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1.
Homocysteine - from disease biomarker to disease prevention.
Smith, AD, Refsum, H
Journal of internal medicine. 2021;(4):826-854
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Abstract
We have reviewed the literature and have identified more than 100 diseases or conditions that are associated with raised concentrations of plasma total homocysteine. The commonest associations are with cardiovascular diseases and diseases of the central nervous system, but a large number of developmental and age-related conditions are also associated. Few other disease biomarkers have so many associations. The clinical importance of these associations becomes especially relevant if lowering plasma total homocysteine by B vitamin treatment can prevent disease and so improve health. Five diseases can at least in part be prevented by lowering total homocysteine: neural tube defects, impaired childhood cognition, macular degeneration, primary stroke, and cognitive impairment in the elderly. We conclude from our review that total homocysteine values in adults of 10 μmol/L or below are probably safe, but that values of 11 μmol/L or above may justify intervention. Homocysteine is more than a disease biomarker: it is a guide for the prevention of disease.
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Epigenetic memory: gene writer, eraser and homocysteine.
Tyagi, SC, Stanisic, D, Singh, M
Molecular and cellular biochemistry. 2021;(2):507-512
Abstract
Naturally chromatin remodeling is highly organized, consisting of histone acetylation (opening/relaxation of the compact chromatin structure), DNA methylation (inhibition of the gene expression activity) and sequence rearrangement by shifting. All this is essentially required for proper "in-printing and off-printing" of genes thus ensuring the epigenetic memory process. Any imbalance in ratios of DNA methyltransferase (DNMT, gene writer), fat-mass obesity-associated protein (FTO, gene eraser) and product (function) homocysteine (Hcy) could lead to numerous diseases. Interestingly, a similar process also happens in stem cells during embryogenesis and development. Despite gigantic unsuccessful efforts undertaken thus far toward the conversion of a stem cell into a functional cardiomyocyte, there has been hardly any study that shows successful conversion of a stem cell into a multinucleated cardiomyocyte. We have shown nuclear hypertrophy during heart failure, however; the mechanism(s) of epigenetic memory, regulation of genes during fertilization, embryogenesis, development and during adulthood remain far from understanding. In addition, there may be a connection of aging, loosing of the memory leading to death, and presumably to reincarnation. This review highlights some of these pertinent issues facing the discipline of biology as a whole today.
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Homocysteine: Its Possible Emerging Role in At-Risk Population Groups.
Azzini, E, Ruggeri, S, Polito, A
International journal of molecular sciences. 2020;(4)
Abstract
Increased plasma homocysteine is a risk factor for several pathological disorders. The present review focused on the role of homocysteine (Hcy) in different population groups, especially in risk conditions (pregnancy, infancy, old age), and on its relevance as a marker or etiological factor of the diseases in these age groups, focusing on the nutritional treatment of elevated Hcy levels. In pregnancy, Hcy levels were investigated in relation to the increased risk of adverse pregnancy outcomes such as small size for gestational age at birth, preeclampsia, recurrent abortions, low birth weight, or intrauterine growth restriction. In pediatric populations, Hcy levels are important not only for cardiovascular disease, obesity, and renal disease, but the most interesting evidence concerns study of elevated levels of Hcy in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Finally, a focus on the principal pathologies of the elderly (cardiovascular and neurodegenerative disease, osteoporosis and physical function) is presented. The metabolism of Hcy is influenced by B vitamins, and Hcy-lowering vitamin treatments have been proposed. However, clinical trials have not reached a consensus about the effectiveness of vitamin supplementation on the reduction of Hcy levels and improvement of pathological condition, especially in elderly patients with overt pathologies, suggesting that other dietary and non-dietary factors are involved in high Hcy levels. The importance of novel experimental designs focusing on intra-individual variability as a complement to the typical case-control experimental designs and the study of interactions between different factors it should be emphasized.
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Genetic, epigenetic and genomic mechanisms of methionine dependency of cancer and tumor-initiating cells: What could we learn from folate and methionine cycles.
