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Background A1298C polymorphism of the MTHFR gene and blood homocysteine levels are reported to be associated with the development of proteinuria in patients with type 2 diabetes mellitus; however, data remain limited. Objectives To determine the characteristics of A1298C polymorphism and blood homocysteine levels as well as their association with proteinuria in patients with type 2 diabetes mellitus. Materials and methods A cross-sectional study with convenient sampling was performed among patients with type 2 diabetes mellitus who visited the Can Tho University of Medicine and Pharmacy Hospital between August 2023 and August 2024. Blood samples were collected for genetic sequencing and homocysteine level testing. Proteinuria was defined as an albumin-to-creatinine ratio ≥30 mg/g. Results In total, 192 patients with a mean age of 63.9 ± 13.1 years were enrolled. Males accounted for 34.9% of the study population. Analysis of A1298C polymorphism revealed genotype distributions of AA, AC, and CC genotypes as 51.6%, 41.1%, and 7.3%, respectively. A significant association was observed between A1298C polymorphism and elevated homocysteine levels, with CC genotype exhibiting a higher prevalence of hyperhomocysteinemia (28.6%) than AA (6.1%) and AC (22.8%) genotypes. Patients carrying AC+CC genotypes had a 2.40-fold higher risk of developing proteinuria (95% confidence interval: 1.30–4.41, p < 0.05) than those with AA genotype. Elevated blood homocysteine levels were associated with an 8.98-fold increased risk of proteinuria (95% confidence interval: 2.06–39.11, p < 0.05). Independent factors associated with proteinuria included age (odds ratio = 0.97), elevated homocysteine levels (odds ratio = 8.79), and AC+CC genotype (odds ratio = 2.08). Conclusion A1298C polymorphism was characterized by allele frequencies of 72.1% for A and 27.9% for C. In addition to age, the presence of the C allele and elevated blood homocysteine levels were identified as independent risk factors for proteinuria in patients with type 2 diabetes mellitus.

Background: Measurement of plasma total homocysteine has become common as new methods have been introduced. A wide range of disorders are associated with increased concentrations of total homocysteine. The purpose of this review is to provide an international expert opinion on the practical aspects of total homocysteine determinations in clinical practice and in the research setting and on the relevance of total homocysteine measurements as diagnostic or screening tests in several target populations. Methods: Published data available on Medline were used as the basis for the recommendations. Drafts of the recommendations were critically discussed at meetings over a period of 3 years. Outcome: This review is divided into two sections: (a) determination of homocysteine (methods and their performance, sample collection and handling, biological determinants, reference intervals, within-person variability, and methionine loading test); and (b) risk assessment and disease diagnosis (homocystinuria, folate and cobalamin deficiencies, cardiovascular disease, renal failure, psychiatric disorders and cognitive impairment, pregnancy complications and birth defects, and screening of elderly and newborns). Each of these subsections concludes with a separate series of recommendations to assist the clinician and the research scientist in making informed decisions. The review concludes with a list of unresolved questions.

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.

Background Dyslipidemia is a well-established risk factor for cardiovascular disease. Serum lipids were affected by several gene polymorphisms, folate, homocysteine and other metabolite levels. We aim to investigate the effects of homocysteine metabolism enzyme polymorphisms ( MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) and their interactions with folate, homocysteine on serum lipid levels in Chinese patients with hypertension. Methods Participants were 480 hypertensive adults that enrolled in September to December 2005 from six different Chinese hospitals (Harbin, Shanghai, Shenyang, Beijing, Xi’an, and Nanjing). Known MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G genotypes were determined by PCR-RFLP methods. Serum folate was measured by chemiluminescent immunoassay, homocysteine was measured by high-performance liquid chromatography, serum lipids parameters were determined by an automatic biochemistry analyzer, low-density lipoprotein was calculated by Friedewald’s equation. Unitary linear regression model was used to assess the associations of gene polymorphisms, folate and homocysteine on serum lipid profiles. Unconditional logistic regression model was applied to test the interactions of folate, homocysteine and gene polymorphisms on dyslipidemia. Results No correlations between gene polymorphisms and homocysteine on serum lipid profiles. Compared with normal folate patients, patients with low folate showed higher odds of hypertriglyceridemia (OR = 2.02, 95 % CI: 1.25-3.25, P = 0.004) and low levels of high-density lipoprotein cholesterol (OR = 1.88, 95 % CI: 1.07-3.28, P = 0.027). Each of four gene polymorphisms ( MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) combined with low folate showed higher odds of hypertriglyceridemia (P for trend: 0.049, 0.004, 0.007 and 0.005, respectively). MTHFR C677T and A1298C with low folate showed higher odds of low levels of high-density lipoprotein cholesterol (P for trend: 0.008 and 0.031). Conclusions Low folate status and homocysteine metabolism gene polymorphisms ( MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) may have a synergistic effect increased the incidence of dyslipidemia in Chinese hypertensive population.

