International Journal of Nutrition
ISSN: 2379-7835
Current Issue
Volume No: 1 Issue No: 1
share this page

Review Article | Open Access
  • Available online freely | Peer Reviewed
  • Epigenetics and Nutrition

    Kenneth Lundstrom 1      

    1PanTherapeuitcs, Rue des Remparts 4, CH1095 Lutry, Switzerland

    Abstract

    Epigenetic mechanisms based on DNA methylation, histone modifications and RNA interference have recently showed important association to the development of a wide variety of diseases such as cancer, cardiovascular, metabolic, skin, autoimmune diseases and neurologic disorders. In the context of preventive aspects, the importance of nutrition on epigenetic function has been revealed. Therefore, drastic changes in dietary modifications may contribute to reduced disease risk. For instance, dietary intervention has been showed to affect DNA methylation in Alzheimer’s disease patients. Moreover, maternal high-fat diet can regulate gene expression through promoter histone modifications. Most importantly, RNA interference and particularly micro-RNA mediated regulation of gene expression has been linked to disease development. Remarkably, dietary intake has been demonstrated to significantly affect various miRNAs and their regulation on gene function. In this review, the relationship between epigenetics and disease and development of drugs based on epigenetic targets is presented as well as the influence of dietary intake on epigenetic mechanisms and its effect on disease prevention and therapy will be discussed.

    Received August 29 ; 2014; Accepted 26 Nov 2014; Published 13 May 2015;

    Academic Editor:Marco Innamorati, Milan State University

    Checked for plagiarism: Yes

    Review by: Single-blind

    Copyright©  2015 Kenneth Lundstrom, et at.

    License
    Creative Commons License    This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Competing interests

    The authors have declared that no competing interests exist.

    Citation:

    Kenneth Lundstrom (2015) Epigenetics and Nutrition. International Journal of Nutrition - 1(1):46-63.
    Download as RIS, BibTeX, Text (Include abstract )
    DOI10.14302/issn.2379-7835.ijn-14-603

    Introduction

    The importance of nutrition in relation to disease prevention and therapeutic interventions has become evident during the past few years. In fact, the daily food intake presents the most important “drugs” used by every one of us 1. Furthermore, the recent progress in genome sequencing and the establishment of nutrigenomics has further revealed the close connection between nutrition and disease 2. In addition, recently nutritional scientists have introduced the term foodomics to describe as the comprehensive high-throughput approach for the exploitation of food science in relation to the improvement of human nutrition 3. In parallel, new findings have closely linked epigenetic mechanisms to disease development, which can be substantially affected by dietary interventions and life-style modifications 4. Therefore, epigenetics has become an important factor also in modern drug discovery and development.

    Epigenetic functions can be defined as mechanisms outside the scope of conventional genetic activities and therefore do not generate any modifications of the primary DNA sequence 5. The three main mechanisms of epigenetics are DNA methylation, histone modifications and RNA interference.

    Concerning DNA methylations, generally a methyl group (CH3) is covalently added to the 5’-position of cytosine upstream of guanosine affecting gene expression in relation to differentiation, genomic imprinting and DNA repair 6. Typically, the methylated CpG dinucleotides are located in promoter regions and therefore can result in down- or up-regulation of gene expression 7. Aberrant DNA methylation patterns have been linked to disease, particularly cancer 8. Furthermore, inactivation of tumor suppressor genes has been associated with hypermethylation 9. In the context of DNA packaging histones play an important role, which has confirmed their epigenetic association 5. Typically, histones H3 and H4 are modified by a number of mechanisms such as acetylation, methylation, ubiquitination and phosphorylation 10. For example, histone methylation due to increased acetylation is associated with repression or activation of transcription 11. Furthermore, deregulation of histone modifications has been associated with mutations in oncogenes, tumor suppressor genes and DNA repair genes. The third epigenetic mechanism relates to RNA interference and particularly micro RNAs (miRNAs) and their role in the regulation of gene expression 12. The 21,23 nucleotide single-stranded miRNAs interfere with mRNA resulting in the modification of gene expression including both down- and up-regulation 13,14. As at least one-third of human mRNAs are estimated to be regulated by miRNAs they have been frequently linked to cancer and other diseases 15.

    In this review, the relationship between epigenetics and disease are described through examples from different disease indications. Furthermore, emphasis is put on recent development of drugs based on epigenetic targets. Attention is also paid to the association of nutrition and epigenetics and how dietary interventions and life-style changes can significantly contribute to reduced health risk and disease prevention.

    Epigenetics and Disease

    Due to the close association of epigenetics and disease much attention has been given to evaluate epigenetics in the light of drug targets and the development of novel medicines. In addition to the potential discovery of novel drug mechanisms the reversible nature of epigenetic mechanisms makes them attractive targets for therapy. Epigenetic mechanisms have been linked to a variety of medical indications including cancer, cardiovascular, liver and skin diseases and neurologic disorders (Table 1).

    Table 1. Epigenetics and Disease.
    Disease Epigenetic function Effect Reference
    Autoimmune
    Inflammation miR-124 dysregulation pathogenesis 55
    RA miRNA dysregulation RA pathogenesis 56
    MS miRNA dysregulation disease indicator for MS 57
    Cancer      
    AML DNA MT inhibition AML treatment 59
    Bone miRNA down-regulation bone metastasis 26
    Brain DNA, H3K27 methylation ependymoma therapy 100
    Breast DNA methylation cancer association 18
    Colon histone modifications up-regulated acetylation 22
    CTCL histone deactylase CTCL treatment 60 61
    Endometrial hypermethylation disease association 17
    Gastric DNA methylation biomarker 101
    Glioma DNA methylation reduced survival 102
    Kidney hypermethylation biomarkers 103
    Liver miRNA up-regulation reduced cell death 104
    Ovarian histone modifications anti-cancer activity 105
    Prostate miRNA, tumor suppressor tumor regression 27 106
    Cardiovascular      
    Stroke DNA methylation, miRNAs association with stroke 53 107
    PH miR-21 based regulation control of PH 108
    CH HDACs suppression of CH 109
    Heart failure differential expression heart disease association 110
    Liver      
    ACHBLF DNA methylation disease associated 41
    NAFLD differential methylation inhibition of HSC 111
    Liver fibrosis miRNA HSC phenotype 45
    NASH DNA methylation correlation to NASH 112
    miR-122 circadian rhythm linkage 113
    Metabolic      
    Diabetes DNA methylation diabetes association 114
      histone modification diabetes protection 115
    Neurological      
    Alzheimer HDAC inhibitors reinstated learning 48
      DNA methylation reduced pathology 75
      miR-29 pathology promotion 35
      miR-107, miR-298, miR-328 link to Alzheimer 38 37
    Huntington histone modifications neurodegeneration 33
    Epilepsy hypermethylation epilepsy therapy 29
    Parkinson DNA methylation Parkinson association 31
    Skin      
    Psoriasis DNA methylation psoriasis pathogenesis 48
      histone modifications PASI correlation 48
      miR.143, miR-223 dysregulation biomarkers for psoriasis 49

