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Research Nut: Walnuts

Walnut inclusion in a palm oil-based atherogenic diet promotes traits predicting stable atheroma plaque in Apoe-deficient mice.

Lázaro. I., J. Bobi, M. Cofán, G. Kapravelou, A.J. Amor, J. Surra, C. Gómez-Guerrero, E. Ortega, J. Osada, A.P. Dantas, A. Sala-Vila, 2023. Walnut inclusion in a palm oil-based atherogenic diet promotes traits predicting stable atheroma plaque in Apoe-deficient mice. Front. Nutr. 10:1079407. https://doi.org/10.3389/fnut.2023.1079407

INTRODUCTION: The lower rates of cardiovascular disease in Southern Europe could be partially explained by the low prevalence of lipid-rich atheroma plaques. Consumption of certain foods affects the progression and severity of atherosclerosis. We investigated whether the isocaloric inclusion of walnuts within an atherogenic diet prevents phenotypes predicting unstable atheroma plaque in a mouse model of accelerated atherosclerosis. METHODS: Apolipoprotein E-deficient male mice (10-week-old) were randomized to receive a control diet (9.6% of energy as fat, n = 14), a palm oil-based high-fat diet (43% of energy as fat, n = 15), or an isocaloric diet in which part of palm oil was replaced by walnuts in a dose equivalent to 30 g/day in humans (n = 14). All diets contained 0.2% cholesterol. RESULTS: After 15 weeks of intervention, there were no differences in size and extension in aortic atherosclerosis among groups. Compared to control diet, palm oil-diet induced features predicting unstable atheroma plaque (higher lipid content, necrosis, and calcification), and more advanced lesions (Stary score). Walnut inclusion attenuated these features. Palm oil-based diet also boosted inflammatory aortic storm (increased expression of chemokines, cytokines, inflammasome components, and M1 macrophage phenotype markers) and promoted defective efferocytosis. Such response was not observed in the walnut group. The walnut group’s differential activation of nuclear factor kappa B (NF-KB; downregulated) and Nrf2 (upregulated) in the atherosclerotic lesion could explain these findings. CONCLUSION: The isocaloric inclusion of walnuts in an unhealthy high-fat diet promotes traits predicting stable advanced atheroma plaque in mid-life mice. This contributes novel evidence for the benefits of walnuts, even in an unhealthy dietary environment.

Key Area: Heart Health

A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial.

Hoffmann, A., A.Y. Meir, T. Hagemann, P. Czechowski, L. Müller, B. Engelmann, S.B. Haange, U. Rolle-Kampczyk, G. Tsaban, H. Zelicha, E. Rinott, A. Kaplan, I. Shelef, M. Stumvoll, M. Blüher, L. Liang, U. Ceglarek, B. Isermann, M. von Bergen, P. Kovacs, M. Keller, I. Shai, 2023. A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial. Metab.: Clin. Exp. 145, 155594. https://doi.org/10.1016/j.metabol.2023.155594

Background: The capacity of a polyphenol-enriched diet to modulate the epigenome in vivo is partly unknown. Given the beneficial metabolic effects of a Mediterranean (MED) diet enriched in polyphenols and reduced in red/processed meat (green-MED), as previously been proven by the 18-month DIRECT PLUS randomized controlled trial, we analyzed the effects of the green-MED diet on methylome and transcriptome levels to highlight molecular mechanisms underlying the observed metabolic improvements. Methods: Our study included 260 participants (baseline BMI = 31.2 kg/m2, age = 5 years) of the DIRECT PLUS trial, initially randomized to one of the intervention arms: A. healthy dietary guidelines (HDG), B. MED (440 mg polyphenols additionally provided by walnuts), C. green-MED (1240 mg polyphenols additionally provided by walnuts, green tea, and Mankai: green duckweed shake). Blood methylome and transcriptome of all study subjects were analyzed at baseline and after completing the 18-month intervention using Illumina EPIC and RNA sequencing technologies. Results: A total of 1573 differentially methylated regions (DMRs; false discovery rate (FDR) < 5 %) were found in the green-MED compared to the MED (177) and HDG (377) diet participants. This corresponded to 1753 differentially expressed genes (DEGs; FDR < 5 %) in the green-MED intervention compared to MED (7) and HDG (738). Consistently, the highest number (6 %) of epigenetic modulating genes was transcriptionally changed in subjects participating in the green-MED intervention. Weighted cluster network analysis relating transcriptional and phenotype changes among participants subjected to the green-MED intervention identified candidate genes associated with serum-folic acid change (all P < 1 × 10-3) and highlighted one module including the KIR3DS1 locus, being negatively associated with the polyphenol changes (e.g. P < 1 × 10-4), but positively associated with the MRI-assessed superficial subcutaneous adipose area-, weight- and waist circumference- 18-month change (all P < 0.05). Among others, this module included the DMR gene Cystathionine Beta-Synthase, playing a major role in homocysteine reduction. Conclusions: The green-MED high polyphenol diet, rich in green tea and Mankai, renders a high capacity to regulate an individual’s epigenome. Our findings suggest epigenetic key drivers such as folate and green diet marker to mediate this capacity and indicate a direct effect of dietary polyphenols on the one‑carbon metabolism.

