Publications by authors named "Sang-Woon Choi"

99 Publications

Dietary modulation of gut microbiota for the relief of irritable bowel syndrome.

Nutr Res Pract 2021 Aug 26;15(4):411-430. Epub 2021 May 26.

Chaum Life Center, CHA University, Seoul 06062, Korea.

Irritable bowel syndrome (IBS) is a frequently diagnosed gastrointestinal (GI) disorder characterized by recurrent abdominal pain, bloating, and changes in the stool form or frequency without any structural changes and overt inflammation. It is not a life-threatening condition but causes a considerable level of discomfort and distress. Among the many pathophysiologic factors, such as altered GI motility, visceral hypersensitivity, and low-grade mucosal inflammation, as well as other immunologic, psychologic, and genetic factors, gut microbiota imbalance (dysbiosis), which is frequently found in IBS, has been highlighted as an etiology of IBS. Dysbiosis may affect gut mucosal homeostasis, immune function, metabolic regulation, and even visceral motor function. As diet is shown to play a fundamental role in the gut microbiota profile, this review discusses the influence of diet on IBS occurring through the modulation of gut microbiota. Based on previous studies, it appears that dietary modulation of the gut microbiota may be effective for the alleviation of IBS symptoms and, also an effective IBS management strategy based on the underlying mechanism; especially because, IBS currently has no specific treatment owing to its uncertain etiology.
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http://dx.doi.org/10.4162/nrp.2021.15.4.411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313387PMC
August 2021

Urine organic acids may be useful biomarkers for metabolic syndrome and its components in Korean adults.

Clin Chem Lab Med 2021 Oct 30;59(11):1824-1831. Epub 2021 Jul 30.

Department of Family medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.

Objectives: Although metabolic syndrome (MetS) and its components are defined clinically, those with MetS may have various derangements in metabolic pathways. Thus, this study aimed to evaluate the traits of urine organic acid metabolites indicating the metabolic intermediates of the pathways in the subjects with MetS.

Methods: This cross-sectional study included 246 men and 283 women in a hospital health check-up setting. Urine organic acid metabolites were assayed via high-performance liquid chromatography-mass spectrometry analyses. A high level of each metabolite was defined as the fifth quintile of the distribution.

Results: The subjects with MetS had high levels of pyruvate, α-ketoglutarate, α-ketoisovalerate, α-ketoisocaproate, formiminoglutamate, and quinolinate (odds ratios from 1.915 to 2.809 in logistic models adjusted for age and sex). Among the metabolites, pyruvate, formiminoglutamate, and quinolinate were not independent of homeostatic model assessment of insulin resistance (HOMA2-IR). Several metabolites were associated with one or more components of MetS and HOMA2-IR.

Conclusions: Urine organic acid metabolites in MetS are characterized in altered carbohydrate and amino acid metabolism. MetS shared some traits in insulin resistance. These findings may promote the understanding of the pathophysiology of MetS.
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http://dx.doi.org/10.1515/cclm-2021-0598DOI Listing
October 2021

Vitamin D and Exercise Are Major Determinants of Natural Killer Cell Activity, Which Is Age- and Gender-Specific.

Front Immunol 2021 23;12:594356. Epub 2021 Jun 23.

Chaum Life Center, CHA University School of Medicine, Seoul, South Korea.

Background: The coronavirus-19 disease (COVID-19) pandemic reminds us of the importance of immune function, even in immunologically normal individuals. Multiple lifestyle factors are known to influence the immune function.

Objective: The aim was to investigate the association between NK cell activity (NKA) and multiple factors including vitamin D, physical exercise, age, and gender.

Methods: This was a cross-sectional association study using health check-up and NKA data of 2,095 subjects collected from 2016 to 2018 in a health check-up center in the Republic of Korea. NKA was measured using the interferon-γ (IFN-γ) stimulation method. The association of NKA with 25-(OH)-vitamin D (25(OH)D) and other factors was investigated by multiple logistic regression analysis.

Results: The average age of subjects was 48.8 ± 11.6 years (52.9% of subjects were female). Among 2,095 subjects, 1,427 had normal NKA (NKA ≥ 500 pg IFN-γ/mL), while 506 had low NKA (100 ≤ NKA < 500 pg/mL), and 162 subjects had very low NKA (NKA < 100 pg/mL). Compared to men with low 25(OH)D serum level (< 20 ng/mL), vitamin D replete men (30-39.9 ng/mL) had significantly lower risk of very low NKA (OR: 0.358; 95% CI: 0.138, 0.929; = 0.035). In women, both low exercise (OR: 0.529; 95% CI: 0.299, 0.939; = 0.030) and medium to high exercise (OR: 0.522; 95% CI: 0.277, 0.981; = 0.043) decreased the risk compared to lack of physical exercise. Interestingly, in men and women older than 60 years, physical exercise significantly decreased the risk. Older-age was associated with increased risk of very low NKA in men, but not in women.

Conclusion: Physical exercise and vitamin D were associated with NKA in a gender- and age-dependent manner. Age was a major risk factor of very low NKA in men but not in women.
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http://dx.doi.org/10.3389/fimmu.2021.594356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261050PMC
August 2021

Elevated levels of urine isocitrate, hydroxymethylglutarate, and formiminoglutamate are associated with arterial stiffness in Korean adults.

Sci Rep 2021 05 13;11(1):10180. Epub 2021 May 13.

Department of Family Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea.

Recent evidence suggests that cellular perturbations play an important role in the pathogenesis of cardiovascular diseases. Therefore, we analyzed the association between the levels of urinary metabolites and arterial stiffness. Our cross-sectional study included 330 Korean men and women. The brachial-ankle pulse wave velocity was measured as a marker of arterial stiffness. Urinary metabolites were evaluated using a high-performance liquid chromatograph-mass spectrometer. The brachial-ankle pulse wave velocity was found to be positively correlated with L-lactate, citrate, isocitrate, succinate, malate, hydroxymethylglutarate, α-ketoisovalerate, α-keto-β-methylvalerate, methylmalonate, and formiminoglutamate among men. Whereas, among women, the brachial-ankle pulse wave velocity was positively correlated with cis-aconitate, isocitrate, hydroxymethylglutarate, and formiminoglutamate. In the multivariable regression models adjusted for conventional cardiovascular risk factors, three metabolite concentrations (urine isocitrate, hydroxymethylglutarate, and formiminoglutamate) were independently and positively associated with brachial-ankle pulse wave velocity. Increased urine isocitrate, hydroxymethylglutarate, and formiminoglutamate concentrations were associated with brachial-ankle pulse wave velocity and independent of conventional cardiovascular risk factors. Our findings suggest that metabolic disturbances in cells may be related to arterial stiffness.
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http://dx.doi.org/10.1038/s41598-021-89639-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119418PMC
May 2021

Trace Elements Status and Metallothioneins DNA Methylation Influence Human Hepatocellular Carcinoma Survival Rate.

