Elevated Plasma Homocysteine Levels Research Articles

Plasma homocysteine levels are positively associated with interstitial lung disease in dermatomyositis patients with anti-aminoacyl-tRNA synthetase antibody.

Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of central and peripheral vascular disorders, including carotid, coronary and peripheral arterial diseases, and Raynaud's phenomenon. Recently, associations of plasma homocysteine levels with autoimmune diseases such as systemic lupus erythematodes and systemic sclerosis have been reported. However, no study analyzed the association between plasma homocysteine levels and dermatomyositis (DM). The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with DM. Plasma homocysteine levels in 28 Japanese patients with DM and 22 healthy controls were examined. We found that the plasma homocysteine levels in DM patients were significantly higher than those in healthy individuals (15.8±1.1 vs 8.5±0.5µmol/L, P<0.01). Presence of mechanic's hand, complication of interstitial lung disease (ILD), high serum Krebs von den Lungen-6 (KL-6), surfactant protein-D and creatine kinase levels, and anti-aminoacyl-tRNA synthetase (ARS) antibody (Ab) positivity were significantly more prevalent among DM patients with elevated plasma homocysteine levels. The plasma homocysteine levels in DM patients with mechanic's hand, ILD and anti-ARS Ab were significantly higher than those in DM without those features. Furthermore, the plasma homocysteine levels were positively correlated with serum KL-6 levels. These results suggest that the pathogenesis of elevated plasma homocysteine levels may be associated with ILD in DM patients, especially with anti-ARS Ab, and further examination is required.

Elevated Homocysteine Levels Associated with Atrial Fibrillation and Recurrent Atrial Fibrillation.

There is increasing evidence linking plasma homocysteine levels and atrial fibrillation (AF). The association between an elevated level of plasma homocysteine and AF was examined by meta-analysis in this study.The PubMed and ScienceDirect databases until August 2019 were utilized to collect previous literature on homocysteine and the potential relation to AF. The pooled effects were evaluated depending on standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals (CIs), and the calculation was performed using Stata 12 software.A total of 11 validated articles were included in the meta-analysis. For pooled effect, the results confirmed that AF patients had higher homocysteine levels than control subjects (SMD: 0.58, 95%CI: 0.09-1.06). Compared with control subjects, homocysteine levels were higher in paroxysmal AF (SMD: 0.45, 95%CI: 0.18-0.72) and persistent AF patients (SMD: 1.21, 95%CI: 0.50-1.92). The pooled analysis suggested that patients with elevated homocysteine levels had markedly higher risk of AF compared with lower homocysteine levels in the categorical variable (OR: 2.21, 95%CI: 1.16-4.21) and continuous variable analyses (OR: 1.13, 95%CI: 1.00-1.27), respectively. In addition, the pooled analysis indicated that recurrent AF patients had significantly higher homocysteine levels than those without recurrence (SMD: 0.65, 95%CI: 0.42-0.88). The pooled analysis of the categorical variables indicated that elevated homocysteine levels were associated with increased risk of AF recurrence (OR: 3.81, 95%CI: 3.11-4.68). However, the association was weak in the pooled analysis of continuous variables (OR: 1.88, 95%CI: 0.74-4.81).Our meta-analysis identified that plasma homocysteine levels were significantly elevated in AF and recurrent AF patients. Elevated homocysteine is associated with increased risk of AF and AF recurrence.

Implication of Hyperhomocysteinemia in Blood Retinal Barrier (BRB) Dysfunction.

