Elevated Hcy Levels Research Articles

Folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolism.

Skin fibrosis, characterized by uncontrolled secretion of extracellular matrix (ECM) proteins such as collagen, can lead to excessive scarring and compromised tissue function. Despite the widespread occurrence of fibrotic diseases, effective therapies are lacking. Recent clinical studies have demonstrated a positive correlation between serum homocysteine (Hcy) levels and the severity of systemic sclerosis. However, it remains unclear whether Hcy accumulation plays a pathogenic role in skin fibrosis. Here, we report that Hcy metabolism in fibroblasts plays a crucial role in regulating the pathogenesis of skin fibrosis. Fibrotic skin fibroblasts exhibited elevated levels of Hcy due to the downregulation of catabolism genes CBS and MTR. Experimental skin fibrosis was induced and exacerbated in mouse skin fibroblasts and tissues through adenoviral knockdown of Cbs or Mtr, whereas overexpression of these catabolic genes mitigated the pathogenesis. Furthermore, exogenous Hcy supplementation induced and aggravated the expression of inflammatory and fibrotic genes, promoting both spontaneous and BLM-induced skin fibrosis. Notably, folate administration enhanced Hcy catabolism and ameliorated skin inflammation and fibrosis by inhibiting JAK2/STAT3 signaling pathway. Collectively, these results indicate that skin fibrosis is associated with Hcy metabolic disorders and suggest that targeting Hcy metabolism or supplementing folate may provide a novel strategy for skin fibrosis.

Homocysteine Metabolites, Endothelial Dysfunction, and Cardiovascular Disease.

Atherosclerosis is accompanied by inflammation that underlies cardiovascular disease (CVD) and its vascular manifestations, including acute stroke, myocardial infarction, and peripheral artery disease, the leading causes of morbidity/mortality worldwide. The monolayer of endothelial cells formed on the luminal surface of arteries and veins regulates vascular tone and permeability, which supports vascular homeostasis. Endothelial dysfunction, the first step in the development of atherosclerosis, is caused by mechanical and biochemical factors that disrupt vascular homeostasis and induce inflammation. Together with increased plasma levels of low-density lipoprotein (LDL), diabetes, hypertension, cigarette smoking, infectious microorganisms, and genetic factors, epidemiological studies established that dysregulated metabolism of homocysteine (Hcy) causing hyperhomocysteinemia (HHcy) is associated with CVD. Patients with severe HHcy exhibit severe CVD and die prematurely due to vascular complications. Biochemically, HHcy is characterized by elevated levels of Hcy and related metabolites such as Hcy-thiolactone and N-Hcy-protein, seen in genetic and nutritional deficiencies in Hcy metabolism in humans and animals. The only known source of Hcy in humans is methionine released in the gut from dietary protein. Hcy is generated from S-adenosylhomocysteine (AdoHcy) and metabolized to cystathionine by cystathionine β-synthase (CBS) and to Hcy-thiolactone by methionyl-tRNA synthetase. Hcy-thiolactone, a chemically reactive thioester, modifies protein lysine residues, generating N-homocysteinylated (N-Hcy)-protein. N-Hcy-proteins lose their normal native function and become cytotoxic, autoimmunogenic, proinflammatory, prothrombotic, and proatherogenic. Accumulating evidence, discussed in this review, shows that these Hcy metabolites can promote endothelial dysfunction, CVD, and stroke in humans by inducing pro-atherogenic changes in gene expression, upregulating mTOR signaling, and inhibiting autophagy through epigenetic mechanisms involving specific microRNAs, histone demethylase PHF8, and methylated histone H4K20me1. Clinical studies, also discussed in this review, show that cystathionine and Hcy-thiolactone are associated with myocardial infarction and ischemic stroke by influencing blood clotting. These findings contribute to our understanding of the complex mechanisms underlying endothelial dysfunction, atherosclerosis, CVD, and stroke and identify potential targets for therapeutic intervention.

Association Between Folate Metabolism Risk, Collateral Circulation, and Hemorrhagic Risk in Moyamoya Disease.

