Atherosclerosis is a leading cause of global mortality, driven by complex interactions between genetic, metabolic, and environmental factors. Among these, hyperhomocysteinemia (HHcy) has emerged as a significant and modifiable risk factor, contributing to endothelial dysfunction, oxidative stress, and vascular inflammation. Despite increasing recognition of its role in atherogenesis, the precise mechanisms and clinical implications of HHcy remain incompletely understood, necessitating a comprehensive review to connect recent mechanistic insights with practical applications.

We analyzed the various mechanisms whereby HHcy accelerates the progression of atherosclerosis, and conducted a comprehensive review of publications in the fields of HHcy and atherosclerosis.

HHcy promotes atherosclerosis through several mechanisms, including inflammation, oxidative stress, epigenetic modification, and lipoprotein metabolism alteration. Moreover, this discussion extends to current strategies for the prevention and clinical management of HHcy-induced atherosclerosis.

This review consolidates and elucidates the latest advancements and insights into the role of HHcy in atherosclerosis. The comprehensive narrative connects fundamental research with clinical applications. Contemporary studies highlight the complex interplay between HHcy and atherosclerosis, establishing HHcy as not only a contributing risk factor but also an accelerator of various atherogenic processes.

Carbon tetrachloride (CCl4), a volatile organic compound, is harmful to multi-organs, including the liver, lungs, muscles, and kidneys. Methyl donors, such as methionine, choline, betaine, and folic acid, are vital to one-carbon metabolism and have great potential to alleviate oxidative stress and inflammation, thus mitigating disease onset. Hence, the current study aims to examine the therapeutic effect of methyl donors against CCl4-induced nephrotoxicity. Nephrotoxicity was developed in male Sprague Dawley rats using CCl4 at a dose of 1 mL/kg (4-week model induction) twice a week via the intraperitoneal route. Thereafter, methyl donor treatments through oral gavage were given for the next 6 weeks with a continuation of CCl4 administration. Biochemical, oxidative stress parameters, histopathological, and qRT-PCR analyses were done at the completion of the 10-week. Biochemical analyses revealed that CCl4 induces nephrotoxicity, as evidenced by increased urea and creatinine levels and decreased albumin levels. These detrimental effects were significantly ameliorated by methyl donor treatment. Moreover, CCl4 decreased the antioxidant enzyme activity (superoxide dismutase; SOD and catalase; CAT) while increasing oxidative stress markers (malondialdehyde; MDA and nitrite). Methyl donor treatment effectively mitigated these oxidative changes. Histopathological analysis demonstrated the nephroprotective effect of methyl donors against CCl4-induced nephrotoxicity, showing reduced tissue damage and protection of renal architecture. At the molecular level, methyl donor treatment alleviated the CCl4-induced increase in kidney injury biomarkers (Kidney injury molecule 1; KIM-1 and Neutrophil gelatinase-associated lipocalin; NGAL), as well as inflammatory (IL-6 and TNF-α) and fibrosis-related genes (Acta-2 and TGF-β). In conclusion, our findings suggest that methyl donors possess anti-inflammatory and anti-fibrotic properties. They protect against CCl4-induced oxidative damage to renal cells, likely due to their reactive oxygen species scavenging capabilities and their ability to restore key early renal injury biomarkers (KIM-1 and NGAL). Methyl donors hold great promise as a cutting-edge therapy approach for preventing CCl4-induced nephrotoxicity.

Vascular injury and pathologies underlie common diseases including ischemic stroke and cerebral small vessel disease (CSVD). Prior work has identified a key role for glial cells, including microglia, in the multifaceted and temporally evolving neuroimmune response to both stroke and CSVD. Transcriptional profiling has led to important advances including identification of distinct gene expression signatures in ischemia-exposed, flow cytometrically sorted microglia and more recently single cell RNA sequencing-identified microglial subpopulations or clusters. There is a reassuring degree of overlap in the results from these two distinct methodologies with both identifying a proliferative and a separate type I interferon responsive microglial element. Similar patterns were later seen using multimodal and spatial transcriptomal profiling in ischemia-exposed microglia and astrocytes. Methodological advances including enrichment of specific neuroanatomic/functional regions (such as the neurovascular unit) prior to single cell RNA sequencing has led to identification of novel cellular subtypes and generation of new credible hypotheses as to cellular function based on the enhanced cell sub-type specific gene expression patterns. A ribosomal tagging strategy focusing on the cellular translatome analyses carried out in the acute phases post stroke has revealed distinct inflammation-regulating roles for microglia and astrocytes in this setting. Early spatial transcriptomics experiments using cerebral ischemia models have identified regionally distinct microglial cell clusters in ischemic core versus penumbra. There is great potential for combination of these methods for multi-omics approaches to further elucidate glial responses in the context of both acute ischemic stroke and chronic CSVD.

Modern hyperprolific sows are increasingly susceptible to health challenges. Their rapid growth rates predispose them to locomotor disorders, while high metabolic demands, reduced backfat thickness, and increased protein accretion heighten their vulnerability to heat stress and dystocia. Additionally, prolonged farrowing negatively affects the oxidative and inflammatory status of these females. Additionally, prevalent conditions such as gastric ulcers and cystitis raise ethical, welfare, and economic concerns. Despite the several studies related to sow nutrition, there are no studies which compile and extrapolate nutrition approaches from the rearing period and their impact on sows' health and longevity. Also, the aim of our review was to shed light on gaps that require further investigation. Controlling body condition scores is crucial for maximizing productivity in sows. During gestation, high-fiber diets help maintain optimal body condition and prevent constipation, particularly during the peripartum period. Antioxidants offer a range of beneficial effects during this critical phase. Additionally, probiotics and acidifiers can enhance gut health and lower the risk of genitourinary infections. On the day of farrowing, energy supplementation emerges as a promising strategy to reduce farrowing duration. Collectively, these strategies address major health challenges, enhancing welfare and promoting sow's longevity.