    ACHBFL, acute-on-chronic hepatitis B liver failure; AML, acute myeloid leukemia; CH, cardiac hypertrophy; CTCL, cutaneous T-cell lymphoma; DNA MT, DNA methyltransferase;; HDACs, histone deacetylases; HSCs, hepatic stellate cells; MS, multiple sclerosis; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PASI, psoriasis area severity index; PH, pulmonary hypertension; RA, rheumatoid arthritis

    Cancer

    Altered DNA methylation has been suggested as the epigenetic mechanism associated with cancer 16. For example, hypermethylation of the SPRY2, RASSF1A, RSK4, CHFR and CDH1 genes has been associated with endometrial cancer 17. A genome-wide analysis of DNA methylation in breast cancer and normal tissue suggested that the function and pathways of several genes showed altered methylation status in cancer tissue indicating a role for DNA methylation in breast cancer 18. Similarly, altered DNA methylation patterns have been observed in prostate 19 and rectal 20 cancer patients. Analysis of the DNA methylome of primary breast cancers revealed heterogeneity in transcription activity and differences in metastatic behavior 21. Profiling of the DNA methylome and transcriptome of 44 matched primary breast tumors and regional metastasis revealed divergent changes primarily in CpG island-poor areas.

    In the context of histone modifications, it was demonstrated that histone H3 lysine 27 acetylation was up-regulated in colon cancer 22. Moreover, epigenomic-based therapies targeting histone modifications have been developed for the treatment of ovarian cancer 23. In another study, a novel class I histone deacetylase (HDAC) inhibitor MPT0G030 has showed induced cell apoptosis and differentiation in human colorectal cancer cells 24. This in vivo anti-cancer activity suggests a great potential for cancer therapy.

    Several studies have revealed the association between miRNAs and cancer. As an example, expression of the p53-specifc miR-34a is capable of inhibition of clonogenic expansion and tumor regression 25. However, when the expression was down-regulated by miR-34a antagomirs, tumor development and metastasis was promoted and prolonged survival in tumor-bearing mice. Down-regulation of miR-143 and miR-145 has been linked to metastasis of the bone 26, whereas miR-200 decrease has been observed in clinical prostate tumors and prostate cancer cell lines 27.

    Neurological Disorders

    DNA methylation plays an important role in normal brain function and aberrant methylation has recently been linked to neurological disorders and mental illnesses 28. Recently, it was demonstrated that hypermethylation of a 5’ end regulatory region of the gria2 gene correlated with epilepsy seizures in a rat model suggesting that inhibitors of DNA methylation could potentially provide therapy for epilepsy 29. Furthermore, it has been revealed that significant differences in DNA methylation exist between control and Alzheimer patients as well as in animal models for Alzheimer’s disease 30. Similarly, distinctive DNA methylation patterns have been associated with Parkinson’s disease 31. Genome-wide analysis of methylation in brain and blood samples showed substantial differences between patients with Parkinson’s disease and healthy individuals.

    Histone modifications have also been linked to Parkinson’s disease. In this context, pathological imbalance between deacetylation and acetylation of histone proteins has been observed in Parkinson patients, which has drawn the attention to HDAC inhibitors for therapeutic applications 32. Likewise, histone modifications have been associated with neurodegeneration in Huntington’s disease 33. Similarly to treatment of Parkinson’s patients, HDAC inhibitors have demonstrated therapeutic efficacy in individuals with Huntington’s disease. Moreover, histone modifications have been suggested to regulate hyperactivity in rats induced by lead exposure 34. Increased histone acetylation was observed after chronic exposure to lead, which provides a better understanding of the etiology of attention-deficit/hyperactivity disorder (ADHD) and potential therapeutic interventions.

    Moreover, miRNAs have been linked to Alzheimer’s disease development, where for instance the miR29 cluster targeting beta-secretase BACE1 is down-regulated in Alzheimer brains leading to elevated BACE1 promoting amyloid pathology 35. Likewise, SNPs within miR29 binding sites of the bace1 gene have been associated to sporadic Alzheimer’s disease 36. Furthermore, miR-107, miR-298 and miR-328 target BACE1 and have also been suggested to being linked to Alzheimer’s disease 37,38.

    Liver Diseases

    In a recent study, DNA methylation profiles of 59 hepatocellular carcinoma (HCC) patients identified three tumor subgroups, which could be correlated with clinic-pathological parameters 39. Studies on disease progression from chronic hepatitis C to cirrhosis and hepatocellular carcinoma indicated an association with increased DNA promoter methylation 40. The DNA methylation frequency could therefore be used to monitor disease progress and methylation accumulates with progression into cancer. Moreover, aberrant DNA methylation of the G protein-coupled bile acid receptor 1 (Gpbar1) promoter has been linked to acute-on-chronic hepatitis B liver failure (ACHBLF) 41. In this context, the frequency of the Gpbar1 promoter methylation was significantly higher in ACHBLF patients compared to individuals with chronic hepatitis B.

    Related to histone modifications there are a number of suggestions linking them to liver disease 42. For example, histone modifications have been associated with alcoholic liver disease 43. Additionally, inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involved histone H3 lysine 9 (H3K9) modifications in combination with DNA methylation 44.

    A number of miRNAs have been identified in regulating proliferation, apoptosis, TGFβ1 signaling, and collagen expression of the hepatitis stellate cell (HSC) phenotype and progression of fibrosis 45. Moreover, differential expression of 100 miRNAs has been demonstrated in non-alcoholic steatohepatitis (NASH) 46. Several miRNAs control lipid and glucose metabolism and such as miR-122 has showed close linkage to the circadian rhythm 47. Also, miR-122 expression is down-regulated in NASH patients and functionally implicated in in mice with non-alcoholic fatty liver disease (NAFLD).