Elevated plasma homocysteine (Hcy) level, known as hyperhomocysteinemia (HHcy) has been linked to different systemic and neurological diseases, well-known as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and has been identified as a risk factor for several ocular disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Different mechanisms have been proposed to explain HHcy-induced visual dysfunction, including oxidative stress, upregulation of inflammatory mediators, retinal ganglion cell apoptosis, and extracellular matrix remodeling. Our previous studies using in vivo and in vitro models of HHcy have demonstrated that Hcy impairs the function of both inner and outer blood retinal barrier (BRB). Dysfunction of BRB is a hallmark of vision loss in DR and AMD. Our findings highlighted oxidative stress, ER stress, inflammation, and epigenetic modifications as possible mechanisms of HHcy-induced BRB dysfunction. In addition, we recently reported HHcy-induced brain inflammation as a mechanism of blood–brain barrier (BBB) dysfunction and pathogenesis of Alzheimer’s disease (AD). Moreover, we are currently investigating the activation of glutamate receptor N-methyl-d-aspartate receptor (NMDAR) as the molecular mechanism for HHcy-induced BRB dysfunction. This review focuses on the studied effects of HHcy on BRB and the controversial role of HHcy in the pathogenesis of aging neurological diseases such as DR, AMD, and AD. We also highlight the possible mechanisms for such deleterious effects of HHcy.

Genotyping 5,10-methylenetetrahydrofolate reductase for patients with coronary artery disease in Southern Taiwan

Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease (CAD). Individuals with homozygous MTHFR (5,10-Methylenetetrahydrofolate reductase) mutation have significantly elevated plasma homocysteine levels. Two common mutations in MTHFR (MTHFR 677C→T and MTHFR 1298A→C) may represent an important genetic risk factor in vascular disease. The aim of this research was to investigate these two point mutations of MTHFR for CAD patients and non-CAD controls in Southern Taiwan by PCR-restriction fragment length polymorphism assay. We found that the distribution of the homozygous mutation for MTHFR677 was higher in 54 CAD patients than in 55 non-CAD subjects (11.1% versus 3.6%, P = 0.275). On the other hand, the frequency of MTHFR 1298CC in CAD patients was similar to that of control subjects (P = 1.000). This may suggest there is a trend toward an increased risk of coronary heart disease for individuals that have a 677TT genotype in the Taiwanese population. Finally, the frequency of homozygosity for the two MTHFR common mutations was still low in CAD cases. There may not be an appreciable association of MTHFR mutation to cardiovascular disease in Taiwan. Perhaps a further study including assessment of plasma concentrations of homocysteine, folate and vitamin B12 would be needed to better clarify the relationship between MTHFR polymorphisms and the occurrence of vascular disease.

4-9FEATURES OF HOMOCYSTEINE LEVEL AND A POTENTIAL WAY OF IT'S CORRECTION IN HYPERTENSIVE PATIENTS

Background: Arterial hypertension (AH) is one of the most wide-spread cardiovascular pathology all over the world. Initiation and progression of AH are linked to many potentially modified metabolic factors, for example-hyperhomocysteinemia. Despite the fact that diagnostics, treatment and prevention of AH is evident, key risk factors correction are still concealed at present. Aim: To study the features of serum HH in hypertensive patients and optimize treatment strategy. Methods: According to the aim of our investigation, we examined 74 high cardiovascular risk level hypertensive patients (before and after 12-weeks of atorvastatin 20 mg per day oral administration based on their standard hypotensive treatment) and 68 healthy volunteers (equivalent with group of observation in age and gender representation) with fasting homocysteine plasma level via ELISA. The statistically significance was considered at P &lt; 0,05. Results: It's set that AH is associated with fasting homocysteine plasma concentration 2,22 times more (P &lt; 0,01) opposite to healthy subjects, that was according to mild level of hyperhomocysteinemia. Besides, it was found that additive 12-weeks treatment with atorvastatin (based on specific antihypertensive approaches) leads to clinically significant reduction of homocysteine plasma level by 28,78% (P &lt; 0,05) in the hypertensive patients. Conclusions: HH is stationed as a key metabolic risk factor in way of arterial hypertension's formation and progression over the high cardiovascular risk population. At the same time, specific hypolipidemic and antiatherosclerotic treatment based on regular atorvastatin administration can be counted as an effective way of reducing elevated plasma homocysteine level and shows alternative pleiotropic effect of statins in AH patients.