Patients with inflammatory bowel diseases (IBDs) are more likely to have depression and anxiety symptoms compared with healthy individuals and those with other chronic illnesses. Previous studies have shown a link between the microbiome composition and depression symptoms; however, many antidepressant medications have antibacterial activity confounding cross-sectional studies of these populations. Therefore, we aimed to determine whether we could detect longitudinal changes in the microbiome of a subset of patients who participated in a previously published mindfulness-based cognitive therapy (MBCT) study to improve depression symptoms in adolescents and young adults with IBD.

Stool samples were collected at baseline and 8 weeks (n = 24 participants, 37 total samples, 13 paired samples). During this time, some participants achieved a 50% reduction in their depression symptoms either through MBCT or treatment as usual with their mental health team (responders). The microbiome composition and function of responders were compared with participants who did not improve their depression scores (nonresponders). Depression scores were determined using the depression, anxiety, and stress score (DASS-21), and metagenomic sequencing of stool samples was performed.

No difference in alpha diversity was found between responders and nonresponders. Beta diversity measures were similarly unchanged. Clinical features including fecal calprotectin, C-reactive protein, and serum IL-6 levels were unchanged.

In this small longitudinal study, we were not able to detect longitudinal changes in the microbiome associated with improvement in depression scores. Follow-up studies that are sufficiently powered to detect changes in the microbiome are required to confirm our results.

Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. Ischemic stroke and heart disease, coronary heart disease, and cardiovascular disease are events resulting from long-lasting and silent atherosclerosis. This paper deals with the synthesis of homocysteine (Hcy), causes of HHcy, mechanism of HHcy-induced atherosclerosis, and treatment of HHcy. Synthesis and metabolism of Hcy involves demethylation, transmethylation, and transsulfuration, and these processes require vitamin B 6 and vitamin B 12 folic acid (vitamin B 9 ). Causes of HHcy include deficiency of vitamins B 6 , B 9 , and B 12 , genetic defects, use of smokeless tobacco, cigarette smoking, alcohol consumption, diabetes, rheumatoid arthritis, low thyroid hormone, consumption of caffeine, folic acid antagonist, cholesterol-lowering drugs (niacin), folic acid antagonist (phenytoin), prolonged use of proton pump inhibitors, metformin, and hypertension. HHcy-induced atherosclerosis may be mediated through oxidative stress, decreased availability of nitric oxide (NO), increased expression of monocyte chemoattractant protein-1, smooth muscle cell proliferation, increased thrombogenicity, and induction of arterial connective tissue. HHcy increases the generation of atherogenic biomolecules such as nuclear factor-kappa B, proinflammatory cytokines (IL-1β, IL-6, and IL-8), cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selection), growth factors (IGF-1 and TGF-β), and monocyte colony-stimulating factor which lead to the development of atherosclerosis. NO which is protective against the development of atherosclerosis is reduced by HHcy. Therapy with folic acid, vitamin B 6 , and vitamin B 12 lowers the levels of Hcy, with folic acid being the most effective. Dietary sources of folic acid, vitamin B 6 , vitamin B 12 , omega-3 fatty acid, and green coffee extract reduce Hcy. Abstaining from drinking coffee and alcohol, and smoking also reduces blood levels of Hcy. In conclusion, HHcy induces atherosclerosis by generating atherogenic biomolecules, and treatment of atherosclerosis-induced diseases may be by reducing the levels of Hcy.

Atherosclerosis, the leading cause of cardiovascular disease, cannot be sufficiently explained by established risk factors, including cholesterol. Elevated plasma homocysteine (Hcy) is an independent risk factor for atherosclerosis and is closely linked to cardiovascular mortality. However, its role in atherosclerosis has not been fully clarified yet. We have previously shown that rabbits fed a diet deficient in B vitamins and choline (VCDD), which are required for Hcy degradation, exhibit an accumulation of macrophages and lipids in the aorta, aortic stiffening and disorganization of aortic collagen in the absence of hypercholesterolemia, and an aggravation of atherosclerosis in its presence. In the current study, plasma Hcy levels were increased by intravenous injections of Hcy into balloon-injured rabbits fed VCDD (VCDD+Hcy) in the absence of hypercholesterolemia. While this treatment did not lead to thickening of aortic wall, intravenous injections of Hcy into rabbits fed VCDD led to massive accumulation of VLDL-triglycerides as well as significant impairment of vascular reactivity of the aorta compared to VCDD alone. In the aorta intravenous Hcy injections into VCDD-fed rabbits led to fragmentation of aortic elastin, accumulation of elastin-specific electron-dense inclusions, collagen disorganization, lipid degradation, and autophagolysosome formation. Furthermore, rabbits from the VCDD+Hcy group exhibited a massive decrease of total protein methylated arginine in blood cells and decreased creatine in blood cells, serum and liver compared to rabbits from the VCDD group. Altogether, we conclude that Hcy contributes to atherogenic transformation of the aorta not only in the presence but also in the absence of hypercholesterolemia.

In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney) from C57BL/6J mice. Through linear regression analysis of Hcy-metabolites and metabolic gene mRNA levels, we discovered that SAH-responsive genes were responsible for most metabolic changes and all metabolic crosstalk mediated by Serine, Taurine, and G3P. SAH-responsive genes worsen glucose metabolism and cause upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and Ac-CoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAH-responsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.

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

The aim of our study was to explore the characteristics of the arterial risk factors and ankle-brachial index (ABI) in patients with lower extremity chronic venous disease (LECVD).

A total of 2642 subjects were employed in our study. The lifestyle and clinical data were collected. The history of vascular diseases contained coronary artery disease, stroke, hypertension, and diabetes. ABI low than 0.9 was considered as lower extremity artery disease (LEAD). A series of blood indicators were measured.

