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Research Area: Cancer

The effect of nut consumption on cancer is a relatively new area of research. Tree nuts contain a wide range of nutrients with recognized benefits to human health including unsaturated fats, protein, vitamins (i.e., vitamin E, folate and niacin), minerals (i.e., magnesium, calcium and potassium) and phytochemicals—all of which may offer anticarcinogenic, anti-inflammatory and antioxidant properties.

In a recent study, researchers concluded that there was an inverse association of dietary nut consumption with cancer risk, especially for cancers of the digestive system[i].  A number of studies have been conducted to date looking at the effect of nuts on colorectal cancer, which affects both men and women, and is the second leading cause of cancer-related deaths in the United States and third most common cancer worldwide. In one study, researchers found an association between high frequency of nut consumption and reduced risk of colorectal cancer[ii]. In another study[iii], colon cancer patients who consumed nuts had a significant decrease in cancer recurrence and death.

While nut consumption is associated with reduced total and certain cause-specific mortality in general populations, its association with cancer outcomes among long-term breast cancer survivors remains unknown. Researchers in one study[IV] examined the associations of nut consumption (including tree nuts and peanuts) at 5-years postdiagnosis, with overall survival and disease-free survival among 3,449 long-term breast cancer survivors from the Shanghai Breast Cancer Survival Study. The data showed that nut consumption was associated with better survival, particularly disease-free survival, among long-term breast cancer survivors.

At Harvard, researchers looked at the association between nut consumption and prostate cancer risk and mortality among 47,299 men. While nut consumption was not associated with a reduced risk of prostate cancer, men who had prostate cancer and consumed tree nuts five or more times per week after diagnosis, had a significant 34 percent lower risk of overall mortality than those who consumed nuts less than once per month[iv].

While more research on tree nuts and cancer is needed, the research that has been done to date is very promising.

[i]Long, J., Z. Ji, P. Yuan, T. Long, K. Liu, J. Li, L. Cheng, 2020. Nut consumption and risk of cancer: A meta-analysis of prospective studies. Cancer Epidemiol Biomarkers Prev. 29(3):565-573.

[ii] Lee, J., A. Shin, J.H. Oh, J. Kim, 2018. The relationship between nut intake and risk of colorectal cancer: a case control study. Nutrition Journal. 17:37 https://doi.org/10.1186/s12937-018-0345-y.

[iii] Fadelu, T., S. Zhang, D. Niedzwiecki, X. Ye, L.B. Saltz, R.J. Mayer, R.B. Mowat, R. Whittom, A. Hantel, A.B. Benson, D.M. Atienza, M. Messino, H.L. Kindler, A. Venook, S. Ogino, K. Ng, K. Wu, W. Willett, E. Giovannucci, J. Meyerhardt, Y. Bao, C.S. Fuchs, 2018. Nut consumption and survival in patients with stage III colon cancer: results from CALGB 89803 (Alliance). J Clin Oncol. 36(11):1112-1120.

[iv] 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.

[v]Wang, W., M. Yang, S.A. Kenfield, F.B. Hu, M.J. Stampfer, W.C. Willett, C.S. Fuchs, E.L. Giovannucci, Y. Bao, 2016. Nut consumption and prostate cancer risk and mortality. Br J Cancer. 115(3):371-374.

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.

Association of total nut, tree nut, peanut, and peanut butter consumption with cancer incidence and mortality: A comprehensive systematic review and dose-response meta-analysis of observational studies.

Naghshi, S., M. Sadeghian, M. Nasiri, S. Mobarak, M. Asadi, O. Sadeghi, 2020. Association of total nut, tree nut, peanut, and peanut butter consumption with cancer incidence and mortality: A comprehensive systematic review and dose-response meta-analysis of observational studies. Adv Nutr. 0:1–16.

Data on the association of nut intake with risk of cancer and its mortality are conflicting. Although previous meta-analyses summarized available findings in this regard, some limitations may distort their findings. Moreover, none of these meta-analyses examined the dose-response associations of total nut intake with the risk of specific cancers as well as associations between specific types of nuts and cancer mortality. Therefore, this study aimed to summarize available findings on the associations of total nut (tree nuts and peanuts), tree nut (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts), peanut (whole peanuts without considering peanut butter), and peanut butter consumption with risk of cancer and its mortality by considering the above-mentioned points. We searched the online databases until March 2020 to identify eligible articles. In total, 43 articles on cancer risk and 9 articles on cancer mortality were included in the current systematic review and meta-analysis. The summary effect size (ES) for risk of cancer, comparing the highest with lowest intakes of total nuts, was 0.86 (95% CI: 0.81, 0.92, P < 0.001, I2 = 58.1%; P < 0.01), indicating a significant inverse association. Such a significant inverse association was also seen for tree nut intake (pooled ES: 0.87, 95% CI: 0.78–0.96, P < 0.01, I2 = 15.8%; P = 0.28). Based on the dose-response analysis, a 5-g/d increase in total nut intake was associated with 3%, 6%, and 25% lower risks of overall, pancreatic, and colon cancers, respectively. In terms of cancer mortality, we found 13%, 18%, and 8% risk reductions with higher intakes of total nuts, tree nuts, and peanuts, respectively. In addition, a 5-g/d increase in total nut intake was associated with a 4% lower risk of cancer mortality. In conclusion, our findings support the protective association between total nut and tree nut intake and the risk of cancer and its mortality.