    Other Diseases

    Epigenetic mechanisms have also been linked to a number of other diseases. For instance, the DNA methylation pattern for multiple genes involved in psoriasis pathogenesis is abnormal and hypoacetylation of histone H4 was observed in peripheral blood mononuclear cells from psoriasis patients 48. Furthermore, miRNAs have been linked to psoriasis, particularly miR-223 and miR-143 showing differential expression in psoriasis patients 49. Epigenetic differences have also been observed in obese and diabetic individuals 50. In this case, epigenetic mechanisms have been associated with maternal diabetes mellitus 51. Related to type 1 diabetes histamine deacetylase 3 (HDAC3) inhibitors protect β-cells from cytokine-induced apoptosis 52. In the case of type 2 diabetes, HDAC3 regulates genes involved in insulin resistance and pancreatic β-cell failure and HDAC3 inhibitors could therefore provide an attractive therapeutic strategy. Furthermore, in stroke patients the total DNA methylation of the tumor necrosis factor-α (TNF-α) promoter was lower 53. Epigenetic function by miRNAs has also been associated with autoimmune disease and rheumatoid arthritis 54. In this context, miR-124 was demonstrated to regulate the proliferation and secretion of monocyte chemoattractant protein-1 (MCP-1) and dysregulation might cause inflammatory pathogenesis 55. Additionally, Let-7a and miR-132 have been linked to rheumatoid arthritis pathogenesis 56 and miR-21 an indicator of progress of multiple sclerosis 57.

    Epigenetic Drugs

    Progress in understanding epigenetic mechanisms and their link to disease has accelerated the development of novel epigenetic drugs. Several epigenome-targeted drugs have already been approved by the US Food and Drug Administration 58. In this context, the DNA methyltransferase inhibitors azacitidine and decitabine have been approved for the treatment of acute myeloid leukemia (AML) 59. Moreover, two HDAC inhibitors, vorinostat 60 and romidepsin 61, are used for cutaneous T-cell lymphoma (CTCL) treatment. Additionally, several epigenetic drugs have been demonstrated to enhance memory function in rodents. Therapeutic efficacy has been observed for Alzheimer’s disease, Schizophrenia and depression in animal models 62. Evaluation of HDAC inhibitors in a murine model of the cyclin-dependent kinas 5 activator p25 protein reinstated learning behavior and synaptic plasticity even after severe neuronal loss 63.

    Related to liver diseases epigenetics has provided some considerable impact on drug development 64. For instance, the DNMT1 inhibitor 5-azadeoxycytidine (5-AzadC) and the EZH2 inhibitor 3-deazaneplanocin A (dZNep) are potent inhibitors of HSC activation 65. Furthermore, in 76% of NAFLD patients differentially methylated CpG sites became hypomethylated in advanced disease whereas 24% underwent hypermethylation 64.

    Personalized Epigenetics & Biomarkers

    In the context of drug development, genetic and epigenetic variations between individuals have triggered the need of designing personalized medicines. Diagnostic biomarkers play an important role in this context, particularly in the prediction of clinical drug responses before treatment 66. This type of pre-screening will allow for disease-specific therapy without the need of subjecting patients to drugs unlikely to provide any clinical benefit. In the case of oncology, isolation and analysis of genetic, biochemical and immunohistochemical markers from tumors and biofluids aid in defining selective treatment 67. Investigation of 19 candidate genes demonstrated that hypermethylation of the AKR1B1 and TM6SF1 promoters can serve as biomarkers for the early detection of breast cancer 68. Likewise, methylation profile studies of 59 patients with hepatocellular carcinoma identified three tumor subgroups, which correlated with clinic-pathological parameters 69.

    Furthermore, histone-modifying genes have also been evaluated as diagnostic markers. For instance, studies on HCC and adjacent non-cancerous patient tissue revealed by RT-qPCR and tissue microarray-based immunohistochemistry (TMA-based IHC) analysis showed up-regulation of the histone phosphorylation gene ARK2 and methylation genes G9a, SUV39H2 and EZH2 70. Clearly, overexpression of EZH2 and SUV39H2 was associated with HCC prognosis and could serve as novel prognostic biomarkers. Another approach has been to apply imaging mass spectrometry to identify modified forms of histone H4 as new biomarkers of microvascular invasion in HCC 71. The analysis showed that 28 of 30 differential protein peaks were overexpressed in HCC patients, of which two peaks were identified as N-terminal acetylated histone H4 dimethylated at lysine 20 and acetylated at lysine 16, respectively.

    Epigenetics and Nutrition

    There are plenty of indications that dietary intake has a strong influence on epigenetics 72 (Table 2). When rodents are subjected to a diet depleted of methyl donors it promotes DNA hypomethylation and the development of steatosis 73. In contrast, a high-calorie diet supplemented with methyl donors prevented NAFLD suggesting that epigenetic modifications which affected hepatic fat metabolism were related to DNA methylation changes.

    Another example is the potential link of nutrition to histone modifications and alcohol-induced liver disease (ALD) 74. Particularly, critical metabolites such as acetate, S-adenosylmethionine (SAM), nicotinamide adenine dinucleotide, and zinc are relevant to alcohol metabolism and ALD. Furthermore, high SAM levels are boosted by a folic acid rich diet, which has been showed to reduce pathology in a mouse model for amyloid pathology 75. Similarly, vitamin deficiency was observed in mice suffering from memory impairment 76. For instance, vitamins and minerals play an important role in miRNA modulation and the potential of viable exogenous miRNAs entering human blood circulation from food sources has added a new dimension to the impact of nutrition on miRNAs and its effect on health 77. Related to breast cancer, selenium has proven promising as an anti-breast cancer trace element affecting DNA methylation and histone modifications 78. Treatment of MCF-7 human breast carcinoma cells with methylselenic acid or selenite resulted in a dose-dependent inhibition of cell proliferation.

    Table 2. Epigenetics and Nutrition.
    Nutritional Source Epigenetic function Disease/Effect Reference
    Polyphenols      
    Polyphenols miR-103/107, 122 Fatty liver disease 116
    Caffeic acid, hesperidin miR-30c, 291, 296, 374, 476b miRNA modulation ApoE mice 117
    Proanthocaynidines miR-30b, 197, 523-3p, 1224-3p Human HepG2 cells 118
    High-fat diet      
    HFD (60% kcal fat) miR-21, 142, 146 Obesity/miRNA modulations 119
    HFD (58% kcal fat) 20 miRNAs Diabetes/miRNA modulations 120
    HFD miR-467b NAFLD/miR-467b down-regulation 121
    Trace elements      
    Methyl-depleted diet DNA methylation Hypomethylation, steatosis 73
    Selenium DNA methylation Anti-breast cancer activity 78
    Selenium histone modifications Anti-breast cancer activity 78
    Vitamins      
    Folic acid histone modifications Reduced amyloid pathology 75
    Vitamins DNA methylation Memory impairment 76
    Vitamins, minerals miRNAs miRNA modulation 77
    Food intake      
    Milk miRNAs packaged in exosomes Regulation of IgA immune network 86
    Milk/human PNBC miR-29b Transcription factor expression 86
    Milk/C57BL/6J miR-29b Decrease in miR-29b concentration 86
    Tobacco      
    Tobacco smoke DNA methylation Biomarkers 87
    Plants      
    Solanaceous plants 2239 miRNAs identified Link to transcription, metabolism 88
    Carcinogens      
    2-AAF miR-34, 200a/200b DNA damage, oxidative stress 122
    DEHP miR-429 miRNA induction 122
    MP miR-429 miRNA induction 122
    Chemoprevention      
    Fish oil miR-16, 19b, 21, 26b miRNA modulations 123
    Pectin miR-27, 93, 203 miRNA modulations 123