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid derived in methionine metabolism. The increased level of Hcy in plasma, hyperhomocysteinemia, is considered to be an independent risk factor for cardio and cerebrovascular diseases. However, it is still not clear if Hcy is a marker or a causative agent of diseases. More and more research data suggest that Hcy is an important indicator for overall health status. This review represents the current understanding of molecular mechanism of Hcy metabolism and its link to hyperhomocysteinemia-related pathologies in humans. The aberrant Hcy metabolism could lead to the redox imbalance and oxidative stress resulting in elevated protein, nucleic acid and carbohydrate oxidation and lipoperoxidation, products known to be involved in cytotoxicity. Additionally, we examine the role of Hcy in thiolation of proteins, which results in their molecular and functional modifications. We also highlight the relationship between the imbalance in Hcy metabolism and pathogenesis of diseases, such as cardiovascular diseases, neurological and psychiatric disorders, chronic kidney disease, bone tissue damages, gastrointestinal disorders, cancer, and congenital defects.

Previous research has shown that nutrients and certain food items influence inflammation. However, little is known about the associations between diet, as a whole, and inflammatory markers. In the present study, we examined the ability of a FFQ-derived dietary inflammatory index (DII) to predict inflammation. Data from a Belgian cross-sectional study of 2524 generally healthy subjects (age 35–55 years) were used. The DII is a population-based, literature-derived dietary index that was developed to predict inflammation and inflammation-related chronic diseases. The DII was calculated from FFQ-derived dietary information and tested against inflammatory markers, namely C-reactive protein (CRP), IL-6, homocysteine and fibrinogen. Analyses were performed using multivariable logistic regression, adjusting for energy, age, sex, BMI, smoking status, education level, use of non-steroidal anti-inflammatory drugs, blood pressure, use of oral contraceptives, anti-hypertensive therapy, lipid-lowering drugs and physical activity. Multivariable analyses showed significant positive associations between the DII and the inflammatory markers IL-6 (>1·6 pg/ml) (OR 1·19, 95 % CI 1·04, 1·36) and homocysteine (>15 μmol/l) (OR 1·56, 95 % CI 1·25, 1·94). No significant associations were observed between the DII and the inflammatory markers CRP and fibrinogen. These results reinforce the fact that diet, as a whole, plays an important role in modifying inflammation.

Homocysteine (Hcy) and Hcy-thiolactone (HTL) affect fibrin clot properties and are linked to cardiovascular disease. Factors that influence fibrin clot properties and stroke are not fully understood. To study sulfur-containing amino acid metabolites, fibrin clot lysis time (CLT) and maximum absorbance (Abs max ) in relation to stroke, we analyzed plasma and urine from 191 stroke patients (45.0% women, age 68 ± 12 years) and 291 healthy individuals (59.7% women, age 50 ± 17 years). Plasma and urinary levels of sulfur-containing amino acid metabolites and fibrin clot properties were significantly different in stroke patients compared to healthy individuals. Fibrin CLT correlated with fibrin Abs max in healthy males (R 2  = 0.439, P  = 0.000), females (R 2  = 0.245, P  = 0.000), female stroke patients (R 2  = 0.187, P  = 0.000), but not in male stroke patients (R 2  = 0.008, P  = ns). Fibrin CLT correlated with age in healthy females but not males while fibrin Abs max correlated with age in both sexes; these correlations were absent in stroke patients. In multiple regression analysis in stroke patients, plasma (p)CysGly, pMet, and MTHFR A1298C polymorphism were associated with fibrin Abs max , while urinary (u)HTL, uCysGly, and pCysGly were significantly associated with fibrin CLT. In healthy individuals, uHTL and uGSH were significantly associated with fibrin Abs max , while pGSH, and CBS T833C 844ins68 polymorphism were associated with fibrin CLT. In logistic regression, uHTL, uHcy, pCysGly, pGSH, MTHFR C677T polymorphism, and Abs max were independently associated with stroke. Our findings suggest that HTL and other sulfur-containing amino acid metabolites influence fibrin clot properties and the risk of stroke.

