Hyperhomocysteinemia in Cardiovascular Diseases: Revisiting Observational Studies and Clinical Trials.

Thromboembolic manifestations are relatively frequent in patients with intermediate/severe hyperhomocysteinemia (>30 µmol/L) related to inherited disorders and deficiencies in vitamin B12 and folate. In contrast, moderate hyperhomocysteinemia (15-30 µmol/L) is a modest predictor of cardiovascular risk. The recognition of homocysteine as a cardiovascular risk factor has been challenged by some but not all randomized clinical trials. We reviewed the main data of this controversy and formulated conclusions to be translated in clinical practice.Homocysteine-lowering trials have been performed in cardiovascular subjects with moderate but not intermediate/severe hyperhomocysteinemia despite the dose-effect risk association. The first meta-analyses found no benefit and led cardiology societies not recommending homocysteine in the assessment of cardiovascular risk. This guideline challenged the need to diagnose and treat the nutritional and genetic causes of intermediate/major hyperhomocysteinemia and was not revised when larger meta-analyses concluded to a reduced risk of stroke. In a recent observational study, 84% of consecutive cardiovascular patients assessed for homocysteine had intermediate or major hyperhomocysteinemia, which was properly assessed in only half of the cases and related to B12 and/or folate deficiency and Addison/Biermer disease in 55% of these cases.In conclusion, revisiting observational studies and clinical trials suggests that cardiovascular patients should be screened for hyperhomocysteinemia, when no other risk factor is found. Patients with intermediate/major hyperhomocysteinemia should be properly assessed and treated for B vitamin deficiencies and inherited disorders according to current guidelines. Further trials are needed to assess the effect of lowering homocysteine according to hyperhomocysteinemia categories at baseline.

Relationships of Serum Homocysteine, Vitamin B12, and Folic Acid Levels with Papulopustular Rosacea Severity: A Case-Control Study.

Background: Rosacea is a chronic inflammatory skin disease with a multifactorial etiology. Recently, associations between serum homocysteine (Hcy) levels and inflammatory skin diseases, such as psoriasis and hidradenitis suppurativa, have been reported. However, no study has explored the levels of serum Hcy, folic acid, and vitamin B12 in patients with rosacea. Objective: To investigate serum Hcy, vitamin B12, and folic acid levels in patients with papulopustular rosacea (PPR), we characterized the association of these levels with PPR severity. Methods: This case-control study included 138 PPR patients and 58 healthy controls. The serum levels of Hcy, vitamin B12, and folic acid were measured. A correlation was assessed between disease severity and serum levels of Hcy, vitamin B12, and folic acid. Results: Serum vitamin B12 and folic acid levels were significantly lower in PPR patients than in the healthy controls (p = 0.011 and p = 0.0173, respectively). Although serum Hcy levels did not significantly differ between PPR patients and healthy controls, PPR severity was positively correlated with serum Hcy levels (p < 0.001). Conclusions: Our results suggest a possible association between hyperhomocysteinemia and vitamin B12 deficiency in patients with PPR.

Homocysteine, Vitamins B6 and Folic Acid in Experimental Models of Myocardial Infarction and Heart Failure-How Strong Is That Link?

Cardiovascular diseases are the leading cause of death and the main cause of disability. In the last decade, homocysteine has been found to be a risk factor or a marker for cardiovascular diseases, including myocardial infarction (MI) and heart failure (HF). There are indications that vitamin B6 plays a significant role in the process of transsulfuration in homocysteine metabolism, specifically, in a part of the reaction in which homocysteine transfers a sulfhydryl group to serine to form α-ketobutyrate and cysteine. Therefore, an elevated homocysteine concentration (hyperhomocysteinemia) could be a consequence of vitamin B6 and/or folate deficiency. Hyperhomocysteinemia in turn could damage the endothelium and the blood vessel wall and induce worsening of atherosclerotic process, having a negative impact on the mechanisms underlying MI and HF, such as oxidative stress, inflammation, and altered function of gasotransmitters. Given the importance of the vitamin B6 in homocysteine metabolism, in this paper, we review its role in reducing oxidative stress and inflammation, influencing the functions of gasotransmitters, and improving vasodilatation and coronary flow in animal models of MI and HF.

Synergistic association of hyperuricemia and hyperhomocysteinemia with chronic kidney disease in middle-aged adults and the elderly population.