Front Oncol 2020 28;10:596040. Epub 2021 Jan 28.

Department of Medicine, University of Verona, Verona, Italy.

Background: Mechanisms underlying hepatocellular carcinoma (HCC) development are largely unknown. The role of trace elements and proteins regulating metal ions homeostasis, i.e. metallothioneins (MTs), recently gained an increased interest. Object of the study was to investigate the role of promoter DNA methylation in MTs transcriptional regulation and the possible prognostic significance of serum trace elements in HCC.

Methods: Forty-nine HCC patients were enrolled and clinically characterized. Cu, Se, and Zn contents were measured by Inductively Coupled Plasma Mass Spectrometry in the serum and, for a subset of 27 patients, in HCC and homologous non-neoplastic liver (N) tissues. and gene expression in hepatic tissues was assessed by Real-Time RT-PCR and the specific promoter DNA methylation by Bisulfite-Amplicon Sequencing.

Results: Patients with Cu serum concentration above the 80 percentile had a significantly decreased survival rate (P < 0.001) with a marked increased hazard ratio for mortality (HR 6.88 with 95% CI 2.60-18.23, P < 0.001). Se and Zn levels were significantly lower in HCC as compared to N tissues (P < 0.0001). and gene expression was significantly down-regulated in HCC as compared to N tissues (P < 0.05). MTs promoter was hypermethylated in 9 out of the 19 HCC tissues showing MTs down-regulation and methylation levels of three specific CpGs paralleled to an increased mortality rate among the 23 patients analyzed (P = 0.015).

Conclusions: and act as potential tumor suppressor genes regulated through promoter DNA methylation and, together with serum Cu concentrations, be related to survival rate in HCC.
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http://dx.doi.org/10.3389/fonc.2020.596040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876470PMC
January 2021

The Relationship of Dietary Pattern and Genetic Risk Score with the Incidence Dyslipidemia: 14-Year Follow-Up Cohort Study.

Nutrients 2020 Dec 16;12(12). Epub 2020 Dec 16.

Department of Food and Nutrition, College of BioNano Technoloyg, Gachon University, Gyeonggi 13120, Korea.

This study was conducted to investigate the relationship between dietary pattern and genetic risk score (GRS) for dyslipidemia risk among Korean adults. Hypercholesterolemia and hypertriglyceridemia defined as total cholesterol ≥240 mg/dL and triglyceride ≥200 mg/dL or use dyslipidemia medication. The GRS was calculated by summing the risk alleles of the selected seven single-nucleotide polymorphisms related to dyslipidemia. Dietary patterns were identified by principal component analysis based on the frequency of 36 food groups, "whole grain and soybean products" pattern, "meat, fish and vegetables" pattern, and "bread and noodle" pattern were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the multivariate Cox proportional hazards regression model. High intake of a "whole grain and soybean products" pattern decreased risks of hypercholesterolemia (HR: 0.82, 95% CI: 0.72-0.93, for trend = 0.0006) and hypertriglyceridemia (HR: 0.85, 95% CI: 0.75-0.97, for trend = 0.0344). In the highest tertile of GRS, the "whole grain and soybean products" pattern was inversely related to hypercholesterolemia risk. Therefore, for people with genotypes that can cause hypercholesterolemia, eating whole grains and soybean products may have a meaningful response, these results could be utilized for genome-based nutrition management.
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http://dx.doi.org/10.3390/nu12123840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765618PMC
December 2020

A Traditional Korean Diet Alters the Expression of Circulating MicroRNAs Linked to Diabetes Mellitus in a Pilot Trial.

Nutrients 2020 Aug 24;12(9). Epub 2020 Aug 24.

CHA Bio Complex, CHA University, Seongnam 13488, Korea.

The traditional Korean diet (K-diet) is considered to be healthy and circulating microRNAs (miRs) have been proposed as useful markers or targets in diet therapy. We, therefore, investigated the metabolic influence of the K-diet by evaluating the expression of plasma and salivary miRs. Ten women aged 50 to 60 years were divided into either a K-diet or control diet (a Westernized Korean diet) group. Subjects were housed in a metabolic unit-like condition during the two-week dietary intervention. Blood and saliva samples were collected before and after the intervention, and changes in circulating miRs were screened by an miR array and validated by individual RT-qPCRs. In the K-diet group, eight plasma miRs were down-regulated by array ( < 0.05), out of which two miRs linked to diabetes mellitus, hsa-miR26a-5p and hsa-miR126-3p, were validated ( < 0.05). Among five down-regulated salivary miRs, hsa-miR-92-3p and hsa-miR-122a-5p were validated, which are associated with diabetes mellitus, acute coronary syndrome and non-alcoholic fatty liver disease. In the control diet group, validated were down-regulated plasma hsa-miR-25-3p and salivary hsa-miR-31-5p, which are associated with diabetes mellitus, adipogenesis and obesity. The K-diet may influence the metabolic conditions associated with diabetes mellitus, as evidenced by changes in circulating miRs, putative biomarkers for K-diet.
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http://dx.doi.org/10.3390/nu12092558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551128PMC
August 2020

A Traditional Korean Diet with a Low Dietary Inflammatory Index Increases Anti-Inflammatory IL-10 and Decreases Pro-Inflammatory NF-κB in a Small Dietary Intervention Study.

Nutrients 2020 Aug 16;12(8). Epub 2020 Aug 16.

CHA Bio Complex, CHA University, Seongnam 13488, Korea.

Chronic low-grade inflammation may increase the risk of chronic disease, while diets rich in anti-inflammatory components may reduce it. To determine the anti-inflammatory properties of the traditional Korean diet (K-diet) that comprises high amounts of vegetables, fiber and phytochemicals, moderate amounts of legumes, and low amounts of animal fat, ten obese women aged 50-60 years were randomly assigned to the K-diet or control diet group. The control diet was a Westernized Korean diet commonly consumed in Korea, which is high in animal fat and protein. Subjects were housed in metabolic unit-like conditions during the 2-week intervention. Plasma was collected before and after the intervention to measure inflammatory cytokines using ELISA. The dietary inflammatory index (DII) was calculated based on nutrients and food intake. The DII score for the K-diet was lower than that of the control diet (-0.94 ± 1.39 vs. 1.04 ± 1.61, < 0.001). In the K-diet group, anti-inflammatory interleukin (IL)-10 levels increased (4.45 ± 0.34 pg/mL vs. 5.94 ± 0.33 pg/mL, = 0.0102), whereas pro-inflammatory nuclear factor kappa B (NF-κB) levels decreased (7.70 ± 0.62 pg/mL vs. 2.71 ± 0.49 pg/mL, = 0.0015), but not in the control group. In the K-diet group, NF-κB levels negatively correlated with IL-10 levels (r = -0.794, = 0.006). The K-diet has anti-inflammatory properties, and IL-10 and NF-κB are putative inflammatory markers for K-diet studies.
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http://dx.doi.org/10.3390/nu12082468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468714PMC
August 2020

High-Fat Diet and Antibiotics Cooperatively Impair Mitochondrial Bioenergetics to Trigger Dysbiosis that Exacerbates Pre-inflammatory Bowel Disease.