Effect of Non- Surgical Periodontal Therapy on Plasma Homocysteine Levels in Patients with Chronic Periodontitis- A Prospective Study

Background: The aim of the study was to evaluate and correlate the effect of non surgical periodontal therapy on homocysteine levels in patients with chronic periodontitis. Methods: Fifty participants were enrolled in the study (n=50) in the age range of 20-45 yrs. Each patient was examined using a mouth mirror and UNC-15 graduated periodontal probe. After recording the clinical parameters &amp; indices (CAL, OHI-S, GI), venous blood was drawn from the antecubital vein and transferred to a vial and centrifuged to isolate the plasma, which was then sent for evaluation of plasma homocysteine level. Non-surgical therapy was performed which consisted of scaling and root planing (SRP). After 90 days, the patient was re-evaluated for clinical parameters and the readings were recorded again. Blood samples were sent for analysis of post treatment plasma homocysteine levels. Results: The plasma Hcy level in periodontitis subjects during pre treatment was 20.7± 3.4 µmol/L which was significantly higher. Post therapy levels reduced to 14.7± 2.2 µmol/L. The OHI’s and GI were also significantly reduced after post therapy. Conclusion: An inflammatory condition like chronic periodontitis is significantly associated with elevated plasma homocysteine levels. However, no significant change was seen in the plasma homocysteine levels between males and females. Periodontal intervention shows statistically significant improvement in plasma homocysteine values.

Homocysteine metabolism in rats with metabolic syndrome and the impacts of nigella sativa oil on some biochemical parameters

The high level of fructose taken in the diet is one of the reasons for the increased prevalence of metabolic syndrome, which is increasing day by day globally in association with the effects of genetic and environmental factors. In the study, 21 male Sprague-Dawley rats of 220±20 gr body weight were used. The rats were assigned to 3 groups as the control group, metabolic syndrome group, and the group where Nigella sativa oil was administered. The serum homocysteine levels were increased in the metabolic syndrome group compared to the control group but without statistical significance (p&amp;gt;0.05). Homocysteine levels decreased significantly after Nigella sativa oil compared to metabolic syndrome group. LDH (p &amp;lt;0.001) and uric acid (p &amp;lt;0.05) levels which were higher in metabolic syndrome group were decreased in Nigella sativa oil group. Hyperhomocysteinemia is a risk factor for endothelial dysfunction. In our study, the treatment of the metabolic syndrome and regulation of the increased levels of homocysteine with Nigella sativa oil in metabolic syndrome were discussed. Some biochemical parameters and improvements in homocysteine levels with Nigella sativa oil has been identified. In this study, we have concluded that the occurrence of elevated levels of plasma homocysteine are closely associated with the development of inflammation, cellular adhesion, hepatic dysfunction, and cell proliferation and that the reduction in the serum levels of homocysteine by the administration of Nigella sativa oil will lead to favorable out comes.

Elevated serum homocysteine as a potential marker for cardiovascular changes in overt hypothyroidism

Overt hypothyroidism(HO) defined as high Thyroid Stimulating Hormone (TSH) lev­els with low levels of free thyroxine (FT4) and / or free triiodothyronine (FT3). Hypothyroidism is associated with an increased risk for atherosclerotic cardiovascular disease. Serum Homocysteine (Hcy) is a independent risk factor for atherosclerosis and cardiovascular diseases. Elevated plasma homocysteine levels have been reported in overt hypothyroidism. : To study levels of Hcy in relation to TSH, FT4 and FT3 levels in overt hypothyroid patients compared to control groups and correlation between Hcy and thyroid hormones. This study included 50 female overt hypothyroid cases with age group between 18-50 years and 50 healthy females controls with same age group. Serum homocysteine was estimated by Homocysteine Enzyme Assay in Cobas Integra 400 plus. TSH, FT4 &amp; FT3 estimated by CLIA method using Beckman coulter Access 2. Parameters of cases and controls are compared using unpaired ‘t’ test and the association between parameters is assessed by using Pearson’s correlation. There is a significant increase in Serum Hcy levels 19.24 ± 7.15 μmol/L and TSH levels 30.91 ± 10.21 µIU/ml respectively (p value &amp;#60;0.0001) and significant decrease in FT4 and FT3 levels (p &amp;#60;0.0001). Hcy was positively correlated with TSH and negatively correlated with FT4 and FT3. Thus, from our study we can conclude that serum Hcy levels can be used as a marker, which points towards the possible risk factor for atherosclerosis and cardiovascular diseases in Overt hypothyroid patients.