ABSTRACT: Chronic kidney disease (CKD) is a major global public health issue. Both hyperhomocysteinemia (HHcy) and hyperuricemia are independent risk factors for CKD. In this study, we evaluated the association of HHcy and hyperuricemia with CKD in the middle-aged and elderly populations in Taiwan.In this cross-sectional study, we collected the data of 5910 patients aged ≥50 years after their self-paid health examination at a single medical center. Homocysteine (Hcy) levels were divided into 4 quartiles (Q1, <8.2; Q2, 8.2-9.8; Q3, 9.9-11.7; and Q4, >11.7 µM/L). Renal function was determined using the Chronic Kidney Disease Epidemiology Collaboration equation. Patients were considered to have CKD if their estimated glomerular filtration rate was < 60 mL/min/1.73 m2.The prevalence of CKD significantly increased with the quartiles of uric acid (UA) and Hcy. In multiple logistic regression analysis, the odds ratios (ORs) of CKD increased with the quartiles of Hcy, independent of UA. There was 22.9 in Q4 in the normal serum UA group and 18.3 in the hyperuricemia group compared with Q1 of Hcy. Both hyperuricemia (OR 2.9) and Q4 of Hcy (OR 8.1) were significant independent risk factors for CKD. Furthermore, hyperuricemia and HHcy had significant synergistic association (synergy index, 1.7) with CKD.The ORs of CKD increased with the quartiles of Hcy, independent of hyperuricemia. Hyperuricemia and HHcy had synergistic association with CKD.

Homocysteine and Age-Related Central Nervous System Diseases: Role of Inflammation.

Hyperhomocysteinemia (HHcy) is remarkably common among the aging population. The relation between HHcy and the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and eye diseases, and age-related macular degeneration (AMD) and diabetic retinopathy (DR) in elderly people, has been established. Disruption of the blood barrier function of the brain and retina is one of the most important underlying mechanisms associated with HHcy-induced neurodegenerative and retinal disorders. Impairment of the barrier function triggers inflammatory events that worsen disease pathology. Studies have shown that AD patients also suffer from visual impairments. As an extension of the central nervous system, the retina has been suggested as a prominent site of AD pathology. This review highlights inflammation as a possible underlying mechanism of HHcy-induced barrier dysfunction and neurovascular injury in aging diseases accompanied by HHcy, focusing on AD.

Four Weeks of Aerobic Training Affects Cardiac Tissue Matrix Metalloproteinase, Lactate Dehydrogenase and Malate Dehydrogenase Enzymes Activities, and Hepatorenal Biomarkers in Experimental Hyperhomocysteinemia in Rats.

The aim of this study was to investigate the effect of the application of homocysteine as well as its effect under the condition of aerobic physical activity on the activities of matrix metalloproteinases (MMP), lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) in cardiac tissue and on hepato-renal biochemical parameters in sera of rats. Male Wistar albino rats were divided into four groups (n = 10, per group): C: 0.9% NaCl 0.2 mL/day subcutaneous injection (s.c.); H: homocysteine 0.45 µmol/g b.w./day s.c.; CPA saline (0.9% NaCl 0.2 mL/day s.c.) and a program of physical activity on a treadmill; and HPA homocysteine (0.45 µmol/g b.w./day s.c.) and a program of physical activity on a treadmill. Subcutaneous injection of substances was applied 2 times a day at intervals of 8 h during the first two weeks of experimental protocol. Hcy level in serum was significantly higher in the HPA group compared to the CPA group (p < 0.05). Levels of glucose, proteins, albumin, and hepatorenal biomarkers were higher in active groups compared with the sedentary group. It was demonstrated that the increased activities of LDH (mainly caused by higher activity of isoform LDH2) and mMDH were found under the condition of homocysteine-treated rats plus aerobic physical activity. Independent application of homocysteine did not lead to these changes. Physical activity leads to activation of MMP-2 isoform and to increased activity of MMP-9 isoform in both homocysteine-treated and control rats.

Late-onset methylmalonic acidemia and homocysteinemia.

INTRODUCTION: Introduction: cobalamin C (Cbl C) deficiency is the most common defect in intracellular cobalamin metabolism, associated with methylmalonic acidemia and homocystinuria. Its late clinical presentation is heterogeneous and may lead to a diagnostic delay. Case report: we report the case of a 45-year-old man with a 20-year history of chronic kidney disease and recently diagnosed spastic paraparesis, both of unknown origin. Metabolic studies revealed elevated levels of homocysteine and methylmalonic acid in the blood and urine. A genetic study confirmed cobalamin C deficiency. Treatment with hydroxocobalamin, betaine, carnitine, and folic acid was started. The patient eventually received a kidney transplant. Discussion: early diagnosis and appropriate treatment improve the clinical evolution of patients with Cbl C deficiency. Determination of homocysteine, organic acids, and other amino acids should be included in the differential diagnosis of patients with nephrological-neurological symptoms without a clear etiology.