Cell Host Microbe 2020 08 14;28(2):273-284.e6. Epub 2020 Jul 14.

Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA. Electronic address:

The clinical spectra of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) intersect to form a scantily defined overlap syndrome, termed pre-IBD. We show that increased Enterobacteriaceae and reduced Clostridia abundance distinguish the fecal microbiota of pre-IBD patients from IBS patients. A history of antibiotics in individuals consuming a high-fat diet was associated with the greatest risk for pre-IBD. Exposing mice to these risk factors resulted in conditions resembling pre-IBD and impaired mitochondrial bioenergetics in the colonic epithelium, which triggered dysbiosis. Restoring mitochondrial bioenergetics in the colonic epithelium with 5-amino salicylic acid, a PPAR-γ (peroxisome proliferator-activated receptor gamma) agonist that stimulates mitochondrial activity, ameliorated pre-IBD symptoms. As with patients, mice with pre-IBD exhibited notable expansions of Enterobacteriaceae that exacerbated low-grade mucosal inflammation, suggesting that remediating dysbiosis can alleviate inflammation. Thus, environmental risk factors cooperate to impair epithelial mitochondrial bioenergetics, thereby triggering microbiota disruptions that exacerbate inflammation and distinguish pre-IBD from IBS.
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http://dx.doi.org/10.1016/j.chom.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429289PMC
August 2020

Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors.

Cancers (Basel) 2019 Oct 11;11(10). Epub 2019 Oct 11.

Chaum Life Center, CHA University School of Medicine, Seoul 06062, Korea.

In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating self-antigen presentation. Recent findings highlighted that NK cells can even target cancer stem cells. The efficacy of allogeneic NK cells has been widely investigated in the treatment of hematologic malignancies. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. In allogeneic NK cell therapy, the mismatch between the killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) can be harnessed to increase the antitumor activity. However, the allogeneic NK cells cause more adverse events and can be rejected by the host immune system after repeated injections. In this regard, the autologous NK cell therapy is safer. This article reviews the published results of clinical trials and discusses strategies to enhance the efficacy of the NK cell therapy. The difference in immunophenotype of the ex vivo expanded NK cells resulted from different culture methods may affect the final efficacy. Furthermore, currently available standard anticancer therapy, molecularly targeted agents, and checkpoint inhibitors may directly or indirectly enhance the efficacy of NK cell therapy. A recent study discovered that NK cell specific genetic defects are closely associated with the tumor immune microenvironment that determines clinical outcomes. This finding warrants future investigations to find the implication of NK cell specific genetic defects in cancer development and treatment, and NK cell deficiency syndrome should be revisited to enhance our understanding. Overall, it is clear that NK cell therapy is safe and promises a new paradigm for the treatment of solid tumors.
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http://dx.doi.org/10.3390/cancers11101534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826624PMC
October 2019

Maternal and Cord Blood Folate Concentrations Are Inversely Associated with Fetal DNA Hydroxymethylation, but Not DNA Methylation, in a Cohort of Pregnant Canadian Women.

J Nutr 2020 02;150(2):202-211

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Aberrancies in fetal DNA methylation programming may modify disease susceptibility of the offspring. Maternal folate status has potential to alter fetal DNA methylation.

Objectives: We examined the association of maternal and cord blood concentrations of folate and unmetabolized folic acid (UMFA), vitamin B-12, vitamin B-6, and choline with fetal DNA methylation and hydroxymethylation and assessed potential modifying effects of 38 fetal genetic variants in 22 genes.

Methods: Nutrient blood concentrations were measured in 368 pregnant women in early pregnancy (12-16 wk of gestation) and at delivery (37-42 wk of gestation) and in cord blood. DNA methylation and hydroxymethylation in cord blood mononuclear cells were quantified by LC-MS/MS. Pearson partial correlations were used to determine the association between individual nutrients and DNA methylation and hydroxymethylation.

Results: Serum and RBC folate and plasma UMFA concentrations (primary outcomes) in early pregnancy, at delivery, and in cord blood were not significantly associated with fetal DNA methylation. In contrast, maternal RBC folate in early pregnancy (r = -0.16, P = 0.04) and cord plasma UMFA (r = -0.23, P = 0.004) were inversely correlated with fetal DNA hydroxymethylation. Neither maternal and cord blood concentrations of other nutrients nor fetal genotypes (secondary outcomes) were significantly associated with fetal DNA methylation or hydroxymethylation. Infants born to mothers with RBC folate concentrations in the highest quartile and serum vitamin B-12 concentrations in the lowest quartile in early pregnancy had significantly lower fetal DNA methylation and higher birth weight compared with those born to mothers with lower RBC folate and higher serum vitamin B-12 concentrations (P = 0.01).

Conclusions: Maternal and cord blood folate concentrations are associated with fetal DNA hydroxymethylation, but not DNA methylation, in a cohort of pregnant Canadian women. The observation that high folate and low vitamin B-12 maternal status in early pregnancy may be associated with decreased fetal DNA methylation and higher birth weight warrants further investigation. This trial was registered at clinicaltrials.gov as NCT02244684.
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http://dx.doi.org/10.1093/jn/nxz232DOI Listing
February 2020

β-Carotene 15,15'-oxygenase inhibits cancer cell stemness and metastasis by regulating differentiation-related miRNAs in human neuroblastoma.

J Nutr Biochem 2019 07 28;69:31-43. Epub 2019 Mar 28.

Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, South Korea. Electronic address:

Neuroblastoma (NB) is the most common pediatric malignancy and is considered to possess cancer stem cells (CSCs) properties which can drive tumor initiation and metastasis. β-carotene 15,15'-oxygenase (BCO1) is the main enzyme that catalyzes the first step in vitamin A biosynthesis from pro-vitamin A carotenoids. Retinoids (vitamin A) play a critical role in NB differentiation. However, the biological functions of BCO1 in NB remained to be elucidated. Here, we investigated the effects of BCO1 on NB CSCs with stably expressing BCO1 in NB cells. We show that BCO1 significantly suppressed self-renewal and markers of NB CSCs. Moreover, BCO1 inhibited the metastatic potential of NB cells and suppressed the enzymatic activity and expression of MMPs, as well as expression of HIF-1α and its downstream targets. In vivo, BCO1 reduced the metastatic incidence and volumes of metastatic tumors and downregulated the expression of CSCs markers, MMPs, and HIF-1α in tumor tissues of a mouse xenograft model. A possible mechanism underlying the anti-cancer activities of BCO1 is proposed based on miRNAs sequencing array data which suggests a role for BCO1 in regulating miRNAs associated with neuronal differentiation, cell-cell adhesion, and the Wnt signaling pathway. Thus, our results demonstrate new chemotherapeutic roles for BCO1 in malignant NB that mediate suppression of cancer stemness and metastasis.
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http://dx.doi.org/10.1016/j.jnutbio.2019.03.010DOI Listing
July 2019

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

Nutr Res Pract 2019 Feb 3;13(1):58-63. Epub 2018 Dec 3.

CHA University School of Medicine, 120, Haeryong-ro, Pocheon-si, Gyeonggi 13488, Korea.

Background/objectives: Telomeres are located at the chromosomal ends and progressively shortened during each cell cycle. Telomerase, which is regulated by and -, 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: CD133CD44 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 ( ). Telomerase activity was also measured by qRT-PCR after incubating the PCR mixture with cell protein extracts, which was adjusted with reference DNA ( ). Transcriptions of and - 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; = 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; = 0.0067). There was a positive correlation between telomere length and telomerase activity (r = 0.9090; < 0.0001). Transcriptions of both and - were also significantly decreased in the same manner.

Conclusion: 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.
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http://dx.doi.org/10.4162/nrp.2019.13.1.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369112PMC
February 2019

Association between Egg Consumption and Metabolic Disease.

Korean J Food Sci Anim Resour 2018 Apr 30;38(2):209-223. Epub 2018 Apr 30.

Department of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam 13120, Korea.

The effect of high egg intake on metabolic syndrome (MetS), a major risk factor for cardiovascular disease (CVD), has not been clearly elucidated. This study was conducted to review the literature related to egg consumption and the risk of metabolic disease as well as to examine the association between high egg intake and MetS in Korean adults. A literature review was conducted using published papers in PubMed and EMBASE through December 2017. We have reviewed 26 articles, which were associated with egg consumption and metabolic diseases, and found that the results were controversial. Therefore, we analyzed data from 23,993 Korean adults aged 19 yrs and older. MetS was defined based on criteria from the Adult Treatment Panel III. Egg consumption of 4-6 times/wk and 1 time/day were significantly associated with reduced prevalence of MetS (Odds ratio (OR)=0.82; 95% Confidence interval (CI)=0.71-0.95 for 4-6 times/wk, OR=0.83; 95% CI=0.69-0.99 for 1 time/day) compared to those who consumed eggs less than once monthly. However, consuming two or more eggs per day was not associated with MetS. As for the components of MetS, an egg intake of once daily decreased the prevalence of abdominal obesity and an intake of 2-7 eggs weekly was shown to prevent a reduction in the high-density lipoprotein cholesterol levels. This study suggests that while consuming eggs 4-7 times weekly is associated with a lower prevalence of MetS, consuming two or more eggs daily is not associated with a reduced risk for MetS.
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http://dx.doi.org/10.5851/kosfa.2018.38.2.209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960820PMC
April 2018

Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice.

Eur J Nutr 2019 Jun 9;58(4):1603-1613. Epub 2018 May 9.

Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul National University College of Medicine, 5 Gil 20, Boramae-Road, Dongjak-Gu, Seoul, 156-707, South Korea.

Purpose: Walnuts (Juglans regia) are known to have anti-cancer and immunomodulatory effects. However, little information is available on the effects of walnut phenolic extract (WPE) on intestinal inflammation and colitis-associated colon cancer.

Methods: COLO205 cells were pretreated with WPE and then stimulated with tumor necrosis factor (TNF)-α. In the acute colitis model, wild type mice (C57BL/6) were administered 4% dextran sulfate sodium (DSS) for 5 days. In the chronic colitis model, interleukin (IL)-10 mice were administered with either the vehicle or WPE (20 mg/kg) by oral gavage daily for 2 weeks. In an inflammation-associated tumor model, wild type mice were administered a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption.

Results: WPE significantly inhibited IL-8 and IL-1α expression in COLO205 cells. WPE attenuated both the TNF-α-induced IκB phosphorylation/degradation and NF-κB DNA binding activity. The administration of oral WPE significantly reduced the severity of colitis in both acute and chronic colitis models, including the IL-10 mice. In immunohistochemical staining, WPE attenuated NF-κB signaling in the colons of both colitis models. Finally, WPE also significantly reduced tumor development in a murine model of colitis-associated colon cancer (CAC).

Conclusions: WPE ameliorates acute and chronic colitis and CAC in mice, suggesting that WPE may have potentials for the treatment of inflammatory bowel disease.
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http://dx.doi.org/10.1007/s00394-018-1704-3DOI Listing
June 2019

Metabolic influence of walnut phenolic extract on mitochondria in a colon cancer stem cell model.

Eur J Nutr 2019 Jun 8;58(4):1635-1645. Epub 2018 May 8.

CHA University School of Medicine, Seongnam, South Korea.

Purpose: Walnut phenolic extract (WPE) reduces proliferation and enhances differentiation of colon cancer stem cells (CSCs). The present study investigated the metabolic influence of WPE on the mitochondrial function of colon CSCs to determine its underlying mechanism.

Methods: CD133CD44 HCT116 colon cancer cells were selected by fluorescence-activated cell sorting and were treated with or without 40 µg/mL WPE. RNA-sequencing (RNA-Seq) was performed to identify differentially expressed genes (DEGs), which were further validated with RT-PCR. WPE-induced alterations in mitochondrial function were investigated through a mitochondrial stress test by determining cellular oxygen consumption rate (OCR), an indicator of mitochondrial respiration, and extracellular acidification rate (ECAR), an indicator of glycolysis, which were further confirmed by glucose uptake and lactate production tests.

