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Research Nut: Walnuts

Alpha-linolenic acid increases cholesterol efflux in macrophage-derived foam cells by decreasing stearoyl CoA desaturase 1 expression: evidence for a farnesoid-X-receptor mechanism of action.

Zhang, J., P.M. Kris-Etherton, J.T. Thompson, D.B. Hannon, P.J. Gillies, J.P. Vanden Heuvel, 2012. Alpha-linolenic acid increases cholesterol efflux in macrophage-derived foam cells by decreasing stearoyl CoA desaturase 1 expression: evidence for a farnesoid-X-receptor mechanism of action. J Nutr Biochem. 23(4):400-9.

Increased cholesterol efflux from macrophage-derived foam cells (MDFCs) is an important protective mechanism to decrease lipid load in the atherosclerotic plaque. Dietary alpha-linolenic acid (ALA), an omega-3 polyunsaturated fatty acid (PUFA), decreases circulating cholesterol, but its role in cholesterol efflux has not been extensively studied. Stearoyl CoA desaturase 1 (SCD1) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids (MUFAs). Endogenous MUFAs are preferentially incorporated into triglycerides, phospholipids and cholesteryl ester, which are abundant in atherosclerotic plaque. This study investigated the mechanisms by which ALA regulated SCD1 and subsequent effect on cholesterol storage and transport in MDFCs. Small interfering RNA (siRNA) also was applied to modify SCD1 expression in foam cells. Alpha-linolenic acid treatment and SCD1 siRNA significantly decreased SCD1 expression in MDFCs. The reduction of SCD1 was accompanied with increased cholesterol efflux and decreased intracellular cholesterol storage within these cells. Alphalinolenic acid activated the nuclear receptor farnesoid-X-receptor, which in turn increased its target gene small heterodimer partner (SHP) expression, and decreased liver-X-receptor dependent sterol regulatory element binding protein 1c transcription, ultimately resulting in repressed SCD1 expression. In conclusion, repression of SCD1 by ALA favorably increased cholesterol efflux and decreased cholesterol accumulation in foam cells. This may be one mechanism by which dietary omega-3 PUFAs promote atherosclerosis regressio

Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice.

Moon, H.-S., X. Liu, J.M. Nagel, J.P. Chamberland, K.N. Diakopoulos, M.T. Brinkoetter, M. Hatziapostolou, Y. Wu, S.C. Robson, D. Iliopoulos, C.S. Mantzoros, 2012. Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice. Gut. doi:10.1136/gutjnl-2012-302092.

Background: Obesity and a high-fat diet are associated with the risk and progression of colon cancer. Low adiponectin levels may play an important role in the development of colon and other obesity-related malignancies. No previous studies have directly investigated the mechanistic effects of adiponectin on colon cancer in the settings of obesity, a high-fat diet and/or adiponectin deficiency. Objective: To investigate the effects of adiponectin on the growth of colorectal cancer in adiponectin-deficient or wild-type-C57BL/6 mice fed a low-fat or high-fat diet. Results: Mice fed a high-fat-diet gained more weight and had larger tumours than mice fed a low-fat-diet. Adiponectin administration suppressed implanted tumour growth, causing larger central necrotic areas. Adiponectin treatment also suppressed angiogenesis assessed by CD31 staining and VEGFb and VEGFd mRNA expression in tumours obtained from mice fed a high-fat diet and from adiponectin-deficient mice. Adiponectin treatment decreased serum insulin levels in mice on a high-fat-diet and increased serum-interleukin (IL)-12 levels in adiponectin-deficient mice. In vitro, it was found that adiponectin directly controls malignant potential (cell proliferation, adhesion, invasion and colony formation) and regulates metabolic (AMPK/S6), inflammatory (STAT3/VEGF) and cell cycle (p21/p27/p53/cyclins) signalling pathways in both mouse MCA38 and human HT29, HCT116 and LoVo colon cancer cell lines in a LKB1-dependent way. Conclusion: These new mechanistic and pathophysiology studies provide evidence for an important role of adiponectin in colon cancer. The data indicate that adiponectin or analogues might be useful agents in the management or chemoprevention of colon cancer.

