Homocysteine, vitamin B12, and folate circulating levels in women with and without polycystic ovary syndrome: A systematic review and meta-analysis.

BACKGROUND: Some studies have reported that homocysteine, vitamin B12, and folic acid levels are associated with polycystic ovary syndrome (PCOS), whereas other studies yielded controversial results. OBJECTIVES: This study aimed to systematize the available evidence of homocysteine, vitamin B12, and folate levels in women with and without PCOS. DESIGN: Systematic review and meta-analysis. DATA SOURCES AND METHODS: A systematic search without language restrictions was performed on PubMed, Ovid/Medline, Scopus, Embase, and Web of Science. In addition, the reference lists of the selected studies were reviewed. The Newcastle-Ottawa Scale was employed to evaluate the quality of studies. The means and standard deviations of the outcomes were pooled as standardized mean differences (SMDs) with 95% confidence intervals (CI). Furthermore, the DerSimonian and Laird method was employed for the quantitative synthesis. RESULTS: A total of 75 studies met the eligibility criteria for at least one outcome. Patients with PCOS had higher circulating homocysteine levels than those without (SMD: 0.82; 95% CI: 0.62-1.02, n = 70 studies, p < 0.001). This trend remained in the sensitivity and subgroup analyses by world regions of studies, assay methods, and insulin resistance. No significant differences were observed in circulating vitamin B12 (SMD: -0.11; 95% CI: -0.25 to 0.03; n = 17 studies, p = 0.13) and folate levels (SMD: -0.2; 95% CI: -0.68 to 0.27; n = 17 studies, p = 0.41) between patients with and without PCOS. CONCLUSIONS: (i) Patients with PCOS exhibited significantly higher homocysteine levels than those without, and (ii) no significant differences were observed in both vitamin B12 and folate levels in women with and without PCOS. REGISTRATION: PROSPERO ID (CRD42023432883).

The effects of the MTHFR 677C>T (rs1801133) genetic variant on susceptibility and disability worsening in multiple sclerosis patients are mediated by homocysteine.

BACKGROUND: Interactions between genetic and environmental variables contribute to the autoimmune inflammatory process in multiple sclerosis (MS). Elevated homocysteine levels, and vitamin D, vitamin B12, and folate deficiencies are some of the environmental factors associated with the pathogenesis of MS. Considering that the relationship between MTHFR 677C>T (rs1801133) genetic variant, homocysteine, and folate in patients with MS remains unclear and that their role were not extensively explored in the clinical course of the disease, we investigated whether this variant and plasma homocysteine and folate levels are associated with MS susceptibility, disability, disability progression, and inflammatory biomarkers. METHODS: The case-control study included 163 patients with MS categorized using the Expanded Disability Status Scale (EDSS) as mild (EDSS<3) and moderate/high (EDSS≥3) disability, and 226 healthy controls (HC). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS) and the MTHFR 677C>T variant was genotyped using real time polymerase chain reaction. The plasma levels of some inflammatory biomarkers were determined. Two new composed scores were proposed: the first, namely as inflammatory activity index (IAI), was entered as a latent vector extracted from the macrophage M1 + T helper (Th)1 + Th17 + Th2 + T regulatory (Treg) cytokines, + tumor necrosis factor (TNF)-α+ soluble TNF receptor (sTNFR)-1 + sTNFR2. The second score, namely MS-severity index was entered as a latent vector extracted from the EDSS + MSSS scores + MS diagnosis. RESULTS: Patients with MS showed higher homocysteine and folate than controls (p < 0.001); homocysteine, and the M1, Th1, Th17, and Th2 Treg cytokine values were different between the three study groups and increased from HC to MS patients with mild disability and to MS patients with moderate/high disability (p < 0.0001). The levels of TNF-α and their soluble receptors sTNFR1 and sTNFR2 were higher in MS patients with EDSS≥3 than in the two other groups (EDSS<3 and HC) (p < 0.001). There was no association between the MTHFR 677 C > T genotypes and MS susceptibility, disability and disability progression (p > 0.05). Moreover, 21.8 % of the disability variance was explained by age, IAI and C-reactive protein (CRP) (all positively associated); 10.9 % of the disability progression variance was predicted by IAI and CRP (both positively) and 25-hydroxyvitamin D (negatively), whereas 54.4 % of the severity index (MS-EDSS-MSSS) was explained by the regression on age, IAI, homocysteine, folate, and CRP (all positively), and adiponectin, body mass index, and 25-hydroxyvitamin D (all negatively), female sex, and the MTHFR 677 TT genotype. In patients and controls, 16.6 % of the variance in the homocysteine was explained by the MTHFR 677 TT genotype and age (both positively), folate (negatively) and male sex. CONCLUSION: The MTHFR 677C>T variant has an indirect effect on the increase in disability in patients with MS, which also depends on factors such as age, sex, ad folate status.

Folate and Vitamin B12 Levels in Chilean Women with PCOS and Their Association with Metabolic Outcomes.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Many women with PCOS have been found to have an unbalanced diet and deficiencies in essential nutrients. This study aimed to assess the levels of folate and vitamin B12 (B12) and their relationship with metabolic factors in women with PCOS. Anthropometric, clinical, and genetic analyses were conducted to evaluate markers related to one-carbon metabolism in women with PCOS and in a control group. The PCOS group had a higher BMI and HOMA-IR (1.7 vs. 3.1; p < 0.0001). HDL cholesterol levels were 23% lower and triglyceride levels were 74% higher in women with PCOS. Although there were no significant differences in folate and B12 levels between the PCOS and control groups, over 60% of women with PCOS had low B12 levels (<300 pg/mL) and high homocysteine levels. In addition, the MTHFR A1298C and C677T polymorphisms were not associated with PCOS. Moreover, erythrocyte folate levels were positively correlated with fasting glucose, triglycerides, and free androgen index, and negatively correlated with SHBG and LH levels. These results suggest that B vitamins may be associated with the metabolic phenotype in PCOS. This study emphasizes the potential link between folate, vitamin B12, and metabolic and hormonal outcomes in women with PCOS.