Patients with ABI low than 0.9 belonged to the group of LEAD. Age, smoking, drinking, hypertension, diabetes mellitus, lipid-lowering drug, antidiabetic, total protein, total protein, triglyceride, low-density lipoprotein cholesterol, glycosylated hemoglobin and homocysteine were the common risk factors shared by LEAD and LECVD (P<0.05). The prevalence of LEAD in patients with LECVD was higher than those without LECVD (P<0.05). In Pearson correlation analysis, LECVD was related to LEAD (P<0.05). Before and after adjusted shared factors, as the performance of the logistic regression models, LEAD was an independent risk factor for the prevalence of LECVD (OR=2.937, 95% CI: [1.956, 4.411], P<0.001).

Our study demonstrated that an ABI lower than 0.9 is an independent risk factor for LECVD.

Chronic sinusitis (CS) is characterized by sinonasal inflammation, mucus overproduction, and edematous mucosal tissue. CS impacts one in seven adults and estimates suggest up to 15% of the general U.S. population may be affected. This research sought to assess a potential role for receptors for advanced glycation end-products (RAGE), an inflammatory receptor expressed in tissues exposed to secondhand smoke (SHS). Human sinus tissue sections were stained for RAGE and S100s, common RAGE ligands. Wild-type mice and mice that over-express RAGE in sinonasal epithelium (RAGE TG) were maintained in room air (RA) or exposed to secondhand smoke (SHS) via a nose-only delivery system five days a week for 6 weeks. Mouse sections were stained for RAGE and tissue lysates were assayed for cleaved caspase 3, cytokines, or matrix metalloproteases. We discovered increased RAGE expression in sinus tissue following SHS exposure and in sinuses from RAGE TG mice in the absence of SHS. Cleaved caspase-3, cytokines (IL-1β, IL-3, and TNF-α), and MMPs (-9 and -13) were induced by SHS and in tissues from RAGE TG mice. These results expand the inflammatory role of RAGE signaling, a key axis in disease progression observed in smokers. In this relatively unexplored area, enhanced understanding of RAGE signaling during voluntary and involuntary smoking may help to elucidate potential therapeutic targets that may attenuate the progression of smoke-related CS.

A stroke, also known as a cerebral hemorrhage, occurs when there is an interruption in the blood supply to a part of the brain, resulting in damage to brain cells. This issue is one of the leading causes of death in developed countries, currently killing about 5 million people annually. Individuals who survive ischemic stroke often face serious vision problems, paralysis, dementia, and other sequelae. The numerous efforts to prevent and/or treat stroke sequelae seem insufficient, which is concerning given the increasing global elderly population and the well-known association between aging and stroke risk. In this review, we aim to present and discuss the importance of vitamins in stroke prevention and/or incidence. Vitamins from diet or dietary supplements influence the body at various levels; they are a relevant factor but are reported only in isolated articles. This review reports and updates the multitarget role of vitamins involved in reducing stroke risk.

Atherosclerosis (AS), characterized by a maladaptive inflammatory response, is one of the most common causes of death among the elderly. Karyopherin subunit alpha 2 (KPNA2), a member of the nuclear transport protein family, has been reported to play a pro-inflammatory role in various pathological processes by regulating the nuclear translocation of pro-inflammatory transcription factors. However, the function of KPNA2 in AS remains unknown. ApoE-/- mice were fed high-fat diets for 12 weeks to establish an AS mice model. Human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) to establish an AS cell model. We found that KPNA2 was upregulated in the aortic roots of atherosclerotic mice and LPS-stimulated cells. KPNA2 knockdown inhibited LPS-induced secretion of pro-inflammatory factors and monocyte-endothelial adhesion in HUVECs, whereas KPNA2 overexpression exerted the opposite effects. p65 and interferon regulatory factor 3 (IRF3), the transcription factors known to regulate the transcription of pro-inflammatory genes, interacted with KPNA2, and their nuclear translocations were blocked following KPNA2 silencing. Furthermore, we found that KPNA2 protein level was decreased by E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBXW7), which was downregulated in the atherosclerotic mice. FBXW7 overexpression induced ubiquitination with subsequent proteasomal degradation of KPNA2. Meanwhile, the effects of KPNA2 deficiency on atherosclerotic lesions were further confirmed by in vivo experiments. Taken together, our study indicates that KPNA2 downregulation, regulated by FBXW7, may alleviate endothelial dysfunction and related inflammation in the progression of AS by suppressing the nuclear translocation of p65 and IRF3.

Depression is often considered one of the prevalent neuropsychiatric symptoms of Alzheimer's disease (AD). β-amyloid (Aβ) metabolism disorders and impaired microglia phagocytosis are potential pathological mechanisms between depression and AD. Folate deficiency (FD) is a risk factor for depression and AD. In this study, we used a chronic unpredictable mild stress (CUMS) rat model and a model of Aβ phagocytosis by BV2 cells to explore the potential mechanisms by which FD affects depression and AD. The results revealed that FD exacerbated depressive behavior and activated microglia in CUMS rats, leading to an increase in intracellular Aβ and phagocytosis-related receptors for advanced glycation end products (RAGE). Then, in vitro results showed that the expression of the RAGE receptor and M2 phenotype marker (CD206) were upregulated by FD treatment in BV2 cells, leading to an increase in Aβ phagocytosis. However, there was no significant difference in the expression of toll-like receptor 4 (TLR4) and clathrin heavy chain (CHC). Furthermore, when using the RAGE-specific inhibitor FPS-ZM1, there was no significant difference in Aβ uptake between folate-normal (FN) and FD BV2 cell groups. In conclusion, these findings suggest FD may promote microglia phagocytosis Aβ via regulating the expression of RAGE or microglia phenotype under Aβ treatment.

Homocysteine (HCY) has been associated with carotid plaque in cross-sectional studies, but the prospective relationship between HCY and incident carotid plaque has not been well established. The purpose of this study was to investigate the association between HCY and incidence of novel carotid plaque in a Chinese community-based population without pre-existing carotid atherosclerosis and to assess the additive effect of HCY and low-density lipoprotein cholesterol (LDL-C) on the incidence of novel plaque.