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms are known risk factors for vascular diseases due to the impact on folate metabolism dysfunction and homocysteine (Hcy) accumulation. This study aimed to investigate the association between folate metabolism risk and hemorrhagic risk in moyamoya disease (MMD). In this prospective study, we enrolled 350 MMD patients with complete genotype data for MTHFR and MTRR. Patients were divided into non-hemorrhagic and hemorrhagic MMD groups. Folate metabolism risk was classified into three levels according to genotype configurations. We analyzed the association between folate metabolism risk and hemorrhagic risk in MMD. Furthermore, the association between folate metabolism risk, collateral circulation, and periventricular anastomosis (PA) was assessed. In vitro experiments were conducted on HBMECs to explore the potential mechanism. TT genotype and T allele in MTHFR C677T were significantly associated with a lower risk of hemorrhage, whereas AC genotype and C allele in MTHFR A1298C were significantly linked to a higher risk of hemorrhage. Patients with high folate metabolism risk exhibited a significantly decreased risk of hemorrhage compared to those with low folate metabolism risk. Further analyses demonstrated that high folate metabolism risk was significantly correlated with poor collateral circulation and PA dilation and elevated levels of Hcy. In vitro experiments showed that increased Hcy levels significantly inhibited the proliferation, migration, and tube formation of HBMECs. This study identified a significant negative correlation between folate metabolism risk and hemorrhagic risk in MMD. URL: http://www.chictr.org.cn . Unique identifier: ChiCTR2200061889.

Association of plasma homocysteine with cognitive impairment in patients with Parkinson’s disease

BackgroundElevated plasma homocysteine (Hcy) has been reported as a risk factor for cognitive impairment in the general population. However, there are conflicting results regarding the relationship between Hcy and cognitive impairment across various cognitive domains in Parkinson’s disease (PD).ObjectiveThis study aims to explore the association between plasma Hcy levels, cognitive impairment, and dysfunction in various cognitive domains among PD patients with and without mild cognitive impairment (MCI).MethodsA total of 101 PD patients underwent plasma Hcy measurement, comprising 50 PD-MCI patients and 51 patients with normal cognition (PD-NC). A battery of neuropsychological tests was administered to assess different cognitive domains. Adjusted generalized linear models were used to assess the correlations between Hcy levels and cognitive functions.ResultsAs anticipated, PD-MCI patients demonstrated a significant decline in cognitive function across all five cognitive domains (memory, executive function, attention/working memory, language, and visuospatial function). Elevated plasma Hcy levels (≥ 10 μmol/L) were associated with a higher odds of PD-MCI, even within the normal range of Hcy levels (< 15 μmol/L). After adjusting for confounding factors, a negative correlation was observed between plasma Hcy levels and the performance on specific cognitive tests evaluating executive functions in PD, such as the Stroop Color-Word Test-C (β = −1.123, 95% CI = −1.845 ∼−0.401, p = 0.0023).ConclusionThis study underscores a significant link between plasma Hcy levels and PD-MCI, particularly concerning executive dysfunction, even within the normal range of Hcy levels (< 15 μmol/L).

Serum homocysteine and left ventricular hypertrophy in adults with chronic kidney disease: A case-control study.

Hyperhomocysteinemia (serum homocysteine concentration > 15 μmol/L) is of high prevalence in chronic kidney disease (CKD). And myocardial hypertrophy is a common complication of CKD. Given that both hyperhomocysteinemia and cardiac hypertrophy have an association with CKD, we hypothesized that high level of plasma homocysteine (Hcy) is associated with a higher prevalence of ventricular hypertrophy(LVH) in adults with CKD. The registration number of the case-control study is ChiCTR2200064834. The information of inpatients with CKD including Echocardiograms and analysis of plasma Hcy concentrations were collected. We performed linear and logistic regression to investigate the association of plasma Hcy with left ventricular hypertrophy (LVH) (LVMI ≥ 95th percentile), adjusted for levels of hemoglobin, ferritin, cystatin C and β-adrenergic blocker therapy. Further, a stratified analysis of the relationship between plasma Hcy and LVH was carried out according to eGFR. The case records for 1068 inpatients with CKD were collected. After data soring and case-control matching, there were 374 samples screened for statistical analysis. Univariate logistic regression indicated a high level of serum Hcy had an association with LVH (OR, 1.16; 95% CI, 1.11-1.20). Finally, multivariable logistic regression suggested that hyperhomocysteinemia was independently associated with LVH (OR, 1.14; 95% CI, 1.10-1.19) after adjustment for hemoglobin, ferritin, cystatin C, and β-adrenergic receptor blocker therapy. We constructed a predicting model including the variable of Hcy for cardiac hypertrophy in CKD. The model had an area under the ROC curve (AUC) of 0.86 (95% CI: 0.82-0.89, P < .001). The decision curve analysis (DCA) showed a superior net clinical benefit of model with Hcy over model without Hcy. Elevated level of serum Hcy is closely associated with LVH in adults with CKD.

Serum Homocysteine and Atrial Fibrillation Recurrence after Catheter Ablation: A Meta-Analysis of 11 Cohort Studies Involving 2147 Patients.