Downregulation of folate receptor α contributes to homocysteine‑induced human umbilical vein endothelial cell injury via activation of endoplasmic reticulum stress.

Elevated plasma homocysteine(Hcy) levels are associated with endothelial dysfunction. Previous studies have indicated the role of endoplasmic reticulum(ER) stress in Hcy‑induced endothelial injury. However, the mechanism of action remains unclear. In the current study, the role of human folate receptor α (hFRα) in Hcy‑induced ER stress was investigated, along with endothelial injury in human umbilical vein endothelial cells (HUVECs). The results showed that a moderate dose of Hcy induced morphological injury and reduced viability of HUVECs. Furthermore, moderate‑dose Hcy reduced hFRα expression in HUVECs. Notably, hFRα inhibition by RNA interference resulted in activation of the protein kinase RNA‑like endoplasmic reticulum kinase pathway and increased apoptosis of HUVECs. In conclusion, this study demonstrated the presence of hFRα in HUVECs, and indicated its role in the regulation of ER stress and cell injury by Hcy.

Elevated plasma homocysteine levels are associated with impaired peripheral microvascular vasomotor response

BackgroundHyperhomocysteinemia (HHcy) has been proposed as an important cardiovascular risk factor (cRF). However, little is known about the association between plasma homocysteine levels and peripheral microvascular endothelial dysfunction (PMED), which is an integrated index of vascular health. MethodsThis cross-sectional and retrospective cohort study included patients who underwent non-invasive PMED assessment using reactive hyperemia peripheral arterial tonometry (RH-PAT). The association between HHcy and PMED, and its impact on MACE (all-cause mortality and atherosclerotic cardiovascular events) was investigated. ResultsA total of 257 patients were enrolled (HHcy > 10.0 µmol/L, N = 51; lower levels of homocysteine [LHcy] ≤ 10 µmol/L, N = 206). Patients with HHcy were older, predominantly males, and with more comorbidities than patients with LHcy (p < 0.05 for all). RH-PAT index was lower in patients with HHcy versus LHcy (p = 0.01). A significant association between HHcy and PMED was observed in older (≥60 years), obese (≥30 kg/m2), present/past smokers and hypertensive patients. HHcy was significantly associated with PMED even after adjusting for other cRF and B-vitamins supplementation. HHcy was associated with an increased risk of MACE with a hazard ratio of 3.65 (95% CI 1.41–9.48, p = 0.01) and an adjusted hazard ratio of 2.44 (95% CI 0.91–6.51, p = 0.08) after adjustment for age (≥60 years). ConclusionHHcy was independently associated with PMED after adjusting for cRF and B-vitamins supplementation. Thus, the link between homocysteine and MACE could be mediated by endothelial dysfunction, and will require further clarification with future studies.

Frequency of elevated plasma homocysteine (Hcy) levels among type 2 Diabetes mellitus (T2DM) patients.