INTRODUCCIÓN: Introducción: la deficiencia de cobalamina C (Cbl C) es el defecto más común en el metabolismo intracelular de la cobalamina, asociado a acidemia metilmalónica y homocistinuria. Su presentación clínica tardía es heterogénea y puede llevar a un retraso en el diagnóstico. Caso clínico: presentamos el caso de un varón de 45 años con 20 años de evolución de enfermedad renal crónica y paraparesia espástica de reciente diagnóstico, ambos de origen desconocido. Los estudios metabólicos revelaron niveles elevados de homocisteína y ácido metilmalónico en sangre y orina. El estudio genético confirmó el déficit de cobalamina C. Se inició tratamiento con hidroxocobalamina, betaína, carnitina y ácido fólico. El paciente pudo recibir un trasplante renal. Discusión: el establecimiento de un diagnóstico precoz y un tratamiento adecuado mejora la evolución clínica de los pacientes con déficit de Cbl C. La determinación de homocisteína, ácidos orgánicos y otros aminoácidos debe incluirse en el diagnóstico diferencial de los pacientes con síntomas nefrológico-neurológicos sin una etiología clara.

Severe homocysteinemia in two givosiran-treated porphyria patients: is free heme deficiency the culprit?

Givosiran is a novel approach to treat patients with acute intermittent porphyrias (AIP) by silencing of ∂-ALA-synthase 1, the first enzyme of heme biosynthesis in the liver. We included two patients in the Envision study who responded clinically well to this treatment. However, in both patients, therapy had to be discontinued because of severe adverse effects: One patient (A) developed local injection reactions which continued to spread all over her body with increasing number of injections and eventually caused a severe systemic allergic reaction. Patient B was hospitalized because of a fulminant pancreatitis. Searching for possible causes, we also measured the patients plasma homocysteine (Hcy) levels in fluoride-containing collection tubes: by LC-MS/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400 µmol/l in patient B. Searching for germline mutations in 10 genes that are relevant for homocysteine metabolism only revealed hetero- and homozygous polymorphisms in the MTHFR gene. Alternatively, an acquired inhibition of cystathionine-beta-synthase which is important for homocysteine metabolism could explain the plasma homocysteine increase. This enzyme is heme-dependent: when we gave heme arginate to our patients, Hcy levels rapidly dropped. Hence, we conclude that inhibition of ∂-ALA-synthase 1 by givosiran causes a drop of free heme in the hepatocyte and therefore the excessive increase of plasma homocysteine. Hyperhomocysteinemia may contribute to the adverse effects seen in givosiran-treated patients which may be due to protein-N-homocysteinylation.

Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran.

Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 µmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 µmol/L; range: 10-129 vs median tHcy: 14.5 µmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5'-phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolate-reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 µmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 µmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-ß-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co-increase of tHcy and methionine resembling classic homocystinuria.

Methylenetetrahydrofolate reductase polymorphisms as genetic markers to predict homocysteinemia and clinical severity in sickle cell disease.

Aim: The present study observed the relationship between the methylenetetrahydrofolate reductase genotypes and clinical outcome in children with sickle cell disorder. Methodology: A total of 249 children were recruited for the study and evaluated clinically for calculating severity score, homocysteine levels and C677T and A1298C genotyping. Results: The frequencies of variant genotypes were 28.1% CT/TT677 and 69.1% AC/CC1298. Plasma homocysteine was significantly elevated in variant groups (p < 0.001). Both the genotypes accorded significant association with homocysteinemia (p < 0.001). Vascular crisis (p = 0.04), frequency of hospitalization (p < 0.001) and severity score (p = 0.02) revealed association with C677T and not with A1298C. The CT/TT677 genotypes showed 3.39-times (p = 0.032) increase in a higher score for severity. Conclusion: C677T depicted significant association with clinical severity in study population.

Factors associated with hyperhomocysteinemia in relatively healthy Taiwanese adults: A retrospective medical record study.