The relationship between serum homocysteine (Hcy) levels and atrial fibrillation (AF) recurrence following catheter ablation remains unclear. This meta-analysis aims to investigate this association. Comprehensive searches in PubMed, Web of Science, Embase, Wanfang, and China National Knowledge Infrastructure (CNKI) databases identified relevant studies published up to May 25, 2024. Cohort studies that measured pre-ablation serum Hcy levels and reported AF recurrence post-ablation were included. Data were analyzed using random-effects models by incorporating the potential influence of heterogeneity, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated for the association between serum Hcy levels and AF recurrence. Eleven retrospective cohort studies involving 2147 patients with AF who underwent catheter ablation were analyzed. Higher pre-ablation serum Hcy levels were associated with an increased risk of AF recurrence (OR for per 1 μmol/l increment of Hcy: 1.22, 95% CI: 1.17 to 1.28, p<0.001; I²=0%). Additionally, studies that categorized Hcy levels also found a higher risk of AF recurrence in patients with elevated Hcy (OR for patients with a high versus a low serum Hcy: 2.75, 95% CI: 2.02 to 3.75, p <0.001; I²=0%). Funnel plots and Egger's regression test indicated low risks of publication bias. In conclusions, elevated pre-ablation serum Hcy levels are significantly associated with an increased risk of AF recurrence post-catheter ablation. These findings suggest that Hcy could be a valuable biomarker for predicting AF recurrence and may inform pre-ablation risk stratification. Further prospective studies are warranted to confirm these results.

Association between homocysteine levels and mortality in CVD: a cohort study based on NHANES database

BackgroundCardiovascular disease (CVD) is a major global health concern with increasing incident cases and deaths. Homocysteine (Hcy) has been investigated for its potential association with CVD, researchers have debated the extent to which Hcy should be considered a risk factor for cardiovascular diseases, as only 50% of CVD can be explained by classical risk factors.MethodsWe conducted a prospective cohort study using NHANES 1999–2006 data, analyzing 1,739 US patients aged at least 30 with CVD. Cox proportional hazards regression and restricted cubic splines were used to examine the relationship between Hcy levels and mortality, adjusting for covariates.ResultA total of 1,739 participants with cardiovascular disease (CVD) were enrolled, with a median follow-up period of 126 months. Among them, 1,194 participants died, including 501 deaths due to cardiovascular causes. After adjusting for covariates, the hazard ratios (HR) and 95% confidence intervals (CI) for CVD mortality at different levels of homocysteine (Hcy) (T1 (< 9.3), T2 (9.3–12.5), T3 (> 12.5)) were 1.26 (0.92, 1.73) (T2), and 1.69 (1.14, 2.51) (T3) (P for trend = 0.0086). The HR and 95% CI for all-cause mortality at different levels of Hcy were 1.22 (1.05, 1.42) (T2) and 1.64 (1.29, 2.09) (T3) (P for trend < 0.0001). Elevated Hcy levels were associated with increased risks of all-cause mortality and CVD deaths, even at levels below the conventional threshold. The nonlinear relationship was observed, with inflection points at 14.5 µmol/L for all-cause mortality and 14.6 µmol/L for CVD mortality. Subgroup analyses revealed interactions with age, serum vitamin B12, and smoking.ConclusionOur study supports the notion that elevated Hcy levels are associated with higher all-cause and CVD mortality risks in CVD participants. The impact of Hcy on health outcomes can be observed at lower concentrations than previously thought.

Establishment of a prediction model for venous thromboembolism in patients with acute exacerbation of chronic obstructive pulmonary disease based on serum homocysteine levels and Wells scores: a retrospective cohort study

BackgroundWe evaluated the diagnostic value of homocysteine (Hcy) levels combined with the Wells score and established a prediction model for venous thromboembolism (VTE) occurrence in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) based on the Hcy level and the Wells score.Patients and methodsClinical information from 914 patients with AECOPD was retrospectively collected in our hospital from June 2020 to October 2023. Receiver operating characteristic curves were plotted to evaluate the diagnostic ability of Hcy concentrations combined with Wells scores and the prediction ability of the model. Univariate and multivariate logistic regressions were used to explore the effects of Hcy levels and the Wells score on VTE occurrence. A nomogram was established for individual risk evaluation.ResultsHcy levels and Wells scores were significantly greater in the VTE group than in the non-VTE group (P < 0.001). The diagnostic ability of Hcy levels combined with the Wells score was greater than that Hcy levels or the Wells score alone. The AUC of the combined parameters was 0.935, with a sensitivity of 0.864 and a specificity of 0.855. Multivariate logistic regression indicated that elevated Hcy levels (OR:5.17, 95%CI: 3.76–7.09, P < 0.001) and Wells score (OR: 5.26, 95%CI: 3.22–8.59, P < 0.001) were independently associated with the risk of developing VTE in AECOPD patients. Decision curve analysis indicated that the net benefit of the nonadherence prediction nomogram was greater than that of the models adjusted for no or all variables, with a threshold of approximately 0.1-1.0.ConclusionsThe established prediction model can be used to evaluate an individual’s risk of developing VTE on the basis of the Hcy level, Wells score, and clinical parameters. AECOPD patients may benefit from the early intervention based on estimated risk probability.