At baseline, we measured HCY and other risk factors in subjects aged ≥ 40 years. All participants underwent carotid ultrasound examinations at baseline and after an average of 6.8 years of follow-up. Incidence of plaque was identified if plaque was absent at baseline, but plaque was detected at the end of follow-up. A total of 474 subjects were included in the analysis.

The incidence of novel carotid plaque was 24.47%. Multivariate regression analyses showed that HCY was independently associated with a 1.05-fold-higher likelihood for incident novel plaque (adjusted odds ratio [OR] = 1.05, 95% confidence interval [CI]: 1.01-1.09, P = 0.008). Using tertile 1 and tertile 2 for reference, the top HCY tertile (T3) showed a 2.28-fold-higher likelihood for incident plaque (adjusted OR = 2.28, 95%CI: 1.33-3.93, P = 0.002). The combination of HCY T3 and LDL-C ≥ 3.4 mmol/L had the highest risk for novel plaque formation (adjusted OR = 3.63, 95%CI: 1.67-7.85, P = 0.001) compared to those without either condition. In the LDL-C ≥ 3.4 mmol/L subgroup, HCY was significantly associated with incidence of plaque (adjusted OR = 1.16, 95%CI: 1.04-1.28, P = 0.005, P-interaction = 0.023).

In the Chinese community-based population, HCY was independently associated with the incidence of novel carotid plaque. There were additive effect between HCY and LDL-C on the incidence of plaque, the highest risk was observed in individuals with both high HCY levels and LDL-C ≥ 3.4 mmol/L. Our findings suggest that HCY may be a potential target for preventing the incidence of carotid plaque, particularly in individuals with elevated LDL-C levels.

Dietary fiber consumption has been linked with improved cardiometabolic health, however, human studies have reported large interindividual variations in the observed benefits. We tested whether the effects of dietary fiber on atherosclerosis are influenced by the gut microbiome. We colonized germ-free ApoE-/- mice with fecal samples from three human donors (DonA, DonB, and DonC) and fed them diets supplemented with either a mix of 5 fermentable fibers (FF) or non-fermentable cellulose control (CC) diet. We found that DonA-colonized mice had reduced atherosclerosis burden with FF feeding compared to their CC-fed counterparts, whereas the type of fiber did not affect atherosclerosis in mice colonized with microbiota from the other donors. Microbial shifts associated with FF feeding in DonA mice were characterized by higher relative abundances of butyrate-producing taxa, higher butyrate levels, and enrichment of genes involved in synthesis of B vitamins. Our results suggest that atheroprotection in response to FF is not universal and is influenced by the gut microbiome.

Ischemic stroke is a highly complex systemic disease characterized by intricate interactions between the brain and gastrointestinal tract. While our current understanding of these interactions primarily stems from experimental models, their relevance to human stroke outcomes is of considerable interest. After stroke, bidirectional communication between the brain and gastrointestinal tract initiates changes in the gastrointestinal microenvironment. These changes involve the activation of gastrointestinal immunity, disruption of the gastrointestinal barrier, and alterations in gastrointestinal microbiota. Importantly, experimental evidence suggests that these alterations facilitate the migration of gastrointestinal immune cells and cytokines across the damaged blood-brain barrier, ultimately infiltrating the ischemic brain. Although the characterization of these phenomena in humans is still limited, recognizing the significance of the brain-gastrointestinal crosstalk after stroke offers potential avenues for therapeutic intervention. By targeting the mutually reinforcing processes between the brain and gastrointestinal tract, it may be possible to improve the prognosis of ischemic stroke. Further investigation is warranted to elucidate the clinical relevance and translational potential of these findings.

Despite the indispensable role that astrocytes play in the neurovascular unit, few studies have investigated the functional impact of astrocyte signaling in cognitive decline and dementia related to vascular pathology. Diet-mediated induction of hyperhomocysteinemia (HHcy) recapitulates numerous features of vascular contributions to cognitive impairment and dementia (VCID). Here, we used astrocyte targeting approaches to evaluate astrocyte Ca2+ dysregulation and the impact of aberrant astrocyte signaling on cerebrovascular dysfunction and synapse impairment in male and female HHcy diet mice. Two-photon imaging conducted in fully awake mice revealed activity-dependent Ca2+ dysregulation in barrel cortex astrocytes under HHcy. Stimulation of contralateral whiskers elicited larger Ca2+ transients in individual astrocytes of HHcy diet mice compared with control diet mice. However, evoked Ca2+ signaling across astrocyte networks was impaired in HHcy mice. HHcy also was associated with increased activation of the Ca2+/calcineurin-dependent transcription factor NFAT4, which has been linked previously to the reactive astrocyte phenotype and synapse dysfunction in amyloid and brain injury models. Targeting the NFAT inhibitor VIVIT to astrocytes, using adeno-associated virus vectors, led to reduced GFAP promoter activity in HHcy diet mice and improved functional hyperemia in arterioles and capillaries. VIVIT expression in astrocytes also preserved CA1 synaptic function and improved spontaneous alternation performance on the Y maze. Together, the results demonstrate that aberrant astrocyte signaling can impair the major functional properties of the neurovascular unit (i.e., cerebral vessel regulation and synaptic regulation) and may therefore represent a promising drug target for treating VCID and possibly Alzheimer's disease and other related dementias.SIGNIFICANCE STATEMENT The impact of reactive astrocytes in Alzheimer's disease and related dementias is poorly understood. Here, we evaluated Ca2+ responses and signaling in barrel cortex astrocytes of mice fed with a B-vitamin deficient diet that induces hyperhomocysteinemia (HHcy), cerebral vessel disease, and cognitive decline. Multiphoton imaging in awake mice with HHcy revealed augmented Ca2+ responses in individual astrocytes, but impaired signaling across astrocyte networks. Stimulation-evoked arteriole dilation and elevated red blood cell velocity in capillaries were also impaired in cortex of awake HHcy mice. Astrocyte-specific inhibition of the Ca2+-dependent transcription factor, NFAT, normalized cerebrovascular function in HHcy mice, improved synaptic properties in brain slices, and stabilized cognition. Results suggest that astrocytes are a mechanism and possible therapeutic target for vascular-related dementia.

