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Physiological Reviews Jan 2019Epidemiological studies established that elevated homocysteine, an important intermediate in folate, vitamin B, and one carbon metabolism, is associated with poor... (Review)
Review
Epidemiological studies established that elevated homocysteine, an important intermediate in folate, vitamin B, and one carbon metabolism, is associated with poor health, including heart and brain diseases. Earlier studies show that patients with severe hyperhomocysteinemia, first identified in the 1960s, exhibit neurological and cardiovascular abnormalities and premature death due to vascular complications. Although homocysteine is considered to be a nonprotein amino acid, studies over the past 2 decades have led to discoveries of protein-related homocysteine metabolism and mechanisms by which homocysteine can become a component of proteins. Homocysteine-containing proteins lose their biological function and acquire cytotoxic, proinflammatory, proatherothrombotic, and proneuropathic properties, which can account for the various disease phenotypes associated with hyperhomocysteinemia. This review describes mechanisms by which hyperhomocysteinemia affects cellular proteostasis, provides a comprehensive account of the biological chemistry of homocysteine-containing proteins, and discusses pathophysiological consequences and clinical implications of their formation.
Topics: Animals; Cardiovascular Diseases; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Risk Factors; Vitamin B 12
PubMed: 30427275
DOI: 10.1152/physrev.00003.2018 -
International Journal of Molecular... Oct 2020Elevated concentration of homocysteine (Hcy) in the blood plasma, hyperhomocysteinemia (HHcy), has been implicated in various disorders, including cardiovascular and... (Review)
Review
Elevated concentration of homocysteine (Hcy) in the blood plasma, hyperhomocysteinemia (HHcy), has been implicated in various disorders, including cardiovascular and neurodegenerative diseases. Accumulating evidence indicates that pathophysiology of these diseases is linked with mitochondrial dysfunction. In this review, we discuss the current knowledge concerning the effects of HHcy on mitochondrial homeostasis, including energy metabolism, mitochondrial apoptotic pathway, and mitochondrial dynamics. The recent studies suggest that the interaction between Hcy and mitochondria is complex, and reactive oxygen species (ROS) are possible mediators of Hcy effects. We focus on mechanisms contributing to HHcy-associated oxidative stress, such as sources of ROS generation and alterations in antioxidant defense resulting from altered gene expression and post-translational modifications of proteins. Moreover, we discuss some recent findings suggesting that HHcy may have beneficial effects on mitochondrial ROS homeostasis and antioxidant defense. A better understanding of complex mechanisms through which Hcy affects mitochondrial functions could contribute to the development of more specific therapeutic strategies targeted at HHcy-associated disorders.
Topics: Animals; Brain; Cardiovascular System; Energy Metabolism; Homocysteine; Humans; Mitochondria; Oxidative Stress
PubMed: 33080955
DOI: 10.3390/ijms21207698 -
Biomolecules May 2021Homocysteine is a non-proteinogenic sulfhydryl-containing amino acid derived from methionine and is a homologue of cysteine [...].
Homocysteine is a non-proteinogenic sulfhydryl-containing amino acid derived from methionine and is a homologue of cysteine [...].
Topics: Animals; Biochemistry; Disease; Homocysteine; Humans; Molecular Biology
PubMed: 34063494
DOI: 10.3390/biom11050737 -
Nutrition Journal Jan 2015It is well known that neuronal damage following a stroke has been attributed to the over stimulation of excitatory amino acids such as glutamate and aspartate through... (Review)
Review
It is well known that neuronal damage following a stroke has been attributed to the over stimulation of excitatory amino acids such as glutamate and aspartate through activation of NMDA receptors. The brain is exposed to most of the constituents of plasma including homocysteine as a result of the disruption of the blood-brain barrier after stroke, head trauma and stress. The question, therefore, arises as to whether or not homocysteine is able to selectively stimulate the release of excitatory amino acids in stroke. This review article will address the importance of homocysteine in nervous system specifically how these amino acids may trigger the release of catecholamines. Our data will thus strengthen the view that a mechanism for the association of hyperhomocysteinemia with increased brain lesion in stroke. As hypothalamus also controls the cardiac function via sympathetic system, the contractility of heart will be compromised. Homocysteine is also known to mediate cardiovascular problems by its adverse effects on cardiovascular endothelium and smooth muscle cells with resultant alterations in subclinical arterial structure and function. The present review will thus summarize both central and peripheral effects of homocysteine and will highlight some of the controversies associated with hyperhomocysteinemia-induced cardiovascular problems.