Results: RNA-Seq analysis identified two major functional clusters: metabolic and mitochondrial clusters. WPE treatment shifted the metabolic profile of cells towards the glycolysis pathway (ΔECAR = 36.98 mpH/min/ptn, p = 0.02) and oxidative pathway (ΔOCR = 29.18 pmol/min/ptn, p = 0.00001). Serial mitochondrial stimulations using respiration modulators, oligomycin, carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone, and rotenone/antimycin A, found an increased potential of mitochondrial respiration (ΔOCR = 111.5 pmol/min/ptn, p = 0.0006). WPE treatment also increased glucose uptake (Δ = 0.39 pmol/µL, p = 0.002) and lactate production (Δ = 0.08 nmol/µL, p = 0.005).

Conclusions: WPE treatment shifts the mitochondrial metabolism of colon CSC towards more aerobic glycolysis, which might be associated with the alterations in the characteristics of colon CSC.
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http://dx.doi.org/10.1007/s00394-018-1708-zDOI Listing
June 2019

DNA Methylation and Hydroxymethylation in Primary Colon Cancer and Synchronous Hepatic Metastasis.

Front Genet 2017 9;8:229. Epub 2018 Jan 9.

Department of Medicine, School of Medicine, University of Verona, Verona, Italy.

Colon cancer is one of the most frequent solid tumor and simultaneous diagnosis of primary colon cancer and liver metastases occurs in about one fourth of cases. The current knowledge on epigenetic signatures, especially those related to hydroxymethylation in primary cancer tissue, synchronous metastasis, and blood circulating cells is lacking. This study aimed to investigate both methylcytosine (mCyt) and hydroxymethylcytosine (hmCyt) status in the DNA of individual patients from colon cancer tissue, synchronous liver metastases, and in cancer-free colon and liver tissues and leukocytes. Patients undergoing curative surgery ( = 16) were enrolled and their laboratory and clinical history data collected. The contents of mCyt and hmCyt were determined by a liquid chromatography/mass spectrometry (LC/MS/MS) method in DNA extracted from primary colon cancer, synchronous hepatic metastatic tissues and homologous cancer-free tissues, i.e., colon and liver tissues as well as leukocytes. The mCyt and hmCyt levels were compared between cancerous and cancer-free tissues, and correlations between leukocytes and colon/liver tissues for both the mCyt and hmCyt levels were evaluated. The mCyt levels were similar in primary colon cancer and liver metastasis tissues (4.69 ± 0.37% vs. 4.77 ± 0.38%, respectively, = 0.535), and both primary and metastatic tissues were hypomethylated compared to cancer-free colon (4.98 ± 0.26%). The difference in the mCyt content between cancerous and cancer-free colon tissues was significantly lower in primary colon cancer ( = 0.004), but not in liver metastasis ( = 0.148). The hmCyt content was similar in primary colon cancer compared to liver metastasis (0.035%, C.I. 0.024-0.052% versus 0.035%, C.I. 0.021-0.058%, respectively, 0.905) and markedly depleted compared to the cancer-free colon (0.081%, C.I. 0.055-0.119%) with a statistically significant difference ( < 0.05) for both comparisons. The mCyt levels showed a borderline correlation between leukocytes and colon cancer tissue (Pearson's correlation coefficient = 0.51, = 0.052) while no correlations were detected for the hmCyt levels. In conclusion, primary colon cancer and synchronous liver metastasis tissues showed a similar epigenetic status but were significantly hypomethylated and hypohydroxymethylated as compared to homologous cancer-free colon tissues.
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http://dx.doi.org/10.3389/fgene.2017.00229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767180PMC
January 2018

Hepcidin and DNA promoter methylation in hepatocellular carcinoma.

Eur J Clin Invest 2018 Feb 28;48(2):e12870. Epub 2017 Dec 28.

Department of Medicine, University of Verona School of Medicine, Verona, Italy.

Background: The liver hormone hepcidin regulates iron homoeostasis that is often altered in hepatocellular carcinoma (HCC). Epigenetic phenomena control gene expression through a dynamic fashion; therefore, considering the plasticity of both iron homoeostasis and epigenetic mechanisms and their role in liver carcinogenesis, we investigated whether hepcidin gene (HAMP) expression is modulated by DNA methylation, thus affecting iron status in human HCC.

Materials And Methods: Thirty-two patients affected by nonviral HCC were enrolled, and their main clinical and biochemical characteristics were obtained. Neoplastic and homologous non-neoplastic liver tissues were analysed for HAMP promoter DNA methylation, for HAMP gene expression and for iron content. An in vitro demethylation assay with a human hepatocarcinoma cell line was performed to evaluate the role of DNA methylation on HAMP transcriptional repression.

Results: Gene expression and DNA methylation analyses on tissues showed that HAMP was transcriptionally repressed in HCC tissues consensually with a promoter hypermethylation. Furthermore, patients with HCC had low serum hepcidin concentrations, and HCC tissues had relative iron depletion as compared to non-neoplastic liver tissues. The cell culture model showed the functional role of DNA hypermethylation by downregulating HAMP gene expression. Through a quantitative methylation analysis on HCC tissues, we then proved that methylation at definite CpG sites within consensus sequences for specific transcription factors is possibly the mechanism underlying HAMP repression.

Conclusions: This study highlights a novel role for HAMP downregulation through DNA promoter hypermethylation and emphasises the significance of epigenetics in the regulation of iron metabolism in HCC.
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http://dx.doi.org/10.1111/eci.12870DOI Listing
February 2018

Differential Tissue-specific and Pathway-specific Anti-obesity Effects of Green Tea and Taeumjowitang, a Traditional Korean Medicine, in Mice.

J Cancer Prev 2017 Sep 30;22(3):147-158. Epub 2017 Sep 30.

Precision Medicine Research Center and Advanced Institutes of Convergence Technology, Seoul National University, Korea.

Background: Traditional medicines have been leveraged for the treatment and prevention of obesity, one of the fastest growing diseases in the world. However, the exact mechanisms underlying the effects of traditional medicine on obesity are not yet fully understood.

Methods: We produced the transcriptomes of epididymal white adipose tissue (eWAT), liver, muscle, and hypothalamus harvested from mice fed a normal diet, high-fat-diet alone, high-fat-diet together with green tea, or a high-fat-diet together with Taeumjowitang, a traditional Korean medicine.

Results: We found tissue-specific gene expression patterns as follows: (i) the eWAT transcriptome was more significantly altered by Taeumjowitang than by green tea, (ii) the liver transcriptome was similarly altered by Taeumjowitang and green tea, and (iii) both the muscle and hypothalamus transcriptomes were more significantly altered by green tea than Taeumjowitang. We then applied integrated network analyses, which revealed that functional networks associated with lymphocyte activation were more effectively regulated by Taeumjowitang than by green tea in the eWAT. In contrast, green tea was a more effective regulator of functional networks associated with glucose metabolic processes in the eWAT.

