Hyperhomocysteinemia as risk factor for depression: A review

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1 PHARMACEUTICAL AND BIOLOGICAL EVALUATIONS October 2015; vol. 2 (Issue 5): ISSN Review Article Hyperhomocysteinemia as risk factor for depression: A review Rinki Kumari 1 *, Aruna Agrawal 2, G.P.I. Singh 3, G.P. Dubey 2 1 Department of Kriya Sharir, Faculty of Ayurveda, Institute of Medical Sciences, B.H.U., Varanasi (U.P) , India 2 Institute of Medical Sciences, Banaras Hindu University, Varanasi , India 3 Adesh University, Barnala Road, Bathinda , India *For correspondence Rinki Kumari, Department of Kriya Sharir, Faculty of Ayurveda, Institute of Medical Sciences, B.H.U., Varanasi (U.P) , India. rinkiv3@gmail.com Received: 03 October 2015 Accepted: 16 October 2015 ABSTRACT Chronic nutritional deficiencies or lack of supplements such as folate, vitamin B-6, omega-3, minerals and vitamin B-12 may disturb normal one-carbon metabolism or methionine cycle which lead to hyperhomocysteinemia. It is also associated with genetic abnormality and epigenetic alterations and also associated with DNA hypomethylation that cause the cell damage and neuronal injury in the brain through the oxidative stress. Hyperhomocysteinemia is also associated with alterations of gene expression and structural changes in the chromatin, involved in the pathogenesis of disease related to homocysteine. MTHFR C677T polymorphism pathway can act synergistically with nutritional deficiencies; increases the level of homocysteine and convert S- adenosylhomocysteine, which is bulky in cell and potent product inhibition of DNA methyltransferases. However, several studies were observed related to hyperhomocysteinemia along with lower folate, vitamin B 12 and vitamin B6 levels in the depression. It is compared to control and interventions to treat vitamin B 12, vitamin B 6 and folate deficiencies in the depressed individuals, here studies could help and improve cognitive performance and decreases the level of total homocysteine. Further, studies on the biochemical status of other micronutrients in same population will help to establish a more comprehensive intervention plan and is defensible. Keywords: Homocysteine, Depression, Renal disease, Cognitive dysfunction Introduction Homocysteine (hcy) is a sulfur containing amino acid that occupies a central location in the metabolic pathway of thiol compound and has gained prime interest among researcher from last decade. 1 This important of research on hcy is primarily because of the strong cumulative finding suggesting hyperhomocysteinemia (HHcy) as risk factors for vascular disease including stroke and several other diseases, independent of long recognized factor such as hypertension, hyperlipidemia, migraines, osteoporosis, and diabetes mellitus. In addition, elevated levels of homocysteine have been linked to increased risk of disease development and death from common conditions. 2 Raised levels of homocysteine are also linked to Alzheimer s, dementia, declining memory, poor concentration and deprived mood. 3 It is also 133