Thromboembolic manifestations are relatively frequent in patients with intermediate/severe hyperhomocysteinemia (>30 µmol/L) related to inherited disorders and deficiencies in vitamin B12 and folate. In contrast, moderate hyperhomocysteinemia (15-30 µmol/L) is a modest predictor of cardiovascular risk. The recognition of homocysteine as a cardiovascular risk factor has been challenged by some but not all randomized clinical trials. We reviewed the main data of this controversy and formulated conclusions to be translated in clinical practice.Homocysteine-lowering trials have been performed in cardiovascular subjects with moderate but not intermediate/severe hyperhomocysteinemia despite the dose-effect risk association. The first meta-analyses found no benefit and led cardiology societies not recommending homocysteine in the assessment of cardiovascular risk. This guideline challenged the need to diagnose and treat the nutritional and genetic causes of intermediate/major hyperhomocysteinemia and was not revised when larger meta-analyses concluded to a reduced risk of stroke. In a recent observational study, 84% of consecutive cardiovascular patients assessed for homocysteine had intermediate or major hyperhomocysteinemia, which was properly assessed in only half of the cases and related to B12 and/or folate deficiency and Addison/Biermer disease in 55% of these cases.In conclusion, revisiting observational studies and clinical trials suggests that cardiovascular patients should be screened for hyperhomocysteinemia, when no other risk factor is found. Patients with intermediate/major hyperhomocysteinemia should be properly assessed and treated for B vitamin deficiencies and inherited disorders according to current guidelines. Further trials are needed to assess the effect of lowering homocysteine according to hyperhomocysteinemia categories at baseline.

Cardiovascular diseases (CVDs) are the leading cause of hospitalization and death worldwide, especially in developing countries. The increased prevalence rate and mortality due to CVDs, despite the development of several approaches for prevention and treatment, are alarming trends in global health. Chronic inflammation and macrophage infiltration are key regulators of the initiation and progression of CVDs. Recent data suggest that epigenetic modifications, such as DNA methylation, posttranslational histone modifications, and RNA modifications, regulate cell development, DNA damage repair, apoptosis, immunity, calcium signaling, and aging in cardiomyocytes; and are involved in macrophage polarization and contribute significantly to cardiac disease development. Cardiac macrophages not only trigger damaging inflammatory responses during atherosclerotic plaque formation, myocardial injury, and heart failure but are also involved in tissue repair, remodeling, and regeneration. In this review, we summarize the key epigenetic modifications that influence macrophage polarization and contribute to the pathophysiology of CVDs, and highlight their potential for the development of advanced epigenetic therapies.

It is a common practice to take into consideration age, diabetes, smoking, treated and untreated systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol for the prediction of atherosclerosis and stroke. There are, however, ultrasound markers in use for the assessment of atherosclerosis and the evaluation of stroke risk. Two areas of investigation are of interest: the carotid artery and the intracranial arterial circulation. Again, within the domain of the carotid artery, two ultrasonic markers have attracted our attention: intima media thickness of the carotid artery and the presence of carotid plaque with its various focal characteristics. In the domain of intracranial circulation, the presence of arterial stenosis and the recruitment of collaterals are considered significant ultrasonic markers for the above-mentioned purpose. On the other hand, a series of serum, urine, and tissue biomarkers are found to be related to atherosclerotic disease. Future studies might address the issue of whether the addition of proven ultrasonic carotid indices to the aforementioned serum, urine, and tissue biomarkers could provide the vascular specialist with a better assessment of the atherosclerotic load and solidify their position as surrogate markers for the evaluation of atherosclerosis and stroke risk.

Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking.

A subset of research volunteers from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure homocysteine and related metabolites in the current pilot study. Genetic expression profiles of inflammatory markers were evaluated using the Human Neuroinflammation NanoString panel. Further analyses included an evaluation of plasma homocysteine effects on amyloid beta, tau, ionized calcium-binding adaptor molecule 1, and glial fibrillary acidic protein immunohistochemistry in the frontal and occipital cortices. Analytes and other study outcomes were evaluated in relation to ante mortem HHcy status: We identified 13 persons with normal ante mortem plasma homocysteine levels (<14 µmol/L) and 18 who had high plasma homocysteine levels (≥14 µmol/L).

Participants with HHcy demonstrated increased levels of several plasma homocysteine cycle metabolites such as total cysteine, S-adenosyl-homocysteine, cystathionine, and choline. Inflammatory gene expression profiles showed a general downregulation in the setting of elevated plasma homocysteine. HHcy was associated with more and longer microglial processes, but smaller and fewer astrocytes, especially in participants of older age at death. HHcy in older participants was also associated with occipital cortex microhemorrhages and increased severity of atherosclerosis throughout the cerebral vasculature.

Increased plasma homocysteine and older age were associated with the downregulation of inflammatory gene expression markers in association with significant glial and vascular pathology changes. Impaired immune function is a plausible mechanism by which HHcy increases cerebrovascular damage leading to impaired cognitive function.