Objectives: To determine the frequency of elevated plasma homocysteine (Hcy) levels among type 2 diabetes mellitus (T2DM) patients. Study Design: Cross sectional study. Setting: Department of Medicine, Abbasi Shaheed Hospital, Karachi. Period: From 28 September 2012 to 26 March 2015. Material &amp; Methods: Type 2 Diabetic patients fulfilling inclusion criteria were enrolled. Patients with conditions known to cause altered homocysteine levels were excluded. Patients’ HbA1c and fasting serum homocysteine levels were obtained. Level &gt;15 μmol/L was labeled as elevated. Data was collected with the help of Performa. Data was analyzed using SPSS version 21. Results: (90) ninety patients were enrolled in this study during study period with mean age of 61.5±7.3 years. Of (90) ninety patients, 45 (50%) were male and 45 (50%) were female with male to female ratio of 1:1. Mean duration of diabetes was 6.9±1.7 years. 40 (44.44%) cases were of controlled diabetes and 43 (47.7%) were on treatment. Of 90 patients 36 (40%) patients had Homocysteinemia. Homocysteine levels were found to be significantly raised in males 51.1% v/s 28.8% (p&lt;0.03), older patients (&gt;60 years of age) 55.5% v/s 16.6% (p&lt;0.001), having diabetes for &gt; 7 years, 59.2% v/s 17%(p&lt;0.00004), in 21% v/s 57.4% cases who were and were not on treatment respectively (p&lt;0.0004), in 22.5% patients with controlled diabetes and 54% patients with uncontrolled diabetes respectively (p&lt;0.002). Conclusion: Hyperhomocystenemia is prevalent (40%) in type 2 diabetics with statistically significant raised levels in males, &gt;60 years of age, non-compliant diabetics, have long duration diabetes, and uncontrolled disease.

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.

Hormetic-Like Effects of L-Homocysteine on Synaptic Structure, Function, and Aβ Aggregation.

Alzheimer’s Disease (AD) is the primary cause of dementia among the elderly population. Elevated plasma levels of homocysteine (HCy), an amino acid derived from methionine metabolism, are considered a risk factor and biomarker of AD and other types of dementia. An increase in HCy is mostly a consequence of high methionine and/or low vitamin B intake in the diet. Here, we studied the effects of physiological and pathophysiological HCy concentrations on oxidative stress, synaptic protein levels, and synaptic activity in mice hippocampal slices. We also studied the in vitro effects of HCy on the aggregation kinetics of Aβ40. We found that physiological cerebrospinal concentrations of HCy (0.5 µM) induce an increase in synaptic proteins, whereas higher doses of HCy (30–100 µM) decrease their levels, thereby increasing oxidative stress and causing excitatory transmission hyperactivity, which are all considered to be neurotoxic effects. We also observed that normal cerebrospinal concentrations of HCy slow the aggregation kinetic of Aβ40, whereas high concentrations accelerate its aggregation. Finally, we studied the effects of HCy and HCy + Aβ42 over long-term potentiation. Altogether, by studying an ample range of effects under different HCy concentrations, we report, for the first time, that HCy can exert beneficial or toxic effects over neurons, evidencing a hormetic-like effect. Therefore, we further encourage the use of HCy as a biomarker and modifiable risk factor with therapeutic use against AD and other types of dementia.

Homocysteine and IgA nephropathy: observational and Mendelian randomization analyses.