Impact of smokeless tobacco on psychological and oxidative stress in unemployed indian youth

In India, tobacco (nicotine) addiction among youth has increased, leading to substantial socioeconomic burdens, mortality, and morbidity. While minimal short-term nicotine consumption may have antioxidant effects, chronic exposure results in various adverse health outcomes. This study examines the impact of chronic nicotine consumption on cellular oxidative stress and psychological stress, and their correlation with Homocysteine (Hcy) levels in unemployed tobacco consumers. This case-control study included 156 healthy, educated, unemployed male volunteers aged 20–40 years, divided into nicotine-addicted (n = 80) and non-addicted (n = 76) groups. Psychological stress was assessed using perceived stress scales (PSS) and coping self-efficacy (CSE) scales. Oxidative stress markers, including Malondialdehyde (MDA), Superoxide Dismutase (SOD), and Catalase, were measured. Hcy levels were quantified using high-performance liquid chromatography (HPLC). Nicotine-addicted participants exhibited significantly higher perceived stress (p = 0.0001) and lower coping self-efficacy (p = 0.0001) compared to non-addicted individuals. MDA levels in erythrocytes were significantly increased (p = 0.0006), while SOD (p = 0.0001) and Catalase (p = 0.02) activities were significantly decreased in the addicted group. Nicotine intake influenced Hcy concentrations, with 55% of addicted individuals falling into moderate, 27.5% into intermediate, and 7.5% into severe Hcy categories. Chronic nicotine intake also reflected the hematological parameters (WBCs, RBCs, HGB, and Platelets). Chronic tobacco consumption induces oxidative stress and perceived psychological stress, leading to elevated Hcy levels in nicotine consumers. The study highlights the detrimental effects of nicotine addiction on cellular defensive mechanisms, emphasizing the need for targeted interventions to address this growing health issue among unemployed Indian youth.

Predictive value of serological indices for guiding bundle of care to prevent the occurrence of poststroke fatigue for ischemic stroke survivors.

Almost half of ischemic stroke (IS) survivors have poststroke fatigue (PSF) during rehabilitation, which can reduce their rehabilitation compliance and quality of life. The primary link of PSF management is early identification, which can guide bundle of care for prevention. This study aimed to explore the predictive value of serological indicators for guiding bundle of care to prevent the occurrence of PSF among IS survivors. This study was a prospective observational study. A total of 350 patients with IS who were hospitalized in 2 tertiary hospitals in Nanning from October 2022 to September 2023 were selected. The general data of patients and serological indicators within 24 hours of admission were collected. Based on the follow-up results, the patients were divided into the PSF group and the NPSF group. Multivariate logistic regression analysis was used to screen the risk factors affecting the occurrence of PSF, and the receiver operating characteristic curve (ROC curve) method was used to analyze the predictive value of this factor. The incidence of acute-phase PSF among elderly patients with IS was 49.26%. The elevated levels of fasting plasma glucose (FPG) (OR = 1.485, 95% CI: 1.145-1.925, P = .003), total cholesterol (TC) (OR = 1.394, 95% CI: 1.013-1.917, P = .041), C-reactive protein (CRP) (OR = 1.394, 95% CI: 1.013-1.917, P = .041), and homocysteine (Hcy) (OR = 1.370, 95% CI: 1.233-1.524, P < .001) were risk factors of PSF in elderly patients with acute IS (P < .05). FPG (area under the curve = 0.632), TC (area under the curve = 0.621), CRP (area under the curve = 0.889), and Hcy (area under the curve = 0.807) had a good predictive value for acute-phase PSF, and the combination of the 4 indicators could further improve the predictive efficacy (area under the curve = 0.938, sensitivity 86.2%, specificity 90.7%, P < .05). The elevated levels of FPG, TC, CRP, and Hcy could predict the risk of PSF, and the combination of the 4 indicators can effectively improve prediction efficiency and provide a reference for guiding the formulation of bundle nursing programs.

Homocysteine metabolites impair the PHF8/H4K20me1/mTOR/autophagy pathway by upregulating the expression of histone demethylase PHF8-targeting microRNAs in human vascular endothelial cells and mice.