    2-AAF, 2-acetylamino fluorine; DEHP, diethylhexalphthalate; HFD, High-fat diet; MP, metapyrilene; NAFLD, non-alcoholic fatty liver disease; PNBC, peripheral nuclear blood cells;

    Recently, the understanding of the relationship between epigenetics, ageing and nutrition has been enlightened by a number of new findings. Emerging evidence suggests that long term changes in DNA methylation during early life, especially related to nutrition, can cause altered susceptibility to a variety of diseases associated with ageing 79. One aspect of early life nutrition is breast feeding, which is well-known for its favorable effects in preventing acute and chronic diseases 80 and association with better neuronal-behavioral development 81. Epigenetic effects of human breast milk might occur and several components of breast milk have been linked to epigenetic changes. In this case, lactoferrin has been associated with reduced NF-κB expression contributing to the prevention of disorders of the immune system 82. Likewise, prostaglandin J enhances peroxisome proliferator-activated receptor gamma (PPARɣ) expression and has been associated with obesity prevention 83. However, additional studies have to be conducted to further determine the link between human breast milk and epigenetic functions. Furthermore, intra-uterine development has been showed to influence health outcome in adult life and epigenetic regulation has been implied 84. In this context, the impact of prenatal drug and substance exposure on childhood development has received plenty of attention, but even life-long health outcome due to epigenetic memory has generated interest.

    In the context of epigenetics and breast milk, miRNAs packaged in exosomes in porcine milk have been suggested to influence development in piglets 85. Isolation of exosomes from porcine milk identified 176 known miRNAs and 315 novel mature miRNAs. Genome pathway analysis indicated that some miRNAs targeted genes enriched in transcription, immunity and metabolism and may be involved in the regulation of the IgA immune network. Moreover, a number of miRNAs encapsulated in exosomes have been isolated from bovine milk 86. As the majority of bovine miRNA sequences are complementary to human transcript genes, there is a possibility that bovine milk miRNAs might regulate human gene expression. Analysis of peripheral blood mononuclear cells in milk drinkers demonstrated that the expression of runt-related transcription factor 2 (RUNX2), a known target for miR-29b, increased 31%. Addition of milk exosomes to mimic postprandial concentrations of miR-29b and miR-200c decreased reporter gene expression by 44% and 17%, respectively in human embryonic kidney 293 cells. Likewise, C57BL/6J mice fed on a milk miRNA-depleted diet for four weeks showed a 61% decrease in miR-29b concentration. In contrast, broccoli sprout feeding elicited no increase in specific miRNA activity. Although additional studies are required, it can be postulated that miRNAs in milk can act as bioactive food compounds in the regulation of human genes.

    Exposure to tobacco smoke was analyzed for the identification of short- and long-term DNA methylation in two cohort studies 87. Based on genome-wide DNA methylation profiles it was possible to establish biomarkers for short-term and lifelong tobacco smoke exposure.

    Genome-wide analysis of solanaceous plants (potato, tomato, tobacco, eggplant, pepper and petunia) identified 2239 miRNAs 88. Bioinformatics suggested that miRNAs were linked to 620 targets, which were classified as transcription factors, metabolic enzymes, and RNA and protein processing enzymes involved in plant growth and development. Furthermore, the recent discovery of oral intake of plant miRNAs through food consumption and its direct influence of gene expression in mice 89 has received much attention. The question is: do we eat gene regulators 90? In support, exogenous plant miRNAs was detected in sera and tissues in animals fed on plants 91. For instance, miRNAs abundant in rice such as miR-168a has been demonstrated to bind to the human and mouse low-density lipoprotein receptor adapter protein 1 (LDLRAP1) mRNA. As decreased LDL removal from the plasma corresponds to inhibition of LDLRAP1 expression, exogenous food-derived plant miRNAs might potentially regulate gene expression in mammals. However, recently another study suggested that although substantial amounts of miRNAs in the diet are commonly consumed orally by humans, mice and honey bees, healthy athletes did not show detectable miR-156a, miR-159a and miR-169a levels in the plasma 92. Likewise, when mice received a diet with animal fat rich in endogenous miR-21 only negligible miR-21 was observed in the plasma and organ tissue. Furthermore, plant miRNAs subjected to oral pollen uptake showed hardly any presence in honeybees. Horizontal delivery of miRNA through food intake therefore seems to be rather infrequent.

    Interestingly, in a recent study the expression levels of a panel of seven human miRNAs were analyzed in plasma and stool samples of individuals with different dietary habits (vegans, vegetarians and omnivores) 93. Clearly, miR-92 was differentially expressed in both plasma and stool samples of individuals with different diet intake indicating miRNA modulation by nutrition.

    Psychosocial Aspect of Nutrition and Disease Prevention

    The impact of nutrition on health in general and the effect of changes in nutrition and life-style on disease development have already been described above. Furthermore, it is important to address the psychosocial factors related to nutrition and their impact on health and disease prevention. In case of weight loss success, women with morbid obesity were subjected to cognitive-behavioral methods including education of exercise and healthy eating practices 94. The study results suggested that the treatment-induced psychosocial changes might be advantageous for more successful behavioral weight-loss management. Moreover, the global concern of the dramatic increase in childhood obesity has been demonstrated to be affected by psychosocial factors such as psychological, environmental and sociocultural factors, which might include above-average food intake of low nutritional quality 95. In another study in adults with severe obesity the temporal aspects of psychosocial predictors were assessed on increased fruit and vegetable intake 96. Significant improvement in self-regulation, mood, self-efficacy, fruit and vegetable intake, and physical activity were observed after 6 months in individuals receiving behavioral support in education for physical activity and nutrition intake. Furthermore, changes to increase fruit and vegetable intake in relation to psychosocial factors were investigated in a Malaysian study, which suggested that intervention strategies should emphasize on increasing perceived benefits and establishing self-efficacy 97. This can be achieved through better knowledge and skills of consuming a diet rich in fruits and vegetables as the mean of promoting healthy living.