Background:High levels of plasma homocysteine occur almost uniformly in patients with end-stage renal disease (ESRD). IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a common cause of ESRD in young adults. Here, we aimed to detect whether homocysteine was elevated and associated with clinical-pathologic manifestations of IgAN patients and tested its causal effects using a two-sample Mendelian randomization (MR) approach.Methods:For observational analysis, 108 IgAN patients, 30 lupus nephritis (LN) patients, 50 minimal change disease (MCD) patients, and 206 healthy controls were recruited from April 2014 to April 2015. Their plasma homocysteine was measured and clinical-pathologic manifestations were collected from medical records. For MR analysis, we further included 1686 IgAN patients. The missense variant methylenetetrahydrofolate reductase C677T (rs1801133) was selected as an instrument, which was genotyped by TaqMan allele discrimination assays.Results:Majority of IgAN patients (93.52%, 101/108) showed elevated levels of plasma homocysteine (>10 μmol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 μmol/L, Z = −5.29, P < 0.01) and in healthy controls (median: 18.32 vs. 10.00 μmol/L, Z = −8.76, P < 0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 μmol/L, Z = −1.32, P = 0.19). Significant differences were observed in sub-groups of IgAN patients according to quartiles of plasma homocysteine for male ratio (22.22% vs. 51.85% vs. 70.37% vs. 70.37%, χ2 = 14.29, P < 0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 μmol/L, χ2 = 34.06, P < 0.01), estimated glomerular filtration rate (median: 100.52 vs. 74.23 vs. 52.68 vs. 42.67 mL·min−1·1.73 m−2, χ2 = 21.75, P < 0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, χ2 = 2.97, P = 0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, χ2 = 11.47, P < 0.01), and pathologic tubular atrophy and interstitial fibrosis (T) (T0/T1/T2: 62.96%/33.33%/3.70% vs. 29.63%/40.74%/29.63% vs. 24.00%/48.00%/28.00% vs. 14.81%/37.04%/48.15%, χ2 = 17.66, P < 0.01). The coefficient of each rs1801133-T allele on homocysteine levels after controlling age and sex was 7.12 (P < 0.01). MR estimates showed causal positive effects of homocysteine on serum creatine (β = 0.76, P = 0.02), systolic blood pressure (β = 0.26, P = 0.02), diastolic blood pressure (β = 0.20, P = 0.01), and pathologic T lesion (β = 0.01, P = 0.01) in IgAN.Conclusions:By observational and MR analyses, consistent results were observed for associations of plasma homocysteine with serum creatinine, blood pressures, and pathologic T lesion in IgAN patients.

Pharmacogenetic Variants in MTHFR Gene are Significant Predictors of Methotrexate Toxicities in Bangladeshi Patients With Acute Lymphoblastic Leukemia

BackgroundThe objective of this pharmacogenetic study was to investigate the relationship of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with methotrexate (MTX)-induced toxicities and plasma homocysteine level in patients with acute lymphoblastic leukemia (ALL) from Bangladesh. Several polymorphisms result in reduced MTHFR activity that causes impaired remethylation of homocysteine to methionine and abnormal MTX metabolism, especially in tissues with high turnover. Therefore, the risk of elevated plasma homocysteine as well as MTX-induced toxicities become higher with MTHFR polymorphisms. Patients and MethodsWe recruited 160 patients with ALL receiving MTX containing chemotherapeutic protocol, and they were genotyped for MTHFR C677T and A1298C polymorphisms with polymerase chain reaction-restriction fragment length polymorphism. We also measured the plasma homocysteine level of 51 patients by the AxSYM homocysteine assay method. ResultsWe found 68.1% CC, 26.3% CT, and 5.6% TT genotype for MTHFR C677T polymorphism and 39.3% AA, 46.9% AC, and 13.8% CC genotype for MTHFR A1298C polymorphism in patients with ALL. Our study suggested that MTX-induced mucositis and diarrhea are significantly associated with MTHFR C677T as well as MTHFR A1298C polymorphisms (P < .05). ConclusionThe risk of elevated plasma homocysteine level was 5 to 6 times higher for both polymorphisms. This study may help to identify the patients who are at higher risk for MTX-related toxicities.

P3485Autophagy insufficiency participates in hyperhomocysteinemia-induced cardiac aging

