Homocysteine Group Research Articles

Maternal Hyperhomocysteinemia as a Predictor of Placenta-Mediated Pregnancy Complications: A Two-Year Novel Study.

Background Placenta-mediated pregnancy complications (PMPCs) are a significant contributor to adverse maternal and fetal outcomes. Though the exact cause of the array of pregnancy-related vascular disorders is still unknown, increased maternal serum homocysteine (Hct) levels have been linked to the pathophysiology. Hyperhomocysteinemia (HHct) has been strongly linked with the risk of developing PMPCs such as preeclampsia (PE), fetal growth restriction (FGR), intrauterine fetal death (IUFD), preterm births and placental abruption. Methodology The present observational study was carried out on 810 low-risk antenatal women in their early second trimester (13-20 weeks gestation age) in the department of obstetrics and gynecology of a tertiary care rural hospital to identify the significance of abnormally raised maternal serum Hct level in developing PMPCs. Results Of the 810 participants studied, 224 (27.65%) had raised Hct levelswhereas the rest of the 586 (72.35%) participants had normal Hct levels. The mean Hct level of raised homocysteine group (18.59 ± 2.46 micromol/L) was substantially raised than the normal Hct group (8.64 ± 3.1 micromol/L). It was observedthat women with elevated serum Hct levels developed PMPCs significantly morethan women with normal serum Hct levels (p-value <0.05).Among HHct subjects, 65.18% developed PE, 34.38% had FGR, 28.13% had a preterm delivery, 4.02% had abruptio placentae and 3.57%had IUFD. Conclusions The focus of the current study is on an easy and quick intervention suchas assessing the often-ignored levels of Hct duringpregnancythat can help predict and prevent PMPCs. It also highlights the necessity for well-thought-out large-scale studies and trials to further examine the phenomena, as pregnancy may be the only time whenrural women willhave the opportunityto receive advice and tobe tested for HHct.

Higher serum homocysteine levels are associated with an increased risk of hemorrhagic transformation in patients with acute ischemic stroke

BackgroundHemorrhagic transformation (HT) is a common complication of acute ischemic stroke (AIS), and may develop into parenchyma hemorrhage (PH). We aimed to investigate the association between serum homocysteine levels and HT as well as PH in all AIS patients, and in those with and without thrombolysis by subgroup analysis.MethodsAIS patients who were admitted within 24 h after onset were enrolled and categorized into the higher homocysteine level group (≥ 15.5 µmol/L) and the lower homocysteine level group (< 15.5 µmol/L). HT was determined by a second round of brain imaging within 7 days during hospitalization, and PH was defined as hematoma in the ischemic parenchyma. Multivariate logistic regression was used to investigate the associations between serum homocysteine levels and HT and PH, respectively.ResultsOf the 427 included patients (mean age 67.35 years, 60.0% males), 56 (13.11%) developed HT and 28 (6.56%) had PH. Serum homocysteine levels were significantly associated with HT (adjusted OR 1.029, 95%CI 1.003–1.055) and PH (adjusted OR 1.041, 95%CI 1.013–1.070). The higher homocysteine group was more likely to have HT (adjusted OR 1.902, 95% CI 1.022–3.539) and PH (adjusted OR 3.073, 95% CI 1.327–7.120) than the lower homocysteine group. Subgroup analysis of patients without thrombolysis also showed the significant differences in HT (adjusted OR 2.064, 95% CI 1.043–4.082) and PH (adjusted OR 2.926, 95% CI 1.196–7.156) between the two groups.ConclusionHigher serum homocysteine levels are associated with an increased risk of HT and PH in AIS patients, especially in those without thrombolysis. Monitoring the serum homocysteine may be conducive to determining individuals at a high risk of HT.

Mutual effect of homocysteine and uric acid on arterial stiffness and cardiovascular risk in the context of predictive, preventive, and personalized medicine