Folate and vitamin B12 related to homocysteine and DNA damage in female university students / Folato e vitamina B12 relacionados com homocisteína e danos no DNA em estudantes universitárias / Folato y vitamina B12 relacionados con homocisteína y daño en el ADN en estudiantes universitarias

Background and Objectives: It is not clear whether the increase in nutrition students' knowledge is associated with healthier eating behavior and fewer micronutrient deficiencies that can cause DNA damage. Deficiency in some vitamins can be a risk factor for increased homocysteine (Hcy) levels, a marker of cardiovascular risk. Therefore, this study aimed to verify whether dietary and serum folate and vitamin B12 are associated with Hcy levels and DNA damage in female university students. Methods: A cross-sectional study was conducted with female university students from southern Brazil. Folate, vitamin B12, and Hcy levels were determined in their diet or serum. DNA damage levels were assessed by the alkaline comet assay (index and frequency) and the buccal micronucleus assay (micronuclei frequency and binucleated cells frequency). Results: Correlation analyses did not show an association between Hcy levels and dietary or serum folate and vitamin B12 consumption. Dietary folate and vitamin B12 were associated with the index and frequency of damages; however, only serum folate was negatively associated with the index and frequency of damages. Additionally, the frequency of binucleated cells was negatively associated with dietary vitamin B12 and positively associated with serum levels. Serum folate was negatively associated with the frequency of micronuclei. Hcy levels were associated with the index and frequency of damages. Conclusion: These findings strengthen the role of healthier dietary patterns with adequate micronutrients as a preventive strategy to reduce the risk of cardiovascular diseases. This approach should play a pivotal role in shaping health policies and advocating for appropriate food choices.(AU)

Justificativa e Objetivos: Não está claro se o aumento do conhecimento dos estudantes de nutrição está associado a um comportamento alimentar mais saudável, com menores deficiências de micronutrientes que podem induzir danos no DNA. A deficiência de algumas vitaminas pode ser um fator de risco para o aumento dos níveis de homocisteína (Hcy), um marcador de risco cardiovascular. Portanto, este estudo verificou se folato e vitamina B12 dietético e sérico estão associados aos níveis de Hcy e danos no DNA em estudantes universitárias. Métodos: Estudo transversal com universitárias do sul do Brasil. Determinou-se folato, vitamina B12 e Hcy dietético e séricos. Os níveis de danos no DNA foram avaliados pelo ensaio do cometa alcalino (índice e frequência) e pelo ensaio de micronúcleos bucais (frequência de micronúcleos e células binucleadas). Resultados: Análises de correlação não mostraram associação entre os níveis de Hcy com o consumo de folato e vitamina B12 dietético ou sérico. Folato e vitamina B12 dietéticos associou-se ao índice e frequência de danos, entretanto, somente folato sérico associou-se negativamente ao índice e frequência de danos. Ainda, a frequência de células binucleadas estava negativamente associada à vitamina B12 da dieta e positivamente associada aos níveis séricos. Folato sérico associou-se negativamente à frequência de micronúcleos. Os níveis de Hcy associou-se ao índice e frequência de danos. Conclusão: Esses achados fortalecem o papel de padrões alimentares mais saudáveis com micronutrientes adequados como estratégia preventiva visando a redução do risco de doenças cardiovasculares. Esta abordagem deve desempenhar um papel fundamental na formulação de políticas de saúde e na defesa de escolhas alimentares apropriadas.(AU)

Justificación y Objetivos: No está claro si el aumento del conocimiento de estudiantes de nutrición está asociado con un comportamiento alimentario más saludable, con menores deficiencias de micronutrientes que puedan inducir daños en ADN. La deficiencia de algunas vitaminas puede ser un factor de riesgo para el aumento de los niveles de homocisteína (Hcy), marcador de riesgo cardiovascular. Consiguiente, este estudio verificó si folato y vitamina B12 dietéticos y séricos están asociados con niveles de Hcy y daños en el ADN en estudiantes universitarias. Métodos: Estudio transversal con universitarias del sur de Brasil. Se determinaron folato, vitamina B12 y Hcy dietéticos y séricos. Los niveles de daño en el ADN se evaluaron por ensayo del cometa alcalino (índice y frecuencia) y el ensayo de micronúcleos bucales (frecuencia de micronúcleos y células binucleadas). Resultados: Los análisis de correlación no mostraron asociación entre los niveles de Hcy con folato y vitamina B12 dietéticos y séricos. Folato y vitamina B12 dietéticos se asociaron con índice y frecuencia de daños, pero, solo folato sérico se asoció negativamente con índice y frecuencia de daños. Además, la frecuencia de células binucleadas estaba negativamente asociada con la vitamina B12 de la dieta y positivamente asociada con los niveles séricos. Folato sérico se asoció negativamente con la frecuencia de micronúcleos. Los niveles de Hcy se asociaron con índice y frecuencia de daños. Conclusión: Estos hallazgos refuerzan el papel de patrones alimentarios más saludables con micronutrientes adecuados como estrategia preventiva para reducir el riesgo de enfermedades cardiovasculares. Este enfoque debería desempeñar un papel fundamental en la elaboración de políticas de salud y en la promoción de elecciones alimenticias apropiadas.(AU)

Association of c.+677 C>T (rs1801133) and c.+1298 A>C (rs1801131) MTHFR genetic variants with cardiometabolic and disease risk in systemic lupus erythematosus patients: A cross-sectional study.