A high-fat diet containing whole walnuts (Juglans regia) reduces tumour size and growth along with plasma insulin-like growth factor 1 in the transgenic adenocarcinoma of the mouse prostate model.

Davis, P.A., V.T. Vasu, K. Gohil, H. Kim, I.H. Khan, C.E. Cross, W. Yokoyama, 2012. A high-fat diet containing whole walnuts (Juglans regia) reduces tumour size and growth along with plasma insulin-like growth factor 1 in the transgenic adenocarcinoma of the mouse prostate model. British Journal of Nutrition. doi:10.1017/S0007114511007288

Prostate cancer (PCa) has been linked to fat intake, but the effects of both different dietary fat levels and types remain inconsistent and incompletely characterised. The effects on PCa in the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer model of an elevated fat (20% of energy as fat) diet containing 155 g of whole walnuts were compared to those of an elevated fat (20% of energy as soyabean oil) diet with matched macronutrients, tocopherols as well as a low-fat (8% of energy as soyabean oil) diet. Mice, starting at 8 weeks of age, consumed one of the three different diets ad libitum; and prostates, livers and blood were obtained after 9, 18 or 24 weeks of feeding. No differences were observed in whole animal growth rates in either high-fat (HF) diet group, but prostate tumour weight and growth rate were reduced in the walnut diet group. Walnut diet group prostate weight, plasma insulin-like growth factor 1, resistin and LDL were lower at 18 weeks, while no statistically significant prostate weight differences by diet were seen at 9 or 24 weeks. Multiple metabolites in the livers differed by diet at 9 and 18 weeks. The walnut diet’s beneficial effects probably represent the effects of whole walnuts’ multiple constituents and not via a specific fatty acid or tocopherols. Moreover, as the two HF diets had dissimilar effects on prostate tumour growth rate and size, and yet had the same total fat and tocopherol composition and content, this suggests that these are not strongly linked to PCa growth.

Walnuts improve semen quality in men consuming a western-style diet: randomized control dietary intervention trial.

Robbins, W.A., L. Xun, L.Z. FitzGerald, S. Esguerra, S.M. Henning, C.L. Carpenter, 2012. Walnuts improve semen quality in men consuming a western-style diet: randomized control dietary intervention trial. Biol Reprod. doi:10.1095/biolreprod.112.101634

Purpose: We tested the hypothesis that 75 gm of whole-shelled walnuts/day added to a Westernstyle diet of healthy young men would beneficially affect semen quality. Methods: A randomized, parallel two-group, dietary intervention trial with single-blind masking of outcome assessors, was conducted with 117 healthy men, age 21 – 35 years, who routinely consumed a Western-style diet. Primary outcome evaluated was improvement from baseline to 12 weeks in conventional semen parameters and sperm aneuploidy. Secondary endpoints included blood serum and sperm fatty acid (FA) profiles, sex hormones, and serum folate. Conclusions: The group consuming walnuts (n=59) experienced improvement in sperm vitality, motility, and morphology and the group continuing their usual diet but avoiding tree nuts (n=58) saw no change. Comparing differences from baseline between the groups, significance was found for vitality p=0.003, motility p=0.009, and morphology (normal forms) p=0.04. Serum FA profiles improved in the walnut group with increases in omega-6 (p=0.0004) and omega-3 p=0.0007) but not the control group. Only the plant source of omega-3, α-linolenic acid (ALA), increased (p=0.0001). Sperm aneuploidy was inversely correlated with sperm ALA, particularly sex chromosome nullisomy (-0.41, p=0.002). Findings demonstrated that walnuts added to a Western-style diet improved sperm vitality, motility and morphology.

The role of adiponectin in cancer: A review of current evidence.

Dalamaga, M., K.N. Diakopoulos, C.S. Mantzoros, 2012. The role of adiponectin in cancer: A review of current evidence. Endocrine Reviews. 33(4):547-94.