Abstract Background The elevated plasma homocysteine (Hcy) level can lead to severe cardiovascular injuries, which participates in the progression of atherosclerosis, heart failure and so on. Except cardiovascular diseases, accumulated researches further revealed that hyperhomocystenemia (HHcy) can also induce aging-related diseases, including Alzheimer's disease, Parkinson's disease, diabetic cardiomyopathy, etc. Though some researches had revealed that Hcy stimulation would lead to endothelial cells senescence, whether cardiac aging could be induced by HHcy still remain unknown. Purpose This study aimed to reveal whether HHcy can induce cardiac aging and the underlying mechanisms. Methods SD rats were utilized to establish HHcy rat model and natural aging rat model. The cardiac function were determined by Echocardiography. Transmission electron microscope were used to detect mitochondria injuries of myocardium. 18F-FDG PET/CT was used to detect the state of glucose metabolism in myocardial cells. Agilent mRNA Array was used to detect possible altered pathways in myocardium of HHcy rats. The autophagy level was determined by detection of both autophagy-related proteins expressions with Western Blot and autophagic flux with mRFP-GFP-LC3. Results HHcy rats showed overall aging phenotypes, which were consistent with natural aging rats. The impaired cardiac function and severely injured myocardium morphology were observed in HHcy rats. Aging-related markers were increased significantly in HHcy rats and Hcy-treated cells, presented as increased p16, p21 and p53 expressions and increased senescence-associated beta-galactosidase (SA-β-gal) activity. Mitochondria dysfunction and morphology injuries were also detected in HHcy rats. Moreover, decreased serum Beclin-1 level was tested in CHD patients with HHcy. The decreased autophagy level was further verified in HHcy rats and Hcy-treated cells. Furthermore, the over-expression of Atg5 could attenuate Hcy induced cellular senescence. Conclusion HHcy can reduce autophagy level, which leading to severe mitochondria injuries, and resulted in cardiac aging eventually. Acknowledgement/Funding Natural Science Foundation of China (81671382,91839107)

Associations Between Elevated Plasma Total Homocysteine Level and Risk of Thromboangiitis Obliterans in a Chinese Population: A Matched Case-Control Study

Elevated plasma total homocysteine level is a risk factor for various vascular diseases; however, an association with risk of thromboangiitis obliterans (TAO) has not been defined. This study aims to assess whether elevated plasma total homocysteine level is associated with risk of TAO. We performed a matched case-control study including 64 patients with TAO and 256 controls. Multivariate logistic regression models were used to estimate the association between elevated plasma homocysteine level and the risk of TAO. Interaction and stratified analyses were conducted according to age, sex, smoking, alcohol consumption, and histories of chronic diseases. Patients with TAO versus controls had a higher mean plasma total homocysteine level (21.2±12.8μmol/L vs. 14.1±4.9μmol/L; P<0.01). The risk of TAO was 3.68-fold increased in participants with plasma total homocysteine level >15μmol/L (95% confidence interval [95% CI], 1.2-11.7). A 1μmol/L increase in plasma total homocysteine level was associated with 20% higher risk of TAO (odds ratio, 1.2; 95% CI, 1.1-1.3). Our findings suggest that the risk of TAO was significantly associated with elevated plasma total homocysteine level independently of other factors analyzed, including smoking. Studies on the use of homocysteine-lowering therapy to prevent TAO would allow testing causality of the latter association.

Joint Association of Serum Homocysteine and High-Sensitivity C-Reactive Protein with Arterial Stiffness in Chinese Population: A 12-Year Longitudinal Study

Background: Elevated plasma homocysteine (Hcy) and high-sensitivity C-reactive protein (hsCRP) levels are independent risk factors for cardiovascular diseases. However, it is unclear whether the coexistence of these conditions accelerates the risk of arterial stiffness. Our study aimed to evaluate the association of combined Hcy and hsCRP with arterial stiffness in Chinese middle-aged adults. Material/Methods: We conducted a 12-year longitudinal study in 220 individuals in Hanzhong, China, from 2005 to 2017. The average age at follow-up was 41.83 ± 3.10 years. Demographic information, medical history, anthropometric measurements, and blood pressure as well as urine and fasting blood samples, including Hcy, hsCRP, and brachial-ankle pulse wave velocity (baPWV) were measured and analyzed. Results: BaPWV levels showed a linear growth trend with the increasing of hsCRP (p for trend <0.01). The ORs in the highest quartile compared to the lowest quartile were 1.985 (95% CI 0.776–5.077; p = 0.152) and 3.960 (95% CI 1.468–10.684; p= 0.007) for Hcy and hsCRP, respectively. When Hcy and hsCRP were combined, subjects in both the highest quartile of Hcy and hsCRP (Hcy ≥15.50 μmol/L and hsCRP ≥0.82 μmol/L) had a 12.68-fold increased risk of developing arterial stiffness at the 12-year follow-up compared to those in the lowest quartile of Hcy and hsCRP (Hcy ≤9.91 μmol/L and hsCRP ≤0.19 μmol/L) after adjusting for potential confounders. Conclusions: The present study demonstrated that the combination of elevated serum Hcy and hsCRP may contribute to an increased risk of arterial stiffness.