Topics: Brain; Cardiovascular Diseases; Catecholamines; Endothelium, Vascular; Homocysteine; Humans; Hyperhomocysteinemia; Hypothalamus; Placebos; Stroke
PubMed: 25577237
DOI: 10.1186/1475-2891-14-6 -
The American Journal of Clinical... Sep 2013The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD.
OBJECTIVE
We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD.
DESIGN
We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls.
RESULTS
Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49).
CONCLUSIONS
We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.
Topics: Coronary Artery Disease; Genes; Genetic Loci; Genetic Predisposition to Disease; Genotype; Homocysteine; Humans; Polymorphism, Genetic; Risk Factors
PubMed: 23824729
DOI: 10.3945/ajcn.112.044545 -
Journal of Inherited Metabolic Disease Feb 2011Mild to moderate hyperhomocysteinemia has been identified as a strong predictor of cardiovascular disease, independent from classical atherothrombotic risk factors. In... (Review)
Review
Mild to moderate hyperhomocysteinemia has been identified as a strong predictor of cardiovascular disease, independent from classical atherothrombotic risk factors. In the last decade, a number of large intervention trials using B vitamins have been performed and have shown no benefit of homocysteine-lowering therapy in high-risk patients. In addition, Mendelian randomization studies failed to convincingly demonstrate that a genetic polymorphism commonly associated with higher homocysteine levels (methylenetetrahydrofolate reductase 677 C>T) is a risk factor for cardiovascular disease. Together, these findings have cast doubt on the role of homocysteine in cardiovascular disease pathogenesis, and the homocysteine hypothesis has turned into a homocysteine controversy. In this review, we attempt to find solutions to this controversy. First, we explain that the Mendelian randomization analyses have limitations that preclude final conclusions. Second, several characteristics of intervention trials limit interpretation and generalizability of their results. Finally, the possibility that homocysteine lowering is in itself beneficial but is offset by adverse side effects of B vitamins on atherosclerosis deserves serious attention. As we explain, such side effects may relate to direct adverse effects of the B-vitamin regimen (in particular, the use of high-dose folic acid) or to proinflammatory and proproliferative effects of B vitamins on advanced atherosclerotic lesions.
Topics: Animals; Dissent and Disputes; Epidemiologic Research Design; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Mendelian Randomization Analysis; Models, Biological; Severity of Illness Index; Vitamin B Complex
PubMed: 20567905
DOI: 10.1007/s10545-010-9151-1 -
Pharmacological Research Nov 2016Over the past several years, hydrogen sulfide (HS) has been shown to be an important player in a variety of physiological functions, including neuromodulation,... (Review)
Review
Over the past several years, hydrogen sulfide (HS) has been shown to be an important player in a variety of physiological functions, including neuromodulation, vasodilation, oxidant regulation, inflammation, and angiogenesis. HS is synthesized primarily through metabolic processes from the amino acid cysteine and homocysteine in various organ systems including neuronal, cardiovascular, gastrointestinal, and kidney. Derangement of cysteine and homocysteine metabolism and clearance, particularly in the renal vasculature, leads to HS biosynthesis deregulation causing or contributing to existing high blood pressure. While a variety of environmental influences, such as diet can have an effect on HS regulation and function, genetic factors, and more recently epigenetics, also have a vital role in HS regulation and function, and therefore disease initiation and progression. In addition, new research into the role of gut microbiota in the development of hypertension has highlighted the need to further explore these microorganisms and how they influence the levels of HS throughout the body and possibly exploiting microbiota for use of hypertension treatment. In this review, we summarize recent advances in the field of hypertension research emphasizing renal contribution and how HS physiology can be exploited as a possible therapeutic strategy to ameliorate kidney dysfunction as well as to control blood pressure.
