.78-0.92; I²=35.5%) and a 21% lower risk of CHD deaths (pooled RR, 0.79; 95% CI, 0.71-0.89; I²=0.0%). A 5% of energy increment in LA intake replacing energy from saturated fat intake was associated with a 9% lower risk of CHD events (RR, 0.91; 95% CI, 0.86-0.96) and a 13% lower risk of CHD deaths (RR, 0.87; 95% CI, 0.82-0.94).CONCLUSIONS: In prospective observational studies, dietary LA intake is inversely associated with CHD risk in a dose-response manner. These data provide support for current recommendations to replace saturated fat with polyunsaturated fat for primary prevention of CHD.