Conclusions: Taeumjowitang and green tea have a differential tissue-specific and pathway-specific therapeutic effect on obesity.
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http://dx.doi.org/10.15430/JCP.2017.22.3.147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624455PMC
September 2017

One-carbon genetic variants and the role of MTHFD1 1958G>A in liver and colon cancer risk according to global DNA methylation.

PLoS One 2017 2;12(10):e0185792. Epub 2017 Oct 2.

Department of Medicine, University of Verona School of Medicine, Verona, Italy.

Several polymorphic gene variants within one-carbon metabolism, an essential pathway for nucleotide synthesis and methylation reactions, are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon metabolism variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism gene variants in hepatocellular-carcinoma, cholangiocarcinoma and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p = 0.007) and related to 63% reduction of overall cancer risk (p = 0.003) and 75% of colon cancer risk (p = 0.006). When considering PBMCs mCyt content, carriers of the MTHFD1 1958GG genotype showed a lower DNA methylation as compared to carriers of the A allele (p = 0.048). No differences were highlighted by evaluating a possible relationship between the other polymorphisms analyzed with cancer risk and DNA methylation. The MTHFD1 1958AA genotype is linked to a significantly reduced cancer risk. The 1958GG genotype is associated to PBMCs DNA hypomethylation as compared to the A allele carriership that may exert a protective effect for cancer risk by preserving from DNA hypomethylation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185792PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624642PMC
October 2017

Genome-wide hepatic DNA methylation changes in high-fat diet-induced obese mice.

Nutr Res Pract 2017 Apr 15;11(2):105-113. Epub 2017 Mar 15.

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.; Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA.; Chaum Life Center, CHA University School of Medicine, Seoul 06062, Korea.

Background/objectives: A high-fat diet (HFD) induces obesity, which is a major risk factor for cardiovascular disease and cancer, while a calorie-restricted diet can extend life span by reducing the risk of these diseases. It is known that health effects of diet are partially conveyed through epigenetic mechanism including DNA methylation. In this study, we investigated the genome-wide hepatic DNA methylation to identify the epigenetic effects of HFD-induced obesity.

Materials And Methods: Seven-week-old male C57BL/6 mice were fed control diet (CD), calorie-restricted control diet (CRCD), or HFD for 16 weeks (after one week of acclimation to the control diet). Food intake, body weight, and liver weight were measured. Hepatic triacylglycerol and cholesterol levels were determined using enzymatic colorimetric methods. Changes in genome-wide DNA methylation were determined by a DNA methylation microarray method combined with methylated DNA immunoprecipitation. The level of transcription of individual genes was measured by real-time PCR.

Results: The DNA methylation statuses of genes in biological networks related to lipid metabolism and hepatic steatosis were influenced by HFD-induced obesity. In HFD group, a proinflammatory (Caspase 1) gene had hypomethylated CpG sites at the 1.5-kb upstream region of its transcription start site (TSS), and its mRNA level was higher compared with that in CD group. Additionally, an energy metabolism-associated gene (NADH dehydrogenase 1 beta subcomplex 9) in HFD group had hypermethylated CpG sites at the 2.6-kb downstream region of its TSS, and its mRNA level was lower compared with that in CRCD group.

Conclusions: HFD alters DNA methylation profiles in genes associated with liver lipid metabolism and hepatic steatosis. The methylation statuses of and were particularly influenced by the HFD. The expression of these genes in HFD differed significantly compared with CD and CRCD, respectively, suggesting that the expressions of and in liver were regulated by their methylation statuses.
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http://dx.doi.org/10.4162/nrp.2017.11.2.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376528PMC
April 2017

Iron Supplementation Reverses the Reduction of Hydroxymethylcytosine in Hepatic DNA Associated With Chronic Alcohol Consumption in Rats.

J Cancer Prev 2016 Dec 30;21(4):264-270. Epub 2016 Dec 30.

Friedman School of Nutrition Science and Policy Tufts University, Boston, MA, USA; Chaum Life Center, CHA University School of Medicine, Seoul, Korea.

Background: Alcohol is known to affect two epigenetic phenomena, DNA methylation and DNA hydroxymethylation, and iron is a cofactor of ten-eleven translocation (TET) enzymes that catalyze the conversion from methylcytosine to hydroxymethylcytosine. In the present study we aimed to determine the effects of alcohol on DNA hydroxymethylation and further effects of iron on alcohol associated epigenetic changes.

Methods: Twenty-four male Sprague-Dawley rats were fed either Lieber-DeCarli alcohol diet (36% calories from ethanol) or Lieber-DeCarli control diet along with or without iron supplementation (0.6% carbonyl iron) for 8 weeks. Hepatic non-heme iron concentrations were measured by colorimetric assays. Protein levels of hepatic ferritin and transferrin receptor were determined by Western blotting. Methylcytosine, hydroxymethylcytosine and unmodified cytosine in DNA were simultaneously measured by liquid chromatography/mass spectrometry method.

Results: Iron supplementation significantly increased hepatic non-heme iron contents ( < 0.05) but alcohol alone did not. However, both alcohol and iron significantly increased hepatic ferritin levels and decreased hepatic transferrin receptor levels ( < 0.05). Alcohol reduced hepatic DNA hydroxymethylation (0.21% ± 0.04% vs. 0.33% ± 0.04%, = 0.01) compared to control, while iron supplementation to alcohol diet did not change DNA hydroxymethylation. There was no significant difference in methylcytosine levels, while unmodified cytosine levels were significantly increased in alcohol-fed groups compared to control (95.61% ± 0.08% vs. 95.26% ± 0.12%, = 0.03), suggesting that alcohol further increases the conversion from hydroxymethylcytosine to unmodified cytosine.

Conclusions: Chronic alcohol consumption alters global DNA hydroxymethylation in the liver but iron supplementation reverses the epigenetic effect of alcohol.
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http://dx.doi.org/10.15430/JCP.2016.21.4.264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207611PMC
December 2016

The RFC1 80G>A, among Common One-Carbon Polymorphisms, Relates to Survival Rate According to DNA Global Methylation in Primary Liver Cancers.

PLoS One 2016 9;11(12):e0167534. Epub 2016 Dec 9.

Department of Medicine, University of Verona School of Medicine, Verona, Italy.