BackgroundArterial stiffness is a major risk factor and effective predictor of cardiovascular diseases and a common pathway of pathological vascular impairments. Homocysteine (Hcy) and uric acid (UA) own the shared metabolic pathways to affect vascular function. Serum uric acid (UA) has a great impact on arterial stiffness and cardiovascular risk, while the mutual effect with Hcy remains unknown yet. This study aimed to evaluate the mutual effect of serum Hcy and UA on arterial stiffness and 10-year cardiovascular risk in the general population. From the perspective of predictive, preventive, and personalized medicine (PPPM/3PM), we assumed that combined assessment of Hcy and UA provides a better tool for targeted prevention and personalized intervention of cardiovascular diseases via suppressing arterial stiffness.MethodsThis study consisted of 17,697 participants from Beijing Health Management Cohort, who underwent health examination between January 2012 and December 2019. Brachial-ankle pulse wave velocity (baPWV) was used as an index of arterial stiffness.ResultsIndividuals with both high Hcy and UA had the highest baPWV, compared with those with low Hcy and low UA (β: 30.76, 95% CI: 18.36–43.16 in males; β: 53.53, 95% CI: 38.46–68.60 in females). In addition, these individuals owned the highest 10-year cardiovascular risk (OR: 1.49, 95% CI: 1.26–1.76 in males; OR: 7.61, 95% CI: 4.63–12.68 in females). Of note, males with high homocysteine and low uric acid were significantly associated with increased cardiovascular risk (OR: 1.30, 95% CI: 1.15–1.47), but not the high uric acid and low homocysteine group (OR: 1.02, 95% CI: 0.90–1.16).ConclusionsThis study found the significantly mutual effect of Hcy and UA on arterial stiffness and cardiovascular risk using a large population and suggested the clinical importance of combined evaluation and control of Hcy and UA for promoting cardiovascular health. The adverse effect of homocysteine on arteriosclerosis should be addressed beyond uric acid, especially for males. Monitoring of the level of both Hcy and UA provides a window opportunity for PPPM/3PM in the progression of arterial stiffness and prevention of CVD. Hcy provides a novel predictor beyond UA of cardiovascular health to identify individuals at high risk of arterial stiffness for the primary prevention and early treatment of CVD. In the progressive stage of arterial stiffness, active control of Hcy and UA levels from the aspects of dietary behavior and medication treatment is conducive to alleviating the level of arterial stiffness and reducing the risk of CVD. Further studies are needed to evaluate the clinical effect of Hcy and UA targeted intervention on arterial stiffness and cardiovascular health.

Effects of four weeks lasting aerobic physical activity on cardiovascular biomarkers, oxidative stress and histomorphometric changes of heart and aorta in rats with experimentally induced hyperhomocysteinemia.

The aim of this study was to examine the effects of hyperhomocysteinemia and aerobic physical activity on changes of cardiovascular biomarkers in sera, oxidative stress in cardiac tissue, and histomorphometric parameters of heart and aorta in rats. Experiments were conducted on male Wistar albino rats organized into four groups (n = 10, per group): C (control group): 0.9% NaCl 0.2mL/day; H (homocysteine group): homocysteine 0.45µmol/g b.w./day; CPA (control + physical activity group): 0.9% NaCl 0.2mL/day and a program of physical activity on a treadmill; and HPA (homocysteine + physical activity group) homocysteine 0.45µmol/g b.w./day and a program of physical activity on a treadmill. Substances were applied subcutaneously twice a day. Lipid peroxidation and relative activity of Mn-superoxide dismutase isoform were significantly higher in active hyperhomocysteinemic rats in comparison to sedentary animals. Atherosclerotic plaques were detected in aorta samples of active hyperhomocysteinemic rats and also, they had increased left ventricle wall and interventricular septum, and transverse diameter of cardiomyocytes compared to sedentary groups. Aerobic physical activity in the condition of hyperhomocysteinemia can lead to increased oxidative stress in cardiac tissue and changes in histomorphometric parameters of the heart and aorta, as well increased lipid parameters and cardiac damage biomarkers in sera of rats.

Study on the Association of Homocysteine and C-Reactive Protein with Neurofunctional Changes in Patients with Acute Ischemic Stroke After Endovascular Stent Treatment.