2 reported that hyperhomocysteinemia in female results in repeated early miscarriage. 1 Therefore, hyperhomocysteinemia has been shown to play a crucial role for disease development determining longevity and health throughout a person s life and seen as a predictor of potential health problems such as cardiovascular disease, neuropsychiatric and neurodegenerative disorders. 4 Hcy is produced in the human body by the chemical conversion of methionine (an essential amino acid), found in fish and green vegetables, it is directly toxic to neurons and blood vessels and can induce DNA strand breakage, oxidative stress, and apoptosis therefore, methionine is taken into the bloodstream and into cells where it is transformed in hcy by removal of methyl group. 5 More methionine contain supplement adds a different methyl group it produces, S- adenosyl methionine (SAMe), which is a useful natural antidepressant, fights against arthritis and is excellent at lowering homocysteine levels. Several studies have reported the SAMe - the best anti-ageing agent. As levels of SAMe increase, another vital chemical is produced from homocysteine called glutathione. SAMe act as an excellent anti-ageing agent and a detoxifier. A low glutathione level has been linked to an increased risk of death from all common causes. 6 However, the key to a long healthy life keep the homocysteine level down and the glutathione level up. In this study we reviewed the interaction between genetic and environmental factors associated with elevate homocysteine levels, causes the changes in neurotransmitters in the brain and cause depression. History of homocysteine In 1932, Butz and du Vigneaud was described about homocysteine but association with to human disease was not suggested until Firstly, elevated homocysteine level in the urine of mental retardation children discovered by Carson and Neil discovered and caused by enzyme defects that blocked the metabolism of homocysteine and this raised the condition is known as homocystinuria. 7 Several studies have also found an association between high homocysteine, impaired cognitive performance and dementia development and progression. The linkage between elevated homocysteine levels and the risk of atherosclerosis and involved in the stimulation of smooth muscle growth, reduce endothelial cell growth, impaired endothelial cell relaxation, decreased synthesis of highdensity lipoprotein, promotion of autoimmune response, and accumulation of inflammatory monocytes in atherosclerotic plaques. It is also associated with premature cardiovascular disease and this symptoms also affect childhood, resulting in approximately 25% patients dying before the age of 30 from cardiovascular actions. 8 During the last 15 years it has been thoroughly documented that even moderately elevated homocysteine levels are a strong risk factors for cardiovascular diseases. 9,10 Homocysteine metabolism Hcy (C4H9NO2S) is a naturally occurring amino acid produced as part of the methylation process and is a derivative of protein that is found in blood plasma. It is a homologue of the amino acid cysteine, differs by an additional methylene (-CH2-) group. Hcy is not obtained from the diet only, is biosynthesized from methionine via a multi-step process that probably occurs in every cell of the body. 6 Hcy is a thiol containing amino acid which is formed by demethylation of methionine and metabolized in two pathways- remethylation and trans sulfuration are responsible for regulating the level of hcy. In the remethylation pathway, hcy is converted back to methionine in the presence methionine synthase (MS) and this enzyme requires vitamin B12 as a cofactor and N- methyltetrahydrofolate as the methyl donor. 5 Methionine cycle Sulfur-containing amino acid methionine, has a methyl ( CH3) (Figure 1) group attached to its sulfur and the precursor of the sulfur-containing amino acids homocysteine, cysteine, and taurine. These are used for adding methyl groups to numerous biomolecules, but only after methionine has been activated. 11 In short, methionine is converted to S Adenosyl Methionine (SAMe), which is a methyl donor 134

3 for numerous biological reactions and in losing its methyl group, SAMe becomes S Adenosyl Homocysteine (SAH), which is then converted to homocysteine. It is either converted back to methionine, or it enters the transsulfuration pathway to form other sulfur-containing amino acids. Hcy can irreversibly enter the transsulfuration pathway (catalyzed by vitamin B6) to produce the cysteine in liver cells and more than 55% of homocysteine is metabolized by transsulfuration in the liver, with glucocorticoids increasing that percentage. Transsulfuration process requires vitamins B6 and B12. 9,10,12 Figure 1: Chemical structure of methionine. In methionine cycle (Figure 2), methyl group of methionine becomes activated by ATP (adenosine triphosphate) with the addition of adenosine to the sulfur of methionine and form S Adenosyl Methionine (SAMe) whereas removal of the methyl group from SAMe results in the formation of S Adenosyl Homocysteine (SAH). During this process, when adenosine molecule removed, SAH convert it into Hcy. 13 In another word, methionine activate S- adenosylmethionine (SAM) by the enzyme methionine adenosyltransferase and usually, hcy level in the blood are low due to its rapid metabolism via one of two pathways: a cobalamin (vitamin B12) and folate dependent remethylation pathway that regenerates methionine, or a pyridoxal 5 phosphate (PLP, vitamin B6) dependent transsulphuration pathway that converts homocysteine into cysteine. In addition, cysteine can be incorporated into proteins and form the antioxidant molecule glutathione (GSH), or oxidized to form the amino acid taurine. However, the complex metabolism of homocysteine within the body is highly dependent on vitamin (cofactor) and essential nutrient. Thus far, this non-protein sulfur-containing amino acid is formed by demethylation of methionine, and act as precursor of S-adenosylmethionine (AdoMet), the primary methyl group donor for biological methylation, including DNA repair, DNA methylation and after demethylation, AdoMet is transformed to S-adenosylhomocysteine Pharmaceutical Figure and Biological 2: Methionine Evaluations cycle. 135