    The behavior to reduce the risk of obesity risk in relation to psychosocial factors was recently investigated in US- and foreign-born Chinese Americans 98. The main reasons for the prevention of adopting obesity risk-reducing behavior related to the convenience of consuming fast food meals, cost, lack of time to prepare home-cooked meals, and the physical environment of unhealthy food. The “Western-identified” individuals showed a significant attitude to promote obesity risk-reduction behavior, whereas “Asian-identified” persons expressed a perceived behavioral control, self-efficacy and the observed benefits were important. Moreover, the effect of nutrition- and health-related psychosocial factors and the association to diet, exercise and weight status was studied in 4356 adults in the US 99. The results indicated small ethnic differences, but the socioeconomic status differences were significant.

    Conclusions

    Epigenetic mechanisms have been frequently linked to a wide spectrum of disease indications and therefore provide novel and attractive means for therapeutic interventions. In this context, a number of drugs mainly based on histone deacetylase inhibitors have already been approved. The reversible nature of epigenetic functions is an additional attraction for drug development. Furthermore, epigenetics have proven fruitful for the generation of diagnostic biomarkers. In this context, DNA methylation and histone modifications have served as biomarker targets, but especially a number of miRNAs can provide valuable prognostic information.

    The influence of nutrition on epigenetic mechanisms has received much attention lately. Food intake has been linked to changes in DNA methylation and histone modifications. Moreover, the presence of miRNAs in the diet has been suggested to affect gene regulation. In this context, miRNAs are encapsulated in exosomes in milk, which have been demonstrated to increase transcription factor expression in peripheral mononuclear blood cells. Recently, some evidence suggests that food-derived plant miRNAs might regulate gene expression in mammals. However, contradictory results indicated that oral uptake of plant miRNAs was hardly detectable in the plasma of mice and men.

    In conclusion, epigenetics presents a novel approach for modern drug development and even more importantly the influence by dietary interventions on epigenetic mechanisms further strengthens the importance of nutrition on health and disease risk, and particularly holds a key role in preventive medicine and improved health for the humankind at a reduced cost in comparison to long-term drug-based treatment of chronic disease.