Systemic lupus erythematosus (SLE) patients present a high prevalence of cardiometabolic risk, associated with worse clinical manifestations and mortality. Folate, an essential micronutrient that participates in vital immune cellular functions, could positively affect the cardiometabolic and disease risk in SLE, through the methylenetetrahydrofolate reductase (MTHFR) enzyme, which participates in the folate metabolism, where single nucleotide variants (SNVs) have been described as a potential genetic risk factor for SLE. The aim of this study was to determine the association of the c.+677 C>T (rs1801133) and c.+1298 A>C (rs1801131) MTHFR genetic variants with cardiometabolic risk and clinical disease variables in SLE patients. A case-control study was conducted on 394 unrelated Mexican-mestizo women: 199 with SLE according to the 1997 SLE-ACR criteria and 196 control subjects (CS). Folic acid and homocysteine levels were evaluated by immunoassays. Genotyping of MTHFR genetic variants was carried out by allelic discrimination. No significant differences were found for folic acid (p = .15) and homocysteine serum levels (p = .59) between groups. According to the CC c.+677 MTHFR genotype, this was associated with low cardiovascular disease (CVD) risk by the Castelli index (OR = 0.42; p = .03) in SLE patients. The TC (OR = 1.3; p = .03) and the TA (OR = 1.6; p < .01) haplotypes from c.+677 C>T plus c.+1298 MTHFR were associated with SLE risk, while the CC MTHFR haplotype (OR = 0.5; p = .01) was found as a non-risk factor for the disease. In conclusion, the TC and the TA MTHFR haplotypes are associated with disease risk; meanwhile, the CC c.+677 MTHFR genotype confers lower cardiometabolic risk in Mexican-mestizo SLE patients.

Homocystein, Vitamin B12 and Folic Acid as Screening Biomarkers in Early Diagnosis and Gastric Cancer Monitoring.

Gastric cancer has been demonstrating a reduction in the number of cases over the past decades, largely attributed to advancements in public health practices and increased accessibility to educational initiatives for the general population. Nevertheless, it persists as the third leading cause of mortality globally among both men and women. These fatalities are typically associated with delayed disease detection. The current study assessed the levels of homocysteine, vitamin B12, and folic acid as a means of establishing a screening biomarker profile that could be integrated into routine testing protocols to facilitate swift diagnosis of the illness. A total of 207 control subjects and 207 individuals with gastric cancer were scrutinized, with biochemical measurements conducted using chemiluminescence for homocysteine, folic acid, and vitamin B12. The two groups were matched based on age, tumor location, subtype, tumor classification, presence of Epstein-Barr Virus infection (EBV), and Helicobacter pylori (H. pylori). Significant statistical variances were identified in the mean levels of the triad of substances among cancer patients when compared to the control group for all corresponding variables. In conclusion, our study indicated that analyzing the triad of homocysteine, vitamin B12, and folic acid holds diagnostic value for gastric cancer and could potentially serve as an effective screening marker for this type of cancer in the future.

Homocysteine as a predictor of apnea-hypopnea index in obstructive sleep apnea: a longitudinal epidemiological study (EPISONO).

BACKGROUND: Obstructive sleep apnea (OSA) affects nearly 1 billion people globally, and has established links with cardiovascular and neurocognitive complications. Although it has some limitations, the apnea-hypopnea index (AHI) is commonly used to gauge OSA severity and therapeutic response. Homocysteine (Hcy) metabolism, when impaired, can elicit cellular senescence mechanisms that may be shared with OSA. Hence, our objective was to explore the role of Hcy concentrations both as a predictor of AHI values and as a potential risk factor for OSA. METHODS: Involving 1042 volunteers aged 20 to 80 years, the initial study (2007) included polysomnographic evaluations, questionnaires on sleep and general health, as well as biochemical analyses. After an 8-year interval, 715 participants from the initial study were invited for a follow-up assessment in 2015. RESULTS: Our findings showed that Hcy was a predictor for an increased AHI, and AHI increased over time. Individuals with plasma Hcy concentrations ≥ 15 µmol/L experienced an average AHI increase of 7.43 events/hour ([beta coefficient] ß = 7.43; 95%CI 2.73 to 12.13) over time, compared to those with plasma concentrations < 10 µmol/L. A similar trend was apparent in those with plasma Hcy concentrations between 10 ≥ and < 15 µmol/L, who had an AHI increase with an average beta coefficient of 3.20 events/hour (95%CI 1.01 to 5.39) compared to those with plasma Hcy concentrations < 10 µmol/L. CONCLUSIONS: In summary, our study suggests that increased plasma Hcy concentrations could be considered a risk factor for the development of OSA. These findings highlight that elevated plasma Hcy concentrations can predict the severity of OSA, underscoring their correlation with the AHI.

The modification of nisin with homocysteine thiolactone and its effect on antimicrobial activity.

The aim of the present study is to make an important contribution to the literature by focusing on the preparation of the N-homocysteine conjugate of nisin and evaluating the effect of the N-homocysteinylation reaction on its antimicriobial activity. The modification process was monitored using both acetic acid urea polyacrylamide gel electrophoresis (AAU-PAGE) and tricine sodium dodecyl sulphate polyacrylamide gel electrophoresis (tricine SDS-PAGE). The antibacterial effectiveness of modified nisin was assessed against Staphylococcus aureus ATCC 6538, Enterococcus faecium ATCC 9097, Bacillus subtilis ATCC 6633, Lactococcus lactis ssp. cremoris AÜ, Listeria monocytogenes NCTC 5348, and Escherichia coli RSKK. Optimal conditions for achieving the highest N-homocysteinylation degree (6.30%) were determined as 6 mg/mL nisin, 150 mM homocysteine thiolactone, 150 rpm shaking rate, pH of 3.0, and a reaction time of 6 h. The modified nisin obtained did not have a significant inhibitory effect on the strains tested except E. faecium. E. faecium was inhibited by the modified nisin and its antibacterial activity was determined as approximately 10% of the antibacterial activity of unmodified nisin. On the other hand, hydrolysis of nisin by trypsin and thermolysin resulted in significant specific side chain modifications induced by the homocysteine-thiolactone reaction, especially at Lys12 and Lys22. The results provide valuable insights into the potential of N-homocysteinylation to improve the antibacterial properties of nisin and also suggest that the effects of specific modifications identified during the modification process should be investigated.