4 (AdoHcy), a potent inhibitor of many AdoMetdependent methyltransferases. 14 Hyperhomocysteinemia Several studies have declared that deficiencies in folate, vitamin B12 and vitamin B6 are associated with hyperhomocysteinemia and accumulation of hcy in the body causing cell damage and potential ill health can result. Higher level of hcy is associated with damage, the arteries are involved in the generations of free radicals which causes cell damage through oxidative stress and prompts many diseases including neurodegenerative, depression, anxiety, heart disease, strokes, cancers and autoimmune diseases and affect the reproductive organs. 3,4,9,10,14,15 In oxidative reaction, free radicals may oxidize low-density lipoproteins producing oxycholesterols and oxidized fats and proteins. This oxidative product associated with developing arterial plaque. In the oxidative reaction, nitric oxide converted in to another an important regulator and mediator, decreased methylation and impaired DNA repair. Disturbed folate carcinogenesis, mess up the immune system, nervous and cardiovascular systems. 16 An epidemiological study suggests that a high level of hcy positively correlates to depressive symptoms and the accumulation of hcy has been implicated in the pathogenesis of depression. Recently some studies have shown hcy is directly involved and acts as primary cause of depressive symptoms is unclear. Risk factor of HHcy A large number of studies had conducted for the identification of the factors (Figure 3) such as deprived diet, lifestyle-smoking and high coffee and alcohol intake, some prescription and corticosteroids drugs, diabetes, genetic make-up, lack of enzymatic activity and rheumatoid arthritis and poor thyroid function, oestrogen deficiency, obesity and lack of exercise and stress, causes the hyperhomocysteinemia. 7,11,13,17 Studies has observed that mutation in MTHFR enzyme, deficiencies in vitamin B and renal dysfunction elevated the moderate level of hcy ( µmol/l) and intermediary Hhcy (> µmol/) are caused by heterozygous mutations of Figure 3: Various factor associated with HHcy. metabolism are suggested to contribute to enzymes (e.g. CBS), severe vitamin deficiencies, 136

5 renal dysfunction whereas several Hhcy (> 100 µmol/l) is due to homozygous mutations of enzymes (CBS and MS). 16 Epigenetic, homocysteine and depression The complex interaction between gene and environmental factors are called epigenetic and are involved in development of different organisms and the pathogenesis of different disorders. It is linked to DNA methylation and histone modification along with alter DNA accessibility and chromatin structure, this means regulating patterns of gene expression and significantly important to normal development and differentiation of distinct cell lineages in the organism and are involved in the regulation of pluripotency genes, which become inactivated during differentiation. 19 Thus, epigenetics are crucial programme of the cell differentiation and development. Numerous studies have shown that some exogenous component (environmental element, nutrient or biochemical component) when interact with genetic material lead to significant modification in the epigenetic programme, cause genetic polymorphism and lead to pathogenesis of different disorder such as atherosclerosis, hypertension, neuropsychiatric, neurodegenerative disorder, metabolic syndrome, and diabetes. 1,16,20 The studies have shown epigenetic alteration and genetic polymorphism associated with disease and directly correlated with methylation status. Although, environmental factors interact with genomic DNA during crucial periods of early life, can influence risks for cardiovascular, mental and metabolic diseases later in life. Additional, genetic deviations also affects the numerous component of folate metabolism as well as methionine cycle such as Hcy, methionine, cysteine and glutathione and the different enzymes, diet and DNA methylation. These variations lead to evaluate the concentration of Hcy in plasma, it is a sensitive indicator of vitamin B and folic acid deficiency, and for a pathogenic process as well as a of pathology. An animal experiment study has declared that epigenetic modification is also influenced the different behavioural patterns during early postnatal life. Consequently, it has been suggested that these unceasing changes on or after epigenetically mediated alterations in gene expression, occur very early in life. 13 However, long lasting deficiencies in the nutrients folate, vitamin B-6, vitamin B-12 and methionine can independently and interactively interrupt customary metabolic cycle and augment Hcy and excess free intracellular Hcy is damage cell. Some studies have declared Hcy is produced by the hydrolysis of S-adenosylhomocysteine (SAH) by the enzyme SAH hydrolase (SAHH) and only this reaction is voluntarily reversible, except this enzyme, three other enzyme are also involved in the metabolism of Hcy-Methionine synthase MS(5-methyltetrahydrofolatehomocysteine S-methyltransferase) and betainehomocysteine methyltransferases (BHMT) and cystathionine-synthase (CBS). Studies suggests that MS and BHMT are unidirectional and remethylated Hcy to methionine whereas CBS is one way reaction and conduct, the everlasting removal of Hcy from the methionine cycle. 4,9,16,19,21 The most common genetic abnormality exists in the homocysteine metabolism is a substitution mutation at nucleotide 677 (C677T) in the gene encoding for the enzyme 5,10- methylenetetrahydrofolate reductase (MTHFR) and the mutation is associated with about 70% reduction in the activity of the enzyme. MTHFR, irreversibly reduces 5,10-methylene-THF to 5- methyl-thf and around 5-15% of the population in central Europe and 9-17 % in Western countries are homozygous (TT) whereas 30-41% was heterozygous (CT), carriers of a thermolabile variant with point mutation in the nucleotide at position 677 (MTHFR 677C-T). The study was reported that about 20% higher risk for degenerative vascular disorders for the homozygous genotype and it may increase with more deficiency of folic acid and vitamin B12 and vitamin B6. 14,15,20,22 Another enzyme cystathionine-b-synthase (CBS), in this homozygous genotype is rare and causes homocystinuria (excess Hcy in urine) along with severe deficiency of CBS activity while about 1% of the population has mutations 137