High-methionine diets induce impaired learning and memory function, dementia-like neurodegeneration, and Alzheimer's disease, while low-methionine diets improve learning and memory function. We speculated that variations in intestinal microbiota may mediate these diametrically opposed effects; thus, this study aimed to verify this hypothesis. The ICR mice were fed either a low-methionine diet (LM, 0.17% methionine), normal methionine diet (NM, 0.86% methionine), or high-methionine diet (HM, 2.58% methionine) for 11 weeks. We found that HM diets damaged nonspatial recognition memory, working memory, and hippocampus-dependent spatial memory and induced anxiety-like behaviors in mice. LM diets improved nonspatial recognition memory and hippocampus-dependent spatial memory and ameliorated anxiety-like behavior, but the differences did not reach a significant level. Moreover, HM diets significantly decreased the abundance of putative short-chain fatty acid (SCFA)-producing bacteria (Roseburia, Blautia, Faecalibaculum, and Bifidobacterium) and serotonin-producing bacteria (Turicibacter) and significantly increased the abundance of proinflammatory bacteria Escherichia-Shigella. Of note, LM diets reversed the results. Consequently, the SCFA and serotonin levels were significantly decreased with HM diets and significantly increased with LM diets. Furthermore, HM diets induced hippocampal oxidative stress and inflammation and selectively downregulated the hippocampus-dependent memory-related gene expression, whereas LM diets selectively upregulated the hippocampus-dependent memory-related gene expression. In conclusion, dietary methionine via dose-dependent inhibition of SCFA production capacity contributed to a potential risk of cognitive dysfunction in mice.

BACKGROUND Raised plasma homocysteine (Hcy) levels have been associated with various diseases and pregnancy complications. Preconception is the primary prevention period to prevent birth defects. This retrospective study aimed to investigate the distribution of plasma Hcy levels among men and women at preconception and further evaluate the factors influencing plasma Hcy levels in a Southern China population. MATERIAL AND METHODS Sex, age, serum folate levels, plasma Hcy levels, and the time of Hcy and folate detection were obtained by medical records. Univariate analysis and multi-factor mixed virtual linear regression were used to explore the distribution and determinants of plasma Hcy levels. RESULTS A total of 3031 participants (1091 men [35.99%] and 1940 women [64.01%]) were included. The average levels of Hcy and the rates of hyperhomocysteinemia (HHcy) in men were higher than those in women (P<0.05). Hcy levels were observed to be lowest during autumn and highest during winter (P<0.05). In the normal Hcy (NHcy) group, serum folate levels were higher than in the HHcy group (P<0.05). Regression analysis suggested that sex, season, and serum folate levels had an effect on Hcy levels, but age was not an influencing factor of Hcy level in the preconception population. CONCLUSIONS This retrospective study showed that Hcy levels are higher in men and in the winter season. Sex, season, and serum folate levels were the influencing factors of Hcy in the preconception population.

Atherosclerosis, the leading cause of cardiovascular disease responsible for the majority of deaths worldwide, cannot be sufficiently explained by established risk factors, including hypercholesterolemia. Elevated plasma homocysteine is an independent risk factor for atherosclerosis and is strongly linked to cardiovascular mortality. However, the role of homocysteine in atherosclerosis is still insufficiently understood. Previous research in this area has been also hampered by the lack of reproducible in vivo models of atherosclerosis that resemble the human situation. Here, we have developed and applied an automated system for vessel wall injury that leads to more homogenous damage and more pronounced atherosclerotic plaque development, even at low balloon pressure. Our automated system helped to glean vital details of cholesterol-independent changes in the aortic wall of balloon-injured rabbits. We show that deficiency of B vitamins, which are required for homocysteine degradation, leads to atherogenic transformation of the aorta resulting in accumulation of macrophages and lipids, impairment of its biomechanical properties and disorganization of aortic collagen/elastin in the absence of hypercholesterolemia. A combination of B vitamin deficiency and hypercholesterolemia leads to thickening of the aorta, decreased aortic water diffusion, increased LDL-cholesterol and impaired vascular reactivity compared to any single condition. Our findings suggest that deficiency of B vitamins leads to atherogenic transformation of the aorta even in the absence of hypercholesterolemia and aggravates atherosclerosis development in its presence.

Hyperhomocysteinemia (HHcy) is considered a risk factor for cardiovascular disease (CVD), including chronic kidney disease (CKD). In this study, we investigated the association between levels of serum homocysteine (Hcy) and mortality, inferred from the presence of CKD. Our study included data of 9895 participants from the 1999 to 2016 National Health and Nutrition Examination Surveys (NHANES). Multivariable-adjusted Cox proportional hazard models using propensity-score, were used to examine dose-response associations between Hcy level and mortality. A total of 9895 participants, 1025 (10.3%) participants were diagnosed with CKD. In a multivariate Cox regression analysis including all participants, Hcy level was significantly associated with all-cause mortality in the nonCKD group, compared to the 1st quartile in the fully adjusted model (2nd quartile: hazard ratio (HR) 1.75, 95% confidence interval (CI) 1.348-2.274, P < .001; 3rd quartile: HR 2.22, 95% CI 1.726-2.855, P < .001; 4th quartile: HR 3.77, 95% CI 2.952-4.830, P < .001). However, this finding was not observed in the CKD group. The observed pattern was similar after propensity score matching. In the nonCKD group, overall mortality increased in proportion to Hcy concentration (2nd quartile: HR 2.19, 95% CI 1.299-3.709, P = .003; 3rd quartile: HR 2.60, 95% CI 1.570-4.332, P < .001; 4th quartile: HR 3.72, 95% CI 2.254-6.139, P < .001). However, the risk of all-cause mortality according to the quartile of Hcy level, did not increase in the CKD group. This study found a correlation between the Hcy level and mortality rate only in the nonCKD group. These altered risk factor patterns may be attributed to protein-energy wasting or chronic inflammation status, that is accompanied by CKD.