ObjectiveTo examine the association of homocysteine (HCY) and C-reactive protein (CRP) with neurofunctional changes in patients with acute ischemic stroke (AIS) after stent treatment.MethodsA total of 110 patients with AIS treated with stents were divided into a high HCY group (n = 59) and a normal HCY group (n = 51) based on the HCY level. Pearson correlation analysis and logistic linear regression analysis were used to analyze the related factors that affect the National Institutes of Health Stroke Scale (NIHSS) score changes after stent treatment.Results(1) The area under the receiver operating characteristic (ROC) curve for HCY was 0.995 (95% confidence interval [CI]: 0.984–1.005, P = 0.000), and the best predictive value was 12.75 µmol/L (sensitivity 89.9%, specificity 98.0%). The area under the ROC curve for CRP was 0.665 (95% CI: 0.564–0.767, P = 0.003), and the best predictive value was 9.7 mg/L; (2) comparison between the high HCY group and the normal HCY group showed statistical differences (P < 0.05) in HCY, CRP, and the NIHSS score at admission, the NIHSS score after treatment, gender, history of diabetes, and history of atrial fibrillation; (3) both HCY and CRP were proven to be correlated with the NIHSS score after treatment (0.188, P = 0.050) and (0.194, P = 0.042), respectively, using Pearson correlation analysis; (4) HCY, low-density lipoprotein, CRP, cystatin C, glucose, history of atrial fibrillation, history of diabetes, and the NIHSS score at admission as the risk factors.ConclusionHigh HCY and CRP levels are related to the neurofunctional changes in patients with AIS treated with stents and can be used as indicators to assess the risk of treating AIS with stents and as serum markers to predict prognoses.

Homocysteine Is a Marker of Increased Cardio-Cerebrovascular Disease Risk in Psoriatic Patients, but It Does Not Reflect the Effect of Biological Therapy in the Longitudinal Observation.

Background Psoriasis is linked to atherosclerosis. Homocysteine (HCYS) has been identified as a marker of increased risk of cardio-cerebrovascular diseases (CCVD) in population. Objective The aim of the study was to determine whether elevated HCYS serves as a marker of increased CCVD in psoriasis and whether biological therapy for long-term monitoring influences HCYS levels. Methods Clinical data, laboratory tests, and comorbid diagnoses were summarized for the two groups of patients based on entrance HCYS levels. Patients (n = 76) were included in the follow-up gradually over a period of 5 years. Results The psoriatic patients with normal (54%) and elevated (46%) HCYS before biological treatment did not vary in clinical data, laboratory tests, treatment, and comorbid diagnoses apart from CCVD. Elevated HCYS group showed a four-fold excess of CCVD (OR 4.2, 95%CI 1.21–4.86, p=0.024). HCYS levels in the longitudinal observation did not vary. Conclusion An increased CCVD risk, independent of other risk factors, is present in psoriatic patients with elevated HCYS. The HCYS level was not influenced by biological therapy in longitudinal observation. Further studies are needed to explore if elevated HCYS could serve as a marker of increased CCVD in any stage of psoriasis and if it should be included in classical screening strategies.

Protective role of selenium on MPP+ and homocysteine-induced TRPM2 channel activation in SH-SY5Y cells

Homocysteine is an intermediate product of biochemical reactions occurring in living organisms. It is known that drugs that increase dopamine synthesis used in Parkinson's disease (PD) cause an increase in the plasma homocysteine level. As the plasma homocysteine level increases, the amount of intracellular free calcium ion ([Ca2+]i) and oxidative stress increase. As a result, it contributes to the excitotoxic effect by causing neurodegeneration. TRPM2 cation channel is activated by high [Ca2+]i and oxidative stress. The role of TRPM2 in the development of neuronal damage due to the increase in homocysteine in PD has not yet been elucidated. In current study, we aimed to investigate the role of the TRPM2 and selenium (Se) in SH-SY5Y neuronal cells treated with homocysteine (HCT) and MPP . SH-SY5Y cells were divided into four groups: control, MPP, MPP + HCT, and MPP + HCT + Se. The results of plate reader assay, confocal microscope imaging, and western blot analyses indicated upregulation of apoptosis, [Ca2+]i, mitochondrial membrane depolarization, caspase activation, and intracellular ROS values in the cells. The MPP + HCT group had considerably higher values than the other groups. The MPP + HCT + Se group had significantly lower values than all the other groups except the control group. In addition, incubation of MPP + HCT and MPP + HCT + Se groups with TRPM2 antagonist 2-APB increased cell viability and reduced intracellular calcium influx and apoptosis levels. It is concluded that the activation of TRPM2 was propagated in HCT and MPP-induced SH-SY5Y cells by the increase of oxidative stress. The antioxidant property of Se regulated the TRPM2 channel activation and neurodegeneration by providing intracellular oxidant/antioxidant balance.