6 in the gene is heterozygous form, leading to moderate elevation of Hcy, is present in 1 in 300 individuals. These mutation have been cases of delayed mental development and neurological dysfunction in infancy whereas some other manifestations become expressed such as, lens dislocations, thromboembolism diseases, CVD, and osteoporosis in adult or older age. 13 Approximately, 80% people who were suffering for homozygous homocystinuria do usually not survive their third decade. Acquired causes of hyperhomocysteinemia include deficiencies of the cofactors (vitamins B12, B6 and folate), increasing age, and diseases such as renal failure and hypothyroidism, medications that interfere with the metabolism of vitamin B12, B6 or folate, and lifestyle factors such as cigarette smoking, alcoholism, diet and physical inactivity. 4 Recently, some report have shown that Hcy is biochemically linked to epigenetic programme and are found in DNA. As above have been described the high levels of Hcy are an associated with vascular disease and used folate or other vitamin B reduced level of Hcy, decline the risk of cardiovascular disease. Although, Hcy plays a crucial role in one carbon metabolism cycle or methyl-donor biosynthesis and the CH3 group involved in DNA methylation originates from AdoMet (act as CH3 donor for different cellular methyltransferase reactions, including histone methylation), an intermediate product in Hcy metabolism whereas Hcy metabolism are distribute, don t formed AdoMet the in mammalian tissues and accumulate Hcy in the cell. Raised Hcy is potentially inhibiting transmethylation reactions. Thus, elevated Hcy may be considered as inclusive DNA hypomethylation effector via AdoHcy accumulation. A large number of studies support the concept that DNA hypomethylation due to hyperhomocysteinemia and AdoHcy, in modulating epigenetic mechanisms may be responsible in part for vascular complications and associated with endothelial dysfunction and aberrant DNA methylation. Specially, DNA hypomethylation affected the expression of genes (MTHFR and CBS) but allelic gene expressions were normalized after Hcy levels were lowered with folate intake. However, AdoHcy is a newly identified factors, able to modify DNA methylation patterns and abnormal DNA methylation is only an index of the potential for epigenetic dysregulation. It can also regulate the rate of cell proliferation and DNA replication, chromatin accessibility, nutritional factors. Other studied have also support the duration and degree of the hyperhomocysteinemic state associated with inflammation, dyslipidemias, oxidative stress, and aging. As a result, the positive correlation is present between Hcy and DNA hypomethylation but some other important aspects is to consider, DNA methylation isn t equally distributed throughout chromosomes of differentiated cells. Therefore, hypermethylated and hypomethylated regions can coexist in the genome, and overall DNA methylation status need not exist in the entire cell. Hyperhomocysteinemia and neurodegenerative or neuropsychiatric disorders Epidemiological studies have suggests that implicate Hcy in the pathophysiology of many neuropsychiatric disorders. 11 In 1999, Kluijtmans et al., reported that CBS deficiency associated with HHCY/ homocystinuria and cause several neurodegenerative diseases and patients suffer from mental retardation and severe cognitive disorders. Numerous animal studies has support that abnormal methionine metabolism (AMM) destruct brain energy metabolism, synaptic plasticity and cause neuronal cell death, and DNA damage and in human AMM are associated with atrophy of the hippocampus and the cortical cerebral regions as well as an increased risk of Alzheimer s disease and other neurodegenerative or neuropsychiatric disorders (dementia, depressive disorders, cerebral seizures, myelopathies, and polyneuropathies). In addition some studies have shown the HHcy may also act as neurotoxic effects through the induction of apoptosis in the brain and NMDA mediated excitotoxicity. 2,14,16,20 An animal experiment study have suggest that HHcy affect the hippocampal neurones to lead to activation of poly-adp-ribose polymerise (PARP) and NAD depletion and further, it cause the mitochondrial dysfunction, oxidative stress, 138