    References

    1.. www.nestleinstitutehealthsciences.com
    2.C S Pareek, Smoczynski R, Tretyn A. (2011) Sequencing technologies and genome sequencing. , J. Appl. Genet 52, 413-35.
    3.Capozzi F, Bordoni A. (2013) Foodomics: a new comprehensive approach to food and nutrition. , Genes Nutr 8, 1-4.
    4.Lundstrom K. (2013) Past, present and future of nutrigenomics and its influence on drug development. , Curr. Drug Dev. Technol 10, 35-46.
    5.L J Su, Mahabir S, G L Ellison, L A McGuinn, B C Reid. (2012) Epigenetic contributions to the relationship between cancer and dietary intake of nutrients, bioactive food components and environmental toxicants. , Front. Genet 2, 1-11.
    6.Fang M, Chen D, C S Yang. (2007) Dietary polyphenols may affect DNA methylation. , J. Nutr 137, 223-28.
    7.T L Boehm, Drahovsky D. (1983) Alteration of enzymatic methylation of DNA cytosines by chemical carcinogens; a mechanism involved in the initiation of carcinogenesis. , J. Natl. Cancer Inst 71, 429-33.
    8.J F Costello, Plass C. (2001) Methylation matters. , J. Med. Genet 38, 285-303.
    9.P A Jones, S B Baylin. (2007) The epigenomics of cancer. , Cell 128, 683-92.
    10.Baccarelli A, Bollati V. (2009) Epigenetics and environmental chemicals. , Curr. Opin. Pediatr 21, 243-51.
    11.Bollati V, Baccarelli A. (2010) Environmental epigenetics. , Heredity 105, 105-12.
    12.Lundstrom K. (2011) MicroRNA in disease and gene therapy. , Curr. Drug Discov. Technol 8, 76-86.
    13.J C Mathers, Strathdee G, C L Relton. (2010) Induction of epigenetic alterations by dietary and other environmental factors. , Adv. Genet 71, 3-39.
    14.S P Barros, Offenbacher S. (2009) Epigenetics: connecting environment and genotype to phenotype and disease. , J. Dent. Res 88, 400-8.
    15.Esquela-Kerscher A, F J Slack. (2006) Oncomirs – microRNAs with a role in cancer. , Nat. Rev. Cancer 6, 259-69.
    16.A P Feinberg. (2014) Epigenetic stochasticity, nuclear structure and cancer: the implications. doi: 10.1111/joim.12224. [Epub ahead of print] , J. Intern. Med
    17.Banno K, Yanokura M, Iida M, Masuda K, Aoki D. (2014) Carcinogenic mechanisms of endometrial cancer: involvement of genetics and epigenetics. , J. Obstet. Gynaecol. Res 40, 1957-67.
    18.Wang F, Yang Y, Fu Z, Xu N, Chen F. (2014) Differential DNA methylation status between breast carcinomatous and normal tissues. , Biomed. Pharmacother 68, 699-707.
    19.Brocks D, Assenov Y, Minner S, Bogatyrova O, Simon R. (2014) Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. , Cell Rep 8, 798-806.
    20.Benard A, E C Zeestraten, I J Goossens-Beumer, Putter H, Velde C J van de. (2014) DNA methylation of apoptosis genes in rectal cancer predicts patient survival and tumor recurrence. , Apoptosis 19, 1581-93.
    21.Reyngold M, Turcan S, Giri D, Kannan K, L A Walsh. (2014) Remodeling of the methylation landscape in breast cancer metastasis. PLoS One 9. 103896.
    22.Karczmarski J, Rubel T, Paziewska A, Mikula M, Bujko M. (2014) Histone H3 lysine 27 acetylation is altered in colon cancer.doi:. 10-1186.
    23.D J Marsh, J S Shah, A J Cole. (2014) Histones and their modifications in ovarian cancer - drivers of disease and therapeutic targets. Front. Oncol.2014Jun12; 4: 144.eCollection 2014.doi:. 10-3389.
    24.L T Wang, J P Liou, Y H Li, Y M Liu, S L Pan. (2014) A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCδ and E-cadherin. , Oncotarget 5, 5651-62.
    25.Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T. (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. , Nat. Med.17 211-5.
    26.Huang S, Guo W, Tang Y, Ren D, Zou X. (2012) miR-143 and miR-145 inhibit stem cell characteristics of PC-3 prostate cancer cells. , Oncol. Rep 28, 1831-7.
    27.Kong D, Li Y, Wang Z, Banerjee S, Ahmad A. (2009) miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. , Stem Cells 27, 1712-21.
    28.Y L Weng, An R, Shin J, Song H, G L Ming. (2013) DNA modifications and neurological disorders. , Neurotherapeutics 10, 556-67.
    29.Z M Machnes, T C Huang, P K Chang, Gill R, Reist N. (2013) DNA methylation mediates persistent epileptiform activity in vitro and in vivo. , PLoS One 8, 76299.
    30.Barrachina M, Ferrer I. (2009) DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain. , J. Neuropathol. Exp. Neurol 68, 880-91.
    31.Masliah E, Dumaop W, Galasko D, Desplats P. (2013) Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes. , Epigenetics 8, 1030-8.
    32.I F Harrison, D T. (2013) Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?. , Pharmacol. Ther 140, 34-52.
    33.Lee J, Y J Hwang, Kim K, N W Kowall, Ryu H. (2013) Epigenetic mechanisms of neurodegeneration in Huntington's disease. , Neurotherapeutics 10, 664-76.
    34.Luo M, Xu Y, Cai R, Tang Y, Ge M M. (2014) Epigenetic histone modification regulates developmental lead exposure induced hyperactivity in rats. , Toxicol. Lett 225, 78-85.
    35.S, Horré K, Nicolaï L, A S Papadopoulou, Mandemakers W. (2008) Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. , Proc. Natl. Acad. Sci. USA 205, 6415-20.
    36.Bettens K, Brouwers N, Engelborghs S, H Van Miegroet, Deyn P P De. (2009) APP and BACE1 miRNA genetic variability has no major role in risk for Alzheimer disease. , Hum. Mutat 30, 1207-13.
    37.W X, B W Rajeev, A J Stromberg, Ren N, Tang G. (2008) The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. , J. Neurosci 28, 1213-25.
    38.Boissonneault V, Plante I, Rivest S, Provost P. (2009) MicroRNA-298 and microRNA-328 regulate expression of mouse beta-amyloid precursor protein-converting enzyme 1. , J. Biol. Chem 284, 1971-81.
    39.W C Mah, Thurnherr T, P K Chow, A Y Chung, Ooi L L. (2014) Methylation profiles reveal distinct subgroup of hepatocellular carcinoma patients with poor prognosis. , PLoS One 9, 104158.
    40.Zekri Ael-R, A, N El-Din El-Rouby M, H I Shousha, A B Barakat. (2013) Disease progression from chronic hepatitis C to cirrhosis and hepatocellular carcinoma is associated with increasing DNA promoter methylation. Asian Pac. , J. Cancer Pres 14, 6721-6.
    41.Gao S, X F Ji, Li F, F K Sun, Zhao J. (2015) Aberrant DNA methylation of G-protein-coupled bile acid receptor Gpbar1 predicts prognosis of acute-on-chronic hepatitis B liver failure. , J. Viral. Hepat 22, 110-7.
    42.Zeybel M, D A Mann, Mann J. (2013) Epigenetic modifications as new targets for liver disease therapies. , J. Hepatol 59, 1349-53.
    43.Mandrekar P. (2011) Epigenetic regulation in alcoholic liver disease.World. , J. Gastroenterol 17, 2456-64.
    44.Zhang C, Li H, Wang Y, Liu W, Zhang Q. (2010) Epigenetic inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involves both DNA methylation and histone modifications. , J. Hepatol 53, 889-95.
    45.S L Chen, M H Zheng, K Q Shi, Yang T, Y P Chen. (2013) A new strategy for treatment of liver fibrosis: letting MicroRNAs do the job. , BioDrugs 27, 25-34.
