Archive

Research Area: Cancer

Almonds vs. carbohydrate snacks in an energy-restricted diet: Weight and cardiometabolic outcomes from a randomized trial. 

Carter, S., A.M. Hill, L.C. Mead, H.Y. Wong, C. Yandell, J.D. Buckley, S.Y. Tan, G.B. Rogers, F. Fraysse, A.M. Coates, 2023. Almonds vs. carbohydrate snacks in an energy-restricted diet: Weight and cardiometabolic outcomes from a randomized trial. Obesity 31(10):2467–2481.

Objective: This study evaluated weight and cardiometabolic outcomes after a 3-month energy-restricted diet (-30%) containing almonds (almond-enriched diet [AED]) or containing carbohydrate-rich snacks (nut-free control diet [NFD]) (Phase 1), followed by 6 months of weight maintenance (Phase 2). Methods: Participants (25-65 years old) with overweight or obesity (BMI 27.5-34.9 kg/m2 ) were randomly allocated to AED (n = 68) or NFD (n = 72). Results: Both groups lost weight during Phase 1 (p < 0.001) (mean [SE], -7.0 [0.5] kg AED vs. -7.0 [0.5] kg NFD, p = 0.858) and Phase 2 (p = 0.009) (-1.1 [0.5] kg AED vs. -1.3 [0.6] NFD, p = 0.756), with improvements in percentage lean mass after Phase 2 (4.8% [0.3%], p < 0.001). Reductions occurred in fasting glucose (-0.2 [0.07] mmol/L, p = 0.003), insulin (-8.1 [4.0] pmol/L, p = 0.036), blood pressure (-4.9 [0.8] mm Hg systolic, -5.0 [0.5] mm Hg diastolic, p < 0.001), total cholesterol (-0.3 [0.1] mmol/L), low-density lipoprotein (LDL) (-0.2 [0.1] mmol/L), very low-density lipoprotein (-0.1 [0.03] mmol/L), and triglycerides (-0.3 [0.06] mmol/L) (all p < 0.001), and high-density lipoprotein increased (0.1 [0.02] mmol/L, p = 0.011) by the end of Phase 2 in both groups. There were group by time interactions for lipoprotein particle concentrations: very small triglyceride-rich (-31.0 [7.7] nmol/L AED vs. -4.8 [7.9] nmol/L NFD, p = 0.007), small LDL (-109.3 [40.5] nmol/L AED vs. -20.7 [41.6] nmol/L NFD, p = 0.017), and medium LDL (-24.4 [43.4] nmol/L AED vs. -130.5 [44.4] nmol/L NFD, p = 0.045). Conclusions: An energy-restricted AED resulted in weight loss and weight loss maintenance comparable to an energy-restricted NFD, and both diets supported cardiometabolic health. The AED resulted in greater improvements in some lipoprotein subfractions, which may enhance reductions in cardiovascular risk.

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.

Impact of dietary walnuts, a nutraceutical option, on circulating markers of metabolic dysregulation in a rodent cachectic tumor model.

Byerley, L. O., H.M. Chang, B. Lorenzen, J. Guidry, W.E. Hardman, 2022. Impact of dietary walnuts, a nutraceutical option, on circulating markers of metabolic dysregulation in a rodent cachectic tumor model. Biomed. Pharmacother. 155, 113728. https://doi.org/10.1016/j.biopha.2022.113728

Background: Nutraceutical foods, like walnuts which are rich in immunonutrients, can have medicinal benefits. Dietary walnuts have been shown to slow or prevent tumor growth in mice genetically programmed to grow breast or prostate tumors. This study investigated whether walnuts could exert the same preventable effect in a transplantable carcinoma rat model. Methods: Eighteen rats were randomly fed a diet containing walnuts (10% of food by weight), and 36 were fed a diet without walnuts (control) for 21 days. On day 22, 18 control diet rats were switched to the walnut diet. All other animals remained on their same diet. Within each diet group, 6 rats were implanted with the Ward colon carcinoma (TB), and 12 were sham-operated. Five days later, 6 sham-operated animals were weight-matched to a TB and then pair-fed for the remainder of the study. The remaining 6 sham-operated, or non-tumor-bearing rats, were ad-lib fed. Results: The tissue of the walnut-eating rats showed higher omega-3 fatty acid (immunonutrient) content which did not slow or prevent tumor growth or the loss of lean and fat mass typical of this TB model. In addition, blood glucose, insulin, IGF-1, and adiponectin levels were significantly lower in the TB, demonstrating metabolic dysregulation. Again, these changes were unaltered by consuming walnuts. Plasma proteomics identified six proteins elevated in the TB, but none could be connected with the observed metabolic dysregulation. Conclusion: Although walnuts’ rich immunonutrient content prevented tumor growth in genetically programmed mice models, there was no effect in this model.