ABSTRACT: Elevated homocysteine levels have been proposed as a risk factor for cardiovascular disease. The aim of this study was to evaluate factors associated with hyperhomocysteinemia in relatively healthy Taiwanese adults.A retrospective cross-sectional study was conducted using data from the health examination database in a medical center located in southern Taiwan. Hyperhomocysteinemia was defined as a plasma homocysteinemia level >15 µmol/L. Factors associated with hyperhomocysteinemia were evaluated using univariate and multiple stepwise logistic regression analyses.A total of 817 adults with a mean age of 55.5 years were included in the present study, and of them, 67 (8.2%) had hyperhomocysteinemia. Results from multiple logistic regression analysis showed that male sex (Odd ratio [OR] = 12.28, 95% CI = 2.94-51.27, P  = .001), advanced age (OR = 1.37 per 10 years, 95% CI = 1.06-1.77, P = .017), triglycerides (OR = 1.02 per 10 mg/dL, 95% CI = 1.01-1.04, P = .010), and uric acid (OR = 1.27, 95% CI = 1.09-1.49, P = .004) were significantly and independently associated with hyperhomocysteinemia.In this retrospective medical record study, male sex, advanced age, higher plasma level of triglyceride, and uric acid were significantly associated with hyperhomocysteinemia in relatively healthy Taiwanese adults.

Hyperhomocysteinemia: Focus on Endothelial Damage as a Cause of Erectile Dysfunction.

Erectile Dysfunction (ED) is defined as the inability to maintain and/or achieve a satisfactory erection. This condition can be influenced by the presence of atherosclerosis, a systemic pathology of the vessels that also affects the cavernous arteries and which can cause an alteration of blood flow at penile level. Among the cardiovascular risk factors affecting the genesis of atherosclerosis, hyperhomocysteinemia (HHcys) plays a central role, which is associated with oxidative stress and endothelial dysfunction. This review focuses on the biological processes that lead to homocysteine-induced endothelial damage and discusses the consequences of HHcys on male sexual function.

Sulfur-Containing Amino Acids and Lipid Metabolism.

The metabolism of methionine and cysteine in the body tissues determines the concentrations of several metabolites with various biologic activities, including homocysteine, hydrogen sulfide (H2S), taurine, and glutathione. Hyperhomocysteinemia, which is correlated with lower HDL cholesterol in blood in volunteers and animal models, has been associated with an increased risk for cardiovascular diseases. In humans, the relation between methionine intake and hyperhomocysteinemia is dependent on vitamin status (vitamins B-6 and B-12 and folic acid) and on the supply of other amino acids. However, lowering homocysteinemia by itself is not sufficient for decreasing the risk of cardiovascular disease progression. Other compounds related to methionine metabolism have recently been identified as being involved in the risk of atherosclerosis and steatohepatitis. Indeed, the metabolism of sulfur amino acids has an impact on phosphatidylcholine (PC) metabolism, and anomalies in PC synthesis due to global hypomethylation have been associated with disturbances of lipid metabolism. In addition, impairment of H2S synthesis from cysteine favors atherosclerosis and steatosis in animal models. The effects of taurine on lipid metabolism appear heterogeneous depending on the populations of volunteers studied. A decrease in the concentration of intracellular glutathione, a tripeptide involved in redox homeostasis, is implicated in the etiology of cardiovascular diseases and steatosis. Last, supplementation with betaine, a compound that allows remethylation of homocysteine to methionine, decreases basal and methionine-stimulated homocysteinemia; however, it adversely increases plasma total and LDL cholesterol. The study of these metabolites may help determine the range of optimal and safe intakes of methionine and cysteine in dietary proteins and supplements. The amino acid requirement for protein synthesis in different situations and for optimal production of intracellular compounds involved in the regulation of lipid metabolism also needs to be considered for dietary attenuation of atherosclerosis and steatosis risk.

Metabolic Consequences of Supplemented Methionine in a Clinical Context.

The central position of methionine (Met) in protein metabolism indicates the importance of this essential amino acid for growth and maintenance of lean body mass. Therefore, Met might be a tempting candidate for supplementation. However, because Met is also the precursor of homocysteine (Hcy), a deficient intake of B vitamins or excessive intake of Met may result in hyperhomocysteinemia (HHcy), which is a risk factor for cardiovascular disease. This review discusses the evidence generated in preclinical and clinical studies on the importance and potentially harmful effects of Met supplementation and elaborates on potential clinical applications of supplemental Met with reference to clinical studies performed over the past 20 y. Recently acquired knowledge about the NOAEL (no observed adverse effect level) of 46.3 mg · kg-1 · d-1 and the LOAEL (lowest observed adverse effect level) of 91 mg · kg-1 · d-1 of supplemented Met will guide the design of future studies to further establish the role of Met as a potential (safe) candidate for nutritional supplementation in clinical applications.

