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

Objective: 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). Methods: 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. Results: 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). ... (AU)

Current progress on the mechanisms of hyperhomocysteinemia-induced vascular injury and use of natural polyphenol compounds.

Cardiovascular disease is one of the most common diseases in the elderly population, and its incidence has rapidly increased with the prolongation of life expectancy. Hyperhomocysteinemia is an independent risk factor for various cardiovascular diseases, including atherosclerosis, and damage to vascular function plays an initial role in its pathogenesis. This review presents the latest knowledge on the mechanisms of vascular injury caused by hyperhomocysteinemia, including oxidative stress, endoplasmic reticulum stress, protein N-homocysteinization, and epigenetic modification, and discusses the therapeutic targets of natural polyphenols. Studies have shown that natural polyphenols in plants can reduce homocysteine levels and regulate DNA methylation by acting on oxidative stress and endoplasmic reticulum stress-related signaling pathways, thus improving hyperhomocysteinemia-induced vascular injury. Natural polyphenols obtained via daily diet are safer and have more practical significance in the prevention and treatment of chronic diseases than traditional drugs.

HMGB1 mediates homocysteine-induced endothelial cells pyroptosis via cathepsin V-dependent pathway.

Endothelial cells injury and pro-inflammation cytokines release are the initial steps of hyperhomocysteinemia (HHcy)-associated vascular inflammation. Pyroptosis is a newly identified pro-inflammation form of programmed cell death, causing cell lysis and IL-1ß release, and characterized by the caspases-induced cleavage of its effector molecule gasdermins (GSDMs). However, the effect of homocysteine (Hcy) on endothelial cells pyroptosis and the underlying mechanisms have not been fully defined. We have previously reported that Hcy induces vascular endothelial inflammation accompanied by the increase of high mobility group box-1 protein (HMGB1) and lysosomal cysteine protease cathepsin V in endothelial cells, and other studies have shown that HMGB1 or cathepsins are involved in activation of NLRP3 inflammasome and caspase-1. Here, we investigated the role of HMGB1 and cathepsin V in the process of Hcy-induced pyroptosis. We observed an increase in plasma IL-1ß levels in HHcy patients and mice models, cathepsin V inhibitor reduced the plasma IL-1ß levels and cleavage of GSDMD full-length into GSDMD N-terminal in the thoracic aorta of hyperhomocysteinemia mice. Using cultured HUVECs, we observed that Hcy promoted GSDMD N-terminal expression, silencing GSDMD or HMGB1 rescued Hcy-induced pyroptosis. HMGB1 also increased GSDMD N-terminal expression, and silencing cathepsin V reversed HMGB1-induced pyroptosis. HMGB1 could increase lysosome permeability, and silencing cathepsin V attenuated HMGB1-induced activation of caspase-1. In conclusion, this study has delineated a novel mechanism that HMGB1 mediated Hcy-induced endothelial cells pyroptosis partly via cathepsin V-dependent pathway.

Myocardial Performance in Elite Athletes: The Role of Homocysteine, Iron, and Lipids.

BACKGROUND The myocardial performance index (MPI) is a comprehensive measure of global systolic and diastolic function of the ventricle, and it has an inverse correlation with maximal oxygen consumption. In this study, the potential association between left ventricle MPI and biochemical biomarkers (including iron, homocysteine, and lipids) in elite athletes was investigated. MATERIAL AND METHODS This cross-sectional observational study consisted of 80 young male elite soccer and basketball players (age: 18-34 years) examined for a seasonal medical check-up. Cardiological examinations and transthoracic echocardiography of these athletes were performed and blood samples were analyzed according to standard laboratory protocols. Tissue Doppler recording was acquired from the mitral annulus using apical 4-chamber view and then the tissue Doppler-derived MPI was computed. RESULTS Athletes were separated into 2 groups based on MPI values (MPI ≤0.40 and MPI >0.40), and baseline demographic, clinical, and biochemical variables of the study participants were compared between these 2 groups. Serum triglyceride, high-density lipoprotein, total cholesterol, homocysteine levels, and iron parameters did not significantly differ between groups, while low-density lipoprotein level was significantly lower in the MPI ≤0.40 group (103.8±26.0 mg/dl vs. 116.8±30.2 mg/dl; p=0.043). Correlation analysis and multivariate linear regression analysis demonstrated a significant association between low-density lipoprotein and MPI. CONCLUSIONS In this study, various biochemical markers were evaluated for possible association with left ventricle MPI as a surrogate of cardiac performance. Among these biomarkers, only low-density lipoprotein was significantly associated with MPI in elite athletes.