Methionine sources at different dietary levels alters the growth and expression of genes related to homocysteine remethylation in the jejunum of broilers.

Sulfur amino acids are essential for the proper development of broilers and are required throughout the bird's life to perform important physiological functions. Studies that seek to understand the actions of sulfur amino acids in the body of birds are essential. The present study evaluated the influence of sulfur amino acid supplementation using DL-Methionine (DL-Met) and DL-Methionine hydroxy analogue (DL-HMTBA), on the performance and expression of genes related to methionine metabolism, in the jejunum of broilers. Four hundred and fifty male broilers (Cobb-700 slow feathering) were distributed in a completely randomized design, in a factorial scheme (2x3), with two sources of methionine (DL-Met and DL-HMTBA) and three levels of methionine (deficiency, requirement and excess). The mRNA expression of the MAT1, MTR, BHMT, MTRR, CBG and GSS genes, and performance data such as feed intake, weight gain, and feed conversion were evaluated. DL-HMTBA increased the expression of BHMT (p = 0.0072) and MTRR (p = 0.0003) in the jejunum of the birds. Methionine deficiency increased the expression of BHMT (p = 0.0805) and MTRR (p = 0.0018). Higher expression of GSS was observed in birds that were supplemented with DL-HMTBA (p = 0.0672). Analyzing our results, it is preferable to supplement sulfur amino acids with DL-Met at the requirement level. Birds fed with DL-HMTBA showed worse weight gain (p = 0.0117) and higher feed conversion (p = 0.0170); methionine deficiency resulted in higher feed intake (p = 0.0214), lower weight gain (p<0.0001) and consequently higher feed conversion (p<0.0001). Based on the information found in this work, it is recommended to supplement sulfur amino acids with DL-Met at the level of compliance with the requirement.

Vitamin B12, folate, and homocysteine in metabolic syndrome: a systematic review and meta-analysis.

Background & aims: Metabolic syndrome (MetS) is associated with life-threatening conditions. Several studies have reported an association of vitamin B12, folic acid, or homocysteine (Hcy) levels with MetS. This systematic review and meta-analysis assessed the association of vitamin B12, folic acid, and Hcy levels with MetS. Methods: PubMed, Scopus, Embase, Ovid/Medline, and Web of Science were searched up to February 13, 2023. Cross-sectional, case-control, or cohort studies were included. A random-effects model was performed using the DerSimonian and Laird method to estimate the between-study variance. Effect measures were expressed as odds ratios (OR) with their corresponding 95% confidence intervals (95% CI). Between-study heterogeneity was evaluated using Cochran's Q test and the I2 statistic. Results: Sixty-six articles (n = 87,988 patients) were included. Higher vitamin B12 levels were inversely associated with MetS (OR = 0.87; 95% CI: 0.81-0.93; p < 0.01; I2 = 90%). Higher Hcy levels were associated with MetS (OR = 1.19; 95% CI: 1.14-1.24; p < 0.01; I2 = 90%). Folate levels were not associated with MetS (OR = 0.83; 95% CI: 0.66-1.03; p = 0.09; I2 = 90%). Conclusion: Higher vitamin B12 levels were inversely associated with MetS, whereas higher Hcy levels were associated with MetS. Studies assessing the pathways underlying this association are required.

Homocysteine May Decrease Glucose Uptake and Alter the Akt/GSK3ß/GLUT1 Signaling Pathway in Hippocampal Slices: Neuroprotective Effects of Rivastigmine and Ibuprofen.

Homocysteine (Hcy) is a risk factor for neurodegenerative diseases, such as Alzheimer's Disease, and is related to cellular and tissue damage. In the present study, we verified the effect of Hcy on neurochemical parameters (redox homeostasis, neuronal excitability, glucose, and lactate levels) and the Serine/Threonine kinase B (Akt), Glucose synthase kinase-3ß (GSK3ß) and Glucose transporter 1 (GLUT1) signaling pathway in hippocampal slices, as well as the neuroprotective effects of ibuprofen and rivastigmine alone or in combination in such effects. Male Wistar rats (90 days old) were euthanized and the brains were dissected. The hippocampus slices were pre-treated for 30 min [saline medium or Hcy (30 µM)], then the other treatments were added to the medium for another 30 min [ibuprofen, rivastigmine, or ibuprofen + rivastigmine]. The dichlorofluorescein formed, nitrite and Na+, K+-ATPase activity was increased by Hcy at 30 µM. Ibuprofen reduced dichlorofluorescein formation and attenuated the effect of Hcy. The reduced glutathione content was reduced by Hcy. Treatments with ibuprofen and Hcy + ibuprofen increased reduced glutathione. Hcy at 30 µM caused a decrease in hippocampal glucose uptake and GLUT1 expression, and an increase in Glial Fibrillary Acidic Protein-protein expression. Phosphorylated GSK3ß and Akt levels were reduced by Hcy (30 µM) and co-treatment with Hcy + rivastigmine + ibuprofen reversed these effects. Hcy toxicity on glucose metabolism can promote neurological damage. The combination of treatment with rivastigmine + ibuprofen attenuated such effects, probably by regulating the Akt/GSK3ß/GLUT1 signaling pathway. Reversal of Hcy cellular damage by these compounds may be a potential neuroprotective strategy for brain damage.

Homocysteine concentrations in overweight children and adolescents.