The effects of a Mediterranean diet intervention on cancer-related fatigue for patients undergoing chemotherapy: a pilot randomized controlled trial.

Kleckner, A. S., J.E. Reschke, I.R. Kleckner, A. Magnuson, A.M. Amitrano, E. Culakova, M. Shayne, C.S. Netherby-Winslow, S. Czap, M.C. Janelsins, K.M. Mustian, L.J. Peppone, 2022. The effects of a Mediterranean diet intervention on cancer-related fatigue for patients undergoing chemotherapy: a pilot randomized controlled trial. Cancers. 14(17):4202. https://doi.org/10.3390/cancers14174202

Cancer-related fatigue is a common, burdensome symptom of cancer and a side-effect of chemotherapy. While a Mediterranean Diet (MedDiet) promotes energy metabolism and overall health, its effects on cancer-related fatigue remain unknown. In a randomized controlled trial, we evaluated a rigorous MedDiet intervention for feasibility and safety as well as preliminary effects on cancer-related fatigue and metabolism compared to usual care. Participants had stage I–III cancer and at least six weeks of chemotherapy scheduled. After baseline assessments, randomization occurred 2:1, MedDiet:usual care. Measures were collected at baseline, week 4, and week 8 including MedDiet adherence (score 0–14), dietary intake, and blood-based metabolic measures. Mitochondrial respiration from freshly isolated T cells was measured at baseline and four weeks. Participants (n = 33) were 51.0 ± 14.6 years old, 94% were female, and 91% were being treated for breast cancer. The study was feasible, with 100% completing the study and >70% increasing their MedDiet adherence at four and eight weeks compared to baseline. Overall, the MedDiet intervention vs. usual care had a small-moderate effect on change in fatigue at weeks 4 and 8 (ES = 0.31, 0.25, respectively). For those with a baseline MedDiet score <5 (n = 21), the MedDiet intervention had a moderate-large effect of 0.67 and 0.48 at weeks 4 and 8, respectively. The MedDiet did not affect blood-based lipids, though it had a beneficial effect on fructosamine (ES = −0.55). Fatigue was associated with mitochondrial dysfunction including lower basal respiration, maximal respiration, and spare capacity (p < 0.05 for FACIT-F fatigue subscale and BFI, usual fatigue). In conclusion, the MedDiet was feasible and attenuated cancer-related fatigue among patients undergoing chemotherapy, especially those with lower MedDiet scores at baseline.

Nut consumption in association with overall mortality and recurrence/disease-specific mortality among long-term breast cancer survivors.

Cong, W., K. Gu, F. Wang, H. Cai, W. Zheng, P. Bao, X.-O. Shu, 2022. Nut consumption in association with overall mortality and recurrence/disease-specific mortality among long-term breast cancer survivors. International Journal of Cancer.doi.org/10.1002/ijc.33824.

High nut consumption is associated with reduced total and certain cause-specific mortality in general populations. However, its association with cancer outcomes among long-term breast cancer survivors remains unknown. We examined the associations of nut consumption (including peanuts and tree nuts), assessed at 5-year postdiagnosis, with overall survival (OS) and disease-free survival (DFS) among 3449 long-term breast cancer survivors from the Shanghai Breast Cancer Survival Study, applying Cox regression analysis. During a median follow-up of 8.27 years post dietary assessment, there were 374 deaths, including 252 breast cancer deaths. Among 3274 survivors without previous recurrence at the dietary assessment, 209 developed breast cancer-specific events, that is, recurrence, metastasis or breast cancer mortality. At 5-year post dietary assessment (ie, 10-year postdiagnosis), regular nut consumers had higher OS (93.7% vs 89.0%) and DFS (94.1% vs 86.2%) rates. After multivariable adjustment, nut consumption was positively associated with OS (Ptrend = .022) and DFS (Ptrend = .003) following a dose-response pattern, with hazard ratios (95% confidence interval) of 0.72 (0.52-1.05) for OS and 0.48 (0.31-0.73) for DFS, for participants with greater than median nut intake compared with nonconsumers. The associations did not vary by nut type. Stratified analyses showed that the associations were more evident among participants with a higher total energy intake for OS (Pinteraction = .02) and among participants with early stage (I-II) breast cancers for DFS (Pinteraction = .04). The nut-DFS associations were not modified by estrogen receptor/progesterone receptor status or other known prognostic factors. In conclusion, nut consumption was associated with better survival, particularly DFS, among long-term breast cancer survivors.

Quantitative determination of selected urolithin metabolites in human urine by simple sample preparation and UPLC-MS/MS analysis.