Excess body weight is associated not only with an increased risk of type 2 diabetes and cardiovascular disease (CVD) but also with various types of malignancies. Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, antiinflammatory, antiatherogenic, proapoptotic, and antiproliferative properties. Circulating adiponectin levels, which are determined predominantly by genetic factors, diet, physical activity, and abdominal adiposity, are decreased in patients with diabetes, CVD, and several obesity-associated cancers. Also, adiponectin levels are inversely associated with the risk of developing diabetes, CVD, and several malignancies later in life. Many cancer cell lines express adiponectin receptors, and adiponectin in vitro limits cell proliferation and induces apoptosis. Recent in vitro studies demonstrate the antiangiogenic and tumor growth-limiting properties of adiponectin. Studies in both animals and humans have investigated adiponectin and adiponectin receptor regulation and expression in several cancers. Current evidence supports a role of adiponectin as a novel risk factor and potential diagnostic and prognostic biomarker in cancer. In addition, either adiponectin per se or medications that increase adiponectin levels or up-regulate signaling pathways downstream of adiponectin may prove to be useful anticancer agents. This review presents the role of adiponectin in carcinogenesis and cancer progression and examines the pathophysiological mechanisms that underlie the association between adiponectin and malignancy in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against obesity-associated malignancies.

The beneficial effects of tree nuts on the aging brain.

Carey, A.N., S.M. Poulose, B. Shukitt-Hale, 2012. The beneficial effects of tree nuts on the aging brain. Nutrition and Aging. 1:55–67.

Dietary patterns may play an important role in protecting the brain from the cellular and cognitive dysfunction associated with the aging process and neurodegenerative diseases. Tree nuts are showing promise as possible dietary interventions for age-related brain dysfunction. Tree nuts are an important source of essential nutrients, like vitamin E, folate, and fiber. Tree nuts also contain a variety of components, such as phytochemicals like flavonoids, proanthocyanidins, and phenolic acids, as well as monounsaturated and omega-3 and omega-6 polyunsaturated fatty acids that have the potential to combat age-related brain dysfunction. Evidence is accumulating that suggests that tree nuts and their bioactive constituents have the potential to reduce oxidative stress and inflammation, as indicated by decreased lipid peroxidation in vivo and reduced production of the free radical nitric oxide and the pro-inflammatory cytokine tumor necrosis factor-alpha in vitro. Also, tree nut consumption might have the ability to mitigate some of the cognitive decline associated with aging. Here we review the current knowledge of how the consumption of nuts may improve brain health, specifically focusing on walnuts, almonds, pistachios, and pecans.

Dietary walnuts inhibit colorectal cancer growth in mice by suppressing angiogenesis.

Nagel, J.M., M. Brinkoetter, F. Magkos, X. Liu, J.P. Chamberland, S. Shah, J. Zhou, G. Blackburn, C.S. Mantzoros, 2012. Dietary walnuts inhibit colorectal cancer growth in mice by suppressing angiogenesis. Nutrition. 28(1):67-75.

OBJECTIVE: Animal studies have demonstrated that dietary supplementation with flaxseed oil inhibits colorectal cancer growth. Recent data indicate that walnuts have strong antiproliferative properties against colon cancer cells in vitro but no previous study has assessed the effects of walnuts in vivo or performed a joint evaluation of flaxseed oil and walnuts. The aim of the present study was to examine the effect of dietary walnuts on colorectal cancer in vivo and to comparatively evaluate their efficacy in relation to flaxseed oil. METHODS: HT-29 human colon cancer cells were injected in 6-wk-old female nude mice. After a 1-wk acclimation period, mice (n = 48) were randomized to diets containing ∼19% of total energy from walnuts, flaxseed oil, or corn oil (control) and were subsequently studied for 25 d. RESULTS: Tumor growth rate was significantly slower in walnut-fed and flaxseed-fed mice compared with corn oil-fed animals (P < 0.05) by 27% and 43%, respectively. Accordingly, final tumor weight was reduced by 33% and 44%, respectively (P < 0.05 versus control); the differences between walnut and flaxseed diets did not reach significance. We found no differences among groups in metabolic and hormonal profile, serum antioxidant capacity, or inflammation (P > 0.05). However, walnuts and flaxseed oil significantly reduced serum expression levels of angiogenesis factors, including vascular endothelial growth factor (by 30% and 80%, respectively), and approximately doubled total necrotic areas despite smaller tumor sizes (P < 0.05 versus control). Dietary walnuts significantly decreased angiogenesis (CD34 staining; P = 0.017 versus control), whereas this effect did not reach significance in the flaxseed oil group (P = 0.454 versus control). CONCLUSION: We conclude that walnuts in the diet inhibit colorectal cancer growth by suppressing angiogenesis. Further studies are needed to confirm our findings in humans and explore underlying mechanisms.