OBJECTIVE: The aim of this study was to describe homocysteine concentrations in overweight and obese children and adolescents and relate them to blood pressure levels, renal function, and insulin resistance. METHODS: This is a cross-sectional and observational study with 64 overweight children and adolescents (mean age: 11.6±3.5 years) in outpatient follow-up. The following parameters were evaluated: body mass index z-score, waist-to-height circumference ratio, pubertal stage, blood pressure, serum homocysteine, glycemia, insulin, lipid profile, renal function, high-sensitivity C-reactive protein, microalbuminuria, and creatinuria. Statistical analysis: analysis of variance and logistic regression (dependent variable: homocysteine) (p<0.05). RESULTS: The mean body mass index z-score was 2.9±1.1. The mean homocysteine concentrations were 8.6±2.2 µmol/L (10th and 90th percentiles: 6.6 and 11.2 µmol/L, respectively), with no difference when compared with children with severe obesity and obesity/overweight (p=0.431). High values of waist-to-height ratio (93.8%), systolic blood pressure (18.8%), diastolic blood pressure (12.5%), glycemia (4.7%), low-density lipoprotein cholesterol (31.1%), triglycerides (35.9%), non-high-density lipoprotein cholesterol (34.4%), and microalbuminuria (21.9%) were obtained. The mean glomerular filtration rate was 122.9±24.6 mL/min/1.73 m². Homocysteine concentrations were not associated with any of the studied variables (R²=0.095). CONCLUSION: Homocysteine concentrations in overweight children and adolescents (mean 8.6±2.2 µmol/L) were not associated with body mass index z-score, blood pressure, renal function, and insulin resistance.

Hyperhomocysteinemia as an Independent Risk Factor for Coronary Heart Disease. Comparison with Conventional Risk Factors / Hiper-homocisteinemia como fator de risco independente para doença coronariana: comparação com fatores de risco convencionais

The present study was designed to evaluate the strength of association of raised plasma homocysteine concentration as a risk factor for coronary heart disease independent of conventional risk factor. It was a case control study conducted at Punjab Institute of Cardiology Lahore. A total of 210 subjects aged 25 to 60 years comprising of 105 newly admitted patients of CHD as cases and 105 age and sex matched healthy individuals with no history of CHD as control were recruited for the study. Fasting blood samples were obtained from cases and controls. Plasma homocysteine was analyzed by fluorescence polarization immunoassay (FPIA) method on automated immunoassay analyzer (Abbott IMX). Total cholesterol, triglyceride and HDL cholesterol were analyzed using calorimetric kit methods. The concentration of LDL cholesterol was calculated using Friedewald formula. The patients were also assessed for traditional risk factors such as age, sex, family history of CVD, hypertension, smoking and physical activity, and were compared with control subjects. The collected data was entered in SPSS version 24 for analysis and interpretation.The mean age in controls and experimental groups were 43.00± 8.42 years and 44.72± 8.59 years with statistically same distribution (p- value= 0.144). The mean plasma homocysteine for cases was 22.33± 9.22 µmol/L where as it was 12.59±3.73 µmol/L in control group. Highly significant difference was seen between the mean plasma level of homocysteine in cases and controls (p˂0.001).Simple logistic regression indicates a strong association of coronary heart disease with hyperhomocysteinemia (OR 7.45), which remained significantly associated with coronary heart disease by multivariate logistic regression (OR 7.10, 95%C1 3.12-12.83, p=0.000). The present study concludes that elevated levels of Plasma homocysteine is an independent risk factor [...].(AU)

O presente estudo foi desenhado para avaliar a força da associação da concentração elevada de homocisteína no plasma como um fator de risco para doença cardíaca coronária independente do fator de risco convencional. Foi um estudo de caso-controle realizado no Punjab Institute of Cardiology Lahore. Um total de 210 indivíduos com idade entre 25 e 60 anos, compreendendo 105 pacientes recém-admitidos de CHD como casos e 105 indivíduos saudáveis pareados por idade e sexo sem histórico de CHD como controle, foi recrutado para o estudo. Amostras de sangue em jejum foram obtidas de casos e controles. A homocisteína plasmática foi analisada pelo método de imunoensaio de polarização de fluorescência (FPIA) em analisador de imunoensaio automatizado (Abbott IMX). Colesterol total, triglicerídeos e colesterol HDL foram analisados usando métodos de kit calorimétrico. A concentração de colesterol LDL foi calculada pela fórmula de Friedewald. Os pacientes também foram avaliados para fatores de risco tradicionais, como idade, sexo, história familiar de DCV, hipertensão, tabagismo e atividade física, e foram comparados com indivíduos de controle. Os dados coletados foram inseridos no SPSS versão 24 para análise e interpretação. A média de idade nos grupos controles e experimentais foi de 43,00 ± 8,42 anos e 44,72 ± 8,59 anos com distribuição estatisticamente igual (p-valor = 0,144). A homocisteína plasmática média para os casos foi de 22,33 ± 9,22 µmol / L, enquanto no grupo controle foi de 12,59 ± 3,73 µmol / L. Diferença altamente significativa foi observada entre o nível plasmático médio de homocisteína em casos e controles (p ˂ 0,001). A regressão logística simples indica uma forte associação de doença cardíaca coronária com hiper-homocisteinemia (OR 7,45), que permaneceu significativamente associada com doença cardíaca coronária por multivariada regressão logística (OR 7,10, 95% C1 3,12-12,83, p = 0,000). O presente estudo conclui [...].(AU)

Hyperhomocysteinemia as an Independent Risk Factor for Coronary Heart Disease. Comparison with Conventional Risk Factors / Hiper-homocisteinemia como fator de risco independente para doença coronariana: comparação com fatores de risco convencionais