[Epilepsy and vascular risk]. / Epilepsia y riesgo vascular.

Epidemiological studies have shown that mortality increases in patients with epilepsy compared to the general population, and this has been associated with an increased risk of cardiovascular or cerebrovascular events. The role played by classic and more speculative vascular risk factors (e.g. oxidative stress) in the development of vascular disease in these subjects has not yet been clearly established. In this context, antiepileptic drugs (AEDs) may have a differential influence on the vascular risk of patients with epilepsy, as enzyme inducers have been linked to the development of early atherosclerosis. The role of AEDs in the pathogenesis of atherosclerosis is not fully understood, but there are several plausible explanations: they can condition an unfavourable lipid profile, they can increase levels of C-reactive protein and homocysteinaemia, as well as clotting factors, and they can increase oxidative stress. Prolonged use of AEDs can be associated with a wide range of chronic adverse effects, and may also play a key role in the pathogenesis of atherosclerosis in patients with epilepsy. Neurologists and epileptologists who prescribe AEDs should be aware of the potentially unfavourable effects, especially in patients at high risk of vascular events. This review examines the pathophysiological mechanisms that may explain increased vascular risk in epilepsy, the evidence regarding accelerated atherosclerosis and its complications, and the potential implications for follow-up and treatment of the disease.

TITLE: Epilepsia y riesgo vascular.Estudios epidemiológicos han demostrado que la mortalidad aumenta en los pacientes con epilepsia en comparación con la población general, lo que se ha asociado con un mayor riesgo de eventos cardiovasculares o cerebrovasculares. No está claramente establecido el papel que desempeñan los factores de riesgo vascular clásicos y otros más especulativos (por ejemplo, el estrés oxidativo) en el desarrollo de la enfermedad vascular en estos sujetos. En este contexto, los fármacos antiepilépticos (FAE) pueden influir de manera diferencial en el riesgo vascular de los pacientes con epilepsia, ya que se ha relacionado a los inductores enzimáticos con el desarrollo de ateroesclerosis precoz. El papel de los FAE en la patogénesis de la ateroesclerosis no se conoce completamente, pero hay varias explicaciones plausibles: pueden condicionar un perfil lipídico desfavorable, pueden aumentar los niveles de proteína C reactiva y homocisteinemia, así como los factores de la coagulación, y pueden incrementar el estrés oxidativo. El uso prolongado de FAE puede asociarse con una amplia gama de efectos adversos crónicos, y también pueden desempeñar un papel fundamental en la patogenia de la ateroesclerosis en pacientes con epilepsia. Neurólogos y epileptólogos que prescriben FAE deben ser conscientes de los efectos potencialmente desfavorables, en especial en pacientes con alto riesgo de eventos vasculares. Esta revisión analiza los mecanismos fisiopatológicos que pueden explicar un mayor riesgo vascular en la epilepsia, la evidencia con respecto a la ateroesclerosis acelerada y sus complicaciones, y las potenciales implicaciones en el seguimiento y el tratamiento de la enfermedad.

Nonlinear association between blood lead and hyperhomocysteinemia among adults in the United States.

Evidence regarding the association between blood lead levels (BLL) and hyperhomocysteinemia (HHcy) in US adults was limited. We aimed to investigate the association of BLL with the risk of HHcy, and to examine possible effect modifiers using US National Health and Nutrition Examination Survey (NHANES) database. We performed a cross-sectional study using data from up to 9,331 participants aged ≥ 20 years of NHANES from 2001 to 2006. BLL was measured by atomic absorption spectrometry. HHcy was defined as plasma homocysteine level > 15 µmol/L. The weighted prevalence of HHcy was 6.87%. The overall mean BLL was 1.9 µg/dL. Overall, there was a nonlinear positive association between Ln-transformed BLL (LnBLL) and the risk of HHcy. The Odds ratios (95% CI) for participants in the second (0.04-0.49 µg/dL), third (0.5-0.95 µg/dL) and fourth quartiles (> 0.95 µg/dL) were 1.12 (95% CI: 0.71, 1.76), 1.13 (95% CI: 0.73, 1.77), and 1.67 (95% CI: 1.07, 2.61), respectively, compared with those in quartile 1. Consistently, a significantly higher risk of HHcy (OR: 1.49; 95% CI: 1.19, 1.88) was found in participants in quartile 4 compared with those in quartiles 1-3. Furthermore, a strongly positive association between LnBLL and HHcy was observed in participants with estimated glomerular filtration rate (eGFR) < 60 mL/min-1/1.73 m-2. Our results suggested that a higher level of BLL (LnBLL > 0.95 µg/dL) was associated with increased risk of HHcy compared with a lower level of BLL (LnBLL ≤ 0.95 µg/dL) among U.S. adults, and the association was modified by the eGFR.