Polymorphisms within one-carbon metabolism genes have been largely studied in relation to cancer risk for the function of this pathway in nucleotide synthesis and DNA methylation. Aims of this study were to explore the possible link among several common functional gene polymorphisms within one-carbon metabolism and survival rate in primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma, and to assess the additional effect of global DNA methylation on survival rate and mortality risk. Forty-seven primary liver cancer patients were genotyped for ten polymorphisms: DHFR 19bp ins/del, TS 2rpt-3rpt, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, BHMT 716 A>G, TC II 776C>G. Methylation was determined in peripheral blood mononuclear cells (PBMCs) DNA as methylcytosine (mCyt) content using LC/MS/MS. Among the polymorphisms analysed, the RFC1 80G>A (rs1051266) influenced the survival rate in primary liver cancers. The RFC1 80AA was associated to a significantly reduced survival rate (22.2%) as compared to both GG and GA genotypes (61.5% and 76% respectively, p = 0.005). When the cancer patients were stratified according to the mCyt median value as high (>5.34%) or low (≤5.34%), the concomitant presence of AA genotype and low mCyt level led to a significantly worse survival rate as compared to the G allele carriership (p<0.0001) with a higher Hazard Ratio (HR = 6.62, p = 0.001). The subjects carrying the AA genotype in association with high mCyt did not show a significant difference in survival rate as compared with the G allele carriers (p = 0.919). The RFC1 80G>A polymorphism influenced the survival rate, and the presence of RFC1 80AA genotype with low global methylation in PBMCs DNA was associated with poorer prognosis and higher mortality risk, therefore highlighting novel molecular signatures potentially helpful to define prognostic markers for primary liver cancers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167534PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147923PMC
July 2017

Epigenetics in non-alcoholic fatty liver disease.

Mol Aspects Med 2017 04 23;54:78-88. Epub 2016 Nov 23.

Chaum Life Center, CHA University of Medicine and Science, Seoul, 06062, South Korea. Electronic address:

Non-alcoholic fatty liver disease (NAFLD), a common hepatic disorder ranging from simple steatosis through steatohepatitis to fibrosis and cirrhosis, is an emerging health concern. NAFLD is a pathologic condition characterized by the buildup of extra fat in liver cells that is not caused by alcohol consumption. Excess hepatic fat accumulation results from increased delivery of triglycerides (TG) to the liver or conversion of surplus carbohydrates to TG. Importantly, a subgroup of NAFLD results in hepatocellular injury and inflammation, which is referred to as non-alcoholic steatohepatitis (NASH), and may progress to irreversible cirrhosis and hepatocellular carcinoma (HCC). NAFLD shares, in part, the common pathogenesis of metabolic syndrome including obesity, hyperlipidemia, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines. Epigenetics, an inheritable phenomenon that affects gene expression without altering the DNA sequence, provides a new perspective on the pathogenesis of NAFLD. Reversible epigenetic changes take place at the transcriptional level and provide a phenotypic connection between the host and environment. An accumulating body of evidence suggests the importance of epigenetic roles in NAFLD, which in turn can be identified as potential therapeutic targets and non-invasive biomarkers of NAFLD. It is anticipated that the epigenetic modifiers in NAFLD may provide novel molecular indicators that can determine not only the initial risk but also the disease progression and prognosis. In the present review, we update the roles of epigenetics as pathologic mechanisms, therapeutic targets and biomarkers in NAFLD.
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http://dx.doi.org/10.1016/j.mam.2016.11.008DOI Listing
April 2017

One-carbon metabolism and epigenetics.

Mol Aspects Med 2017 04 19;54:28-36. Epub 2016 Nov 19.

Tufts University School of Nutrition Science and Policy, Boston, MA, USA; Chaum Life Center, CHA University, Seoul, South Korea.

The function of one-carbon metabolism is that of regulating the provision of methyl groups for biological methylation reactions including that of DNA and histone proteins. Methylation at specific sites into the DNA sequence and at histone tails are among the major epigenetic feature of mammalian genome for the regulation of gene expression. The enzymes within one-carbon metabolism are dependent from a number of vitamins or nutrients that serve either as co-factors or methyl acceptors or donors among which folate, vitamin B12, vitamin B6, betaine, choline and methionine have a major role. Several evidences show that there is a strict inter-relationship between one-carbon metabolism nutrients and epigenetic phenomena. Epigenetics is closely involved in gene transcriptional regulation through modifications super-imposed to the nucleotide sequence of DNA, such as DNA methylation, through chromatin remodeling systems that involves post-translational modifications of histones or through non-coding RNAs-based mechanisms. The epigenetic features of the genome are potentially modifiable by the action of several environmental factors among which nutrients cover a special place and interest considering their potential of influencing regulatory pathways at a molecular level by specific nutritional intervention and eventually influence disease prevention and outcomes. The present review will focus on the link between one-carbon nutrients and epigenetic phenomena based on the current knowledge from findings in cell culture, animal models and human studies.
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http://dx.doi.org/10.1016/j.mam.2016.11.007DOI Listing
April 2017

Diet- and Genetically-induced Obesity Produces Alterations in the Microbiome, Inflammation and Pathway in the Intestine of Apc Mice: Comparisons and Contrasts.

J Cancer 2016 12;7(13):1780-1790. Epub 2016 Aug 12.

Nutrition and Cancer Prevention Laboratory, School of Public Health and Health Sciences, University of Massachusetts, Amherst, USA.; Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, USA.

Obesity is an established risk factor for colorectal cancer (CRC). Our previous study indicated that obesity increases activity of the pro-tumorigenic -signaling. Presently, we sought to further advance our understanding of the mechanisms by which obesity promotes CRC by examining associations between microbiome, inflammation and -signaling in Apc mice whose obesity was induced by one of two modalities, diet- or genetically-induced obesity. Three groups were employed: ApcLepr fed a low fat diet (10% fat), ApcLepr fed a high fat diet (60% fat, diet-induced obesity), and ApcLepr fed a low fat diet (genetically-induced obesity). All animals received diets for 16 weeks from 8 to 24 weeks of age. The abundance of 19 bowel cancer-associated bacterial taxa were examined by real-time PCR. The abundance of and decreased, but increased, in diet-induced obese mice (p < 0.05). In contrast, in genetically-induced obese mice, decreased, but and increased (p < 0.05). Both diet- and genetically-induced obesity altered the expression of genes involved in bacterial recognition () and increased inflammation as indicated by elevated levels of cytokines (IFNγ and TNF-α for genetically-induced obesity, and IL-6 for diet-induced obesity). The elevated inflammation was associated with altered expression of genes that are integral components of the -signaling cascade in a fashion indicating its activation. These findings demonstrate that the composition of the small intestinal microbiome is affected differently in diet- and genetically-induced obesity, but both are associated with elevated intestinal inflammation and alterations of the pathway towards enhancing tumorigenesis.
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http://dx.doi.org/10.7150/jca.15792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039360PMC
August 2016

Walnut Phenolic Extract and Its Bioactive Compounds Suppress Colon Cancer Cell Growth by Regulating Colon Cancer Stemness.