Elevated levels of brain homocysteine directly modulate the pathological phenotype of a mouse model of tauopathy.

A high circulating level of homocysteine (Hcy), also known as hyperhomocysteinemia, is a risk factor for Alzheimer's disease (AD). Previous studies show that elevated Hcy promotes brain amyloidosis and behavioral deficits in mouse models of AD. However, whether it directly modulates the development of tau neuropathology independently of amyloid beta in vivo is unknown. Herein, we investigate the effect of diet-induced elevated levels of brain Hcy on the phenotype of a relevant mouse model of human tauopathy. Compared with controls, tau mice fed with low folate and B vitamins diet had a significant increase in brain Hcy levels and worsening of behavioral deficits. The same mice had a significant elevation of tau phosphorylation, synaptic pathology, and astrocytes activation. In vitro studies demonstrated that Hcy effect on tau phosphorylation was mediated by an upregulation of 5-lipoxygenase via cdk5 kinase pathway activation. Our findings support the novel concept that high Hcy level in the central nervous system is a metabolic risk factor for neurodegenerative diseases, specifically characterized by the progressive accumulation of tau pathology, namely tauopathies.

Association between homocysteine and conventional predisposing factors on risk of stroke in patients with hypertension.

Previous studies have focused mostly on independent effects of the stroke risk factors, whereas little attention has been paid to interactions between individual factors which may be important for stroke prevention. We collected data related to the patients' demographic characteristics, history of chronic diseases and lifestyle factors in 2258 patients with primary hypertension. Logistic regression models based on odds ratio (OR) with their associated 95% confidence interval (CI) were used to estimate an independent effect of homocysteine (Hcy) on the risk of stroke but also include the interactions between Hcy and other risk factors. Hcy was associated with an increased OR of the risk of stroke in both hypertension patients (OR, 1.027; 95% CI, 1.016-1.038; P < 0.001) and H-type hypertension patients (OR, 1.026; 95% CI, 1.014-1.037; P < 0.001), after adjustment for potential confounding factors. Among the hypertension participants, three tests of interactions between Hcy and other risk factors were statistically significant: sex, systolic blood pressure and diastolic blood pressure. In conclusion, complexities of the interactions of Hcy stratified by sex and blood pressure need to be considered in predicting overall risk and selecting certain treatments for stroke prevention.

[Homocysteine induces calcium overload in neonatal rat atrial cells through activation of sodium current and CaMK⠡δ].