The association between homocysteine levels and cardiovascular disease risk among middle-aged and elderly adults in Taiwan

BackgroundOur study aimed to determine the association between homocysteine levels and cardiovascular disease (CVD) risk in middle-aged and elderly adults in a community in northern Taiwan.MethodsParticipants in our study included adults aged 50 to 85 years old during community health examinations in 2019. A total of 396 people were enrolled, the ethnicity of all participants is Chinese. We divided participants according to tertiles of ln[homocysteine] level (low, middle and high groups). The CVD risk was calculated by the Framingham cardiovascular risk score (FRS). An FRS ≥ 20% indicated high CVD risk. Pearson correlation coefficients were calculated between homocysteine level and other cardio-metabolic risk factors while adjusting for age. Multivariate logistic regression analysis was used to determine the association of high and middle ln[homocysteine] groups with high CVD risk after adjusting age, sex, uric acid, creatinine, and body mass index (BMI). The Youden index and receiver operating characteristic (ROC) curves were performed to determine the optimized cut-off value.ResultsThere were 396 people enrolled for analysis; 41.4% of participants were male, and the average age was 64.79 (± 8.76). In our study, we showed a positive correlation of homocysteine with FRS. In the logistic regression models, higher ln[homocysteine] levels was associated with higher CVD risk with a odds ratio (OR) of 2.499 and 95% confidence interval (CI) of 1.214 to 5.142 in the high homocysteine level group compared with the low homocysteine group after adjusting for traditional CVD risk factors. The area under the ROC curve was 0.667, and a ln[homocysteine] cut-off value of 2.495 µmol/L was determined.ConclusionsMiddle-aged and elderly people with increased homocysteine levels were associated with higher FRSs in this Taiwan community. Furthermore, homocysteine was an independent risk factor for high CVD risk in this study.

Associations of MTRR A66G polymorphism and promoter methylation with ischemic stroke in patients with hyperhomocysteinemia.

Patients with hyperhomocysteinemia (HHcy) have a higher risk of developing ischemic stroke (IS). The association between MTRR A66G polymorphism and promoter methylation with IS in patients with HHcy is also uncertain. The present study aimed to investigate the association between the MTRR polymorphism and methylation with IS in HHcy patients. This case-control study included a total of 304 HHcy patients (95 with IS and 209 without IS). Multivariate logistic regression analyses were applied to explore the association between MTRR polymorphism and classical atherothrombotic risk factors with the risk of IS. The log-additive and dominant models were markedly different in participants with IS compared to the control group (p = 0.031 and 0.016, respectively). The log-additive and dominant showed a significant association with IS in the low level plasma homocysteine groups (p = 0.024 and 0.014, respectively). No significant difference of methylation between IS and without IS group (p > 0.05). Patients with high plasma homocysteine had a 4.041-4.941 fold higher risk of IS (p = 0.01, 0.016 and 0.041, respectively) compared to the low plasma homocysteine group. Age, diabetes, hypertension and plasma homocysteine were the risk factors for IS in patients with HHcy (p = 0.033, 0.000, 0.001 and 0.038, respectively). MTRR A66G polymorphism and an elevated plasma plasma homocysteine level were significantly associated with an increased risk of IS in patients with HHcy. Age, diabetes, hypertension and Hcy were all found to be associated with IS.

Cytokine Treatment for Myocarditis May Directly Impact Cardiomyocytes Negatively

The purpose of our study was to determine if direct administration of CXCL1/KC to cardiomyocytes causes negative changes to cell density or proliferation. This molecule has been shown to reduce inflammation in certain instances. Homocysteine models the direct effect of an inflammatory agent on cardiomyocytes. Our question was whether these molecules directly impact cell density through an interaction with the cell proliferation process. We hypothesized that cells treated with CXCL1/KC would maintain the same cell density as untreated cells. In contrast, cells treated with Homocysteine or both Homocysteine and CXCL1/KC, were expected to have a higher cell density that than that of untreated cells. To test these hypotheses, HL-1 cardiomyocytes were cultured and treated in chambers on a glass slide. DAPI staining, which allows individual nuclei to be counted, was viewed under fluorescence and pictures were analyzed using Image J. Our hypotheses were rejected because there was a significant difference between the Homocysteine group and both the Homocysteine+CXCL1/KC and CXCL1/KC groups. This was extended to signify that the cell density of the CXCL1/KC and Homocysteine+CXCL1/KC groups was decreased cell proliferation had been reduced. The difference between the CXCL1/KC and Homocysteine groups likely indicates effects possessed by each treatment. Comparing results from the Homocysteine+CXCL1/KC treatment to the Homocysteine treatment, Homocysteine treatment increased cell density enough so that the decreased proliferation which may have been caused by the CXCL1/KC was significant compared to the Homocysteine sample. Future studies could examine additional applicable models such as mouse heart tissue or a living mouse.