Nutrients 2016 Jul 21;8(7). Epub 2016 Jul 21.

Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea.

Walnut has been known for its health benefits, including anti-cardiovascular disease and anti-oxidative properties. However, there is limited evidence elucidating its effects on cancer stem cells (CSCs) which represent a small subset of cancer cells that provide resistance against chemotherapy. This study aimed to evaluate the anti-CSCs potential of walnut phenolic extract (WPE) and its bioactive compounds, including (+)-catechin, chlorogenic acid, ellagic acid, and gallic acid. In the present study, CD133⁺CD44⁺ cells were isolated from HCT116 cells using fluorescence-activated cell sorting (FACS) and then treated with WPE. As a result, survival of the CD133⁺CD44⁺ HCT116 cells was inhibited and cell differentiation was induced by WPE. In addition, WPE down-regulated the CSC markers, CD133, CD44, DLK1, and Notch1, as well as the β-catenin/p-GSK3β signaling pathway. WPE suppressed the self-renewal capacity of CSCs. Furthermore, the WPE exhibited stronger anti-CSC effects than its individual bioactive compounds. Finally, the WPE inhibited specific CSC markers in primary colon cancer cells isolated from primary colon tumor. These results suggest that WPE can suppress colon cancer by regulating the characteristics of colon CSCs.
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http://dx.doi.org/10.3390/nu8070439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963915PMC
July 2016

Compositional analysis of walnut lipid extracts and properties as an anti-cancer stem cell regulator via suppression of the self-renewal capacity.

Food Sci Biotechnol 2016 30;25(2):623-629. Epub 2016 Apr 30.

1Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, 03760 Korea.

Colon cancer is a leading cause of cancer-related deaths worldwide. Effects of walnut ( L.) lipid extracts (WLEs) on the self-renewal capacity of cancer stem cells (CSCs) in colon cancer were investigated. The dominant component of WLEs was α-linoleic acid (64.6%), followed by α-linolenic acid (14.6%), and oleic acid (12.6%). A higher concentration of γ-tocopherol (37.1%) was also present than of α-tocopherol (0.6%). CD133CD44CSCs treated with WLEs showed inhibition of colony formation and sphere formation, indicating a decrease in the self-renewal capacity. Treatment with WLEs also resulted in down-regulation of protein levels, including Notch1, phospho-GSK3β (p-GSK3β), and β-catenin, which are associated with CSCs and the self-renewing capacity. WLEs rich in essential fatty acids and γ-tocopherol can exert therapeutic actions on colon cancer via targeting of CSCs.
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http://dx.doi.org/10.1007/s10068-016-0087-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049195PMC
April 2016

Oral Supplementation with Cocoa Extract Reduces UVB-Induced Wrinkles in Hairless Mouse Skin.

J Invest Dermatol 2016 05 15;136(5):1012-1021. Epub 2016 Feb 15.

WCU Biomodulation Major, Center for Food and Bioconvergence, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea; Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea; Institute on Aging, Seoul National University, Seoul, Republic of Korea. Electronic address:

Cacao beans contain various bioactive phytochemicals that could modify the pathogeneses of certain diseases. Here, we report that oral administration of cacao powder (CP) attenuates UVB-induced skin wrinkling by the regulation of genes involved in dermal matrix production and maintenance. Transcriptome analysis revealed that 788 genes are down- or upregulated in the CP supplemented group, compared with the UVB-irradiated mouse skin controls. Among the differentially expressed genes, cathepsin G and serpin B6c play important roles in UVB-induced skin wrinkle formation. Gene regulatory network analysis also identified several candidate regulators responsible for the protective effects of CP supplementation against UVB-induced skin damage. CP also elicited antiwrinkle effects via inhibition of UVB-induced matrix metalloproteinases-1 expression in both the human skin equivalent model and human dermal fibroblasts. Inhibition of UVB-induced activator protein-1 via CP supplementation is likely to affect the expression of matrix metalloproteinases-1. CP supplementation also downregulates the expression of cathepsin G in human dermal fibroblasts. 5-(3',4'-Dihydroxyphenyl)-γ-valerolactone, a major in vivo metabolite of CP, showed effects similar to CP supplementation. These results suggest that cacao extract may offer a protective effect against photoaging by inhibiting the breakdown of dermal matrix, which leads to an overall reduction in wrinkle formation.
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http://dx.doi.org/10.1016/j.jid.2015.11.032DOI Listing
May 2016

Hepatic DNA hydroxymethylation is site-specifically altered by chronic alcohol consumption and aging.

Eur J Nutr 2017 Mar 14;56(2):535-544. Epub 2015 Nov 14.

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.

Purpose: Global DNA hydroxymethylation is markedly decreased in human cancers, including hepatocellular carcinoma, which is associated with chronic alcohol consumption and aging. Because gene-specific changes in hydroxymethylcytosine may affect gene transcription, giving rise to a carcinogenic environment, we determined genome-wide site-specific changes in hepatic hydroxymethylcytosine that are associated with chronic alcohol consumption and aging.

Methods: Young (4 months) and old (18 months) male C57Bl/6 mice were fed either an ethanol-containing Lieber-DeCarli liquid diet or an isocaloric control diet for 5 weeks. Genomic and gene-specific hydroxymethylcytosine patterns were determined through hydroxymethyl DNA immunoprecipitation array in hepatic DNA.

Results: Hydroxymethylcytosine patterns were more perturbed by alcohol consumption in young mice than in old mice (431 differentially hydroxymethylated regions, DhMRs, in young vs 189 DhMRs in old). A CpG island ~2.5 kb upstream of the glucocorticoid receptor gene, Nr3c1, had increased hydroxymethylation as well as increased mRNA expression (p = 0.015) in young mice fed alcohol relative to the control group. Aging alone also altered hydroxymethylcytosine patterns, with 331 DhMRs, but alcohol attenuated this effect. Aging was associated with a decrease in hydroxymethylcytosine ~1 kb upstream of the leptin receptor gene, Lepr, and decreased transcription of this gene (p = 0.029). Nr3c1 and Lepr are both involved in hepatic lipid homeostasis and hepatosteatosis, which may create a carcinogenic environment.

Conclusions: These results suggest that the location of hydroxymethylcytosine in the genome is site specific and not random, and that changes in hydroxymethylation may play a role in the liver's response to aging and alcohol.
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http://dx.doi.org/10.1007/s00394-015-1098-4DOI Listing
March 2017
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