Guéant, JL, Oussalah, A, Zgheib, R, Siblini, Y, Hsu, SB, Namour, F
Biochimie. 2020;:123-128
Abstract
Methionine-dependency is a common feature of cancer cells, which cannot proliferate without constant inputs of exogenous methionine even in the presence of its precursor, homocysteine. The endogenous synthesis of methionine is catalyzed by methionine synthase, which transfers the methyl group of 5-methyltetrahydrofolate (5-methylTHF) to homocysteine in the presence of vitamin B12 (cobalamin, cbl). Diverse mechanisms can produce it, including somatic mutations, aberrant DNA methylation (epimutations) and altered expression of genes. Around twenty somatic mutations have been reported as a cause of methionine dependency. Some of them are contributors but not sufficient on their own to cause methionine dependency. Epigenetic invalidation of MMACHC gene expression triggers methionine dependency of the MeWo-LC1 melanoma cancer cell line. This epimutation is generated by aberrant antisense transcription of the adjacent gene PRDX1. Methionine dependency involves the abnormal expression of 1-CM genes in cancer stem cells. It is related to an increased demand for methionine and SAM, which is not compensated by the increased production of formate by glycine decarboxylase pathway in lung cancer tumor spheres. Tumor spheres of glioblastoma U251 are methionine-dependent through disruption of folate metabolism. The rescue of the growth of glioblastoma stem cells by folate shows the considerable importance to evaluate the influence of supplements and dietary intake of folate on the risk of tumor development, in particular in countries subjected to mandatory food fortification in folic acid. Dietary methionine restriction or the use of methioninase represent promising anticancer therapeutic strategies that deserve to be explored in combination with chemotherapy.
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Nutritional Deficiencies, Bariatric Surgery, and Serum Homocysteine Level: Review of Current Literature.
Komorniak, N, Szczuko, M, Kowalewski, B, Stachowska, E
Obesity surgery. 2019;(11):3735-3742
Abstract
Obesity is currently one of the biggest global health problems. In the case of severe obesity, bariatric surgeries are considered to be the most important method of treatment. The 2 most commonly performed bariatric surgery procedures include Roux-en-Y gastric bypass and sleeve gastrectomy. However, these methods are not free from complications, and the most common ones (moderately long or long term) are micronutrient deficiencies. The deficiency of vitamins B6, B12, and folic acid as cofactors of the folate cycle contributes to the development of hyperhomocysteinemia. It seems that apart from nutritional factors, there are other aspects that have a significant influence on the concentration of homocysteine in blood, such as the type of conducted bariatric surgery, the post-surgical concentration of betaine and creatinine, and the clearance of methionine (i.e., the mutations of the gene that encodes the MTHFR reductase as well as other genes associated with the process of methylation, e.g., methionine synthase). Their presence might be one of the causes of the increased concentration of homocysteine after surgery despite the fact that patients take vitamin-mineral supplementation.
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6.
Homocysteine: A modifiable culprit of cognitive impairment for us to conquer?
Ji, Y, Lyu, P, Jin, W, Li, X, Li, X, Dong, Y
Journal of the neurological sciences. 2019;:128-136
Abstract
BACKGROUND Cognitive impairment, including mild cognitive impairment and its progressive deterioration to dementia, results in great hazards to the patient and the surrounding society. While some of the risk factors are unmodifiable, such as age, lower educational attainment, and genetic factors, another proposed one-homocysteine, an amino acid produced in the methylation cycle of protein metabolism is modifiable by cheap and easily accessible B-vitamins treatments in medical practice. OBJECTIVE AND METHODS To investigate the relationship between homocysteine and cognitive impairment, elucidate the underlying pathophysiological mechanisms and exploit any potential therapeutic values of homocysteine-lowering treatments in prevention and/or treatment in cognitive decline, we searched on the PUBMED databases surrounding around the physiological homocysteine metabolism, detrimental effects of abnormal homocysteine concentrations on the brain, and review observational and interventional experiments to date estimating the relationship between homocysteine and cognitive impairment with relatively powerful evidence. RESULTS Intrinsic and environmental factors help maintain the normal homocysteine concentrations, and pathological homocysteine concentrations exert adverse effects mediated by cellular and vascular pathways. Although many observational studies have suggested a causal link between hyperhomocysteinemia and cognitive impairment, the majority of randomized controlled trials failed to observe marked benefits on cognition by homocysteine-lowering treatments using B-vitamins, partly arising from some design limitations including: not identifying individuals at earlier stages of cognitive impairment who are most likely to benefit, overlooking any latent safety hazards of multiple vitamin supplementation, lack of sensitive and domain-specific cognitive tests, and interference of other underappreciated factors. CONCLUSION More studies are required to better explain the related pathophysiological mechanisms, improve experimental methods, and investigate the preventive or/and therapeutic effects of homocysteine-lowering strategies on cognitive impairment.
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7.
Medicines associated with folate-homocysteine-methionine pathway disruption.