    46.Yu-Yuan L. (2012) Genetic and epigenetic variants influencing the development of nonalcoholic fatty liver disease. , World J. Gastroenterol 18, 6546-51.
    47.Esau C, Davis S, S F Murray, YuXX Pandey S K. (2006) miR-122 regulation of lipid metabolism revealed by in vitro antisense targeting. , Cell Metab 3, 87-98.
    48.R M Trowbridge, M R Pittelkow. (2014) Epigenetics in the pathogenesis and pathophysiology of psoriasis vulgaris. , J. Drugs Dermatol 13, 111-8.
    49.M B Løvendorf, J R Zibert, Gyldenløve M, M A Røpke, Skov L. (2014) MicroRNA-223 and miR-143 are important systemic biomarkers for disease activity in psoriasis. , J. Dermatol. Sci 75, 133-9.
    50.J A Martínez, F I Milagro, K J Claycombe, K L Schalinske. (2014) Epigenetics in adipose tissue, obesity, weight loss, and diabetes. , Adv. Nutr 5, 71-81.
    51.Z J Ge, C L Zhang, Schatten H, Q Y Sun. (2014) Maternal diabetes mellitus and the origin of non-communicable diseases in offspring: the role of epigenetics. , Biol. Reprod 90, 139.
    52.B C Meier, B K Wagner. (2014) Inhibition of HDAC3 as a strategy for developing novel diabetes therapeutics. , Epigenomics 6, 209-14.
    53.A M Gómez-Uriz, Goyenechea E, Campión J, deArce A, Martinez M T. (2014) Epigenetic patterns of two gene promoters (TNF-α and PON) in stroke considering obesity condition and dietary intake. , J. Physiol. Biochem 70, 603-14.
    54.Qu Z, Li W, Fu B. (2014) MicroRNAs in autoimmune diseases. , BioMed. Res. International2014 1-8.
    55.Nakamachi Y, Kawano S, Takenokuchi M, Nishimura K, Sakai Y. (2009) MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. , Arthritis and Rheumatism 60, 1294-304.
    56.K M Pauley, Satoh M, A L Chan, M R Bubb, W H Reeves. (2008) Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. , Arthritis Research and Therapy 10, 101.
    57.Lindberg R L P, Hoffmann F, Kuhle J, Kappos L. (2010) Circulating microRNAs as indicators for disease course of multiple sclerosis. , Multiple Sclerosis 16, 41-196.
    58.Mummaneni P, Shord S S. (2014) Epigenetics and oncology. , Pharmacotherapy 34, 495-505.
    59.E H. (2013) Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia. , Leukemia 27, 1803-12.
    60.Iwamoto M, E J Friedman, Sandhu P, N G Agrawal, E H Rubin. (2013) Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor. , Cancer Chemother. Pharmacol 72, 493-508.
    61.H M Prince, Dickinson M, Khol A. (2013) Romidepsin for cutaneous T-cell lymphoma. , Future Oncol 9, 1819-27.
    62.Fisher A. (2014) Epigenetic memory: the Lamarckian brain. , Embo J 33, 945-67.
    63.Fischer A, Sananbenesi F, P T, Lu B, L H Tsai. (2005) Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. , Neuron 48, 825-38.
    64.D A Mann. (2014) Epigenetics in liver disease. , Hepatology 60, 1418-25.
    65.Mann J, D C Chu, Maxwell A, Oakley F, N L Zhu. (2010) MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. , Gastroenterology 138, 705-14.
    66.Woodcock J. (2010) Assessing the clinical utility of diagnostics used in drug therapy. , Clin. Pharmacol. Ther 88, 765-73.
    67.Nicolaides N C, D J O’Shanessy, Albone E, Grasso L. (2014) Co-development of diagnostics vectors to support targeted therapies and theranostics: essential tools in personalized cancer therapy. , Front. Oncol 4, 1-14.
    68.Groot J S de, Pan X, Meeldijk J, Wall E van der, Diest P J van. (2014) Validation of DNA promoter hypermethylation biomarkers in breast cancer-a short report. , Cell Oncol 37, 297-303.
    69.W C Mah, Thurnherr T, P K Chow, A Y Chung, L. (2014) Methylation profiles reveal distinct subgroup of hepatocellular carcinoma patients with poor prognosis. PLoS One 9. 104158.
    70.S Y Hung, Lin H H, K T Yeh, J G Chang. (2014) Histone-modifying genes as biomarkers in hepatocellular carcinoma. , Int. J. Clin. Exp. Pathol 7, 2496-507.
    71.Poté N, Alexandrov T, J Le Faouder, Laouirem S, Léger T. (2013) Imaging mass spectrometry reveals modified forms of histone H4 as new biomarkers of microvascular invasion in hepatocellular carcinomas. , Hepatology 58, 983-94.
    72.Lundstrom K. (2012) Micro-RNA and Diet in Disease Prevention and Treatment. , J. Med. Res. Sci 2, 11-18.
    73.I P Pogrigbny, V P Tryndyak, T V Bagnyukova, Melnyk S, Montgomery B. (2009) Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyldeficient diet. , J. Hepatol; 51, 176-86.
    74.Moghe A, Joshi-Barve S, Ghare S, Gobejishvili L, Kirpich I. (2011) Histone modifications and alcohol-induced liver disease: are altered nutrients the missing link?. , World J. Gastroenterol 17, 2465-72.
    75.T F Chen, R F Huang, S E Lin, J F Lu, M C Tang. (2010) Folic Acid potentiates the effect of memantine on spatial learning and neuronal protection in an Alzheimer's disease transgenic model. , J. Alzheimers Dis 20, 607-15.
    76.Fuso A, Nicolia V, Ricceri L, R A Cavallaro, Isopi E. (2012) S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice. , Neurobiol. Aging 33, 1-16.
    77.E L Beckett, Yates Z, Veysey M, Duesing K, Lucock M. (2014) The role of vitamins and minerals in modulating the expression of microRNA. , Nutr. Res. Rev 27, 94-106.
    78.Miranda J X de, F D Andrade, A D Conti, Dagli M L, F S Moreno. (2014) Effects of selenium compounds on proliferation and epigenetic marks of breast cancer cells. pii: S0946-672X(14)00122-9. J.Trace Elem.Med.Biol.2014Jul16.
    79.K A Lillycrop, S P Hoile, Grenfell L, G C Burdge. (2014) DNA methylation, ageing and the influence of early life nutrition. Proc. Nutr. Soc 73, 413-21.
    80.Verduci E, Banderali G, Barberi S, Radaelli G, Lops A. (2014) Epigenetic effects of human breast milk. , Nutrients 6, 1711-24.
    81.E L Mortensen, K F Michaelsen, Sanders S A, J M Reinisch. (2002) The association between duration of breastfeeding and adult intelligence.JAMA287. 2365-71.
    82.Minekawa R, Takeda T, Sakata M, Hayashi M, Isobe A. (2004) Human breast milk suppresses the transcriptional regulation of IL-1beta-induced NF-kappaB signaling in human intestinal cells. , Am. J. Physiol. Cell. Physiol 287, 1404-11.
    83.A M Sharma, Staels B. (2007) Review: Peroxisome proliferator-activated receptor gamma and adipose tissue--understanding obesity-related changes in regulation of lipid and glucose metabolism. , J. Clin. Endocrinol. Metab 92, 386-95.
    84.A M Vaiserman. (2013) Long-term health consequences of early-life exposure to substance abuse: an epigenetic perspective. , J. Dev. Orig. Health Dis 4, 269-79.
    85.Chen T, Q Y Xi, R S Ye, Cheng X, Qi Q E. (2014) Exploration of microRNAs in porcine milk exosomes. , BMC Genomics 15, 100.
    86.S R Baier, Nguyen C, Xie F, J R Wood, Zempleni J. (2014) MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells, HEK-293 kidney cell cultures, and mouse livers. , J. Nutr.144 1495-500.