Walnut phenolic extracts reduce telomere length and telomerase activity in a colon cancer stem cell model.

Shin, P.K., Y. Zoh, J. Choi, M.S. Kim,Y. Kim, S.W. Choi, 2019. Walnut phenolic extracts reduce telomere length and telomerase activity in a colon cancer stem cell model. Nutr Res Pract. 13(1):58-63.

Background/Objectives: Telomeres are located at the chromosomal ends and progressively shortened during each cell cycle. Telomerase, which is regulated by hTERT and c-MYC, maintains telomeric DNA sequences. Especially, telomerase is active in cancer and stem cells to maintain telomere length for replicative immortality. Recently we reported that walnut phenolic extract (WPE) can reduce cell viability in a colon cancer stem cell (CSC) model. We, therefore, investigated the effect of WPE on telomere maintenance in the same model. Materials/Methods: CD133+CD44+ cells from HCT116, a human colon cancer cell line, were sorted by Fluorescence-activated cell sorting (FACS) and treated with WPE at the concentrations of 0, 10, 20, and 40 µg/mL for 6 days. Telomere lengths were assessed by quantitative real-time PCR (qRT-PCR) using telomere specific primers and DNA extracted from the cells, which was further adjusted with single-copy gene and reference DNA (ddCt). Telomerase activity was also measured by qRT-PCR after incubating the PCR mixture with cell protein extracts, which was adjusted with reference DNA (dCt). Transcriptions of hTERT and c-MYC were determined using conventional RT-PCR. Results: Telomere length of WPE-treated cells was significantly decreased in a dose-dependent manner (5.16 ± 0.13 at 0 µg/mL, 4.79 ± 0.12 at 10 µg/mL 3.24 ± 0.08 at 20 µg/mL and 3.99 ± 0.09 at 40 µg/mL; P = 0.0276). Telomerase activities concurrently decreased with telomere length (1.47 ± 0.04, 1.09 ± 0.01, 0.76 ± 0.08, and 0.88 ± 0.06; P = 0.0067). There was a positive correlation between telomere length and telomerase activity (r = 0.9090; P < 0.0001). Transcriptions of both hTERT and c-MYC were also significantly decreased in the same manner. Conclusions: In the present cell culture model, WPE reduced telomere maintenance, which may provide a mechanistic link to the effect of walnuts on the viability of colon CSCs.

Dietary walnut supplementation alters mucosal metabolite profiles during DSS-induced colonic ulceration.

Nakanishi, M., A. Matz, C. Klemashevich, D.W. Rosenberg, 2019. Dietary walnut supplementation alters mucosal metabolite profiles during DSS-induced colonic ulceration.  Nutrients. 11(5). pii: 1118. doi: 10.3390/nu11051118

Walnuts contain a complex array of natural compounds and phytochemicals that exhibit a wide range of health benefits, including protection against inflammation and colon cancer. In this study, we assess the effects of dietary supplementation with walnuts on colonic mucosal injury induced in mice by the ulcerogenic agent, dextran sodium sulfate (DSS). C57Bl/6J mice were started on the Total Western Diet supplemented with freshly-ground whole walnuts (0, 3.5, 7 and 14% g/kg) 2 weeks prior to a 5-day DSS treatment and walnut diets were continued throughout the entire experimental period. Mice were examined at 2 days or 10 days after withdrawal of DSS. In a separate study, a discovery-based metabolite profiling analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed on fecal samples and colonic mucosa following two weeks of walnut supplementation. Dietary walnut supplementation showed significant effects in the 10-day post-DSS recovery-phase study, in which the extent of ulceration was significantly reduced (7.5% vs. 0.3%, p < 0.05) with 14% walnuts. In the metabolite-profiling analysis, walnuts caused a significant increase in several polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and 9-oxo-10(E),12(E)-octadecadienoic acid (9-oxoODA), as well as kynurenic acid. In colon tissue samples, walnuts caused a significant increase in the levels of S-adenosylhomocysteine (SAH) and betaine, important components of fatty acid β-oxidation. These metabolite changes may contribute in part to the observed protection against DSS-induced inflammatory tissue injury.