Elevated CD14++CD16+ Monocytes in Hyperhomocysteinemia-Associated Insulin Resistance in Polycystic Ovary Syndrome.

Hyperhomocysteinemia, chronic low-grade inflammation, and insulin resistance are predominant features in women with polycystic ovary syndrome (PCOS). CD14++CD16+ inflammatory monocytes are elevated in cardiovascular diseases and diabetes, in which inflammation is one of the pathogenesis. We aimed to determine whether homocysteine levels are associated with monocyte subtypes or insulin resistance in women with PCOS. A cross-sectional study was conducted between December 2014 and June 2015 at Peking University Third Hospital. Among 196 Chinese patients with PCOS enrolled, 102 had homocysteine levels ≥10 µmol/L and 94 exhibited normal homocysteine levels. Monocyte surface markers and related cytokines were detected in peripheral blood samples using a flow cytometry, and data on insulin resistance and homocysteine levels were collected. Our results showed that fasting insulin and homeostasis model assessment indices that reflect the severity of insulin resistance were increased in the hyperhomocysteinemia PCOS group. Simple linear regression analysis revealed that homocysteine level is one of the influence factors of insulin resistance in PCOS. Compared with the normal homocysteine group, patients with hyperhomocysteinemia had increased numbers of CD14++CD16+ inflammatory monocyte in their peripheral blood and elevated plasma levels of interleukin-1β and interleukin-6, 2 typical cytokines secreted by the inflammatory monocytes. Unlike CD14+CD16++ nonclassical monocytes, CD14++CD16+ inflammatory monocytes are characterized by high expression of Human leukocyte antigen-antigen D related (HLA-DR). Our findings indicate that CD14++CD16+ inflammatory monocytes are associated with hyperhomocysteinemia and insulin resistance in patients with PCOS. Notably, CD14++CD16+ monocytes may contribute to the pathogenesis of insulin resistance in women with PCOS.

MicroRNA-34a promotes CMECs apoptosis and upregulate inflammatory cytokines, thus worsening CMECs damage and inhibiting angiogenesis by negatively targeting the Notch signaling pathway.

Recently, microRNA-34a (miR-34a) has been reported to lead to secretion of proinflammatory cytokine in endothelial cells, whereas whether miR-34a plays a protective role in damaged cardiac microvascular endothelial cells (CMECs) remains to be determined. Herein, the purpose of this study is to explore the effect of miR-34a in mediating Notch signaling pathway in apoptosis and angiogenesis of damaged CMECs. The primary mice CMECs were isolated, cultivated, and identified before establishment of damaged CMEC model by incubation with homocysteine (HCY) for 24 hours. Quantitative reverse-transcription polymerase chain reaction and Western blot analysis were applied to determine the expressions of miR-34a and Notch1. Cell viability and cell apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Hochest 33258 staining. Capillary-like structures formation assay was used to detect the capillary-like structures in CMECs. The expressions of inflammatory cytokines and angiogenesis factors were determined by enzyme-linked immunosorbent assay. In contrast to the blank group, the HCY and negative control groups demonstrated with elevated expressions of miR-34a, interleukin (IL)-1β, IL-6, and increased cell apoptosis rate, but decreased expressions of Notch1, IL-10, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and human growth factor (HGF), as well as attenuated cell viability and capillary-like structures of cells formation ability. In comparison with HCY group, the expressions of miR-34a, IL-1β, IL-6, and apoptosis rate were increased, whereas the expressions of Notch1, VEGF, bFGF, HGF, cell viability, and capillary-like structures of cells formation were inhibited in miR-34a mimic group. This study demonstrates that miR-34a can promote CMEC apoptosis and upregulate inflammatory cytokines, thus worsening CMEC damage and inhibiting angiogenesis by negatively targeting the Notch signaling pathway.

Elevated plasma homocysteine upon ischemic stroke is associated with increased long-term mortality in women.