Ceramide-activated NAD(P)H oxidase has been reported to participate in homocysteine (Hcys)-induced abnormal metabolism of the extracellular matrix (ECM) in rat glomerular mesangial cells. However, it remains unknown whether this ceramide–redox signaling pathway contributes to glomerular injury induced by hyperhomocysteinemia (hHcys) in vivo. The present study was designed to address this question, defining the role of ceramide and activated NAD(P)H oxidase in the development of hHcys-induced glomerular injury. Uninephrectomized Sprague–Dawley rats were fed a folate-free diet for 8 weeks to produce hHcys and the de novo ceramide synthesis inhibitor myriocin or the NAD(P)H oxidase inhibitor apocynin was administrated. Rats with folate-free diet significantly increased plasma Hcys levels, renal ceramide levels, and NAD(P)H oxidase activity accompanied by marked glomerular injury. Treatment of rats with myriocin significantly reduced ceramide levels and improved glomerular injury, as shown by decreased urinary albumin excretion and reduced glomerular damage index. ECM components changed towards to normal levels with decreased tissue inhibitor of metalloproteinase-1 and increased matrix metalloproteinase-1 activity. NAD(P)H oxidase activity and Rac GTPase activity were reduced by 69 and 66%, respectively. In rats treated with apocynin, similar beneficial effects in protecting glomeruli from hHcys-induced injury were observed. These results support the view that de novo ceramide production is involved in Hcys-induced NAD(P)H oxidase activity in the kidney of hHcys rats and indicate the important role of ceramide-mediated redox signaling in hHcys-induced glomerular injury in rats.

Background: Newborn screening for total homocysteine (tHcy) in blood may identify babies with vitamin B12 (B12) deficiency or homocystinuria, but data on the causes of increased tHcy in screening samples are sparse. Methods: Serum concentrations of tHcy, cystathionine, methionine, folate, and B12 and the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism were determined in 4992 capillary blood samples collected as part of the routine screening program in newborn children. Methylmalonic acid (MMA), gender (SRY genotyping), and the frequency of six cystathionine β-synthase (CBS) mutations were determined in 20–27% of the samples, including all samples with tHcy >15 μmol/L (n = 127), B12 <100 pmol/L (n = 159), or methionine >40 μmol/L (n = 154). Results: The median (5th–95th percentile) tHcy concentration was 6.8 (4.2–12.8) μmol/L. B12 status, as determined by serum concentrations of B12, tHcy, and MMA, was moderately better in boys than in girls. tHcy concentrations between 10 and 20 μmol/L were often associated with low B12, whereas tHcy >20 μmol/L (n = 43) was nearly always explained by increased methionine. tHcy did not differ according to folate concentrations or MTHFR 677C>T genotypes. None of the babies had definite CBS deficiencies, but heterozygosity led to low cystathionine, increased methionine, but normal tHcy concentrations. Conclusion: Increased tHcy is a common but not specific finding in newborns. The metabolite and vitamin profiles will point to the cause of hyperhomocysteinemia. Screening for tHcy and related factors should be further evaluated in regions with high prevalence of homocystinuria and in babies at high risk of B12 deficiency.

Folate (vitamin B9) plays a crucial role in fundamental cellular processes, including nucleic acid biosynthesis, methyl group biogenesis and amino acid metabolism. The detection and correction of folate deficiency prevents megaloblastic anaemia and reduces the risk of neural tube defects. Coexisting deficiencies of folate and vitamin B12 are associated with cognitive decline, depression and neuropathy. Folate deficiency and excess has also been implicated in some cancers. Excessive exposure to folic acid, a synthetic compound used in supplements and fortified foods, has also been linked to adverse health effects. Of at least three distinct laboratory markers of folate status, it is the total abundance of folate in serum/plasma that is used by the majority of laboratories. The analysis of folate in red cells is also commonly performed. Since the folate content of red cells is fixed during erythropoiesis, this marker is indicative of folate status over the preceding ~4 months. Poor stability, variation in polyglutamate chain length and unreliable extraction from red cells are factors that make the analysis of folate challenging. The clinical use of measuring specific folate species has also been explored. 5-Methyltetrahydrofolate, the main form of folate found in blood, is essential for the vitamin B12-dependent methionine synthase mediated remethylation of homocysteine to methionine. As such, homocysteine measurement reflects cellular folate and vitamin B12 use. When interpreting homocysteine results, age, sex and pregnancy, specific reference ranges should be applied. The evaluation of folate status using combined markers of abundance and cellular use has been adopted by some laboratories. In the presence of discordance between laboratory results and strong clinical features of deficiency, treatment should not be delayed. High folate status should be followed up with the assessment of vitamin B12 status, a review of previous results and reassessment of folic acid supplementation regime.