Background: The relationship between methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphism with the risk of intracerebral hemorrhage (ICH) has remained to be controversial in recent years. This meta-analysis is aimed to confirm the association of these. Methods: Systematically searching the related studies from the PubMed, Embase, Cochrane Library, China national knowledge internet database from 1 January 1990 to 1 June 2022. The odd ratio (ORs) and 95% confidence interval (CIs) of gene-disease correlation in various gene models were calculated by fixed or random effect model of meta-analysis. We included 20 case-control studies in this meta-analysis with a total of 1,989 ICH patients and 4,032 health controls originated from Asian, Caucasian, and African populations. Results: The statistical analysis demonstrated the association of MTHFR C677T gene polymorphism with ICH in allele model [ORT VS. C = 1.20 (95%CI: 1.06-1.36)]; homozygote model [OR TT VS. CC = 1.50 (95%CI: 1.20-1.88)]; dominant model [OR CT+ TT VS. CC = 1.23 (95%CI: 1.03-1.48)] and recessive model [ORTT VS. CT+CC = 1.37 (95%CI: 1.17-1.60)]. Besides, we also found the relationship of MTHFR C677T gene polymorphism with Asian in four comparison model (ORT VS. C = 1.19.95%CI:1.09-1.37, ORTT VS. CC = 1.46.95%CI: 1.15-1.85, OR CT+ TT VS. CC = 1.25.95%CI: 1.01-1.54, ORTT VS. CT+CC = 1.34.95%CI: 1.54-1.17) and Caucasian in four comparison model (ORT VS. C = 1.90.95%CI: 1.22-2.97, ORTT VS. CC = 2.67.95%CI: 1.42-5.00, OR CT+ TT VS. CC = 1.56.95%CI: 1.05-2.32, ORTT VS. CT+CC = 2.25.95%CI: 1.46-4.00). But no statistically significant correlation between A1298C polymorphism and the occurrence of ICH was detected in four studies. Conclusion: MTHFR C677T gene polymorphism increases the risk of ICH in Asian and Caucasian populations but has no impact on the incidence in African communities. More importantly, the risk of ICH increases in TT genotype individuals in comparison to CT and CC genotype individuals in Asian and Caucasian populations.

Atrial fibrillation (AF) is one of the most prevalent rhythm disorders worldwide, with around 37.574 million cases around the globe (0.51 % global population).  Different studies showed a high informative value of different biomarkers, including such related to the systemic inflammation, biomechanical stress and fibrosis. In this review article we aimed to study only the relation of homocysteine to the AF development. Homocysteine is a sulfur-containing amino acid, that is produced in the process of methionine metabolism. Which is a non-canonical amino acid, that is derived from the food proteins. From the scientific point of view there is a relation between hyperhomocysteinemia and myocardial fibrosis, but these mechanisms are complicated and not sufficiently studied. Homocysteine regulates activity of the ion channels through their redox state. Elevated homocysteine level can condition electrical remodeling of the cardiomyocytes through the increase of sodium current and change in the function of rapid sodium channels, increase of inwards potassium current and decrease in amount of rapid potassium channels. High homocysteine concentration also leads to the shortening of the action potential, loss of the rate adaptation of the action potential and persistent circulation of the re-entry waves. In a series of experimental studies on mice there was an association found between the homocysteine level and activity of vascular inflammation. Elevation of homocysteine level is an independent factor of the thromboembolic events and AF relapses. Population studies showed, that homocysteine is an independent risk factor for AF. So, homocysteine is an interesting target for up-stream therapy.

Different clinical subtypes of mild cognitive impairment (MCI) involve heterogeneous underlying etiologies. This study investigated the association between demographics, neuropsychological performance, apolipoprotein E (APOE) genotype and magnetic resonance imaging (MRI) measures in patients with MCI (amnestic [aMCI] and non-amnestic [naMCI]).

This case-control study included 130 aMCI patients, 58 naMCI patients, and 1,106 healthy controls (HCs). APOE genotypes, medial temporal lobe atrophy (MTA), neurological evaluation results, and white matter hyperintensities (WMH) were investigated. Serum folate and vitamin B12 concentrations were analyzed by radioimmunoassay, and plasma hyperhomocysteinemia (Hcy) was assessed by a high-performance liquid chromatography-fluorescence method.

Serum folate levels were significantly lower, but plasma Hcy levels were higher, in patients with aMCI and naMCI than in healthy controls. There were significantly higher MTA scores in the aMCI group than the healthy control group. Multiple linear regression showed that serum Hcy and folate concentrations were positively associated with MTA (p < 0.05), while APOE4 showed a significant negative association with MTA in the aMCI group (p < 0.01). In addition, moderate/severe WMH showed a significant negative association with MTA in the naMCI and HC groups (p < 0.01).

The combined presence of APOE4 and Hcy is associated with aMCI in elderly individuals, while moderate/severe WMH is related to naMCI, which suggests etiological differences across MCI subtypes.

A nationwide survey was conducted from October 2018 to September 2019 to assess the prevalence of hyperhomocysteinemia (Hhcy) and its influencing factors in China. A standardized questionnaire was used to collect information. Hhcy was defined as the level of serum homocysteine (HCY) ⩾ 15.0µmol/L. The H-type hypertension (HHYP) was defined as hypertension with an elevated serum HCY 15.0µmol/L). Finally, 110 551 residents ⩾ 40 years of age from 31 provinces in the mainland of China were included. Overall, the median serum HCY level was 10.9µmol/L (interquartile range 7.9-15.1). A total of 28 633 participants (25.9%) were defined as Hhcy. The Hhcy prevalence ranged from 7.9% in Shanghai to 56.8% in Tianjin. The data showed that serum HCY levels were associated with age, male gender, cigarette smoking, hypertension, diabetes, ethnicity, endurance in exercise (inverse), and fruit and vegetable intake (inverse). In addition, 15 486 participants were defined as HHYP, and the rate was 14.0%. HHYP was an independent predictor of stroke with an adjusted odds ratio of 1.752 (95% CI 1.338-2.105). The geographical distribution pattern of the Hhcy epidemic reflects dynamic differences, and national strategies should be carried out to further improve the care of patients with Hhcy across China.