The present study was designed to evaluate the strength of association of raised plasma homocysteine concentration as a risk factor for coronary heart disease independent of conventional risk factor. It was a case control study conducted at Punjab Institute of Cardiology Lahore. A total of 210 subjects aged 25 to 60 years comprising of 105 newly admitted patients of CHD as cases and 105 age and sex matched healthy individuals with no history of CHD as control were recruited for the study. Fasting blood samples were obtained from cases and controls. Plasma homocysteine was analyzed by fluorescence polarization immunoassay (FPIA) method on automated immunoassay analyzer (Abbott IMX). Total cholesterol, triglyceride and HDL cholesterol were analyzed using calorimetric kit methods. The concentration of LDL cholesterol was calculated using Friedewald formula. The patients were also assessed for traditional risk factors such as age, sex, family history of CVD, hypertension, smoking and physical activity, and were compared with control subjects. The collected data was entered in SPSS version 24 for analysis and interpretation.The mean age in controls and experimental groups were 43.00± 8.42 years and 44.72± 8.59 years with statistically same distribution (p- value= 0.144). The mean plasma homocysteine for cases was 22.33± 9.22 µmol/L where as it was 12.59±3.73 µmol/L in control group. Highly significant difference was seen between the mean plasma level of homocysteine in cases and controls (p˂0.001).Simple logistic regression indicates a strong association of coronary heart disease with hyperhomocysteinemia (OR 7.45), which remained significantly associated with coronary heart disease by multivariate logistic regression (OR 7.10, 95%C1 3.12-12.83, p=0.000). The present study concludes that elevated levels of Plasma homocysteine is an independent risk factor [...].

O presente estudo foi desenhado para avaliar a força da associação da concentração elevada de homocisteína no plasma como um fator de risco para doença cardíaca coronária independente do fator de risco convencional. Foi um estudo de caso-controle realizado no Punjab Institute of Cardiology Lahore. Um total de 210 indivíduos com idade entre 25 e 60 anos, compreendendo 105 pacientes recém-admitidos de CHD como casos e 105 indivíduos saudáveis pareados por idade e sexo sem histórico de CHD como controle, foi recrutado para o estudo. Amostras de sangue em jejum foram obtidas de casos e controles. A homocisteína plasmática foi analisada pelo método de imunoensaio de polarização de fluorescência (FPIA) em analisador de imunoensaio automatizado (Abbott IMX). Colesterol total, triglicerídeos e colesterol HDL foram analisados usando métodos de kit calorimétrico. A concentração de colesterol LDL foi calculada pela fórmula de Friedewald. Os pacientes também foram avaliados para fatores de risco tradicionais, como idade, sexo, história familiar de DCV, hipertensão, tabagismo e atividade física, e foram comparados com indivíduos de controle. Os dados coletados foram inseridos no SPSS versão 24 para análise e interpretação. A média de idade nos grupos controles e experimentais foi de 43,00 ± 8,42 anos e 44,72 ± 8,59 anos com distribuição estatisticamente igual (p-valor = 0,144). A homocisteína plasmática média para os casos foi de 22,33 ± 9,22 µmol / L, enquanto no grupo controle foi de 12,59 ± 3,73 µmol / L. Diferença altamente significativa foi observada entre o nível plasmático médio de homocisteína em casos e controles (p ˂ 0,001). A regressão logística simples indica uma forte associação de doença cardíaca coronária com hiper-homocisteinemia (OR 7,45), que permaneceu significativamente associada com doença cardíaca coronária por multivariada regressão logística (OR 7,10, 95% C1 3,12-12,83, p = 0,000). O presente estudo conclui [...].

Reduced circulating folate among older adults caused by continuous work: nested cross-sectional study conducted in a country with folic acid fortification program.

Population aging is 1 of the biggest challenges facing public health today, and cognitive dysfunction is an important concern. Cognitive impairment may be associated with high folate concentrations and low vitamin B12 concentrations; the latter is a common problem among elderly people. Therefore, we hypothesized there was a high circulating folate concentration among older people living in a country with a mandatory folic acid fortification program. We conducted a cross-sectional study to investigate nutritional status of folate and vitamin B12 among aged people. Three dietary recalls, serum folate (sfolate), erythrocyte (red blood cell) folate (RBC folate), and serum vitamin B12 and homocysteine were collected. Linear regression models were used to investigate factors associated with circulating vitamins. We interviewed 169 participants. Half reported inadequate consumption of folate. However, RBC folate deficiency was observed in 27%, 13% in the serum, and a 10% excess of sfolate. One-quarter reported inadequate consumption of B12, but only 5% had deficiency. Factors negatively associated with circulating folate were continuous work and smoking, and positively associated with polyunsaturated fatty acid. Factor negatively associated with the circulating B12 were use of a dental prosthesis and intake of saturated fatty acid. Permanent investigation of excess of sfolate and B12 deficiency, especially among older adults living in countries exposed to a mandatory folic acid fortification program, is important because of the possible relation to the cognitive function.

Homocysteine is associated with higher risks of ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: High levels of homocysteine (Hct) have been associated with great risks of ischemic stroke. However, some controversy still exists. We performed a systematic review and meta-analysis to compare the levels of Hct between patients with ischemic stroke and controls. METHODS: We performed a systematic literature search for articles reporting Hct levels of patients with occurrence of ischemic stroke. We employed a random-effects inverse-variance weighted meta-analytical approach in order to pool standardized mean differences, with estimation of τ2 through the DerSimonian-Laird method. RESULTS: The initial search yielded 1361 studies. After careful analysis of abstracts and full texts, the meta-analysis included data from 38 studies, which involved almost 16 000 stroke events. However, only 13 studies reported means and standard deviations for cases and controls, and therefore were used in the meta-analysis. Those studies presented data from 5002 patients with stroke and 4945 controls. Standardized mean difference was 1.67 (95% CI 1.00-2.25, P < 0.01), indicating that Hct levels were significantly larger in patients with ischemic stroke compared to controls. Between-study heterogeneity was very large (I2 = 99%), particularly because three studies showed significantly large mean differences. CONCLUSION: This meta-analysis shows that patients with ischemic stroke have higher levels of Hct compared to controls. Whether this is a modifiable risk factor remains to be assessed through larger prospective cohorts.