Objective: To investigate the effect and related mechanism of homocysteine (Hcy) on calcium overload in neonatal rat atrial cells (NRICs). Methods: NRICs were assigned to 9 groups after culture for 3 days: (1) control group; (2) Hcy group (0, 50, 100, 200, 500 µmol/L for 48 hours); (3) antioxidant group (NAC, 10 µmol/L for 24 hours); (4) Hcy+NAC group (500 µmol/L Hcy for 48 hours, then treated with 10 µmol/L NAC for 24 hours); (5) calcium/calmodulin dependent protein kinase Ⅱδ (CaMKⅡδ) inhibitor group (KN-93, 3 µmol/L KN-93 for 5 hours); (6) specific sodium current inhibitor group (ELE, 1 µmol/L ELE for 5 hours); (7) Hcy+KN-93 group (500 µmol/L Hcy for 48 hours, then treated with 3 µmol/L KN-93 for 5 hours); (8) Hcy+ELE group (500 µmol/L Hcy for 48 hours, then treated with 1 µmol/L ELE for 5 hours; (9) Hcy+KN-93+ELE group (500 µmol/L Hcy for 48 hours, then treated with 3 µmol/L KN-93 and 1 µmol/L ELE for 5 hours). Moreover, NRICs were also treated with CaMKⅡδ-siRNA lentivirus, and Nav1.5-siRNA lentivirus, negative lentivirus carrier containing green fluorescent protein (GFP) for 24 hours. The MOI values of the three groups were 10. Infection efficiency of lentivirus was determined by observing the percentage of GFP fluorescence under inverted fluorescence microscope after transfection for 24 hours, and cultured regularly with simultaneous Puro screening, then cells were grouped as Hcy+CaMKⅡδ-siRNA group, Hcy+Nav1.5-siRNA group and Hcy+negative group. The concentration of Ca(2+) in NRICs ([Ca(2+)]i) of various groups was detected through Fluo-4/AM fluorescence probe, then 2', 7'- two chlorofluorescein diacetate (DCFH-DA) was used as a probe to detect reactive oxygen species (ROS) in NRICs by flow cytometry. The malondialdehyde (MDA) was detected by the activity of superoxide dismutase (SOD) and xanthine oxidase was detected by thiobarbituric acid colorimetry. The protein and mRNA expression level of CaMKⅡδ and Nav1.5 in NRICs were detected by Western blot and quantitative real-time PCR. Results: (1) ROS, MDA and SOD were similar between NAC group and control group, ROS and MDA were significantly increased, while SOD was significantly reduced in Hcy group in a concentration-dependent manner. (2) [Ca(2+)]i: The level of [Ca(2+)]i was (155.57+7.25), (187.43+13.07), (248.98+27.22) and (307.36+15.09) nmol/L in 50, 100, 200 and 500 µmol/L Hcy groups, which was significantly higher than that in the control group ((123.18+7.24) nmol/L, P<0.01). In addition, the level of [Ca(2+)]i in Hcy+NAC group ((222.87+23.71)nmol/L) was significantly lower than that in Hcy 500 µmol/L group ((305.15+39.45) nmol/L, P<0.05), while [Ca(2+)]i level was similar between NAC group and the control group. (3) The protein expression of CaMKⅡδ and Nav1.5 was significantly upregulated in Hcy groups than in the control group. The protein expression level of CaMKⅡδ-Thr287 was significantly lower in NAC group than in Hcy 500 µmol/L group (P<0.01), however, there was no significant difference on the protein expression levels of CaMKⅡδ-Thr287 and Nav1.5 between NAC group and control group (all P>0.05). (4) The protein expression levels of CaMKⅡδ-Thr287 and the concentration of [Ca(2+)]i were significantly lower in Hcy+KN-93 group and Hcy+KN-93+ELE group than in Hcy 500 µmol/L group (P<0.05). [Ca(2+)]i concentration was significantly lower in Hcy+KN-93 group, Hcy+ELE group and KN-93+ELE+Hcy group than in Hcy 500 µmol/L group (P<0.05). (5) The mRNA and protein expression levels of CaMKⅡδ and Nav1.5 in each group infected with lentivirus: the GFP expression was ideal post lentivirus transfection for 24 hours (up to 90%), which was significantly lower in the CaMKⅡδ-siRNA group and Nav1.5-siRNA group than in the negative infection group (all P<0.05), which was similar between negative infection group and control group (P>0.05). Moreover, the mRNA and protein expression levels of CaMKⅡδ and CaMKⅡδ-Thr287 was significantly lower in Hcy+Nav1.5-siRNA group than in Hcy+negative infection group (P<0.05). The protein and mRNA levels of Nav1.5 were similar between Hcy+CaMKⅡδ-siRNA group and Hcy+negative infection group (P>0.05). Conclusions: Hcy can induce calcium overload in NRICs by increasing oxidative stress, upregulating the sodium channel protein, and activating the late sodium current and phosphorylating CaMKⅡδ.