Provatas, A.A., S.A. Ayers, A.A. Callas, J.W. Birk, T.A. Lacson, D.W. Rosenberg, 2021. Quantitative determination of selected urolithin metabolites in human urine by simple sample preparation and UPLC-MS/MS analysis. Curr Top Anal Chem.  Vol 13, pg 69-80.

We report a simple, reliable, and validated method for the rapid screening and quantification of nine urolithin (UL) metabolites in human urine. Ultraperformance liquid chromatograph coupled with a tandem mass spectrometer (UPLC-MS/MS) was utilized for UL analysis following a simple sample preparation. Optimization of chromatographic and mass spectrometric conditions was performed to maximize the sensitivity and selectivity of the targeted analytes. A validation of the methodology was conducted to account for matrix interferences, linearity, method detection limits (MDLs), UL chemical stability, precision and accuracy of the ULs of interest. MDLs were achieved for the selected ULs ranging from 9.2-18.2 ng·mL-1. Excellent linear coefficients of determination were obtained for the range of calibration standards of 5.0-5,000 ng·mL-1, with R2 values between 0.9991 and 0.9998. The surrogate compound, 6,7-dihydroxycoumarin, was used to monitor the extraction efficiency and chrysin as the quantitative internal standard. The recoveries of the analytes were 88-99% with surrogate recoveries greater than 82%. This analytical method was developed and validated for processing samples associated with a human study, where it is hypothesized that walnut supplementation improves colonic health and lowers colorectal cancer risk, in part through enhancing UL formation.

Association of nut consumption with risk of total cancer and 5 specific cancers: evidence from 3 large prospective cohort studies.

Fang, Z., Y. Wu, Y. Li, X. Zhang, W.C. Willett, A.H. Eliassen, B. Rosner, M. Song, L.A. Mucci, E.L. Giovannucci, 2021. Association of nut consumption with risk of total cancer and 5 specific cancers: evidence from 3 large prospective cohort studies. Amer J Clin Nutr. 114(6):1925–1935. https://doi.org/10.1093/ajcn/nqab295

Background: The associations between nut consumption and cancer risk have not been extensively investigated. Objectives: We aimed to examine the associations between nut consumption, especially specific types of nuts (peanut, tree nut, walnut, and tree nut other than walnut), and cancer risk. Methods: Nut consumption was assessed by FFQ at baseline and updated every 2–4 y in the Nurses’ Health Study (1980– 2014), the Nurses’ Health Study II (1991–2015), and the Health Professionals Follow-up Study (1986–2018). We examined the associations between the intake of total and specific types of nuts and risk of total cancer and common cancers, including lung, colorectal, breast, bladder, and aggressive prostate cancer. Cox proportional hazards models were used to obtain the HRs and 95% CIs in each cohort as well as pooled. Results: During 5,873,671 person-years of follow-up in 180,832 women and 45,560 men, we documented 44,561 incident cancer cases. As compared with nonconsumers, the pooled multivariable HRs of total nut consumption for ≥5 times/wk were 0.99 (95% CI: 0.94, 1.04; P-trend = 0.54) for total cancer, 0.88 (95% CI: 0.74, 1.04; P-trend = 0.18) for lung cancer, 1.07 (95% CI: 0.92, 1.26; P-trend = 0.89) for colorectal cancer, 0.90 (95% CI: 0.71, 1.14; P-trend = 0.65) for bladder cancer, 0.96 (95% CI: 0.85, 1.08; Ptrend = 0.36) for breast cancer, and 1.18 (95% CI: 0.92, 1.51; Ptrend = 0.52) for aggressive prostate cancer Conclusions: In 3 large prospective cohorts, frequent nut consumption was not associated with risk of total cancer and common individual cancers.

Dietary intake of walnut prevented Helicobacter pylori-associated gastric cancer through rejuvenation of chronic atrophic gastritis.

Park, J.M., Y.M. Han, Y.J. Park, K.B. Hahm, 2021. Dietary intake of walnut prevented Helicobacter pylori-associated gastric cancer through rejuvenation of chronic atrophic gastritis. J Clin Biochem Nutr. 68(1): 37–50.