Clinical Significance of Peptidase M20 Domain Containing 1 Ii Patients with Carotid Atherosclerosis. / Significado Clínico do Domínio da Peptidase M20 Contendo 1 em Pacientes com Aterosclerose Carotídea.

BACKGROUND: Atherosclerosis is the main cause for most cardiovascular diseases, and new biomarkers for this condition are always needed. Peptidase M20 domain containing 1 (PM20D1) is associated with both lipid metabolism and obesity. However, no study focuses on the role of PM20D1 in carotid atherosclerosis. OBJECTIVE: The present study aimed to investigate the role of PM20D1 in carotid atherosclerosis patients. METHODS: The present prospective observational study contained a total of 231 carotid atherosclerosis patients, who went to our department between July 2018 and December 2019. Blood samples and medical characteristics were also obtained from 231 healthy individuals with the same body mass index distribution of carotid atherosclerosis patients. Serum PM20D1 was determined using enzyme-linked immunosorbent assay. Clinical and demographic characteristics of all patients were collected, including age, sex, body mass index and medical history. Levels of C-reactive protein, tumor necrosis factor, homocysteine, as well as total cholesterol, triglyceride, high-density leptin cholesterol and low-density leptin cholesterol were recorded. Statistical analysis was conducted using the SPSS software, with p<0.05 as statistically different. RESULTS: Serum PM20D1 levels were markedly lower in carotid atherosclerosis patients when compared to the healthy control, which were significantly lower in severe carotid atherosclerosis patients and carotid atherosclerosis/stroke patients. Patients with unstable plaques showed markedly lower PM20D1 when compared to patients with stable plaques. No significant difference was found among carotid atherosclerosis patients with different body mass index. Patients with higher PM20D1 levels showed significantly lower expression of C-reactive protein, tumor necrosis factor, homocysteine, triglyceride, total cholesterol and low-density leptin cholesterol. PM20D1 was negatively correlated with C-reactive protein, tumor necrosis factor, homocysteine, total cholesterol and low-density leptin cholesterol in carotid atherosclerosis patients, and could be used as a biomarker for severe carotid atherosclerosis patients or carotid atherosclerosis patients with stroke. Sex, tumor necrosis factor, homocysteine and PM20D1 were risk factors for carotid atherosclerosis. CONCLUSION: PM20D1 was decreased in carotid atherosclerosis patients and was associated with severity, plaque stability, and levels of C-reactive protein, tumor necrosis factor, homocysteine, triglyceride, total cholesterol and low-density leptin cholesterol in carotid atherosclerosis patients.

FUNDAMENTO: A aterosclerose é a principal causa da maioria das doenças cardiovasculares, e novos biomarcadores para essa condição são sempre necessários. O domínio da peptidase M20 contendo 1 (PM20D1) está associado ao metabolismo lipídico e à obesidade. No entanto, nenhum estudo se concentra no papel do PM20D1 na aterosclerose carotídea. OBJETIVO: O objetivo deste estudo foi investigar o papel do PM20D1 em pacientes com aterosclerose carotídea. MÉTODOS: Estudo observacional prospectivo conduzido com um total de 231 pacientes com aterosclerose carotídea que estiveram em nosso departamento entre julho de 2018 e dezembro de 2019. Amostras de sangue e dados médicas foram obtidos de outros 231 indivíduos saudáveis com o mesmo índice de massa corporal (IMC) dos pacientes com aterosclerose carotídea. O PM20D1 sérico foi determinado por ensaio imunossorvente ligado a enzima (ELISA). As características clínicas e demográficas de todos os pacientes foram listadas, incluindo idade, sexo biológico, IMC e histórico médico. Os níveis de proteína C reativa (PCR), fator de necrose tumoral, homocisteína, colesterol total, triglicerídeos, leptina-colesterol de alta densidade e leptina-colesterol de baixa densidade foram registrados. Realizou-se análise estatística no software SPSS, com p<0,05 considerado estatisticamente significante. RESULTADOS: Os níveis séricos de PM20D1 foram marcadamente mais baixos em pacientes com aterosclerose carotídea comparados aos controles saudáveis, sendo significativamente mais baixos em pacientes com aterosclerose carotídea grave e pacientes com aterosclerose carotídea/acidente vascular cerebral. Pacientes com placas instáveis apresentaram PM20D1 marcadamente menor quando comparados a pacientes com placas estáveis. Nenhuma diferença significativa foi encontrada entre pacientes com aterosclerose carotídea com diferentes IMC. Pacientes com níveis mais elevados de PM20D1 apresentaram expressão significativamente menor de PCR, fator de necrose tumoral, homocisteína, triglicerídeos, colesterol total e colesterol de baixa densidade. PM20D1 correlacionou-se negativamente com PCR, fator de necrose tumoral, homocisteína, colesterol total e leptina de baixa densidade em pacientes com aterosclerose carotídea, podendo ser usado como biomarcador para pacientes com aterosclerose carotídea grave ou com aterosclerose carotídea e acidente vascular cerebral. Sexo biológico, fator de necrose tumoral, homocisteína e PM20D1 foram considerados fatores de risco para aterosclerose carotídea. CONCLUSÃO: O PM20D1 estava diminuído em pacientes com aterosclerose carotídea e foi associado com gravidade, estabilidade da placa, níveis de PCR, fator de necrose tumoral, homocisteína, triglicerídeos, colesterol total e colesterol de baixa densidade em pacientes com aterosclerose carotídea.

Rivastigmine Reverses the Decrease in Synapsin and Memory Caused by Homocysteine: Is There Relation to Inflammation?