[Progress in study on the correlation of polyunsaturated fatty acids, vitamin D and homocysteine with postpartum depression].

Postpartum depression(PPD) is a common emotional disorder in the puerperium, which has negative impact on women, infants and family. There is growing evidence that abnormal concentration of a number of nutrients (including polyunsaturated fatty acids, vitamin D and homocysteine) is associated with depression in postpartum population. Further studies on the mechanisms for the functions of nutrients and regulation of nutritional states in the puerperium will be of great value in the prevention, early diagnosis and treatment of PPD.

Antagonistic effects of endostatin-vascular endothelial growth inhibitor chimeric recombinant adenovirus on homocysteine-induced vascular endothelial cells injury in vitro and in vivo.

BACKGROUND: The study is inclined to investigate the antagonistic effects of endostatin-vascular endothelial growth inhibitor chimeric recombinant adenovirus (Ad-hENDO-VEGI) on homocysteine (Hcy)-induced vascular endothelial cells (VECs) injury in vitro and in vivo. METHODS: Human VECs cell line ECV304 was selected and infected with Ad-hENDO-VEGI. The LDH leakage, SOD activity, and MDA levels were measured by the automatic biochemical analyzer. Cell survival rate was counted by Trypanblau dying. The TNF-α and MCP-1 protein expressions were detected by ELISA assay. The protein expressions of fusion protein of Ad-hENDO-VEGI, nuclear factor kappa B p65 (NF-kappa B p65), and NF-kappa B inhibitor alpha (I-kappa B-α) were detected by Western blotting. A rat model of hyper-homocysteinemia was constructed. Thirty-six Wistar rats were randomly divided into 3 groups: the control group, the model group, and the Ad-hENDO-VEGI group. Serum Hcy levels in rats were measured with enzymatic cycling method. Endothelial vasodilation function was evaluated with the treatment of sodium nitroprusside and acetylcholine. RESULTS: After Ad-hENDO-VEGI infection, high expressions (41 kD) of fusion proteins in ECV304 cells were observed. The injury severity of Hcy on ECV304 cells had a dose-dependent manner, and the injury reached a steady stage at 1.0 mmol/L. Thus, 1.0 mmol/L Hcy was selected for further experiments. With an increase of Ad-hENDO-VEGI in ECV304 cells after Hcy treatment, LDH leakage, MDA, TNF-α, MCP-1, and nuclear NF-kappa B p65 protein expression were gradually decreased, and cell survival rate, SOD activity, and I-kappa B-α protein expression were gradually increased. Compared with the control group, the model group had a higher Hcy level and attenuated vasodilator response. The Ad-hENDO-VEGI group exhibited a lower Hcy level and enhanced vasodilator response than the model group. CONCLUSION: These results indicated that Ad-hENDO-VEGI could down-regulate NF-kappa B p65 expression and suppress inflammatory response, thereby alleviating Hcy-induced VECs injury.

Cigarette smoking reduced renal function deterioration in hypertensive patients may be mediated by elevated homocysteine.

Elevated homocysteine (HCY) and smoking are both important risk factors for hypertensive patients. However, whether they have crossing effect on renal function deterioration of hypertensive patients and what is the underlying mechanism are unclear. In the present study, 3033 participants diagnosed as essential hypertension with estimated glomerular filtration rate (eGFR)> 30 ml/min/1.73 m2 from southern China were enrolled in this cross-sectional study. We collected the demographic and clinical data. In addition, the mediation effects were analyzed. The results showed that, comparing with non-smokers, smokers had significant higher levels of HCY (13.10 (11.20-16.87) vs. 11.00 (8.90-13.40) umol/L, P < 0.001) and lower eGFR (79.71 (66.83-91.05) vs. 82.89 (69.80-95.85) ml/min/1.73m2, P < 0.001). HCY levels and smoking were independently associated with decreased eGFR. Meanwhile, eGFR levels were significantly negatively correlated with HCY (P < 0.001), and this correlation might be stronger in current smokers. Current smoker consuming over 20 cigarettes per day would accelerate early renal function deterioration (OR = 1.859, P = 0.019). The mediation effects analysis further showed that the association between smoking and renal function deterioration was mediated by HCY. And elevated HCY was accounted for 56.94% of the estimated causal effect of smoking on renal function deterioration in hypertensive patients. Our findings indicated that cigarette smoking was associated with renal function deterioration in hypertensive patients, and the association between cigarette smoking and renal function deterioration was probably mediated by elevated HCY. Therefore, HCY-lowering therapy may be beneficial for renal function deterioration in hypertensive smoking patients.

Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension.

Over the past several years, hydrogen sulfide (H2S) has been shown to be an important player in a variety of physiological functions, including neuromodulation, vasodilation, oxidant regulation, inflammation, and angiogenesis. H2S is synthesized primarily through metabolic processes from the amino acid cysteine and homocysteine in various organ systems including neuronal, cardiovascular, gastrointestinal, and kidney. Derangement of cysteine and homocysteine metabolism and clearance, particularly in the renal vasculature, leads to H2S biosynthesis deregulation causing or contributing to existing high blood pressure. While a variety of environmental influences, such as diet can have an effect on H2S regulation and function, genetic factors, and more recently epigenetics, also have a vital role in H2S regulation and function, and therefore disease initiation and progression. In addition, new research into the role of gut microbiota in the development of hypertension has highlighted the need to further explore these microorganisms and how they influence the levels of H2S throughout the body and possibly exploiting microbiota for use of hypertension treatment. In this review, we summarize recent advances in the field of hypertension research emphasizing renal contribution and how H2S physiology can be exploited as a possible therapeutic strategy to ameliorate kidney dysfunction as well as to control blood pressure.

Exfoliation syndrome: assembling the puzzle pieces.

PURPOSE: To summarize various topics and the cutting edge approaches to refine XFS pathogenesis that were discussed at the 21st annual Glaucoma Foundation Think Tank meeting in New York City, Sept. 19-20, 2014. METHODS: The highlights of three categories of talks on cutting edge research in the field were summarized. RESULTS: Exfoliation syndrome (XFS) is a systemic disorder with a substantial ocular burden, including high rates of cataract, cataract surgery complications, glaucoma and retinal vein occlusion. New information about XFS is akin to puzzle pieces that do not quite join together to reveal a clear picture regarding how exfoliation material (XFM) forms. CONCLUSION: Meeting participants concluded that it is unclear how the mild homocysteinemia seen in XFS might contribute to the disarrayed extracellular aggregates characteristic of this syndrome. Lysyl oxidase-like 1 (LOXL1) variants are unequivocally genetic risk factors for XFS but exactly how these variants contribute to the assembly of exfoliation material (XFM) remains unclear. Variants in a new genomic region, CACNA1A associated with XFS, may alter calcium concentrations at the cell surface and facilitate XFM formation but much more work is needed before we can place this new finding in proper context. It is hoped that various animal model and ex vivo systems will emerge that will allow for proper assembly of the puzzle pieces into a coherent picture of XFS pathogenesis. A clear understanding of XFS pathogenesis may lead to 'upstream solutions' to reduce the ocular morbidity produced by XFS.

Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells.

Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis. In addition to Hcy, related metabolites accumulate in HHcy but their role in endothelial dysfunction is unknown. Here, we examine how Hcy-thiolactone, N-Hcy-protein, and Hcy affect gene expression and molecular pathways in human umbilical vein endothelial cells. We used microarray technology, real-time quantitative polymerase chain reaction, and bioinformatic analysis with PANTHER, DAVID, and Ingenuity Pathway Analysis (IPA) resources. We identified 47, 113, and 30 mRNAs regulated by N-Hcy-protein, Hcy-thiolactone, and Hcy, respectively, and found that each metabolite induced a unique pattern of gene expression. Top molecular pathways affected by Hcy-thiolactone were chromatin organization, one-carbon metabolism, and lipid-related processes [-log(P value) = 20-31]. Top pathways affected by N-Hcy-protein and Hcy were blood coagulation, sulfur amino acid metabolism, and lipid metabolism [-log(P value)] = 4-11; also affected by Hcy-thiolactone, [-log(P value) = 8-14]. Top disease related to Hcy-thiolactone, N-Hcy-protein, and Hcy was 'atherosclerosis, coronary heart disease' [-log(P value) = 9-16]. Top-scored biological networks affected by Hcy-thiolactone (score = 34-40) were cardiovascular disease and function; those affected by N-Hcy-protein (score = 24-35) were 'small molecule biochemistry, neurological disease,' and 'cardiovascular system development and function'; and those affected by Hcy (score = 25-37) were 'amino acid metabolism, lipid metabolism,' 'cellular movement, and cardiovascular and nervous system development and function.' These results indicate that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease.

Role of homocysteine in the development of cardiovascular disease.

It is well known that neuronal damage following a stroke has been attributed to the over stimulation of excitatory amino acids such as glutamate and aspartate through activation of NMDA receptors. The brain is exposed to most of the constituents of plasma including homocysteine as a result of the disruption of the blood-brain barrier after stroke, head trauma and stress. The question, therefore, arises as to whether or not homocysteine is able to selectively stimulate the release of excitatory amino acids in stroke. This review article will address the importance of homocysteine in nervous system specifically how these amino acids may trigger the release of catecholamines. Our data will thus strengthen the view that a mechanism for the association of hyperhomocysteinemia with increased brain lesion in stroke. As hypothalamus also controls the cardiac function via sympathetic system, the contractility of heart will be compromised. Homocysteine is also known to mediate cardiovascular problems by its adverse effects on cardiovascular endothelium and smooth muscle cells with resultant alterations in subclinical arterial structure and function. The present review will thus summarize both central and peripheral effects of homocysteine and will highlight some of the controversies associated with hyperhomocysteinemia-induced cardiovascular problems.

Endothelial dysfunction: the link between homocysteine and hydrogen sulfide.

High level of homocysteine (hyperhomocysteinemia, HHcy) is associated with increased risk for vascular disease. Evidence for this emerges from epidemiological studies which show that HHcy is associated with premature peripheral, coronary artery and cerebrovascular disease independent of other risk factors. Possible mechanisms by which homocysteine causes vascular injury include endothelial injury, DNA dysfunction, proliferation of smooth muscle cells, increased oxidative stress, reduced activity of glutathione peroxidase and promoting inflammation. HHcy has been shown to cause direct damage to endothelial cells both in vitro and in vivo. Clinically, this manifests as impaired flow-mediated vasodilation and is mainly due to a reduction in nitric oxide synthesis and bioavailability. The effect of impaired nitric oxide release can in turn trigger and potentiate atherothrombogenesis and oxidative stress. Endothelial damage is a crucial aspect of atherosclerosis and precedes overt manifestation of disease. In addition, endothelial dysfunction is also associated with hypertension, diabetes, ischemia reperfusion injury and neurodegenerative diseases. Homocysteine is a precursor of hydrogen sulfide (H2S) which is formed by transulfuration process catalyzed by the enzymes, cystathionine ß-synthase and cystathionine γ-lyase. H2S is a gasotransmitter that has emerged recently as a novel mediator in cardiovascular homeostasis. As a potent vasodilator, it plays several roles which include regulation of vessel diameter, protection of endothelium from redox stress, ischemia reperfusion injury and chronic inflammation. However, the precise mechanism by which it mediates these beneficial effects is complex and still remains unclear. Current evidence indicates H2S modulates cellular functions by a variety of intracellular signaling processes. In this review, we summarize the mechanisms of HHcy-induced endothelial dysfunction and the metabolism and physiological functions of H2S as a protective agent.

Resting brain perfusion and selected vascular risk factors in healthy elderly subjects.