The inability to efficiently metabolize homocysteine (Hcy) due to nutritional and genetic deficiencies, leads to hyperhomocysteinemia (HHcy) and endothelial dysfunction, a hallmark of atherosclerosis which underpins cardiovascular disease (CVD). PHF8 is a histone demethylase that demethylates H4K20me1, which affects the mammalian target of rapamycin (mTOR) signaling and autophagy, processes that play important roles in CVD. PHF8 is regulated by microRNA (miR) such as miR-22-3p and miR-1229-3p. Biochemically, HHcy is characterized by elevated levels of Hcy, Hcy-thiolactone and N-Hcy-protein. Here, we examined the effects of these metabolites on miR-22-3p, miR-1229-3p, and their target PHF8, as well as on the downstream consequences of these effects on H4K20me1, mTOR-, and autophagy-related proteins and mRNAs expression in human umbilical vein endothelial cells (HUVEC). We found that treatments with N-Hcy-protein, Hcy-thiolactone, or Hcy upregulated miR-22-3p and miR-1229-3p, attenuated PHF8 expression, upregulated H4K20me1, mTOR, and phospho-mTOR. Autophagy-related proteins (BECN1, ATG5, ATG7, lipidated LC3-II, and LC3-II/LC3-I ratio) were significantly downregulated by at least one of these metabolites. We also found similar changes in the expression of miR-22-3p, Phf8, mTOR- and autophagy-related proteins/mRNAs invivo in hearts of Cbs-/- mice, which show severe HHcy and endothelial dysfunction. Treatments with inhibitors of miR-22-3p or miR-1229-3p abrogated the effects of Hcy-thiolactone, N-Hcy-protein, and Hcy on miR expression and on PHF8, H4K20me1, mTOR-, and autophagy-related proteins/mRNAs in HUVEC. Taken together, these findings show that Hcy metabolites upregulate miR-22-3p and miR-1229-3p expression, which then dysregulate the PHF8/H4K20me1/mTOR/autophagy pathway, important for vascular homeostasis.

Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome.

Metabolic syndrome (MetS) represents a constellation of metabolic abnormalities, typified by obesity, hypertension, hyperglycemia, and hyperlipidemia. It stems from intricate dysregulations in metabolic pathways governing energy and substrate metabolism. While comprehending the precise etiological mechanisms of MetS remains challenging, evidence underscores the pivotal roles of aberrations in lipid metabolism and insulin resistance (IR) in its pathogenesis. Notably, nicotinamide N-methyltransferase (NNMT) has recently surfaced as a promising therapeutic target for addressing MetS. Single nucleotide variants in the NNMT gene are significantly correlated with disturbances in energy metabolism, obesity, type 2 diabetes (T2D), hyperlipidemia, and hypertension. Elevated NNMT gene expression is notably observed in the liver and white adipose tissue (WAT) of individuals with diabetic mice, obesity, and rats afflicted with MetS. Knockdown of NNMT elicits heightened energy expenditure in adipose and hepatic tissues, mitigates lipid accumulation, and enhances insulin sensitivity. NNMT catalyzes the methylation of nicotinamide (NAM) using S-adenosyl-methionine (SAM) as the donor methyl group, resulting in the formation of S-adenosyl-l-homocysteine (SAH) and methylnicotinamide (MNAM). This enzymatic process results in the depletion of NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and the generation of SAH, a precursor of homocysteine (Hcy). Consequently, this cascade leads to reduced NAD+ levels and elevated Hcy levels, implicating NNMT in the pathogenesis of MetS. Moreover, experimental studies employing RNA interference (RNAi) strategies and small molecule inhibitors targeting NNMT have underscored its potential as a therapeutic target for preventing or treating MetS-related diseases. Nonetheless, the precise mechanistic underpinnings remain elusive, and as of yet, clinical trials focusing on NNMT have not been documented. Therefore, further investigations are warranted to elucidate the intricate roles of NNMT in MetS and to develop targeted therapeutic interventions.