BackgroundIschemic stroke is a leading cause of death worldwide, despite preventive and therapeutic advances during the last twenty years. Blood-borne biomarkers have been studied in association to short- and long-term outcome, in order to investigate possible modifiable predictors of disability and death. Increased homocysteine has been associated with increased vascular risk and unfavorable outcome, but homocysteine lowering treatment has not consistently been successful in risk reduction. The aim of this study was to investigate homocysteine levels upon acute ischemic stroke in association to long-term mortality.MethodsOf 622 patients included in our hospital-based registry, 331 survived the first month after admission, and had a diagnosis of ischemic stroke and available homocysteine values. All-cause and vascular mortality were investigated based on the national patient- and cause of death-registries. Survival analysis and Cox proportional hazard models were used to investigate time to death and predictors of outcome.ResultsOf 331 patients, 148 (45%) had low homocysteine (<13 micromol/L) and 183 (55%) had high homocysteine (> = 13 micromol/L). During 10 years of follow-up (median 5.5 years), 47 patients (32%) with low homocysteine and 94 (51%) with high homocysteine died (p<0.0001). Estimated median survival was not reached for the low homocysteine group, and was 80 months in the high homocysteine group (p with log-rank test 0.002). High homocysteine was not independently associated with increased risk for death after adjustment for age, sex, comorbidities, and eGFR (HR 1.29, 95% CI 0.86–1.93; p = 0.2). Subgroup analysis by sex showed that high homocysteine was an independent predictor of mortality in women after adjustment for age and vascular comorbidities (HR 1.85; 95% CI 1.03–3.31; p = 0.04), but not in men (HR 0.87; 95% CI 0.52–1.43; p = 0.6).ConclusionIncreased plasma homocysteine (> = 13 micromol/L) upon acute ischemic stroke was not independently associated with mortality in our study. In the subgroup of women, high homocysteine was associated with increased five-year risk of death. Our study’s retrospective design and the exploratory nature of subgroup analysis, prevent robust conclusions based on that observation. Future studies on homocysteine levels before as well as upon stroke will shed further light on a possible causal association.

The clinical effects of methylenetetrahydrofolate reductase C677T gene mutation on mild vascular cognitive impairment in patients with cerebral infarction

Objective To study the clinical effects of methylenetetrahydrofolate reductase(MTHFR)C677T gene mutation on mild vascular cognitive impairment(VCI)in patients with cerebral infarction. Methods The prospective study was conducted in 180 patients with atherosclerotic acute cerebral infarction hospitalized from June 2015 to May 2016.180 patients were divided into normal homocysteine(Hcy)group(Hcy 5.46~16.20 μmol / L, n=130)and high Hcy group(Hcy>16.20 μmol / L, n=50). MTHFR C677T genotypes were detected by polymerase chain reaction-restriction endonuclease fragment length polymorphism.The VCI state and risk factors for VCI were analyzed with Montreal Cognitive Assessment scale(MoCA)and Mini Mental State Examination(MMSE)score in patients with acute cerebral infarction on admission and 14 days, 30 days and 90 days after admission. Results MMSE and MoCA scores at 14 days, 30 days, 90 days after admission were lower in high Hcy group than in normal Hcy group(P<0.05 or P<0.01). MMSE and MoCA scores were lower in T/T genotype than in C/C genotype(P<0.05)at 14 day after admission, and lower in C/T genotype than in C/C genotype at 30 day and 90 day follow-up(P<0.05 or P<0.01). Logistic regression analysis showed that Hcy may be independent risk factors for mild VCI(OR=1.274, 95%CI: 1.027~1.264, P=0.018). Conclusions MTHFR C677T gene mutations may cause hyper-homocysteinemia, and promote the emergence of VCI in patients with cerebral infarction.MTHFR C677T gene mutations may be a genetic susceptibility factor for VCI. Key words: Brain infarction; Methylenetetrahydrofolate reductase; Cognition disorders

The Cardiovascular Effect of Systemic Homocysteine Is Associated with Oxidative Stress in the Rostral Ventrolateral Medulla.

It has been demonstrated that homocysteine (HCY) is a significant risk factor of hypertension, which is characterized by overactivity of sympathetic tone. Excessive oxidative stress in the rostral ventrolateral medulla (RVLM), a key region for control of sympathetic outflow, contributes to sympathetic hyperactivity in hypertension. Therefore, the goal of the present study is to determine the effect of systemic HCY on production of reactive oxygen species (ROS) in the RVLM. In the rat model of the diet-induced hyperhomocysteinemia (L-methionine, 1 g/kg/day, 8 weeks), we found that the HCY resulted in a significant increase (≈3.7-fold, P < 0.05) in ROS production in the RVLM, which was paralleled with enhanced sympathetic tone and blood pressure (BP). Compared to the vehicle group, levels of BP and basal renal sympathetic nerve activity in the HCY group were significantly (P < 0.05, n = 5) increased by an average of 27 mmHg and 31%, respectively. Furthermore, the rats treated with L-methionine (1 g/kg/day, 8 weeks) showed an upregulation of NADPHase (NOX4) protein expression and a downregulation of superoxide dismutase protein expression in the RVLM. The current data suggest that central oxidative stress induced by systemic HCY plays an important role in hypertension-associated sympathetic overactivity.