BACKGROUND AND PURPOSE: Both cerebral hypoperfusion and vascular risk factors have been implicated in early aging of the brain and the development of neurodegenerative disease. However, the current knowledge of the importance of cardiovascular health on resting brain perfusion is limited. The aim of the present study was to elucidate the relation between brain perfusion variability and risk factors of endothelial dysfunction and atherosclerosis in healthy aged subjects. METHODS: Thirty-eight healthy subjects aged 50-75 years old were included. Mean global brain perfusion was measured using magnetic resonance phase contrast mapping and regional brain perfusion by use of arterial spin labeling. RESULTS: Mean global brain perfusion was inversely correlated with caffeine and hematocrit, and positively with end-tidal PCO2. Furthermore, the mean global brain perfusion was inversely correlated with circulating homocysteine, but not with asymmetric dimethylarginine, dyslipidemia or the carotid intima-media thickness. The relative regional brain perfusion was associated with circulating homocysteine, with a relative parietal hypoperfusion and a frontal hyperperfusion. No effect on regional brain perfusion was observed for any of the other risk factors. A multiple regression model including homocysteine, caffeine, hematocrit and end-tidal PCO2, explained nearly half of the observed variability. CONCLUSION: Both intrinsic and extrinsic factors influenced global cerebral perfusion variation between subjects. Further, the results suggest that the inverse relation between homocysteine and brain perfusion is owing to other mechanisms, than reflected by asymmetric dimethylarginine, and that homocysteine may be a marker of cerebral perfusion in aging brains.

Homocysteine is associated with plasma high-sensitivity cardiac troponin T levels in a community-dwelling population.

OBJECTIVES: Homocysteine (HCY) is associated with an increased risk for cardiovascular disease, possibly leading to myocardial damage. Cardiac troponin T (TnT), a marker of cardiomyocyte injury, can be detected by high-sensitivity TnT (hsTnT) assay. The current study investigated the relationship between plasma HCY and hsTnT levels in a community-based population. METHODS: We related plasma levels of hsTnT to HCY levels in 1,497 participants (mean age, 62.4 years; 629 men, 868 women) from a community-based population in Beijing, People's Republic of China. RESULTS: In multiple logistic regression models, serum HCY was associated with a higher likelihood of detectable hsTnT (odds ratio 1.5; 95% confidence interval 1.07-2.10; P=0.018). A subsequent subgroup analysis found that in subjects aged 65 years and older, the association between hsTnT levels and HCY levels was strengthened. The association between hsTnT and HCY was not present in the younger subgroup (<65 years old). CONCLUSION: Levels of serum HCY are associated with hsTnT levels in the elderly, indicating a relationship between HCY and subclinical myocardial damage.

Nutriepigenetic regulation by folate-homocysteine-methionine axis: a review.

Although normally folic acid is given during pregnancy, presumably to prevent neural tube defects, the mechanisms of this protection are unknown. More importantly it is unclear whether folic acid has other function during development. It is known that folic acid re-methylates homocysteine (Hcy) to methionine by methylene tetrahydrofolate reductase-dependent pathways. Folic acid also generates high-energy phosphates, behaves as an antioxidant and improves nitric oxide (NO) production by endothelial NO synthase. Interestingly, during epigenetic modification, methylation of DNA/RNA generate homocysteine unequivocally. The enhanced overexpression of methyl transferase lead to increased yield of Hcy. The accumulation of Hcy causes vascular dysfunction, reduces perfusion in the muscles thereby causing musculopathy. Another interesting fact is that children with severe hyperhomocysteinaemia (HHcy) have skeletal deformities, and do not live past teenage. HHcy is also associated with the progeria syndrome. Epilepsy is primarily caused by inhibition of gamma-amino-butyric-acid (GABA) receptor, an inhibitory neurotransmitter in the neuronal synapse. Folate deficiency leads to HHcy which then competes with GABA for binding on the GABA receptors. With so many genetic and clinical manifestations associated with folate deficiency, we propose that folate deficiency induces epigenetic alterations in the genes and thereby results in disease.