Homocysteine levels in first-episode patients with psychiatric disorders

A high homocysteine (Hcy) level is a risk factor for schizophrenia, depression, and bipolar disorder. However, the role of hyperhomocysteinemia as either an independent factor or an auxiliary contributor to specific psychiatric symptoms or disorders remains unclear. This study aimed to examine Hcy levels in first-episode inpatients with psychotic symptoms and various psychiatric diseases to elucidate the association between Hcy levels and psychiatric disorders. This study enrolled 191 patients (aged 18–40 years) with psychiatric disorders. Seventy-five patients were diagnosed with schizophrenia, 48 with acute and transient psychotic disorders, 36 with manic episodes with psychosis, 32 with major depressive episodes with psychosis, and 56 healthy controls. Serum Hcy levels were measured using the enzyme cycle method. A Hcy concentration level of &amp;gt; 15 μmol/L was defined as hyperhomocysteinemia. Hcy levels were significantly higher in first-episode patients with psychiatric disorders compared to healthy controls (5.99 ± 3.60 vs. 19.78 ± 16.61 vs. 15.50 ± 9.08 vs. 20.00 ± 11.33 vs. 16.22 ± 12.06, F = 12.778, P &amp;lt; 0.001). Hcy levels were significantly higher in males with schizophrenia, acute and transient psychotic disorder, and major depressive disorder but not in mania [schizophrenia, (t = -4.727, P &amp;lt; 0.001); acute and transient psychotic disorders, (t = -3.389, P = 0.001); major depressive episode with psychosis, (t = -3.796, P &amp;lt; 0.001); manic episodes with psychosis, (t = -1.684, P = 0.101)]. However, serum Hcy levels were not significantly different among the psychiatric disorder groups (F = 0.139, P = 0.968). Multivariate linear regression showed that males had an increased risk for homocysteinemia. (95% CI = 8.192–15.370, P &amp;lt; 0.001). These results suggest that first-episode patients with psychiatric disorders have higher Hcy levels than in the general population, and men are at greater risk for psychiatric disorders. In conclusion, elevated Hcy levels may contribute to the pathogenesis of first-episode patients with psychotic symptoms.

Study on the Correlation between Hcy and Hs-CRP Levels and Cognitive Function in Patients with Bipolar Disorder and Borderline Personality Disorder.

This study aims to explore the correlation and clinical significance of homocysteine and high-sensitivity C-reactive protein levels with cognitive function in patients with bipolar disorder (BD) and borderline personality disorder (BPD). Patients with BD admitted to our hospital from January 2022 to December 2022 were chosen retrospectively. BPD patients were categorized into comorbidity groups, while those without BPD were assigned to non-comorbidity groups, each consisting of 60 cases. Enzyme-linked immunosorbent assay (ELISA) was utilized to assess serum levels of homocysteine (Hcy) and high-sensitivity C-reactive protein (hs-CRP) in both patient groups. Clinical symptoms were evaluated by the Hamilton Depression Rating Scale (HAMD) and the Young Mania Rating Scale (YMRS). Cognitive function was evaluated and compared using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Pearson correlation analysis was performed on the correlation between patients' serum Hcy and hs-CRP levels and HAMD, YMRS, and RBANS scores. In the comorbidity group, patients exhibited significantly elevated serum Hcy and hs-CRP levels compared to the non-comorbidity group (p < 0.05). Patients in the comorbidity group displayed higher HAMD and YMRS scores than those in the non-comorbidity group (p < 0.05). Additionally, attention, speech, visual span, immediate memory, and delayed memory in the comorbidity group were notably lower than in the non-comorbidity group (p < 0.05). The speech, visual span, and immediate memory of RBANS in bipolar depressive patients with comorbid BPD were lower than those in bipolar depressive patients without comorbid BPD (p < 0.05), the speech of RBANS in bipolar manic patients with comorbid BPD was lower than those in bipolar manic patients without comorbid BPD (p < 0.05). Pearson correlation analysis showed that the expression of Hcy and hs-CRP in the comorbid group was positively correlated with HAMD and YMRS scores, and negatively correlated with attention, speech, visual span, immediate memory, and delayed memory, and these differences were statistically significant (p < 0.05). High serum Hcy and hs-CRP expression levels may regulate inflammatory responses, aggravating cognitive impairment in patients with BD and BPD. Serum Hcy and hs-CRP expression levels are significantly related to cognitive dysfunction. They are expected to guide the prevention and treatment of BD comorbid BPD patients.

Nonlinear Relationship Between Homocysteine and Mild Cognitive Impairment in Early Parkinson's Disease: A Cross-Sectional Study.