Protective effect of quercetin on homocysteine-induced oxidative stress

ObjectiveThe aim of this study was to evaluate whether quercetin (QUER) treatment could have a protective effect against oxidative stress induced by homocysteinemia in rats. Materials and methodsThirty-two male Sprague-Dawley rats (adult) were assigned randomly to four groups: the control group was given physiological saline (PS; 1.5 mL/d); the QUER group was given QUER (50 mg/kg body weight [BW] daily) in distilled water and 0.25 mL PS; the homocysteine (HCY) group was given HCY (1 mg/kg BW daily) in distilled water and 1.25 mL PS; and the QUER + HCY group was given QUER 1 h before the administration of HCY. QUER, HCY, and PS were injected intraperitoneally every other day for 30 d. Plasma malondialdehyde (MDA), carbonyl, erythrocyte-reduced glutathione (GSH), plasma sulphydril (−SH) levels, erythrocyte catalase (CAT), and superoxide dismutase (SOD) activities were determined. ResultsPlasma CAT levels in the QUER group were found to be significantly higher than in the control group, whereas plasma MDA levels in the QUER group significantly decreased compared with the control group. In the HCY group, plasma MDA and carbonyl levels significantly increased and GSH and SOD levels significantly decreased compared with the control group. Plasma MDA levels significantly decreased and GSH and CAT levels significantly increased in the QUER + HCY group compared with the HCY group. Plasma −SH levels were significantly lower in the HCY group than in the control group. Plasma −SH levels were higher in the QUER + HCY group than in the HCY group, but they were not significant. ConclusionThe exposure of rats to HCY leads to oxidative stress reflected in increased MDA and decreased antioxidant enzyme levels. Administration of QUER might attenuate oxidative damage induced by HCY or have a protective effect against it.

H-type hypertension is an important risk factor of carotid atherosclerotic plaques

ABSTRACTAim: To investigate the association of H-type hypertension with carotid atherosclerotic plaques in Chinese. Methods: This hospital-based large population study included 13192 patients and all the patients were sequentially recruited between May 2010 and May 2013 at the Health Medical Center of the Chinese PLA General Hospital. The subjects were divided into four groups: the H-type of hypertension group, isolated systolic hypertension, simple homocysteine (Hcy) group, and the control group without hypertension and Hcy. Univariate logistic regression analysis was performed to investigate the association of H-type hypertension with the odds of carotid atherosclerotic plaques. Results: Among the 13192 subjects, there were 9007 (68.28% of all subjects) patients with hyperhomocysteinemia and 3543 patients with H-type hypertension, which was 26.86% of all subjects and 74.45% of hypertension patients. 34.55% of all subjects (4558) had carotid atherosclerotic plaques. The carotid atherosclerotic plaques positive rate among four groups was significantly different (χ2 = 647.8988, P = 0.000). The carotid atherosclerotic plaques’ positive rate of patients with H-type hypertension was 49.31%, which was significantly higher than the other three groups. Univariate logistic regression analysis results indicated that significant correlations exist between high-Hcy hypertension and carotid atherosclerotic plaques. Incidence of carotid atherosclerotic plaques in H-type hypertension patients was 1.63 times that in patients with isolated systolic hypertension. Conclusion: H-type hypertension is independently associated with higher risk of carotid atherosclerotic plaques. H-type hypertension and Hcy should be the major intervention measures to decrease the incidence of carotid atherosclerotic plaques as well as the stroke in Health Practice Management.