Antioxidant and anti-inflammatory properties of walnut constituents: focus on personalized cancer prevention and the microbiome.

Fan, N., J.L. Fusco, D.W. Rosenberg, 2023. Antioxidant and anti-inflammatory properties of walnut constituents: focus on personalized cancer prevention and the microbiome. Antioxidants. 12(5):982. https://doi.org/10.3390/antiox12050982

Walnuts have been lauded as a ‘superfood’, containing a remarkable array of natural constituents that may have additive and/or synergistic properties that contribute to reduced cancer risk. Walnuts are a rich source of polyunsaturated fatty acids (PUFAs: alpha-linolenic acid, ALA), tocopherols, antioxidant polyphenols (including ellagitannins), and prebiotics, including fiber (2 g/oz). There is a growing body of evidence that walnuts may contribute in a positive way to the gut microbiome, having a prebiotic potential that promotes the growth of beneficial bacteria. Studies supporting this microbiome-modifying potential include both preclinical cancer models as well as several promising human clinical trials. Mediated both directly and indirectly via its actions on the microbiome, many of the beneficial properties of walnuts are related to a range of anti-inflammatory properties, including powerful effects on the immune system. Among the most potent constituents of walnuts are the ellagitannins, primarily pedunculagin. After ingestion, the ellagitannins are hydrolyzed at low pH to release ellagic acid (EA), a non-flavonoid polyphenolic that is subsequently metabolized by the microbiota to the bioactive urolithins (hydroxydibenzo[b,d]pyran-6-ones). Several urolithins, including urolithin A, reportedly have potent anti-inflammatory properties. These properties of walnuts provide the rationale for including this tree nut as part of a healthy diet for reducing overall disease risk, including colorectal cancer. This review considers the latest information regarding the potential anti-cancer and antioxidant properties of walnuts and how they may be incorporated into the diet to provide additional health benefits.

Key Area: Cancer

Effect of a Mediterranean diet or mindfulness-based stress reduction during pregnancy on child neurodevelopment: A prespecified analysis of the IMPACT BCN Randomized Clinical Trial.

Crovetto, F., A. Nakaki, A. Arranz, R. Borras, K. Vellvé, C. Paules, M.L. Boutet, S. Castro-Barquero, T. Freitas, R. Casas, A. Martín-Asuero, T. Oller Guzmán, I. Morilla, A. Martínez-Àran, A. Camacho, M. Pasqual, M. Izquierdo Renau, Ó. J. Pozo, A. Gomez-Gomez, R. Estruch, E. Vieta, F. Crispi, E. Gratacós, 2023. Effect of a Mediterranean diet or mindfulness-based stress reduction during pregnancy on child neurodevelopment: A prespecified analysis of the IMPACT BCN Randomized Clinical Trial. JAMA Network Open, 6(8), e2330255. https://doi.org/10.1001/jamanetworkopen.2023.30255

Importance: Maternal suboptimal nutrition and high stress levels are associated with adverse fetal and childhood neurodevelopment. Objective: To test the hypothesis that structured interventions based on a Mediterranean diet or mindfulness-based stress reduction (MBSR) during pregnancy improve child neurodevelopment at age 2 years. Design, setting, and participants: This was a prespecified analysis of the parallel-group Improving Mothers for a Better Prenatal Care Trial Barcelona (IMPACT BCN) randomized clinical trial, which was conducted at a university hospital in Barcelona, Spain, from February 2017 to March 2020. A total of 1221 singleton pregnancies (19 to 23 weeks’ gestation) with high risk of delivering newborns who were small for gestational age were randomly allocated into 3 groups: a Mediterranean diet intervention, an MBSR program, or usual care. A postnatal evaluation with the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III), was performed. Data were analyzed from July to November 2022. Interventions: Participants in the Mediterranean diet group received monthly individual and group educational sessions and free provision of extra virgin olive oil and walnuts. Those in the stress reduction group underwent an 8-week MBSR program adapted for pregnancy. Individuals in the usual care group received pregnancy care per institutional protocols. Main outcomes and measures: Neurodevelopment in children was assessed by Bayley-III at 24 months of corrected postnatal age. Results: A total of 626 children (293 [46.8%] female and 333 [53.2%] male) participated at a mean (SD) age of 24.8 (2.9) months. No differences were observed in the baseline characteristics between intervention groups. Compared with children from the usual care group, children in the Mediterranean diet group had higher scores in the cognitive domain (β, 5.02; 95% CI, 1.52-8.53; P = .005) and social-emotional domain (β, 5.15; 95% CI, 1.18-9.12; P = .01), whereas children from the stress reduction group had higher scores in the social-emotional domain (β, 4.75; 95% CI, 0.54-8.85; P = .02). Conclusions and relevance: In this prespecified analysis of a randomized clinical trial, maternal structured lifestyle interventions during pregnancy based on a Mediterranean diet or MBSR significantly improved child neurodevelopmental outcomes at age 2 years.

Key Area: Cognitive Health