    87.Guida F, Campanella G, Sandanger T, Lund E, Vermeulen R. (2014) 0220 Identification of short-term, long-term and lifelong DNA methylation markers of exposure to tobacco smoke: evidence from EPIC and NOWAC studies. , Occup. Environ. Med.71Suppl1,A29-30
    88.Gu M, Liu W, Meng Q, Zhang W, Chen A. (2014) Identification of microRNAs in six solanaceous plants and their potential link with phosphate and mycorrhizal signaling. , Integr. Plant Biol 56, 1164-78.
    89.Vaucherat H, Chupeau Y. (2012) Ingested plant miRNAs regulate gene expression in animals. , Cell Res 22, 3-5.
    90.Witzany G. (2012) Do we eat gene regulators?. , Comm. Integr. Biol 5, 230-2.
    91.Zhang L, Hou D, Chen X, Li D, Zhu L. (2012) Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. , Cell Res 22, 107-126.
    92.J W Snow, A E Hale, S K Isaacs, A L Baggish, S Y Chan. (2013) Ineffective delivery of diet-derived microRNAs to recipient animal organisms. , RNA Biol.10 1107-16.
    93.Tarallo S, Pardini B, Mancuso G, Rosa F, C Di Gaetano. (2014) MicroRNA expression in relation to different dietary habits: a comparison in stool and plasma samples. , Mutagenesis 29, 385-91.
    94.J, P H Johnson. (2014) Theory-based psychosocial factors that discriminate between weight-loss success and failure over 6 months in women with morbid obesity receiving behavioral treatments. Eat Weight Disord. Oct 21. [Epub ahead of print].
    95.Stein D, S L Weinberger-Litman, Latzer Y. (2014) Psychosocial perspectives and the issue of prevention in childhood obesity. , Front. Public Health 2, 104.
    96.J, N J Mareno. (2014) Temporal aspects of psychosocial predictors of increased fruit and vegetable intake in adults with severe obesity: meditation by physical activity. , Community Health 39, 454-63.
    97.Chee Yen W, Mohd Shariff Z, Kandiah M, N Mohd Taib M. (2014) Stages of change to increase fruit and vegetable intake and its relationships with fruit and vegetable intake and related psychosocial factors. , Nutr. Res. Pract 8, 297-303.
    98.Liou D, Bauer K, Bai Y. (2014) Investigating obesity risk-reduction behaviours and psychosocial factors in Chinese Americans. , Perspect Public Health 134, 321-30.
    99.Wang Y, Chen X. (2012) Between-group differences in nutrition- and health-related psychosocial factors among US adults and their associations with diet, exercise, and weight status. , J. Acad. Nutr.e3 Diet; 112, 486-498.
    100.S C Mack, Witt H, R M Piro, Gu L, Zuyderduyn S. (2014) Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. , Nature 506, 445-50.
    101.Yoda Y, Takeshima H, Niwa T, J G Kim, Ando T. (2015) Integrated analysis of cancer-related pathways affected by genetic and epigenetic alterations in gastric cancer. , Gastric Cancer 18, 65-76.
    102.Sooman L, Ekman S, Tsakonas G, Jaiswal A, Navani S. (2014) PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas. , Tumour Biol 35, 4479-88.
    103.C J Ricketts, V K Hill, W M Linehan. (2014) Tumor-specific hypermethylation of epigenetic biomarkers, including SFRP1, predicts for poorer survival in patients from the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) project. PLoS One 9:e85621.
    104.Henrici A, Montalbano R, Neureiter D, Krause M, Stiewe T. (2013) The pan-deacetylase inhibitor panobinostat suppresses the expression of oncogenic miRNAs in hepatocellular carcinoma cell lines. Mol. doi: 10.1002/mc.22122.Carcinog.2013;Dec23.[Epub ahead of print].
    105.Adhireksan Z, G E Davey, Campomanes P, Groessl M, Clavel C M.et al.(2014) Ligand substitutions between ruthenium-cymene compounds can control protein versus DNA targeting and anticancer activity. , Nat. Commun 5, 3462.
    106.Saini S, Majid S, Shahryari V, Arora S, Yamamura S. (2012) miRNA-708 control CD44(+) prostate cancer-initiating cells. , Cancer Res 72, 3618-30.
    107.Kalani A, P K Kamat, S C Tyagi, Tyagi N. (2013) Synergy of homocysteine, microRNA, and epigenetics: a novel therapeutic approach for stroke. , Mol. Neurobiol 48, 157-68.
    108.V N Parikh, R C Jin, Rabello S, Gulbahce N, White K. (2012) MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. , Circulation 125, 1520-32.
    109.Khali Abi, C. (2014) The emerging role of epigenetics in cardiovascular disease. , Ther. Adv. Chronic Dis 5, 178-87.
    110.Ikeda S, S W Kong, Lu J, Bisping E, Zhang H. (2007) Altered microRNA expression in human heart disease. , Physiol. Genomics 31, 367-73.
    111.S K Murphy, Yang H, C A Moylan, Pang H, Dellinger A. (2013) Relationship between the methylome and transcriptome in patients with non-alcoholic fatty liver disease. , Gastroenterology 145, 1076-87.
    112.Ahrens M, Ammerpohl O, W von Schonfels, Kolarova J, Bens S. (2013) DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. , Cell Metab 18, 296-302.
    113.Yu-Yuan L. (2012) Genetic and epigenetic variants influencing the development of nonalcoholic fatty liver disease. , World J. Gastroenterol 18, 6546-51.
    114.Jayaraman S. (2014) Novel methods of diabetes 1 treatment. , Discov. Med 17, 347-55.
    115.Patel T, Patel V, Sing R, Jayaraman S. (2011) Chromatin remodeling resets the immune system to protect against autoimmune diabetes in mice. , Immunol. Cell Biol 89, 640-9.
    116.Joven J, Espinel E, Rull A, Aragones G, Rodriguez-Gallego E. (2012) Plant-derived polyphenols regulate expression of miRNA paralogs miR-103/107 and miR-122 and prevent diet-induced fatty liver disease in hyperlipidemic mice. , Biochim Biophys Acta 1820, 894-9.
    117.Milenkovic D, Deval C, Gouranton E, J F Landrier, Schalbert A. (2012) Modulation of miRNA expression by dietary polyphenols in apoE deficient mice: a new mechanism of the action of polyphenols. , PLoS One 7, 29837.
    118.Arola-Arnal A, Bladé C. (2011) Proanthocyanidins modulate microRNA expression in human. HepG2 cells. PLoS One 6:e25982 .
    119.D V Chartoumpekis, Zaravinos A, P G Ziros, R P Iskrenova, A I Psyrogiannis. (2012) Differential expression of microRNAs in adipose tissue after long-term high-fat diet-induced obesity in mice. , PLoS One 7, 34872.
    120.G Q Chen, W J Lian, G M Wang, Wang S, Yang Y Q. (2012) Altered microRNA expression in skeletal muscle results from high-fat diet-induced insulin resistance in mice. , Mol. Med. Rep 5, 1362-8.
    121.Ahn J, Lee H, Chung C H, Ha T. (2011) High fat diet induced downregulation of microRNA-467b increased lipoprotein lipase in hepatic steatosis. , Biochem. Biophys. Res. Commun 414, 664-69.
    122.Koufaris C, Wright J, Currie R A, N J Gooderham. (2012) Hepatic microRNA profiles offer predictive and mechanistic insights after exposure to genotoxic and epigenetic hepatocarcinogens. , Toxicol Sci 128, 532-43.
    123.M S Shah, Schwartz S L, Zhao C, L A Davidson, Zhou B. (2011) Integrated microRNA and mRNA expression profiling in a rat colon carcinogenesis model: effect of a chemo-protective diet. , Physiol. Genomics 43, 640-54.