Cognitive impairment, a prevalent non-motor symptom in advanced Parkinson's disease (PD), has been associated with hyperhomocysteinemia, an important risk factor for PD progression and cognitive decline in PD. However, evidence regarding the association between homocysteine (Hcy) and cognitive function during early PD remains insufficient. Therefore, this study aims to examine the correlation between Hcy levels and cognitive function in the early stage of PD. The study included 218 individuals in the early stages of PD who were consecutively admitted to the Suining Central Hospital Neurology Department. All the individuals completed the Parkinson's Disease Cognitive Rating Scale (PD-CDR). The Unified Parkinson's Disease Rating Scale part III (UPDRS-III) was employed for measuring the severity of motor symptoms, while the Hoehn-Yahr scale was used to measure the clinical symptom stage. Fasting venous blood samples were also drawn to measure the Hcy concentration, red blood cell folate, and vitamin B12. In this cross-sectional study, 47 (21.5%) patients with PD showed cognitive dysfunction. The serum Hcy levels were significantly higher in the cognitive impairment PD (PDCI) group compared with the cognitive normal PD group (P<0.001). The Generalized Additive Model (GAM) analysis revealed a nonlinear relationship between Hcy and the risk of PDCI. Multiple logistic regression analyses demonstrated a positive relationship between elevated Hcy and the risk of PDCI in the fully adjusted model ([OR]:3.1, 95% CI, 1.1-8.5, P=0.028). Segmented linear regression analysis showed that when Hcy levels were above 17.7 umol/l, the risk of PDCI increased by 1.6 times for every 1 unit elevated in Hcy (95% CI:1.1-2.2, P=0.008). This study revealed a nonlinear positive correlation between the risk of PDCI and elevated serum Hcy levels in early PD patients, suggesting hyperhomocysteinemia as one of the treatable factors for cognitive impairment in the early stages of PD.

Homocysteine metabolites inhibit autophagy by upregulating miR-21-5p, miR-155-5p, miR-216-5p, and miR-320c-3p in human vascular endothelial cells

Nutritional and genetic deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis, which is a major cause of cardiovascular disease (CVD). Impaired autophagy causes the accumulation of damaged proteins and organelles and is associated with CVD. Biochemically, HHcy is characterized by elevated levels of Hcy and its metabolites, Hcy-thiolactone and N-Hcy-protein. However, whether these metabolites can dysregulate mTOR signaling and autophagy in endothelial cells is not known. Here, we examined the influence of Hcy-thiolactone, N-Hcy-protein, and Hcy on autophagy human umbilical vein endothelial cells. We found that treatments with Hcy-thiolactone, N-Hcy-protein, or Hcy significantly downregulated beclin 1 (BECN1), autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and microtubule-associated protein 1 light chain 3 (LC3) mRNA and protein levels. We also found that these changes were mediated by upregulation by Hcy-thiolactone, N-Hcy-protein, and Hcy of autophagy-targeting microRNA (miR): miR-21, miR-155, miR-216, and miR-320c. The effects of these metabolites on levels of miR targeting autophagy as well as on the levels of BECN1, ATG5, ATG7, and LC3 mRNA and protein were abrogated by treatments with inhibitors of miR-21, miR-155, miR-216, and mir320c. Taken together, our findings show that Hcy metabolites can upregulate miR-21, miR-155, miR-216, and mir320c, which then downregulate autophagy in human endothelial cells, important for vascular homeostasis.

Homocysteine modifies the association of coronary stenosis and HIV infection in an inner city African American population.

People with HIV (PWH) whose disease is controlled on anti-retroviral regimens remain at an increased risk for coronary artery disease (CAD). Traditional cardiovascular risk factors do not fully explain the residual risk in PWH suggesting contributions from nontraditional factors. Homocysteine (Hcy) may be one of these as prior work in adults without HIV demonstrate that Hcy may impair endothelial function by decreasing the availability of nitric oxide, promoting the development of atherosclerosis. In addition, plasma Hcy levels are higher in PWH than in individuals living without HIV. The aim of this study was to investigate whether Hcy levels influence the association between HIV and coronary stenosis in an inner city African American population. African Americans from the Heart Study in Baltimore, with and without HIV, recruited from inner-city Baltimore between June 2004 and February 2015, were included in this analysis. Participants underwent coronary CT angiography to evaluate the presence of coronary stenosis, defined as luminal stenosis >10%. Hcy was measured from stored serum samples. In this analysis, the median [IQR] age of the 664 participants was 56 [50-66] years; 68.1% were living with HIV and 43.1% were women. Elevated Hcy (>15µmol/L) was more prevalent in those with coronary stenosis (23.3%, 95% CI: 18.4%-28.2%) than in those without coronary stenosis (13.1%, 95% CI: 9.7%-16.5%) (p = 0.0007), and HIV was associated with coronary stenosis in those participants with an elevated Hcy (Prevalence Ratio: 1.94, 95% CI: 1.04-3.64, p = 0.0038) and not in those with a Hcy ≤15µmol/L (Prevalence Ratio: 1.02, 95% CI: 0.83-1.25, p = 0.87). Our data suggest an association between elevated Hcy levels (>15µmol/L) and the prevalence of coronary stenosis in PWH from this inner city African American population.