Vidmar, M, Grželj, J, Mlinarič-Raščan, I, Geršak, K, Dolenc, MS
Archives of toxicology. 2019;(2):227-251
Abstract
Folate is vital for cell development and growth. It is involved in one-carbon transfer reactions essential for the synthesis of purines and pyrimidines. It also acts in conjunction with cobalamin (vitamin B12) as a fundamental cofactor in the remethylation cycle that converts homocysteine to methionine. A deficiency in folate or vitamin B12 can lead to elevated homocysteine level, which has been identified as an independent risk factor in several health-related conditions. Adequate folate levels are essential in women of childbearing age and in pregnant women, and folate deficiency is associated with several congenital malformations. Low folate levels can be caused by dietary deficiencies, a genetic predisposition or treatment with medicines that affect folate concentration. Women who are pregnant or of child-bearing age commonly use medicines, so it is important to identify the basic biochemical mechanisms by which medicines interfere with the folate-homocysteine-methionine pathway. This review focuses on prescription medicines associated with folate disruption. It also summarizes their undesirable/toxic effects. Recommendations regarding folate supplementation during medical therapy are also reviewed.
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8.
The Effects of Homocysteine on the Skeleton.
Saito, M, Marumo, K
Current osteoporosis reports. 2018;(5):554-560
Abstract
PURPOSE OF REVIEW Homocystinuria is a congenital metabolic disorder in which cystathionine β-synthase deficiency results in a prominent increase in homocysteine (serum levels > 100 μM), causing mental retardation, atherosclerotic cerebral infarction, and osteoporosis accompanied by fragility fractures. Encountering a case with excessive homocysteinemia such as that seen in hereditary homocystinuria is unlikely during usual medical examinations. However, in individuals who have vitamin B or folate deficiency, serum homocysteine concentrations are known to increase. These individuals may also have a polymorphism in methylenetetrahydrofolate reductase, MTHFR (C677T: TT type), which regulates homocysteine metabolism. These changes in homocysteine levels may elicit symptoms resembling those of homocystinuria (e.g., Alzheimer's disease, atherosclerosis, osteoporosis). RECENT FINDINGS High serum homocysteine has been shown to have detrimental effects on neural cells, vascular endothelial cells, osteoblasts, and osteoclasts. Homocysteine is also known to increase oxidative stress, disrupt cross-linking of collagen molecules, and increase levels of advanced glycation end products, which results in reduced bone strength through a mechanism that goes beyond low bone density and increased bone resorption. Therefore, high serum homocysteine may be regarded as a factor that can reduce both bone mass and impair bone quality. In this review, we outline the epidemiology and pathophysiology of osteoporosis associated with hyperhomocysteinemia.
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9.
Colorectal polyp risk is linked to an elevated level of homocysteine.
Sun, M, Sun, M, Zhang, L, Shi, S
Bioscience reports. 2018;(2)
Abstract
Several studies have reported an association between levels of folate, homocysteine, and vitamin B12 and the risk of colorectal polyps. Here, our aim is to examine the possible effect of folate, homocysteine, and vitamin B12 levels on the risk of colorectal polyps by means of meta-analysis based quantitative synthesis. According to our inclusion/exclusion criteria, a total of 13 case-control studies were enrolled. The P-value of the association test, standard mean difference (SMD), and 95% confidence interval (CI) were calculated. Pooled analysis data showed a negative correlation between the risk of colorectal polyps and the levels of serum folate, red blood cell (RBC) folate, or vitamin B12 (all P>0.05). Nevertheless, for homocysteine level, we also observed a statistically significant difference between cases and controls in the overall and subgroup analysis of hospital-based control (HB), population-based control (PB), Chinese, Caucasian, or Asian (all P<0.05, SMD > 0). We found that increased levels of homocysteine may be statistically and significantly related to the risk of colorectal polyps.
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10.
The current status of homocysteine as a risk factor for cardiovascular disease: a mini review.
Chrysant, SG, Chrysant, GS
Expert review of cardiovascular therapy. 2018;(8):559-565
Abstract
Hyperhomocysteinemia has been considered as a risk factor for systemic atherosclerosis, cardiovascular disease (CVD) and stroke and many epidemiologic and case-controlled studies have demonstrated its association with these complications. In addition, treatment of hyperhomocysteinemia with folic acid ± B vitamins prevents the development of atherosclerosis, CVD and strokes. However, subsequent prospective, randomized, placebo-controlled trials have not shown an association of high homocysteine levels or their lowering with treatment with the incidence of atherosclerosis, CVD or strokes, due possibly, to the fortification of flower with folic acid. Therefore, at present, there is a controversy regarding the significance of homocysteine as a risk factor for CVD and stroke and whether patients should be routinely screened for homocysteine. Areas covered: For these reasons, a focused Medline search of the English language literature was conducted between 2010 and 2017 using the terms, homocysteine, risk factor, atherosclerosis, cardiovascular disease, stroke, treatment, and 38 papers with pertinent information were selected. Expert commentary: The review of data disclosed that there is a great controversy regarding the significance of homocysteine as a risk factor for CVD and stroke. The data from these papers together with collateral literature will be discussed in this mini review.