Maternal Fructose Intake Increases Liver H2 S Synthesis but Exarcebates its Fructose-Induced Decrease in Female Progeny.

SCOPE: Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases (CVD). However, consumption of beverages containing fructose is allowed during gestation. Homocysteine (Hcy) is a well-known risk factor for CVD while hydrogen sulfide (H2 S), a product of its metabolism, has been proved to exert opposite effects to Hcy. METHODS AND RESULTS: First, it is investigated whether maternal fructose intake produces subsequent changes in Hcy metabolism and H2 S synthesis of the progeny. Carbohydrates are supplied to pregnant rats in drinking water (10% wt/vol) throughout gestation. Adult female descendants from fructose-fed, control or glucose-fed mothers are studied. Females from fructose-fed mothers have elevated homocysteinemia, hepatic H2 S production, cystathionine γ-lyase (CSE) (the key enzyme in H2 S synthesis) expression and plasma H2 S, versus the other two groups. Second, it is studied how adult female progeny from control (C/F), fructose- (F/F), and glucose-fed (G/F) mothers responded to liquid fructose and compared them to the control group (C/C). Interestingly, hepatic CSE expression and H2 S synthesis are diminished by fructose intake, this effect being more pronounced in F/F females. CONCLUSION: Maternal fructose intake produces a fetal programming that increases hepatic H2 S production and, in contrast, exacerbates its fructose-induced drop in female progeny.

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia.

Hyperhomocysteinemia (hHcy) represents a strong risk factor for atherosclerosis-associated diseases, like stroke, dementia or Alzheimer's disease. A methionine (Met)-rich diet leads to an elevated level of homocysteine in plasma and might cause pathological alterations across the brain. The hippocampus is being constantly studied for its selective vulnerability linked with neurodegeneration. This study explores metabolic and histo-morphological changes in the rat hippocampus after global ischemia in the hHcy conditions using a combination of proton magnetic resonance spectroscopy and magnetic resonance-volumetry as well as immunohistochemical analysis. After 4 weeks of a Met-enriched diet at a dose of 2 g/kg of animal weight/day, adult male Wistar rats underwent 4-vessel occlusion lasting for 15 min, followed by a reperfusion period varying from 3 to 7 days. Histo-morphological analyses showed that the subsequent ischemia-reperfusion insult (IRI) aggravates the extent of the sole hHcy-induced degeneration of the hippocampal neurons. Decreased volume in the grey matter, extensive changes in the metabolic ratio, deeper alterations in the number and morphology of neurons, astrocytes and their processes were demonstrated in the hippocampus 7 days post-ischemia in the hHcy animals. Our results suggest that the combination of the two risk factors (hHcy and IRI) endorses and exacerbates the rat hippocampal neurodegenerative processes.

Vitamin B Supplementation and Nutritional Intake of Methyl Donors in Patients with Chronic Kidney Disease: A Critical Review of the Impact on Epigenetic Machinery.

Cardiovascular morbidity and mortality are several-fold higher in patients with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) than in the general population. Hyperhomocysteinemia has undoubtedly a central role in such a prominent cardiovascular burden. The levels of homocysteine are regulated by methyl donors (folate, methionine, choline, betaine), and cofactors (vitamin B6, vitamin B12,). Uremia-induced hyperhomocysteinemia has as its main targets DNA methyltransferases, and this leads to an altered epigenetic control of genes regulated through methylation. In renal patients, the epigenetic landscape is strictly correlated with the uremic phenotype and dependent on dietary intake of micronutrients, inflammation, gut microbiome, inflammatory status, oxidative stress, and lifestyle habits. All these factors are key contributors in methylome maintenance and in the modulation of gene transcription through DNA hypo- or hypermethylation in CKD. This is an overview of the epigenetic changes related to DNA methylation in patients with advanced CKD and ESRD. We explored the currently available data on the molecular dysregulations resulting from altered gene expression in uremia. Special attention was paid to the efficacy of B-vitamins supplementation and dietary intake of methyl donors on homocysteine lowering and cardiovascular protection.