Out-of-hand nut consumption is associated with improved nutrient intake and health risk markers in US children and adults: National Health and Nutrition Examination Survey 1999-2004.

O’Neil, C.E., D.R. Keast, T.A. Nicklas, V.L. Fulgoni, 2012. Out-of-hand nut consumption is associated with improved nutrient intake and health risk markers in US children and adults: National Health and Nutrition Examination Survey 1999-2004. Nutrition Research. 32:185-194.

The purpose of this study was to determine the association of out-of-hand nut (OOHN) consumption with nutrient intake, diet quality, and the prevalence of risk factors for cardiovascular disease and metabolic syndrome. Data from 24-hour recalls from individuals aged 2+ years (n = 24,385) participating in the 1999-2004 National Health and Nutrition Examination Survey were used. The population was divided into children aged 2 to 11, 12 to 18, and adults 19+ years, and each group was dichotomized into OOHN consumers and nonconsumers. Out-of-hand nut consumers were defined as those individuals consuming ¼ oz of nuts or more per d. Means, standard errors, and covariate-adjusted analyses of variance were determined using appropriate sample weights. Diet quality was determined using the Healthy Eating Index-2005. Significance was set at P < .05. The percent of OOHN consumers increased with age: 2.1% ± 0.3%, 2.6% ± 0.3%, 6.5% ± 0.5%, and 9.6% ± 0.5% those aged 2 to 11, 12 to 18, 19 to 50, and 51+ years, respectively. The 2 latter groups were combined into a single group of consumers aged 19+ years for subsequent analyses. Consumers of OOHN from all age groups had higher intakes of energy, monounsaturated and polyunsaturated fatty acids, dietary fiber, copper, and magnesium and lower intakes of carbohydrates, cholesterol, and sodium than did nonconsumers. Diet quality was higher in OOHN consumers of all age groups. In children aged 2 to 11 years, consumers had a higher prevalence of overweight/obesity. In those aged 12 to 18 years, weight and percent overweight were lower in consumers. Adult consumers had higher high-density lipoprotein cholesterol, red blood cell folate, and serum folate levels and lower insulin, glycohemoglobin, and C-reactive protein levels than did nonconsumers. Adult consumers also had a 19% decreased risk of hypertension and a 21% decreased risk of low high-density lipoprotein cholesterol levels. Data suggested that OOHN consumption was associated with improved nutrient intake, diet quality, and, in adults, a lower prevalence of 2 risk factors for metabolic syndrome. Consumption of OOHN, as part of a healthy diet, should be encouraged by health professionals.

The ability of walnut extract and fatty acids to protect against the deleterious effects of oxidative stress and inflammation in hippocampal cells.

Carey, A.N., D.R. Fisher, J.A. Joseph, B. Shukitt-Hale, 2012. The ability of walnut extract and fatty acids to protect against the deleterious effects of oxidative stress and inflammation in hippocampal cells. Nutr. Neurosci. doi: 10.1179/1476830512Y.0000000023.