Topics: Animals; Epigenesis, Genetic; Homocysteine; Humans; Hydrogen Sulfide; Hypertension, Renovascular; Metabolome; Microbiota
PubMed: 27602985
DOI: 10.1016/j.phrs.2016.09.002 -
Journal of the American College of... Mar 1996Homocysteine is increasingly recognized as a risk factor for coronary artery disease. An understanding of its metabolism and of the importance of vitamins B6 and B12 and... (Review)
Review
Homocysteine is increasingly recognized as a risk factor for coronary artery disease. An understanding of its metabolism and of the importance of vitamins B6 and B12 and folate as well as enzyme levels in its regulation will aid the development of therapeutic strategies that, by lowering circulating concentrations, may also lower risk. Possible mechanisms by which elevated homocysteine levels lead to the development and progression of vascular disease include effects on platelets, clotting factors and endothelium. This review presents the clinical and basic scientific evidence supporting the risk and mechanisms of vascular disease associated with elevated homocysteine concentrations as well as the results of preliminary therapeutic trials.
Topics: Coronary Artery Disease; Folic Acid; Homocysteine; Homocystinuria; Humans; Pyridoxine; Risk Factors; Vitamin B 12
PubMed: 8606260
DOI: 10.1016/0735-1097(95)00508-0 -
Biomolecules Jul 2023Homocysteine is increasingly recognized as an important molecule in a wide variety of cellular functions [...].
Homocysteine is increasingly recognized as an important molecule in a wide variety of cellular functions [...].
Topics: Homocysteine; Molecular Biology; Biochemistry
PubMed: 37509148
DOI: 10.3390/biom13071111 -
Clinical Chemistry and Laboratory... Oct 2016High total homocysteine (tHcy) concentrations contribute to an increased risk of cardiovascular diseases and neurodegenerative disorders. Several investigations have... (Review)
Review
High total homocysteine (tHcy) concentrations contribute to an increased risk of cardiovascular diseases and neurodegenerative disorders. Several investigations have focused on the effect of exercise on tHcy concentrations, but results remain controversial. The differences among the methodologies in the investigations make difficult the interpretation of results. This review differentiates the effects of exercise on tHcy and establishes the relation with the implicated biomarkers on tHcy metabolism related to exercise. The electronic database MEDLINE (http://www.ncbi.nlm.nih.gov) was used for searching studies published between years 2002 and 2015. 'Homocysteine', 'Training ', 'Exercise', 'Physical Activity' as well as combinations out of these terms were entered in the database. Articles were grouped in: 1) Acute effect of exercise on tHcy, 2) chronic exercise and tHcy, 3) relationship of physical activity (PA) level and cardiorespiratory fitness with tHcy, and 4) biomarkers related to tHcy and exercise. From a total of 30 articles, most of the studies analyzing the acute effect of exercise showed an increase on tHcy concentrations. Studies analyzing the chronic effect on tHcy concentrations showed contradictory results and no consensus exists probably due to the differences in the methodology, exercise interventions and participants characteristics. Low cardiorespiratory fitness seems to be associated with high tHcy; in contrast, the relation of PA levels and tHcy needs further research. Regarding biomarkers related to tHcy and exercise, some studies showed an increase of folate, vitamin B12, and creatine after acute exercise that could to be due to requirement of protein turnover and an increased metabolic demand of vitamin-B.
Topics: Cardiovascular Diseases; Exercise; Homocysteine; Humans
PubMed: 26876813
DOI: 10.1515/cclm-2015-1040