Preeclampsia-Like Features and Partial Lactation Failure in Mice Lacking Cystathionine γ-Lyase—An Animal Model of Cystathioninuria

Elevated plasma homocysteine levels are considered as a risk factor for cardiovascular diseases as well as preeclampsia—a pregnancy disorder characterized by hypertension and proteinuria. We previously generated mice lacking cystathionine γ-lyase (Cth) as cystathioninuria models and found them to be with cystathioninemia/homocysteinemia. We investigated whether Cth-deficient (Cth−/−) pregnant mice display any features of preeclampsia. Cth−/− females developed normally but showed mild hypertension (~10 mmHg systolic blood pressure elevation) in late pregnancy and mild proteinuria throughout development/pregnancy. Cth−/− dams had normal numbers of pups and exhibited normal maternal behavior except slightly lower breastfeeding activity. However, half of them could not raise their pups owing to defective lactation; they could produce/store the first milk in their mammary glands but not often provide milk to their pups after the first ejection. The serum oxytocin levels and oxytocin receptor expression in the mammary glands were comparable between wild-type and Cth−/− dams, but the contraction responses of mammary gland myoepithelial cells to oxytocin were significantly lower in Cth−/− dams. The contraction responses to oxytocin were lower in uteruses isolated from Cth−/− mice. Our results suggest that elevated homocysteine or other unknown factors in preeclampsia-like Cth−/− dams interfere with oxytocin that regulates milk ejection reflex.

Hypothesis and Theory: Circulating Alzheimer's-Related Biomarkers in Type 2 Diabetes. Insight From the Goto-Kakizaki Rat.

Epidemiological data suggest an increased risk of developing Alzheimer's disease (AD) in individuals with type 2 diabetes (T2D). AD is anatomically associated with an early progressive accumulation of Aβ leading to a gradual Tau hyperphosphorylation, which constitute the main characteristics of damaged brain in AD. Apart from these processes, mounting evidence suggests that specific features of diabetes, namely impaired glucose metabolism and insulin signaling in the brain, play a key role in AD. Moreover, several studies report a potential role of Aβ and Tau in peripheral tissues such as pancreatic β cells. Thus, it appears that several biological pathways associated with diabetes overlap with AD. The link between peripheral insulin resistance and brain insulin resistance with concomitant cognitive impairment may also potentially be mediated by a liver/pancreatic/brain axis, through the excessive trafficking of neurotoxic molecules across the blood-brain barrier. Insulin resistance incites inflammation and pro-inflammatory cytokine activation modulates the homocysteine cycle in T2D patients. Elevated plasma homocysteine level is a risk factor for AD pathology and is also closely associated with metabolic syndrome. We previously demonstrated a strong association between homocysteine metabolism and insulin via cystathionine beta synthase (CBS) activity, the enzyme implicated in the first step of the trans-sulfuration pathway, in Goto-Kakizaki (GK) rats, a spontaneous model of T2D, with close similarities with human T2D. CBS activity is also correlated with DYRK1A, a serine/threonine kinase regulating brain-derived neurotrophic factor (BDNF) levels, and Tau phosphorylation, which are implicated in a wide range of disease such as T2D and AD. We hypothesized that DYRK1A, BDNF, and Tau, could be among molecular factors linking T2D to AD. In this focused review, we briefly examine the main mechanisms linking AD to T2D and provide the first evidence that certain circulating AD biomarkers are found in diabetic GK rats. We propose that the spontaneous model of T2D in GK rat could be a suitable model to investigate molecular mechanisms linking T2D to AD.