Association of Serum Homocysteine with Gestational Diabetes Mellitus (GDM): A Case-Control Study

Gestational diabetes mellitus (GDM) is associated with an increased risk of maternal and fetal mortality and morbidity. There is an increasing trend in the prevalence of GDM in Bangladesh. The role of homocysteine (Hcy) as an independent risk factor of GDM has not been extensively studied. The aim of this study was to evaluate the association of serum homocysteine levels in gestationaldiabetes mellitus. It was a case-control study among pregnant women attending the inpatient and outpatient departments of Obstetrics and Gynecology,BSMMU, Shahbag Dhaka, from April 2020 to March 2021. A total of 80 singleton pregnant women between 18-35 years of age were included in this study in their 24-40 weeks of gestation. Among them, 40 diagnosed women with GDM were considered as the cases and the rest of the 40 matched healthy pregnant women were selected as controls matching for age and gestational age.The overall average Hcy levels in the cases and controls were 5.48±1.3 μmol/L and 4.06±0.98 μmol/L, respectively. Both in the late second trimester and the third-trimester serum Hcy levels were significantly higher in the GDM cases than non-GDM healthy pregnant women (p&lt;0.05). Considering Hcy level of 6.38 μmol/L as the cut-off value, GDM was 4.75 times more likely in pregnant women with elevated serum Hcy level (≥6.38) than those with &lt; 6.38 μmol/L (OR=4.75; 95% CI = 0.941-23.985). There was a significant positive correlation of serum Hcy level with both fasting blood sugar level (r = +0.600, p&lt;0.001) and 2 hrs after 75g glucose level (r = +0.438, p&lt;0.001). Elevated level of serum homocysteine was found associated with GDM. Bangabandhu Sheikh Mujib Med. Coll. J. 2024;3(1):32-37

Serum interleukin-17 A and homocysteine levels in children with autism

BackgroundAutism Spectrum Disorder (ASD) is a neurodevelopmental condition that typically emerges early in childhood. This study aimed to explore the potential link between serum levels of vitamin B12 and homocysteine (Hcy) and the severity of ASD symptoms in children.MethodsIn this study, 50 children diagnosed with ASD comprised the observation group, while 50 healthy children constituted the control group. Serum levels of IL-17 A, Hcy, folate, and vitamin B12 were compared between the study group and control group, as well as among children with different degrees of ASD severity. The correlation between the Childhood Autism Rating Scale (CARS) score and serum levels of IL-17 A, Hcy, folate, and vitamin B12 was examined. Additionally, the relationship between serum IL-17 A and Hcy levels and their association with the severity ASD were explored.ResultsCompared to the control group, the observation group demonstrated elevated serum Hcy and IL-17 A levels alongside decreased folate and vitamin B12 levels. Individuals with severe ASD exhibited higher Hcy and IL-17 A levels but lower folate and vitamin B12 levels compared to those with mild to moderate ASD. The CARS score showed negative correlations with serum folate and vitamin B12 levels and positive correlations with serum IL-17 A and Hcy levels in ASD patients. Additionally, serum Hcy and IL-17 A levels were correlated with ASD severity.ConclusionChildren diagnosed with ASD presented with reduced serum vitamin B12 levels and increased levels of Hcy, potentially contributing to the onset and severity of ASD.

Association of Serum Homocysteine With Peripheral Arterial Disease in Patients Without Diabetes: A Study Based on National Health and Nutrition Examination Survey Database

This study aimed to investigate the association of serum homocysteine (Hcy) levels with peripheral arterial disease (PAD) in patients without diabetes on the basis of data from the National Health and Nutrition Examination Survey. The study used data from 3 survey cycles (1999 to 2004) in the National Health and Nutrition Examination Survey database as the research dataset. Serum Hcy levels were considered an independent variable, whereas PAD was a dependent variable. Weighted logistic regression and restricted cubic spline methods were used to explore the relation between Hcy level and PAD risk in patients without diabetes. A total of 4,819 samples were included. In the weighted logistics regression model, a significant positive association was observed between Hcy levels and the risk of PAD (odds ratio >1, p <0.05). Subgroup analysis results indicated a particularly significant association between Hcy levels and PAD risk in the older population (age ≥60 years), those with a history of smoking, and those without a history of myocardial infarction (all odds ratio >1, p <0.05) (p <0.05). Exploring the nonlinear association between Hcy levels and PAD risk through restricted cubic spline curves revealed an overall significant trend (p allover <0.05). In conclusion, elevated Hcy levels increased the risk of PAD, with a more pronounced effect observed in populations of patients without diabetes, especially in older patients (age ≥60 years), those with smoking history, and those without a history of myocardial infarction.