7 caspase activation and neuronal apoptosis. Homocysteine and depression Several studies have shown a large number of neuro-psychiatric population especially in those with depression are suffering from folate deficiency. 10,12,23 One of the most important nutrient factor, lack or poor nutrient causes depression and lead to folate deficiency (Figure 4), ultimately affect to methylation, which result in hyperhomocysteinemia whereas study have supported that folate replacement will improve the mental state, by methylation in the nervous system to mood and regulate the level of Hcy. 10 Hyperhomocysteinemia affected through functional deficiency of either folic acid or vitamin B12 and methionine form in the addition of methyl group from folate or vitamin B12 as a cofactor. Methionine is the immediate precursor of SAM, the methyl donor in innumerable methylation reactions in the brain. Various studies have shown the relationship between nutritional deficiencies and physical illness and changes in behavioural pattern. One of the most common behavioural disorder is Depression- as a specific feature of stroke was first described in a small case-control study and was found low level of disability in stroke patients linked to depression. Stroke or vascular disease is often associated with heart disease, and depression is a symptom and risk for heart disease. 12 Generally, depression is common in numerous countries as a bipolar disorder, schizophrenia, and obsessive-compulsive disorder (OCD) and is more concern and strictly follows the biochemical-rooted. Nutritional neuroscience is associated with human cognition, behaviour, and emotions. Nutritional deficiency can play a key role in the pathogenesis of depression as well as severity of depression. 5 Several studies have given concept that dietary intake pattern of the general population are also involved in the development of depression and may include poor appetite, skipping meals, and a dominant desire for sweet foods. These food patterns are linked to deficient in many nutrients, especially folic acid, essential vitamins, minerals, and omega-3 fatty acids. These major symptoms such as increased sadness and anxiety, loss of appetite, sadden mood, and a loss of interest in pleasurable Figure 4: Hypothesized pathogenesis of depression. 139

8 activities associated with depression. 21 Dietary supplements containing amino acids and some other essential components are converted to neurotransmitters through biochemical pathway and reduced depression symptom and alleviate depression and other mental issue(anxiety disorders, attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD), autism, and addiction). 24,25 These nutritional supplements containing phenyl alanine and tyrosine cause alertness and arousal. In the Hcy metabolism, methionine produced and combines with adenosine triphosphate (ATP) to produce S-adenosylmethionine (SAM), facilitates the synthesis of various neurotransmitters in the brain that transmit signals across a synapse from one neuron to another "target" neuron and conduct the proper neuroplasticity. 18 Some studies have suggested the relationship between depression and folic acid, vitamin B12 & B6 and its deficiency elevate the level of homocysteine in depressive patients and associated with deficiencies in neurotransmitters (serotonin, dopamine, noradrenaline, γ- aminobutyric acid and GABA) because folic acid, vitamin B12 & B6 that are precursors to neurotransmitters. 24,25 The association between homocysteine and neurotransmitters in depressed patients with increased total plasma homocysteine levels had significantly lowers the levels of serum, RBCs, and CSF folate, as well as lower levels of CSF S-adenosylmethionine (SAMe) (act as antidepressant) and have significantly lower CSF concentrations of 5- hydroxyindoleacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenylglycol (MHPG). Bottiglieri et al had reported that high homocysteine levels had more severe Hamilton Depression Rating Scale (HDRS) scores and with high rates of C677T MHTFR mutation. 5,13,24 25 Conclusions Some evidence have supported the status of folate and hcy correlate the depression which is mild to moderated and increase the mortality rates of cardiovascular in depression. Folate and Vitamin B12 & 6 rich supplementation have an enormous response to antidepressant treatment and effectively improves the response to fluoxetine. However, recent research in brain biochemistry indicates the association between nutritional intake, and central nervous system can improve the individual's psychological health status. Some clinical trial study have indicated that if vitamin B12 is administered in a specific clinical timing window, enhances cerebral and cognitive functions and frequently promotes the functioning of factors related to the frontal lobe, the language function of people with cognitive disorders. Therefore, this mood improvement was particularly associated with improved vitamin B2 and B6 status. Some other studies have shown folate can play a critical role in brain metabolic pathways and its deficiency leads to many neuropsychiatric manifestation including depression. Low levels of folate have less effect of antidepressant whereas a controlled study have shown that 500 mcg of folic acid enhanced the effectiveness of antidepressant therapy and lowering the concentration of Hcy and protect the neuronal cell from the oxidative stress through generated antioxidant and conduct the proper synaptic signalling pathway in the brain. Funding: No funding sources Conflict of interest: None declared References 1. Herrmann W, Herrmann M, Obeid R. Hyperhomocysteinaemia : A Critical Review of Old and New Aspects. 2007; Greenlund KJ, Srinivasan SR, Xu J, Dalferes E, Myers L, Pickoff A, et al. Plasma Homocysteine Distribution and Its Association With Parental History of Coronary Artery Disease in Black, Agrawal A, Ilango K, Singh PK, Karmakar D, Singh GPI, Kumari R, et al. Age dependent levels of plasma homocysteine and cognitive performance. Behavioural Brain Research. 2015;283:

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