The fact that Fat-1 transgenic mice producing n-3 polyunsaturated fatty acids via overexpressed 3-desaturase significantly mitigated Helicobacter pylori (H. pylori)-associated gastric tumorigenesis through rejuvenation of chronic atrophic gastritis (CAG) led us to study whether dietary intake of walnut plentiful of n-3 PUFAs can be nutritional intervention to prevent H. pylori-associated gastric cancer. In our model that H. pylori-initiated, high salt diet-promoted gastric carcinogenesis, pellet diet containing 100 mg/kg and 200 mg/kg walnut was administered up to 36 weeks. As results, control mice (24 weeks) developed significant chronic CAG, in which dietary walnuts significantly ameliorated chronic atrophic gastritis. Expressions of COX-2/PGE2/NF-κB/c-Jun, elevated in 24 weeks control group, were all significantly decreased with walnut (p<0.01). Tumor suppressive enzyme, 15-PGDH, was significantly preserved with walnut. Control mice (36 weeks) all developed significant tumors accompanied with severe CAG. However, significantly decreased tumorigenesis was noted in group treated with walnuts, in which expressions of COX-2/PGE2/NF-κB/IL-6/STAT3, all elevated in 36 weeks control group, were significantly decreased with walnut. Defensive proteins including HO-1, Nrf2, and SOCS-1 were significantly increased in walnut group. Proliferative index as marked with Ki-67 and PCNA was significantly regulated with walnut relevant to 15-PGDH preservation. Conclusively, walnut can be an anticipating nutritional intervention against H. pylori.

Walnut polyphenol extracts inhibit Helicobacter pylori-induced STAT3Tyr705 phosphorylation through activation of PPAR-γ and SOCS1 induction.

Park, J.M., J.M. An, Y.M. Han, Y.J. Surh, S.J. Hwang, S.J. Kim, K.B. Hahm, 2020. Walnut polyphenol extracts inhibit Helicobacter pylori-induced STAT3Tyr705 phosphorylation through activation of PPAR-γ and SOCS1 induction. J Clin Biochem Nutr.67(3):248-256.

The health beneficial effects of walnut plentiful of n-3 polyunsaturated fatty acid had been attributed to its anti-inflammatory and anti-oxidative properties against various clinical diseases. Since we have published Fat-1 transgenic mice overexpressing 3-desaturase significantly mitigated Helicobacter pylori (H. pylori)-associated gastric pathologies including rejuvenation of chronic atrophic gastritis and prevention of gastric cancer, in this study, we have explored the underlying molecular mechanisms of walnut against H. pylori infection. Fresh walnut polyphenol extracts (WPE) were found to suppress the phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3) induced by H. pylori infection in RGM-1 gastric mucosal cells. Notably, H. pylori infection significantly decreased suppressor of cytokine signaling 1 (SOCS1), but WPE induced expression of SOCS1, by which the suppressive effect of walnut extracts on STAT3Tyr705 phosphorylation was not seen in SOCS1 KO cells. WPE induced significantly increased nuclear translocation nuclear translocation of PPAR-γ in RGM1 cells, by which PPAR-γ KO inhibited transcription of SOCS1 and suppressive effect of WPE on p-STAT3Tyr705 was not seen. WPE inhibited the expression of c-Myc and IL-6/IL-6R signaling, which was attenuated in the RGM1 cells harboring SOCS1 specific siRNA. Conclusively, WPE inhibits H. pylori-induced STAT3 phosphorylation in a PPAR-γ and SOCS1-dependent manner.

Colon cancer prevention with walnuts: a longitudinal study in mice from the perspective of a gut enterotype-like cluster.

Chen Y., M. Nakanishi, E.J. Bautista, V. Qendro, E. Sodergren, D.W. Rosenberg, G.M. Weinstock, 2020. Colon cancer prevention with walnuts: a longitudinal study in mice from the perspective of a gut enterotype-like cluster. Cancer Prev Res (Phila). 13(1):15-24.

There is limited understanding of how walnut consumption inhibits the development of colorectal cancer. A possible mechanism may involve alterations to the gut microbiota. In this study, the effects of walnut on gut microbiota were tested in a mouse tumor bioassay using the colonotropic carcinogen, azoxymethane (AOM) added to the total Western diet (TWD). 16S rRNA pyrosequencing identified three enterotype-like clusters (E1, E2, and E3) in this murine model. E1, E2, and E3 are associated with AOM exposure, walnut consumption, and TWD diet, respectively. E2 and E3 showed distinct taxonomic and functional characteristics, while E1 represented an intermediate state. At the family level, E1 and E3 were both enriched with Bacteroidaceae, but driven by two different operational taxonomic units (OTU; OTU-2 for E1, OTU-4 for E3). E2 was overrepresented with Porphyromonadaceae and Lachnospiraceae, with OTU-3 (family Porphyromonadaceae) as the “driver” OTU for this cluster. Functionally, E3 is overrepresented with genes of glycan biosynthesis and metabolism, xenobiotic metabolism, and lipid metabolism. E2 is enriched with genes associated with cell motility, replication and repair, and amino acid metabolism. Longitudinally, E2 represents the gut microbial status of early life in these mice. In comparison with E1 and E3, E2 is associated with a moderate lower tumor burden (P = 0.12). Our results suggest that walnuts may reduce the risk of colorectal cancer within a Western diet by altering the gut microbiota. Our findings provide further evidence that colorectal cancer risk is potentially modifiable by diet via alterations to the microbiota.