Previous research from our lab has demonstrated that dietary walnut supplementation protects against agerelated cognitive declines in rats; however, the cellular mechanisms by which walnuts and polyunsaturated fatty acids (PUFAs) may affect neuronal health and functioning in aging are undetermined. Objectives: We assessed if pretreatment of primary hippocampal neurons with walnut extract or PUFAs would protect cells against dopamine- and lipopolysaccharide-mediated cell death and calcium dysregulation. Methods: Rat primary hippocampal neurons were pretreated with varying concentrations of walnut extract, linoleic acid, alpha-linolenic acid, eicosapentaenoic acid, or docosahexaenoic acid prior to exposure to either dopamine or lipopolysaccharide. Viability was assessed using the Live/Dead Cellular Viability/Cytotoxicity Kit. Also, the ability of the cells to return to baseline calcium levels after depolarization was measured with fluorescent imaging. Results: Results indicated that walnut extract, alpha-linolenic acid, and docosahexaenoic acid provided significant protection against cell death and calcium dysregulation; the effects were pretreatment concentration dependent and stressor dependent. Linoleic acid and eicosapentaenoic acid were not as effective at protecting hippocampal cells from these insults. Discussion: Walnut extract and omega-3 fatty acids may protect against age-related cellular dysfunction, but not all PUFAs are equivalent in their beneficial effects.

Nut consumption is associated with decreased health risk factors for cardiovascular disease and metabolic syndrome in U.S. adults: NHANES 1999–2004.

O’Neil, C.E., D.R. Keast, T.A. Nicklas, V.L. Fulgoni, 2011. Nut consumption is associated with decreased health risk factors for cardiovascular disease and metabolic syndrome in U.S. adults: NHANES 1999–2004. Journal of the American College of Nutrition. 30(6):502–510.

Background: Few recent epidemiologic studies have assessed the effect that nut consumption (including tree nuts and peanuts) has on health risks, including metabolic syndrome (MetS). Objective: This study compared the health risk for cardiovascular disease, type 2 diabetes, and MetS of nut consumers with that of nonconsumers. Design: Adults 19+ years (n = 13,292) participating in the 1999–2004 National Health and Nutrition Examination Survey were used. Intake from 24-hour recalls was used to determine intake. Nut/tree nut consumers consumed ≥¼ ounce per day. Covariate-adjusted means, standard errors, and prevalence rates were determined for the nut consumption groups. Results: The prevalence of nut consumers was 18.6% ± 0.7% and 21.0% ± 0.9% in those 19–50 years and 51 years and older, respectively. Nut consumption was associated with a decreased body mass index (27.7 kg/m2 ± 0.2 vs 28.1 ± 0.1 kg/m2, p<0.05), waist circumference (95.6 ± 0.4 cm vs 96.4 ± 0.3 cm, p < 0.05), and systolic blood pressure (121.9 ± 0.4 mmHg vs 123.20 ± 0.3 mmHg, p < 0.01) compared with nonconsumers. Tree nut consumers also had a lower weight (78.8 ± 0.7 kg vs 80.7 ± 0.3 kg, p < 0.05). Nut consumers had a lower percentage of two risk factors for MetS: hypertension (31.5% ± 1.0% vs 34.2% ± 0.8%, p < 0.05) and low high density lipoprotein-cholesterol (HDL-C) (29.6% ± 1.0% vs 34.8% ± 0.8%, p < 0.01). Tree nut consumers had a lower prevalence of four risk factors for MetS: abdominal obesity (43.6% ± 1.6% vs 49.5% ± 0.8%, p < 0.05), hypertension (31.4% ± 1.2% vs 33.9% ± 0.8%, p < 0.05), low HDL-C (27.9% ± 1.7% vs 34.5% ± 0.8%, p < 0.01), high fasting glucose (11.4% ± 1.4% vs 15.0% ± 0.7%, p < 0.05), and a lower prevalence of MetS (21.2% ± 2.1% vs 26.6% ± 0.7%, p < 0.05). Conclusion: Nut/tree nut consumption was associated with a decreased prevalence of selected risk factors for cardiovascular disease, type 2 diabetes, and MetS.