Elevated levels of homocysteine (Hcy) in the blood, called hyperhomocysteinemia (HHcy), is a prevalent risk factor for it has been shown that Hcy induces oxidative stress and increases microglial activation and neuroinflammation, as well as causes cognitive impairment, which have been linked to the neurodegenerative process. This study aimed to evaluate the effect of mild hyperhomocysteinemia with or without ibuprofen and rivastigmine treatments on the behavior and neurochemical parameters in male rats. The chronic mild HHcy model was chemically induced in Wistar rats by subcutaneous administration of Hcy (4055 mg/kg body weight) twice daily for 30 days. Ibuprofen (40 mg/kg) and rivastigmine (0.5 mg/kg) were administered intraperitoneally once daily. Motor damage (open field, balance beam, rotarod, and vertical pole test), cognitive deficits (Y-maze), neurochemical parameters (oxidative status/antioxidant enzymatic defenses, presynaptic protein synapsin 1, inflammatory profile parameters, calcium binding adapter molecule 1 (Iba1), iNOS gene expression), and cholinergic anti-inflammatory pathway were investigated. Results showed that mild HHcy caused cognitive deficits in working memory, and impaired motor coordination reduced the amount of synapsin 1 protein, altered the neuroinflammatory picture, and caused changes in the activity of catalase and acetylcholinesterase enzymes. Both rivastigmine and ibuprofen treatments were able to mitigate this damage caused by mild HHcy. Together, these neurochemical changes may be associated with the mechanisms by which Hcy has been linked to a risk factor for AD. Treatments with rivastigmine and ibuprofen can effectively reduce the damage caused by increased Hcy levels.

Gut dysbiosis and homocysteine: a couple for boosting neurotoxicity in Huntington disease.

Huntington's disease (HD), a neurodegenerative disorder caused by an expansion of the huntingtin triplet (Htt), is clinically characterized by cognitive and neuropsychiatric alterations. Although these alterations appear to be related to mutant Htt (mHtt)-induced neurotoxicity, several other factors are involved. The gut microbiota is a known modulator of brain-gut communication and when altered (dysbiosis), several complaints can be developed including gastrointestinal dysfunction which may have a negative impact on cognition, behavior, and other mental functions in HD through several mechanisms, including increased levels of lipopolysaccharide, proinflammatory cytokines and immune cell response, as well as alterations in Ca2+ signaling, resulting in both increased intestinal and blood-brain barrier (BBB) permeability. Recently, the presence of dysbiosis has been described in both transgenic mouse models and HD patients. A bidirectional influence between host brain tissues and the gut microbiota has been observed. On the one hand, the host diet influences the composition and function of microbiota; and on the other hand, microbiota products can affect BBB permeability, synaptogenesis, and the regulation of neurotransmitters and neurotrophic factors, which has a direct effect on host metabolism and brain function. This review summarizes the available evidence on the pathogenic synergism of dysbiosis and homocysteine, and their role in the transgression of BBB integrity and their potential neurotoxicity of HD.

The Role of High Concentrations of Homocysteine for the Development of Fetal Growth Restriction / O papel de altas concentrações de homocisteína para o desenvolvimento da restrição de crescimento fetal

Abstract Objective To assess homocysteine (Hcy) levels in the three trimesters of pregnancy in women with fetal growth restriction (FGR) and to evaluate the role of Hcy as a possible predictor of FGR. Methods A total of 315 singleton pregnant women were included in the present prospective cohort study and were monitored since the 1st trimester of pregnancy before delivery. Newborns were monitored for the first 7 days of life. Patients who had risk factors for FGR were excluded. Fetal growth restriction was defined according to uterine fundal height (< 10 percentile), ultrasound fetometry (< 5 percentile), and anthropometry of newborns (<5 percentile). The concentrations of Hcy were detected at between 10 and 14, between 20 and 24, and between 30 and 34 weeks of pregnancy by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristics (ROC) curve test and diagnostic odds ratio (DOR) were performed to evaluate the results of ELISA. Results The concentration of Hcy in patients with FGR was 19.65 umol/L at between 10 and 14 weeks, compared with 9.28 umol/L in patients with normal fetal growth (p<0.0001). The optimal cut-off level for Hcy in the 1st trimester of pregnancy was>13.9 umol/L with AUC 0.788, sensitivity of 75%, specificity of 83.6%, and DOR of 15.2. Conclusion Assessment of serum Hcy concentration may be used as a predictor of FGR, with the highest diagnostic utility in the 1st trimester of pregnancy.

Resumo Objetivo Avaliar os níveis de homocisteína (Hcy) em três trimestres da gravidez em mulheres com restrição de crescimento fetal (FGR, na sigla em inglês) e avaliar o papel da Hcy como possível preditor de FGR. Métodos Um total de 315 gestantes solteiras foram incluídas no presente estudo de coorte prospectivo e monitoradas desde o 1° trimestre de gravidez antes do parto. Os recém-nascidos foram acompanhados durante os primeiros 7 dias de vida. Pacientes que apresentam fatores de risco para FGR foram excluídos. A FGR foi definida de acordo com a altura do fundo do útero (< percentil 10), ultrassonografia fetometria (< percentil 5) e antropometria dos recém-nascidos (< percentil 5). As concentrações de Hcy foram detectadas entre 10 e 14, entre 20 e 24 e entre 30 e 34 semanas de gravidez por ensaio de imunoabsorção enzimática (ELISA, na sigla em inglês). O teste da curva das características de operação do receptor (ROC, na sigla em inglês) e a razão de chances de diagnóstico (DOR, na sigla em inglês) foram realizados para avaliar os resultados do ELISA. Resultados A concentração de Hcy em pacientes com FGR foi de 19,65 umol/L entre 10 e 14 semanas, em comparação com 9,28 umol/L em pacientes com crescimento fetal normal (p<0,0001). O nível de corte ideal para Hcy no 1° trimestre da gravidez foi>13,9 umol/L com AUC 0,788, sensibilidade de 75%, especificidade de 83,6%, e DOR 15,2. Conclusão A avaliação da concentração sérica de Hcy pode ser usada como um preditor de FGR, com maior utilidade diagnóstica no 1° trimestre de gravidez.