Stroke is a leading cause of morbidity and mortality worldwide. It inflicts immeasurable suffering on patients and their loved ones and carries an immense social cost. Efforts to mitigate the impact of stroke have focused on identifying therapeutic targets for the prevention and treatment. The gut microbiome represents one such potential target given its multifaceted effects on conditions known to cause and worsen the severity of stroke. Vitamin B12 (VB12) serves as a cofactor for two enzymes, methylmalonyl-CoA synthase and methionine synthase, vital for methionine and nucleotide biosynthesis. VB12 deficiency results in a buildup of metabolic substrates, such as homocysteine, that alter immune homeostasis and contribute to atherosclerotic disorders, including ischemic stroke. In addition to its support of cellular function, VB12 serves as a metabolic cofactor for gut microbes. By shaping microbial communities, VB12 further impacts local and peripheral immunity. Growing evidence suggests that gut dysbiosis-related immune dysfunction induced by VB12 deficiency may potentially contributes to stroke pathogenesis, its severity, and patient outcomes. In this review, we discuss the complex interactions of VB12, gut microbes and the associated metabolites, and immune homeostasis throughout the natural history of ischemic stroke.

Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and plaque vulnerability. Macrophage apoptosis mediated by endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of HHcy-aggravated atherosclerosis. Endoplasmic reticulum oxidoreductase 1α (Ero1α) is critical for ER stress-induced apoptosis. We hypothesized that Ero1α may contribute to ER-stress induced macrophage apoptosis and plaque stability in advanced atherosclerotic lesions by HHcy.

Apoe^-/- mice were maintained on drinking water containing homocysteine (Hcy, 1.8 g/L) to establish HHcy atherosclerotic models. The role of Ero1α in atherosclerotic plaque stability, macrophage apoptosis and ER stress were monitored in the plaque of aortic roots in HHcy Apoe^-/- mice with or without silence or overexpression of Ero1α through lentivirus. Mouse peritoneal macrophages were used to confirm the regulation of Ero1α on ER stress dependent apoptosis in the presence of HHcy.

Atherosclerotic plaque vulnerability and macrophage apoptosis were promoted in Apoe^-/- mice by high Hcy diet, accompanied by the upregulation of Ero1α expression and ER stress. Inhibition of Ero1α prevented macrophage apoptosis and atherosclerotic plaque vulnerability, and vice versa. Consistently, in mouse peritoneal macrophages, ER stress and apoptosis were attenuated by Ero1α deficiency, but enhanced by Ero1α overexpression.

Hcy, via upregulation of Ero1α expression, activates ER stress-dependent macrophage apoptosis to promote vulnerable plaque formation in atherosclerosis. Ero1α may be a potential therapeutic target for atherosclerosis induced by Hcy.

Homocysteine is a common risk factor for cognitive impairment and sarcopenia. However, very few studies have shown an association between sarcopenia and serum homocysteine levels after adjustment for cognitive function.

The purpose of this study was to investigate the relationship between homocysteine and sarcopenia in memory clinic patients.

This cross-sectional study investigated outpatients in a memory clinic. We enrolled 1,774 participants (≥65 years old) with measured skeletal muscle mass index (SMI), hand grip strength (HGS), and homocysteine. All participants had undergone cognitive assessments and were diagnosed with dementia, mild cognitive impairment, or normal cognition. Patient characteristics were compared according to sarcopenia presence, SMI level, or HGS. Multivariate logistic regression analysis was performed to determine the association of homocysteine with sarcopenia, low SMI, or low HGS. Next, linear regression analysis was performed using HGS as a continuous variable.

Logistic regression analysis showed that low HGS was significantly associated with homocysteine levels (p = 0.002), but sarcopenia and low SMI were not. In linear regression analysis, HGS was negatively associated with homocysteine levels after adjustment for Mini-Mental State Examination score (β= -2.790, p < 0.001) or clinical diagnosis of dementia (β= -3.145, p < 0.001). These results were similar for men and women.

Our results showed a negative association between homocysteine and HGS after adjustment for cognitive function. Our findings strengthen the assumed association between homocysteine and HGS. Further research is needed to determine whether lower homocysteine levels lead to prevent muscle weakness.

One-carbon metabolism is crucial for the maintenance of healthy pregnancy and alterations in this pathway have been associated with various pregnancy-related complications. Therefore, the present study was conducted to test the hypothesis that the altered folic acid, vitamin B12 and homocysteine levels are associated with the risk of early pregnancy loss (EPL). Plasma folic acid, vitamin B12 and homocysteine levels were analyzed in 83 females with EPL and 70 healthy pregnant females in their first trimester. Further, meta-analyses of folic acid, vitamin B12 and homocysteine were also performed involving various eligible studies. Results from our case-control study and meta-analysis showed that folic acid deficiency is not associated with the risk of EPL. On the other hand, low vitamin B12 and hyperhomocysteinemia were individually found to be significant risk factors for EPL in the present study (P < .01, P < .05, respectively) and meta-analysis as well (P < .001, P < .05, respectively). Vitamin B12 deficiency in combination with hyperhomocysteinemia was a more serious risk factor for EPL (Odds Ratio = 4.98, P = 0.002). Therefore, we conclude that vitamin B12 deficiency and elevated homocysteine levels are independent risk factors for EPL, and of higher risk when combined. The assessment of vitamin B12 and homocysteine levels may serve as a good screening marker for EPL risk.

[Figure: see text].

Preeclampsia (PE) presents a major obstetrical problem for mother and fetus which is characterized by the onset of hypertension and proteinuria in formerly normotensive women. Altered folate-mediated one-carbon metabolism is one of the factors for PE development either due to nutritional insufficiencies such as folate deficiency or polymorphisms in genes that code for the key enzymes of the cycle. Commonly, there are four genes in the cycle whose polymorphisms have been described in relation to PE. These factors could cause elevation of homocysteine; the toxic metabolite, which subsequently leads to the development of PE. Sufficient levels of folate have been considered important during pregnancy and may reduce the risk of development of PE. This review aims at discussing genetic polymorphisms and nutritional deficiencies as probable predisposing factors and suggests considering fetal genotypes, varied ethnicities, and interaction of various other factors involved to render better conclusiveness to the present studies.