Related research between acute inflammatory reaction and hemodynamic changes of pulmonary embolism rabbit with hyperhomocysteinemia

To explore the association between acute inflammatory reaction and hemodynamic changes of acute pulmonary embolism rabbit with hyperhomocysteinemia. A total of 30 Japanese white rabbits were randomly divided into homocysteine group and control group according to the random number table, which were treated with 2% methionine and normal saline, respectively. Rabbit model of acute pulmonary embolism was established by autologous blood clots reinfusion after 8 weeks, then the level of serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), right ventricular systolic pressure (RVSP), right atria systolic pressure (RASP), pulmonary artery pressure (PAP) were checked before and after thrombosis at different time points. At last, area of embolism, degree of lung congestion and incidence of lung infarction were evaluated after the rabbits were sacrificed. Both homocysteine group and control group serum TNF-α, IL-1β increased at 30, 60, 120 min after embolism, and serum TNF-α, IL-1β of homocysteine group [(12.4 ± 1.0), (15.7 ± 1.1), (23.2 ± 1.4) and (7.6 ± 1.0), (10.2 ± 2.1), (18.8 ± 1.3) pg/ml] increased more obviously than control group [(10.2 ± 1.0), (11.7 ± 1.4), (12.1 ± 1 .2) and (6.4 ± 1.1), (8.5 ± 1.9), (10.0 ± 2.1) pg/ml] (all P<0.05). All of RVSP, RASP, and PAP increased in each group after embolism, while homocysteine group RVSP [(52.8 ± 3.3), (54.7 ± 4.5), (46.4 ± 4.4) mmHg], RASP [(3.9 ± 1.2), (4.5 ± 2.0), (4.5 ± 1.9) mmHg] and PAP[(52.9 ± 3.3), (55.1 ± 2.9), (47.5 ± 3.6) mmHg] increased more obviously compared with control group [(39.4 ± 2.5), (39.4 ± 3.3), (34.5 ± 3.9) mmHg, (2.3 ± 1.1), (3.3 ± 1.1), (3.3 ± 1.2) mmHg and (37.7 ± 2.7), (40.2 ± 2.9), (33.7 ± 4.2) mmHg] (all P<0.05). Inflammatory response of acute pulmonary embolism rabbit increases in hyperhomocysteinemia and the degree of embolism increases as well, which may lead to increase of hemodynamic instability.

Study on the mechanism of homocysteine-induced microglia expression of interleukin -1β and tumor necrosis factor-α

Objective To investigate the mechanism of homocysteine-induced microglia (BV-2 cells) expression of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Methods The BV-2 cells were divided into blank control group, cysteine (Cys) group, homocysteine (Hcy) group and homocysteine and glutathione (Hcy+ GSH) group, and the BV-2 cells in these groups were incubated with cysteine or homocysteine or homocysteine and glutathione together for 72 h. The mRNA expressions of IL-1β and TNF-α were assessed by RT-qPCR. The protein expressions of IL-1β and TNF-α in supernatant were detected by enzyme linked immunosorbent assay (ELISA). Western blot was used to observe the changes of NF-κB/p65 expression. Results There were significant differences in mRNA and protein expressions of IL-1β and TNF-α and NF-κB/p65 protein expression between groups (F=48.63, 130.76, 702.91, 293.69, 212.06, respectively, all P=0.000). The secretions of IL-1β and TNF-α were significantly improved by homocysteine (P<0.05), and were reversed by the treatment with glutathione (P<0.05). Western blot assay result showed that NF-κB/p65 was elevated after treatment with homocysteine (P<0.05). Conclusions Homocysteine can induce microglia expression of interleukin -1β and tumor necrosis factor-α, and NF-κB signaling pathway may be involved in this process. Key words: Hyperhomocysteinemia; Interleukin-beta; Tumor necrosis factor-αlpha; NF-kappaB

Correlations between homocysteine and grey matter volume in patients with Alzheimer's disease.

Previous studies have reported that elevated total homocysteine levels are associated with cognitive dysfunction. However, few studies have examined the radiological markers of associated neuropathology in Alzheimer's disease (AD). We hypothesized that elevated levels of homocysteine are associated with cerebral grey matter volume loss. We compared the grey matter in a high homocysteine group and a normal homocysteine group using an optimized voxel-based morphometry. The study included 79 patients with AD who were divided into two groups: a high homocysteine group and a normal homocysteine group. The participants underwent brain magnetic resonance imaging using a standardized protocol and neurocognitive evaluation. Homocysteine tests and other routine laboratory examinations for dementia assessment were carried out in all patients. There was no significant difference in grey matter volume between the patients with high homocysteine levels and those with normal homocysteine levels. A multiple regression analysis also revealed that the levels of homocysteine were not associated with the grey matter volume in patients with AD. Homocysteine levels were not correlated significantly with Mini-Mental State Examination, Global Deterioration Scale, or Clinical Dementia Rating. Our results showed that elevated homocysteine levels are not associated with reduced cerebral grey matter volume in AD. Larger samples will be needed to assess potential correlations between homocysteine and neuroanatomical pathology in the future.